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Pharmasset Announces Complete Enrollment of RG7128 Phase 2b Clinical Study
- Roche Initiating Additional Clinical Studies with RG7128 - INFORM Studies Delayed
PRINCETON, N.J., Feb 17, 2010 /PRNewswire via COMTEX News Network/ -- Pharmasset, Inc. (Nasdaq: VRUS) announced today the complete enrollment by Roche of the 12 week RG7128 Phase 2b study (PROPEL) of approximately 400 treatment-naive patients with hepatitis C virus (HCV) genotypes 1 and 4. The study remains blinded to Roche and Pharmasset.
Roche has initiated a 24 week Phase 2b study with RG7128 in combination with pegylated interferon and ribavirin in treatment-naïve patients with HCV genotypes 1 and 4 in order to evaluate the safety and efficacy of RG7128 in combination with standard of care for longer durations. The data from this study could provide the flexibility for combining RG7128 with direct acting antivirals currently in development with varying durations of therapy. This study is currently enrolling at sites in the US and Canada and is expected to complete enrollment in the second quarter.
In addition, Roche is planning to initiate a Phase 2b study of RG7128 in combination with pegylated interferon and ribavirin in patients with HCV genotypes 2 and 3 later in 2010. RG7128 has previously demonstrated antiviral activity with a 90% RVR in HCV genotypes 2 and 3 prior non-responders in a 28 day clinical study.
Roche has also announced that it will not conduct the previously planned 28 day INFORM-2 study, designed to evaluate the combination of RG7128 with RG7227, InterMune's HCV protease inhibitor, with and without pegylated interferon and ribavirin. Roche has decided instead to conduct longer duration studies, including the INFORM-3 clinical study of RG7128 and RG7227 with and without pegylated interferon and ribavirin. INFORM-3 will commence after Roche and InterMune identify the optimal dose of ritonavir-boosted RG7227 from ongoing studies. Roche is continuing to conduct dose ranging safety and efficacy studies of RG7227, and has announced a consequent delay of the INFORM-3 clinical study.
Modifications to the INFORM program will have no impact on the primary registration pathway for RG7128. In addition, Roche has indicated that it is evaluating the potential of combining RG7128 with non-protease complementary compounds.
"We are pleased that our partner Roche has completed the enrollment of the initial Phase 2b study of RG7128, and we look forward to the announcement of data from the PROPEL study," said M. Michelle Berrey, M.D., MPH, Chief Medical Officer of Pharmasset. "We believe that the initiation of additional Phase 2b studies indicates Roche's continued commitment to RG7128. We are also encouraged by Roche's willingness to consider alternatives for potential combination with RG7128 in interferon-sparing combination studies."
About Pharmasset
Pharmasset is a clinical-stage pharmaceutical company committed to discovering, developing, and commercializing novel drugs to treat viral infections. Pharmasset's primary focus is on the development of oral therapeutics for the treatment of hepatitis C virus (HCV) and, secondarily, on the development of Racivir(TM) for the treatment of human immunodeficiency virus (HIV). Our research and development efforts focus on nucleoside/tide analogs, a class of compounds which act as alternative substrates for the viral polymerase, thus inhibiting viral replication. We currently have three clinical-stage product candidates. RG7128, a nucleoside analog for chronic HCV infection, is in two Phase 2b clinical trials in combination with Pegasys(R) plus Copegus(R) and is also in the INFORM studies, the first series of studies designed to assess the potential of combinations of small molecules without Pegasys(R) and Copegus(R) to treat chronic HCV. These clinical studies are being conducted through a strategic collaboration with Roche. Our other clinical stage candidates include PSI-7977, an isomer of PSI-7851 and an unpartnered, next- generation HCV nucleotide analog that is in a Phase 2a trial; and Racivir, for the treatment of HIV, which has completed a Phase 2 clinical trial. We also have in our pipeline two purine nucleotide analogs, PSI-938 and PSI-879, in advanced preclinical development.
Pegasys(R) and Copegus(R) are registered trademarks of Roche.
Contact
Richard E. T. Smith, Ph.D.
VP, Investor Relations and Corporate Communications
Office: +1 (609) 613-4181
Forward-Looking Statements
Pharmasset "Safe Harbor" Statement under the Private Securities Litigation Reform Act of 1995: Statements in this press release regarding our business that are not historical facts are "forward-looking statements" that involve risks and uncertainties, including, without limitation, the risk that adverse events could cause the cessation or delay of any of the ongoing or planned clinical trials and/or our development of our product candidates, the risk that the results of previously conducted studies involving our product candidates will not be repeated or observed in ongoing or future studies involving our product candidates, the risk that our collaboration with Roche will not continue or will not be successful, and the risk that any one or more of our product candidates will not be successfully developed and commercialized. For a discussion of these and other risks and uncertainties, any of which could cause our actual results to differ from those contained in the forward-looking statements, see the section of our Annual Report on Form 10-K for the fiscal year ended September 30, 2009 and our Quarterly Report on Form 10Q for the period ended December 31, 2009 filed with the Securities and Exchange Commission entitled "Risk Factors" and discussions of potential risks and uncertainties in our subsequent filings with the Securities and Exchange Commission.
SOURCE Pharmasset, Inc.
Sunday, February 21, 2010
Alcohol Use and Treatment of Hepatitis C Virus:
Alcohol Use and Treatment of Hepatitis C Virus: Results of a National Multicenter Study
Gastroenterology May 2006
VA-HCV-001 Study GroupBhupinder S. AnandCorresponding Author Informationemail address, Sue Currie‡, Eric Dieperink§, Edmund J. Bini∥, Hui Shen¶, Samuel B. Ho§, Teresa Wright‡
Department of Medicine, Michael E. DeBakey VA Medical Center, Houston, Texas
‡ Department of Medicine, San Francisco VA Medical Center, San Francisco, California
§ Department of Medicine, Minneapolis VA Medical Center, Minneapolis, Minnesota
∥ Department of Medicine, VA New York Harbor Healthcare System, Brooklyn, New York
¶ Department of Medicine, University of California, San Francisco, San Francisco, California
"Our findings show that physicians are reluctant to treat patients with a history of alcohol use, even when they are abstinent for 1 year or more. The only negative impact of alcohol use on treatment outcomes was a higher treatment discontinuation rate in recent drinkers. Patients who were able to complete treatment had similar ETR and SVR rates compared with nondrinkers, irrespective of the duration of abstinence. These findings were consistent among the subgroups of genotype 1 and black patients. Our observations are clinically important because they indicate that alcohol use should not be considered an exclusion criterion when evaluating patients for anti-HCV treatment, especially in view of the fact that nearly one third of patients with HCV infection have a history of recent alcohol use. The current attitude among physicians against offering treatment to patients who use alcohol should be reassessed. Moreover, greater emphasis should be placed on developing strategies to improve patient education and support to improve adherence to antiviral therapy."
ABSTRACT
Background & Aims: Patients with hepatitis C virus (HCV) infection who use alcohol have been excluded from clinical trials; therefore, outcomes with antiviral therapy are unknown. The aim of the study was to determine the impact of alcohol use on HCV treatment outcomes.
Methods: Subjects using alcohol were categorized as follows: no alcohol versus regular alcohol use, quantity consumed (none, <6 drinks/day, ≥6 drinks/day), CAGE score <2 or ≥2, and recent alcohol use (past 12 months). Patients were treated with interferon plus ribavirin.
Results: A total of 4061 subjects were enrolled, and 726 (18%) received treatment. Alcohol use (past and within 12 months) reduced treatment candidacy. Past alcohol use did not affect the end-of-treatment response, sustained virologic response (SVR), and treatment discontinuation rates. However, recent alcohol use resulted in higher treatment discontinuation (40% vs 26%; P = .0002) and tended to reduce the SVR (14% vs 20%; P = .06), but when patients who discontinued treatment were excluded from analysis, the trend in favor of nondrinkers for SVR disappeared (25% vs 23%). These findings were also consistent in subgroup analyses on race and genotype.
Conclusions: Eligibility for anti-HCV treatment was reduced in past and recent drinkers. Recent alcohol use was associated with increased treatment discontinuation and lower SVR. However, patients who use alcohol and completed the treatment had a response comparable to that of nondrinkers. Patients with a history of alcohol use should not be excluded from HCV therapy. Instead, additional support should be provided to these patients to ensure their ability to complete treatment.
Chronic hepatitis C is a common cause of end-stage liver disease, cirrhosis, and hepatocellular carcinoma and is the leading indication for liver transplantation.1 Left untreated, significant costs related to hepatitis C virus (HCV) infection in both direct medical care and indirect losses are projected.2, 3 At the same time, antiviral therapy continues to improve, with sustained virologic response (SVR) rates nearing 60% in randomized controlled trials.4, 5 However, as recent studies make clear, response to therapy in clinical populations is well below that seen in controlled trials.6, 7, 8 This is likely due to several factors, including patients not fully engaging in care; the impact of comorbid psychiatric, substance use, and medical problems; and difficulties in adhering to complicated treatment regimens.7, 9 Substance use disorders, particularly alcohol use, are a common reason for excluding patients from antiviral therapy. Typically, clinicians require complete abstinence from alcohol for at least 6 months before initiating antiviral treatment. However, few data exist in patients with hepatitis C regarding the impact of alcohol use on adherence to antiviral therapy or its influence on treatment outcomes.
See editorial on page 1912.
Alcohol abuse and HCV frequently coexist in the same patient. HCV infection is detected in 16% to more than 40% of alcoholic patients with or without liver disease.10, 11, 12, 13 Several studies have shown increased histologic liver damage in chronic alcoholic patients with HCV infection, in the form of higher rate of fibrosis progression and development of cirrhosis compared with HCV infection in nondrinking subjects.14, 15, 16, 17, 18, 19 However, the effect of any amount of alcohol use on antiviral treatment outcomes is much less clear. Several studies suggest that cumulative lifetime alcohol use worsens antiviral treatment outcomes.20, 21, 22, 23 In one of these studies, Ohnishi et al suggested that prolonged abstinence from alcohol improves interferon treatment outcomes.20 In an Italian study, Loguercio et al showed that the SVR decreased as alcohol use increased.24 These studies have several limitations, including small sample size, retrospective data analysis, and inclusion of patients treated with interferon monotherapy. None of these studies assessed the effect of alcohol use on treatment compliance and treatment outcomes with interferon and ribavirin combination therapy. The present study was performed to determine prospectively the effect of various levels of alcohol intake on treatment outcomes in patients with HCV infection.
Materials and Methods
This was a multicenter study to evaluate the epidemiology, natural history, and treatment response in unselected patients with HCV infection. The criteria for patient enrollment in the screening phase included a positive antibody to HCV serologic test and patient consent. The study was approved by the institutional review boards at each participating site.
Screening Phase
At enrollment, the patients were screened to determine whether or not they were suitable candidates for treatment with interferon and ribavirin. Additionally, patient counseling on HCV disease and risk factor assessments were performed. The inclusion criteria for treatment were male or female patients 18 years of age or older, a positive HCV RNA level by qualitative or quantitative polymerase chain reaction, and no previous HCV treatment with interferon and ribavirin combination therapy. The treatment exclusion criteria included patients with active hepatitis B virus infection and other forms of liver disease such as hemochromatosis, Wilson’s disease, and α1-antitrypsin deficiency; hemoglobinopathies; evidence of advanced liver disease or hepatocellular carcinoma; preexisting uncontrolled severe depression or other psychiatric diseases; evidence of ischemia or significant cardiac disease; or other comorbidities such as renal disease.
All patients were counseled to stop drinking and were provided with detailed counseling about the risks associated with continued use of drugs and alcohol and the factors associated with virus transmission. Patients with ongoing substance or alcohol use and those who declined to quit their substance use were not considered for treatment. Practitioners, in conjunction with patients, discussed treatment candidacy eligibility based on the risk factors, laboratory results, and standardized treatment inclusion and exclusion criteria. Patients who were determined to be treatment candidates and agreed to proceed with the recommended therapy entered the treatment phase of the protocol. In patients not selected for therapy, the caregivers were required to state why a patient was not considered a treatment candidate.
Alcohol Questionnaire
The patients completed a questionnaire on alcohol use during the screening phase of the study (see Appendix). Information collected included the type of alcoholic beverage usually used (beer, wine, mixed drinks), the highest number of drinks consumed on a regular basis, the total duration of alcohol use, and the number of drinks usually consumed during the past 12 months. In addition, the CAGE score was determined for each patient. The CAGE score is a validated screening instrument designed to assess alcohol dependence or abuse.25 The total CAGE score ranges from 0 to 4, based on responses to the following 4 questions: have you ever felt you should cut down your drinking, have people ever annoyed you by criticizing your drinking, have you ever felt bad or guilty about your drinking, and have you ever had a drink first thing in the morning to steady your nerves or to get rid of a hangover (an eye opener).
Categorization of Alcohol Use
Alcohol use was categorized in 4 different ways. In category 1, the patients were divided into nondrinkers and drinkers. Nondrinkers included patients who either did not drink at all or drank only occasionally, whereas drinkers included patients who consumed alcohol on a regular basis, which was defined as at least one drink a day. In category 2, the patients were divided into 3 subgroups: nondrinkers (as defined previously), moderate drinkers (<6 drinks a day), and heavy drinkers (≥6 drinks/day). In category 3, the patients were divided into 2 groups based on the CAGE score (CAGE score <2 or ≥2). In category 4, the patients were divided into 2 groups based on current alcohol use patterns (active drinking within the past 12 months and not actively drinking). Thus, categories 1, 2, and 3 were based on the alcohol use patterns of patients in the past (beyond 1 year), while category 4 assessed drinking status within the past 12 months at the time of baseline enrollment. All patients who were actively drinking were advised to stop alcohol use, and those who agreed were considered for therapy.
Treatment Phase
Patients selected for treatment were started on interferon alfa 2b 3 million units 3 times a day and ribavirin 1000–1200 mg/day (1000 mg for weight ≤75 kg and 1200 mg for weight ≥75 kg) for 24 weeks (genotypes 2 and 3) and 48 weeks (all other genotypes). Patients were assessed for efficacy and safety of treatment by regular follow-up visits scheduled at week 1–2 and every 4 weeks after initiation of therapy. At each follow-up visit, the patients were questioned about drug-related adverse effects, and blood tests were performed for hematologic and biochemical assessment. The study coordinator was required to fill out a form indicating compliance with therapy at weeks 12, 24, and 48 during the treatment phase of the study. The primary efficacy end point of treatment was SVR, which was defined as undetectable plasma HCV RNA (<100 copies/mL by qualitative polymerase chain reaction assay; Amplicor Roche Diagnostics, Nutley, NJ) 24 weeks after the end of treatment. Viral response was analyzed on an intention-to-treat basis, and lack of HCV RNA data was counted as viral nonresponse. The secondary end points were the end-of-treatment response (ETR) at treatment week 24 (for genotypes 2 and 3) or week 48 (genotype 1) and early treatment discontinuation (defined as stopping treatment with interferon and ribavirin before the scheduled end of therapy).
Statistical Analysis
Statistical analysis was conducted using SAS version 8.2 for Windows (SAS Institute, Inc, Cary, NC). Prevalence and 95% confidence intervals (CIs) were calculated based on binomial distributions. Summary statistics included frequency tables for categorical variables and medians and interquartile ranges for continuous variables. Continuous variables such as age and cumulative time of infection were categorized for contingency analyses. Bivariate analyses examining associations between antibody to HCV status and demographic, risk exposure, and alcohol-related variables were conducted using the χ2 test of association, and odds ratios (ORs) and 95% CIs were calculated. Mantel–Haenszel χ2 calculations were conducted to test for associations when 3 alcohol dose variables were used, such as nondrinkers, light drinkers (≤2 drinks/day), and moderate/heavy drinkers (>2 drinks/day). Independent associations between the dependent and independent variables were assessed using unconditional logistic regression analyses. Similar Mantel–Haenszel χ2 analysis was conducted on 2 subgroups, persons with genotype 1 and black patients, to test for associations between recent drinkers and nondrinkers in these groups on SVR and early treatment discontinuation. Severity of liver disease at baseline (Table 1), categorized by regular alcohol use of drinkers versus nondrinkers who were considered for treatment, was measured using the medium interquartile range due to the nonnormal distribution of the laboratory values. The nonparametric test, Wilcoxon–Mann–Whitney test, was then used to compare associations between the 2 groups accordingly.
Results
Twenty-four Veterans Administration hospitals throughout the United States participated in the study. The study was performed from 1999 to 2001. A total of 4462 patients with a positive HCV antibody test were enrolled at baseline. Of these, 4061 provided complete data on the alcohol use questionnaire. All patients were assessed for treatment with interferon alfa 2b and ribavirin based on the inclusion and exclusion criteria described previously. A total of 986 patients (24.2%) were found to be suitable candidates for treatment, and 726 (17.9%) were started on antiviral therapy. The common reasons for not being a treatment candidate were ongoing or recent substance abuse (20.2%), active psychiatric disease (18.3%), and comorbid medical disease (17.9%). The remaining patients who were considered treatment candidates but were not treated included those who declined or deferred treatment, those who were enrolled in other clinical research trials, and those who were lost to follow-up. In addition, 28 patients with combined human immunodeficiency virus and HCV infections were excluded from the 726 patients analyzed in the present study.
Patient Demographics
For the group as a whole, the mean (±SD) age of the patients was 50.3 (±7.6) years. There were 701 men (96.6%) and 25 women (3.4%). The racial profile of the patients consisted of 452 (62.5%) non-Hispanic white subjects, 166 (22.9%) non-Hispanic black subjects, and 78 (10.7%) nonblack Latino subjects; the remaining patients belonged to other racial groups such as Asian and American Indian. The duration of the infection was 25.8 (±8.6) years. The age at infection was 23.3 (±9.0) years. The mean weight was 91.9 (±18) kg (lower quartile, 79.4; upper quartile, 102.4), and the mean body mass index was 29.3 (±5.2) kg/m2 (lower quartile, 25.8; upper quartile, 32.1). The most common source of infection was intravenous drug use, seen in 60% of patients. The majority of patients were Vietnam-era veterans (76.8%). At liver histology, advanced fibrosis in the form of bridging fibrosis (stage 3) and cirrhosis (stage 4) was seen in 37.3% of patients. Genotype 1 was present in the majority of patients (74.8%). There was no statistical difference between patients who were offered and accepted the treatment and those who were offered and did not accept treatment with respect to any of the demographic features described.
Demographics and Treatment Candidacy
There were only minor differences in the demographic characteristics of drinkers compared with nondrinkers who were accepted for treatment (Table 2). Drinkers were more often men and were more likely to have a history of injection drug use (P = .024), incarceration (P < .001), and cocaine use (P < .001) compared with nondrinkers. Other risk factors, service in Vietnam, duration of infection, age at infection, and racial profile were similar in the 2 groups.
Status of Liver Disease and Treatment Candidacy
The baseline liver test results in drinkers and nondrinkers who were accepted for treatment are shown in Table 2. There were no significant differences in any of the liver test results and platelet counts between the 2 groups. Moreover, liver fibrosis assessed by staging the severity from 0 (no fibrosis) to 4 (cirrhosis) showed no difference between the 2 groups.
Alcohol Use and Treatment Candidacy
Alcohol use had a negative impact on a patient being considered for antiviral therapy, as judged by all 4 categories of alcohol use (Table 3). The most significant effect was observed in patients with a history of recent alcohol use. However, alcohol use within the past year did not automatically disqualify a patient from treatment. For example, 20% of patients who admitted to recent drinking were enrolled in the treatment phase of the study (vs 27% of nondrinkers). When the amount of daily alcohol use was assessed, patients who admitted to heavy drinking (≥6 drinks/day) in the past were just as likely to be treated (23%) compared with those drinking <6 drinks/day (24%).
Alcohol Use and Response to Antiviral Therapy
The effect of alcohol use on the response to treatment is shown in Table 4. At the end of the treatment phase of the study, 218 patients (30%) were HCV polymerase chain reaction negative. The ETR in heavy alcohol users in the past (≥6 drinks/day) was not significantly different compared with nondrinkers and moderate drinkers (31% vs 32% vs 27%, respectively). Similarly, recent alcohol use did not impact the ETR rates compared with those not drinking within the past 12 months (28% vs 31%). After discontinuation of therapy, 12% of patients had a virologic relapse, resulting in an overall SVR rate of 18% (133/726 patients). The SVR was not significantly different between heavy drinkers, moderate drinkers, and nondrinkers (19% vs 15% vs 20%, respectively) (Table 3). The SVR rate tended to be lower in patients drinking within the past 12 months compared with nondrinkers, but the difference failed to reach statistical significance (14% vs 20%; P = .06).
Alcohol Use and Adherence to Antiviral Treatment
Treatment adherence, as defined by the patient’s ability to complete antiviral treatment, is shown in Table 4. For the group as a whole, 215 of the 726 patients (30%) started on treatment failed to complete the full course of therapy. A history of alcohol use did not have a significant impact on treatment completion rates except in recent drinkers. In this group, the early discontinuation rate was significantly higher compared with nondrinkers (40% vs 26%; P < .0002). The treatment discontinuation rate for current drinkers who had high CAGE scores was not significantly different from that for patients with lower CAGE scores (42% vs 38%; P = .55). Moreover, the treatment discontinuation rate was not influenced by the amount of alcohol used in the past; there was no difference in the early discontinuation rate between moderate and heavy drinkers (33% vs 29%, respectively).
Effect of Different Amounts of Alcohol Use on Treatment Outcomes in Recent Drinkers
Because recent alcohol use may have a greater impact on treatment outcomes, patients drinking in the past 12 months were divided into 3 groups: nondrinkers, light (social) drinkers (≤2 drinks/day), and moderate/heavy drinkers (>2 drinks/day). The results are shown in Table 5. There was a significant negative effect on the treatment discontinuation rates between abstinent subjects compared with light and moderate/heavy drinkers (P < .001). There was no significant difference on the ETR response between the 3 groups. There was a trend toward a better SVR rate based on the dose of alcohol intake: 20%, 16%, and 13% in nondrinkers, light drinkers, and moderate/heavy drinkers, respectively. However, these differences failed to reach statistical significance. When patients who discontinued treatment early were excluded from the analysis, the trend in favor of nondrinkers for SVR disappeared compared with those who were drinking in the past year (Table 6). The most common reason for treatment discontinuation was the development of adverse events. Other reasons included a patient’s decision to no longer continue treatment (unrelated to adverse events), an inability to continue treatment due to incarceration, and patients who were lost to follow-up. There was no difference in the treatment discontinuation rates between nondrinkers, light drinkers, and heavy drinkers with respect to any of the previously described factors (Table 7).
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Alcohol Use, Race, and Genotype
The interaction between the patients’ race and genotype with alcohol use was analyzed. For the whole group, black subjects were more frequently infected with genotype 1 (87% vs 65%; P < .001) and were less likely to have an SVR (8.4% vs 21.6%; P < .001) compared with nonblack subjects. Black subjects with genotype 1 had a lower SVR rate than nonblack subjects (6.1% vs 14.1%; P = .004), but there was no difference in the SVR rate for genotypes 2 and 3 (nonblack subjects vs black subjects, 50.0% vs 36.5%, respectively; P = .47). The effect of race and genotype on treatment outcomes is shown in Table 8. The ETR and SVR rates were better in non–genotype 1 and in nonblack patients, but there was no significant difference in the treatment outcomes (ETR, SVR, and early discontinuation of therapy) between drinkers and nondrinkers based on all 4 categories of alcohol use. The impact of viral level (divided into <1 million IU/mL and ≥1 million IU/mL) in patients with genotype 1 on treatment response was assessed. Patients with genotype 1 and viral level <1 million IU/mL had better ETR (24% vs 16%; P < .05) and SVR (18% vs 9%; P < .009) compared with those with a viral level >1 million IU/mL.
Discussion
Despite the frequent presence of HCV infection in subjects with chronic alcoholism, the impact of alcohol use on treatment outcomes with antiviral agents is poorly understood. Substance use disorders, particularly alcohol use, are a common reason for excluding patients from antiviral therapy.26 Indeed, all the large multicenter registration trials designed to assess the efficacy of interferon alone or combined with ribavirin for the treatment of HCV infection either completely excluded patients with a history of alcohol abuse or placed a restriction on prior alcohol use to a minimum of 6 months of abstinence. These requirements severely limited the inclusion of such subjects in well-conducted clinical trials. The current data on the effect of alcohol use on HCV treatment outcomes therefore are based on mostly retrospective studies performed on a small number of subjects.20, 21, 22, 23, 24
This is the first prospective study to assess in a large cohort of patients the impact of past and recent alcohol use on antiviral treatment candidacy, adherence, and outcomes. Our study provided several interesting results. Alcohol use was extremely common in patients treated with antiviral therapy, with 80% (584/726) drinking on a regular basis in the past and 27% (194/726) in the past year. The reasons for this decline in alcohol use in the past year are not clear but may be related to more frequent patient interaction with medical practitioners because of their HCV infection.
Alcohol use had a significant negative impact on treatment candidacy. Compared with nondrinkers, physicians were less inclined to offer treatment to patients with a history of alcohol use despite being abstinent for at least 1 year before therapy. As expected, recent drinkers were even less likely to be offered therapy. The overall ETR and SVR rates were 30% (218/726) and 18% (133/726), respectively. These rates are lower than those reported in registration trials, in which the ETR and SVR rates ranged between 50% and 61% and between 36% and 47%, respectively.27, 28, 29, 30 The virologic response rates in the present study cannot be compared with the large registration trials because the latter included highly selected patients, including a very low enrollment of black Americans, who respond less well to antiviral therapy.31, 32 Other investigators have also reported response rates that were well below those observed in the registration trials.6, 7, 8
Alcohol use did not have any impact on the ETR, SVR, or treatment discontinuation rates in patients who had stopped drinking at least 1 year prior. By contrast, in recent drinkers, the treatment discontinuation rate was higher (P = .0002) and the SVR rate was lower but not significantly (P = .06) compared with nondrinkers. However, when patients who had failed to complete the full course of therapy were excluded from the analysis, there was no difference in the SVR rate between recent drinkers and nondrinkers, indicating that alcohol use did not interfere with the efficacy of antiviral therapy. In a recent study, alcohol use among human immunodeficiency virus–infected persons was associated with lower adherence to antiretroviral therapy compared with nondrinkers.33 Therefore, rather than excluding alcohol users from antiviral therapies, strategies should be developed to improve treatment adherence in this patient group. Fortunately, simple and effective methods exist, such as brief behavioral counseling interventions for reducing alcohol use.34 These techniques can be expanded to include treatment adherence and compliance.
The 2002 National Institutes of Health Consensus Conference on HCV made a special mention of the lack of data on the impact of light (social) alcohol use, defined as the consumption of ≤2 drinks/day.35 In the present study, we specifically analyzed the influence of light alcohol use on HCV treatment outcomes. Light drinking had no effect on the ETR (35% vs 31%) and SVR (16% vs 20%) rates compared with nondrinkers, but the treatment discontinuation rate was higher compared with nondrinkers (35% vs 26%; P < .0001). In addition, we did not find any interaction between viral genotype and patients’ racial background with alcohol use and treatment outcomes.
Our study had several limitations. A precise estimate of alcohol use in a clinical setting is fraught with problems, such as subject compliance and accuracy of recall. However, we believe the present data provide a fairly accurate estimate of the past and recent drinking habits of the study subjects. Alcohol use was categorized in several ways, including the CAGE score, which is easy to administer in a clinical setting; a score of ≥2 is associated with a sensitivity and specificity of 74% and 91%, respectively, for alcohol abuse or dependence.25 When selecting patients for therapy, there was no fixed period of abstinence before initiation of treatment and the decision was left to the treating physicians. Therefore, patients with differing periods of abstinence before therapy were included in the study. During treatment, although patients were counseled against drug and alcohol use at each follow-up visit, no objective assessment was made of continuing alcohol use. The study medications consisted of interferon alfa and ribavirin, and our findings may not reflect the results obtained with pegylated interferons, the current standard of care for HCV treatment. Although the investigators were advised to follow the Veterans Administration treatment guidelines, personal bias in selecting patients for treatment cannot be completely excluded. However, we do not expect this to be any different from what occurs in routine clinical practice and in that respect is more representative of patient selection in “the real world,” outside of controlled clinical trials. Finally, being a study based on US veterans, our cohort was 95% male, which may have introduced gender-based inconsistency in the study results.
In conclusion, alcohol use is extremely common in patients with HCV being considered for treatment at Veterans Administration facilities. Our findings show that physicians are reluctant to treat patients with a history of alcohol use, even when they are abstinent for 1 year or more. The only negative impact of alcohol use on treatment outcomes was a higher treatment discontinuation rate in recent drinkers. Patients who were able to complete treatment had similar ETR and SVR rates compared with nondrinkers, irrespective of the duration of abstinence. These findings were consistent among the subgroups of genotype 1 and black patients. Our observations are clinically important because they indicate that alcohol use should not be considered an exclusion criterion when evaluating patients for anti-HCV treatment, especially in view of the fact that nearly one third of patients with HCV infection have a history of recent alcohol use. The current attitude among physicians against offering treatment to patients who use alcohol should be reassessed. Moreover, greater emphasis should be placed on developing strategies to improve patient education and support to improve adherence to antiviral therapy.
Gastroenterology May 2006
VA-HCV-001 Study GroupBhupinder S. AnandCorresponding Author Informationemail address, Sue Currie‡, Eric Dieperink§, Edmund J. Bini∥, Hui Shen¶, Samuel B. Ho§, Teresa Wright‡
Department of Medicine, Michael E. DeBakey VA Medical Center, Houston, Texas
‡ Department of Medicine, San Francisco VA Medical Center, San Francisco, California
§ Department of Medicine, Minneapolis VA Medical Center, Minneapolis, Minnesota
∥ Department of Medicine, VA New York Harbor Healthcare System, Brooklyn, New York
¶ Department of Medicine, University of California, San Francisco, San Francisco, California
"Our findings show that physicians are reluctant to treat patients with a history of alcohol use, even when they are abstinent for 1 year or more. The only negative impact of alcohol use on treatment outcomes was a higher treatment discontinuation rate in recent drinkers. Patients who were able to complete treatment had similar ETR and SVR rates compared with nondrinkers, irrespective of the duration of abstinence. These findings were consistent among the subgroups of genotype 1 and black patients. Our observations are clinically important because they indicate that alcohol use should not be considered an exclusion criterion when evaluating patients for anti-HCV treatment, especially in view of the fact that nearly one third of patients with HCV infection have a history of recent alcohol use. The current attitude among physicians against offering treatment to patients who use alcohol should be reassessed. Moreover, greater emphasis should be placed on developing strategies to improve patient education and support to improve adherence to antiviral therapy."
ABSTRACT
Background & Aims: Patients with hepatitis C virus (HCV) infection who use alcohol have been excluded from clinical trials; therefore, outcomes with antiviral therapy are unknown. The aim of the study was to determine the impact of alcohol use on HCV treatment outcomes.
Methods: Subjects using alcohol were categorized as follows: no alcohol versus regular alcohol use, quantity consumed (none, <6 drinks/day, ≥6 drinks/day), CAGE score <2 or ≥2, and recent alcohol use (past 12 months). Patients were treated with interferon plus ribavirin.
Results: A total of 4061 subjects were enrolled, and 726 (18%) received treatment. Alcohol use (past and within 12 months) reduced treatment candidacy. Past alcohol use did not affect the end-of-treatment response, sustained virologic response (SVR), and treatment discontinuation rates. However, recent alcohol use resulted in higher treatment discontinuation (40% vs 26%; P = .0002) and tended to reduce the SVR (14% vs 20%; P = .06), but when patients who discontinued treatment were excluded from analysis, the trend in favor of nondrinkers for SVR disappeared (25% vs 23%). These findings were also consistent in subgroup analyses on race and genotype.
Conclusions: Eligibility for anti-HCV treatment was reduced in past and recent drinkers. Recent alcohol use was associated with increased treatment discontinuation and lower SVR. However, patients who use alcohol and completed the treatment had a response comparable to that of nondrinkers. Patients with a history of alcohol use should not be excluded from HCV therapy. Instead, additional support should be provided to these patients to ensure their ability to complete treatment.
Chronic hepatitis C is a common cause of end-stage liver disease, cirrhosis, and hepatocellular carcinoma and is the leading indication for liver transplantation.1 Left untreated, significant costs related to hepatitis C virus (HCV) infection in both direct medical care and indirect losses are projected.2, 3 At the same time, antiviral therapy continues to improve, with sustained virologic response (SVR) rates nearing 60% in randomized controlled trials.4, 5 However, as recent studies make clear, response to therapy in clinical populations is well below that seen in controlled trials.6, 7, 8 This is likely due to several factors, including patients not fully engaging in care; the impact of comorbid psychiatric, substance use, and medical problems; and difficulties in adhering to complicated treatment regimens.7, 9 Substance use disorders, particularly alcohol use, are a common reason for excluding patients from antiviral therapy. Typically, clinicians require complete abstinence from alcohol for at least 6 months before initiating antiviral treatment. However, few data exist in patients with hepatitis C regarding the impact of alcohol use on adherence to antiviral therapy or its influence on treatment outcomes.
See editorial on page 1912.
Alcohol abuse and HCV frequently coexist in the same patient. HCV infection is detected in 16% to more than 40% of alcoholic patients with or without liver disease.10, 11, 12, 13 Several studies have shown increased histologic liver damage in chronic alcoholic patients with HCV infection, in the form of higher rate of fibrosis progression and development of cirrhosis compared with HCV infection in nondrinking subjects.14, 15, 16, 17, 18, 19 However, the effect of any amount of alcohol use on antiviral treatment outcomes is much less clear. Several studies suggest that cumulative lifetime alcohol use worsens antiviral treatment outcomes.20, 21, 22, 23 In one of these studies, Ohnishi et al suggested that prolonged abstinence from alcohol improves interferon treatment outcomes.20 In an Italian study, Loguercio et al showed that the SVR decreased as alcohol use increased.24 These studies have several limitations, including small sample size, retrospective data analysis, and inclusion of patients treated with interferon monotherapy. None of these studies assessed the effect of alcohol use on treatment compliance and treatment outcomes with interferon and ribavirin combination therapy. The present study was performed to determine prospectively the effect of various levels of alcohol intake on treatment outcomes in patients with HCV infection.
Materials and Methods
This was a multicenter study to evaluate the epidemiology, natural history, and treatment response in unselected patients with HCV infection. The criteria for patient enrollment in the screening phase included a positive antibody to HCV serologic test and patient consent. The study was approved by the institutional review boards at each participating site.
Screening Phase
At enrollment, the patients were screened to determine whether or not they were suitable candidates for treatment with interferon and ribavirin. Additionally, patient counseling on HCV disease and risk factor assessments were performed. The inclusion criteria for treatment were male or female patients 18 years of age or older, a positive HCV RNA level by qualitative or quantitative polymerase chain reaction, and no previous HCV treatment with interferon and ribavirin combination therapy. The treatment exclusion criteria included patients with active hepatitis B virus infection and other forms of liver disease such as hemochromatosis, Wilson’s disease, and α1-antitrypsin deficiency; hemoglobinopathies; evidence of advanced liver disease or hepatocellular carcinoma; preexisting uncontrolled severe depression or other psychiatric diseases; evidence of ischemia or significant cardiac disease; or other comorbidities such as renal disease.
All patients were counseled to stop drinking and were provided with detailed counseling about the risks associated with continued use of drugs and alcohol and the factors associated with virus transmission. Patients with ongoing substance or alcohol use and those who declined to quit their substance use were not considered for treatment. Practitioners, in conjunction with patients, discussed treatment candidacy eligibility based on the risk factors, laboratory results, and standardized treatment inclusion and exclusion criteria. Patients who were determined to be treatment candidates and agreed to proceed with the recommended therapy entered the treatment phase of the protocol. In patients not selected for therapy, the caregivers were required to state why a patient was not considered a treatment candidate.
Alcohol Questionnaire
The patients completed a questionnaire on alcohol use during the screening phase of the study (see Appendix). Information collected included the type of alcoholic beverage usually used (beer, wine, mixed drinks), the highest number of drinks consumed on a regular basis, the total duration of alcohol use, and the number of drinks usually consumed during the past 12 months. In addition, the CAGE score was determined for each patient. The CAGE score is a validated screening instrument designed to assess alcohol dependence or abuse.25 The total CAGE score ranges from 0 to 4, based on responses to the following 4 questions: have you ever felt you should cut down your drinking, have people ever annoyed you by criticizing your drinking, have you ever felt bad or guilty about your drinking, and have you ever had a drink first thing in the morning to steady your nerves or to get rid of a hangover (an eye opener).
Categorization of Alcohol Use
Alcohol use was categorized in 4 different ways. In category 1, the patients were divided into nondrinkers and drinkers. Nondrinkers included patients who either did not drink at all or drank only occasionally, whereas drinkers included patients who consumed alcohol on a regular basis, which was defined as at least one drink a day. In category 2, the patients were divided into 3 subgroups: nondrinkers (as defined previously), moderate drinkers (<6 drinks a day), and heavy drinkers (≥6 drinks/day). In category 3, the patients were divided into 2 groups based on the CAGE score (CAGE score <2 or ≥2). In category 4, the patients were divided into 2 groups based on current alcohol use patterns (active drinking within the past 12 months and not actively drinking). Thus, categories 1, 2, and 3 were based on the alcohol use patterns of patients in the past (beyond 1 year), while category 4 assessed drinking status within the past 12 months at the time of baseline enrollment. All patients who were actively drinking were advised to stop alcohol use, and those who agreed were considered for therapy.
Treatment Phase
Patients selected for treatment were started on interferon alfa 2b 3 million units 3 times a day and ribavirin 1000–1200 mg/day (1000 mg for weight ≤75 kg and 1200 mg for weight ≥75 kg) for 24 weeks (genotypes 2 and 3) and 48 weeks (all other genotypes). Patients were assessed for efficacy and safety of treatment by regular follow-up visits scheduled at week 1–2 and every 4 weeks after initiation of therapy. At each follow-up visit, the patients were questioned about drug-related adverse effects, and blood tests were performed for hematologic and biochemical assessment. The study coordinator was required to fill out a form indicating compliance with therapy at weeks 12, 24, and 48 during the treatment phase of the study. The primary efficacy end point of treatment was SVR, which was defined as undetectable plasma HCV RNA (<100 copies/mL by qualitative polymerase chain reaction assay; Amplicor Roche Diagnostics, Nutley, NJ) 24 weeks after the end of treatment. Viral response was analyzed on an intention-to-treat basis, and lack of HCV RNA data was counted as viral nonresponse. The secondary end points were the end-of-treatment response (ETR) at treatment week 24 (for genotypes 2 and 3) or week 48 (genotype 1) and early treatment discontinuation (defined as stopping treatment with interferon and ribavirin before the scheduled end of therapy).
Statistical Analysis
Statistical analysis was conducted using SAS version 8.2 for Windows (SAS Institute, Inc, Cary, NC). Prevalence and 95% confidence intervals (CIs) were calculated based on binomial distributions. Summary statistics included frequency tables for categorical variables and medians and interquartile ranges for continuous variables. Continuous variables such as age and cumulative time of infection were categorized for contingency analyses. Bivariate analyses examining associations between antibody to HCV status and demographic, risk exposure, and alcohol-related variables were conducted using the χ2 test of association, and odds ratios (ORs) and 95% CIs were calculated. Mantel–Haenszel χ2 calculations were conducted to test for associations when 3 alcohol dose variables were used, such as nondrinkers, light drinkers (≤2 drinks/day), and moderate/heavy drinkers (>2 drinks/day). Independent associations between the dependent and independent variables were assessed using unconditional logistic regression analyses. Similar Mantel–Haenszel χ2 analysis was conducted on 2 subgroups, persons with genotype 1 and black patients, to test for associations between recent drinkers and nondrinkers in these groups on SVR and early treatment discontinuation. Severity of liver disease at baseline (Table 1), categorized by regular alcohol use of drinkers versus nondrinkers who were considered for treatment, was measured using the medium interquartile range due to the nonnormal distribution of the laboratory values. The nonparametric test, Wilcoxon–Mann–Whitney test, was then used to compare associations between the 2 groups accordingly.
Results
Twenty-four Veterans Administration hospitals throughout the United States participated in the study. The study was performed from 1999 to 2001. A total of 4462 patients with a positive HCV antibody test were enrolled at baseline. Of these, 4061 provided complete data on the alcohol use questionnaire. All patients were assessed for treatment with interferon alfa 2b and ribavirin based on the inclusion and exclusion criteria described previously. A total of 986 patients (24.2%) were found to be suitable candidates for treatment, and 726 (17.9%) were started on antiviral therapy. The common reasons for not being a treatment candidate were ongoing or recent substance abuse (20.2%), active psychiatric disease (18.3%), and comorbid medical disease (17.9%). The remaining patients who were considered treatment candidates but were not treated included those who declined or deferred treatment, those who were enrolled in other clinical research trials, and those who were lost to follow-up. In addition, 28 patients with combined human immunodeficiency virus and HCV infections were excluded from the 726 patients analyzed in the present study.
Patient Demographics
For the group as a whole, the mean (±SD) age of the patients was 50.3 (±7.6) years. There were 701 men (96.6%) and 25 women (3.4%). The racial profile of the patients consisted of 452 (62.5%) non-Hispanic white subjects, 166 (22.9%) non-Hispanic black subjects, and 78 (10.7%) nonblack Latino subjects; the remaining patients belonged to other racial groups such as Asian and American Indian. The duration of the infection was 25.8 (±8.6) years. The age at infection was 23.3 (±9.0) years. The mean weight was 91.9 (±18) kg (lower quartile, 79.4; upper quartile, 102.4), and the mean body mass index was 29.3 (±5.2) kg/m2 (lower quartile, 25.8; upper quartile, 32.1). The most common source of infection was intravenous drug use, seen in 60% of patients. The majority of patients were Vietnam-era veterans (76.8%). At liver histology, advanced fibrosis in the form of bridging fibrosis (stage 3) and cirrhosis (stage 4) was seen in 37.3% of patients. Genotype 1 was present in the majority of patients (74.8%). There was no statistical difference between patients who were offered and accepted the treatment and those who were offered and did not accept treatment with respect to any of the demographic features described.
Demographics and Treatment Candidacy
There were only minor differences in the demographic characteristics of drinkers compared with nondrinkers who were accepted for treatment (Table 2). Drinkers were more often men and were more likely to have a history of injection drug use (P = .024), incarceration (P < .001), and cocaine use (P < .001) compared with nondrinkers. Other risk factors, service in Vietnam, duration of infection, age at infection, and racial profile were similar in the 2 groups.
Status of Liver Disease and Treatment Candidacy
The baseline liver test results in drinkers and nondrinkers who were accepted for treatment are shown in Table 2. There were no significant differences in any of the liver test results and platelet counts between the 2 groups. Moreover, liver fibrosis assessed by staging the severity from 0 (no fibrosis) to 4 (cirrhosis) showed no difference between the 2 groups.
Alcohol Use and Treatment Candidacy
Alcohol use had a negative impact on a patient being considered for antiviral therapy, as judged by all 4 categories of alcohol use (Table 3). The most significant effect was observed in patients with a history of recent alcohol use. However, alcohol use within the past year did not automatically disqualify a patient from treatment. For example, 20% of patients who admitted to recent drinking were enrolled in the treatment phase of the study (vs 27% of nondrinkers). When the amount of daily alcohol use was assessed, patients who admitted to heavy drinking (≥6 drinks/day) in the past were just as likely to be treated (23%) compared with those drinking <6 drinks/day (24%).
Alcohol Use and Response to Antiviral Therapy
The effect of alcohol use on the response to treatment is shown in Table 4. At the end of the treatment phase of the study, 218 patients (30%) were HCV polymerase chain reaction negative. The ETR in heavy alcohol users in the past (≥6 drinks/day) was not significantly different compared with nondrinkers and moderate drinkers (31% vs 32% vs 27%, respectively). Similarly, recent alcohol use did not impact the ETR rates compared with those not drinking within the past 12 months (28% vs 31%). After discontinuation of therapy, 12% of patients had a virologic relapse, resulting in an overall SVR rate of 18% (133/726 patients). The SVR was not significantly different between heavy drinkers, moderate drinkers, and nondrinkers (19% vs 15% vs 20%, respectively) (Table 3). The SVR rate tended to be lower in patients drinking within the past 12 months compared with nondrinkers, but the difference failed to reach statistical significance (14% vs 20%; P = .06).
Alcohol Use and Adherence to Antiviral Treatment
Treatment adherence, as defined by the patient’s ability to complete antiviral treatment, is shown in Table 4. For the group as a whole, 215 of the 726 patients (30%) started on treatment failed to complete the full course of therapy. A history of alcohol use did not have a significant impact on treatment completion rates except in recent drinkers. In this group, the early discontinuation rate was significantly higher compared with nondrinkers (40% vs 26%; P < .0002). The treatment discontinuation rate for current drinkers who had high CAGE scores was not significantly different from that for patients with lower CAGE scores (42% vs 38%; P = .55). Moreover, the treatment discontinuation rate was not influenced by the amount of alcohol used in the past; there was no difference in the early discontinuation rate between moderate and heavy drinkers (33% vs 29%, respectively).
Effect of Different Amounts of Alcohol Use on Treatment Outcomes in Recent Drinkers
Because recent alcohol use may have a greater impact on treatment outcomes, patients drinking in the past 12 months were divided into 3 groups: nondrinkers, light (social) drinkers (≤2 drinks/day), and moderate/heavy drinkers (>2 drinks/day). The results are shown in Table 5. There was a significant negative effect on the treatment discontinuation rates between abstinent subjects compared with light and moderate/heavy drinkers (P < .001). There was no significant difference on the ETR response between the 3 groups. There was a trend toward a better SVR rate based on the dose of alcohol intake: 20%, 16%, and 13% in nondrinkers, light drinkers, and moderate/heavy drinkers, respectively. However, these differences failed to reach statistical significance. When patients who discontinued treatment early were excluded from the analysis, the trend in favor of nondrinkers for SVR disappeared compared with those who were drinking in the past year (Table 6). The most common reason for treatment discontinuation was the development of adverse events. Other reasons included a patient’s decision to no longer continue treatment (unrelated to adverse events), an inability to continue treatment due to incarceration, and patients who were lost to follow-up. There was no difference in the treatment discontinuation rates between nondrinkers, light drinkers, and heavy drinkers with respect to any of the previously described factors (Table 7).
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Alcohol Use, Race, and Genotype
The interaction between the patients’ race and genotype with alcohol use was analyzed. For the whole group, black subjects were more frequently infected with genotype 1 (87% vs 65%; P < .001) and were less likely to have an SVR (8.4% vs 21.6%; P < .001) compared with nonblack subjects. Black subjects with genotype 1 had a lower SVR rate than nonblack subjects (6.1% vs 14.1%; P = .004), but there was no difference in the SVR rate for genotypes 2 and 3 (nonblack subjects vs black subjects, 50.0% vs 36.5%, respectively; P = .47). The effect of race and genotype on treatment outcomes is shown in Table 8. The ETR and SVR rates were better in non–genotype 1 and in nonblack patients, but there was no significant difference in the treatment outcomes (ETR, SVR, and early discontinuation of therapy) between drinkers and nondrinkers based on all 4 categories of alcohol use. The impact of viral level (divided into <1 million IU/mL and ≥1 million IU/mL) in patients with genotype 1 on treatment response was assessed. Patients with genotype 1 and viral level <1 million IU/mL had better ETR (24% vs 16%; P < .05) and SVR (18% vs 9%; P < .009) compared with those with a viral level >1 million IU/mL.
Discussion
Despite the frequent presence of HCV infection in subjects with chronic alcoholism, the impact of alcohol use on treatment outcomes with antiviral agents is poorly understood. Substance use disorders, particularly alcohol use, are a common reason for excluding patients from antiviral therapy.26 Indeed, all the large multicenter registration trials designed to assess the efficacy of interferon alone or combined with ribavirin for the treatment of HCV infection either completely excluded patients with a history of alcohol abuse or placed a restriction on prior alcohol use to a minimum of 6 months of abstinence. These requirements severely limited the inclusion of such subjects in well-conducted clinical trials. The current data on the effect of alcohol use on HCV treatment outcomes therefore are based on mostly retrospective studies performed on a small number of subjects.20, 21, 22, 23, 24
This is the first prospective study to assess in a large cohort of patients the impact of past and recent alcohol use on antiviral treatment candidacy, adherence, and outcomes. Our study provided several interesting results. Alcohol use was extremely common in patients treated with antiviral therapy, with 80% (584/726) drinking on a regular basis in the past and 27% (194/726) in the past year. The reasons for this decline in alcohol use in the past year are not clear but may be related to more frequent patient interaction with medical practitioners because of their HCV infection.
Alcohol use had a significant negative impact on treatment candidacy. Compared with nondrinkers, physicians were less inclined to offer treatment to patients with a history of alcohol use despite being abstinent for at least 1 year before therapy. As expected, recent drinkers were even less likely to be offered therapy. The overall ETR and SVR rates were 30% (218/726) and 18% (133/726), respectively. These rates are lower than those reported in registration trials, in which the ETR and SVR rates ranged between 50% and 61% and between 36% and 47%, respectively.27, 28, 29, 30 The virologic response rates in the present study cannot be compared with the large registration trials because the latter included highly selected patients, including a very low enrollment of black Americans, who respond less well to antiviral therapy.31, 32 Other investigators have also reported response rates that were well below those observed in the registration trials.6, 7, 8
Alcohol use did not have any impact on the ETR, SVR, or treatment discontinuation rates in patients who had stopped drinking at least 1 year prior. By contrast, in recent drinkers, the treatment discontinuation rate was higher (P = .0002) and the SVR rate was lower but not significantly (P = .06) compared with nondrinkers. However, when patients who had failed to complete the full course of therapy were excluded from the analysis, there was no difference in the SVR rate between recent drinkers and nondrinkers, indicating that alcohol use did not interfere with the efficacy of antiviral therapy. In a recent study, alcohol use among human immunodeficiency virus–infected persons was associated with lower adherence to antiretroviral therapy compared with nondrinkers.33 Therefore, rather than excluding alcohol users from antiviral therapies, strategies should be developed to improve treatment adherence in this patient group. Fortunately, simple and effective methods exist, such as brief behavioral counseling interventions for reducing alcohol use.34 These techniques can be expanded to include treatment adherence and compliance.
The 2002 National Institutes of Health Consensus Conference on HCV made a special mention of the lack of data on the impact of light (social) alcohol use, defined as the consumption of ≤2 drinks/day.35 In the present study, we specifically analyzed the influence of light alcohol use on HCV treatment outcomes. Light drinking had no effect on the ETR (35% vs 31%) and SVR (16% vs 20%) rates compared with nondrinkers, but the treatment discontinuation rate was higher compared with nondrinkers (35% vs 26%; P < .0001). In addition, we did not find any interaction between viral genotype and patients’ racial background with alcohol use and treatment outcomes.
Our study had several limitations. A precise estimate of alcohol use in a clinical setting is fraught with problems, such as subject compliance and accuracy of recall. However, we believe the present data provide a fairly accurate estimate of the past and recent drinking habits of the study subjects. Alcohol use was categorized in several ways, including the CAGE score, which is easy to administer in a clinical setting; a score of ≥2 is associated with a sensitivity and specificity of 74% and 91%, respectively, for alcohol abuse or dependence.25 When selecting patients for therapy, there was no fixed period of abstinence before initiation of treatment and the decision was left to the treating physicians. Therefore, patients with differing periods of abstinence before therapy were included in the study. During treatment, although patients were counseled against drug and alcohol use at each follow-up visit, no objective assessment was made of continuing alcohol use. The study medications consisted of interferon alfa and ribavirin, and our findings may not reflect the results obtained with pegylated interferons, the current standard of care for HCV treatment. Although the investigators were advised to follow the Veterans Administration treatment guidelines, personal bias in selecting patients for treatment cannot be completely excluded. However, we do not expect this to be any different from what occurs in routine clinical practice and in that respect is more representative of patient selection in “the real world,” outside of controlled clinical trials. Finally, being a study based on US veterans, our cohort was 95% male, which may have introduced gender-based inconsistency in the study results.
In conclusion, alcohol use is extremely common in patients with HCV being considered for treatment at Veterans Administration facilities. Our findings show that physicians are reluctant to treat patients with a history of alcohol use, even when they are abstinent for 1 year or more. The only negative impact of alcohol use on treatment outcomes was a higher treatment discontinuation rate in recent drinkers. Patients who were able to complete treatment had similar ETR and SVR rates compared with nondrinkers, irrespective of the duration of abstinence. These findings were consistent among the subgroups of genotype 1 and black patients. Our observations are clinically important because they indicate that alcohol use should not be considered an exclusion criterion when evaluating patients for anti-HCV treatment, especially in view of the fact that nearly one third of patients with HCV infection have a history of recent alcohol use. The current attitude among physicians against offering treatment to patients who use alcohol should be reassessed. Moreover, greater emphasis should be placed on developing strategies to improve patient education and support to improve adherence to antiviral therapy.
Validation of a Hepatitis C Screening Tool in Primary Care
"There was an 8.3% (95% confidence interval, 6.7%-10.2%) prevalence of HCV antibodies. The patients who were HCV antibody positive were more likely to be male, older, and insured by Medicaid (P ≤ .02). Those who had risk factors within the medical, exposure, and social history domains were more likely to be HCV antibody positive..... Results of the multivariate analysis showed that a positive response to the medical history (OR, 1.9; 95% CI, 1.1-3.6), exposure history (OR, 3.4; 95% CI, 2.0-5.9), or social history (OR, 6.1; 95% CI, 3.7-10.3) domains was significantly associated with increased odds of HCV antibody positivity (Table 3)......In our inner-city primary care population, the prevalence rate was more than 4 times the reported national prevalence rate. Improved understanding of prevalence rates in particular communities will allow resources to be focused where they are needed. Finally, treatment earlier in the course of the disease is associated with acceptable cost per quality-adjusted life-years estimates....The exposure history domain questions were about past contact with another persons' blood, eg, during an accident or injury. The personal care history domain items were sharing toothbrushes, receiving tattoos or piercings, and acupuncture. The social history domain questions were about illicit drug use, incarceration, and past and current sexual activity. Medical history domain questions were iatrogenic risks for transmission, including blood transfusions, dialysis, and other medical procedures as well as elevated liver function test results."
"Our validation demonstrates that a negative result on a risk assessment tool can eliminate the need for HCV antibody testing in the majority of patients assessed. Furthermore, it can accurately identify those patients at moderately increased risk who would benefit from antibody screening. The posttest probability estimates based on the population's prevalence as shown in Table 5 can help in deciding which patients to screen for HCV antibodies. There are large patient populations in which HCV prevalence is low to moderate but in which screening remains low.3-4,27 In populations with this risk profile, a screen with 2 or more positive domains can sufficiently alter the posttest probability so the decision can be made as to whether or not a patient needs to be tested for HCV antibodies. A negative risk factor assessment lowers the posttest probability enough among low- to moderate-risk patients that further screening may not be needed.""
Validation of a Hepatitis C Screening Tool in Primary Care
Thomas McGinn, MD, MPH; Nicola O’Connor-Moore, MPH, RN; David Alfandre, MD, MSPH; Donald Gardenier, MS, MPA, APRN; Juan Wisnivesky, MD, MPH
Divisions of General Internal Medicine (Drs McGinn, Alfandre, and Wisnivesky and Mr Gardenier) and Pulmonary and Critical Care Medicine (Dr Wisnivesky), Mount Sinai School of Medicine, New York, New York; and Westchester Medical Center, Valhalla, New York (Ms O’Connor-Moore).
Arch Intern Med. Oct 13 2008;168(18):2009-2013.
ABSTRACT
Background - Although hepatitis C virus (HCV) has an estimated national prevalence of 1.8%, testing rates are lower than those recommended by guidelines, particularly in primary care. A critical step is the ability to identify patients at increased risk who should be screened. We sought to prospectively derive and validate a clinical predication tool to assist primary care providers in identifying patients who should be tested for HCV antibodies.
Methods - A total of 1000 randomly selected patients attending an inner-city primary care clinic filled out a 27-item questionnaire assessing 5 HCV risk factor domains: work, medical, exposure, personal care, and social history. Afterward, the patients underwent HCV antibody testing. Multivariable logistic regression analysis was performed to identify risk factors associated with HCV antibodies.
Results - There was an 8.3% (95% confidence interval, 6.7%-10.2%) prevalence of HCV antibodies. The patients who were HCV antibody positive were more likely to be male, older, and insured by Medicaid (P ≤ .02). Those who had risk factors within the medical, exposure, and social history domains were more likely to be HCV antibody positive. The area under the receiver operating characteristic curve for the screening tool based on these 3 domains was 0.77. With an increasing number of positive domains, there was a higher likelihood of HCV antibody positivity. Only 2% of patients with 0 risk factors had HCV antibodies.
Conclusions - A prediction tool can be used to accurately identify patients at high risk of HCV who may benefit from serologic screening. Future studies should assess whether wider use of this tool may lead to improved outcomes.
INTRODUCTION
Worldwide, hepatitis C virus (HCV) is one of the most common blood-borne pathogens, with an average prevalence of 3.1%.1 The HCV antibody has an estimated prevalence of 1.8% in the United States.2 In inner-city ambulatory primary care and Veterans Administration populations, however, the rate of HCV infection is as high as 8% and 17%, respectively.3-4 The Centers for Disease Control and Prevention (CDC) recommends that all persons be assessed for HCV risk factors and that those with risk factors be screened for HCV antibodies.5 Unfortunately, rates at which primary care patients are assessed for historical risk factors, as well as the rates at which patients at increased risk are screened for HCV antibodies, remain below the CDC goals.6-7
With the potential for increased clinical benefits with earlier diagnosis,8 a new priority for health care providers generally, and primary care providers in particular, is HCV risk factor assessment and antibody testing. While some HCV risk factors are well known, others remain less clearly associated with HCV antibody positivity.9 Because universal HCV antibody screening, regardless of risk factors, is neither cost-effective nor practical,10 assessment of HCV risk factors is a critical tool for primary care providers to identify patients appropriate for antibody testing, particularly in settings with a higher prevalence of disease.11 Well-validated clinical prediction tools have been widely used in other areas of medicine, as they are useful in improving diagnostic accuracy by quantifying the relative contribution of key historical, laboratory, and physical examination data to diagnostic evaluation.12 Clinical prediction tools for HCV screening have been an underused resource. We performed a prospective validation and refinement of an HCV risk assessment tool that could be used by primary care providers to identify patients who require screening for HCV antibody in at-risk populations.
METHODS
Our study population comprised randomly selected patients who were attending an adult primary care clinic. The clinic serves approximately 40 000 patients per year and is affiliated with a large academic medical center and tertiary hospital located in the East Harlem neighborhood of New York, New York. The practice's patient population is composed predominantly of persons of African American and Hispanic ethnicity as well as lower socioeconomic status. All patients who were seen in the primary care practice between March 2002 and August 2003 were eligible for the study. With the use of a random number table, potential study subjects were randomly selected among individuals who had come to the clinic either for a scheduled visit with their primary care provider or for an unscheduled visit for an urgent problem. Exclusion criteria included age younger than 18 years or language other than English or Spanish. The study protocol was approved by the institutional review board, and all patients signed informed consent before study participation.
Face-to-face interviews conducted by recruiters in English or Spanish were used to administer a 27-item risk factor assessment questionnaire.10, 13-15 The screening questionnaire, which was previously developed at Jefferson Medical Center, Philadelphia, Pennsylvania, was based on our clinical experience and on the literature. It has been widely used in clinical settings, including our own, but has never previously been validated or published. Each item in the instrument could be answered yes or no. The questionnaire grouped risk factors into 5 domains: work history, exposure history, personal care history, social history, and medical history. The work history domain questions asked whether subjects had ever had jobs identified in the literature as having a potentially higher risk of HCV exposure: physicians, nurses, medical assistants, home attendants, and laboratory personnel as well as tattoo artists and corrections officers. The exposure history domain questions were about past contact with another persons' blood, eg, during an accident or injury. The personal care history domain items were sharing toothbrushes, receiving tattoos or piercings, and acupuncture. The social history domain questions were about illicit drug use, incarceration, and past and current sexual activity. Medical history domain questions were iatrogenic risks for transmission, including blood transfusions, dialysis, and other medical procedures as well as elevated liver function test results. Collected data included the following subject demographic information: age, sex, race and ethnicity, insurance coverage, and education level.
As part of the baseline survey, participants were also asked to report whether they had ever tested positive for HCV antibodies. The medical records of the patients who reported a history of HCV were reviewed: those with a documented laboratory blood test that was positive for HCV were classified as "positives" for the purposes of the study. A sample of peripheral blood was obtained from all other study subjects for HCV antibody testing (HCV EIA 2.0 Recombinant c100-3, HC31, and HC-34; Abbott Laboratories, Abbott Park, Illinois). Patients who were found to be reactive for HCV antibodies were also considered positives for the analyses.
Mean (SDs) were calculated for continuous variables. Univariate analysis was performed to compare the demographic characteristics among HCV antibody–positive and –negative patients. These analyses were conducted using the {chi}2 test for proportions and the pooled t test for continuous variables. Odds ratios (ORs) with 95% confidence intervals (CIs) were calculated to assess for a potential association between the 5 HCV risk factor domains and the presence of HCV antibodies.
We used logistic regression analysis to identify HCV risk factor domains that were independently associated with the presence of HCV antibody. The 5 risk factor domains were included in the model. Other covariates, such as age, sex, and insurance status, were not included in the model, as these variables are probably proxies for other risk factors, particularly among our study cohort, and were therefore not generalizable to other populations. Variable testing was performed using the Wald test, and the goodness of fit of the final model was evaluated using the Hosmer-Lemeshow test. Adjusted ORs based on this model are given with 95% CIs.
To facilitate the clinical use of the instrument, we created an HCV risk screening tool based on the responses to the 5 domains. Furthermore, we evaluated the diagnostic performance of a simplified rule based only on the domains that were independently associated with HCV antibody on multivariate analysis. Each of the 5 domains was given an equal weight, assigning 1 point to the patient when 1 or more risk factors were present in the domain. Therefore, a total score of 0 to 5 was computed as the sum of the points for each positive domain. Sensitivity and specificity were calculated according to standard methods.16-17 We used the receiver operator characteristic (ROC) curve analysis to assess the diagnostic accuracy of the HCV screening instrument. The area under the ROC curve was calculated using the method of Hanley and McNeil.16
Power calculations showed that a total of 1000 patients were required for the study to have 80% power to identify whether an HCV risk factor domain with a prevalence of at least 15% in the study population was associated with 2.0 increased odds of HCV antibody positivity. All analyses used 2-tailed significance levels of P < .05 and were conducted with SAS statistical software (SAS Institute, Cary, North Carolina).
RESULTS
Between March 2002 and August 2003, a total of 1485 patients who presented to the primary care clinic were asked to participate in the study. Of those, 1000 agreed to participate. Older patients, with a mean age of 55 years (P < .001), and African Americans (P < .001) were less likely to participate. Conversely, patients with Medicaid insurance (P < .001) and Hispanic ethnicity (P < .001) were more likely to participate.
Of the 1000 patients enrolled in the study, 83 were positive for HCV antibodies (8.3%; 95% CI, 6.7%-10.2%). Of these, 58 were known to be HCV antibody positive and 25 were newly diagnosed as being HCV antibody positive. The characteristics of the cohort are described in Table 1. Patients who were HCV antibody positive were older (P = .01), more likely to be male (P = .02), and more likely to be insured by Medicaid (P < .001). Participants with HCV antibodies did not differ from those without HCV antibodies in race/ethnicity distribution, level of education completed, or type of appointment that had brought them to the practice that day (P > .05 for all comparisons).
Univariate analysis of the HCV risk factor domains showed that a positive medical history, exposure history, or social history was significantly associated with HCV antibody positivity (P < .01 for all comparisons [Table 2]). There was a trend toward higher rates of HCV antibody positivity among patients with a positive personal history (P = .06). Conversely, a positive response to the work history domain was not associated with a positive HCV antibody test result (P = .53).
Picture 2.png
Results of the multivariate analysis showed that a positive response to the medical history (OR, 1.9; 95% CI, 1.1-3.6), exposure history (OR, 3.4; 95% CI, 2.0-5.9), or social history (OR, 6.1; 95% CI, 3.7-10.3) domains was significantly associated with increased odds of HCV antibody positivity (Table 3). A positive work history or personal history, however, was not associated with the results of HCV antibody testing after adjustment for the effect of other risk factor domains. Secondary multivariate analysis limited to patients with a new diagnosis of HCV revealed similar results, except that the medical history domain was no longer significantly associated with HCV risk (P = .42).
Picture 3.png
Table 4 lists the operating characteristics of the simplified 3-domain screening tool as a function of the number of positive domains. One or more positive domains indicates the need for further HCV antibody testing. The tool had a sensitivity of 90% and a specificity of 31% for detecting HCV antibodies in participants with 1 or more positive domains. In participants with 3 or more positive domains, the tool had a sensitivity of 34% and a specificity of 97%.
Table 5 shows posttest probabilities based on different HCV antibody prevalence rates. Among populations with a prevalence of 1% to 2%, 3 or more positive domains results in a posttest probability of 17%. When the prevalence is 8%, 2 or more positive domains raises the posttest probability to 23%, while 3 or more positive domains raises the posttest probability to 46%. Based on negative likelihood ratios, a risk factor assessment with no positive domains in a population with 8% prevalence results in a 2% posttest probability.
COMMENT
In this study, we validated a 3-domain HCV risk factor assessment tool in a sample of 1000 inner-city primary care patients. The tool had good operating characteristics and may help assess HCV risk factors and identify patients who require HCV antibody testing. The goal of assessing more patients for HCV risk factors is particularly relevant given that many patients may be unaware that they have HCV infection,18 and many primary care practitioners are not assessing HCV risk factors in their patients in appropriate numbers.6 Therefore, use of this tool may improve the quality of care, particularly among underserved populations, in which HCV antibody prevalence is often higher.
Current CDC guidelines recommend HCV antibody screening in all individuals with risk factors for infection regardless of the setting or patient characteristics.8, 19 Rather than prioritizing HCV risk factor assessment according to the setting, then, it is vital to consider all HCV risk behaviors that occur in all patients within every setting. Adopting risk assessment strategies that identify higher risk behaviors in all patient groups holds the most promise for identifying the greatest number of patients for whom antibody testing is indicated.20 Undertaking this task in all primary care settings is likely to reach the largest number of potential patients.
The potential benefits of HCV screening are multiple. First, earlier identification facilitates virologic suppression, as treatment earlier in the course of the disease is associated with better efficacy.21-22 Second, early diagnosis together with patient education and subsequent lifestyle modifications may reduce the risk of transmission of HCV infection to other individuals.23-24 Third, routine screening will lead to a fuller determination of HCV prevalence. In our inner-city primary care population, the prevalence rate was more than 4 times the reported national prevalence rate. Improved understanding of prevalence rates in particular communities will allow resources to be focused where they are needed. Finally, treatment earlier in the course of the disease is associated with acceptable cost per quality-adjusted life-years estimates.25-26
Our validation demonstrates that a negative result on a risk assessment tool can eliminate the need for HCV antibody testing in the majority of patients assessed. Furthermore, it can accurately identify those patients at moderately increased risk who would benefit from antibody screening. The posttest probability estimates based on the population's prevalence as shown in Table 5 can help in deciding which patients to screen for HCV antibodies. There are large patient populations in which HCV prevalence is low to moderate but in which screening remains low.3-4,27 In populations with this risk profile, a screen with 2 or more positive domains can sufficiently alter the posttest probability so the decision can be made as to whether or not a patient needs to be tested for HCV antibodies. A negative risk factor assessment lowers the posttest probability enough among low- to moderate-risk patients that further screening may not be needed.
This study had some limitations. The population surveyed came from an inner-city primary care practice, and the results may therefore not be generalizable to other populations or settings. Despite being an optimal population to study because it is both high risk and underserved, the prediction rule should be validated in other settings and among other populations to confirm its diagnostic accuracy. Furthermore, the self-administered questionnaire assessing risk factor history among patients with known disease presents the possibility of recall bias. However, in the secondary analysis, which included only new, previously unknown diagnoses of HCV, the results were similar except for the medical history. Nevertheless, the likelihood of patients not recalling these usually major aspects of their medical history (eg, transfusion, organ transplantation, or dialysis) is probably low. Finally, there were significant differences between the subjects who chose to participate and those who refused. African Americans and slightly older patients were less likely to participate in the study, while Hispanics and patients with Medicaid were more likely to participate. The effect of this potential sampling bias in our results is unclear and should be evaluated in future studies.
In conclusion, we have demonstrated the value of a simplified tool to assess HCV risk in patients attending a primary care practice. This tool can be used to screen all individuals for HCV risk factors and could diminish the need for antibody screening in patients who are at very low or no risk. Widespread use of the tool may facilitate and increase overall screening and detection of HCV in diverse populations of primary care patients. By targeting only patients at higher risk, it may lead to more cost-effective screening for a disease that is causing significant morbidity and mortality particularly in inner-city populations. An impact analysis or randomized control trial of this model is warranted to demonstrate both clinical value and cost-effectiveness.
"Our validation demonstrates that a negative result on a risk assessment tool can eliminate the need for HCV antibody testing in the majority of patients assessed. Furthermore, it can accurately identify those patients at moderately increased risk who would benefit from antibody screening. The posttest probability estimates based on the population's prevalence as shown in Table 5 can help in deciding which patients to screen for HCV antibodies. There are large patient populations in which HCV prevalence is low to moderate but in which screening remains low.3-4,27 In populations with this risk profile, a screen with 2 or more positive domains can sufficiently alter the posttest probability so the decision can be made as to whether or not a patient needs to be tested for HCV antibodies. A negative risk factor assessment lowers the posttest probability enough among low- to moderate-risk patients that further screening may not be needed.""
Validation of a Hepatitis C Screening Tool in Primary Care
Thomas McGinn, MD, MPH; Nicola O’Connor-Moore, MPH, RN; David Alfandre, MD, MSPH; Donald Gardenier, MS, MPA, APRN; Juan Wisnivesky, MD, MPH
Divisions of General Internal Medicine (Drs McGinn, Alfandre, and Wisnivesky and Mr Gardenier) and Pulmonary and Critical Care Medicine (Dr Wisnivesky), Mount Sinai School of Medicine, New York, New York; and Westchester Medical Center, Valhalla, New York (Ms O’Connor-Moore).
Arch Intern Med. Oct 13 2008;168(18):2009-2013.
ABSTRACT
Background - Although hepatitis C virus (HCV) has an estimated national prevalence of 1.8%, testing rates are lower than those recommended by guidelines, particularly in primary care. A critical step is the ability to identify patients at increased risk who should be screened. We sought to prospectively derive and validate a clinical predication tool to assist primary care providers in identifying patients who should be tested for HCV antibodies.
Methods - A total of 1000 randomly selected patients attending an inner-city primary care clinic filled out a 27-item questionnaire assessing 5 HCV risk factor domains: work, medical, exposure, personal care, and social history. Afterward, the patients underwent HCV antibody testing. Multivariable logistic regression analysis was performed to identify risk factors associated with HCV antibodies.
Results - There was an 8.3% (95% confidence interval, 6.7%-10.2%) prevalence of HCV antibodies. The patients who were HCV antibody positive were more likely to be male, older, and insured by Medicaid (P ≤ .02). Those who had risk factors within the medical, exposure, and social history domains were more likely to be HCV antibody positive. The area under the receiver operating characteristic curve for the screening tool based on these 3 domains was 0.77. With an increasing number of positive domains, there was a higher likelihood of HCV antibody positivity. Only 2% of patients with 0 risk factors had HCV antibodies.
Conclusions - A prediction tool can be used to accurately identify patients at high risk of HCV who may benefit from serologic screening. Future studies should assess whether wider use of this tool may lead to improved outcomes.
INTRODUCTION
Worldwide, hepatitis C virus (HCV) is one of the most common blood-borne pathogens, with an average prevalence of 3.1%.1 The HCV antibody has an estimated prevalence of 1.8% in the United States.2 In inner-city ambulatory primary care and Veterans Administration populations, however, the rate of HCV infection is as high as 8% and 17%, respectively.3-4 The Centers for Disease Control and Prevention (CDC) recommends that all persons be assessed for HCV risk factors and that those with risk factors be screened for HCV antibodies.5 Unfortunately, rates at which primary care patients are assessed for historical risk factors, as well as the rates at which patients at increased risk are screened for HCV antibodies, remain below the CDC goals.6-7
With the potential for increased clinical benefits with earlier diagnosis,8 a new priority for health care providers generally, and primary care providers in particular, is HCV risk factor assessment and antibody testing. While some HCV risk factors are well known, others remain less clearly associated with HCV antibody positivity.9 Because universal HCV antibody screening, regardless of risk factors, is neither cost-effective nor practical,10 assessment of HCV risk factors is a critical tool for primary care providers to identify patients appropriate for antibody testing, particularly in settings with a higher prevalence of disease.11 Well-validated clinical prediction tools have been widely used in other areas of medicine, as they are useful in improving diagnostic accuracy by quantifying the relative contribution of key historical, laboratory, and physical examination data to diagnostic evaluation.12 Clinical prediction tools for HCV screening have been an underused resource. We performed a prospective validation and refinement of an HCV risk assessment tool that could be used by primary care providers to identify patients who require screening for HCV antibody in at-risk populations.
METHODS
Our study population comprised randomly selected patients who were attending an adult primary care clinic. The clinic serves approximately 40 000 patients per year and is affiliated with a large academic medical center and tertiary hospital located in the East Harlem neighborhood of New York, New York. The practice's patient population is composed predominantly of persons of African American and Hispanic ethnicity as well as lower socioeconomic status. All patients who were seen in the primary care practice between March 2002 and August 2003 were eligible for the study. With the use of a random number table, potential study subjects were randomly selected among individuals who had come to the clinic either for a scheduled visit with their primary care provider or for an unscheduled visit for an urgent problem. Exclusion criteria included age younger than 18 years or language other than English or Spanish. The study protocol was approved by the institutional review board, and all patients signed informed consent before study participation.
Face-to-face interviews conducted by recruiters in English or Spanish were used to administer a 27-item risk factor assessment questionnaire.10, 13-15 The screening questionnaire, which was previously developed at Jefferson Medical Center, Philadelphia, Pennsylvania, was based on our clinical experience and on the literature. It has been widely used in clinical settings, including our own, but has never previously been validated or published. Each item in the instrument could be answered yes or no. The questionnaire grouped risk factors into 5 domains: work history, exposure history, personal care history, social history, and medical history. The work history domain questions asked whether subjects had ever had jobs identified in the literature as having a potentially higher risk of HCV exposure: physicians, nurses, medical assistants, home attendants, and laboratory personnel as well as tattoo artists and corrections officers. The exposure history domain questions were about past contact with another persons' blood, eg, during an accident or injury. The personal care history domain items were sharing toothbrushes, receiving tattoos or piercings, and acupuncture. The social history domain questions were about illicit drug use, incarceration, and past and current sexual activity. Medical history domain questions were iatrogenic risks for transmission, including blood transfusions, dialysis, and other medical procedures as well as elevated liver function test results. Collected data included the following subject demographic information: age, sex, race and ethnicity, insurance coverage, and education level.
As part of the baseline survey, participants were also asked to report whether they had ever tested positive for HCV antibodies. The medical records of the patients who reported a history of HCV were reviewed: those with a documented laboratory blood test that was positive for HCV were classified as "positives" for the purposes of the study. A sample of peripheral blood was obtained from all other study subjects for HCV antibody testing (HCV EIA 2.0 Recombinant c100-3, HC31, and HC-34; Abbott Laboratories, Abbott Park, Illinois). Patients who were found to be reactive for HCV antibodies were also considered positives for the analyses.
Mean (SDs) were calculated for continuous variables. Univariate analysis was performed to compare the demographic characteristics among HCV antibody–positive and –negative patients. These analyses were conducted using the {chi}2 test for proportions and the pooled t test for continuous variables. Odds ratios (ORs) with 95% confidence intervals (CIs) were calculated to assess for a potential association between the 5 HCV risk factor domains and the presence of HCV antibodies.
We used logistic regression analysis to identify HCV risk factor domains that were independently associated with the presence of HCV antibody. The 5 risk factor domains were included in the model. Other covariates, such as age, sex, and insurance status, were not included in the model, as these variables are probably proxies for other risk factors, particularly among our study cohort, and were therefore not generalizable to other populations. Variable testing was performed using the Wald test, and the goodness of fit of the final model was evaluated using the Hosmer-Lemeshow test. Adjusted ORs based on this model are given with 95% CIs.
To facilitate the clinical use of the instrument, we created an HCV risk screening tool based on the responses to the 5 domains. Furthermore, we evaluated the diagnostic performance of a simplified rule based only on the domains that were independently associated with HCV antibody on multivariate analysis. Each of the 5 domains was given an equal weight, assigning 1 point to the patient when 1 or more risk factors were present in the domain. Therefore, a total score of 0 to 5 was computed as the sum of the points for each positive domain. Sensitivity and specificity were calculated according to standard methods.16-17 We used the receiver operator characteristic (ROC) curve analysis to assess the diagnostic accuracy of the HCV screening instrument. The area under the ROC curve was calculated using the method of Hanley and McNeil.16
Power calculations showed that a total of 1000 patients were required for the study to have 80% power to identify whether an HCV risk factor domain with a prevalence of at least 15% in the study population was associated with 2.0 increased odds of HCV antibody positivity. All analyses used 2-tailed significance levels of P < .05 and were conducted with SAS statistical software (SAS Institute, Cary, North Carolina).
RESULTS
Between March 2002 and August 2003, a total of 1485 patients who presented to the primary care clinic were asked to participate in the study. Of those, 1000 agreed to participate. Older patients, with a mean age of 55 years (P < .001), and African Americans (P < .001) were less likely to participate. Conversely, patients with Medicaid insurance (P < .001) and Hispanic ethnicity (P < .001) were more likely to participate.
Of the 1000 patients enrolled in the study, 83 were positive for HCV antibodies (8.3%; 95% CI, 6.7%-10.2%). Of these, 58 were known to be HCV antibody positive and 25 were newly diagnosed as being HCV antibody positive. The characteristics of the cohort are described in Table 1. Patients who were HCV antibody positive were older (P = .01), more likely to be male (P = .02), and more likely to be insured by Medicaid (P < .001). Participants with HCV antibodies did not differ from those without HCV antibodies in race/ethnicity distribution, level of education completed, or type of appointment that had brought them to the practice that day (P > .05 for all comparisons).
Univariate analysis of the HCV risk factor domains showed that a positive medical history, exposure history, or social history was significantly associated with HCV antibody positivity (P < .01 for all comparisons [Table 2]). There was a trend toward higher rates of HCV antibody positivity among patients with a positive personal history (P = .06). Conversely, a positive response to the work history domain was not associated with a positive HCV antibody test result (P = .53).
Picture 2.png
Results of the multivariate analysis showed that a positive response to the medical history (OR, 1.9; 95% CI, 1.1-3.6), exposure history (OR, 3.4; 95% CI, 2.0-5.9), or social history (OR, 6.1; 95% CI, 3.7-10.3) domains was significantly associated with increased odds of HCV antibody positivity (Table 3). A positive work history or personal history, however, was not associated with the results of HCV antibody testing after adjustment for the effect of other risk factor domains. Secondary multivariate analysis limited to patients with a new diagnosis of HCV revealed similar results, except that the medical history domain was no longer significantly associated with HCV risk (P = .42).
Picture 3.png
Table 4 lists the operating characteristics of the simplified 3-domain screening tool as a function of the number of positive domains. One or more positive domains indicates the need for further HCV antibody testing. The tool had a sensitivity of 90% and a specificity of 31% for detecting HCV antibodies in participants with 1 or more positive domains. In participants with 3 or more positive domains, the tool had a sensitivity of 34% and a specificity of 97%.
Table 5 shows posttest probabilities based on different HCV antibody prevalence rates. Among populations with a prevalence of 1% to 2%, 3 or more positive domains results in a posttest probability of 17%. When the prevalence is 8%, 2 or more positive domains raises the posttest probability to 23%, while 3 or more positive domains raises the posttest probability to 46%. Based on negative likelihood ratios, a risk factor assessment with no positive domains in a population with 8% prevalence results in a 2% posttest probability.
COMMENT
In this study, we validated a 3-domain HCV risk factor assessment tool in a sample of 1000 inner-city primary care patients. The tool had good operating characteristics and may help assess HCV risk factors and identify patients who require HCV antibody testing. The goal of assessing more patients for HCV risk factors is particularly relevant given that many patients may be unaware that they have HCV infection,18 and many primary care practitioners are not assessing HCV risk factors in their patients in appropriate numbers.6 Therefore, use of this tool may improve the quality of care, particularly among underserved populations, in which HCV antibody prevalence is often higher.
Current CDC guidelines recommend HCV antibody screening in all individuals with risk factors for infection regardless of the setting or patient characteristics.8, 19 Rather than prioritizing HCV risk factor assessment according to the setting, then, it is vital to consider all HCV risk behaviors that occur in all patients within every setting. Adopting risk assessment strategies that identify higher risk behaviors in all patient groups holds the most promise for identifying the greatest number of patients for whom antibody testing is indicated.20 Undertaking this task in all primary care settings is likely to reach the largest number of potential patients.
The potential benefits of HCV screening are multiple. First, earlier identification facilitates virologic suppression, as treatment earlier in the course of the disease is associated with better efficacy.21-22 Second, early diagnosis together with patient education and subsequent lifestyle modifications may reduce the risk of transmission of HCV infection to other individuals.23-24 Third, routine screening will lead to a fuller determination of HCV prevalence. In our inner-city primary care population, the prevalence rate was more than 4 times the reported national prevalence rate. Improved understanding of prevalence rates in particular communities will allow resources to be focused where they are needed. Finally, treatment earlier in the course of the disease is associated with acceptable cost per quality-adjusted life-years estimates.25-26
Our validation demonstrates that a negative result on a risk assessment tool can eliminate the need for HCV antibody testing in the majority of patients assessed. Furthermore, it can accurately identify those patients at moderately increased risk who would benefit from antibody screening. The posttest probability estimates based on the population's prevalence as shown in Table 5 can help in deciding which patients to screen for HCV antibodies. There are large patient populations in which HCV prevalence is low to moderate but in which screening remains low.3-4,27 In populations with this risk profile, a screen with 2 or more positive domains can sufficiently alter the posttest probability so the decision can be made as to whether or not a patient needs to be tested for HCV antibodies. A negative risk factor assessment lowers the posttest probability enough among low- to moderate-risk patients that further screening may not be needed.
This study had some limitations. The population surveyed came from an inner-city primary care practice, and the results may therefore not be generalizable to other populations or settings. Despite being an optimal population to study because it is both high risk and underserved, the prediction rule should be validated in other settings and among other populations to confirm its diagnostic accuracy. Furthermore, the self-administered questionnaire assessing risk factor history among patients with known disease presents the possibility of recall bias. However, in the secondary analysis, which included only new, previously unknown diagnoses of HCV, the results were similar except for the medical history. Nevertheless, the likelihood of patients not recalling these usually major aspects of their medical history (eg, transfusion, organ transplantation, or dialysis) is probably low. Finally, there were significant differences between the subjects who chose to participate and those who refused. African Americans and slightly older patients were less likely to participate in the study, while Hispanics and patients with Medicaid were more likely to participate. The effect of this potential sampling bias in our results is unclear and should be evaluated in future studies.
In conclusion, we have demonstrated the value of a simplified tool to assess HCV risk in patients attending a primary care practice. This tool can be used to screen all individuals for HCV risk factors and could diminish the need for antibody screening in patients who are at very low or no risk. Widespread use of the tool may facilitate and increase overall screening and detection of HCV in diverse populations of primary care patients. By targeting only patients at higher risk, it may lead to more cost-effective screening for a disease that is causing significant morbidity and mortality particularly in inner-city populations. An impact analysis or randomized control trial of this model is warranted to demonstrate both clinical value and cost-effectiveness.
Peginterferon Alfa-2a Plus Ribavirin Is More Effective Than Peginterferon Alfa-2b Plus Ribavirin for Treating Chronic Hepatitis C Virus Infectio
Peginterferon Alfa-2a Plus Ribavirin Is More Effective Than Peginterferon Alfa-2b Plus Ribavirin for Treating Chronic Hepatitis C Virus Infection
- pdf publication attached
Gastroenterology Jan 2010
Presented in part as an oral communication at the 43rd Annual Meeting of the European Association for the Study of the Liver; April 23-27, 2008; Milan, Italy.
Antonio Ascione, Massimo De Luca, Maria Teresa Tartaglione, Filippo Lampasi, Giovan Giuseppe Di Costanzo, Alfonso Galeota Lanza, Francesco Paolo Picciotto, Giuseppina Marino-Marsilia, Luca Fontanella, Gioacchino Leandro Department of Gastroenterology, Liver Unit, Cardarelli Hospital, Napoli, Italy Department of Gastroenterology, Pathology Unit, Cardarelli Hospital, Napoli, Italy
Department of Medicine, Centre for Liver Disease, Fatebenefratelli Hospital, Napoli, Italy
Gastroenterology Unit, IRCSS de Bellis, Castellana Grotte, Italy
Conflicts of interest The authors disclose the following: Dr Ascione has received lecture fees from Bayer Healthcare, Bristol-Myers Squibb, Gilead, Grifols, Novartis, Schering-Plough, Roche, and Roche Diagnostics. The remaining authors discloses no conflicts.
Received 23 March 2009; accepted 15 October 2009. published online 22 October 2009.
"An SVR was achieved in 68.8% of patients randomized to peginterferon alfa-2a and 54.4% of those randomized to peginterferon alfa-2b (difference, 14.4%; 95% CI, 3.7%-24.6%; P = .008). The apparently high SVR rates may be due to the low number of patients with cirrhosis enrolled in the study (n = 59; 18.4%)...... In patients without cirrhosis, the SVR rate was 75.6% in peginterferon alfa-2a recipients and 55.9% in peginterferon alfa-2b recipients (P = .005); in patients with cirrhosis, the SVR rates were 42.4% and 46.1%, respectively (P = .77)..... In subgroup analyses, the SVR rate was 47.3% in patients with genotype 1/4 (54.8% in recipients of peginterferon alfa-2a and 39.8% in recipients of peginterferon alfa-2b; difference, 15%; P = .040)......Among those infected with genotype 2/3, the overall SVR rate was much higher (81.3%). The SVR rate was considerably higher in patients infected with genotype 2 than genotype 3 (83.8% vs 74.3%, respectively). Although this difference is not statistically significant (P = .21), we believe that these genotypes should no longer be considered to be a homogeneous group....
Another interesting finding of this study is the relationship between SVR and the baseline HCV RNA level. In the 143 patients with an HCV RNA level ≤500,000 IU/mL, the 2 treatments were not statistically different (SVR of 68.4% in patients treated with peginterferon alfa-2a and 65.7% in patients treated with peginterferon alfa-2b; P = .727). In patients with baseline serum HCV RNA levels >500,000 IU/mL, the SVR rate was 69.0% in those treated with peginterferon alfa-2a and 46.2% in those treated with peginterferon alfa-2b (P = .002)."
ABSTRACT
Background & Aims
Patients with chronic hepatitis C virus (HCV) infection are frequently treated with a combination of pegylated interferon (peginterferon) and ribavirin. This study compared the efficacy and safety of peginterferon alfa-2a and peginterferon alfa-2b, each in combination with ribavirin.
Methods
A total of 320 consecutive, treatment-naive, HCV RNA-positive patients with chronic hepatitis were randomly assigned to once-weekly peginterferon alfa-2a (180 μg, group A) or peginterferon alfa-2b (1.5 μg/kg, group B) plus ribavirin 1000 mg/day (body weight <75 kg) or 1200 mg/day (body weight ≥75 kg) for 48 weeks (genotype 1 or 4) or 24 weeks (genotype 2 or 3). The primary end point was sustained virological response (SVR) by intention-to-treat.
Results
More patients in group A than group B achieved an SVR (110/160 [68.8%] vs 87/160 [54.4%]; P = .008). Higher SVR rates were obtained in group A than group B among patients with genotype 1/4 (51/93 [54.8%] vs 37/93 [39.8%]; P = .04), with genotype 2/3 (59/67 [88.1%] vs 50/67 [74.6%]; P = .046), without cirrhosis (96/127 [75.6%] vs 75/134 [55.9%]; P = .005), and with baseline levels HCV RNA >500,000 IU/mL (58/84 [69%] vs 43/93 [46.2%]; P = .002). SVR rates in groups A and B were not statistically different among patients with baseline HCV RNA ≤500,000 IU/mL (52/76 [68.4%] vs 44/67 [65.7%]; P = .727) or in patients with cirrhosis (14/33 [42.4%] vs 12/26 [46.1%]; P = .774).
Conclusions
In patients with chronic HCV infection, peginterferon alfa-2a plus ribavirin produced a significantly higher SVR rate than peginterferon alfa-2b plus ribavirin.
Abbreviations used in this paper: CI, confidence interval, ETR, end-of-treatment response, EVR, early virological response, peginterferon, pegylated interferon, SVR, sustained virological response
Pegylated interferon (peginterferon) plus ribavirin is the treatment of choice for chronic infection with hepatitis C virus (HCV). When administered in a pegylated formulation, the half-life of interferon is prolonged because of covalent binding of the polyethylene glycol molecule to the interferon moiety. Consequently, sustained virological response (SVR) rates have increased from <20% to >60% with the combination of peginterferon plus ribavirin in patients with chronic HCV infection.1, 2, 3, 4
There are 2 commercially available peginterferons, and randomized controlled trials have shown that both peginterferon alfa-2a and peginterferon alfa-2b are effective and safe when administered in combination with ribavirin. Recently, data from 2 small clinical studies suggest that peginterferon alfa-2a produces a 14%-15% greater rate of early virological response (EVR) or SVR than peginterferon alfa-2b, although both studies failed to show a statistically significant difference because of insufficient sample sizes.5, 6 The present study aimed to compare the efficacy and safety of peginterferon alfa-2a versus peginterferon alfa-2b in combination with an identical dose of ribavirin in patients with chronic HCV infection.
Discussion
In this study, peginterferon alfa-2a produced a significantly greater SVR rate than peginterferon alfa-2b in patients with chronic HCV infection. Previous comparative studies have investigated the antiviral activity and pharmacokinetic properties of the 2 formulations.9, 10, 11 A pharmacokinetic analysis in 22 patients showed that peginterferon alfa-2a was still detectable 168 hours after administration at a dosage of 180 μg/wk but that peginterferon alfa-2b administered at a dosage of 1.0 μg · kg-1 · wk-1 (ie, lower than in the present study) was undetectable in 92% of patients at the same time point.9 At week 12, mean serum HCV RNA levels were significantly lower in patients treated with peginterferon alfa-2a than peginterferon alfa-2b (P < .01). In contrast, the pharmacodynamic profile (induction of 2'-5'-oligoadenylate synthetase, neopterin, and β2 -microglobulin activity) of the 2 peginterferons was similar in the same patients.10 In another study11 in 36 patients with genotype 1, those receiving peginterferon alfa-2b 1.5 μg · kg-1 · wk-1 had significantly greater up-regulation of interferon alfa response genes than those receiving peginterferon alfa-2a 180 μg/wk (ribavirin 13 mg · kg-1 · day-1 was administered after week 4). Patients treated with peginterferon alfa-2b also had greater log10 maximum and log10 time-weighted average decreases in serum HCV RNA levels, and a correspondingly greater proportion of peginterferon alfa-2b-treated patients achieved ≥2 log10 reduction in serum HCV RNA levels by week 8 (72% vs 44% of peginterferon alfa-2a-treated patients; P = .09). Although these data suggest that peginterferon alfa-2b has better biological activity, the between-group differences were not statistically significant.
To date, only 2 randomized clinical studies have compared the efficacy of the peginterferon formulations, neither of which was sufficiently powered to detect a statistically significant difference in SVR rates.5, 6 Despite a difference of 15% in the EVR rate between patients treated with peginterferon alfa-2a 180 μg/wk plus ribavirin (n = 58) and peginterferon alfa-2b 1.5 μg · kg-1 · wk-1 plus ribavirin (n = 58) in one study, the difference was not statistically significant (82% vs 67%, respectively; P = .08).5 An SVR rate of 48.6% was obtained in patients with genotype 1 who received peginterferon alfa-2a 180 μg/wk plus ribavirin (n = 37) and 35.1% in those treated with peginterferon alfa-2b 1.5 μg · kg-1 · wk-1 plus ribavirin (n = 37) in a second study, but the sample size was too small to show a statistically significant difference.6 The 14.4% difference in SVR rate in favor of peginterferon alfa-2a in the present study is consistent with the between-group differences of 14%-15% in rates of EVR and SVR in these 2 trials.
In the retrospective phase of the large (n = 2149) PROBE study (sponsored by Hoffmann-La Roche),12 the rate of SVR was higher in genotype 1 patients treated with peginterferon alfa-2a than with peginterferon alfa-2b (45% vs 38.4%; P = .04). The prospective phase of this study is yet to be completed.
Similar to the PROBE study, a recently published observational retrospective study of a large cohort (N = 9544) of US veterans13 reported that treatment of genotype 1 patients with peginterferon alfa-2a was associated with a higher likelihood of SVR than treatment with peginterferon alfa-2b.
In the present study, the 2 peginterferons were administered at dosages recommended in treatment guidelines with a sample size adequate to draw reliable conclusions concerning efficacy and safety. Ribavirin was administered at weight-based dosages that were stable during the study, so the only independent variable was the type of peginterferon. An SVR was achieved in 68.8% of patients randomized to peginterferon alfa-2a and 54.4% of those randomized to peginterferon alfa-2b (difference, 14.4%; 95% CI, 3.7%-24.6%; P = .008). The apparently high SVR rates may be due to the low number of patients with cirrhosis enrolled in the study (n = 59; 18.4%).
In subgroup analyses, the SVR rate was 47.3% in patients with genotype 1/4 (54.8% in recipients of peginterferon alfa-2a and 39.8% in recipients of peginterferon alfa-2b; difference, 15%; P = .040). Genotype 4 is very uncommon in southern Italy. Table 1 shows that the number of these patients is only 5 (1.6% of the total) not equally distributed because they were randomized together with genotype 1. For this reason, 4 patients were treated with peginterferon alfa-2a and one with peginterferon alfa-2b. Only one of them responded, and she was in the peginterferon alfa-2b arm.
Among those infected with genotype 2/3, the overall SVR rate was much higher (81.3%). The SVR rate was considerably higher in patients infected with genotype 2 than genotype 3 (83.8% vs 74.3%, respectively). Although this difference is not statistically significant (P = .21), we believe that these genotypes should no longer be considered to be a homogeneous group.
In patients without cirrhosis, the SVR rate was 75.6% in peginterferon alfa-2a recipients and 55.9% in peginterferon alfa-2b recipients (P = .005); in patients with cirrhosis, the SVR rates were 42.4% and 46.1%, respectively (P = .77).
Another interesting finding of this study is the relationship between SVR and the baseline HCV RNA level. In the 143 patients with an HCV RNA level ≤500,000 IU/mL, the 2 treatments were not statistically different (SVR of 68.4% in patients treated with peginterferon alfa-2a and 65.7% in patients treated with peginterferon alfa-2b; P = .727). In patients with baseline serum HCV RNA levels >500,000 IU/mL, the SVR rate was 69.0% in those treated with peginterferon alfa-2a and 46.2% in those treated with peginterferon alfa-2b (P = .002).
However, it is important to note that our subgroup analyses are post hoc and thus the results should be regarded with caution. Our subgroup results should be verified with a prospective trial that is specifically designed and powered to confirm or not confirm our results.
A multivariate analysis showed that male gender, absence of cirrhosis, use of peginterferon alfa-2a, and infection with genotype 2/3 were independently associated with SVR.
Only 30 of 320 patients (9.4%) did not experience adverse events, with no difference between group A and group B.
The results of a very large randomized trial comparing 2 regimens of peginterferon therapy in patients with genotype 1 in the United States were recently reported (IDEAL trial).14 The IDEAL trial showed no difference in SVR rates between patients treated with peginterferon alfa-2a plus ribavirin and those treated with peginterferon alfa-2b plus ribavirin. There was a number of fundamental differences between the IDEAL trial and the current study that may help to explain the different outcomes: (1) a multicenter postapproval industry-sponsored trial versus an investigator-initiated single-center trial, (2) a US population with higher body mass index and more black/Latino patients versus a European population, (3) 2 different ribavirin regimens with different starting doses and dose reduction rules versus equal ribavirin doses in all patients, (4) a genotype 1-only study vs all genotypes, and (5) different laboratories for testing the main indicator of response (HCV RNA by polymerase chain reaction). In fact, using a fixed dose of ribavirin in all the genotypes treated and in the 2 groups treated with peginterferons might have given a better indication of the different performance of the 2 peginterferons themselves without a confounding effect of differing ribavirin doses and dose reductions. The results of the 2 studies, when analyzed together, may indeed be quite compatible with closer inspection of end-of-treatment and relapse results in the IDEAL trial. However, because these trials were designed so differently and conducted in very different populations with HCV infection, we do not believe they can be directly compared. The reader should not draw conclusions across populations from either study.
In conclusion, this single-center, randomized, head-to-head study indicates that (1) the safety profile of the 2 preparations is similar and (2) in the populations studied, the rate of SVR obtained with peginterferon alfa-2a plus ribavirin is higher than that achieved with peginterferon alfa-2b plus ribavirin.
Results
Between March 2004 and December 2006, 408 patients were screened, of whom 320 (78%) were enrolled (Supplementary Figure 1). All patients were white, and the baseline characteristics of the 2 treatment groups were similar (Table 1).
A liver biopsy specimen was obtained in the chronic hepatitis group in 230 patients (88.1%), in whom the fibrosis grade was 2.13 (±1.03). Thirty-one patients (9.7%) refused to submit to the procedure. In this group, we used the criteria for diagnosis outlined in Patients and Methods because it was absolutely necessary to exclude cirrhosis. In patients with clear-cut signs of cirrhosis (19/320 [5.9%]), biopsy was not ethically justified because of the risk and no benefit for the patient. The criteria we used for clinical diagnosis of cirrhosis were presence of esophageal varices at endoscopy, low platelet count (<100 x 109/L), and ultrasound alterations typical for liver cirrhosis. The diagnosis was assumed as correct only if all 3 criteria were satisfied.
Efficacy
Overall, an EVR, as reported in Table 2, was obtained by 253 of 320 patients (79.1%): 136 (85%) in group A and 117 in group B (73%). This difference is statistically significant (difference, 12%; 95% CI, 2.9%-21%; P = .009). The majority of patients obtained a complete EVR, while the number of those who obtained a partial EVR was only 8.8%, with no difference between group A and group B.
An ETR was obtained in 237 patients (74.1%), 134 (83.8%) in group A versus 103 patients (64.4%) in group B (difference, 19.4%; 95% CI, 9.8%-28.5%; P < .0001), and an SVR was obtained in 197 patients (61.6%; 95% CI, 56.2%-66.9%), including 110 of 160 (68.8%; 95% CI, 61.6%-75.9%) in group A versus 87 of 160 (54.4%; 95% CI, 46.7%-62.1%) in group B. The difference between the 2 groups is 14.4% (95% CI, 3.7%-24.6%; P = .008). The total number of patients who experienced a relapse during follow-up was 40 of 320 (12.5%), including 24 of 160 (15%) in group A versus 16 of 160 (10%) in group B (difference, 5%; 95% CI, -2.3% to 12.4%; P = .176). Among patients without cirrhosis, an SVR was achieved by 171 of 261 patients (65.5%), including 96 of 127 (75.6%) in group A and 75 of 134 (55.9%) in group B (difference, 19.7%; 95% CI, 8.11%-30.4%; P = .005). Among the 59 patients with cirrhosis, 26 obtained an SVR (44.1%), including 14 of 33 (42.4%) in group A versus 12 of 26 (46.1%) in group B (difference, 3.7%; 95% CI, -20.4% to 27.6%; P = .774).
An SVR was obtained in 96 of 143 patients (67.1%) with a baseline HCV RNA level ≤500,000 IU/mL, including 52 of 76 (68.4%) in group A and 44 of 67 (65.7%) in group B (difference, 2.7%; 95% CI, -12.4% to 17.9%; P = .727). In 177 patients with a baseline HCV RNA level >500,000 IU/mL, 101 achieved an SVR (57.1%), including 58 of 84 (69%) in group A and 43 of 93 (46.2%) in group B (difference, 22.8%; 95% CI, 8.2%-36.0%; P = .002). An ETR was obtained in 116 of 186 patients (62.4%) infected with genotype 1 or 4, including 70 of 93 (75.3%) in group A versus 46 of 93 (49.5%) in group B (difference, 25.8%; 95% CI, 11.9%-38.4%; P = .0003), and an SVR was obtained in 88 of 186 patients (47.3%), including 51 of 93 (54.8%) in group A and 37 of 93 (39.8%) in group B (difference, 15%; 95% CI, 0.72%-28.5%; P = .040). Relapse during follow-up occurred in 28 patients (15.1%) overall, including 19 of 93 (20.4%) in group A and 9 of 93 (9.7%) in group B (difference, 10.7%; 95% CI, 0.38%-21.1%; P = .040). Among 134 patients infected with genotype 2 or 3, 121 (90.3%) achieved an ETR, including 64 of 67 (95.5%) in group A and 57 of 67 (85.1%) in group B (difference, 10.4%; 95% CI, 0.16%-21.3%; P = .80), and an SVR was obtained by 109 of 134 patients (81.3%), including 59 of 67 (88.1%) in group A and 50 of 67 (74.6%) in group B (difference, 13.5%; 95% CI, 0.14%-26.4%; P = .046). A total of 12 of 134 patients with genotype 2 or 3 experienced a relapse during follow-up (8.9%), including 5 of 67 (7.5%) in group A and 7 of 67 (10.4%) in group B (difference, 2.9%; 95% CI, -7.32% to 13.5%; P = .54). Patients infected with genotype 2 had a higher overall SVR rate (83/99; 83.8%) than those infected with genotype 3 (26/35; 74.3%), although the difference was not statistically significant (P = .21). Among those with genotype 2 infection, 45 of 49 patients (91.8%) in group A and 38 of 50 (76%) in group B (P = .06) obtained an SVR. Among those infected with genotype 3, an SVR was obtained by 14 of 18 patients (77.8%) in group A and 12 of 17 (70.6%) in group B (P = .92).
Factors Related to SVR
According to multivariate stepwise analysis, we included in the model the following preselected variables: age, body weight, body mass index, sex, absence of cirrhosis, ALT level, HCV RNA level, HCV genotype, and schedule of treatment. Male gender (odds ratio, 1.93; 95% CI, 1.17-3.20; P = .011), absence of cirrhosis (odds ratio, 2.36; 95% CI, 1.28-4.41; P = .007), treatment with peginterferon alfa-2a (odds ratio, 2.32; 95% CI, 1.39-3.88; P = .001), and infection with genotype 2 or 3 (odds ratio, 4.83; 95% CI, 2.81-8.31; P < .0001) were all independently associated with SVR.
Adverse Events and Dose Reductions
The dosage of peginterferon and/or ribavirin was reduced in most patients, and only 30 of 320 patients (9.4%) reported no adverse events. The type and incidence of adverse events were very similar in the 2 treatment groups. Twenty-six patients (8.1%) were classified as nonresponders because of interruption of therapy due to any type of adverse event, including 4 of 26 (15.4%) in group A and 22 of 26 (84.6%) in group B (P = .0005). In detail, for adverse events, the causes for stopping therapy in group A were dermatitis (1), severe depression (1), pruritus (1), and hyperthyroidism (1). In group B, the causes were fatigue (2), myalgia (2), severe depression (3), nausea (1), pruritus (2), alopecia (1), irritability (1), hyperthyroidism (1), decreased appetite (2), dermatitis (1), and cough (1). Of the 5 patients with laboratory abnormalities, one patient discontinued because of a high decrease in platelet count, 2 patients discontinued because of neutropenia, and the other 2 patients discontinued because of anemia. The use of erythropoietin and granulocyte-stimulating growth factors was prohibited by regulation of the National Health System at time of the planning of the study. Only recently the National Health System has allowed the use of the 2 drugs, but only for responders, to avoid the loss of therapeutic response; however, this was done when it was no longer necessary for our patients because the trial was at the end.
More than 50% of patients were unable to comply with the 80/80/80 rule, especially those infected with genotype 1 or 4 (Table 3). No patient was lost to follow-up. No serious adverse events were reported. Serious adverse events were defined as follows: death, any kind of life-threatening event, and any kind of adverse effect requiring hospitalization.
Patients and Methods
Selection of Patients
Consecutive interferon-naive adults (aged 18 years or older) seen at the Liver Unit of Cardarelli Hospital (Napoli, Italy) who had chronic HCV infection were eligible for enrollment. Patients were required to have a detectable serum HCV RNA level, have an alanine aminotransferase (ALT) level >1.5 times the upper limit of normal for ≥6 months, have a liver biopsy performed within 12 months of starting treatment graded according to Scheuer's7 criteria (unless not indicated or refused), have a negative pregnancy test result, use contraceptive methods during therapy and for 6 months after the end of treatment, and have abstained from alcohol use for at least 6 months. Cirrhosis was assessed on the basis of clinical and laboratory test results, liver-spleen ultrasonography, and upper gastrointestinal endoscopy in patients ineligible for and in those who refused a liver biopsy. Patients were excluded if they had a hemoglobin level <120 g/L; had a neutrophil count <1.5 x 109/L or a platelet count <70 x 109/L; had an abnormal serum creatinine level; were hepatitis B surface antigen positive or human immunodeficiency virus positive; had any other cause of liver disease; had a history of liver decompensation; had clinically relevant depression or any other psychiatric disease; had cancer; had severe cardiac, pulmonary, or renal disease; or had uncontrolled diabetes or severe hypertension with vascular complications, including retinopathy.
Study Design
This prospective, randomized, open-label, single-center trial was conducted at the Liver Unit of Cardarelli Hospital. The study design was approved by the independent ethical committee of the institution, and all patients provided written informed consent to treatment. Patients who accepted the treatment were assigned to one of the 2 treatment arms on the basis of a computer-generated randomization list that was not available to the treating physician. The physician received the communication on the allocation of each patient from an independent researcher who did not know the patient or his or her characteristics except the genotype in order to use the list prepared for genotype 1 or 4 or the list for genotype 2 or 3. Patients at the end of the diagnostic process, if they accepted to be treated, were randomized.
Patients assigned to group A received subcutaneous peginterferon alfa-2a 180 μg once weekly (Pegasys; Hoffmann-LaRoche, Basel, Switzerland) plus ribavirin (Copegus; Hoffmann-LaRoche). Those assigned to group B received subcutaneous peginterferon alfa-2b 1.5 μg/kg body wt once weekly (PegIntron; Schering-Plough Corp, Kenilworth, NJ) plus ribavirin (Rebetol; Schering-Plough Corp). The dosage of ribavirin was determined by body weight (1000 mg/day in patients <75 kg; 1200 mg/day in patients ≥75 kg). Treatment was administered for 24 weeks in patients infected with HCV genotype 2 or 3 and for 48 weeks in patients infected with HCV genotype 1 or 4. Drug dosages and treatment durations were established according to recommendations of the Italian Association for the Study of the Liver (Associazione Italiana per lo Studio del Fegato), which were prepared in the autumn of 2003 and released in February 2004.
Adherence was measured according to the "80/80/80" rule,8 which refers to the quantity of peginterferon and ribavirin administered (percentage of the planned total dose) and the total duration of treatment (percentage of the planned duration). Patients who took at least 80% of the 2 drugs for at least 80% of the scheduled time were considered to be adherent.
Serum HCV RNA was evaluated with a qualitative polymerase chain reaction assay (Cobas Amplicor HCV Test v2.0, Roche Diagnostics (Hoffmann-LaRoche, Basel, Switzerland); limit of detection, 50 IU/mL) before treatment (week 0); at study weeks 12, 24, and 48 in all patients; and at week 72 in patients infected with genotype 1 or 4. A quantitative HCV RNA test (Cobas Amplicor HCV Monitor Test v2.0, Roche Diagnostics; limit of quantization, 600 IU/mL) was performed at weeks 0, 12, and 24. HCV genotype was assessed by INNO-LiPA (Innogenetics NV, Gent, Belgium) HCV test.
Patients were assessed every 2 weeks during the first 2 months and every month thereafter during treatment as well as 3 and 6 months after the end of therapy. Complete blood counts and serum aminotransferase (aspartate aminotransferase/ALT) levels were assessed every 2 weeks for the first 2 months of therapy and monthly thereafter or more frequently if necessary. Serum creatinine level and routine laboratory test results were checked monthly. Thyroid function tests were performed at baseline and every 3 months thereafter or more frequently if necessary. Cardiac, chest, renal, and ocular assessment was performed before and at the end of therapy. Hepatobiliary ultrasonography was conducted at study entry and every 6 months during the study and follow-up periods.
Definition of Response and End Points
End-of-treatment response (ETR) and SVR were defined, respectively, as a negative qualitative HCV RNA level at the end of treatment and after 24 weeks of untreated follow-up. EVR was defined as qualitative HCV RNA negative (complete EVR) or a reduction from baseline HCV RNA level of >2 log10 IU/mL at week 12 (partial EVR). All patients with detectable HCV RNA at week 24 stopped treatment and were classified as nonresponders. Virological relapse was defined as reversion to HCV RNA-positive status in a patient who had an undetectable HCV RNA level (<50 IU/mL) at the end of treatment. Adverse events were recorded during each outpatient visit. No patient received treatment with erythropoietin or granulocyte colony-stimulating factor. The end point of the study was SVR.
Dose Modifications
The dosage of peginterferon was reduced by half if the neutrophil count decreased to <0.75 x 109/L or the platelet count decreased to <50 x 109/L. Peginterferon treatment was discontinued if the neutrophil count was <0.50 x 109/L or the platelet count was <25 x 109/L. Peginterferon dosages were reduced in 25% decrements or discontinued because of adverse events. The dosage of ribavirin was reduced in 200-mg decrements, as necessary, if hemoglobin level decreased to <100 g/L or by ≥30 g/L, or in the event of a severe cough or intolerable itching. Ribavirin treatment was discontinued if hemoglobin level decreased to <85 g/L.
Statistical Analysis
The study was designed to have 80% power to detect a difference of 15% or more in SVR rates between the 2 treatment groups. Based on this assumption, 160 patients were enrolled in each treatment group. Continuous variables are expressed as mean and SD or median and range. Frequencies were calculated for categorical variables, with the difference between groups reported with 95% confidence intervals (CIs). The Mann-Whitney rank sum test was used to compare continuous variables. The χ2 test was used, with Yates' correction where applicable, to compare categorical variables. Multivariable logistic stepwise regression analysis was used to explore the independent effect of the treatment and the baseline factors (age, body weight, body mass index, sex, presence of cirrhosis, ALT level, HCV RNA level, HCV genotype) on the likelihood of achieving SVR. All P values were 2 sided with a .05 threshold for statistical significance. All statistical procedures were performed using SPSS version 13.0 for Windows (SPSS Inc, Chicago, IL). All patients who took at least one dose of the study medication were included in the efficacy analysis according to intention-to-treat principle. Patients who withdrew from the study for any reason were considered to be nonresponders in the efficacy assessment. Safety results are reported for the entire population and by HCV genotype because of the difference in treatment duration. In fact, patients treated for longer durations are at greater risk for adverse effects.
- pdf publication attached
Gastroenterology Jan 2010
Presented in part as an oral communication at the 43rd Annual Meeting of the European Association for the Study of the Liver; April 23-27, 2008; Milan, Italy.
Antonio Ascione, Massimo De Luca, Maria Teresa Tartaglione, Filippo Lampasi, Giovan Giuseppe Di Costanzo, Alfonso Galeota Lanza, Francesco Paolo Picciotto, Giuseppina Marino-Marsilia, Luca Fontanella, Gioacchino Leandro Department of Gastroenterology, Liver Unit, Cardarelli Hospital, Napoli, Italy Department of Gastroenterology, Pathology Unit, Cardarelli Hospital, Napoli, Italy
Department of Medicine, Centre for Liver Disease, Fatebenefratelli Hospital, Napoli, Italy
Gastroenterology Unit, IRCSS de Bellis, Castellana Grotte, Italy
Conflicts of interest The authors disclose the following: Dr Ascione has received lecture fees from Bayer Healthcare, Bristol-Myers Squibb, Gilead, Grifols, Novartis, Schering-Plough, Roche, and Roche Diagnostics. The remaining authors discloses no conflicts.
Received 23 March 2009; accepted 15 October 2009. published online 22 October 2009.
"An SVR was achieved in 68.8% of patients randomized to peginterferon alfa-2a and 54.4% of those randomized to peginterferon alfa-2b (difference, 14.4%; 95% CI, 3.7%-24.6%; P = .008). The apparently high SVR rates may be due to the low number of patients with cirrhosis enrolled in the study (n = 59; 18.4%)...... In patients without cirrhosis, the SVR rate was 75.6% in peginterferon alfa-2a recipients and 55.9% in peginterferon alfa-2b recipients (P = .005); in patients with cirrhosis, the SVR rates were 42.4% and 46.1%, respectively (P = .77)..... In subgroup analyses, the SVR rate was 47.3% in patients with genotype 1/4 (54.8% in recipients of peginterferon alfa-2a and 39.8% in recipients of peginterferon alfa-2b; difference, 15%; P = .040)......Among those infected with genotype 2/3, the overall SVR rate was much higher (81.3%). The SVR rate was considerably higher in patients infected with genotype 2 than genotype 3 (83.8% vs 74.3%, respectively). Although this difference is not statistically significant (P = .21), we believe that these genotypes should no longer be considered to be a homogeneous group....
Another interesting finding of this study is the relationship between SVR and the baseline HCV RNA level. In the 143 patients with an HCV RNA level ≤500,000 IU/mL, the 2 treatments were not statistically different (SVR of 68.4% in patients treated with peginterferon alfa-2a and 65.7% in patients treated with peginterferon alfa-2b; P = .727). In patients with baseline serum HCV RNA levels >500,000 IU/mL, the SVR rate was 69.0% in those treated with peginterferon alfa-2a and 46.2% in those treated with peginterferon alfa-2b (P = .002)."
ABSTRACT
Background & Aims
Patients with chronic hepatitis C virus (HCV) infection are frequently treated with a combination of pegylated interferon (peginterferon) and ribavirin. This study compared the efficacy and safety of peginterferon alfa-2a and peginterferon alfa-2b, each in combination with ribavirin.
Methods
A total of 320 consecutive, treatment-naive, HCV RNA-positive patients with chronic hepatitis were randomly assigned to once-weekly peginterferon alfa-2a (180 μg, group A) or peginterferon alfa-2b (1.5 μg/kg, group B) plus ribavirin 1000 mg/day (body weight <75 kg) or 1200 mg/day (body weight ≥75 kg) for 48 weeks (genotype 1 or 4) or 24 weeks (genotype 2 or 3). The primary end point was sustained virological response (SVR) by intention-to-treat.
Results
More patients in group A than group B achieved an SVR (110/160 [68.8%] vs 87/160 [54.4%]; P = .008). Higher SVR rates were obtained in group A than group B among patients with genotype 1/4 (51/93 [54.8%] vs 37/93 [39.8%]; P = .04), with genotype 2/3 (59/67 [88.1%] vs 50/67 [74.6%]; P = .046), without cirrhosis (96/127 [75.6%] vs 75/134 [55.9%]; P = .005), and with baseline levels HCV RNA >500,000 IU/mL (58/84 [69%] vs 43/93 [46.2%]; P = .002). SVR rates in groups A and B were not statistically different among patients with baseline HCV RNA ≤500,000 IU/mL (52/76 [68.4%] vs 44/67 [65.7%]; P = .727) or in patients with cirrhosis (14/33 [42.4%] vs 12/26 [46.1%]; P = .774).
Conclusions
In patients with chronic HCV infection, peginterferon alfa-2a plus ribavirin produced a significantly higher SVR rate than peginterferon alfa-2b plus ribavirin.
Abbreviations used in this paper: CI, confidence interval, ETR, end-of-treatment response, EVR, early virological response, peginterferon, pegylated interferon, SVR, sustained virological response
Pegylated interferon (peginterferon) plus ribavirin is the treatment of choice for chronic infection with hepatitis C virus (HCV). When administered in a pegylated formulation, the half-life of interferon is prolonged because of covalent binding of the polyethylene glycol molecule to the interferon moiety. Consequently, sustained virological response (SVR) rates have increased from <20% to >60% with the combination of peginterferon plus ribavirin in patients with chronic HCV infection.1, 2, 3, 4
There are 2 commercially available peginterferons, and randomized controlled trials have shown that both peginterferon alfa-2a and peginterferon alfa-2b are effective and safe when administered in combination with ribavirin. Recently, data from 2 small clinical studies suggest that peginterferon alfa-2a produces a 14%-15% greater rate of early virological response (EVR) or SVR than peginterferon alfa-2b, although both studies failed to show a statistically significant difference because of insufficient sample sizes.5, 6 The present study aimed to compare the efficacy and safety of peginterferon alfa-2a versus peginterferon alfa-2b in combination with an identical dose of ribavirin in patients with chronic HCV infection.
Discussion
In this study, peginterferon alfa-2a produced a significantly greater SVR rate than peginterferon alfa-2b in patients with chronic HCV infection. Previous comparative studies have investigated the antiviral activity and pharmacokinetic properties of the 2 formulations.9, 10, 11 A pharmacokinetic analysis in 22 patients showed that peginterferon alfa-2a was still detectable 168 hours after administration at a dosage of 180 μg/wk but that peginterferon alfa-2b administered at a dosage of 1.0 μg · kg-1 · wk-1 (ie, lower than in the present study) was undetectable in 92% of patients at the same time point.9 At week 12, mean serum HCV RNA levels were significantly lower in patients treated with peginterferon alfa-2a than peginterferon alfa-2b (P < .01). In contrast, the pharmacodynamic profile (induction of 2'-5'-oligoadenylate synthetase, neopterin, and β2 -microglobulin activity) of the 2 peginterferons was similar in the same patients.10 In another study11 in 36 patients with genotype 1, those receiving peginterferon alfa-2b 1.5 μg · kg-1 · wk-1 had significantly greater up-regulation of interferon alfa response genes than those receiving peginterferon alfa-2a 180 μg/wk (ribavirin 13 mg · kg-1 · day-1 was administered after week 4). Patients treated with peginterferon alfa-2b also had greater log10 maximum and log10 time-weighted average decreases in serum HCV RNA levels, and a correspondingly greater proportion of peginterferon alfa-2b-treated patients achieved ≥2 log10 reduction in serum HCV RNA levels by week 8 (72% vs 44% of peginterferon alfa-2a-treated patients; P = .09). Although these data suggest that peginterferon alfa-2b has better biological activity, the between-group differences were not statistically significant.
To date, only 2 randomized clinical studies have compared the efficacy of the peginterferon formulations, neither of which was sufficiently powered to detect a statistically significant difference in SVR rates.5, 6 Despite a difference of 15% in the EVR rate between patients treated with peginterferon alfa-2a 180 μg/wk plus ribavirin (n = 58) and peginterferon alfa-2b 1.5 μg · kg-1 · wk-1 plus ribavirin (n = 58) in one study, the difference was not statistically significant (82% vs 67%, respectively; P = .08).5 An SVR rate of 48.6% was obtained in patients with genotype 1 who received peginterferon alfa-2a 180 μg/wk plus ribavirin (n = 37) and 35.1% in those treated with peginterferon alfa-2b 1.5 μg · kg-1 · wk-1 plus ribavirin (n = 37) in a second study, but the sample size was too small to show a statistically significant difference.6 The 14.4% difference in SVR rate in favor of peginterferon alfa-2a in the present study is consistent with the between-group differences of 14%-15% in rates of EVR and SVR in these 2 trials.
In the retrospective phase of the large (n = 2149) PROBE study (sponsored by Hoffmann-La Roche),12 the rate of SVR was higher in genotype 1 patients treated with peginterferon alfa-2a than with peginterferon alfa-2b (45% vs 38.4%; P = .04). The prospective phase of this study is yet to be completed.
Similar to the PROBE study, a recently published observational retrospective study of a large cohort (N = 9544) of US veterans13 reported that treatment of genotype 1 patients with peginterferon alfa-2a was associated with a higher likelihood of SVR than treatment with peginterferon alfa-2b.
In the present study, the 2 peginterferons were administered at dosages recommended in treatment guidelines with a sample size adequate to draw reliable conclusions concerning efficacy and safety. Ribavirin was administered at weight-based dosages that were stable during the study, so the only independent variable was the type of peginterferon. An SVR was achieved in 68.8% of patients randomized to peginterferon alfa-2a and 54.4% of those randomized to peginterferon alfa-2b (difference, 14.4%; 95% CI, 3.7%-24.6%; P = .008). The apparently high SVR rates may be due to the low number of patients with cirrhosis enrolled in the study (n = 59; 18.4%).
In subgroup analyses, the SVR rate was 47.3% in patients with genotype 1/4 (54.8% in recipients of peginterferon alfa-2a and 39.8% in recipients of peginterferon alfa-2b; difference, 15%; P = .040). Genotype 4 is very uncommon in southern Italy. Table 1 shows that the number of these patients is only 5 (1.6% of the total) not equally distributed because they were randomized together with genotype 1. For this reason, 4 patients were treated with peginterferon alfa-2a and one with peginterferon alfa-2b. Only one of them responded, and she was in the peginterferon alfa-2b arm.
Among those infected with genotype 2/3, the overall SVR rate was much higher (81.3%). The SVR rate was considerably higher in patients infected with genotype 2 than genotype 3 (83.8% vs 74.3%, respectively). Although this difference is not statistically significant (P = .21), we believe that these genotypes should no longer be considered to be a homogeneous group.
In patients without cirrhosis, the SVR rate was 75.6% in peginterferon alfa-2a recipients and 55.9% in peginterferon alfa-2b recipients (P = .005); in patients with cirrhosis, the SVR rates were 42.4% and 46.1%, respectively (P = .77).
Another interesting finding of this study is the relationship between SVR and the baseline HCV RNA level. In the 143 patients with an HCV RNA level ≤500,000 IU/mL, the 2 treatments were not statistically different (SVR of 68.4% in patients treated with peginterferon alfa-2a and 65.7% in patients treated with peginterferon alfa-2b; P = .727). In patients with baseline serum HCV RNA levels >500,000 IU/mL, the SVR rate was 69.0% in those treated with peginterferon alfa-2a and 46.2% in those treated with peginterferon alfa-2b (P = .002).
However, it is important to note that our subgroup analyses are post hoc and thus the results should be regarded with caution. Our subgroup results should be verified with a prospective trial that is specifically designed and powered to confirm or not confirm our results.
A multivariate analysis showed that male gender, absence of cirrhosis, use of peginterferon alfa-2a, and infection with genotype 2/3 were independently associated with SVR.
Only 30 of 320 patients (9.4%) did not experience adverse events, with no difference between group A and group B.
The results of a very large randomized trial comparing 2 regimens of peginterferon therapy in patients with genotype 1 in the United States were recently reported (IDEAL trial).14 The IDEAL trial showed no difference in SVR rates between patients treated with peginterferon alfa-2a plus ribavirin and those treated with peginterferon alfa-2b plus ribavirin. There was a number of fundamental differences between the IDEAL trial and the current study that may help to explain the different outcomes: (1) a multicenter postapproval industry-sponsored trial versus an investigator-initiated single-center trial, (2) a US population with higher body mass index and more black/Latino patients versus a European population, (3) 2 different ribavirin regimens with different starting doses and dose reduction rules versus equal ribavirin doses in all patients, (4) a genotype 1-only study vs all genotypes, and (5) different laboratories for testing the main indicator of response (HCV RNA by polymerase chain reaction). In fact, using a fixed dose of ribavirin in all the genotypes treated and in the 2 groups treated with peginterferons might have given a better indication of the different performance of the 2 peginterferons themselves without a confounding effect of differing ribavirin doses and dose reductions. The results of the 2 studies, when analyzed together, may indeed be quite compatible with closer inspection of end-of-treatment and relapse results in the IDEAL trial. However, because these trials were designed so differently and conducted in very different populations with HCV infection, we do not believe they can be directly compared. The reader should not draw conclusions across populations from either study.
In conclusion, this single-center, randomized, head-to-head study indicates that (1) the safety profile of the 2 preparations is similar and (2) in the populations studied, the rate of SVR obtained with peginterferon alfa-2a plus ribavirin is higher than that achieved with peginterferon alfa-2b plus ribavirin.
Results
Between March 2004 and December 2006, 408 patients were screened, of whom 320 (78%) were enrolled (Supplementary Figure 1). All patients were white, and the baseline characteristics of the 2 treatment groups were similar (Table 1).
A liver biopsy specimen was obtained in the chronic hepatitis group in 230 patients (88.1%), in whom the fibrosis grade was 2.13 (±1.03). Thirty-one patients (9.7%) refused to submit to the procedure. In this group, we used the criteria for diagnosis outlined in Patients and Methods because it was absolutely necessary to exclude cirrhosis. In patients with clear-cut signs of cirrhosis (19/320 [5.9%]), biopsy was not ethically justified because of the risk and no benefit for the patient. The criteria we used for clinical diagnosis of cirrhosis were presence of esophageal varices at endoscopy, low platelet count (<100 x 109/L), and ultrasound alterations typical for liver cirrhosis. The diagnosis was assumed as correct only if all 3 criteria were satisfied.
Efficacy
Overall, an EVR, as reported in Table 2, was obtained by 253 of 320 patients (79.1%): 136 (85%) in group A and 117 in group B (73%). This difference is statistically significant (difference, 12%; 95% CI, 2.9%-21%; P = .009). The majority of patients obtained a complete EVR, while the number of those who obtained a partial EVR was only 8.8%, with no difference between group A and group B.
An ETR was obtained in 237 patients (74.1%), 134 (83.8%) in group A versus 103 patients (64.4%) in group B (difference, 19.4%; 95% CI, 9.8%-28.5%; P < .0001), and an SVR was obtained in 197 patients (61.6%; 95% CI, 56.2%-66.9%), including 110 of 160 (68.8%; 95% CI, 61.6%-75.9%) in group A versus 87 of 160 (54.4%; 95% CI, 46.7%-62.1%) in group B. The difference between the 2 groups is 14.4% (95% CI, 3.7%-24.6%; P = .008). The total number of patients who experienced a relapse during follow-up was 40 of 320 (12.5%), including 24 of 160 (15%) in group A versus 16 of 160 (10%) in group B (difference, 5%; 95% CI, -2.3% to 12.4%; P = .176). Among patients without cirrhosis, an SVR was achieved by 171 of 261 patients (65.5%), including 96 of 127 (75.6%) in group A and 75 of 134 (55.9%) in group B (difference, 19.7%; 95% CI, 8.11%-30.4%; P = .005). Among the 59 patients with cirrhosis, 26 obtained an SVR (44.1%), including 14 of 33 (42.4%) in group A versus 12 of 26 (46.1%) in group B (difference, 3.7%; 95% CI, -20.4% to 27.6%; P = .774).
An SVR was obtained in 96 of 143 patients (67.1%) with a baseline HCV RNA level ≤500,000 IU/mL, including 52 of 76 (68.4%) in group A and 44 of 67 (65.7%) in group B (difference, 2.7%; 95% CI, -12.4% to 17.9%; P = .727). In 177 patients with a baseline HCV RNA level >500,000 IU/mL, 101 achieved an SVR (57.1%), including 58 of 84 (69%) in group A and 43 of 93 (46.2%) in group B (difference, 22.8%; 95% CI, 8.2%-36.0%; P = .002). An ETR was obtained in 116 of 186 patients (62.4%) infected with genotype 1 or 4, including 70 of 93 (75.3%) in group A versus 46 of 93 (49.5%) in group B (difference, 25.8%; 95% CI, 11.9%-38.4%; P = .0003), and an SVR was obtained in 88 of 186 patients (47.3%), including 51 of 93 (54.8%) in group A and 37 of 93 (39.8%) in group B (difference, 15%; 95% CI, 0.72%-28.5%; P = .040). Relapse during follow-up occurred in 28 patients (15.1%) overall, including 19 of 93 (20.4%) in group A and 9 of 93 (9.7%) in group B (difference, 10.7%; 95% CI, 0.38%-21.1%; P = .040). Among 134 patients infected with genotype 2 or 3, 121 (90.3%) achieved an ETR, including 64 of 67 (95.5%) in group A and 57 of 67 (85.1%) in group B (difference, 10.4%; 95% CI, 0.16%-21.3%; P = .80), and an SVR was obtained by 109 of 134 patients (81.3%), including 59 of 67 (88.1%) in group A and 50 of 67 (74.6%) in group B (difference, 13.5%; 95% CI, 0.14%-26.4%; P = .046). A total of 12 of 134 patients with genotype 2 or 3 experienced a relapse during follow-up (8.9%), including 5 of 67 (7.5%) in group A and 7 of 67 (10.4%) in group B (difference, 2.9%; 95% CI, -7.32% to 13.5%; P = .54). Patients infected with genotype 2 had a higher overall SVR rate (83/99; 83.8%) than those infected with genotype 3 (26/35; 74.3%), although the difference was not statistically significant (P = .21). Among those with genotype 2 infection, 45 of 49 patients (91.8%) in group A and 38 of 50 (76%) in group B (P = .06) obtained an SVR. Among those infected with genotype 3, an SVR was obtained by 14 of 18 patients (77.8%) in group A and 12 of 17 (70.6%) in group B (P = .92).
Factors Related to SVR
According to multivariate stepwise analysis, we included in the model the following preselected variables: age, body weight, body mass index, sex, absence of cirrhosis, ALT level, HCV RNA level, HCV genotype, and schedule of treatment. Male gender (odds ratio, 1.93; 95% CI, 1.17-3.20; P = .011), absence of cirrhosis (odds ratio, 2.36; 95% CI, 1.28-4.41; P = .007), treatment with peginterferon alfa-2a (odds ratio, 2.32; 95% CI, 1.39-3.88; P = .001), and infection with genotype 2 or 3 (odds ratio, 4.83; 95% CI, 2.81-8.31; P < .0001) were all independently associated with SVR.
Adverse Events and Dose Reductions
The dosage of peginterferon and/or ribavirin was reduced in most patients, and only 30 of 320 patients (9.4%) reported no adverse events. The type and incidence of adverse events were very similar in the 2 treatment groups. Twenty-six patients (8.1%) were classified as nonresponders because of interruption of therapy due to any type of adverse event, including 4 of 26 (15.4%) in group A and 22 of 26 (84.6%) in group B (P = .0005). In detail, for adverse events, the causes for stopping therapy in group A were dermatitis (1), severe depression (1), pruritus (1), and hyperthyroidism (1). In group B, the causes were fatigue (2), myalgia (2), severe depression (3), nausea (1), pruritus (2), alopecia (1), irritability (1), hyperthyroidism (1), decreased appetite (2), dermatitis (1), and cough (1). Of the 5 patients with laboratory abnormalities, one patient discontinued because of a high decrease in platelet count, 2 patients discontinued because of neutropenia, and the other 2 patients discontinued because of anemia. The use of erythropoietin and granulocyte-stimulating growth factors was prohibited by regulation of the National Health System at time of the planning of the study. Only recently the National Health System has allowed the use of the 2 drugs, but only for responders, to avoid the loss of therapeutic response; however, this was done when it was no longer necessary for our patients because the trial was at the end.
More than 50% of patients were unable to comply with the 80/80/80 rule, especially those infected with genotype 1 or 4 (Table 3). No patient was lost to follow-up. No serious adverse events were reported. Serious adverse events were defined as follows: death, any kind of life-threatening event, and any kind of adverse effect requiring hospitalization.
Patients and Methods
Selection of Patients
Consecutive interferon-naive adults (aged 18 years or older) seen at the Liver Unit of Cardarelli Hospital (Napoli, Italy) who had chronic HCV infection were eligible for enrollment. Patients were required to have a detectable serum HCV RNA level, have an alanine aminotransferase (ALT) level >1.5 times the upper limit of normal for ≥6 months, have a liver biopsy performed within 12 months of starting treatment graded according to Scheuer's7 criteria (unless not indicated or refused), have a negative pregnancy test result, use contraceptive methods during therapy and for 6 months after the end of treatment, and have abstained from alcohol use for at least 6 months. Cirrhosis was assessed on the basis of clinical and laboratory test results, liver-spleen ultrasonography, and upper gastrointestinal endoscopy in patients ineligible for and in those who refused a liver biopsy. Patients were excluded if they had a hemoglobin level <120 g/L; had a neutrophil count <1.5 x 109/L or a platelet count <70 x 109/L; had an abnormal serum creatinine level; were hepatitis B surface antigen positive or human immunodeficiency virus positive; had any other cause of liver disease; had a history of liver decompensation; had clinically relevant depression or any other psychiatric disease; had cancer; had severe cardiac, pulmonary, or renal disease; or had uncontrolled diabetes or severe hypertension with vascular complications, including retinopathy.
Study Design
This prospective, randomized, open-label, single-center trial was conducted at the Liver Unit of Cardarelli Hospital. The study design was approved by the independent ethical committee of the institution, and all patients provided written informed consent to treatment. Patients who accepted the treatment were assigned to one of the 2 treatment arms on the basis of a computer-generated randomization list that was not available to the treating physician. The physician received the communication on the allocation of each patient from an independent researcher who did not know the patient or his or her characteristics except the genotype in order to use the list prepared for genotype 1 or 4 or the list for genotype 2 or 3. Patients at the end of the diagnostic process, if they accepted to be treated, were randomized.
Patients assigned to group A received subcutaneous peginterferon alfa-2a 180 μg once weekly (Pegasys; Hoffmann-LaRoche, Basel, Switzerland) plus ribavirin (Copegus; Hoffmann-LaRoche). Those assigned to group B received subcutaneous peginterferon alfa-2b 1.5 μg/kg body wt once weekly (PegIntron; Schering-Plough Corp, Kenilworth, NJ) plus ribavirin (Rebetol; Schering-Plough Corp). The dosage of ribavirin was determined by body weight (1000 mg/day in patients <75 kg; 1200 mg/day in patients ≥75 kg). Treatment was administered for 24 weeks in patients infected with HCV genotype 2 or 3 and for 48 weeks in patients infected with HCV genotype 1 or 4. Drug dosages and treatment durations were established according to recommendations of the Italian Association for the Study of the Liver (Associazione Italiana per lo Studio del Fegato), which were prepared in the autumn of 2003 and released in February 2004.
Adherence was measured according to the "80/80/80" rule,8 which refers to the quantity of peginterferon and ribavirin administered (percentage of the planned total dose) and the total duration of treatment (percentage of the planned duration). Patients who took at least 80% of the 2 drugs for at least 80% of the scheduled time were considered to be adherent.
Serum HCV RNA was evaluated with a qualitative polymerase chain reaction assay (Cobas Amplicor HCV Test v2.0, Roche Diagnostics (Hoffmann-LaRoche, Basel, Switzerland); limit of detection, 50 IU/mL) before treatment (week 0); at study weeks 12, 24, and 48 in all patients; and at week 72 in patients infected with genotype 1 or 4. A quantitative HCV RNA test (Cobas Amplicor HCV Monitor Test v2.0, Roche Diagnostics; limit of quantization, 600 IU/mL) was performed at weeks 0, 12, and 24. HCV genotype was assessed by INNO-LiPA (Innogenetics NV, Gent, Belgium) HCV test.
Patients were assessed every 2 weeks during the first 2 months and every month thereafter during treatment as well as 3 and 6 months after the end of therapy. Complete blood counts and serum aminotransferase (aspartate aminotransferase/ALT) levels were assessed every 2 weeks for the first 2 months of therapy and monthly thereafter or more frequently if necessary. Serum creatinine level and routine laboratory test results were checked monthly. Thyroid function tests were performed at baseline and every 3 months thereafter or more frequently if necessary. Cardiac, chest, renal, and ocular assessment was performed before and at the end of therapy. Hepatobiliary ultrasonography was conducted at study entry and every 6 months during the study and follow-up periods.
Definition of Response and End Points
End-of-treatment response (ETR) and SVR were defined, respectively, as a negative qualitative HCV RNA level at the end of treatment and after 24 weeks of untreated follow-up. EVR was defined as qualitative HCV RNA negative (complete EVR) or a reduction from baseline HCV RNA level of >2 log10 IU/mL at week 12 (partial EVR). All patients with detectable HCV RNA at week 24 stopped treatment and were classified as nonresponders. Virological relapse was defined as reversion to HCV RNA-positive status in a patient who had an undetectable HCV RNA level (<50 IU/mL) at the end of treatment. Adverse events were recorded during each outpatient visit. No patient received treatment with erythropoietin or granulocyte colony-stimulating factor. The end point of the study was SVR.
Dose Modifications
The dosage of peginterferon was reduced by half if the neutrophil count decreased to <0.75 x 109/L or the platelet count decreased to <50 x 109/L. Peginterferon treatment was discontinued if the neutrophil count was <0.50 x 109/L or the platelet count was <25 x 109/L. Peginterferon dosages were reduced in 25% decrements or discontinued because of adverse events. The dosage of ribavirin was reduced in 200-mg decrements, as necessary, if hemoglobin level decreased to <100 g/L or by ≥30 g/L, or in the event of a severe cough or intolerable itching. Ribavirin treatment was discontinued if hemoglobin level decreased to <85 g/L.
Statistical Analysis
The study was designed to have 80% power to detect a difference of 15% or more in SVR rates between the 2 treatment groups. Based on this assumption, 160 patients were enrolled in each treatment group. Continuous variables are expressed as mean and SD or median and range. Frequencies were calculated for categorical variables, with the difference between groups reported with 95% confidence intervals (CIs). The Mann-Whitney rank sum test was used to compare continuous variables. The χ2 test was used, with Yates' correction where applicable, to compare categorical variables. Multivariable logistic stepwise regression analysis was used to explore the independent effect of the treatment and the baseline factors (age, body weight, body mass index, sex, presence of cirrhosis, ALT level, HCV RNA level, HCV genotype) on the likelihood of achieving SVR. All P values were 2 sided with a .05 threshold for statistical significance. All statistical procedures were performed using SPSS version 13.0 for Windows (SPSS Inc, Chicago, IL). All patients who took at least one dose of the study medication were included in the efficacy analysis according to intention-to-treat principle. Patients who withdrew from the study for any reason were considered to be nonresponders in the efficacy assessment. Safety results are reported for the entire population and by HCV genotype because of the difference in treatment duration. In fact, patients treated for longer durations are at greater risk for adverse effects.
Conatus Pharmaceuticals Initiates Phase II Clinical Trial in Combination With Pegylated Interferon and Ribavirin for the Treatment of Hepatitis C Viru
Conatus Pharmaceuticals Initiates Phase II Clinical Trial in Combination With Pegylated Interferon and Ribavirin for the Treatment of Hepatitis C Virus (HCV)
SAN DIEGO, Jan. 28 /PRNewswire/ -- Conatus Pharmaceuticals Inc. announced today the initiation of a Phase II clinical trial evaluating CTS-1027 in combination with pegylated interferon (Pegasys®) and ribavirin (Copegus®) in refractory HCV patients. Antiviral activity, safety and tolerability of the triple combination will be assessed after up to 48 weeks of therapy.
"There is a significant unmet medical need in HCV patients who have not responded to pegylated interferon and ribavirin. These patients often progress to cirrhosis, a life-threatening condition. CTS-1027 has the potential to increase the effectiveness of the combination of pegylated interferon and ribavirin in this population," said Dr. Paul J. Pockros, Head, Division of Gastroenterology and Director of the SC Liver Research Consortium and The Scripps Clinic in La Jolla, CA.
CTS-1027 is an oral, small molecule compound that inhibits the activity of key members of a class of protease enzymes, the matrix metalloproteinases or MMPs. CTS-1027's anti-inflammatory and anti-fibrotic effects have been well-established in models of acute hepatitis and liver fibrosis. In addition, CTS-1027 has been shown to reduce and/or block HCV replication in in vitro preclinical models.
This clinical trial is an open-label design testing an optimized dose of CTS-1027 in combination with Pegasys® and Copegus® in HCV-infected patients who were prior null responders to pegylated interferon and ribavirin treatment. Dosing will last for up to 48 weeks. The Company expects approximately 60 patients to be enrolled. The clinical trial will be conducted at up to fifteen medical centers in the U.S. Additional information about the trial can be found at: www.clinicaltrials.gov (Identifier NCT01051921) or www.clinicaltrials.gov/ct2/show/NCT01051921?term=cts1027&rank=2.
"Our studies suggest that CTS-1027 treatment has the potential to amplify the effectiveness of pegylated interferon and ribavirin therapy. We believe that treating the most refractory patients will give us the best indication as to whether CTS-1027 can enhance the activity of existing therapy," said Steven J. Mento, President and CEO of Conatus. "The field is moving towards combinations of small molecules, and CTS-1027 represents a novel approach that we hope will benefit patients infected with HCV."
Conatus Pharmaceuticals Inc. is a privately-held specialty pharmaceutical company engaged in the development of innovative human therapeutics to treat liver disease. Chronic liver disease affects millions of people worldwide and can be caused by many different conditions or "insults" to the liver including Hepatitis C and other viral infections, obesity, chronic alcohol abuse or autoimmune diseases. Conatus was founded by the executive management team of Idun Pharmaceuticals in July 2005 following the successful sale of Idun to Pfizer. For additional information, please visit www.conatuspharma.com.
Pegasys® and Copegus® are registered trademarks of F. Hoffman-La Roche, Inc.
SOURCE Conatus Pharmaceuticals Inc.
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RELATED LINKS
http://www.conatuspharma.com
SAN DIEGO, Jan. 28 /PRNewswire/ -- Conatus Pharmaceuticals Inc. announced today the initiation of a Phase II clinical trial evaluating CTS-1027 in combination with pegylated interferon (Pegasys®) and ribavirin (Copegus®) in refractory HCV patients. Antiviral activity, safety and tolerability of the triple combination will be assessed after up to 48 weeks of therapy.
"There is a significant unmet medical need in HCV patients who have not responded to pegylated interferon and ribavirin. These patients often progress to cirrhosis, a life-threatening condition. CTS-1027 has the potential to increase the effectiveness of the combination of pegylated interferon and ribavirin in this population," said Dr. Paul J. Pockros, Head, Division of Gastroenterology and Director of the SC Liver Research Consortium and The Scripps Clinic in La Jolla, CA.
CTS-1027 is an oral, small molecule compound that inhibits the activity of key members of a class of protease enzymes, the matrix metalloproteinases or MMPs. CTS-1027's anti-inflammatory and anti-fibrotic effects have been well-established in models of acute hepatitis and liver fibrosis. In addition, CTS-1027 has been shown to reduce and/or block HCV replication in in vitro preclinical models.
This clinical trial is an open-label design testing an optimized dose of CTS-1027 in combination with Pegasys® and Copegus® in HCV-infected patients who were prior null responders to pegylated interferon and ribavirin treatment. Dosing will last for up to 48 weeks. The Company expects approximately 60 patients to be enrolled. The clinical trial will be conducted at up to fifteen medical centers in the U.S. Additional information about the trial can be found at: www.clinicaltrials.gov (Identifier NCT01051921) or www.clinicaltrials.gov/ct2/show/NCT01051921?term=cts1027&rank=2.
"Our studies suggest that CTS-1027 treatment has the potential to amplify the effectiveness of pegylated interferon and ribavirin therapy. We believe that treating the most refractory patients will give us the best indication as to whether CTS-1027 can enhance the activity of existing therapy," said Steven J. Mento, President and CEO of Conatus. "The field is moving towards combinations of small molecules, and CTS-1027 represents a novel approach that we hope will benefit patients infected with HCV."
Conatus Pharmaceuticals Inc. is a privately-held specialty pharmaceutical company engaged in the development of innovative human therapeutics to treat liver disease. Chronic liver disease affects millions of people worldwide and can be caused by many different conditions or "insults" to the liver including Hepatitis C and other viral infections, obesity, chronic alcohol abuse or autoimmune diseases. Conatus was founded by the executive management team of Idun Pharmaceuticals in July 2005 following the successful sale of Idun to Pfizer. For additional information, please visit www.conatuspharma.com.
Pegasys® and Copegus® are registered trademarks of F. Hoffman-La Roche, Inc.
SOURCE Conatus Pharmaceuticals Inc.
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RELATED LINKS
http://www.conatuspharma.com
Celebrating Valentine's Day: A Sweet Treat for Hepatitis C
Celebrating Valentine's Day: A Sweet Treat for Hepatitis C
February 8, 2010
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Upon first glance, the Valentine's Day tradition of gifting chocolates may seem counterintuitive for someone with Hepatitis C. Though, research boasts two reasons why choosing the right kind of chocolate will show you care about your sweetheart's liver health.
by Nicole Cutler, L.Ac.
Simply stepping into any grocery, drug or general retail store will remind you of the national Valentine's Day tradition of giving your loved one a box of chocolates. An annual holiday on February 14th that celebrates love and affection between intimate companions, Valentine's Day is usually associated with three things: cards, flowers and chocolates. Due to the liver health concerns of those living with the Hepatitis C virus, individuals with this infection likely assume they are better off without chocolate during this love-filled holiday.
Some Food Worsens Hepatitis C
Managing chronic Hepatitis C must be met with conscious awareness of the healthfulness of every eaten item. This is because the liver of someone with this virus is under enormous stress - and the liver is the organ that must filter out every chemical and toxin ingested. Additionally, foods loaded with fat can fan the flames of liver inflammation. Consequently, processed, fatty foods present an unnecessary challenge to a liver with Hepatitis C. In an effort to preserve the health of their liver, those with Hepatitis C are consistently advised to consume a nutritious, low-fat, whole food diet.
Chocolate
Most people lump chocolate into the candy category, relegating it as a high-sugar, high-fat and high-calorie junk food full of chemicals. This is accurate for some commercially sold chocolate bars. However, not all chocolate bars are created equally. High quality dark chocolate without nougat, caramel or other sugary fillings has the privilege of claiming a variety of health benefits.
Because chocolate is made from plants, it contains many of the same characteristics of darkly colored vegetables. Dark chocolate contains a high amount of flavonoids, antioxidant-rich compounds that have a collection of health benefits. Experts believe that dark chocolate contains a very large number of antioxidants - nearly eight times the number found in strawberries.
However, these flavonoids are specific to dark chocolate, as milk chocolate does not contain nearly the same levels of antioxidants - and white chocolate has none at all. According to Mauro Serafini, Ph.D., of Italy's National Institute for Food and Nutrition Research, the reason dark chocolate has proven to be healthier than milk chocolate, is because the milk in milk chocolate may actually interfere with the absorption of antioxidants, canceling out its positive benefits.
There are two primary reasons that dark chocolate can actually be helpful for those with Hepatitis C: stress relief and blood pressure reduction.
Stress Relief
As a potentially life-threatening disease that has just a 50 percent cure rate, living with chronic Hepatitis C is often associated with stress. Unfortunately, stress increases congestion in the liver and can thus encourage Hepatitis C-inflicted liver damage.
Researchers have found that dark chocolate is a reasonable approach for relieving stress. As published in ACS' Journal of Proteome Research, investigators found that eating about an ounce and a half of dark chocolate a day for two weeks reduced levels of stress hormones in the bodies of people feeling highly stressed.
Blood Pressure Reduction
Individuals who have more advanced cases of Hepatitis C may suffer from portal hypertension. When Hepatitis C has caused significant scarring of the liver, the blood pressure in the portal vein (the vein that carries blood from the digestive organs to the liver) rises. People with portal hypertension who also have high blood pressure are more susceptible to catastrophic health events.
Based on research published in the January 2010 edition of the American Journal of Hypertension, dark chocolate has the ability to lower blood pressure. While the ideal formulation and dosage has yet to be identified, experts believe that small amounts of dark chocolate are beneficial to people with hypertension or portal hypertension.
High-quality dark chocolate's liver benefits are not a prescription to overindulge. Chocolate is still high in calories and fat and, as with most sweets, should be consumed in moderation. A small piece of dark chocolate each day seems appropriate.
By reducing stress and blood pressure, a little bit of dark chocolate can be beneficial to someone with Hepatitis C. Thus, whether you, your valentine or both of you has this virus, February 14th can be celebrated by keeping the chocolate gifting tradition alive.
References:
http://en.wikipedia.org/wiki/Valentine%27s_Day, Valentine's Day, Retrieved February 3, 2010, Wikimedia Foundation Inc., 2010.
http://longevity.about.com/od/lifelongnutrition/p/chocolate.htm, Health Benefits of Chocolate, Mark Stibich, PhD, Retrieved February 4, 2010, About.com, 2010.
http://www.integrative-healthcare.org/mt/archives/2006/02/dark_chocolate.html, Dark Chocolate for the Love of Life, Nicole Cutler, L.Ac., Retrieved February 4, 2010, Natural Wellness, 2010.
http://www.medicalnewstoday.com/articles/170829.php, Dark Chocolate May Improve Metabolic Stress Response Say Nestlé Researchers, Retrieved February 2, 2010, MediLexicon International Ltd, 2010.
http://www.ncbi.nlm.nih.gov/pubmed/19910929?itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSum&ordinalpos=5, Effect of cocoa products on blood pressure: systematic review and meta-analysis, Desch S, et al, Retrieved February 2, 2010, American Journal of Hypertension, January 2010.
http://www.ncbi.nlm.nih.gov/pubmed/20034049?itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSum&ordinalpos=1, Increased caffeine consumption is associated with reduced hepatic fibrosis, Modi AA, et al, Retrieved February 2, 2010, Hepatology, January 2010.
http://www.rxpgnews.com/hepatitis-c-virus/Caffeine_intake_found_to_cause_less_liver_fibrosis_230400.shtml, Caffeine intake in chronic hepatitis C patients associated with less liver fibrosis, Retrieved February 2, 2010, RxPG, January 2010.
http://www.topnews.in/health/it-s-official-dark-chocolate-helps-beat-blues-25854, It's official: Dark chocolate helps beat the blues, Mohit Joshi, Retrieved February 2, 2010, TopNews.in, January 2010.
February 8, 2010
Printer-friendly version
Bookmark and Share
Upon first glance, the Valentine's Day tradition of gifting chocolates may seem counterintuitive for someone with Hepatitis C. Though, research boasts two reasons why choosing the right kind of chocolate will show you care about your sweetheart's liver health.
by Nicole Cutler, L.Ac.
Simply stepping into any grocery, drug or general retail store will remind you of the national Valentine's Day tradition of giving your loved one a box of chocolates. An annual holiday on February 14th that celebrates love and affection between intimate companions, Valentine's Day is usually associated with three things: cards, flowers and chocolates. Due to the liver health concerns of those living with the Hepatitis C virus, individuals with this infection likely assume they are better off without chocolate during this love-filled holiday.
Some Food Worsens Hepatitis C
Managing chronic Hepatitis C must be met with conscious awareness of the healthfulness of every eaten item. This is because the liver of someone with this virus is under enormous stress - and the liver is the organ that must filter out every chemical and toxin ingested. Additionally, foods loaded with fat can fan the flames of liver inflammation. Consequently, processed, fatty foods present an unnecessary challenge to a liver with Hepatitis C. In an effort to preserve the health of their liver, those with Hepatitis C are consistently advised to consume a nutritious, low-fat, whole food diet.
Chocolate
Most people lump chocolate into the candy category, relegating it as a high-sugar, high-fat and high-calorie junk food full of chemicals. This is accurate for some commercially sold chocolate bars. However, not all chocolate bars are created equally. High quality dark chocolate without nougat, caramel or other sugary fillings has the privilege of claiming a variety of health benefits.
Because chocolate is made from plants, it contains many of the same characteristics of darkly colored vegetables. Dark chocolate contains a high amount of flavonoids, antioxidant-rich compounds that have a collection of health benefits. Experts believe that dark chocolate contains a very large number of antioxidants - nearly eight times the number found in strawberries.
However, these flavonoids are specific to dark chocolate, as milk chocolate does not contain nearly the same levels of antioxidants - and white chocolate has none at all. According to Mauro Serafini, Ph.D., of Italy's National Institute for Food and Nutrition Research, the reason dark chocolate has proven to be healthier than milk chocolate, is because the milk in milk chocolate may actually interfere with the absorption of antioxidants, canceling out its positive benefits.
There are two primary reasons that dark chocolate can actually be helpful for those with Hepatitis C: stress relief and blood pressure reduction.
Stress Relief
As a potentially life-threatening disease that has just a 50 percent cure rate, living with chronic Hepatitis C is often associated with stress. Unfortunately, stress increases congestion in the liver and can thus encourage Hepatitis C-inflicted liver damage.
Researchers have found that dark chocolate is a reasonable approach for relieving stress. As published in ACS' Journal of Proteome Research, investigators found that eating about an ounce and a half of dark chocolate a day for two weeks reduced levels of stress hormones in the bodies of people feeling highly stressed.
Blood Pressure Reduction
Individuals who have more advanced cases of Hepatitis C may suffer from portal hypertension. When Hepatitis C has caused significant scarring of the liver, the blood pressure in the portal vein (the vein that carries blood from the digestive organs to the liver) rises. People with portal hypertension who also have high blood pressure are more susceptible to catastrophic health events.
Based on research published in the January 2010 edition of the American Journal of Hypertension, dark chocolate has the ability to lower blood pressure. While the ideal formulation and dosage has yet to be identified, experts believe that small amounts of dark chocolate are beneficial to people with hypertension or portal hypertension.
High-quality dark chocolate's liver benefits are not a prescription to overindulge. Chocolate is still high in calories and fat and, as with most sweets, should be consumed in moderation. A small piece of dark chocolate each day seems appropriate.
By reducing stress and blood pressure, a little bit of dark chocolate can be beneficial to someone with Hepatitis C. Thus, whether you, your valentine or both of you has this virus, February 14th can be celebrated by keeping the chocolate gifting tradition alive.
References:
http://en.wikipedia.org/wiki/Valentine%27s_Day, Valentine's Day, Retrieved February 3, 2010, Wikimedia Foundation Inc., 2010.
http://longevity.about.com/od/lifelongnutrition/p/chocolate.htm, Health Benefits of Chocolate, Mark Stibich, PhD, Retrieved February 4, 2010, About.com, 2010.
http://www.integrative-healthcare.org/mt/archives/2006/02/dark_chocolate.html, Dark Chocolate for the Love of Life, Nicole Cutler, L.Ac., Retrieved February 4, 2010, Natural Wellness, 2010.
http://www.medicalnewstoday.com/articles/170829.php, Dark Chocolate May Improve Metabolic Stress Response Say Nestlé Researchers, Retrieved February 2, 2010, MediLexicon International Ltd, 2010.
http://www.ncbi.nlm.nih.gov/pubmed/19910929?itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSum&ordinalpos=5, Effect of cocoa products on blood pressure: systematic review and meta-analysis, Desch S, et al, Retrieved February 2, 2010, American Journal of Hypertension, January 2010.
http://www.ncbi.nlm.nih.gov/pubmed/20034049?itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSum&ordinalpos=1, Increased caffeine consumption is associated with reduced hepatic fibrosis, Modi AA, et al, Retrieved February 2, 2010, Hepatology, January 2010.
http://www.rxpgnews.com/hepatitis-c-virus/Caffeine_intake_found_to_cause_less_liver_fibrosis_230400.shtml, Caffeine intake in chronic hepatitis C patients associated with less liver fibrosis, Retrieved February 2, 2010, RxPG, January 2010.
http://www.topnews.in/health/it-s-official-dark-chocolate-helps-beat-blues-25854, It's official: Dark chocolate helps beat the blues, Mohit Joshi, Retrieved February 2, 2010, TopNews.in, January 2010.
Debio-025 Activity/Safety in 3 Studies Over 3 Years
Debio-025 Activity/Safety in 3 Studies Over 3 Years
In naives, genotype 1 and 2:
1000 mg once daily produced slightly greater than 2 log reduction in HCV RNA after 29 days in genotype 1/4 and 4 logs in genotype 2/3 but at this dose 8/18 patients receiving monotherapy had hyperbilirubinemia but not at lower dose of 600 mg:
EASL 2008: Efficacy and safety of increasing doses of the cyclophilin ...
Debio 025 at daily doses of 1000 or 60 mg demonstrates an additive anti-HCV ... Debio 025in daily doses of 200 or 600 mg in combination with PegIFNa-2 was ...
www.natap.org/2008/EASL/EASL_20.htm
In this study 400 mg monotherapy did not produce antivial activity in null-responders, using a loading dose however showed better results suggested better antiviral activity, at these doses there did not appear to be hyperbilirubinemia:
EASL 2009: EFFICACY AND SAFETY OF THE CYCLOPHILIN INHIBITOR DEBIO 025 IN ...
EFFICACY AND SAFETY OF THE CYCLOPHILIN INHIBITOR DEBIO 025 IN COMBINATION WITH PEGYLATED INTERFERON ALPHA-2A AND RIBAVIRIN IN PREVIOUSLY NULL-RESPONDER ...
www.natap.org/2009/EASL/EASL_40.htm
The cyclophilin inhibitor DEBIO-025 has a potent dual anti-HIV and anti-HCV activity in treatment-naive HIV/HCV co-infected subjects
AASLD 2006: The cyclophilin inhibitor DEBIO-025 has a potent dual anti-HIV and ...
DEBIO-025, a cyclophilin inhibitor, demonstrated strong antiviral activity in vitro against HCV1 and HIV-1. In a previous phase I study, DEBIO-025 showed ...
www.natap.org/2006/AASLD/AASLD_30.htm
In a previous phase I study, DEBIO-025 showed antiviral effect (< 1 Log10 reduction) in HIV-1-positive asymptomatic subjects treated with DEBIO-025 400 and 1200 mg daily for 10 days2. In this early study presented at AASLD 2006, Treatment-naive HIV-1 mono or HIV/HCV co-infected subjects received 1200 mg DEBIO-025 or placebo twice daily for 15 days. HCV genotypes in the 16 HIV-1/HCV co-infected subjects on active treatment were evenly distributed between genotype 1 (n=5), genotype 3 (n=6), and genotype 4 (n=5). HIV-1/HCV co-infected DEBIO-025-treated subjects experienced a significantly greater maximum HCV viral load reduction compared to placebo subjects, achieving a least squares mean of 3.6 vs. 0.7. The 3 HCV genotypes identified in the study responded well to the dose administered (Figure 2). one null-responder (genotype 4) achieved at least a 2 Log10 drop in HCV viral load during treatment. Three subjects (one of each genotype) decreased viral loads below detectable levels at treatment Day 15 (2 subjects) and Day 8 (1 subject). Total bilirubin increased by a median of 22 _mol/L (range -1 to +88) during treatment, leading to hyperbilirubinaemia in 10 subjects. A total of 4/19 (21%) subjects discontinued DEBIO-025 treatment prematurely for this reason. No increase in ALT/AST or _-GT was observed, and there were no signs of haemolysis. Bilirubin returned rapidly to baseline levels after treatment cessation. This phenomenon was not observed in previous DEBIO-025 studies at doses up to 1200 mg OD for 10 days
In naives, genotype 1 and 2:
1000 mg once daily produced slightly greater than 2 log reduction in HCV RNA after 29 days in genotype 1/4 and 4 logs in genotype 2/3 but at this dose 8/18 patients receiving monotherapy had hyperbilirubinemia but not at lower dose of 600 mg:
EASL 2008: Efficacy and safety of increasing doses of the cyclophilin ...
Debio 025 at daily doses of 1000 or 60 mg demonstrates an additive anti-HCV ... Debio 025in daily doses of 200 or 600 mg in combination with PegIFNa-2 was ...
www.natap.org/2008/EASL/EASL_20.htm
In this study 400 mg monotherapy did not produce antivial activity in null-responders, using a loading dose however showed better results suggested better antiviral activity, at these doses there did not appear to be hyperbilirubinemia:
EASL 2009: EFFICACY AND SAFETY OF THE CYCLOPHILIN INHIBITOR DEBIO 025 IN ...
EFFICACY AND SAFETY OF THE CYCLOPHILIN INHIBITOR DEBIO 025 IN COMBINATION WITH PEGYLATED INTERFERON ALPHA-2A AND RIBAVIRIN IN PREVIOUSLY NULL-RESPONDER ...
www.natap.org/2009/EASL/EASL_40.htm
The cyclophilin inhibitor DEBIO-025 has a potent dual anti-HIV and anti-HCV activity in treatment-naive HIV/HCV co-infected subjects
AASLD 2006: The cyclophilin inhibitor DEBIO-025 has a potent dual anti-HIV and ...
DEBIO-025, a cyclophilin inhibitor, demonstrated strong antiviral activity in vitro against HCV1 and HIV-1. In a previous phase I study, DEBIO-025 showed ...
www.natap.org/2006/AASLD/AASLD_30.htm
In a previous phase I study, DEBIO-025 showed antiviral effect (< 1 Log10 reduction) in HIV-1-positive asymptomatic subjects treated with DEBIO-025 400 and 1200 mg daily for 10 days2. In this early study presented at AASLD 2006, Treatment-naive HIV-1 mono or HIV/HCV co-infected subjects received 1200 mg DEBIO-025 or placebo twice daily for 15 days. HCV genotypes in the 16 HIV-1/HCV co-infected subjects on active treatment were evenly distributed between genotype 1 (n=5), genotype 3 (n=6), and genotype 4 (n=5). HIV-1/HCV co-infected DEBIO-025-treated subjects experienced a significantly greater maximum HCV viral load reduction compared to placebo subjects, achieving a least squares mean of 3.6 vs. 0.7. The 3 HCV genotypes identified in the study responded well to the dose administered (Figure 2). one null-responder (genotype 4) achieved at least a 2 Log10 drop in HCV viral load during treatment. Three subjects (one of each genotype) decreased viral loads below detectable levels at treatment Day 15 (2 subjects) and Day 8 (1 subject). Total bilirubin increased by a median of 22 _mol/L (range -1 to +88) during treatment, leading to hyperbilirubinaemia in 10 subjects. A total of 4/19 (21%) subjects discontinued DEBIO-025 treatment prematurely for this reason. No increase in ALT/AST or _-GT was observed, and there were no signs of haemolysis. Bilirubin returned rapidly to baseline levels after treatment cessation. This phenomenon was not observed in previous DEBIO-025 studies at doses up to 1200 mg OD for 10 days
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