Peginterferon Alfa-2b or Alfa-2a with Ribavirin for Treatment of Hepatitis C

Peginterferon Alfa-2b or Alfa-2a with Ribavirin for Treatment of Hepatitis C Infection -

NEJM July 22 2009


John G. McHutchison, M.D., Eric J. Lawitz, M.D., Mitchell L. Shiffman, M.D., Andrew J. Muir, M.D., Greg W. Galler, M.D., Jonathan McCone, M.D., Lisa M. Nyberg, M.D., William M. Lee, M.D., Reem H. Ghalib, M.D., Eugene R. Schiff, M.D., Joseph S. Galati, M.D., Bruce R. Bacon, M.D., Mitchell N. Davis, M.D., Pabak Mukhopadhyay, Ph.D., Kenneth Koury, Ph.D., Stephanie Noviello, M.D., Lisa D. Pedicone, Ph.D., Clifford A. Brass, M.D., Janice K. Albrecht, Ph.D., Mark S. Sulkowski, M.D., for the IDEAL Study Team



ABSTRACT



Background - Treatment guidelines recommend the use of peginterferon alfa-2b or peginterferon alfa-2a in combination with ribavirin for chronic hepatitis C virus (HCV) infection. However, these regimens have not been adequately compared.



Methods - At 118 sites, patients who had HCV genotype 1 infection and who had not previously been treated were randomly assigned to undergo 48 weeks of treatment with one of three regimens: peginterferon alfa-2b at a standard dose of 1.5 µg per kilogram of body weight per week or a low dose of 1.0 µg per kilogram per week, plus ribavirin at a dose of 800 to 1400 mg per day, or peginterferon alfa-2a at a dose of 180 µg per week plus ribavirin at a dose of 1000 to 1200 mg per day. We compared the rate of sustained virologic response and the safety and adverse-event profiles between the peginterferon alfa-2b regimens and between the standard-dose peginterferon alfa-2b regimen and the peginterferon alfa-2a regimen.



Results - Among 3070 patients, rates of sustained virologic response were similar among the regimens: 39.8% with standard-dose peginterferon alfa-2b, 38.0% with low-dose peginterferon alfa-2b, and 40.9% with peginterferon alfa-2a (P=0.20 for standard-dose vs. low-dose peginterferon alfa-2b; P=0.57 for standard-dose peginterferon alfa-2b vs. peginterferon alfa-2a). Estimated differences in response rates were 1.8% (95% confidence interval [CI], –2.3 to 6.0) between standard-dose and low-dose peginterferon alfa-2b and –1.1% (95% CI, –5.3 to 3.0) between standard-dose peginterferon alfa-2b and peginterferon alfa-2a. Relapse rates were 23.5% (95% CI, 19.9 to 27.2) for standard-dose peginterferon alfa-2b, 20.0% (95% CI, 16.4 to 23.6) for low-dose peginterferon alfa-2b, and 31.5% (95% CI, 27.9 to 35.2) for peginterferon alfa-2a. The safety profile was similar among the three groups; serious adverse events were observed in 8.6 to 11.7% of patients. Among the patients with undetectable HCV RNA levels at treatment weeks 4 and 12, a sustained virologic response was achieved in 86.2% and 78.7%, respectively.



Conclusions - In patients infected with HCV genotype 1, the rates of sustained virologic response and tolerability did not differ significantly between the two available peginterferon–ribavirin regimens or between the two doses of peginterferon alfa-2b.



Hepatitis C virus (HCV) chronically infects approximately 180 million people worldwide1 and is a frequent cause of liver disease, including liver failure and hepatocellular carcinoma.2 HCV treatment is recommended for persons at the greatest risk for progression of liver disease.3 On the basis of noncomparative studies demonstrating similar safety and efficacy between the two treatments,4,5 consensus guidelines recommend the use of either peginterferon alfa-2b or peginterferon alfa-2a in combination with ribavirin for the treatment of chronic hepatitis C. However, differences between the peginterferons with respect to structural modifications and dosing (weight-adjusted vs. fixed) may lead to important differences in clinical outcomes, and there is some evidence of such differences.6,7,8,9 Randomized, comparative effectiveness trials are necessary to provide patients with evidence-based treatment options.



The Individualized Dosing Efficacy vs. Flat Dosing to Assess Optimal Pegylated Interferon Therapy (IDEAL) study was initiated to compare standard-dose and low-dose regimens of peginterferon alfa-2b, plus ribavirin, after it was observed that both dose levels yielded similar rates of sustained virologic response in the absence of ribavirin.10 A third treatment group, peginterferon alfa-2a plus ribavirin, was added to the study because (in addition to standard-dose peginterferon alfa-2b plus ribavirin) it is the other approved regimen. The objective was to compare the safety and efficacy of the two standard regimens and the experimental low-dose peginterferon alfa-2b regimen.



Methods



Study Patients



We enrolled patients from 118 centers in the United States. Eligible patients were 18 years of age or older, had compensated liver disease due to chronic HCV genotype 1 infection and a detectable plasma HCV RNA level, and had not been previously treated for hepatitis C infection. The patients had an absolute neutrophil count of 1500 or more per cubic millimeter, a platelet count of 80,000 or more per cubic millimeter, and hemoglobin level of 12 g (for women) or 13 g (for men) or more per deciliter. Patients were excluded if they had coinfection with human immunodeficiency virus or hepatitis B, any other cause of liver disease, poorly controlled diabetes mellitus (glycated hemoglobin value >8.5%), morbid obesity (weight >125 kg), severe depression or a severe psychiatric disorder, or active substance abuse. All patients had undergone liver biopsy within 3 years before screening. A pathologist at the central site, who was unaware of the treatment assignments, reviewed all the biopsy specimens and determined the METAVIR fibrosis stage and inflammatory grade, as well as the percentage of the tissue containing hepatocytes with steatosis.11



Study Oversight



The study sponsor and the academic principal investigators were jointly responsible for the study design, protocol, statistical analysis plan, and data analysis. The principal investigators had unrestricted access to the data, wrote the manuscript, and vouch for the accuracy and integrity of the data and analyses. A publication committee comprising the academic principal investigators and three independent experts prepared the prespecified data-analysis plan and ensured the unbiased interpretation of the data.



Study Design



Patients were randomly assigned, in a 1:1:1 ratio and with the use of an interactive voice system, to one of the three treatment groups and were stratified according to HCV RNA level (600,000 IU per cubic millimeter or >600,000 IU per cubic millimeter) and self-reported race (black or nonblack). The three treatment groups were as follows: peginterferon alfa-2b at the standard dose, 1.5 µg per kilogram of body weight per week, or at a lower dose, 1.0 µg per kilogram per week, both in combination with oral ribavirin at a dose according to body weight (40 to 65 kg, 800 mg per day; >65 to 85 kg, 1000 mg per day; >85 to 105 kg, 1200 mg per day; and >105 to 125 kg, 1400 mg per day); or peginterferon alfa-2a at a dose of 180 µg per week, plus oral ribavirin at a dose of 1000 to 1200 mg per day, according to body weight (<75 kg, 1000 mg per day; 75 kg, 1200 mg per day).



The study was double-blinded with regard to the dose of peginterferon alfa-2b. For patients receiving peginterferon alfa-2a, the dose of ribavirin was determined on the basis of prescribing information from the Food and Drug Administration (FDA). Because weight-based ribavirin dosing was not approved by the FDA for use with peginterferon alfa-2b when the study was initiated, the dose of ribavirin administered in the two groups receiving peginterferon alfa-2b was calculated to deliver a mean (±SD) of 13±2 mg per kilogram per day, on the basis of data derived from previous trials and from the product information from the European Medicines Agency.4,7,12 Patients underwent treatment for up to 48 weeks and follow-up for 24 weeks. The study was approved by each center's institutional review board and was conducted in accordance with provisions of the Declaration of Helsinki and Good Clinical Practice guidelines.



Efficacy Assessments



HCV RNA levels were measured with the use of the Cobas TaqMan assay (Roche), which has a lower limit of quantitation of 27 IU per cubic millimeter. Measurements were obtained at screening visits 1 and 2 (baseline); weeks 2, 4, 12, 24, and 48 during the treatment period; and follow-up weeks 4, 12, and 24. Per established guidelines, patients with an insufficient virologic response at 12 weeks (a detectable HCV RNA level and a decrease of <2 log10 IU from the baseline level) or at 24 weeks (a detectable HCV RNA level) were considered to have treatment failure, and therapy was discontinued.



Safety Assessments



Adverse events were graded by the investigators as mild, moderate, severe, or life-threatening, according to a modified World Health Organization grading system. Non–life-threatening adverse events were managed by reduction of the dose of peginterferon alfa or ribavirin (or both). The peginterferon-dose reduction was a two-step process: the dose was reduced if the neutrophil count was below 750 per cubic millimeter, and treatment with both drugs was permanently discontinued if the neutrophil count was below 500 per cubic millimeter. For patients receiving peginterferon alfa-2b, the ribavirin-dose reduction occurred in two steps, as established by Jacobson et al.7 The first step was a reduction of either 200 mg (in patients receiving 800 to 1200 mg of ribavirin per day) or 400 mg (in patients receiving 1400 mg per day); the second step was reduction by another 200 mg, if required for resolution of the adverse event. For patients receiving peginterferon alfa-2a, ribavirin-dose reduction consisted of a reduction to 600 mg per day, on the basis of FDA-approved prescribing information. For all patients, ribavirin-dose reduction was required if the hemoglobin level was less than 10 g per deciliter; treatment with both drugs was permanently discontinued if the level was below 8.5 g per deciliter. In patients with a hemoglobin level less than 10 g per deciliter, use of erythrocyte-stimulating agents was permitted after ribavirin-dose reduction. Drug doses could be increased once the cytopenia resolved (i.e., the neutrophil count was 750 per cubic millimeter or the hemoglobin level was 10 g per deciliter).



End Points



Analyses included data from all patients who underwent randomization and who received at least one dose of study medication. The primary end point was a sustained virologic response, defined as undetectable HCV RNA levels 24 weeks after the completion of therapy. If the 24-week post-treatment HCV RNA measurement was missing, the 12-week post-treatment level was used. (This was done for 38, 21, and 25 patients receiving standard-dose and low-dose peginterferon alfa-2b and peginterferon alfa-2a, respectively, all of whom had had undetectable HCV RNA at 12 weeks after treatment.)



The study involved two primary comparisons: standard-dose versus low-dose peginterferon alfa-2b regimens and standard-dose peginterferon alfa-2b versus peginterferon alfa-2a. Secondary end points included the rates of virologic response during the treatment phase and relapse, defined as an undetectable HCV RNA level at the end of the treatment phase, with a detectable HCV RNA level during the follow-up period.



Statistical Analysis



For both primary comparisons, the trial was designed as a superiority study to detect clinically meaningful differences in the rates of sustained virologic response among the three regimens. The study had a statistical power of 80% to detect a significant absolute difference in rates of sustained virologic response of 6.5% between the standard-dose and low-dose peginterferon alfa-2b regimens and of 7% between the standard-dose peginterferon alfa-2b regimen and the peginterferon alfa-2a regimen. A one-sided test was used to compare the two peginterferon alfa-2b regimens, with an assumption that the standard-dose regimen would be at least as effective as the low-dose regimen. A two-sided test was used to compare standard-dose peginterferon alfa-2b and peginterferon alfa-2a. Because there were two primary treatment comparisons, the Holm–Bonferroni method was used to maintain the overall type 1 error rate at 0.05. According to this method, the lowest P value must be below 0.025 to be considered to indicate statistical significance. If this criterion is met, then the higher P value must be below 0.05 to be considered to indicate statistical significance. If the lowest P value is greater than 0.025, no other tests are performed.



P values for the two primary treatment comparisons were calculated on the basis of a logistic-regression model controlling for the stratification factors (race and baseline HCV RNA level). Since neither of the two comparisons was significant, all P values are considered to be nominal and are labeled as such. Similarly, nominal two-sided 95% confidence intervals are reported, calculated for the two primary comparisons according to a Mantel–Haenszel approach controlling for the stratification factors. Summary statistics are reported for each of the three treatment regimens for subgroups of patients defined by prespecified baseline characteristics and one characteristic defined post hoc (baseline fasting glucose level). Multivariable logistic-regression analyses involving treatment regimen, prespecified baseline characteristics, and three post hoc factors (baseline fasting glucose level, hemoglobin value, and platelet count) were performed to study sustained virologic response and relapse. A stepwise procedure was used to identify independent predictors of sustained virologic response and relapse (with P=0.05 as the threshold level for variables to be entered into and retained in the final model). This type of approach was prespecified in the analysis plan for sustained virologic response but not for relapse. As was prespecified, we also explored the relationship between the magnitude and rapidity of virologic response during the treatment phase and the probability of achieving a sustained virologic response.



Results



Characteristics of the Study Patients



Between March 2004 and June 2006, a total of 4469 patients were screened, and 3070 underwent randomization and treatment (Figure 1). Baseline demographic characteristics were balanced among the three treatment groups (Table 1). The majority of patients were men in their 40s; 18.6% of the patients were black; and the mean body weight was 83.4 kg. After stratification on the basis of body weight, 1061 of 2035 patients (52.1%) receiving peginterferon alfa-2b were assigned to receive the same dose of ribavirin as the corresponding patients receiving peginterferon alfa-2a, whereas 773 of the 2035 patients (38.0%) were assigned a lower dose of ribavirin, and 201 of the 2035 (9.9%) were assigned a higher dose. During the treatment period, the mean and median daily ribavirin doses received were significantly higher among patients receiving peginterferon alfa-2a than those in either peginterferon alfa-2b group, regardless of ribavirin-dose reduction, use of erythrocyte-stimulating agents, or efficacy outcome (sustained virologic response, relapse, or nonresponse). The proportion of patients who received, on average, more than 13 mg of ribavirin per kilogram per day was greater in the peginterferon alfa-2a group (56.0%) than in either peginterferon alfa-2b group (29.1% in the standard-dose group and 32.6% in the low-dose group) (P<0.001 for each comparison).




Efficacy



The rates of sustained virologic response did not differ significantly among the three treatment groups, with a rate of 39.8% (95% confidence interval [CI], 36.8 to 42.8) for standard-dose peginterferon alfa-2b, 38.0% (95% CI, 35.0 to 41.0) for low-dose peginterferon alfa-2b, and 40.9% (95% CI, 37.9 to 43.9%) for peginterferon alfa-2a, (P=0.20 for standard-dose vs. low-dose peginterferon alfa-2b; P=0.57 for standard-dose peginterferon alfa-2b vs. peginterferon alfa-2a) (Table 2). Estimated differences in response rates were 1.8% (95% CI, –2.3 to 6.0) between standard-dose and low-dose peginterferon alfa-2b and –1.1% (95% CI, –5.3 to 3.0) between standard-dose peginterferon alfa-2b and peginterferon alfa-2a. Therefore, the two primary trial end points of superiority were not met. Response rates at the end of the treatment phase were higher with peginterferon alfa-2a than with either peginterferon alfa-2b regimen, but the virologic relapse rate was also higher. In all three groups, HCV RNA suppression at treatment weeks 4 and 12 was strongly associated with achievement of sustained virologic response (Table 3). Fewer than 5% of patients who had a reduction from the baseline HCV RNA level of less than 1 log10 IU per cubic millimeter at week 4 also had a sustained virologic response. A prolonged time (>12 weeks of therapy) to undetectable HCV RNA level was associated with a higher likelihood of relapse after treatment (Table 3). Stepwise multivariable logistic-regression analyses identified several baseline factors as independent predictors of sustained virologic response: baseline HCV RNA level (<600,000 IU per cubic millimeter), race (nonblack), minimal fibrosis (METAVIR score of F0, F1, or F2), absence of steatosis, normal baseline fasting glucose level, and elevated baseline serum alanine aminotransferase level. Using the same method, we found that these factors were independently associated with relapse, as were age over 40 years and peginterferon alfa-2a treatment (Table 1 of the Supplementary Appendix, available with the full text of this article at NEJM.org).



Ribavirin Dosing



Rates of sustained virologic response were similar among the three treatment groups, within the subgroups of patients receiving the same dose of ribavirin (those weighing >65 to <75 kg and those weighing >85 to 105 kg) (Table 2). The ribavirin dose was reduced, owing to an adverse event, in 30.2% of patients. The rate of sustained virologic response among these patients was 52.2% in the peginterferon alfa-2a, 51.8% in the standard-dose peginterferon-2b group, and 49.3% in the low-dose peginterferon alfa-2b group. In comparison, the rate of sustained virologic response was higher among patients who had a hemoglobin level that was less than 10 g per deciliter during the treatment phase but who required a ribavirin-dose reduction, as compared with those with levels of 10 g per deciliter or above: 48.8% (422 of 865 patients) versus 36.7% (793 of 2158 patients) (P<0.001).



Safety



The types and frequencies of adverse events were similar among the three groups (Table 4). The most common adverse events included influenza-like symptoms, depression, and the hematologic events of anemia and neutropenia. The proportions of patients with neutropenia who met the criterion for peginterferon-dose reduction (a neutrophil count of <750 and >500 per cubic millimeter were 21.1% receiving peginterferon alfa-2a, 19.4% receiving standard-dose peginterferon alfa-2b, and 12.5% receiving low-dose peginterferon alfa-2b. However, only 2.1 to 5.9% of patients met the discontinuation criterion based on neutropenia. The proportion of patients meeting the hemoglobin criterion for ribavirin-dose reduction (a hemoglobin level <10 and >8.5 g per deciliter) was somewhat higher with standard-dose peginterferon alfa-2b (28.2%) and peginterferon alfa-2a (25.8%) than with low-dose peginterferon alfa-2b (23.2%); only 2.1 to 3.8% of patients met the discontinuation criterion (hemoglobin level <8.5 g per deciliter).



Most psychiatric adverse events were mild or moderate and were not treatment-limiting; however, 1.8 to 2.6% of patients did discontinue treatment. Twelve patients (0.4%) died during the study: seven during the treatment period and five during or after the follow-up period. Two of these deaths were considered by the investigator to be possibly related to study medications: a suicide at 6 months after the end of treatment with standard-dose peginterferon alfa-2b and a myocardial infarction during treatment with peginterferon alfa-2a.



Discussion



Treatment with peginterferon alfa-2a or peginterferon alfa-2b, plus ribavirin, for 48 weeks is recommended for patients infected with HCV genotype 1, the most common variant in the United States and Europe.13 Despite this recommendation, few data comparing these treatment regimens are available. Accordingly, several findings of our large, randomized comparative study affect the care of these patients.



The safety and adverse-event profiles and the efficacy data were similar among patients treated with low-dose or standard-dose peginterferon alfa-2b or peginterferon alfa-2a, in combination with differing ribavirin regimens. The finding that low-dose peginterferon alfa-2b resulted in a similar rate of sustained virologic response as the other regimens was unexpected. Since monotherapy with standard-dose peginterferon alfa-2b has been associated with higher rates of virologic response during the treatment period,10 we aimed to test the hypothesis that use of standard-dose peginterferon alfa-2b with ribavirin would result in a higher rate of sustained virologic response than with the low-dose regimen. Although our data do not support this hypothesis, a significant interaction between treatment group and sex (P=0.01) (Table 2 in the Supplementary Appendix) suggests that women may have higher rates of sustained virologic response with standard-dose than with low-dose peginterferon alfa-2b. Although the interaction with race was not significant, blacks tended to have higher rates of sustained virologic response with the standard dose of peginterferon alfa-2b. Host, virologic, and treatment factors associated with eradication of HCV genotype 1 infection were identified. Consistent with previous observations,14,15,16,17,18,19,20 a sustained virologic response was less frequent among blacks, persons with advanced hepatic fibrosis and steatosis, and those with high baseline HCV RNA levels. Although it was not a prespecified covariate, impaired fasting glucose was also associated with a lower likelihood of sustained virologic response. These data suggest a need for additional research to test the hypothesis that dietary and pharmacologic interventions to correct glucose intolerance can improve treatment response. The magnitude of HCV RNA suppression during the treatment phase was also closely linked to the likelihood of having a sustained virologic response. Among the 10% of patients with undetectable HCV RNA levels at treatment week 4, 86% had a sustained virologic response. The 24% of patients with a minimal decline in HCV RNA level (decline of <1 log10 IU from the baseline value) at treatment week 4 had a probability of sustained virologic response of less than 5%. Thus, virologic response at treatment week 4 is an important predictor of sustained virologic response; HCV RNA levels should be routinely assessed at this time point.



The time to the first undetectable HCV RNA level was associated with the probability of virologic relapse after the end of treatment. Approximately 50% of patients who had HCV suppression for the first time by treatment week 24 also had virologic relapse, as compared with less than 10% of patients who had HCV suppression at treatment week 4. After week 4, patients receiving peginterferon alfa-2a had a higher rate of HCV RNA suppression than did those who were receiving peginterferon alfa-2b; however, this difference was not sustained after the end of the treatment period. Thus, although the rates of sustained virologic response were similar among the three groups, patients treated with peginterferon alfa-2a were more likely to have a response while receiving therapy, followed by relapse after the completion of therapy, whereas patients treated with peginterferon alfa-2b were more likely to discontinue therapy at treatment week 12 or 24 because of an insufficient virologic response.



Increased ribavirin exposure during the treatment phase was associated with an increased likelihood of sustained virologic response among all treated patients. Ribavirin exposure was lower in patients who received peginterferon alfa-2b, which was administered according to four dosing categories (based on body weight), as compared with those who received peginterferon alfa-2a, which was administered according to two. Patients weighing between 75 and 85 kg received 1000 mg of ribavirin per day if they were also receiving peginterferon alfa-2b, as compared with 1200 mg per day if they were also receiving peginterferon alfa-2a. In this large weight group (792 patients), the rate of sustained virologic response was higher by approximately 10 percentage points in the peginterferon alfa-2a group, suggesting that the ribavirin dose for persons who weigh between 75 and 85 kg should be 1200 mg per day in the peginterferon alfa-2b groups. Surprisingly, reducing the ribavirin dose because of treatment-related anemia (as was done in 30% of patients) did not appear to reduce the likelihood of sustained virologic response. Despite the reduction of ribavirin dose by as much as 50% in patients receiving peginterferon alfa-2a, patients with anemia had a higher rate of sustained virologic response than did those without anemia, suggesting that the magnitude of anemia may be a pharmacodynamic marker of drug exposure. The data indicate that the initial ribavirin dose should be at least 13 mg per kilogram per day and that the conservative management of anemia, involving a ribavirin-dose reduction in either one or two steps, appears to maintain safety and not to compromise efficacy.



The findings are subject to several limitations. Because the initial ribavirin dose varied among the patients, the study compares HCV treatment regimens and is not a direct comparison of the type of peginterferon. Nonetheless, more than 51% of patients received the same dose of ribavirin in combination with either peginterferon alfa-2a or peginterferon alfa-2b, and their rates of sustained virologic response were similar. Second, the procedure for ribavirin-dose reduction differed between the peginterferon alfa-2a group and the peginterferon alfa-2b groups. Yet, the rate of sustained virologic response was higher among patients who had the ribavirin dose reduced because of anemia than among those who did not. Third, since the study was conducted in the United States, these comparative data may not be generalizable to other regions or HCV genotypes. Fourth, owing to insurmountable differences in drug formulation (lyophilized powder in the case of peginterferon alfa-2b or solution in the case of peginterferon alfa-2a), patients and investigators were aware of the type of peginterferon being given. After careful inspection, however, no irregularity in data collection or reporting was detected.



In conclusion, the rates of sustained virologic response and the safety and adverse-event profiles were similar among patients infected with HCV genotype 1 who received standard-dose or low-dose peginterferon alfa-2b or peginterferon alfa-2a, in combination with ribavirin.



Supported by grants from Schering-Plough.

HIV Regimens Lacking Nucleosides Tied to Higher SVR Rate With HCV Therapy

HIV Regimens Lacking Nucleosides Tied to Higher SVR Rate With HCV Therapy

5th IAS Conference on HIV Pathogenesis, Treatment and Prevention, July 19-22, 2009, Cape Town

Mark Mascolini

HIV-infected people taking antiretroviral regimens lacking nucleosides (NRTIs) had a higher sustained virologic response (SVR) rate than people taking nucleosides after 48 weeks of pegylated interferon/ribavirin for HCV infection in a small, partially randomized trial [1]. The trial found equivalent SVRs in people with and without HIV.

German researchers evaluated interferon/ribavirin in three groups: 60 HCV-infected people without HIV, 46 HIV/HCV-infected people taking no antiretrovirals, and 68 HIV/HCV-infected people taking antiretrovirals. The investigators randomized 48 people in this last group to an NRTI-containing regimen and 20 to an NRTI-free combination (two protease inhibitors or a protease inhibitor plus a nonnucleoside).

The HIV group not taking antiretrovirals was younger and had higher CD4 counts than the HIV-infected people taking antiretrovirals (median 39 years in the no-antiretroviral group versus 41 in the NRTI-containing group and 43 in the NRTI-free group; median 580 CD4s in the no-antiretroviral group versus 490 in the NRTI group and 390 in the no-NRTI group). Besides having a lower CD4 count than the NRTI-containing group, the NRTI-free group had a higher pretreatment HCV load (5.8 versus 5.4 log). Eleven people (55%) in the NRTI-free group and 30 (63%) in the NRTI-containing group had hard-to-treat HCV genotype 1 or 4.

HCV therapy consisted of 180 micrograms of pegylated interferon alfa-2a and 800 mg of ribavirin for 24 weeks in people with HCV genotype 2 or 3 and for 48 weeks in people with genotype 1 or 4. The protocol was amended to extend treatment to 48 weeks for everyone and to use a weight-based dose of ribavirin.

SVR rates were equivalent across the three main study groups, but in the antiretroviral-treated group, a significantly higher proportion of people taking no NRTIs than taking NRTIs had an SVR:



· HIV-negative SVR 54%

· All HIV-positive SVR 54%

· HIV-positive, no antiretroviral therapy SVR 59%

· HIV-positive, on antiretroviral therapy SVR 52%

· HIV-positive, NRTI-containing therapy SVR 42%

· HIV-positive, NRTI-free regimen SVR 75%


The SVR difference between people taking or not taking NRTIs was statistically significant (P = 0.012), while the difference between the groups on versus off antiretroviral therapy was not significant. The NRTI-containing and NRTI-free groups did not differ in proportions with genotypes 1 or 4 versus 2 or 3, use of weight-adjusted ribavirin, treatment duration, number of adverse events, or rate of treatment discontinuations for adverse events. The investigators did not attempt a statistical analysis to determine which factors favored an SVR without rather than with NRTIs. Nor did they explain the 2.4-to-1 randomization favoring NRTI-containing antiretroviral therapy or discuss statistical power calculations.

In the NRTI-containing group, two factors made an SVR less likely. A higher proportion without an SVR had genotype 1 or 4 (79% versus 40% with an SVR, P = 0.003), and pretreatment HCV load was higher in people who did not attain an SVR (5.7 versus 5.1 log with an SVR, P < 0.001). Factors that did not predict SVR in this analysis were gender, age, HIV transmission risk group, CD4 count, and type of NRTI-containing therapy.

Reference
1. Vogel M, Ahlenstiel G, Klausen G, et al. The effect of nucleoside free HAART on the treatment of chronic HCV infection. 5th IAS Conference on HIV Pathogenesis, Treatment and Prevention. July 19-22, 2009. Cape Town. Abstract WEPEB235.

Proof-of-Concept Study of IDX184 for the Treatment of Hepatitis C Virus

Idenix Pharmaceuticals Successfully Completes Proof-of-Concept Study of IDX184 for the Treatment of Hepatitis C Virus (HCV)



CAMBRIDGE, Mass., July 20 /PRNewswire-FirstCall/ -- Idenix Pharmaceuticals, Inc. (NASDAQ: IDIX) , a biopharmaceutical company engaged in the discovery and development of drugs for the treatment of human viral diseases, today announced that it has successfully completed a three-day proof-of-concept study of IDX184. Idenix is developing IDX184, a novel liver-targeted prodrug of 2'-methyl guanosine nucleotide, for the treatment of HCV.



This double-blind, placebo-controlled, monotherapy, dose-escalation study evaluated the safety and antiviral activity of IDX184. In this study, 41 treatment-naive HCV genotype-1-infected patients were randomized to receive either IDX184 or placebo once-daily for three days. Four dosing cohorts (25 mg, 50 mg, 75 mg and 100 mg) of IDX184 were evaluated. IDX184 was well tolerated in this study with no serious adverse events reported and no discontinuations from the study. Patterns of adverse events were similar between IDX184- and placebo-treated patients. Viral load declines were observed in 30 of the 31 IDX184-treated patients, with no response in one patient in the 25 mg cohort. Significant viral load reductions were observed in the three higher dose cohorts (50, 75 and 100 mg/day). Post-treatment viral load data suggest no evidence of drug accumulation. The table below summarizes mean HCV RNA reductions observed in this study per cohort:



End of Treatment Mean Patients with 1 log10 or

Change in HCV RNA Greater Reduction in HCV

Cohort Dose (log10) RNA at End of Treatment

------ ---- --------------------- --------------------------

A (n=6*) 25 mg/day -0.47 1

------- ------------ ----- ---

B (n=8) 50 mg/day -0.69 1

------ ------------ ----- ---

C (n=8) 75 mg/day -0.70 2

------ ------------ ----- ---

D (n=9) 100 mg/day -0.74 4

------ ------------ ----- ---

Control Placebo

(n=8) +0.01 0



* Eight subjects were randomized to this cohort, two of whom were excluded

from the viral load evaluation due to an error in dosing.







"We are pleased with the results of this study, which support the potential for IDX184 to be a best-in-class nucleoside/tide polymerase inhibitor with demonstrated antiviral activity and tolerability, coupled with a low once-daily dose," said Douglas Mayers, M.D., chief medical officer of Idenix. "Now that we have successfully completed the proof-of-concept study in HCV-infected patients, we plan to advance IDX184 into a 14-day dose-ranging study in combination with the current standard-of-care, pegylated interferon and ribavirin, to determine the optimal IDX184 doses to advance into broader clinical trials."



In the 75 and 100 mg/day cohorts, patients receiving IDX184 experienced improvements in two key markers of liver injury, with mean AST and ALT levels decreasing to below the upper limit of normal. These improvements were sustained for up to 6 days post-dosing, and most levels returned to baseline 14 days post-treatment.



"We have made great progress in our HCV discovery and development programs this year," said Jean-Pierre Sommadossi, Ph.D., chairman and chief executive officer of Idenix. "With the successful completion of the proof-of-concept study for IDX184 and plans to file investigational new drug applications in the coming months from our non-nucleoside polymerase inhibitor and protease inhibitor programs, we are closer to achieving our ultimate goal of developing novel combinations of direct-acting antivirals for the treatment of hepatitis C."



The company plans to report the full data set from this study at a scientific meeting later this year.



About IDX184



IDX184 is a novel, liver-targeted 2'-methyl guanosine nucleotide prodrug, which includes Idenix's proprietary liver-targeting technology. This technology enables the delivery of nucleoside monophosphate to the liver, leading to the formation of high levels of nucleoside triphosphate, potentially maximizing drug efficacy and limiting systemic side effects with low, once-daily dosing of drug.



Conference Call Information



Idenix will hold a conference call and webcast today at 4:30 p.m. ET. To access the call please dial 800-774-5358 U.S./Canada or 706-758-9475 International and enter passcode 20088902 or to listen to a live webcast and view accompanying slides, go to "Calendar of Events" in the Idenix Investor Center at www.idenix.com. A replay of the call will also be available from 6:30 p.m. ET on July 20, 2009 until August 3, 2009 12:00 a.m. ET. To access the replay, please dial 800-642-1687 U.S./Canada or 706-645-9291 International and enter passcode 20088902. An archived webcast will also be available for two weeks after the call on the Idenix website.



About Idenix



Idenix Pharmaceuticals, Inc., headquartered in Cambridge, Massachusetts, is a biopharmaceutical company engaged in the discovery and development of drugs for the treatment of human viral diseases. Idenix's current focus is on the treatment of infections caused by hepatitis C virus. For further information about Idenix, please refer to www.idenix.com.



Forward-looking Statements



This press release contains "forward-looking statements" within the meaning of The Private Securities Litigation Reform Act of 1995. Such forward-looking statements can be identified by the use of forward-looking terminology such as "expect," "plans," "anticipates," "will," "expects," "goal" or similar expressions, or by express or implied statements with respect to the company's clinical development programs or commercialization activities in hepatitis C, or any potential pipeline candidates, including any expressed or implied statements regarding the efficacy and safety of IDX184, the likelihood and success of any future clinical trials involving IDX184 or successful development of novel combinations of direct-acting antivirals for the treatment of hepatitis C. Such forward-looking statements involve known and unknown risks, uncertainties and other factors that may cause actual results to be materially different from any future results, performance or achievements expressed or implied by such statements. There can be no guarantees that the company will advance any clinical product candidate or other component of its potential pipeline to the clinic, to the regulatory process or to commercialization. In particular, management's expectations could be affected by unexpected regulatory actions or delays; uncertainties relating to, or unsuccessful results of, clinical trials, including additional data relating to the ongoing clinical trials evaluating its product candidates; the company's ability to obtain additional funding required to conduct its research, development and commercialization activities; the company's dependence on its collaboration with Novartis Pharma AG and GlaxoSmithKline, respectively; changes in the company's business plan or objectives; the ability of the company to attract and retain qualified personnel; competition in general; and the company's ability to obtain, maintain and enforce patent and other intellectual property protection for its product candidates and its discoveries. These and other risks which may impact management's expectations are described in greater detail under the caption "Risk Factors" in the company's annual report on Form 10-K for the year ended December 31, 2008 and the Quarterly Report on Form 10-Q for the quarter ended March 31, 2009, as filed with the Securities and Exchange Commission (SEC) and other filings that the company makes with the SEC.



All forward-looking statements reflect the company's expectations only as of the date of this release and should not be relied upon as reflecting the company's views, expectations or beliefs at any date subsequent to the date of this release. Idenix anticipates that subsequent events and developments may cause these views, expectations and beliefs to change. However, while Idenix may elect to update these forward-looking statements at some point in the future, it specifically disclaims any obligation to do so.



SOURCE Idenix Pharmaceuticals, Inc.

Website: http://www.idenix.com

Hep C out of control in England

Out of Control: Spiralling Number of Deadly Hepatitis C Infections As Government Strategy Fails. Urgent Call to Action to Halt Imminent Liver Crisis

Thursday, 16 July 2009
http://www.responsesource.com

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16 July, 2009, London: New research demonstrates that a large majority (70%) of Strategic Health Authorities (SHAs) in England are failing to oversee the Government’s strategy to tackle hepatitis C1, leaving infection rates of this deadly virus to increase and causing the disease to spiral out of control – putting thousands of lives at risk. A further study shows SHAs ignoring NICE guidance with only 29% of diagnosed patients2 being treated across the country, less than half of the 60% that NICE recommends.3

"We have to act now to stop this. It is not acceptable that people are dying when there are treatments available to save lives. The strategies that have been developed are simply not being implemented and there is no more time for excuses, we must act to ensure that the strategy is delivered. The time for paperwork is over, we need action not documents." says Graham Foster, Professor of Hepatology, Queen Mary, University of London.

Click here to download interactive map of SHA regions and view soundbites from key spokespeople:http://www.hepcoutofcontrol.org.uk

Five years wasted since Hepatitis C Action Plan for England launched

In 2004 the Department of Health published the Hepatitis C Action Plan for England, which outlines specific actions to improve research, monitoring, awareness and prevention efforts and overall patient care. However, an audit in 2008 found that half of PCTs were only partially implementing the Action Plan and in 15% of PCTs there was minimal implementation or none at all.4 One year on, it is apparent that SHAs, which manage the NHS locally and are a key link between the Department of Health and the NHS, have not intervened to improve PCT implementation of the Action Plan, despite the fact that responsibility for oversight is placed with them. As the latest research shows, one SHA (South East) is not aware of any local arrangements in place to deliver the Plan, and in most areas of the country there is no plan in place to ensure improvements to hepatitis C services and treatment for patients.

Charles Gore, CEO of The Hepatitis C Trust, the charity that has published the research, says “Patients are dying and that is the Trust’s concern. There is failure at every level in addressing hepatitis C. SHAs, PCTs and all relevant NHS bodies must be held accountable to avoid dire consequences. Time has run out and the Government need to show leadership and take control now. It is time to prioritise liver disease; it is time for a liver strategy; and it is time for a liver czar.”

Liver deaths and new infections increasing in England compared to the rest of Europe
Overall, mortality from liver disease is declining in Europe5, in sharp contrast to the situation in England where deaths attributable to hepatitis C have doubled in the past decade.6 Furthermore, the number of people with hepatitis C cirrhosis is expected to double to 8,280 by 2015.7 Unless the Government responds now, poor treatment rates, coupled with an increase in incidence of around 12,995 infections per year (more than 1,000 per month)8 mean that the hepatitis C epidemic will continue to soar in the UK.

Treating and curing so few patients means that deaths will continue to escalate, the demand for last ditch interventions such as liver transplants will rise and more people will become infected with the disease. This imminent crisis can be effectively managed and people’s lives can be saved. It is time to prioritise liver disease; it is time for a liver strategy; and it is time for a liver czar.

The Hepatitis C Trust calls for:

1.A national liver czar responsible for driving forward improvements in liver services, particularly hepatitis C.
2.A national liver strategy to address the growing crisis of liver disease, with clearly defined actions for addressing hepatitis C.
3.A robust governance structure for hepatitis C to oversee the monitoring, benchmarking and evaluation of actions by all levels of the NHS. These should be reported annually in the HPA report on hepatitis C.
4.A review of the implementation of NICE treatment and an audit of the barriers to achieving recommended treatment uptake levels.

Association between dietary nutrient composition and the incidence of cirrhosis

Association between dietary nutrient composition and the incidence of cirrhosis or liver cancer in the united states population



Hepatology July 2009


George N. Ioannou 1 2 3 *, Olivia B. Morrow 2, Marah L. Connole 2, Sum P. Lee 1 2 3

1Division of Gastroenterology, Department of Medicine, Veterans Affairs Puget Sound Health Care System, Seattle, WA

2Research Enhancement Award Program, Veterans Affairs Puget Sound Health Care System, Seattle, WA

3Division of Gastroenterology, Department of Medicine, University of Washington, Seattle, WA






Abstract




Little is known about the impact of dietary factors on the progression of liver disease. Our aim was to determine whether dietary intake was associated with the risk of cirrhosis-related or liver cancer-related death or hospitalization in the U.S. population. Participants included 9221 persons aged 25-74 years without evidence of cirrhosis at entry into the study or during the first 5 years of follow-up, who were subsequently followed for a mean of 13.3 years as part of the first National Health and Nutrition Examination Survey. Dietary intake was ascertained at baseline using a 24-hour dietary recall questionnaire. During follow-up, 123 of 9221 participants had a diagnosis of cirrhosis (n = 118) or liver cancer (n = 5) in hospitalization records or death certificates, including 36 who were diagnosed only on the basis of death certificates.

Participants who reported a diet high in protein were at a higher risk of hospitalization or death due to cirrhosis or liver cancer (P = 0.001), whereas those who reported a diet high in carbohydrates were at a lower risk (P = 0.003), after adjusting for potential confounders (daily consumption of protein, carbohydrate, fat, tea or coffee, and alcohol, gender, race, age, educational attainment, U.S. geographical region, diabetes, body mass index, and subscapular-to-triceps skinfold ratio).

Although total fat consumption was not significantly associated with the risk of cirrhosis or liver cancer, cholesterol consumption was associated with higher risk (P = 0.007), whereas serum cholesterol level was not associated with risk of cirrhosis or liver cancer. Conclusion: Diet may be an important and potentially modifiable determinant of liver disease.





Dietary factors are likely to be important determinants of the development of hepatic steatosis and its progression to steatohepatitis for the following reasons: (1) Dietary factors are important and probably causative risk factors for obesity, insulin resistance, and diabetes, which are the most important, known risk factors for hepatic steatosis. (2) Dietary lipid composition influences both the quantity and composition of lipids that are delivered to the liver and incorporated into hepatocyte lipid droplets. This is important because recent data derived primarily from animal models suggest that specific lipid molecules, such as saturated fatty acids, may promote lipotoxicity,[1][2] whereas others, such as n-3 polyunsaturated fatty acids (PUFAs), may actually have beneficial effects.[3][4] Therefore, it is possible that the quantity and composition of dietary lipid can either promote or protect against the development or progression of hepatic steatosis. (3) In rabbits[5][6] and mice[7] a high cholesterol diet has been shown to induce profound steatosis, inflammation, and centrilobular fibrosis.



Hepatic steatosis is the defining feature of nonalcoholic fatty liver disease (NAFLD) but it is also a common and probably pathogenetic feature of hepatitis C virus (HCV) infection and alcoholic liver disease. Although HCV infection and alcohol consumption can cause hepatic steatosis by themselves, obesity-related steatosis also occurs in the setting of HCV infection and alcoholic liver disease.[8] Therefore, if dietary composition affects the development or progression of hepatic steatosis, it is likely to play a part in the natural history of the three most important liver conditions in the U.S.: NAFLD, HCV infection, and alcoholic liver disease.



Dietary nutrients may also cause hepatic injury through pathways that do not involve the development or progression of hepatic steatosis. Carbohydrates, proteins, and lipids are all extensively metabolized in the liver and it is conceivable that they may influence the progression of chronic liver disease, either positively or negatively. In hepatitis B virus (HBV) transgenic mice, a diet low in animal protein was associated with decreased liver injury and decreased incidence of hepatocellular carcinoma.[9][10] In the presence of oxidative stress, dietary cholesterol may be oxidized in the liver to oxysterols, which can induce cell damage and malignant transformation and regulate signal transduction pathways.



Our aim was to investigate whether dietary nutrient composition was associated with the subsequent development of cirrhosis or liver cancer in a representative sample of the U.S. population.



Abbreviations



BMI, body mass index; HBV, hepatitis B virus; HCV, hepatitis C virus; ICD-9, International Classification of Diseases, 9th Revision; NAFLD, nonalcoholic fatty liver disease; NASH, nonalcoholic steatohepatitis; NHANES, National Health and Nutrition Examination Survey; NHEFS, NHANES I Epidemiologic Follow-up Study; PUFA, polyunsaturated fatty acid.





Results



During an average follow-up time of 13.3 years, 123 out of 9,221 participants had a new diagnosis of cirrhosis (n = 118) or liver cancer (n = 5) in hospitalization records or death certificates, including 36 who were diagnosed only on the basis of death certificates (Table 1). Patients who developed cirrhosis or liver cancer were older, more obese with more central fat distribution, had lower educational attainment and higher alcohol consumption, and were more likely to be male, diabetic, and nonwhite.



The total number of calories and the total quantity of fat consumed were not associated with the incidence of cirrhosis or liver cancer in univariate or multivariate analyses (Table 2). Increasing carbohydrate consumption was associated with significantly reduced incidence of cirrhosis or liver cancer in unadjusted and adjusted analyses in both percent and absolute energy models (adjusted hazard ratio of 0.42, 95% confidence interval [CI] 0.2-0.8, comparing the top to the bottom quartile). In contrast, protein consumption was associated with a significantly increased risk of cirrhosis or liver cancer after adjusting for potential confounders in absolute energy models, but not in percent energy models.



Although total fat consumption was not significantly associated with cirrhosis or liver cancer, we identified associations with specific lipid components (Table 3). In particular, higher consumption of cholesterol was associated with a higher risk of cirrhosis or liver cancer in both unadjusted and adjusted analyses. Persons in the top quartile of cholesterol consumption were more than twice as likely to develop cirrhosis or liver cancer compared to persons in the bottom quartile of cholesterol consumption. Consumption of saturated fatty acids, oleic acid, or linoleic acid was not associated with the risk of cirrhosis or liver cancer. In contrast, consumption of fatty acids other than the ones quantified by the NHANES I investigators was associated with a reduced risk of cirrhosis or liver cancer in total energy models (but not in percent energy models). Given that saturated fatty acids, oleic acid (the most common dietary monounsaturated fatty acid), linoleic acid (an n-6 PUFA), and cholesterol were quantified by NHANES I investigators, the other fats consist mostly of n-3 and n-6 PUFAs (other than linoleic acid).



Exploratory subgroup analyses by BMI and alcohol consumption are shown in Table 4. The most significant associations that we observed in the entire population (that is, with cholesterol, carbohydrate, and protein intake) were only observed among persons with elevated BMI (>/=25 kg/m2) and not among persons with normal BMI (<25 kg/m2). In contrast, the associations between dietary nutrients and cirrhosis or liver cancer were similar among persons with or without excessive alcohol consumption.



In the analyses presented in Tables 2 we excluded the first 5 years of follow-up, reasoning that cirrhosis or liver cancer that was present and undiagnosed at entry into the cohort would have led to hospitalization or death within 5 years. We also varied the number of years from entry into the cohort that were excluded from analysis from 0 to 6 and found in each analysis that protein and cholesterol consumption were associated with higher risk of cirrhosis or liver cancer, whereas carbohydrate and other fat consumption were significantly associated with lower risk of cirrhosis or liver cancer. When we repeated our analyses using only the 7032 participants who were hospitalized at least once or who died during follow-up, we found near-identical results. Dietary content of protein, carbohydrate, total fat, saturated fatty acid, oleic acid, linoleic acid, cholesterol, or other fat was not independently associated with the number of hospitalizations during follow-up.



Because dietary cholesterol consumption was so strongly associated with the incidence of cirrhosis or liver cancer, we evaluated whether serum cholesterol levels were also associated with cirrhosis or liver cancer, but we found no such association in either univariate or multivariate analyses. Therefore, ingested, dietary cholesterol was associated with cirrhosis or liver cancer, but hepatically synthesized cholesterol, which is the main determinant of serum cholesterol, was not associated with cirrhosis or liver cancer.



Finally, we used NHANES III data collected between 1988-1994 (Table 5) to investigate the association between dietary composition and the presence of HCV infection (which was not ascertained in NHANES I). There was no association between any measure of dietary composition and HCV infection after adjusting for the same confounders that we adjusted for in our NHANES I analyses. Therefore, it is extremely unlikely that the significant associations that we present in Tables 2 and 3 would have changed if we could have adjusted for HCV infection. Also, the lack of association between HCV infection and dietary composition strongly suggests that the presence of underlying liver disease does not cause a change in dietary intake and, instead, makes it more plausible that differences in dietary intake of proteins, carbohydrates, cholesterol, and perhaps other lipid components contribute to the development of cirrhosis or liver cancer.



Discussion



Our results show for the first time that dietary nutrient composition is a strong predictor of hospitalization or death due to cirrhosis or liver cancer in the U.S. population. In particular, we identified that protein and cholesterol consumption were associated with elevated risk, whereas consumption of carbohydrates was associated with reduced risk of hospitalization or death related to cirrhosis or liver cancer. We also observed a weaker association between consumption of PUFAs and reduced risk of cirrhosis or liver cancer, although PUFA consumption was not ascertained well in NHANES I.



The strong association between cholesterol intake and cirrhosis or liver cancer is potentially our study's most important finding. In rabbits[5][6] and mice[7] a high cholesterol diet has been shown to induce profound steatosis, inflammation, and centrilobular fibrosis. It was postulated that the hepatic steatosis, which was predominantly microvesicular, was the result of a cholesterol-induced reduction in mitochondrial beta oxidation of fatty acids.[5] Some dietary cholesterol is already oxidized to oxysterols and it is also possible for dietary cholesterol to be converted in the liver to oxysterols, which promote cytotoxic and carcinogenic effects. Hepatic oxidative stress is a prominent feature of nonalcoholic steatohepatitis (NASH), HCV infection, and alcoholic liver disease, and could lead to generation of oxysterols from dietary cholesterol. Despite the profound importance of cholesterol in nonhepatic diseases such as atherosclerosis, dietary cholesterol and oxysterols have received little attention as potential lipotoxic molecules in the human liver. We are not aware of any other human studies linking cholesterol intake to human liver disease. Our finding that dietary cholesterol but not serum cholesterol was associated with cirrhosis or liver cancer could have profound implications if confirmed by other studies. For example, it would suggest that drugs blocking intestinal cholesterol absorption could have more beneficial effects to the liver than drugs blocking hepatic cholesterol synthesis, which lower serum cholesterol levels by up-regulation of hepatic low-density lipoprotein receptors.



We did not have strong a priori hypotheses as to the direction of associations between protein or carbohydrate consumption and cirrhosis or liver cancer. Thus, our findings of a positive association of protein consumption and a negative association of carbohydrate consumption with hospitalization or death related to cirrhosis or liver cancer should be considered with caution. High protein intake in humans, in particular, animal protein, has been associated with hepatocellular carcinoma in an ecological study from rural China.[17] In HBV transgenic mice, a diet low in animal protein was associated with decreased liver injury and decreased incidence of hepatocellular carcinoma.[9][10] (We did not have information on whether ingested protein was of animal or plant origin.) Twenty-five patients with biopsy-proven NASH had diets richer in protein (as well as saturated fat and cholesterol and poorer in PUFAs and fiber) than 25 age-, BMI-, and gender-matched healthy controls.[18] We are not aware of any studies investigating the effects of carbohydrate intake on the progression of liver disease in humans. Contrary to our findings, a recent study found that patients with NAFLD consumed 2-3 times more fructose than controls, which may be linked to the development of steatosis because the hepatic metabolism of fructose favors de novo lipogenesis.[19] Our data did not allow us to determine the specific fructose intake; we speculate that fructose intake was much lower in the period of our study (1971-1992) than it is now due to the dramatic increase in the consumption of soft drinks containing high fructose corn syrup.



Although hepatic steatosis is defined by excessive deposition of lipid within hepatocytes, little is known about the exact nature of these lipids in humans. Evidence is emerging from cell culture and animal model experiments that specific lipid molecules, such as saturated fatty acids, may exert lipotoxicity,[1][2] whereas others, such as n-3 PUFAs, may actually have beneficial effects.[3][4] In human studies, hepatic levels of n-3 PUFAs were shown to progressively decrease from control patients to patients with NAFLD to NASH.[20][21] In a randomized controlled trial, n-3 PUFA supplementation reduced ultrasonographic steatosis, alanine aminotransferase levels, and insulin resistance in patients with suspected NAFLD.[22] We did not find any association between dietary intake of saturated fatty acids or the monounsaturated fatty acid oleic acid and cirrhosis or liver cancer. Although we did not have direct estimates of dietary PUFAs, especially n-3 PUFAs, we approximated PUFA intake by subtracting the intake of saturated fat, oleic acid, linoleic acid, and cholesterol from total fat intake. Using this approximation, we identified that persons in the top quartile of PUFA intake were half as likely to develop cirrhosis or liver cancer than persons in the bottom quartile in absolute energy models, but not in percent energy models; however, the test of trends across quartiles of other fat intake was just short of statistical significance (P = 0.05) even in the absolute energy models. Future studies should investigate these associations with more specific ascertainment of n-3 and n-6 PUFA intake.



Subgroup analyses showed that the significant associations of protein, carbohydrate, and cholesterol intake with cirrhosis or liver cancer that we described in the entire study population, were limited to overweight or obese persons (BMI 25 kg/m2) (Table 4). No such associations were observed in normal-weight persons. In contrast, alcohol consumption did not appear to modify substantially the associations between dietary nutrients and cirrhosis or liver cancer. This suggests that high protein and cholesterol and low carbohydrate intake are more likely to mediate their hepatic effects through obesity-related fatty liver disease.



Our study has some limitations, including the absence of data on HCV infection, which is a major cause of cirrhosis and liver cancer in the U.S. However, we have shown that in the more recent NHANES III study, HCV infection was not associated with any of the dietary components that we investigated; hence, HCV infection is unlikely to be an important source of uncontrolled confounding. It is possible that our results are subject to misclassification because a 24-hour dietary recall may not reflect long-term dietary intake accurately. However, such inaccuracies in the assessment of dietary intake using a 24-hour dietary recall are expected to be random and to have no relation to the study's outcome, that is, the development of cirrhosis or liver cancer. It is well described that such random, nondifferential misclassification of exposure does not lead to spurious associations, but, rather, tends to reduce real associations toward the null.[23] Therefore, we believe that the associations that we describe between cholesterol, protein, and carbohydrate intake and the development of cirrhosis or liver cancer are likely to be true and the magnitude of these associations is likely to be even greater than what we report. Multiple studies have used the NHANES 24-hour dietary recall data to study the associations between baseline dietary factors and the subsequent development of disease or mortality as we did.[24-26] The quality of the NHANES 24-hour dietary recalls is considered very good because the National Center for Health Statistics employed specially trained, experienced interviewers who performed more than 20,000 24-hour dietary recalls as part of NHANES I.



Although we simultaneously adjusted for all the dietary components that we investigated, it is possible that these dietary components may be surrogate markers for the intake of other known or unknown nutrients that could have important effects on the liver, such as dietary antioxidants. We could not determine from the available 24-hour dietary recall data whether the protein intake that was associated with increased risk of cirrhosis-related death or hospitalization was animal protein or plant protein. The associations that we describe could occur if an underlying chronic liver disease were to influence taste, smell, and food preference before the development of cirrhosis. However, in the NHANES III study there was no association between the presence of a chronic liver disease (HCV infection) and dietary intake. Our study measures hospitalizations and deaths due to cirrhosis or liver cancer, not the actual incidence. Thus, patients with undiagnosed cirrhosis, or diagnosed cirrhosis that did not lead to hospitalization or death, were not captured.



At the same time, our study has some important strengths. Dietary intake was ascertained prospectively in a large, nationally representative sample of the U.S. population with 13 years of prospective follow-up (after excluding from analysis the first 5 years following entry into the study). Hospitalizations or deaths due to cirrhosis were ascertained prospectively by specially trained personnel without any knowledge of baseline dietary intake. Many determinants of liver disease progression are currently unknown, as evidenced by the fact that we cannot predict accurately which patients with any of the major liver diseases (HCV, HBV, NAFLD, and alcoholic liver disease) will progress to cirrhosis and which ones will have a relatively benign course. Our study raises the possibility that dietary factors may be important, modifiable, and hitherto unrecognized determinants of liver disease progression.



Patients and Methods



Study Design.



Data were derived from the first National Health and Nutrition Examination Survey (NHANES I) performed by the National Center for Health Statistics. NHANES I is a cross-sectional study of a nationwide probability sample from the civilian, noninstitutionalized population of the coterminous United States conducted between 1971-1975.[11] The survey included 14,407 participants aged 25-74 years who completed extensive dietary questionnaires and underwent physical examinations and laboratory investigations. The NHANES I Epidemiologic Follow-up Study (NHEFS)[12] sought to locate these 14,407 individuals in the years 1982-1984, 1986, 1987, and 1992 and collected data on specific health conditions that they developed in the intervening period through personal interviews, hospitalization records, and death certificates. We merged together NHANES I and NHEFS to form a nationally representative cohort of 14,407 persons with about 20 years of follow-up. We used the NHANES I-NHEFS cohort to determine whether dietary composition at baseline is associated with the subsequent incidence of death or hospitalization related to liver cancer or cirrhosis.



Study Population.



Among 14,407 NHANES I participants aged 25-74 years, 13,861 were successfully traced in at least one of the four follow-up occasions (that is 1982-1984, 1986, 1987, or 1992). In order to limit our analysis to incident cases of cirrhosis and liver cancer, we attempted to exclude participants who suffered from these conditions at the time of entry into the study. Specifically, we excluded participants who reported at baseline ever being told by a physician that they had jaundice (n = 886), hepatitis (n = 47), or a malignant tumor (n = 47), who had hepatomegaly or splenomegaly at baseline examination (n = 237), or whose level of serum albumin was less than 3 g/dL (n = 10). Serum bilirubin levels and platelet counts, which may be abnormal in advanced cirrhosis, were available only in a small minority of participants and therefore could not be used to identify participants with possible cirrhosis. Because cirrhosis and liver cancer may be present for a long time before they are clinically diagnosed, we also excluded participants who were diagnosed with these conditions within the first 5 years of follow-up, or who had less than 5 years of follow-up (n = 687). We excluded 46 participants with missing values in any of the following potential confounding variables included in our models: age, gender, race, alcohol consumption, body mass index (BMI), subscapular-to-triceps skinfold ratio, geographical location, and educational attainment. The 24-hour dietary recall questionnaire, as well as questions on diabetes and coffee consumption, were administered only to the subsample of NHANES participants recruited at locations 1-65. This subsample was designed so that it would still constitute a random sample of the U.S. population. An additional 2,680 NHANES I participants did not complete a 24-hour dietary recall questionnaire and did not answer questions on diabetes or coffee consumption because they were not recruited at locations 1-65, leaving 9221 participants in the current analyses.



Ascertainment of Baseline Dietary Intake.



A dietary interview was conducted by professional staff at entry into the study in 1971-1975, including a 24-hour dietary recall questionnaire. The 24-hour recall provides information on specific food items and their quantities ingested for all regular meals and between-meal foods or snacks consumed from midnight to midnight on the day preceding the interview. A Nutrient Composition Data Bank was then used to calculate the grams of protein, carbohydrate, and fat consumed during the 24-hour period. In addition, the 24-hour intake of the following specific fats was calculated: cholesterol, saturated fatty acids, oleic acid (a monounsaturated fatty acid), and linoleic acid (an n-6 PUFA). The estimated dietary intake of other lipids of interest such as n-3 PUFAs or n-6 PUFAs other than linoleic acid was not provided by the NHANES I investigators.



Hospitalizations and Deaths Due to Liver Cirrhosis or Liver Cancer During Follow-up.



Deaths and hospitalizations due to liver cirrhosis or liver cancer that occurred during follow-up were ascertained from hospitalization records and death certificates. Specially trained NHEFS personnel abstracted the diagnoses in these documents into International Classification of Diseases, 9th Revision (ICD-9) diagnosis codes. We used the ICD-9 code 155.0 for liver cancer and the following ICD-9 codes for cirrhosis: alcoholic cirrhosis 571.2; cirrhosis without mention of alcohol 571.5; pigmentary cirrhosis 275.0; esophageal varices 456.0-456.2; hepatic coma 572.2; portal hypertension 572.3; and hepatorenal syndrome 572.4. Esophageal varices, hepatic coma, portal hypertension, and hepatorenal syndrome have been included in the diagnosis of liver cirrhosis because the overwhelming majority of these conditions in the U.S. are the result of liver cirrhosis. If acute necrosis of the liver (ICD-9 code 570.0) was diagnosed together with hepatic coma or hepatorenal syndrome, then the person was considered not to have cirrhosis. Other complications of cirrhosis such as ascites or peritonitis have not been included as evidence of cirrhosis because they are commonly caused by other conditions. The date of the first hospital admission for each condition was used as the date of incidence. For subjects who had a death certificate recording one of these conditions but did not have a hospitalization for any of them, the date of death was used as the date of incidence. Henceforth we use the term incidence of cirrhosis or liver cancer for brevity, but what we have ascertained is the incidence of hospitalizations and deaths related to cirrhosis or liver cancer.



Ascertainment of Potential Confounding Variables.



We considered the following baseline characteristics, which may be associated with both dietary intake and development of cirrhosis or liver cancer as potential confounders: age; BMI; subscapular to triceps skinfold ratio (a measure of central as opposed to peripheral subcutaneous fat); race, categorized as white (n = 7644) and nonwhite (n = 1638, of whom 1545 were black and only 93 of other race, too small a number for additional racial categories); gender; alcohol consumption over the previous 12 months, categorized as none, >0 to <1 drink/day, 1 to <2 drinks/day, and >/=2 drinks/day; coffee or tea consumption categorized into <1, 1-2, and >2 cups/day; educational attainment, categorized as completion of high school or not; self-reported diabetes mellitus; and geographical area of residence in the U.S., categorized into Northeast, Midwest, South, and West.



Viral hepatitis B and C testing was not available in 1971-1974 when the NHANES I participants were recruited. We wanted to ensure that viral hepatitis C, an important cause of cirrhosis in the U.S., was not associated with the dietary consumption of carbohydrates, proteins, and fats (including cholesterol, saturated fatty acids, oleic acid, and linoleic acid) in order to exclude the possibility that viral hepatitis was an important source of unmeasured confounding in our NHANES I cohort. To do this, we used data from NHANES III, a cross-sectional study conducted between 1988-1994 that included measurements of viral hepatitis serologies.



Statistical Analysis.



The Cox proportional-hazards model[13] was used to determine the hazard ratio comparing persons within different quartiles of a dietary nutrient intake with respect to the risk for cirrhosis or liver cancer with or without adjusting for the potential confounders listed above. For each macronutrient we present results from two statistical models, corresponding to percent energy and absolute energy.[14] In percent energy models each macronutrient is modeled as the percent of total energy that it provides calculated as the number of calories from each macronutrient divided by the total number of calories consumed (for alcohol, models will use categorized drinks per day); total energy is included as a linear covariate, with or without adjusting for the potential confounders listed above. Percent energy models can be interpreted as the effect of substituting energy from each specific macronutrient for other macronutrients, thus keeping the total dietary energy intake constant. In absolute energy models, each macronutrient is modeled as the absolute energy that it provides, adjusted for the energy provided by each of the other macronutrients, with or without adjusting for potential confounders. Absolute energy models can be interpreted as increasing energy from a specific macronutrient while keeping the energy from each other macronutrient constant. All dietary components were categorized into quartiles and modeled either as dummy variables (where each quartile is compared to the lowest quartile) or as a single variable to give a test of trends for increasing quartile. The date 5 years from ascertainment of dietary intake was used as time zero for the Cox proportional-hazards models because any cases occurring within the first 5 years were excluded. We performed sensitivity analyses in which we varied the number of years following entry into the cohort that we excluded from analysis from 0 to 6 years.



We performed additional analyses limited to persons (n = 7032) who were hospitalized at least once or who died during follow-up, such that all had hospitalization records or death certificates available to look for the diagnosis of cirrhosis or liver cancer. We also determined whether dietary composition was independently associated with the number of hospitalizations during follow-up.



Due to the importance of obesity and alcohol consumption in liver disease, especially as causes of hepatic steatosis, we performed subgroup analyses stratifying persons into obese (BMI >25 kg/m2) or nonobese, and into persons with excessive alcohol consumption or not. Alcohol consumption was considered excessive in women who consumed 1, and in men who consumed 2 alcoholic drinks/day.[15][16]



Using the NHANES III cross-sectional data (1988-1994), we investigated whether there was an association between quartiles of dietary carbohydrate, protein, or fat intake and the presence of HCV infection, with or without adjusting for the confounders listed above by logistic regression. HCV infection was defined by the presence of HCV RNA.

Longer HAART Use Predicts Hepatitis B Clearance

Longer HAART Use Predicts Hepatitis B Clearance
By Michael Smith, North American Correspondent, MedPage Today
Published: July 15, 2009
Reviewed by Dori F. Zaleznik, MD; Associate Clinical Professor of Medicine, Harvard Medical School, Boston and
Dorothy Caputo, MA, RN, BC-ADM, CDE, Nurse Planner Earn CME/CE credit
for reading medical news



TORONTO, July 15 -- In patients with both HIV and hepatitis B, prolonged use of drugs active against both viruses improves the odds of clearing the hepatitis, researchers said.
Action Points

■Note that this study found that longer use of antiretrovirals that are also active against hepatitis B increased the odds of clearing the infection.
In a retrospective, longitudinal study, patients who were on such highly active antiretroviral therapy (HAART) for a longer period had nearly three times the likelihood of clearing the HBeAg antigen associated with active hepatitis B, according to Marina Núñez, MD, PhD, and a colleague at Wake Forest University School of Medicine in Winston-Salem, N.C.


Those patients also had a 54% improvement in the chance of clearing the so-called surface antigen -- HBsAg -- the researchers said in the May/June issue of HIV Clinical Trials.


In addition, the researchers found that patients with higher levels of alanine aminotransferase at baseline were at a higher risk of being diagnosed with cirrhosis within a few years.


"One of the most interesting findings was the confirmation that a simple marker, such as transaminase levels before treatment, is useful in identifying patients at higher risk of developing (hepatitis B-related) complications in a few years," Dr. Núñez said in a statement.


The researchers looked at medical records of 72 patients treated at Wake Forest University Baptist Medical Center between 1990 and 2008 who had both HIV and hepatitis B.


During follow-up, 64 (or 88.9%) of the patients had HAART containing drugs active against hepatitis B, including tenofovir (Viread), lamivudine (3TC), or emtricitabine (Emtriva).


Most patients took at least two active drugs during follow-up, but 11.1% took only one antiretroviral with hepatitis B activity.


Six out of 34 patients positive for HBeAg (or 17.6%) cleared the antigen, the researchers found. The only factor that was associated with HBeAg clearance was long use of the medications.


For those who cleared the antigen, the average use of antihepatitis medications was 4.0 years, compared with 1.7 for those who did not. The difference yielded an odds ratio of 2.66, with a 95% confidence interval from 1.15 to 6.16, which was significant at P=0.02.


And 5.5% of the patients cleared the HBsAg antigen. Again the only factor predicting clearance was longer use of hepatitis B-active HAART.


For those who cleared the antigen, average time on the drugs was 4.25 years, compared with 1.676 for the others, yielding an odds ratio of 1.54, with a 95% confidence interval from 1.02 to 2.31, which was significant at P=0.04.


Finally, higher alanine aminotransferase levels before HAART initiation were associated with the diagnosis of cirrhosis during follow-up -- the odds ratio was 1.02, with a 95% confidence interval from 1.002 to 1.03, which was significant at P=0.02.


The findings "stress the importance of good control of the HIV and (hepatitis B) infections," Dr. Núñez said.


In patients with elevated liver enzymes, "it is even more important to control the (hepatitis B) infection in an attempt to decrease the risks of complications," she said. "Those patients should also be more closely screened for liver complications."


The study had a number of limitations including its retrospective nature, small sample size, predominantly African-American male population, late diagnosis of HIV, indeterminant duration of hepatitis B infection, and radiologic rather than histologic diagnosis of cirrhosis.




The study was supported by the 2008 Medical Student Summer Research Training Program, supported through grants from the NIH Health, Wake Forest University School of Medicine Departments, Centers, and Institutes, and private gifts.
The researchers made no disclosures.



Primary source: HIV Clinical Trials
Source reference:
Lee, T Núñez, M "Longer duration of HBV-active antiretroviral therapy is linked to favorable virological outcome in HIV-HBV co-infected patients" HIV Clin Trials 2009; 10 (3).

A Study of Telaprevir Combined with Peginterferon in Non-Responders

A Study of Telaprevir Combined with Peginterferon Alfa-2a and Ribavirin in Patients with Well-documented Non-response or Relapse After Previous Peginterferon Alfa-2a and Ribavirin Treatment: Interim Analysis



Reported by Jules Levin
59th Annual Meeting of the American Association for the Study of Liver Diseases, San Francisco, CA, USA, October 31-November 4 2008

Mitchell L Shiffman,1 Thomas Berg,2 Fred Poordad,3 Jean-Pierre Bronowicki,4 Andrew J Muir,5 Stuart C Gordon,6 Shelley George,7 Nathalie Adda,7 John G McHutchison5 1Virginia Commonwealth University Medical Center, Richmond, VA, USA; 2Charite Virchow Klinikum, Berlin, Germany; 3Cedars-Sinai Medical Center, Los Angeles, CA, USA; 4CHU Nancy, Vandoeuvre-les-Nancy, France; 5Duke Clinical Research Institute and Duke University, Durham, NC, USA; 6Henry Ford Hospital, Detroit, MI, USA; 7Vertex Pharmaceuticals Inc., Cambridge, MA, USA

Author Conclusions
In this interim analysis of telaprevir-based treatment in HCV genotype 1-infected patients with well-characterized null response, partial response or relapse to prior Peg-IFN plus RBV treatment:
-- 65% were HCV RNA <10 IU/mL at Week 4
-- 68% were HCV RNA <10 IU/mL at Week 12
-- 59% were HCV RNA <10 IU/mL at Week 24.
(From Jules: At week 24, 43% of null-responders (n=42) achieved undetectable HCV viral load, 82% of partial responders did also (n=22), and 71% of relapsers (n=7) did as well. See tables in this article below)

As of the data cut-off point, incidence of viral breakthrough through Week 24 was:
-- prior relapser = 0 patients, prior viral breakthrough = 1 patient, prior partial responder = 2 patients (6%), null responder = 10 patients (20%) (5 patients within the first 4 weeks).

The safety profile was consistent with that previously described in the PROVE trials. Four subjects discontinued due to rash, and one due to anemia.

Continuing follow-up of these patients will be required to evaluate the ultimate clinical significance of these promising early findings.

A Phase 3 study in patients who previously failed Peg-IFN and RBV (REALIZE) is ongoing.

Introduction

Many hepatitis C virus (HCV) genotype 1 patients do not achieve sustained virologic response (SVR) after a 48-week regimen of peginterferon alfa-2a/2b (Peg-IFN, P) and ribavirin (RBV, R).1-3

Retreatment of prior PR non-responders (null and partial responders) and relapsers with PR achieved SVR rates of less than 10% and 40%, respectively.4-7

Telaprevir (TVR, VX-950) is a specifically targeted antiviral therapy for HCV (STAT-C) that potently and selectively inhibits the HCV NS3-4A protease.8

This is an ongoing, open-label study of TVR combined with Peg-IFN and RBV (T/PR) in patients with HCV genotype 1 infection who did not achieve SVR in PR control arms of the Phase 2 PROVE (investigation of HCV PROtease inhibition for Viral Evaluation) studies.

Methods

Primary objectives:
-- Provide access to TVR-based treatment to patients enrolled in the Peg-IFN alfa-2a plus RBV control groups of VX05-950-104 (Study 104, PROVE1), VX05-950-104EU (Study 104EU, PROVE2) and VX06-950-106 (Study 106, PROVE3) who stopped treatment due to inadequate response to treatment, or who relapsed after treatment
-- Demonstrate the efficacy of T/PR in well characterized, HCV genotype 1-infected patients who did not achieve SVR with prior Peg-IFN and RBV treatment
-- Evaluate the safety of T/PR in these patients.

Secondary objectives:
-- Perform intrapatient comparisons of antiviral response to T/PR with the antiviral response to prior PR treatment
-- Determine the antiviral response to T/PR in patients characterized as null responders, partial responders, having virologic breakthrough, or relapsers during prior PR treatment in PROVE1, PROVE2 and PROVE3.

Study 107 Design

Open-label treatment of patients from control arms of PROVE1, PROVE2 and PROVE3 who met either on-treatment criteria for non-response or who relapsed after completion of 48 weeks of Peg-IFN + RBV (Figure 1).

Patients who discontinued therapy because of adverse events (AEs) in the PROVE studies were not eligible for inclusion.

Stopping rule criteria in Study 107 is shown in Table 1.


Methods

Preliminary Analysis
This pre-planned preliminary analysis included all enrolled patients who received at least one dose of study regimen and who completed at least the Week 4 assessment up to the data cut-off point.




Virologic Responses

This preliminary analysis is based on the patients who reached at least Week 4 assessment (intent-to-treat [ITT] analysis; Table 5).

Table 5. Week 4 HCV RNA by Prior Response to Control Peg-IFN + RBV Arm in the PROVE Studies (ITT Analysis).
From Jules: 75% of null-responders (36/48) had <25 IU/mL at week 4; 97% of partial responders ((32/33) had <25 IU/mL at week 4; 100% of relapsers (22/22) had undetectable at week 4.




Table 6 shows the virologic responses obtained by prior response to control Peg-IFN + RBV arm in the PROVE studies at Week 12 (ITT analysis).

Table 6. Week 12 HCV RNA by Prior Response to Control Peg-IFN + RBV arm in the PROVE Studies (ITT Analysis).
From Jules: 58% of null-responders (28/48) had <10 IU/ml (undetectable viral oad) at week 12 79% of partial responders had <10 Iu/mL at week 12; 73% of relapsers (16/22) had <10 Iu/mL at week 12.


Figure 3 shows the proportion of patients achieving undetectable HCV RNA through Week 24 (modified ITT)
-- Includes only in the denominator by visit, patients who have either reached that visit, or discontinued before, or were detectable. All patients who were still on treatment but haven't yet reached the designated visit are not counted in the denominator.

Figure 3. Proportion of Patients Achieving Undetectable HCV RNA Through Week 24 by Prior Response to Peg-IFN + RBV Arm in the PROVE Studies (Modified ITT Analysis).
From Jules: At week 24, 43% of null-responders (n=42) achieved undetectable HCV viral load, 82% of partial responders did also (n=22), and 71% of relapsers (n=7) did as well.


Figure 4 shows the proportion of patients with virologic breakthrough following T/PR treatment.
-- No virologic breakthrough was observed in patients who previously relapsed in the PROVE studies (on control Peg-IFN + RBV arm).

Figure 4. Cumulative Virologic Breakthrough* Following T/PR Treatment According to Prior Response to Control Peg-IFN + RBV Arm in the PROVE Studies. From Jules: Null-responders had the most virologic breakthroughs: 12% (n=6) at week 8, and 20% (n=10) at week 24. Partial responders had very low breakthrough rates, 6% at week 24 (n=2).




Viral curves through Week 24 are shown in Figures 5a-c.

Figure 5. Viral curves through Week 24 for A) Null Responders, B) Partial Responders and C) Relapsers.
From Jules: I expect null-responders would do well with 2 oral drugs on board, as you can see in the graph on the right in Study 107 when receiving telaprevir patients had a good initial decline in viral load but some patients started to rebound, so with 2 oral drugs on board I they would respond well and not rebound. Roche is just starting the first study of 2 oral drugs now, with R7128+ITMN191. But this first study is an initial study.




Safety and Tolerability

The types of AEs encountered were those that are expected with Peg-IFN + RBV, and are consistent with those previously reported in patients treated with TVR-based regimens in the PROVE studies (Table 7).


REFERENCES

1. Manns MP, et al. Lancet 2001;358:958-65.
2. Fried MW, et al. N Engl J Med 2002;347:975-82.
3. Hadziyannis SJ, et al. Ann Intern Med 2004;140:346-55.
4. Shiffman ML. Hepatology 2002;36:S128-34.
5. Shiffman ML, et al. Gastroenterology 2004;126:1015-23.
6. Ahmed F, et al. Gastroenterol Clin North Am 2004;33:513-26.
7. Poynard T, et al. 43rd EASL 2008, Milan, Italy, April 23-27 2008.
8. Lin K, et al. Antimicrob Agents Chemother 2004;40:4784-92.

Hepatitis C Virus Infection and the Risk of Coronary Disease

Hepatitis C Virus Infection and the Risk of Coronary Disease



- "HCV-infected persons are younger and have lower lipid levels and a lower prevalence of hypertension. Despite a favorable risk profile, HCV infection is associated with a higher risk of CAD after adjustment for traditional risk factors."

"To summarize, the increased risk of CAD in HCV-infected persons may be related to a differential level of cytokines, which are markers of inflammation, thrombosis, and endothelial dysfunction [33-35, 37]; behavioral and social risk profile [42-44]; malnutrition and/or inflammation pathway activation [36]; or liver injury. More likely, a combination of these factors acts in concert to negate the protective effect of a favorable risk profile and increases the overall risk of CAD.

In conclusion, in a comparison of HCV-infected subjects with HCV-uninfected control subjects, HCV infection is associated with a higher risk of CAD, even after adjustment for traditional risk factors. The reason(s) and mechanism(s) of this association need further study."

Clinical Infectious Diseases July 15 2009;49:225-232

Adeel A. Butt,1,2,3 Wang Xiaoqiang,2,3 Matthew Budoff,5 David Leaf,6,7 Lewis H. Kuller,4 and Amy C. Justice8,9

1University of Pittsburgh School of Medicine, 2Center for Health Equity Research and Promotion, 3VA Pittsburgh Healthcare System, and 4Department of Epidemiology, University of Pittsburgh Graduate School of Public Health, Pittsburgh, Pennsylvania; 5Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center, 6VA Greater Los Angeles Healthcare System, and 7David Geffen School of Medicine at UCLA, Los Angeles, California; and 8VA Connecticut Healthcare System, West Haven, and 9Yale University School of Medicine and Public Health, New Haven, Connecticut

Background. The association between hepatitis C virus (HCV) infection and coronary artery disease (CAD) is controversial. We conducted this study to determine and quantify this association.

Methods. We used an established, national, observational cohort of all HCV-infected veterans receiving care at all Veterans Affairs facilities, the Electronically Retrieved Cohort of HCV Infected Veterans, to identify HCV-infected subjects and HCV-uninfected control subjects. We used the Cox proportional-hazards model to determine the risk of CAD among HCV-infected subjects and control subjects.

Results. We identified 82,083 HCV-infected and 89,582 HCV-uninfected subjects. HCV-infected subjects were less likely to have hypertension, hyperlipidemia, and diabetes but were more likely to abuse alcohol and drugs and to have renal failure and anemia. HCV-infected subjects had lower mean (u: standard deviation) total plasma cholesterol (175 u: 40.8 mg/dL vs. 198 u: 41.0 mg/dL), low-density lipoprotein cholesterol (102 u: 36.8 mg/dL vs. 119 u: 38.2 mg/dL), and triglyceride (144 u: 119 mg/dL vs. 179 u: 151 mg/dL) levels, compared with HCV-uninfected subjects (p<.001 for all comparisons). In multivariable analysis, HCV infection was associated with a higher risk of CAD (hazard ratio, 1.25; 95% confidence interval, 1.20-1.30). Traditional risk factors (age, hypertension, chronic obstructive pulmonary disease, diabetes, and hyperlipidemia) were associated with a higher risk of CAD in both groups, whereas minority race and female sex were associated with a lower risk of CAD.

Conclusions. HCV-infected persons are younger and have lower lipid levels and a lower prevalence of hypertension. Despite a favorable risk profile, HCV infection is associated with a higher risk of CAD after adjustment for traditional risk factors.

Several infectious etiologies for coronary artery disease (CAD) have been proposed in recent years on the basis of epidemiological associations, but there is no consensus regarding a causative role [1-3]. The association between hepatitis C virus (HCV) infection and CAD is less clear. A small number of reported studies have shown conflicting results; some have reported no association between HCV infection and CAD [4-7], whereas others have reported an increased risk [8] or an increase in measures of subclinical atherosclerosis (e.g., carotid intima-media thickness) [9-11]. Many of the studies showing no association between HCV infection and CAD used a case-control design in which subjects with known CAD were compared with control subjects without CAD and the prevalence of HCV infection was compared between the 2 groups without adjustment for all CAD risk factors.

Persons with HCV infection are at an increased risk of developing hepatic steatosis, which shares many clinical features with the metabolic syndrome [12, 13]. Hepatic steatosis has also been associated with elevated levels of markers of inflammation and endothelial dysfunction [14]. These factors suggest a biologically plausible mechanism of increased risk of CAD in at least a subset of HCV-infected persons. We set out to determine the association between HCV infection and CAD in a large, national, electronically retrieved cohort of HCV-infected veterans (ERCHIVES). Such large observational studies with carefully identified controls are better suited to identify any true association between HCV infection and cardiovascular disease.

Discussion

To our knowledge, this is the largest study to determine the role of HCV infection in the risk of CAD. We found that HCV-infected subjects were at a significantly higher risk of developing CAD, compared with HCV-uninfected subjects, even after adjustment for traditional risk factors for cardiovascular disease. The reason for the increased risk is unclear, especially because several cardiovascular risk factors were less prevalent in the HCV-infected subjects. For example, HCV-infected subjects were younger; had lower total cholesterol, LDL-C, and triglyceride levels; and had a lower prevalence of hypertension. Because the risk of CAD was higher after adjustment for the traditional risk factors, HCV infection itself or other unknown factors are at least partly responsible for the increased risk.

Recent studies support the role of inflammation in the pathogenesis of CAD [29-32]. According to these studies, a complex balance between proinflammatory and anti-inflammatory cytokines dictates the initiation, propagation, and rupture of atherosclerotic lesions. Some studies have shown that the levels of inflammatory markers (e.g., high sensitivity C-reactive protein, interleukin 6, and tumor necrosis factor α) are higher in HCV-infected subjects, compared with HCV-uninfected control subjects [33-35]. Since inflammation and thrombosis are critical pathways in the genesis of CAD and since HCV infection is also associated with alterations in inflammatory markers, this might be the common pathway that increases CAD risk. Markers of thrombosis and inflammation have also been associated with more-severe CAD, and the malnutrition inflammation scores are elevated in HCV-infected persons with CAD, compared with those without CAD [36, 37]. Most studies have shown an increased prevalence of diabetes among HCV-infected persons, which is a major cardiovascular risk factor. Although we did not find an increased prevalence of diabetes among the HCV-infected persons in the current study, we did not adjust for body mass index in the 2 groups. In our previous work, we found that HCV-infected persons have a lower body mass index, compared with HCV-uninfected persons (authors' unpublished data), which could at least partly explain this finding. Another possibility is that HCV-infected persons are seen less frequently for care and are less likely to receive a diagnosis of diabetes. In fact, nonadherence to follow-up visits was the most common reason that HCV-infected people were not prescribed treatment for HCV infection in one study [38]. Although diabetes was not more prevalent among the HCV-infected group in our study, when present, it was associated with a significantly higher risk of CAD in both groups.

The proportion of subjects with evidence of liver injury was higher among the HCV-infected persons. This finding is intuitive and confirms multiple previous studies. Liver injury was associated with an increased risk of CAD, but this risk was contributed to by the HCV-uninfected subjects and was not significant for the HCV-infected subjects. Furthermore, the lack of association between HCV infection and CAD in the subset of persons with liver injury (in the absence of a diagnosis of alcohol abuse or dependence) suggests a role for liver injury in determining the risk of CAD.

Our finding of lower lipid levels in the HCV-infected persons is consistent with previous studies [39-41]. Postulated mechanisms for lower lipid levels in HCV-infected persons include binding of HCV particles to various lipid fractions, impaired hepatocyte assembly of very-low-density lipoprotein because of inhibition of microsomal transfer protein, and entry of HCV into hepatocytes through the LDL-C receptors [39]. Although the lipid levels were lower in the HCV-infected subjects, the risk of CAD associated with hyperlipidemia was similar in the HCV-infected and -uninfected subjects.

Other traditional risk factors (e.g., age, male sex, hypertension, COPD [a surrogate for heavy smoking], and diabetes) were associated with a higher risk of CAD in both HCV-infected and -uninfected groups, as shown in other studies. Unanticipated was the association of black race with a lower risk of CAD. Numerous studies indicate that minority race is associated with a higher risk of cardiovascular risk factors (e.g., hypertension and diabetes), but this did not translate into a higher risk of CAD in our study. Whether the lower risk of CAD found in our study is related to access-to-care issues or other factors needs further study. The finding of a positive association between drug abuse or dependence and CAD in the HCV-infected persons is an interesting finding. Cocaine use has been well established as a risk factor for acute myocardial infarction in persons with and without preexisting coronary disease [42]. Although coronary vasospasm has been implicated as the most likely mechanism, arrhythmias and increased atherosclerosis due to adventitial mast cells have also been proposed to effect such risk [43, 44]. Whether our observation is associated with such behavioral risk factors is unclear at this time.

There are many strengths to our study. We studied a large national population, rather than a geographically limited sample. The VA health care system is a unique population that offers significant advantages for large studies of outcomes. Foremost is the availability of data at centralized centers, from which appropriate clinical, laboratory, pharmacy, and outcome parameters can be retrieved. The VA is the largest single provider of comprehensive health care to HCV-infected persons in the United States. Its extensive electronic medical information-gathering system is linked nationally and provides unparalleled opportunity for longitudinal follow-up of patients. The patients at the VA medical centers are cared for regardless of their ability to pay. Patients may relocate multiple times and will still be cared for by the same system, with health care providers having access to patient information from other sites.

A limitation of our study is the use of ICD-9 codes for the diagnosis of CAD. Although it would be ideal to use adjudicated clinical measures for the diagnosis of CAD, it would not be possible in such a large national study. ICD-9 codes have been used in other large national studies for cardiovascular outcomes. Another limitation is the lack of inclusion of body mass index and family history of CAD, which are important risk factors for CAD. Although we do not believe that family history of CAD may be different in HCV-infected and -uninfected persons, the former are more likely to have a lower body mass index. If true, the higher risk found in our study is actually an underestimation of the true risk. We used the diagnosis of COPD as a surrogate for heavy smoking status, because it is likely to pick up only a subset of smokers with the most severe consequences of smoking. It may be argued that persons who receive a diagnosis of an acute coronary event may not have presented to a VA facility for care and instead may have been taken to the nearest emergency facility. If true, this is likely to affect both HCV-infected and -uninfected persons equally.

To summarize, the increased risk of CAD in HCV-infected persons may be related to a differential level of cytokines, which are markers of inflammation, thrombosis, and endothelial dysfunction [33-35, 37]; behavioral and social risk profile [42-44]; malnutrition and/or inflammation pathway activation [36]; or liver injury. More likely, a combination of these factors acts in concert to negate the protective effect of a favorable risk profile and increases the overall risk of CAD.

In conclusion, in a comparison of HCV-infected subjects with HCV-uninfected control subjects, HCV infection is associated with a higher risk of CAD, even after adjustment for traditional risk factors. The reason(s) and mechanism(s) of this association need further study.

Results

Our final analysis set consisted of 171,665 subjects (82,083 HCV-infected and 89,582 HCV-uninfected subjects) (figure 2). HCV-infected subjects were less likely to have hypertension, hyperlipidemia, and diabetes but were more likely to abuse alcohol or drugs and to have renal failure and anemia, compared with HCV-uninfected control subjects (table 1). Mean plasma levels of total cholesterol, LDL-C, and triglycerides were significantly lower in the HCV-infected subjects, compared with HCV-uninfected subjects.

In univariable analysis, factors associated with a higher risk of CAD in the whole group were increasing age, hypertension, COPD, diabetes, hyperlipidemia, renal failure, and anemia. Female sex and Hispanic race were associated with a lower risk of CAD. When we analyzed HCV-infected and -uninfected subjects separately, the same factors were associated with risk of CAD, except that black race was associated with a higher risk in the HCV-infected group, and drug abuse or dependence was associated with a lower risk of CAD in the HCV-uninfected group. The magnitude of effect for hypertension, COPD, and renal failure was slightly greater in the HCV-infected group than in the HCV-uninfected group (table 2).

In multivariable Cox regression analysis of the whole group, HCV infection was associated with a higher risk of CAD (hazard ratio, 1.27; 95% confidence interval [CI], 1.22-1.31). As in the univariable model, traditional risk factors (increasing age, hypertension, COPD, diabetes, hyperlipidemia, and renal failure) were associated with a higher risk of CAD, whereas minority race and female sex were associated with a lower risk of CAD. When we analyzed HCV-infected and -uninfected subjects separately, the same factors were associated with the risk of CAD. Drug abuse or dependence was associated with a higher risk of CAD in the HCV-infected group but not in the HCV-uninfected group (table 3). In Kaplan-Meier analysis, HCV-infected subjects had a higher risk of CAD after adjustment for traditional risk factors (age, race, sex, hypertension, diabetes, hyperlipidemia, and COPD) (figure 3).

We determined the number of inpatient and outpatient visits to any VA facility for subjects with and without a diagnosis of incident CAD, and we compared the number of visits in the years before and the years after the CAD diagnosis to determine whether there may be a bias in seeking care at a VA facility versus a non-VA facility. For this analysis, we excluded visits to outpatient mental health facilities, group therapy, and substance abuse clinics, as well as laboratory visits and visits related to hemodialysis. The median number of visits before CAD diagnosis among subjects who later developed CAD was 7, compared with 5 visits among subjects who never developed CAD. In years after the CAD diagnosis, the median number of visits was 13.5 among those with CAD and 7 among those without CAD, which suggests that a high proportion of veterans seek care from VA facilities after a diagnosis of coronary events.

To determine the role of liver injury in the risk of CAD among HCV-infected and -uninfected subjects, we computed the risk of liver injury in the hazards of CAD in the Cox proportional-hazards model. The overall hazard ratio was 1.09 (95% CI, 1.05-1.14); for HCV-infected and -uninfected groups, the hazard ratios were 1.05 (95% CI, 0.80-1.06) and 1.15 (95% CI, 1.09-1.22), respectively. We conducted further analyses limited to those subjects who had evidence of liver injury in the absence of a diagnosis of alcohol abuse or dependence. In multivariable Cox proportional-hazards analysis, HCV infection was not associated with a higher risk of CAD (hazard ratio, 0.99; 95% CI, 0.93-1.06). All other associations (age, sex, hypertension, COPD, diabetes, dyslipidemia, renal failure, and anemia) remained significant as in the previous models.

Methods

The creation of ERCHIVES has been described elsewhere [15-18]. The current study used an updated cohort of subjects identified from 2001 through 2006. In brief, we assembled a national cohort of HCV-infected veterans from the VA National Patient Care Database, the VA Pharmacy Benefits Management database, and the Decisions Support System database in VA fiscal years 2001-2006 (1 October 2001 through 30 September 2006; the original cohort included subjects identified in 1998-2003) (figure 1). Demographic and clinical data were extracted from the National Patient Care Database. The utility and accuracy of the VA administrative data and VA Pharmacy Benefits Management data have been previously reported by our group and others [17, 19-24]. The National Patient Care Database contains hospitalization records, including discharge diagnoses from 1970 onward. The discharge diagnoses are coded according to the International Classification of Diseases, 9th Revision (ICD-9) For 1997 onward, the National Patient Care Database also contains outpatient visit records, including diagnoses and clinic visits. The validity of ICD-9 codes has been tested previously for a range of comorbid conditions, and the sensitivity, specificity, and agreement (κ values) have been found to correlate well with chart abstractions [20, 23, 25, 26].

The laboratory values were retrieved from the Decisions Support System database, which contains selected laboratory data collected from 2000 onward during routine clinical care of veterans. The laboratory data included measurements of HCV antibody, total cholesterol, low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), triglyceride, hemoglobin, alanine and aspartate aminotransferase, serum albumin, bilirubin, international normalization ratio, and glucose levels. To validate the Decisions Support System data, we compared data collected in the Decisions Support System and the Immunology Case Registry for 22,647 human immunodeficiency virus (HIV)-infected veterans with an inpatient or outpatient visit in fiscal year 2002 for 9 laboratory tests. For 6 of the 9 laboratory tests, the Decisions Support System provided laboratory values for more individuals. Overlapping results were nearly perfectly correlated [27].

For our study, HCV infection was defined by the presence of HCV antibody or a positive result of qualitative or quantitative testing for HCV RNA. CAD was defined by the presence of at least 1 inpatient or 2 outpatient ICD-9 codes for myocardial infarction or congestive heart failure or any code for coronary artery bypass grafting or percutaneous transluminal coronary angioplasty. Dyslipidemia was defined by the presence of any of the following: (1) total cholesterol level >200 mg/dL on 2 separate occasions, (2) total cholesterol level >200 mg/dL on 1 occasion and LDL-C level >130 mg/dL on 1 occasion, and (3) prescription of cholesterol-lowering medication for >30 days. Subjects were considered to have diabetes if they met any of the following criteria: (1) glucose level 200 mg/dL on 2 separate occasions; (2) ICD-9 codes (2 outpatient or 1 inpatient) and treatment with an oral hypoglycemic or insulin for 30 days; (3) ICD-9 codes (2 outpatient or 1 inpatient) and glucose level 126 mg/dL on 2 separate occasions; and (4) glucose level 200 mg/dL on 1 occasion and treatment with an oral hypoglycemic or insulin for 30 days. We compared our definition with the presence of at least 1 inpatient or at least 2 outpatient codes for diabetes. Our definition had a sensitivity of 86.6%, specificity of 97.5%, and agreement of 95.5%, with a κ value of 0.85, suggesting a very high degree of correlation. Renal failure was defined by an estimated glomerular filtration rate <30 mL/min/1.73 m2, as calculated by the simplified modification of diet in renal disease (i.e., MDRD) equation. Liver injury was defined by alanine or aspartate aminotransferase levels above the upper limit of normal. Because the diagnostic codes for smoking have been found to be inaccurate (A. Justice, personal communication), we used the diagnosis of chronic obstructive pulmonary disease (COPD) as a surrogate for heavy smoking. The number of pack years of smoking has been demonstrated to correlate with a diagnosis of COPD in HIV-infected and -uninfected persons among veterans [28].

Case patients were all HCV-infected subjects initially identified in the ERCHIVES on the basis of a positive result of an HCV antibody test or a positive result of an HCV RNA test performed during routine clinical care. Control subjects were matched by age (in 5-year increments), sex, race, and year of entry into care in the VA health care system. We retained subjects with complete clinical and laboratory data and excluded subjects who were coinfected with HIV. We also excluded subjects who had a diagnosis of CAD at baseline. We analyzed all subjects with complete data, as well as HCV-infected subjects and their corresponding individually matched HCV-uninfected control subjects with complete data for our analysis (figure 1).

Baseline characteristics were compared using the χ:2 test or the t test as appropriate. Predictors of incident CAD were determined in univariable and multivariable Cox regression analyses. Unadjusted and adjusted Kaplan-Meier plots were drawn to plot the hazards of developing CAD over time. We used Stata, version 8.2 (Stata Corp), for statistical analyses.

To determine whether the exclusion of any subjects may have led to a bias in our analysis, we compared the subjects who were excluded with those who were retained in the final analysis. We also compared the characteristics of subjects who were excluded because of a prevalent diagnosis of CAD at entry into the cohort. Finally, we determined the number of inpatient and outpatient visits for HCV-infected and -uninfected subjects, as well as for those with and without CAD, to indirectly analyze any diagnosis bias due to care outside the VA health care system.