.jpg)
Hepatocellular Carcinoma --- United States, 2001--2006 Weekly
May 7, 2010 / 59(17);517-520
Hepatocellular Carcinoma --- United States, 2001-2006
LINK to this URL:
http://www.cdc.gov/mmwr/preview/mmwrhtml/mm5917a3.htm
"Chronic HBV and HCV infections that persist for decades are major risk factors for HCC. Both infections cause chronic inflammation that can progress to fibrosis, cirrhosis, and eventually malignancy (3). HBV infection also can be directly oncogenic (3). In addition, alcohol consumption, steatohepatitis, and type II diabetes have been linked to HCC (2); these risk factors for HCC amplify the effects of viral hepatitis but also might cause HCC in the absence of viral hepatitis (2).....Asians/Pacific Islanders, black adult males, and persons living in the United States who were born in regions where HBV is endemic (e.g., Asia and sub-Saharan Africa) have high rates of both HBV infection and HCC"
"The results demonstrate a continuation of long-term increases in HCC incidence and persistent HCC racial/ethnic disparities. Development of viral hepatitis services, including screening with care referral for persons chronically infected with HBV or HCV, full implementation of vaccine-based strategies to eliminate hepatitis B, and improved public health surveillance are needed to help reverse the trend in HCC.....Overall, the HCC rate increased from 2.7 per 100,000 persons in 2001 to 3.2 in 2006, with an APC of 3.5%. The median age for diagnosis of HCC was 64 years overall, 62 years for males, and 69 years for females. The highest incidence rate was among persons aged 70--79 years (13.7), followed by persons aged ³80 years (10.0), 60--69 years (9.6), 50--59 years (6.8), and 40--49 years (2.1)....The incidence rate for males (5.0 per 100,000 persons) was approximately three times higher than the rate for females (1.3).....The HCC incidence rate was highest among Asians/Pacific Islanders (7.8 per 100,000 persons), followed by blacks (4.2), American Indians/Alaska Natives (3.2), and whites (2.6). The incidence rate for Hispanics (5.7 per 100,000 persons) was higher than the rate for non-Hispanics (2.8). >From 2001 to 2006, the largest significant increases in HCC incidence rates were among whites (APC = 3.8), blacks (APC = 4.8), and persons aged 50--59 years (9.1). The HCC incidence rate did not increase among Asians/Pacific Islanders."
Liver cancer, primarily hepatocellular carcinoma (HCC), is the third leading cause of death from cancer worldwide and the ninth leading cause of cancer deaths in the United States (1,2). Chronic hepatitis B virus (HBV) and hepatitis C virus (HCV) infections account for an estimated 78% of global HCC cases (3). To determine trends in HCC incidence in the United States, CDC analyzed data for the period 2001--2006 (the most recent data available) from CDC's National Program of Cancer Registries (NPCR) and the National Cancer Institute's Surveillance, Epidemiology, and End Results (SEER) surveillance system. This report summarizes the results of that analysis, which determined that the average annual incidence rate of HCC for 2001--2006 was 3.0 per 100,000 persons and increased significantly from 2.7 per 100,000 persons in 2001 to 3.2 in 2006, with an average annual percentage change in incidence rate (APC) of 3.5%. The largest increases in HCC incidence rates were among whites (APC = 3.8), blacks (APC = 4.8), and persons aged 50--59 years (APC = 9.1). Among states, HCC incidence rates varied widely, ranging from 1.4 per 100,000 in South Dakota to 5.5 in Hawaii. The results demonstrate a continuation of long-term increases in HCC incidence and persistent HCC racial/ethnic disparities. Development of viral hepatitis services, including screening with care referral for persons chronically infected with HBV or HCV, full implementation of vaccine-based strategies to eliminate hepatitis B, and improved public health surveillance are needed to help reverse the trend in HCC.
CDC examined all HCC cases diagnosed during 2001--2006 and reported to NPCR or SEER from 45 cancer registries (covering 90.4% of the U.S. population) that met the criteria for data quality and completeness.* Only microscopically confirmed HCC cases (coded to the liver ICD-O-3 site code C22.0 with ICD-O-3 histology codes 8170--8175) were included. Incidence rates per 100,000 persons were age adjusted to the 2000 U.S. standard population. APCs were calculated using least squares regression. Statistical significance was determined at p<0.05. Data were analyzed by state, sex, race, ethnicity, and age group. Persons categorized as either non-Hispanic or Hispanic might be of any race.
During 2001--2006, a total of 48,596 HCC cases were reported, with an average annual incidence rate of 3.0 per 100,000 persons. Overall, the HCC rate increased from 2.7 per 100,000 persons in 2001 to 3.2 in 2006, with an APC of 3.5%. The median age for diagnosis of HCC was 64 years overall, 62 years for males, and 69 years for females. The highest incidence rate was among persons aged 70--79 years (13.7), followed by persons aged ³80 years (10.0), 60--69 years (9.6), 50--59 years (6.8), and 40--49 years (2.1) (Table 1).
The incidence rate for males (5.0 per 100,000 persons) was approximately three times higher than the rate for females (1.3) (Table 1). The HCC rate for males increased from 4.5 in 2001 to 5.4 in 2006, and the rate for females increased from 1.2 to 1.4 (Figure). During 2001--2006, the APC for males (3.6%) was significantly higher than the APC for females (2.3%) (Table 1).
The HCC incidence rate was highest among Asians/Pacific Islanders (7.8 per 100,000 persons), followed by blacks (4.2), American Indians/Alaska Natives (3.2), and whites (2.6). The incidence rate for Hispanics (5.7 per 100,000 persons) was higher than the rate for non-Hispanics (2.8) (Table 1). From 2001 to 2006, the largest significant increases in HCC incidence rates were among whites (APC = 3.8), blacks (APC = 4.8), and persons aged 50--59 years (9.1). The HCC incidence rate did not increase among Asians/Pacific Islanders (Table 1).
Among states, HCC incidence rates ranged from 1.4 per 100,000 persons in South Dakota to 5.5 in Hawaii. Eleven states had significant increases in incidence rates, with the highest APCs reported for Oklahoma (11.7), Iowa (9.0), and Georgia (7.4) (Table 2).
Reported by
S O'Connor, MD, JW Ward, MD, Div of Viral Hepatitis, National Center for HIV/AIDS, Viral Hepatitis, STD, and TB Prevention; M Watson, MPH, B Momin, MPH, LC Richardson, MD, Div of Cancer Prevention and Control, National Center for Chronic Disease Prevention and Health Promotion, CDC.
Editorial Note
This report provides the most recent population-based estimates of HCC incidence rates and trends in the United States and the first state-specific HCC trends. The findings indicate continued increases in HCC incidence, consistent with earlier reports using different methodology (2,4). However, requiring microscopic confirmation of HCC likely produced more conservative incidence rate estimates than analyses of NPCR/SEER data published previously (2,4).
Chronic HBV and HCV infections that persist for decades are major risk factors for HCC. Both infections cause chronic inflammation that can progress to fibrosis, cirrhosis, and eventually malignancy (3). HBV infection also can be directly oncogenic (3). In addition, alcohol consumption, steatohepatitis, and type II diabetes have been linked to HCC (2); these risk factors for HCC amplify the effects of viral hepatitis but also might cause HCC in the absence of viral hepatitis (2).
The age and race profile of persons with HCC reflects the demographic characteristics of persons with chronic viral hepatitis. During 2001--2006, HCC incidence was highest among Asians/Pacific Islanders, Hispanics (compared with non-Hispanics), blacks, persons aged ³50 years, and males. The largest increases occurred among whites, blacks, persons aged 50--59 years, and males. Rates were highest among persons born during 1946--1964 (who are now aged 46--64 years), particularly black males (3,4). In the absence of testing and care, the risk for HCC is expected to increase with aging of the cohort of persons with HCV infection (5).
Asians/Pacific Islanders, black adult males, and persons living in the United States who were born in regions where HBV is endemic (e.g., Asia and sub-Saharan Africa) have high rates of both HBV infection and HCC (2,5--8). As shown in this analysis, the rate of HCC did not increase among Asians/Pacific Islanders during 2001--2006. Some reasons for this might be early implementation of hepatitis B vaccination programs, changes in immigration patterns, and the impact of hepatitis B therapy on disease progression (3,4).
The findings in this report are subject to at least three limitations. First, misclassification of race and ethnicity in the registries and multiracial status of patients might underestimate HCC rates in certain populations. Second, although some states collect information on specific Asian subgroups, these data are not available at the national level; published reports from selected geographic areas suggest that certain ethnic Asian/Pacific Islander subgroups have greater risk for HCC than other Asian/Pacific Islander subgroups (3). Finally, cancer registries do not routinely collect information on etiologic factors for HCC, including chronic viral hepatitis.
Most cases of HCC are preventable. Prevention of HBV and HCV transmission and progression of chronic viral disease leads to declines in HCC incidence (9). However, new HBV and HCV infections continue to occur (6,7). Populations at greatest risk for new infection include children born to HBV-infected mothers and adults with sexual and drug use risk behaviors. Of the estimated 3.8--5.3 million persons living with chronic viral hepatitis in the United States, most are unaware of their infection (5). Early identification of viral hepatitis with referral to prevention and care services can decrease transmission to others. Treatment of viral hepatitis is cost-effective, and medical management can decrease morbidity (10).
In a recent report on prevention of hepatitis and liver cancer, the Institute of Medicine (IOM) called for a national comprehensive approach comprised of interventions to prevent HBV and HCV transmission and interventions to reduce the morbidity associated with chronic HBV and HCV infections (5). IOM recommends improved viral hepatitis surveillance, community education to address health disparities, support for vaccine-based strategies to eliminate HBV transmission, and development of prevention and health services that target key populations (i.e., drug users, foreign-born persons, and persons infected with human immunodeficiency virus), including screening for HBV and HCV infections linked to appropriate medical management.
Sunday, June 20, 2010
Efficacy of entecavir in treatment-naïve patients with hepatitis B virus-related decompensated cirrhosis
Efficacy of entecavir in treatment-naïve patients with hepatitis B virus-related decompensated cirrhosis
Articles in Press
Jnl of Hepatology Jan 2010
Ju Hyun Shim, Han Chu Lee, Kang Mo Kim, Young-Suk Lim, Young-Hwa Chung, Yung Sang Lee, Dong Jin Suh Department of Internal Medicine, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
Received 8 May 2009; received in revised form 31 July 2009; accepted 1 September 2009. published online 19 November 2009.
Corrected Proof
ABSTRACT
Background & Aims
The effect of entecavir (ETV) therapy on viral suppression and hepatic function in hepatitis B virus (HBV) patients with decompensated cirrhosis has not been established. We evaluated ETV as first-line monotherapy in these patients.
Methods
We consecutively enrolled 70 HBV-infected patients with decompensated cirrhosis primarily treated with 0.5mg/day ETV, and evaluated the clinical outcomes by intention-to-treat analyses. We also compared the virological responses of 55 patients treated for 12months (decompensated group) with those of 144 chronic hepatitis or compensated cirrhosis patients (compensated group).
Results
The cumulative transplantation-free survival was 87.1% at 1year. ETV treatment for 12months resulted in improved Child-Turcotte-Pugh (CTP) and model for end-stage liver disease (MELD) scores. Sixty-six percent (36/55) of patients achieved CTP class A and 49% (27/55) showed improvement in the CTP score of 2 points after 12months of ETV. The 1-year cumulative rates of HBV DNA negativity and HBeAg loss were 92.3% and 54.0%, respectively, by intention-to-treat analysis. The rates of HBV DNA negativity, HBeAg seroconversion/loss and ALT normalization at month 12 were similar for the decompensated and compensated groups. Cox regression analysis showed that pretreatment HBeAg seropositivity was a negative predictor of HBV DNA clearance during ETV therapy (hazard ratio, 0.514; 95% confidence interval 0.367-0.719; p<0.001).
Conclusions
One-year initial ETV therapy was similarly effective in both compensated and decompensated liver disease HBV patients. In addition, it improved underlying liver function in decompensated patients.
Introduction
Approximately 15-40% of hepatitis B virus (HBV) carriers are at increased risk of serious sequelae such as cirrhosis, hepatic decompensation and hepatocellular carcinoma (HCC) [1], [2]. In Korea, 5-7% of individuals within the general population are identified as HBV carriers [3], accounting for about 70% of liver cirrhosis and HCC cases [4]. The 5-year survival rate in decompensated cirrhosis patients is a low 14% compared with 84% for those with compensated cirrhosis [5].
A high viral load may be predictive of future progression to cirrhosis or HCC in HBV-infected patients [6], [7]. The oral antiviral drug lamivudine (LAM) slows deterioration in chronic hepatitis B (CHB) and advanced liver disease patients by delaying hepatic decompensation and HCC development [8]. However, LAM is no longer considered an optimal first-line therapy in CHB patients, owing to its higher resistance rate and lower potency compared to entecavir (ETV) and telbivudine [9], [10], [11], [12]. Latest recommendations suggest using ETV and tenofovir as primary oral agents irrespective of hepatitis B e antigen (HBeAg) serostatus [13].
ETV is considered an excellent treatment alternative for nucleos(t)ide-naïve patients due to insignificant resistance rates and strong antiviral effects [9], [12], and is thus widely prescribed. In recent 48-week trials of ETV treatment for CHB, 67% of HBeAg-positive and 90% of HBeAg-negative patients showed HBV DNA reduction to undetectable levels [9], [12], consistent with data obtained from patients with advanced liver fibrosis or compensated cirrhosis [14]. Furthermore, over 5years of treatment, the cumulative probability of development of mutations in the virus conferring genotypic resistance to ETV was only 1.2% in nucleos(t)ide-naïve patients [15]. Hence, early ETV therapy may halt disease progression more effectively in chronically infected patients compared with LAM.
At present, limited information is available on the impact of ETV therapy on viral suppression and hepatic function in CHB patients, particularly those with decompensated cirrhosis. In addition, the issue of when to use ETV as a first-line option in CHB therapy remains to be established.
In the present study, we evaluated the efficacy of ETV monotherapy in HBV-infected patients. We compared outcomes between decompensated cirrhosis patients and those with CHB or compensated cirrhosis. In addition, we investigated the effect of ETV therapy on hepatic function in patients with decompensated cirrhosis.
Patients and methods
Study population
From January 2007 to March 2008, 70 consecutive treatment-naive patients with HBV-related decompensated cirrhosis were orally treated with 0.5mg/day ETV alone at our institution. Of these patients, 6 (8.6%) died during the follow-up period, and all deaths were due to hepatic failure within 6months of ETV therapy (Fig. 1). Three patients (4.3%) underwent orthotopic liver transplantation (OLT) 3 or 4months after the commencement of ETV therapy. At the time of OLT, all three had intractable ascites and/or grade 3 or 4 hepatic encephalopathy, with model for end-stage liver disease (MELD) score 15. Six patients (8.6%) were lost to follow-up before evaluation at 12months, but were still alive. We analyzed clinical data from the remaining 55 patients with decompensated cirrhosis (decompensated group; Fig. 1), along with those from 144 consecutive patients with CHB or compensated cirrhosis (compensated group) who underwent 0.5mg/day ETV treatment for at least 12months during the same period. None of these patients had evidence of HCC at the time of initiation of ETV. CHB patients showing hepatic decompensation during acute exacerbation, defined as an elevation of alanine aminotransferase (ALT) activity to more than 10 times the upper limit of normal and more than twice the baseline value [16] were not included in the decompensated group. No patient had been previously administered antiviral therapy involving interferon-α or nucleos(t)ide analogs. All patients with or without HBeAg were persistently positive for hepatitis B surface antigen (HBsAg) for more than 6months, and contained serum HBV DNA levels of 4log10copies/ml or greater at baseline. Patients displaying antibodies against hepatitis C (anti-HCV) or human immunodeficiency virus (anti-HIV) or who had undergone liver or other organ transplants were excluded.
Decompensated liver disease was established based on a Child-Turcotte-Pugh (CTP) score7 (class B and C) or the presence of portal hypertension complications such as ascites, variceal bleeding or hepatic encephalopathy [17], [18]. Liver cirrhosis was diagnosed based on clinical, radiological, or histological assessments. The study was approved by the institutional review board of our hospital.
Laboratory and radiological testing
Baseline serological and imaging data such as ultrasonography (USG) or spiral computed tomography (CT) were obtained for all subjects. Serum hepatitis viral markers, including HBsAg, anti-HBs, HBeAg, anti-HBe, anti-HCV and anti-HIV, were confirmed using commercially available enzyme immunoassays (Abbott Laboratories, Chicago, IL). Serum HBV DNA levels were quantified using the Abbott Real-Time PCR assay (Abbott Laboratories, Chicago, IL) with a linear dynamic range of detection of 5.1x101-3.4x109copies/ml, according to the manufacturer's instructions. Other laboratory parameters were assayed using standard analytical procedures.
Follow-up studies
Compensated and decompensated groups were followed-up every 3-6months with tests for liver function, prothrombin time (PT), HBeAg, anti-HBe, and HBV DNA levels, in company with USG or spiral CT. Clinical examination and counseling regarding treatment adherence were performed for all patients at every clinic visit.
Statistical analysis
The two groups were compared using Student's t-test or Mann-Whitney test for continuous variables and chi-square or Fisher's exact test for categorized variables, where appropriate. Covariates with p-values<0.20 in univariate analysis were included in multivariate analysis using Cox proportional hazards models to determine whether pretreatment clinical and laboratory variables were significant in predicting HBV DNA clearance during ETV treatment. A p-value<0.05 was considered to indicate significance.
Results
Patient demographics
The baseline characteristics of the two study groups are shown in Table 1. The 199 total patients comprised 131 males and 68 females, and the gender ratio was similar for each group. The mean age was greater in the decompensated than the compensated group (52.6 vs. 46.8years, p<0.001). The two groups were similar in terms of serum HBV DNA levels. The mean serum ALT levels were lower in the decompensated group (101.9 vs. 156.5IU/L, p=0.021). The proportion of subjects positive for HBeAg was similar in both groups (49.1% vs. 62.5%, p=0.086). As anticipated, the decompensated group showed lower scores than the compensated group in terms of CTP and MELD scores, hepatic function (total bilirubin, albumin, PT) and platelet counts (p<0.001 for all). In the decompensated group, 31 (56.4%) patients had ascites, 7 (12.7%) had episodes of hepatic encephalopathy, and 13 (23.6%) experienced variceal bleeding. No patient in either group discontinued ETV during the study period.
The 70 patients with decompensated cirrhosis (Table 2) had a mean serum HBV DNA concentration at baseline of 7.18log10copies/ml and 34 (48.6%) patients were positive for HBeAg. All components of the CTP score, except for hepatic encephalopathy, were significantly poorer in the 9 patients (12.9%) who died or underwent OLT within 6months of ETV therapy than in the other 61 patients (87.1%) with decompensated cirrhosis (p<0.05 for all). These two subgroups, however, did not differ in serum HBV DNA or ALT levels, HBeAg serostatus, MELD score, or number of episodes of variceal bleeding.
Virological, serological, and biochemical responses
Viral and host responses to ETV therapy in the decompensated and compensated groups are presented in Table 3. Overall, ETV therapy over 12months resulted in a progressive decrease in serum HBV DNA levels (-5.52log10copies/ml at month 6, and -6.76log10copies/ml at month 12). The mean reductions in serum HBV DNA levels at months 6 and 12 did not differ significantly between the decompensated and compensated groups (Fig. 2). Undetectable serum HBV DNA levels were observed in 162 of the total 199 (81.4%) patients during the 12months of ETV therapy, and in each group a similar proportion of patients achieved undetectable viremia. Virological breakthrough (>1log10 increase in serum HBV DNA level from the nadir) was not noted in any patient throughout the follow-up period.
Of the 117 patients initially positive for HBeAg, 21 (17.9%) and 28 (23.9%) exhibited HBeAg seroconversion at months 6 and 12, respectively, with similar proportions being observed in both decompensated and compensated groups (18.5 vs. 17.8% at month 6, p=0.930; and 22.2 vs. 24.4% at month 12, p=0.812). This distribution was consistent with the HBeAg clearance rate (33.3 vs. 25.6% at month 6, p=0.427; and 48.1 vs. 41.1% at month 12, p=0.517). With regard to ALT response, the frequency of ALT normalization occurred uniformly at 12months of ETV therapy in both groups (76.4% vs. 75.0%, p=0.535). No differences were also observed in terms of the likelihood of HBV DNA suppression to undetectable levels and ALT normalization at 12months between the groups when stratified according to HBeAg serostatus (Table 4).
When all 70 patients with decompensated cirrhosis receiving ETV therapy were included in an intention-to-treat analysis of efficacy, the cumulative rates of HBV DNA negativity and HBeAg loss at 12months were 92.3% and 54.0%, respectively (Fig. 3A and B).
Pretreatment factors predicting HBV DNA negativity during ETV therapy
The overall 1-year cumulative rate of HBV DNA negativity was 84.4% in all 199 patients (Fig. 4A), i.e., 81.3% and 92.7% in the decompensated and compensated groups, respectively (p=0.099; Fig. 4B). During 12months of ETV therapy, the cumulative rate of HBV DNA negativity was significantly higher in HBeAg-negative than in HBeAg-positive patients (97.6% vs. 75.2%, p<0.001; Fig. 4C). Cox regression analysis with adjustment for baseline potential confounders (age, HBeAg status, serum HBV DNA levels, and categories of liver disease) showed that baseline HBeAg seropositivity was the only independent predictive factor adversely affecting HBV DNA negativity during ETV therapy (hazard ratio, 0.514; 95% confidence interval, 0.367-0.719, p<0.001; Table 5).
Changes in hepatic function after 12months of ETV therapy in the decompensated group
To evaluate the influence of ETV therapy on hepatic function reserve in the decompensated group, we measured the CTP score and its components (i.e., total bilirubin, albumin, and PT), along with MELD score and compared these values pre- and post-treatment (Fig. 5). For all 55 patients, the mean albumin (2.8 vs. 3.2g/dl), total bilirubin (3 vs. 1.9mg/dl), PT (16.3 vs. 13.9s), CTP score (8.1 vs. 6.6), and MELD score (11.1 vs. 8.8) improved after 12months of ETV treatment than at baseline (p<0.05 for all). Twenty-seven patients (49.1%) showed an improvement of >2 points in CTP score. Of the remaining 28 patients (50.9%), 9 achieved CTP class A with 1 point of improvement; 3 did not achieve CTP class A despite 1 point in improvement; 12 showed no change; and 4 experienced aggravation. Of the 27 patients who showed >2 point CTP score improvement, 15 (55.6%) improved within 3months and 20 (74.1%) improved within 6months of commencing ETV. As a result, 36 (65.5%) of the 55 patients achieved CTP class A (score 5 or 6) after 12months of ETV.
On-treatment outcomes of HCC occurrence and OLT-free survival in patients with decompensated cirrhosis
The 70 patients with decompensated cirrhosis had a cumulative incidence of HCC of 6.9% at month 24, with 4 patients developing HCC during the entire follow-up period (Fig. 6). In addition, the cumulative incidence of mortality or OLT was 12.9% at month 12 and 17.0% at month 24, respectively (Fig. 6), with 36.4% at month 24 in patients with CTP class C. After 6months of ETV therapy, only one patient in the decompensated group died of uncontrollable variceal bleeding and no patient received a liver transplant.
Discussion
The results presented here clearly confirm that first-line ETV monotherapy provides comparable overall antiviral benefits in HBV-infected patients with decompensated cirrhosis as has been shown in patients with chronic hepatitis or compensated cirrhosis, regardless of HBeAg serostatus. Moreover, ETV monotherapy improved hepatic function significantly, especially in patients with decompensated cirrhosis. Previous studies showed that LAM was also effective in viral suppression with no serious adverse effects in HBV-related decompensated cirrhosis and resulted in improved hepatic function and reduced morbidity [19], [20], [21], [22]. However, the antiviral effects of ETV in cirrhotic patients with hepatic decompensation in the clinical setting have not been established [13], [16], [23].
Using real-time PCR analysis, we found that 1year of ETV therapy resulted in HBV DNA levels that were undetectable in 81.5% of HBeAg-positive and 96.4% of HBeAg-negative patients with decompensated cirrhosis. These values are considerably better than other published rates in compensated CHB patients. These figures were achieved despite the lack of patients achieving undetectable HBV DNA at a wider detection limit of below 51copies/ml in our study using real-time PCR analysis compared with previous studies using commercial assays [9], [12]. Similar findings were observed regarding ALT normalization which occurred in 77.8% of HBeAg-positive and 75.0% of HBeAg-negative patients with decompensated cirrhosis. Interestingly, the proportions of compensated and decompensated patients showing ALT normalization at 12months were similar despite poorly matched pretreatment ALT levels. In general, patients with advanced liver disease often have relatively lower liver enzyme elevations despite a higher viral load compared to patients with well-compensated liver disease [23].
Notably, HBeAg seropositivity was an important predictor for suboptimal viral response to ETV treatment. The reasons underlying this finding remain to be established. This result is consistent with previous data showing that in terms of virological and biochemical responses, ETV therapy was more favorable for CHB patients negative for HBeAg than those positive for HBeAg, although not when compared head-to-head [9], [12], which may be conceivable since the long-term natural course is reported to be poorer in HBeAg-negative patients compared with HBeAg-positive patients [24], [25].
In contrast to similar outcomes in HBeAg seroconversion at 12months (23.9% vs. 21%), the overall rate of HBeAg loss in our study subjects was much higher than that reported in other study populations (46.8% vs. 22%) [9]. The high HBeAg rate of loss may reflect the lower HBeAg titer in Korean CHB patients. Indeed, a Korean study reported that 22% of HBeAg-positive patients had a mixed infection of precore mutant and wild-type [26]. In addition, our prior data showed that HBeAg seroconversion was 34% in patients with pretreatment serum ALT levels over twice the ULN, compared with 5% in those with pretreatment ALT levels less than twice the ULN [27]. In the present study, serum ALT values over twice ULN were identified in 63.8% of all patients.
Emerging data have revealed the positive effect of LAM therapy on the functional enhancement of underlying liver disease in patients with HBV-related decompensated cirrhosis and HCC, thus leading to improvements in the biochemical and clinical parameters of patients [19], [20], [28]. Similarly, the CTP and MELD scores, both of which reflect liver function, and their components, including serum albumin and total bilirubin levels as well as PT, dramatically improved during the period of ETV treatment in our patients with decompensated cirrhosis. All practice guidelines suggest that antiviral treatment should be considered in decompensated cirrhosis patients regardless of HBV DNA levels [13], [16], [23]. In HBV-infected patients with significant functional compromise, corresponding early intervention with ETV may possibly prevent clinical progression to hepatic failure, taper complication risk, and even delay or avoid OLT as a bridging therapy by substantially stabilizing the HBV status.
In Korea, living donor-OLT is currently performed in approximately 80% of the liver transplant because of a cadaveric organ shortage. Therefore, OLT is generally recommended for patients with CTP class C or a MELD score >15. We initially recommend OLT if the patients are under the above conditions, and start ETV therapy if a donor liver is not available. When donor livers become available, we reevaluate the patients' status and perform OLT if the patients are still in CTP class C or a MELD score >15. In our series, the 2-year OLT-free survival was 83%. There were six deaths and three liver transplants within 6months of starting ETV treatment. Of these, the three transplanted patients and three of the patients who died were evaluable for virological response at month 3, and all showed a marked decrease in serum HBV DNA to <103copies/ml. The early antiviral response to LAM at week 8 did not predict 6-month mortality in patients with decompensated CHB [29]. Although significant clinical improvement with ETV therapy was achieved most frequently within 6months of therapy, approximately 80% of early mortality or OLT in our population occurred within 4months of onset of ETV therapy. This observation is consistent with the previous LAM therapy data [19], [20], [22]. Given that patients who died or underwent OLT early in ETV treatment had significantly higher pretreatment CTP scores, OLT should not be delayed in patients with CTP class C or a MELD score >15 at baseline, or be urgently considered in patients displaying suboptimal improvement in hepatic reserves after 3months of ETV treatment.
Whereas the LAM studies of Yao and colleagues [19], [22] showed a dramatic decline in CTP scores of >3 points in more than 60% of patients, less than half of our patients showed significantly improved CTP scores (>2 points). These dissimilar results may reflect that decompensated patients with acute exacerbation of CHB were excluded from the present study in contrast to the previous studies [19], [22].
In the context of clinical antiviral resistance, virological breakthrough was not noted throughout our study period, although genotypic analysis of ETV-resistant HBV variants was not performed. A previous study on 17 Korean patients matched with ours for pretreatment characteristics found that 7 patients (41.2%) experienced virological breakthrough during approximately 2years of LAM treatment, including 6 (86%) with YMDD mutants [30].
The long-term efficacy of ETV in vivo is unclear at present. Since the potency and resistance rates of ETV outweigh those of LAM [9], [12], similar or better outcomes are expected. However, this requires confirmation in further studies.
In conclusion, the present study provides evidence that 1year of initial ETV treatment is comparably efficacious in arresting HBV replication and clearing HBeAg in HBV-infected patients with either compensated or decompensated liver disease. In addition, ETV markedly improved the underlying hepatic reserve in decompensated cirrhotic patients, mostly within 6months of treatment. Thus, our findings may establish a rationale for the use of ETV as a first-line monotherapeutic agent in these patients. Further ongoing follow-up investigations are necessary to obtain long-term data in conjunction with genotypic assays of ETV resistance.
Articles in Press
Jnl of Hepatology Jan 2010
Ju Hyun Shim, Han Chu Lee, Kang Mo Kim, Young-Suk Lim, Young-Hwa Chung, Yung Sang Lee, Dong Jin Suh Department of Internal Medicine, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
Received 8 May 2009; received in revised form 31 July 2009; accepted 1 September 2009. published online 19 November 2009.
Corrected Proof
ABSTRACT
Background & Aims
The effect of entecavir (ETV) therapy on viral suppression and hepatic function in hepatitis B virus (HBV) patients with decompensated cirrhosis has not been established. We evaluated ETV as first-line monotherapy in these patients.
Methods
We consecutively enrolled 70 HBV-infected patients with decompensated cirrhosis primarily treated with 0.5mg/day ETV, and evaluated the clinical outcomes by intention-to-treat analyses. We also compared the virological responses of 55 patients treated for 12months (decompensated group) with those of 144 chronic hepatitis or compensated cirrhosis patients (compensated group).
Results
The cumulative transplantation-free survival was 87.1% at 1year. ETV treatment for 12months resulted in improved Child-Turcotte-Pugh (CTP) and model for end-stage liver disease (MELD) scores. Sixty-six percent (36/55) of patients achieved CTP class A and 49% (27/55) showed improvement in the CTP score of 2 points after 12months of ETV. The 1-year cumulative rates of HBV DNA negativity and HBeAg loss were 92.3% and 54.0%, respectively, by intention-to-treat analysis. The rates of HBV DNA negativity, HBeAg seroconversion/loss and ALT normalization at month 12 were similar for the decompensated and compensated groups. Cox regression analysis showed that pretreatment HBeAg seropositivity was a negative predictor of HBV DNA clearance during ETV therapy (hazard ratio, 0.514; 95% confidence interval 0.367-0.719; p<0.001).
Conclusions
One-year initial ETV therapy was similarly effective in both compensated and decompensated liver disease HBV patients. In addition, it improved underlying liver function in decompensated patients.
Introduction
Approximately 15-40% of hepatitis B virus (HBV) carriers are at increased risk of serious sequelae such as cirrhosis, hepatic decompensation and hepatocellular carcinoma (HCC) [1], [2]. In Korea, 5-7% of individuals within the general population are identified as HBV carriers [3], accounting for about 70% of liver cirrhosis and HCC cases [4]. The 5-year survival rate in decompensated cirrhosis patients is a low 14% compared with 84% for those with compensated cirrhosis [5].
A high viral load may be predictive of future progression to cirrhosis or HCC in HBV-infected patients [6], [7]. The oral antiviral drug lamivudine (LAM) slows deterioration in chronic hepatitis B (CHB) and advanced liver disease patients by delaying hepatic decompensation and HCC development [8]. However, LAM is no longer considered an optimal first-line therapy in CHB patients, owing to its higher resistance rate and lower potency compared to entecavir (ETV) and telbivudine [9], [10], [11], [12]. Latest recommendations suggest using ETV and tenofovir as primary oral agents irrespective of hepatitis B e antigen (HBeAg) serostatus [13].
ETV is considered an excellent treatment alternative for nucleos(t)ide-naïve patients due to insignificant resistance rates and strong antiviral effects [9], [12], and is thus widely prescribed. In recent 48-week trials of ETV treatment for CHB, 67% of HBeAg-positive and 90% of HBeAg-negative patients showed HBV DNA reduction to undetectable levels [9], [12], consistent with data obtained from patients with advanced liver fibrosis or compensated cirrhosis [14]. Furthermore, over 5years of treatment, the cumulative probability of development of mutations in the virus conferring genotypic resistance to ETV was only 1.2% in nucleos(t)ide-naïve patients [15]. Hence, early ETV therapy may halt disease progression more effectively in chronically infected patients compared with LAM.
At present, limited information is available on the impact of ETV therapy on viral suppression and hepatic function in CHB patients, particularly those with decompensated cirrhosis. In addition, the issue of when to use ETV as a first-line option in CHB therapy remains to be established.
In the present study, we evaluated the efficacy of ETV monotherapy in HBV-infected patients. We compared outcomes between decompensated cirrhosis patients and those with CHB or compensated cirrhosis. In addition, we investigated the effect of ETV therapy on hepatic function in patients with decompensated cirrhosis.
Patients and methods
Study population
From January 2007 to March 2008, 70 consecutive treatment-naive patients with HBV-related decompensated cirrhosis were orally treated with 0.5mg/day ETV alone at our institution. Of these patients, 6 (8.6%) died during the follow-up period, and all deaths were due to hepatic failure within 6months of ETV therapy (Fig. 1). Three patients (4.3%) underwent orthotopic liver transplantation (OLT) 3 or 4months after the commencement of ETV therapy. At the time of OLT, all three had intractable ascites and/or grade 3 or 4 hepatic encephalopathy, with model for end-stage liver disease (MELD) score 15. Six patients (8.6%) were lost to follow-up before evaluation at 12months, but were still alive. We analyzed clinical data from the remaining 55 patients with decompensated cirrhosis (decompensated group; Fig. 1), along with those from 144 consecutive patients with CHB or compensated cirrhosis (compensated group) who underwent 0.5mg/day ETV treatment for at least 12months during the same period. None of these patients had evidence of HCC at the time of initiation of ETV. CHB patients showing hepatic decompensation during acute exacerbation, defined as an elevation of alanine aminotransferase (ALT) activity to more than 10 times the upper limit of normal and more than twice the baseline value [16] were not included in the decompensated group. No patient had been previously administered antiviral therapy involving interferon-α or nucleos(t)ide analogs. All patients with or without HBeAg were persistently positive for hepatitis B surface antigen (HBsAg) for more than 6months, and contained serum HBV DNA levels of 4log10copies/ml or greater at baseline. Patients displaying antibodies against hepatitis C (anti-HCV) or human immunodeficiency virus (anti-HIV) or who had undergone liver or other organ transplants were excluded.
Decompensated liver disease was established based on a Child-Turcotte-Pugh (CTP) score7 (class B and C) or the presence of portal hypertension complications such as ascites, variceal bleeding or hepatic encephalopathy [17], [18]. Liver cirrhosis was diagnosed based on clinical, radiological, or histological assessments. The study was approved by the institutional review board of our hospital.
Laboratory and radiological testing
Baseline serological and imaging data such as ultrasonography (USG) or spiral computed tomography (CT) were obtained for all subjects. Serum hepatitis viral markers, including HBsAg, anti-HBs, HBeAg, anti-HBe, anti-HCV and anti-HIV, were confirmed using commercially available enzyme immunoassays (Abbott Laboratories, Chicago, IL). Serum HBV DNA levels were quantified using the Abbott Real-Time PCR assay (Abbott Laboratories, Chicago, IL) with a linear dynamic range of detection of 5.1x101-3.4x109copies/ml, according to the manufacturer's instructions. Other laboratory parameters were assayed using standard analytical procedures.
Follow-up studies
Compensated and decompensated groups were followed-up every 3-6months with tests for liver function, prothrombin time (PT), HBeAg, anti-HBe, and HBV DNA levels, in company with USG or spiral CT. Clinical examination and counseling regarding treatment adherence were performed for all patients at every clinic visit.
Statistical analysis
The two groups were compared using Student's t-test or Mann-Whitney test for continuous variables and chi-square or Fisher's exact test for categorized variables, where appropriate. Covariates with p-values<0.20 in univariate analysis were included in multivariate analysis using Cox proportional hazards models to determine whether pretreatment clinical and laboratory variables were significant in predicting HBV DNA clearance during ETV treatment. A p-value<0.05 was considered to indicate significance.
Results
Patient demographics
The baseline characteristics of the two study groups are shown in Table 1. The 199 total patients comprised 131 males and 68 females, and the gender ratio was similar for each group. The mean age was greater in the decompensated than the compensated group (52.6 vs. 46.8years, p<0.001). The two groups were similar in terms of serum HBV DNA levels. The mean serum ALT levels were lower in the decompensated group (101.9 vs. 156.5IU/L, p=0.021). The proportion of subjects positive for HBeAg was similar in both groups (49.1% vs. 62.5%, p=0.086). As anticipated, the decompensated group showed lower scores than the compensated group in terms of CTP and MELD scores, hepatic function (total bilirubin, albumin, PT) and platelet counts (p<0.001 for all). In the decompensated group, 31 (56.4%) patients had ascites, 7 (12.7%) had episodes of hepatic encephalopathy, and 13 (23.6%) experienced variceal bleeding. No patient in either group discontinued ETV during the study period.
The 70 patients with decompensated cirrhosis (Table 2) had a mean serum HBV DNA concentration at baseline of 7.18log10copies/ml and 34 (48.6%) patients were positive for HBeAg. All components of the CTP score, except for hepatic encephalopathy, were significantly poorer in the 9 patients (12.9%) who died or underwent OLT within 6months of ETV therapy than in the other 61 patients (87.1%) with decompensated cirrhosis (p<0.05 for all). These two subgroups, however, did not differ in serum HBV DNA or ALT levels, HBeAg serostatus, MELD score, or number of episodes of variceal bleeding.
Virological, serological, and biochemical responses
Viral and host responses to ETV therapy in the decompensated and compensated groups are presented in Table 3. Overall, ETV therapy over 12months resulted in a progressive decrease in serum HBV DNA levels (-5.52log10copies/ml at month 6, and -6.76log10copies/ml at month 12). The mean reductions in serum HBV DNA levels at months 6 and 12 did not differ significantly between the decompensated and compensated groups (Fig. 2). Undetectable serum HBV DNA levels were observed in 162 of the total 199 (81.4%) patients during the 12months of ETV therapy, and in each group a similar proportion of patients achieved undetectable viremia. Virological breakthrough (>1log10 increase in serum HBV DNA level from the nadir) was not noted in any patient throughout the follow-up period.
Of the 117 patients initially positive for HBeAg, 21 (17.9%) and 28 (23.9%) exhibited HBeAg seroconversion at months 6 and 12, respectively, with similar proportions being observed in both decompensated and compensated groups (18.5 vs. 17.8% at month 6, p=0.930; and 22.2 vs. 24.4% at month 12, p=0.812). This distribution was consistent with the HBeAg clearance rate (33.3 vs. 25.6% at month 6, p=0.427; and 48.1 vs. 41.1% at month 12, p=0.517). With regard to ALT response, the frequency of ALT normalization occurred uniformly at 12months of ETV therapy in both groups (76.4% vs. 75.0%, p=0.535). No differences were also observed in terms of the likelihood of HBV DNA suppression to undetectable levels and ALT normalization at 12months between the groups when stratified according to HBeAg serostatus (Table 4).
When all 70 patients with decompensated cirrhosis receiving ETV therapy were included in an intention-to-treat analysis of efficacy, the cumulative rates of HBV DNA negativity and HBeAg loss at 12months were 92.3% and 54.0%, respectively (Fig. 3A and B).
Pretreatment factors predicting HBV DNA negativity during ETV therapy
The overall 1-year cumulative rate of HBV DNA negativity was 84.4% in all 199 patients (Fig. 4A), i.e., 81.3% and 92.7% in the decompensated and compensated groups, respectively (p=0.099; Fig. 4B). During 12months of ETV therapy, the cumulative rate of HBV DNA negativity was significantly higher in HBeAg-negative than in HBeAg-positive patients (97.6% vs. 75.2%, p<0.001; Fig. 4C). Cox regression analysis with adjustment for baseline potential confounders (age, HBeAg status, serum HBV DNA levels, and categories of liver disease) showed that baseline HBeAg seropositivity was the only independent predictive factor adversely affecting HBV DNA negativity during ETV therapy (hazard ratio, 0.514; 95% confidence interval, 0.367-0.719, p<0.001; Table 5).
Changes in hepatic function after 12months of ETV therapy in the decompensated group
To evaluate the influence of ETV therapy on hepatic function reserve in the decompensated group, we measured the CTP score and its components (i.e., total bilirubin, albumin, and PT), along with MELD score and compared these values pre- and post-treatment (Fig. 5). For all 55 patients, the mean albumin (2.8 vs. 3.2g/dl), total bilirubin (3 vs. 1.9mg/dl), PT (16.3 vs. 13.9s), CTP score (8.1 vs. 6.6), and MELD score (11.1 vs. 8.8) improved after 12months of ETV treatment than at baseline (p<0.05 for all). Twenty-seven patients (49.1%) showed an improvement of >2 points in CTP score. Of the remaining 28 patients (50.9%), 9 achieved CTP class A with 1 point of improvement; 3 did not achieve CTP class A despite 1 point in improvement; 12 showed no change; and 4 experienced aggravation. Of the 27 patients who showed >2 point CTP score improvement, 15 (55.6%) improved within 3months and 20 (74.1%) improved within 6months of commencing ETV. As a result, 36 (65.5%) of the 55 patients achieved CTP class A (score 5 or 6) after 12months of ETV.
On-treatment outcomes of HCC occurrence and OLT-free survival in patients with decompensated cirrhosis
The 70 patients with decompensated cirrhosis had a cumulative incidence of HCC of 6.9% at month 24, with 4 patients developing HCC during the entire follow-up period (Fig. 6). In addition, the cumulative incidence of mortality or OLT was 12.9% at month 12 and 17.0% at month 24, respectively (Fig. 6), with 36.4% at month 24 in patients with CTP class C. After 6months of ETV therapy, only one patient in the decompensated group died of uncontrollable variceal bleeding and no patient received a liver transplant.
Discussion
The results presented here clearly confirm that first-line ETV monotherapy provides comparable overall antiviral benefits in HBV-infected patients with decompensated cirrhosis as has been shown in patients with chronic hepatitis or compensated cirrhosis, regardless of HBeAg serostatus. Moreover, ETV monotherapy improved hepatic function significantly, especially in patients with decompensated cirrhosis. Previous studies showed that LAM was also effective in viral suppression with no serious adverse effects in HBV-related decompensated cirrhosis and resulted in improved hepatic function and reduced morbidity [19], [20], [21], [22]. However, the antiviral effects of ETV in cirrhotic patients with hepatic decompensation in the clinical setting have not been established [13], [16], [23].
Using real-time PCR analysis, we found that 1year of ETV therapy resulted in HBV DNA levels that were undetectable in 81.5% of HBeAg-positive and 96.4% of HBeAg-negative patients with decompensated cirrhosis. These values are considerably better than other published rates in compensated CHB patients. These figures were achieved despite the lack of patients achieving undetectable HBV DNA at a wider detection limit of below 51copies/ml in our study using real-time PCR analysis compared with previous studies using commercial assays [9], [12]. Similar findings were observed regarding ALT normalization which occurred in 77.8% of HBeAg-positive and 75.0% of HBeAg-negative patients with decompensated cirrhosis. Interestingly, the proportions of compensated and decompensated patients showing ALT normalization at 12months were similar despite poorly matched pretreatment ALT levels. In general, patients with advanced liver disease often have relatively lower liver enzyme elevations despite a higher viral load compared to patients with well-compensated liver disease [23].
Notably, HBeAg seropositivity was an important predictor for suboptimal viral response to ETV treatment. The reasons underlying this finding remain to be established. This result is consistent with previous data showing that in terms of virological and biochemical responses, ETV therapy was more favorable for CHB patients negative for HBeAg than those positive for HBeAg, although not when compared head-to-head [9], [12], which may be conceivable since the long-term natural course is reported to be poorer in HBeAg-negative patients compared with HBeAg-positive patients [24], [25].
In contrast to similar outcomes in HBeAg seroconversion at 12months (23.9% vs. 21%), the overall rate of HBeAg loss in our study subjects was much higher than that reported in other study populations (46.8% vs. 22%) [9]. The high HBeAg rate of loss may reflect the lower HBeAg titer in Korean CHB patients. Indeed, a Korean study reported that 22% of HBeAg-positive patients had a mixed infection of precore mutant and wild-type [26]. In addition, our prior data showed that HBeAg seroconversion was 34% in patients with pretreatment serum ALT levels over twice the ULN, compared with 5% in those with pretreatment ALT levels less than twice the ULN [27]. In the present study, serum ALT values over twice ULN were identified in 63.8% of all patients.
Emerging data have revealed the positive effect of LAM therapy on the functional enhancement of underlying liver disease in patients with HBV-related decompensated cirrhosis and HCC, thus leading to improvements in the biochemical and clinical parameters of patients [19], [20], [28]. Similarly, the CTP and MELD scores, both of which reflect liver function, and their components, including serum albumin and total bilirubin levels as well as PT, dramatically improved during the period of ETV treatment in our patients with decompensated cirrhosis. All practice guidelines suggest that antiviral treatment should be considered in decompensated cirrhosis patients regardless of HBV DNA levels [13], [16], [23]. In HBV-infected patients with significant functional compromise, corresponding early intervention with ETV may possibly prevent clinical progression to hepatic failure, taper complication risk, and even delay or avoid OLT as a bridging therapy by substantially stabilizing the HBV status.
In Korea, living donor-OLT is currently performed in approximately 80% of the liver transplant because of a cadaveric organ shortage. Therefore, OLT is generally recommended for patients with CTP class C or a MELD score >15. We initially recommend OLT if the patients are under the above conditions, and start ETV therapy if a donor liver is not available. When donor livers become available, we reevaluate the patients' status and perform OLT if the patients are still in CTP class C or a MELD score >15. In our series, the 2-year OLT-free survival was 83%. There were six deaths and three liver transplants within 6months of starting ETV treatment. Of these, the three transplanted patients and three of the patients who died were evaluable for virological response at month 3, and all showed a marked decrease in serum HBV DNA to <103copies/ml. The early antiviral response to LAM at week 8 did not predict 6-month mortality in patients with decompensated CHB [29]. Although significant clinical improvement with ETV therapy was achieved most frequently within 6months of therapy, approximately 80% of early mortality or OLT in our population occurred within 4months of onset of ETV therapy. This observation is consistent with the previous LAM therapy data [19], [20], [22]. Given that patients who died or underwent OLT early in ETV treatment had significantly higher pretreatment CTP scores, OLT should not be delayed in patients with CTP class C or a MELD score >15 at baseline, or be urgently considered in patients displaying suboptimal improvement in hepatic reserves after 3months of ETV treatment.
Whereas the LAM studies of Yao and colleagues [19], [22] showed a dramatic decline in CTP scores of >3 points in more than 60% of patients, less than half of our patients showed significantly improved CTP scores (>2 points). These dissimilar results may reflect that decompensated patients with acute exacerbation of CHB were excluded from the present study in contrast to the previous studies [19], [22].
In the context of clinical antiviral resistance, virological breakthrough was not noted throughout our study period, although genotypic analysis of ETV-resistant HBV variants was not performed. A previous study on 17 Korean patients matched with ours for pretreatment characteristics found that 7 patients (41.2%) experienced virological breakthrough during approximately 2years of LAM treatment, including 6 (86%) with YMDD mutants [30].
The long-term efficacy of ETV in vivo is unclear at present. Since the potency and resistance rates of ETV outweigh those of LAM [9], [12], similar or better outcomes are expected. However, this requires confirmation in further studies.
In conclusion, the present study provides evidence that 1year of initial ETV treatment is comparably efficacious in arresting HBV replication and clearing HBeAg in HBV-infected patients with either compensated or decompensated liver disease. In addition, ETV markedly improved the underlying hepatic reserve in decompensated cirrhotic patients, mostly within 6months of treatment. Thus, our findings may establish a rationale for the use of ETV as a first-line monotherapeutic agent in these patients. Further ongoing follow-up investigations are necessary to obtain long-term data in conjunction with genotypic assays of ETV resistance.
Entecavir in decompensated HBV cirrhosis: The future is looking brighter
Entecavir in decompensated HBV cirrhosis: The future is looking brighter
Articles in Press
Jnl of Hepatology Jan 2010
Robert J. Fontana
Department of Internal Medicine, University of Michigan Medical Center, Ann Arbor, MI 48109-0362, United States
Received 26 October 2009; accepted 26 October 2009. published online 19 November 2009. Corrected Proof
Practice guidelines recommend treatment of selected patients with chronic hepatitis B virus (HBV) infection who are at risk of developing progressive liver disease based upon their serum ALT and HBV DNA levels and/or liver histology [1], [2]. The seven approved medications for chronic HBV consistently lead to histological improvements in patients that suppress HBV replication during short-term treatment [3]. In addition, the rate of developing clinical outcomes and decompensation can be significantly reduced by using prolonged lamivudine therapy in patients with advanced but compensated fibrosis compared to no treatment [4]. However, the clinical and histological benefit with the oral nucleos(t)ide analogues is substantially reduced when drug-resistant variants of HBV emerge [3], [4]. As a result, the oral agents that most effectively suppress HBV replication with the lowest rate of drug resistance during prolonged use (entecavir, tenofovir) have emerged as preferred first line agents over the other available drugs (lamivudine, adefovir, telbivudine) [1], [2].
Practice guidelines also recommend prescribing an oral nucleos(t)ide analogue (but not the interferons) for patients with decompensated HBV cirrhosis independent of the patients serum ALT, HBV DNA level, and eAg status [1], [2]. These latter recommendations are largely based upon open-label studies of lamivudine and adefovir in decompensated HBV patients wherein antiviral therapy was associated with improved outcomes including a delay or prevention in the need for liver transplantation (Table 1) [5], [6], [7], [8]. For example, a prospective study of 154 decompensated HBV patients treated with lamivudine demonstrated improved laboratory and clinical parameters with treatment compared to baseline values. A biphasic survival pattern was also noted with most deaths occurring within the first 6months of treatment; patients with higher pretreatment bilirubin, creatinine, and HBV DNA levels were at greatest risk for early death while early suppression of HBV replication was not associated with more favorable outcomes [6]. Adefovir treatment in 226 patients with lamivudine refractory decompensated HBV also led to significant improvements in their CTP and MELD scores at 1-year compared to baseline [7], [8]. However, 14% still died within the first year and at least 33% required liver transplantation for long-term survival. Although antiviral drug resistance is substantially less common with adefovir monotherapy compared to lamivudine, concerns remain regarding the slow rate of suppressing HBV replication with adefovir as well as the potential for dose-dependent nephrotoxicity in decompensated HBV patients [9], [10].
Entecavir suppresses HBV replication more rapidly and effectively than lamivudine in patients with compensated chronic HBV [11]. In addition, entecavir was a more potent and rapid suppressor of HBV replication compared to adefovir in compensated patients [12]. Furthermore, entecavir does not have any reported nephrotoxicity and the resistance profile at 5years in treatment naïve HBV patients has been excellent (i.e., ~1%) [13]. Tenofovir is also a significantly more potent suppressor of HBV replication than adefovir and no drug-resistant variants have been reported with 3years of continuous treatment in compensated patients [14], [15]. Expanded use of these two newer drugs has been sought in difficult to treat patient populations, including hemodialysis patients and subjects with decompensated HBV cirrhosis. However, safety and efficacy data are very sparse to non-existent in these special patient populations and this is due to uncertainties in drug dosing and difficulties in conducting adequately powered prospective studies.
In this issue of the Journal, the effectiveness of entecavir (at a dose of 0.5mg per day) in a cohort of 70 consecutive Korean patients with decompensated HBV is reported [16]. The virological responses in the 55 decompensated HBV patients at 1year are also compared to 144 compensated patients treated with entecavir from the same center. Of note, none of these patients had previously been treated with an oral nucleos(t)ide analogue nor harbored drug-resistant variants of HBV. As expected, the mean MELD (11.5 vs. 7) and CTP scores (8.1 vs. 5.3) were significantly higher in the decompensated patients but the mean pretreatment HBV DNA levels (7.2 vs. 7.5log10) and proportion of HBeAg+patients (49.1% vs. 62.5%) was similar. Overall, the 1-year transplant-free survival rate was 87.1% in the decompensated patients. As previously reported with lamivudine, the majority of adverse outcomes occurred within the first 6months of treatment and these nine patients had more severe liver failure at entry compared to the others. However, the baseline HBV DNA levels and presence of HBeAg+ were similar in the non-survivors compared to the survivors. Similarly, the early response to antiviral therapy among those who died or underwent transplant was similar to the survivors. Nearly 50% of the entecavir treated patients had a clinically significant decrease in their CTP score of >2 points at 1-year. In addition, the rate of HBeAg loss in both the decompensated and compensated patients was remarkably high at 1year (48% and 41%, respectively). Finally, the kinetics of HBV DNA suppression were comparable in the decompensated and compensated patients.
Shim et al. are to be congratulated for providing important prospectively collected data on the utility of entecavir in a large group of patients with decompensated HBV cirrhosis. They convincingly show that entecavir at a dose of 0.5mg per day is effective in treating naïve decompensated HBV patients with nearly 90% achieving undetectable HBV DNA at month 12. In addition, suppression of HBV DNA was maintained during follow-up with no instances of viral rebound or entecavir-resistant HBV identified. However, the authors also note that not all decompensated patients improved with entecavir therapy and five patients developed HCC during follow-up. Furthermore, twelve subjects (22%) showed no change in their CTP score at 1-year; four subjects actually "experienced aggravation" of their liver disease with worsening CTP scores. Whether this "aggravation" was related to entecavir treatment or progression of their underlying liver disease is unclear.
All of the approved oral nucleos(t)ide analogues for HBV carry a BLACK-BOX warning in their labeling regarding potential mitochondrial toxicity that can manifest itself as lactic acidosis, myopathy, neuropathy, or even hepatotoxicity. Entecavir had the lowest risk of causing mitochondrial DNA depletion in an in vitro test system compared to the other oral antiviral agents [17], [18]. Nonetheless, a recent report from Germany showed that 5 of 16 hospitalized patients with decompensated HBV developed symptomatic lactic acidosis after receiving entecavir for 4-240days [19]. Although lactic acidosis resolved in four patients following entecavir discontinuation or dose reduction, one patient with fulminant HBV died. Whether these adverse events were due to direct mitochondrial toxicity or other causes in these patients who all had MELD scores>20 remains unclear. It is important to remember that mitochondrial toxicity can present as late as 1year after initiating oral nucleos(t)ide analogue therapy and that concomitant drugs, medical co-morbidities, and other host factors may alter drug pharmacokinetics in various tissues [18], [20]. Unfortunately, Shim et al. do not report upon entecavir dose adjustments during treatment nor serial renal, metabolic, or safety labs in their patients.
Preliminary reports from two other ongoing, multi-center studies also suggest that entecavir may be of benefit in selected patients with decompensated HBV (Table 1). In the first study, 195 patients with decompensated HBV were randomized to entecavir (1.0mg per day) or adefovir (10mg per day) [21]. In contrast to the Shim study, 34% of patients had lamivudine-resistant HBV. Interim results at week 48 demonstrate a significantly greater reduction in HBV DNA and serum ALT levels in the entecavir treated patients compared to the adefovir treated patients. In addition, 1-year mortality rates were similar in both treatment arms. These preliminary data confirm the superior antiviral efficacy of entecavir compared to adefovir in decompensated HBV patients. However, continued follow-up is needed since the rate of entecavir-resistant HBV can substantially increase over time in patients with lamivudine-resistant HBV and lead to potentially severe disease flares [13], [22].
A second ongoing, multi-center study set out to compare the safety and efficacy of tenofovir vs. tenofovir+emtricitabine vs. entecavir in 112 decompensated HBV patients [23]. In this study, the median pretreatment MELD and CTP scores of 10.5 and 7, respectively, were substantially lower than those reported in the other studies (Table 1). The frequency of undetectable HBV DNA at weeks 12, 24, and 48 was comparable in the three treatment groups. However, amongst the subjects with lamivudine-resistant HBV, 71% of the 18 patients in the tenofovir containing arms had undetectable HBV DNA at week 48 compared to 33% in the three entecavir treated patients. Improvements in CTP and MELD scores at week 48 were comparable between the three treatment arms but the rate of HBeAg seroconversion was 0% in the entecavir arm compared to 21% and 13% in the tenofovir and tenofovir/emtricitabine arms, respectively. Rates of nephrotoxicity, treatment "tolerability" and patient mortality were similar in the three treatment arms through week 48. Clearly, continued follow-up of these patients is needed to determine which of the newer antiviral agents can offer the best risk-benefit ratio in this challenging patient population. Although a tenofovir based regimen may be preferred in decompensated patients with lamivudine-resistant HBV, there are growing concerns regarding the long-term safety of tenofovir in some HBV patients including nephrotoxicity and metabolic bone disease [24], [25]. Furthermore, since patients with decompensated cirrhosis frequently are malnourished and may have low vitamin D levels, prospective studies of bone density and metabolic parameters during prolonged tenofovir treatment are warranted as well as potential calcium and vitamin D supplementation [26].
In summary, the study of Shim et al. and others (Table 1) are bright stars in the horizon for the management of decompensated HBV cirrhosis. The aggregate efficacy and safety data now support the use of entecavir as a first line treatment option for nucleos(t)ide naïve patients with decompensated HBV cirrhosis. However, continued follow-up from these ongoing studies including long-term efficacy, safety, and resistance data are needed. Further studies are also needed to identify the optimal agent(s) for patients with decompensated lamivudine-resistant HBV cirrhosis. In the meanwhile, decompensated HBV patients receiving oral nucleos(t)ide analogues must undergo frequent clinical and laboratory assessment to insure medication compliance and surveillance for virological and clinical response as well as drug side effects, drug resistance, and HCC. Finally, the data of Shim et al. confirm the importance of early liver transplant evaluation in decompensated HBV patients with high MELD scores at presentation due to our inability to reliably identify those patients with a poor short-term prognosis.
References
[1]. Lok ASF, McMahon BJ. Chronic hepatitis B: update 2009. Hepatology. 2009;50:1-36.
[2]. EASL clinical practice guidelines: management of chronic hepatitis B . J Hepatol. 2009;50:227-242.
[3]. Shamliyan TA, MacDonald R, Shaukat A, Taylor BC, Yuan JM, Johnson JR, et al. Antiviral therapy for adults with chronic hepatitis B: a systematic review for a National Institutes of Health Consensus Development Conference. Ann Intern Med. 2009;150:111-124.
[4]. Liaw YF, Sung JJ, Chow WC, et al. Lamivudine for patients with chronic hepatitis B and advanced liver disease. N Engl J Med. 2004;351:1521-1531.
[5]. Fontana RJ. Management of patients with decompensated HBV cirrhosis. Semin Liver Dis. 2003;23:89-100.
[6]. Fontana RJ, Hann HW, Perrillo RP, et al. Determinants of early mortality in patients with decompensated chronic hepatitis B treated with antiviral therapy. Gastroenterology. 2002;123:719-727.
[7]. Schiff ER, Lai CL, Hadziyannis S, et al. Adefovir dipivoxil therapy for lamivudine-resistant hepatitis B in pre- and post-liver transplantation patients. Hepatology. 2003;38:1419-1427.
[8]. Schiff ER, Lai CL, Hadziyanis S, et al. Adefovir dipivoxil for wait-listed and post-liver transplantation patients with lamivudine-resistant hepatitis B: final long-term results. Liver Transplant. 2007;13:349-360.
[9]. Hadziyannis S, Tassopoulos N, Heathcote E, et al. Long-term therapy with adefovir dipivoxil for HBeAg-negative chronic hepatitis B for up to 5years. Gastroenterology. 2006;131:1741-1751.
[10]. Izzedine H, Launay-Vacher V, Deray G. Antiviral drug-induced nephrotoxicity. Am J Kidney Dis. 2005;45:804-817.
[11]. Chang TT, Gish RG, De Man R, et al. A comparison of entecavir and lamivudine for HBeAg-positive chronic hepatitis B. N Engl J Med. 2006;354:1001-1010.
[12]. Leung N, Peng CY, Hann HW, et al. Early hepatitis B virus DNA reduction in hepatitis B e-antigen positive patients with chronic hepatitis B: a randomized, international study of entecavir versus adefovir. Hepatology. 2009;49:72-79.
[13]. Tenney DJ, Rose RE, Baldick CJ, Pokornowski KA, Eggers BJ, Fang J, et al. Long-term monitoring shows hepatitis B virus resistance to entecavir in nucleoside-naïve patients is rare through 5years of therapy. Hepatology. 2009;49:1503-1514.
[14]. Marcellin P, Buti M, Krastev Z, et al. Tenoofivir disporixl fumarate versus adefovir dipivoxil for chronic hepatitis B. N Engl J Med. 2008;359:2442-2455.
[15]. Smow-Lampart A, Chappell BJ, Curtis M, Zhu Y, Heatthcote EJ, Marcellin GP, et al. Resistance surveillance for up to 144weeks in HBeAg+ and HBeAg- patients treated with tenofovir DF showed no relationship between virologic breakthrough and emergence of genotypic changes in HBV polymerase. Hepatology. 2009;50:532A
[16]. Shim JH, Lee HC, Kim KM, Lim YS, Chung YH, Lee YS, et al. Efficacy of entecavir in treatment-naive patients with hepatitis B virus-related decompensated cirrhosis. J Hepatol 2010. doi:10.1016/j.jhep.2009.11.077
[17]. Mazzucco EC, Hamatake RK, Colonno RJ, Tenney DJ. Entecavir for treatment of hepatitis B virus displays no in vitro mitochondrial toxicity or DNA polymerase gamma inhibition. Antimicrob Agents Chemother. 2008;52:598-605.
[18]. Fontana RJ. Side effects of long-term oral antiviral therapy for hepatitis B. Hepatology. 2009;49(5 Suppl.):S185-S195.
[19]. Lange CM, Bojunga J, Hofmann WP, Wunder K, Mihm U, Zeuzem S, et al. Severe lactic acidosis during treatment of chronic hepatitis B with entecavir in patients with impaired liver function. Hepatology. 2009
[20]. Kim BK, Oh J, Kwon BK, Choe WH, Ko SY, Rhee KH, et al. Clevudine myopathy in patients with chronic hepatitis B. J Hepatol. 2009;51:829-834.
[21]. Liaw YF, Raptopoulou-Gigi M, Cheinquer H, Sarin SK, Tanwandee T, Leung N, et al. Efficacy, safety of entecavir versus adefovir in chronic hepatitis B patients with evidence of hepatic decompensation. Hepatology. 2009;50:505A;
[22]. Pellicelli AM, Barbarini G, Romano M, Furlan C, Paffetti A, Villani R, et al. Entecavir therapy for lamivudine resistant HBV cirrhotic patients waiting for OLT: viral, biochemical outcomes at one year. Hepatology. 2009;50:514A;
[23]. Schiff ER, Liaw Y, Lee C, Akarc US, George PV, Wong F, et al. Interim results of a double-blind, randomized phase 2 study of the safety of tenofovir disoproxil fumarate, emtricitabine plus tenofovir disoproxil fumarate, entecavir in the treatment of chronic hepatitis B subjects with decompensated liver disease. Hepatology. 2009;50:222;
[24]. Gallant J, Staszewski ES, Pozniak AL, DeJesus E, Suleiman JM, Miller MD, et al. Efficacy and safety of tenofovir DV vs. stavudine in combination therapy in anti-retroviral naïve patients: a 3-year randomized trial. JAMA. 2004;292:191-201.
[25]. Raijnders JG, Vries-Sluijs T, Hansen BE, Zaaijer HL, Prins JM, Schuttten M, et al. Five-year tenofovir therapy is associated with maintained virologic response but significant decline in renal function in HIV-HBV coinfected patients. Hepatology. 2009;50:506A;
[26]. Constable C, Childs K, Bachon ML, Carriero DC, Mullen MP, Dieterich DT, et al. Does tenofovir increase the risk of abnormal bone and calcium metabolism?. Hepatology. 2009;51:518A;
Articles in Press
Jnl of Hepatology Jan 2010
Robert J. Fontana
Department of Internal Medicine, University of Michigan Medical Center, Ann Arbor, MI 48109-0362, United States
Received 26 October 2009; accepted 26 October 2009. published online 19 November 2009. Corrected Proof
Practice guidelines recommend treatment of selected patients with chronic hepatitis B virus (HBV) infection who are at risk of developing progressive liver disease based upon their serum ALT and HBV DNA levels and/or liver histology [1], [2]. The seven approved medications for chronic HBV consistently lead to histological improvements in patients that suppress HBV replication during short-term treatment [3]. In addition, the rate of developing clinical outcomes and decompensation can be significantly reduced by using prolonged lamivudine therapy in patients with advanced but compensated fibrosis compared to no treatment [4]. However, the clinical and histological benefit with the oral nucleos(t)ide analogues is substantially reduced when drug-resistant variants of HBV emerge [3], [4]. As a result, the oral agents that most effectively suppress HBV replication with the lowest rate of drug resistance during prolonged use (entecavir, tenofovir) have emerged as preferred first line agents over the other available drugs (lamivudine, adefovir, telbivudine) [1], [2].
Practice guidelines also recommend prescribing an oral nucleos(t)ide analogue (but not the interferons) for patients with decompensated HBV cirrhosis independent of the patients serum ALT, HBV DNA level, and eAg status [1], [2]. These latter recommendations are largely based upon open-label studies of lamivudine and adefovir in decompensated HBV patients wherein antiviral therapy was associated with improved outcomes including a delay or prevention in the need for liver transplantation (Table 1) [5], [6], [7], [8]. For example, a prospective study of 154 decompensated HBV patients treated with lamivudine demonstrated improved laboratory and clinical parameters with treatment compared to baseline values. A biphasic survival pattern was also noted with most deaths occurring within the first 6months of treatment; patients with higher pretreatment bilirubin, creatinine, and HBV DNA levels were at greatest risk for early death while early suppression of HBV replication was not associated with more favorable outcomes [6]. Adefovir treatment in 226 patients with lamivudine refractory decompensated HBV also led to significant improvements in their CTP and MELD scores at 1-year compared to baseline [7], [8]. However, 14% still died within the first year and at least 33% required liver transplantation for long-term survival. Although antiviral drug resistance is substantially less common with adefovir monotherapy compared to lamivudine, concerns remain regarding the slow rate of suppressing HBV replication with adefovir as well as the potential for dose-dependent nephrotoxicity in decompensated HBV patients [9], [10].
Entecavir suppresses HBV replication more rapidly and effectively than lamivudine in patients with compensated chronic HBV [11]. In addition, entecavir was a more potent and rapid suppressor of HBV replication compared to adefovir in compensated patients [12]. Furthermore, entecavir does not have any reported nephrotoxicity and the resistance profile at 5years in treatment naïve HBV patients has been excellent (i.e., ~1%) [13]. Tenofovir is also a significantly more potent suppressor of HBV replication than adefovir and no drug-resistant variants have been reported with 3years of continuous treatment in compensated patients [14], [15]. Expanded use of these two newer drugs has been sought in difficult to treat patient populations, including hemodialysis patients and subjects with decompensated HBV cirrhosis. However, safety and efficacy data are very sparse to non-existent in these special patient populations and this is due to uncertainties in drug dosing and difficulties in conducting adequately powered prospective studies.
In this issue of the Journal, the effectiveness of entecavir (at a dose of 0.5mg per day) in a cohort of 70 consecutive Korean patients with decompensated HBV is reported [16]. The virological responses in the 55 decompensated HBV patients at 1year are also compared to 144 compensated patients treated with entecavir from the same center. Of note, none of these patients had previously been treated with an oral nucleos(t)ide analogue nor harbored drug-resistant variants of HBV. As expected, the mean MELD (11.5 vs. 7) and CTP scores (8.1 vs. 5.3) were significantly higher in the decompensated patients but the mean pretreatment HBV DNA levels (7.2 vs. 7.5log10) and proportion of HBeAg+patients (49.1% vs. 62.5%) was similar. Overall, the 1-year transplant-free survival rate was 87.1% in the decompensated patients. As previously reported with lamivudine, the majority of adverse outcomes occurred within the first 6months of treatment and these nine patients had more severe liver failure at entry compared to the others. However, the baseline HBV DNA levels and presence of HBeAg+ were similar in the non-survivors compared to the survivors. Similarly, the early response to antiviral therapy among those who died or underwent transplant was similar to the survivors. Nearly 50% of the entecavir treated patients had a clinically significant decrease in their CTP score of >2 points at 1-year. In addition, the rate of HBeAg loss in both the decompensated and compensated patients was remarkably high at 1year (48% and 41%, respectively). Finally, the kinetics of HBV DNA suppression were comparable in the decompensated and compensated patients.
Shim et al. are to be congratulated for providing important prospectively collected data on the utility of entecavir in a large group of patients with decompensated HBV cirrhosis. They convincingly show that entecavir at a dose of 0.5mg per day is effective in treating naïve decompensated HBV patients with nearly 90% achieving undetectable HBV DNA at month 12. In addition, suppression of HBV DNA was maintained during follow-up with no instances of viral rebound or entecavir-resistant HBV identified. However, the authors also note that not all decompensated patients improved with entecavir therapy and five patients developed HCC during follow-up. Furthermore, twelve subjects (22%) showed no change in their CTP score at 1-year; four subjects actually "experienced aggravation" of their liver disease with worsening CTP scores. Whether this "aggravation" was related to entecavir treatment or progression of their underlying liver disease is unclear.
All of the approved oral nucleos(t)ide analogues for HBV carry a BLACK-BOX warning in their labeling regarding potential mitochondrial toxicity that can manifest itself as lactic acidosis, myopathy, neuropathy, or even hepatotoxicity. Entecavir had the lowest risk of causing mitochondrial DNA depletion in an in vitro test system compared to the other oral antiviral agents [17], [18]. Nonetheless, a recent report from Germany showed that 5 of 16 hospitalized patients with decompensated HBV developed symptomatic lactic acidosis after receiving entecavir for 4-240days [19]. Although lactic acidosis resolved in four patients following entecavir discontinuation or dose reduction, one patient with fulminant HBV died. Whether these adverse events were due to direct mitochondrial toxicity or other causes in these patients who all had MELD scores>20 remains unclear. It is important to remember that mitochondrial toxicity can present as late as 1year after initiating oral nucleos(t)ide analogue therapy and that concomitant drugs, medical co-morbidities, and other host factors may alter drug pharmacokinetics in various tissues [18], [20]. Unfortunately, Shim et al. do not report upon entecavir dose adjustments during treatment nor serial renal, metabolic, or safety labs in their patients.
Preliminary reports from two other ongoing, multi-center studies also suggest that entecavir may be of benefit in selected patients with decompensated HBV (Table 1). In the first study, 195 patients with decompensated HBV were randomized to entecavir (1.0mg per day) or adefovir (10mg per day) [21]. In contrast to the Shim study, 34% of patients had lamivudine-resistant HBV. Interim results at week 48 demonstrate a significantly greater reduction in HBV DNA and serum ALT levels in the entecavir treated patients compared to the adefovir treated patients. In addition, 1-year mortality rates were similar in both treatment arms. These preliminary data confirm the superior antiviral efficacy of entecavir compared to adefovir in decompensated HBV patients. However, continued follow-up is needed since the rate of entecavir-resistant HBV can substantially increase over time in patients with lamivudine-resistant HBV and lead to potentially severe disease flares [13], [22].
A second ongoing, multi-center study set out to compare the safety and efficacy of tenofovir vs. tenofovir+emtricitabine vs. entecavir in 112 decompensated HBV patients [23]. In this study, the median pretreatment MELD and CTP scores of 10.5 and 7, respectively, were substantially lower than those reported in the other studies (Table 1). The frequency of undetectable HBV DNA at weeks 12, 24, and 48 was comparable in the three treatment groups. However, amongst the subjects with lamivudine-resistant HBV, 71% of the 18 patients in the tenofovir containing arms had undetectable HBV DNA at week 48 compared to 33% in the three entecavir treated patients. Improvements in CTP and MELD scores at week 48 were comparable between the three treatment arms but the rate of HBeAg seroconversion was 0% in the entecavir arm compared to 21% and 13% in the tenofovir and tenofovir/emtricitabine arms, respectively. Rates of nephrotoxicity, treatment "tolerability" and patient mortality were similar in the three treatment arms through week 48. Clearly, continued follow-up of these patients is needed to determine which of the newer antiviral agents can offer the best risk-benefit ratio in this challenging patient population. Although a tenofovir based regimen may be preferred in decompensated patients with lamivudine-resistant HBV, there are growing concerns regarding the long-term safety of tenofovir in some HBV patients including nephrotoxicity and metabolic bone disease [24], [25]. Furthermore, since patients with decompensated cirrhosis frequently are malnourished and may have low vitamin D levels, prospective studies of bone density and metabolic parameters during prolonged tenofovir treatment are warranted as well as potential calcium and vitamin D supplementation [26].
In summary, the study of Shim et al. and others (Table 1) are bright stars in the horizon for the management of decompensated HBV cirrhosis. The aggregate efficacy and safety data now support the use of entecavir as a first line treatment option for nucleos(t)ide naïve patients with decompensated HBV cirrhosis. However, continued follow-up from these ongoing studies including long-term efficacy, safety, and resistance data are needed. Further studies are also needed to identify the optimal agent(s) for patients with decompensated lamivudine-resistant HBV cirrhosis. In the meanwhile, decompensated HBV patients receiving oral nucleos(t)ide analogues must undergo frequent clinical and laboratory assessment to insure medication compliance and surveillance for virological and clinical response as well as drug side effects, drug resistance, and HCC. Finally, the data of Shim et al. confirm the importance of early liver transplant evaluation in decompensated HBV patients with high MELD scores at presentation due to our inability to reliably identify those patients with a poor short-term prognosis.
References
[1]. Lok ASF, McMahon BJ. Chronic hepatitis B: update 2009. Hepatology. 2009;50:1-36.
[2]. EASL clinical practice guidelines: management of chronic hepatitis B . J Hepatol. 2009;50:227-242.
[3]. Shamliyan TA, MacDonald R, Shaukat A, Taylor BC, Yuan JM, Johnson JR, et al. Antiviral therapy for adults with chronic hepatitis B: a systematic review for a National Institutes of Health Consensus Development Conference. Ann Intern Med. 2009;150:111-124.
[4]. Liaw YF, Sung JJ, Chow WC, et al. Lamivudine for patients with chronic hepatitis B and advanced liver disease. N Engl J Med. 2004;351:1521-1531.
[5]. Fontana RJ. Management of patients with decompensated HBV cirrhosis. Semin Liver Dis. 2003;23:89-100.
[6]. Fontana RJ, Hann HW, Perrillo RP, et al. Determinants of early mortality in patients with decompensated chronic hepatitis B treated with antiviral therapy. Gastroenterology. 2002;123:719-727.
[7]. Schiff ER, Lai CL, Hadziyannis S, et al. Adefovir dipivoxil therapy for lamivudine-resistant hepatitis B in pre- and post-liver transplantation patients. Hepatology. 2003;38:1419-1427.
[8]. Schiff ER, Lai CL, Hadziyanis S, et al. Adefovir dipivoxil for wait-listed and post-liver transplantation patients with lamivudine-resistant hepatitis B: final long-term results. Liver Transplant. 2007;13:349-360.
[9]. Hadziyannis S, Tassopoulos N, Heathcote E, et al. Long-term therapy with adefovir dipivoxil for HBeAg-negative chronic hepatitis B for up to 5years. Gastroenterology. 2006;131:1741-1751.
[10]. Izzedine H, Launay-Vacher V, Deray G. Antiviral drug-induced nephrotoxicity. Am J Kidney Dis. 2005;45:804-817.
[11]. Chang TT, Gish RG, De Man R, et al. A comparison of entecavir and lamivudine for HBeAg-positive chronic hepatitis B. N Engl J Med. 2006;354:1001-1010.
[12]. Leung N, Peng CY, Hann HW, et al. Early hepatitis B virus DNA reduction in hepatitis B e-antigen positive patients with chronic hepatitis B: a randomized, international study of entecavir versus adefovir. Hepatology. 2009;49:72-79.
[13]. Tenney DJ, Rose RE, Baldick CJ, Pokornowski KA, Eggers BJ, Fang J, et al. Long-term monitoring shows hepatitis B virus resistance to entecavir in nucleoside-naïve patients is rare through 5years of therapy. Hepatology. 2009;49:1503-1514.
[14]. Marcellin P, Buti M, Krastev Z, et al. Tenoofivir disporixl fumarate versus adefovir dipivoxil for chronic hepatitis B. N Engl J Med. 2008;359:2442-2455.
[15]. Smow-Lampart A, Chappell BJ, Curtis M, Zhu Y, Heatthcote EJ, Marcellin GP, et al. Resistance surveillance for up to 144weeks in HBeAg+ and HBeAg- patients treated with tenofovir DF showed no relationship between virologic breakthrough and emergence of genotypic changes in HBV polymerase. Hepatology. 2009;50:532A
[16]. Shim JH, Lee HC, Kim KM, Lim YS, Chung YH, Lee YS, et al. Efficacy of entecavir in treatment-naive patients with hepatitis B virus-related decompensated cirrhosis. J Hepatol 2010. doi:10.1016/j.jhep.2009.11.077
[17]. Mazzucco EC, Hamatake RK, Colonno RJ, Tenney DJ. Entecavir for treatment of hepatitis B virus displays no in vitro mitochondrial toxicity or DNA polymerase gamma inhibition. Antimicrob Agents Chemother. 2008;52:598-605.
[18]. Fontana RJ. Side effects of long-term oral antiviral therapy for hepatitis B. Hepatology. 2009;49(5 Suppl.):S185-S195.
[19]. Lange CM, Bojunga J, Hofmann WP, Wunder K, Mihm U, Zeuzem S, et al. Severe lactic acidosis during treatment of chronic hepatitis B with entecavir in patients with impaired liver function. Hepatology. 2009
[20]. Kim BK, Oh J, Kwon BK, Choe WH, Ko SY, Rhee KH, et al. Clevudine myopathy in patients with chronic hepatitis B. J Hepatol. 2009;51:829-834.
[21]. Liaw YF, Raptopoulou-Gigi M, Cheinquer H, Sarin SK, Tanwandee T, Leung N, et al. Efficacy, safety of entecavir versus adefovir in chronic hepatitis B patients with evidence of hepatic decompensation. Hepatology. 2009;50:505A;
[22]. Pellicelli AM, Barbarini G, Romano M, Furlan C, Paffetti A, Villani R, et al. Entecavir therapy for lamivudine resistant HBV cirrhotic patients waiting for OLT: viral, biochemical outcomes at one year. Hepatology. 2009;50:514A;
[23]. Schiff ER, Liaw Y, Lee C, Akarc US, George PV, Wong F, et al. Interim results of a double-blind, randomized phase 2 study of the safety of tenofovir disoproxil fumarate, emtricitabine plus tenofovir disoproxil fumarate, entecavir in the treatment of chronic hepatitis B subjects with decompensated liver disease. Hepatology. 2009;50:222;
[24]. Gallant J, Staszewski ES, Pozniak AL, DeJesus E, Suleiman JM, Miller MD, et al. Efficacy and safety of tenofovir DV vs. stavudine in combination therapy in anti-retroviral naïve patients: a 3-year randomized trial. JAMA. 2004;292:191-201.
[25]. Raijnders JG, Vries-Sluijs T, Hansen BE, Zaaijer HL, Prins JM, Schuttten M, et al. Five-year tenofovir therapy is associated with maintained virologic response but significant decline in renal function in HIV-HBV coinfected patients. Hepatology. 2009;50:506A;
[26]. Constable C, Childs K, Bachon ML, Carriero DC, Mullen MP, Dieterich DT, et al. Does tenofovir increase the risk of abnormal bone and calcium metabolism?. Hepatology. 2009;51:518A;
Idenix Pharmaceuticals Initiates Proof-of-Concept Study for Protease Inhibitor IDX320 in Hepatitis C Patients
News Release
Idenix Pharmaceuticals Initiates Proof-of-Concept Study for Protease Inhibitor IDX320 in Hepatitis C Patients
CAMBRIDGE, Mass., June 10, 2010 /PRNewswire via COMTEX/ --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 initiated a 3-day proof-of-concept study of IDX320, a protease inhibitor for the treatment of hepatitis C virus (HCV) infection, under a Clinical Trial Application (CTA). The study is evaluating IDX320 in treatment-naive hepatitis C genotype 1-infected patients.
"The potent and multi-genotypic activity demonstrated in vitro,as well as the favorable pharmacokinetics observed in healthy volunteers, suggests a promising profile for further development of IDX320," said Jean-Pierre Sommadossi, Ph.D., chief executive officer of Idenix. "The landscape for combination development in HCV is evolving quickly. Assuming favorable results from the IDX320 proof-of-concept study, we plan to discuss with regulatory agencies a direct-acting antiviral combination strategy with IDX320 and IDX184, our HCV nucleotide polymerase inhibitor."
Douglas Mayers, M.D., Idenix's chief medical officer commented, "We are encouraged by the results seen to date with IDX320 and are hopeful that future clinical studies will allow us to continue advancing this program with the ultimate goal of treating a wide range of patients infected with HCV."
The proof-of-concept trial in HCV-infected patients is a Phase I/II randomized, parallel-arm, double-blind, placebo-controlled study evaluating the safety and antiviral activity of IDX320 in treatment-naive adult patients infected with chronic hepatitis C. The study will evaluate four doses of IDX320, ranging from 50 to 400 mg once-per-day, administered for three days. Each cohort of the study will evaluate eight patients randomized six to IDX320 and two to placebo.
About IDX320
IDX320, a macrocyclic HCV protease inhibitor, is an inhibitor of NS3/4A proteases from genotypes 1a, 1b, 2a and 4a (IC50 values from 0.8 to 1.9 nM), as well as from genotype 3a (IC50=23 nM). IDX320 did not inhibit nine tested cellular proteases (IC50 > 10 uM) in vitro, suggesting high selectivity. IDX320 bound tightly to the HCV protease enzyme with a long dissociation half-life (> 9 hours). After single 2 mg/kg oral doses of IDX320 in two animal species, favorable bioavailability and a long plasma half-life were observed, with substantial plasma concentrations 24 hours post dose. Comparable drug exposure was confirmed in healthy volunteers (n=6) receiving a single 200 mg oral dose. Further, no significant in vitro inhibition of human drug metabolizing enzymes, CYP450s and UGT1A1, by IDX320 suggests low potential for drug-drug interactions in patients.
About IDX184
IDX184 is a novel, liver-targeted nucleotide prodrug of 2'-methyl guanosine monophosphate, 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. IDX184 in combination with pegylated interferon and ribavirin has demonstrated a generally favorable safety profile and potent antiviral activity in an ongoing Phase IIa study.
News Release
Idenix Pharmaceuticals Reports Progress on Clinical Programs and First Quarter 2010 Financial Results
CAMBRIDGE, Mass., May 3, 2010 /PRNewswire via COMTEX/ --Idenix Pharmaceuticals, Inc. (Nasdaq: IDIX), a biopharmaceutical company engaged in the discovery and development of drugs for the treatment of human viral diseases, today reported unaudited financial results for the first quarter ended March 31, 2010. At March 31, 2010, Idenix's cash, cash equivalents and marketable securities totaled $33.8 million.
Research and Development Highlights
Phase IIa: IDX184, a liver-targeted hepatitis C virus (HCV) nucleotide prodrug
* In April 2010, Idenix announced interim data from an ongoing 14-day phase IIa study evaluating its lead HCV drug candidate, IDX184, a liver-targeted HCV nucleotide prodrug, in combination with pegylated interferon and ribavirin (PegIFN/RBV) in treatment-naive HCV genotype 1-infected patients. Patients receiving 50 and 100 mg of IDX184 in combination with pegylated interferon and ribavirin (PegIFN/RBV) demonstrated potent antiviral activity at 14 days with mean (+/- standard deviation) viral load reductions of 1.2 (+/- 1.1) log(10) IU/mL in the placebo cohort (n=8), 2.7 (+/- 1.3) log(10) IU/mL in the 50 mg IDX184 QD cohort (n=16), 4.0 (+/- 1.7) log(10) IU/mL in the 50 mg IDX184 BID cohort (n=8) and 4.2 (+/- 1.9) log(10) IU/mL in the 100 mg IDX184 QD cohort (n=8). Fifty percent of subjects receiving a total daily dose of 100 mg IDX184 achieved undetectable virus levels by Day 14. The side effect profile of IDX184 combined with PegIFN/RBV has been consistent with the laboratory and side effect profile of PegIFN/RBV. The most common adverse events reported were fatigue, myalgia, headache and nausea. Enrollment of the 150 mg once-daily cohort is now complete.
Phase I: IDX320, an HCV protease inhibitor
* In the first quarter of 2010, Idenix completed a double-blind, placebo-controlled phase I clinical trial evaluating single and multiple ascending doses of its HCV protease inhibitor, IDX320, in healthy volunteers. A three-day proof-of-concept study in treatment-naive HCV genotype 1-infected patients is expected to begin in the second quarter.
Phase I: IDX375, an HCV non-nucleoside polymerase inhibitor
* In the first quarter of 2010, Idenix continued the phase I clinical trial evaluating higher single and multiple doses of the free acid form of IDX375 in healthy volunteers. The company expects that these studies in healthy volunteers will be followed by a three-day proof-of-concept study in treatment-naive genotype 1-infected patients in the second half of 2010.
Phase IIb: GSK2248761/IDX899, a non-nucleoside reverse transcriptase inhibitor
* GSK2248761, for the treatment of HIV-1, has progressed through long-term chronic toxicology studies and drug-drug interaction studies in healthy volunteers. Idenix was notified by ViiV Healthcare Company, an affiliate of GlaxoSmithKline (GSK), that an operational preclinical milestone triggering a $6.5 million payment related to the development of GSK2248761 was achieved. GSK anticipates a broad phase IIb clinical development program to begin in 2010.
"We are pleased with the continued clinical progress of our broad pipeline of hepatitis C drug candidates from three major HCV drug classes," said Jean-Pierre Sommadossi, Ph.D., chairman and chief executive officer of Idenix. "With the anticipated completion of the 14-day phase IIa clinical trial of IDX184 and the three-day proof-of-concept study of IDX320 by mid-year 2010, we believe we will be a step closer toward exploring our first combination study utilizing these two direct-acting antiviral drug candidates."
Sommadossi continued, "We are excited to see the further advancement of GSK2248761 in the ViiV Healthcare pipeline. We look forward to the initiation of the phase IIb program this year."
First Quarter 2010 Financial Results
For the first quarter ended March 31, 2010, Idenix reported total revenues of $2.7 million, compared to total revenues of $4.0 million in the first quarter of 2009. The company reported a net loss of $16.2 million, or a loss of $0.24 per basic and diluted share, for the first quarter ended March 31, 2010, compared to a net loss of $12.9 million, or a loss of $0.23 per basic and diluted share for the first quarter ended March 31, 2009.
During the first quarter of 2010, Idenix initiated a plan to restructure its operations at the company's research facility in Montpellier, France to reduce its workforce by approximately 17 positions in connection with its ongoing cost saving initiatives. In the first quarter of 2010, Idenix recorded charges of $2.2 million for employee severance costs related to the Montpellier facility restructuring together with charges related to an earlier reduction of the company's United States workforce by 13 positions in January 2010. Idenix expects the restructurings to result in annualized savings of approximately $3.0 million to $4.0 million.
On April 29, 2010, Idenix announced the pricing of an underwritten offering of 6,460,672 shares of its common stock at a price of $4.35 per share. After the underwriting discount and estimated offering expenses payable by the company, the company expects to receive net proceeds of approximately $26.2 million. All of the shares are being sold by Idenix. The offering is expected to close on May 4, 2010, subject to customary closing conditions.
2010 Financial Guidance
The company expects that its current cash, cash equivalents and marketable securities, together with the anticipated royalty payments associated with product sales of Tyzeka(R)/Sebivo(R) (telbivudine), proceeds from the recent offering and the milestone payment from ViiV Healthcare Company can fund operations into the second half of 2011. This guidance assumes no additional milestone payments, license fees, reimbursement for development programs and no financing activities.
Conference Call and Webcast Information
Idenix will hold a conference call today at 4:30 p.m. ET. To access the call please dial (800) 471-3635 U.S./Canada or (706) 758-9475 International and enter passcode 70646639. To listen to a live webcast of the call, go to "Calendar of Events" in the Idenix Investor Center at www.idenix.com. Please log in approximately 10 minutes before the call to ensure a timely connection. A replay of the conference call and webcast will be available until May 17, 2010. To access the replay, please dial (800) 642-1687 U.S./Canada or (706) 645-9291 International and enter the passcode 70646639.
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 patients with chronic hepatitis C infection. For further information about Idenix, please refer to www.idenix.com.
Idenix Pharmaceuticals Initiates Proof-of-Concept Study for Protease Inhibitor IDX320 in Hepatitis C Patients
CAMBRIDGE, Mass., June 10, 2010 /PRNewswire via COMTEX/ --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 initiated a 3-day proof-of-concept study of IDX320, a protease inhibitor for the treatment of hepatitis C virus (HCV) infection, under a Clinical Trial Application (CTA). The study is evaluating IDX320 in treatment-naive hepatitis C genotype 1-infected patients.
"The potent and multi-genotypic activity demonstrated in vitro,as well as the favorable pharmacokinetics observed in healthy volunteers, suggests a promising profile for further development of IDX320," said Jean-Pierre Sommadossi, Ph.D., chief executive officer of Idenix. "The landscape for combination development in HCV is evolving quickly. Assuming favorable results from the IDX320 proof-of-concept study, we plan to discuss with regulatory agencies a direct-acting antiviral combination strategy with IDX320 and IDX184, our HCV nucleotide polymerase inhibitor."
Douglas Mayers, M.D., Idenix's chief medical officer commented, "We are encouraged by the results seen to date with IDX320 and are hopeful that future clinical studies will allow us to continue advancing this program with the ultimate goal of treating a wide range of patients infected with HCV."
The proof-of-concept trial in HCV-infected patients is a Phase I/II randomized, parallel-arm, double-blind, placebo-controlled study evaluating the safety and antiviral activity of IDX320 in treatment-naive adult patients infected with chronic hepatitis C. The study will evaluate four doses of IDX320, ranging from 50 to 400 mg once-per-day, administered for three days. Each cohort of the study will evaluate eight patients randomized six to IDX320 and two to placebo.
About IDX320
IDX320, a macrocyclic HCV protease inhibitor, is an inhibitor of NS3/4A proteases from genotypes 1a, 1b, 2a and 4a (IC50 values from 0.8 to 1.9 nM), as well as from genotype 3a (IC50=23 nM). IDX320 did not inhibit nine tested cellular proteases (IC50 > 10 uM) in vitro, suggesting high selectivity. IDX320 bound tightly to the HCV protease enzyme with a long dissociation half-life (> 9 hours). After single 2 mg/kg oral doses of IDX320 in two animal species, favorable bioavailability and a long plasma half-life were observed, with substantial plasma concentrations 24 hours post dose. Comparable drug exposure was confirmed in healthy volunteers (n=6) receiving a single 200 mg oral dose. Further, no significant in vitro inhibition of human drug metabolizing enzymes, CYP450s and UGT1A1, by IDX320 suggests low potential for drug-drug interactions in patients.
About IDX184
IDX184 is a novel, liver-targeted nucleotide prodrug of 2'-methyl guanosine monophosphate, 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. IDX184 in combination with pegylated interferon and ribavirin has demonstrated a generally favorable safety profile and potent antiviral activity in an ongoing Phase IIa study.
News Release
Idenix Pharmaceuticals Reports Progress on Clinical Programs and First Quarter 2010 Financial Results
CAMBRIDGE, Mass., May 3, 2010 /PRNewswire via COMTEX/ --Idenix Pharmaceuticals, Inc. (Nasdaq: IDIX), a biopharmaceutical company engaged in the discovery and development of drugs for the treatment of human viral diseases, today reported unaudited financial results for the first quarter ended March 31, 2010. At March 31, 2010, Idenix's cash, cash equivalents and marketable securities totaled $33.8 million.
Research and Development Highlights
Phase IIa: IDX184, a liver-targeted hepatitis C virus (HCV) nucleotide prodrug
* In April 2010, Idenix announced interim data from an ongoing 14-day phase IIa study evaluating its lead HCV drug candidate, IDX184, a liver-targeted HCV nucleotide prodrug, in combination with pegylated interferon and ribavirin (PegIFN/RBV) in treatment-naive HCV genotype 1-infected patients. Patients receiving 50 and 100 mg of IDX184 in combination with pegylated interferon and ribavirin (PegIFN/RBV) demonstrated potent antiviral activity at 14 days with mean (+/- standard deviation) viral load reductions of 1.2 (+/- 1.1) log(10) IU/mL in the placebo cohort (n=8), 2.7 (+/- 1.3) log(10) IU/mL in the 50 mg IDX184 QD cohort (n=16), 4.0 (+/- 1.7) log(10) IU/mL in the 50 mg IDX184 BID cohort (n=8) and 4.2 (+/- 1.9) log(10) IU/mL in the 100 mg IDX184 QD cohort (n=8). Fifty percent of subjects receiving a total daily dose of 100 mg IDX184 achieved undetectable virus levels by Day 14. The side effect profile of IDX184 combined with PegIFN/RBV has been consistent with the laboratory and side effect profile of PegIFN/RBV. The most common adverse events reported were fatigue, myalgia, headache and nausea. Enrollment of the 150 mg once-daily cohort is now complete.
Phase I: IDX320, an HCV protease inhibitor
* In the first quarter of 2010, Idenix completed a double-blind, placebo-controlled phase I clinical trial evaluating single and multiple ascending doses of its HCV protease inhibitor, IDX320, in healthy volunteers. A three-day proof-of-concept study in treatment-naive HCV genotype 1-infected patients is expected to begin in the second quarter.
Phase I: IDX375, an HCV non-nucleoside polymerase inhibitor
* In the first quarter of 2010, Idenix continued the phase I clinical trial evaluating higher single and multiple doses of the free acid form of IDX375 in healthy volunteers. The company expects that these studies in healthy volunteers will be followed by a three-day proof-of-concept study in treatment-naive genotype 1-infected patients in the second half of 2010.
Phase IIb: GSK2248761/IDX899, a non-nucleoside reverse transcriptase inhibitor
* GSK2248761, for the treatment of HIV-1, has progressed through long-term chronic toxicology studies and drug-drug interaction studies in healthy volunteers. Idenix was notified by ViiV Healthcare Company, an affiliate of GlaxoSmithKline (GSK), that an operational preclinical milestone triggering a $6.5 million payment related to the development of GSK2248761 was achieved. GSK anticipates a broad phase IIb clinical development program to begin in 2010.
"We are pleased with the continued clinical progress of our broad pipeline of hepatitis C drug candidates from three major HCV drug classes," said Jean-Pierre Sommadossi, Ph.D., chairman and chief executive officer of Idenix. "With the anticipated completion of the 14-day phase IIa clinical trial of IDX184 and the three-day proof-of-concept study of IDX320 by mid-year 2010, we believe we will be a step closer toward exploring our first combination study utilizing these two direct-acting antiviral drug candidates."
Sommadossi continued, "We are excited to see the further advancement of GSK2248761 in the ViiV Healthcare pipeline. We look forward to the initiation of the phase IIb program this year."
First Quarter 2010 Financial Results
For the first quarter ended March 31, 2010, Idenix reported total revenues of $2.7 million, compared to total revenues of $4.0 million in the first quarter of 2009. The company reported a net loss of $16.2 million, or a loss of $0.24 per basic and diluted share, for the first quarter ended March 31, 2010, compared to a net loss of $12.9 million, or a loss of $0.23 per basic and diluted share for the first quarter ended March 31, 2009.
During the first quarter of 2010, Idenix initiated a plan to restructure its operations at the company's research facility in Montpellier, France to reduce its workforce by approximately 17 positions in connection with its ongoing cost saving initiatives. In the first quarter of 2010, Idenix recorded charges of $2.2 million for employee severance costs related to the Montpellier facility restructuring together with charges related to an earlier reduction of the company's United States workforce by 13 positions in January 2010. Idenix expects the restructurings to result in annualized savings of approximately $3.0 million to $4.0 million.
On April 29, 2010, Idenix announced the pricing of an underwritten offering of 6,460,672 shares of its common stock at a price of $4.35 per share. After the underwriting discount and estimated offering expenses payable by the company, the company expects to receive net proceeds of approximately $26.2 million. All of the shares are being sold by Idenix. The offering is expected to close on May 4, 2010, subject to customary closing conditions.
2010 Financial Guidance
The company expects that its current cash, cash equivalents and marketable securities, together with the anticipated royalty payments associated with product sales of Tyzeka(R)/Sebivo(R) (telbivudine), proceeds from the recent offering and the milestone payment from ViiV Healthcare Company can fund operations into the second half of 2011. This guidance assumes no additional milestone payments, license fees, reimbursement for development programs and no financing activities.
Conference Call and Webcast Information
Idenix will hold a conference call today at 4:30 p.m. ET. To access the call please dial (800) 471-3635 U.S./Canada or (706) 758-9475 International and enter passcode 70646639. To listen to a live webcast of the call, go to "Calendar of Events" in the Idenix Investor Center at www.idenix.com. Please log in approximately 10 minutes before the call to ensure a timely connection. A replay of the conference call and webcast will be available until May 17, 2010. To access the replay, please dial (800) 642-1687 U.S./Canada or (706) 645-9291 International and enter the passcode 70646639.
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 patients with chronic hepatitis C infection. For further information about Idenix, please refer to www.idenix.com.
RG7128, a prodrug of PSI-6130
RG7128, a prodrug of PSI-6130
RG7128 is being developed by Pharmasset and Roche through our collaboration to develop nucleoside polymerase inhibitors for the treatment of chronic hepatitis C virus (HCV) infections. RG7128 is a pro-drug of a molecule we discovered named PSI-6130, an oral cytidine nucleoside analog. A pro-drug is a chemically modified form of a molecule designed to enhance the absorption, distribution and metabolic properties of that molecule. PSI-6130 is the active component of RG7128. At low concentrations, PSI-6130 was shown to be an inhibitor of HCV replication, specifically targeting the HCV RNA polymerase.
Phase 2b Trial (ongoing)
On April 24, 2009, Roche and we began dosing in a Phase 2b study with RG7128. The Phase 2b trial is anticipated to enroll about 400 treatment-naive, genotype-1 or genotype-4 HCV-infected patients. The trial will evaluate the dose and duration of treatment of RG7128 in combination with Pegasys plus Copegus. The primary efficacy endpoint of the trial will be the proportion of patients that achieve an SVR. Patients are expected to be enrolled into one of 5 arms:
* 24 weeks of total treatment, with RG7128 500mg BID in combination with Pegasys plus Copegus for 12 weeks, followed by 12 weeks of Pegasys plus Copegus
* 24 weeks of total treatment, with RG7128 1000mg BID in combination with Pegasys plus Copegus for 12 weeks, followed by 12 weeks of Pegasys plus Copegus
* 24 weeks of total treatment, with RG7128 1000mg BID in combination with Pegasys plus Copegus for 8 weeks, followed by a further 16 weeks of Pegasys plus Copegus
* 48 weeks of total treatment, with RG7128 1000mg BID in combination with Pegasys plus Copegus for 12 weeks, followed by a further 36 weeks of Pegasys plus Copegus.
* A control arm with only Pegasys plus Copegus for 48 weeks.
Patients in the 24 week arms will discontinue treatment at week 24 if they achieved an RVR. Patients who do not achieve an RVR will continue on the standard of care, Pegasys plus Copegus, until week 48. Patients are expected to be enrolled as two cohorts, with randomization of the second cohort, of about 300 patients, being initiated based on 12 week safety data of the first 100 patient cohort.
INFORM-1 Trial (ongoing)
On April 25, 2009, Roche, InterMune, Inc., and we announced the first results from our initial study of an interferon-free regimen for the treatment of patients chronically infected with HCV. This study, INFORM-1, combined for the first time in patients two oral, direct acting antiviral drugs, RG7128 and RG7227, an inhibitor of the HCV NS3/4 protease, which is being developed by InterMune, Inc., in collaboration with Roche. INFORM-1 is a randomized, double-blind, ascending dose Phase I trial. Patients receiving the combination of RG7227 and RG7128 for 14 days, without pegylated interferon or ribavirin, experienced a median reduction in HCV RNA of -4.8 to -5.2 log 10 IU/mL in the highest doses tested to date. The addition of RG7128 to RG7227 resulted in sustained HCV RNA reductions over the dosing period, with approximately 63% of patients having levels of virus in their blood below the limit of the quantification of the diagnostic assay (less than 40 IU/mL). Furthermore, 25% of patients in the highest dosage groups were below the limit of detection of the virus in their blood (less than 15 IU/mL) on the 14th day of dosing.
The combination was well tolerated over 14 days, with no treatment-related serious adverse events (SAEs), dose reductions or discontinuations. Pharmacokinetic analysis confirmed that there were no drug-drug interactions between the compounds.
The companies are now exploring combinations of RG7128 dosed twice-daily at 1000mg with RG7227 dosed twice-daily at 600mg and 900mg. In this expanded study, the companies also plan to explore this combination in treatment-experienced patients with HCV, or those who did not achieve SVR with a previous interferon-based treatment.
Phase 1 Studies
During September 2008, we completed the clinical activities in Part 3 of a Phase 1 clinical trial with RG7128 that was initiated by Roche and us in October 2006 under an IND filing. This expanded Phase 1 trial was a multiple center, observer-blinded, randomized and placebo-controlled study designed to investigate the pharmacokinetics, pharmacodynamics, safety, tolerability and food effect of RG7128 in healthy volunteers and in patients chronically infected with HCV genotype 1, 2 or 3. This Phase 1 trial also provided antiviral potency data over 14 and 28 days in patients chronically infected with HCV genotype 1 and following 28 days of treatment in patients chronically-infected with HCV genotypes 2 or 3. This adaptive Phase 1 study was comprised of three parts:
Part 1 was a single ascending dose study conducted in 46 healthy volunteers. The primary objective of Part 1 was to assess the safety, tolerability and pharmacokinetics of RG7128 following single ascending doses under fasting conditions. The secondary objective of Part 1 was to explore the effect of food on the pharmacokinetics of RG7128. Single oral doses of RG7128 were administered to 46 healthy volunteers in five sequential dose groups (500 mg, 1500 mg, 4500 mg, 6000 mg and 9000 mg) and one food effect group (1500 mg). Results from the single ascending dose portion of the study indicated:
* All doses of RG7128 studied (500 mg to 9000 mg) were generally safe and well-tolerated.
* All patients completed the study, and none experienced gastrointestinal adverse events or serious adverse events during the study.
* No hematologic or other safety laboratory abnormalities of clinical significance were noted.
* No maximum tolerated dose was identified.
Part 2 was a multiple ascending dose study conducted in 40 patients chronically infected with HCV genotype 1 who had previously failed interferon therapy. The primary objective of Part 2 was to assess the safety, tolerability and pharmacokinetics of RG7128 after once-daily (“QD”) or twice-daily (“BID”) dosing for 14 days. The secondary objective was to assess antiviral efficacy by measuring the change in HCV RNA. Results from the multiple ascending dose portion of the study indicated:
* RG7128 demonstrated potent, dose-dependent antiviral activity in four patient cohorts (8 active, 2 placebo per cohort) receiving 750 mg or 1500 mg administered either QD or BID for 14 days as monotherapy. The maximum decrease in HCV RNA from baseline was demonstrated in the patient cohort that received 1500 mg BID. RG7128 demonstrated mean HCV RNA decreases from baseline of 0.9 log (87.4% reduction), 1.5 log (96.8% reduction), 2.1 log (99.2% reduction) and 2.7 log (99.8% reduction) in patients receiving 750 mg QD, 1500 mg QD, 750 mg BID and 1500 mg BID, respectively. Based on the mean data, all four dose groups reached nadir values at Day 15. A maximum 4.2 log (99.9% reduction) HCV RNA decrease was demonstrated in a patient following 14 days of monotherapy with 1500 mg BID of RG7128, a value also below the level of detection, which was less than 15 International Units per milliliter (IU/ml).
* There was no evidence of viral rebound in any dose cohort during the 14 days of dosing.
* RG7128 was generally safe and well tolerated over 14 days of treatment of patients chronically infected with HCV genotype 1 who had previously failed interferon therapy. There were no serious adverse events, no adverse events requiring dose modification, and no dose-related gastrointestinal adverse events.
Part 3 was a 4-week study of RG7128 in combination with the current standard of care for chronic HCV infection, Pegasys (pegylated interferon) plus Copegus (ribavirin) in 81 treatment-naïve patients chronically infected with HCV genotype 1, and additionally, in 25 prior treatment non-responders, or patients who did not achieve an SVR with previous interferon-based therapy, who were chronically infected with HCV genotypes 2 or 3. The primary objective of this study was to assess the safety, tolerability, and pharmacokinetics of RG7128 in the clinically-relevant setting of combination therapy with the current standard of care for chronic HCV infection. The secondary objective of Part 3 was to evaluate the short-term change in HCV RNA. The study included three oral dose regimens of RG7128 (500 mg, 1500 mg and 1000 mg—cohorts 1,2 and 3, respectively) in patients chronically infected with HCV genotype 1 and one oral dose regimen of RG7128 (1500 mg—cohort 4) in patients chronically infected with HCV genotypes 2 or 3. All four dose regimens were administered twice-daily with Pegasys plus Copegus for 4 weeks. Dose cohorts 1, 2 and 4 enrolled 25 patients, with 20 patients randomized to receive RG7128 and five patients randomized to receive placebo, and cohort 3 enrolled 31 patients, with 25 patients randomized to receive RG7128 and six patients randomized to receive placebo, all administered in combination with standard of care. After completing four weeks of the triple combination regimen and a follow-up of four weeks of Pegasys plus Copegus, all patients are scheduled to receive up to 40 weeks of open-label standard of care dosing under a separate protocol.
Results from cohorts 1, 2 and 3 in 81 treatment-naïve patients chronically infected with HCV genotype 1 indicated:
* Following 4 weeks of treatment with RG7128 500mg BID with Pegasys plus Copegus (cohort 1), patients achieved a mean 3.8 log10 IU/mL decrease in HCV RNA and 30% (6 of 20) achieved undetectable levels of HCV RNA (<15 IU/ml), or rapid virologic response (“RVR”).
* Following 4 weeks of treatment with RG7128 1500mg BID with Pegasys plus Copegus (cohort 2), patients achieved a mean 5.1 log10 IU/mL decrease in HCV RNA and 85% (17 of 20) achieved RVR.
* Following 4 weeks of treatment with RG7128 1000mg BID with Pegasys plus Copegus (cohort 3), preliminary results indicated patients achieved a mean 5.1 log10 IU/mL decrease in HCV RNA and 88% (22 of 25) patients achieved RVR.
* Following 4 weeks of treatment with placebo with Pegasys plus Copegus, patients achieved a mean 2.9 log10 IU/mL decrease in HCV RNA and 18.75% (3 of 16) achieved RVR.
For cohorts 1, 2 and 3 in treatment-naïve genotype 1 patients, safety and tolerability for the 4-week treatment period were similar for RG7128 with Pegasys plus Copegus compared to placebo with Pegasys plus Copegus. There were no serious adverse events reported during the 4-week treatment periods of triple therapy, and most of the adverse events reported were of mild to moderate intensity. Headache and fatigue were the most frequently reported adverse events in patients who received active RG7128 plus Pegasys plus Copegus, with an overall frequency of 66% and 42% reporting at least one of these events, respectively. These events were also the most frequently reported adverse events in patients who received placebo with Pegasys and Copegus. In general, the adverse events reported were consistent with the clinical safety profile for Pegasys and Copegus, including the frequency and severity of these adverse events, as well as any general body system observations. Grade 3/4 neutropenia was observed in 31% of the placebo patients and in 12% to 30% of the RG7128 patients in each active dosing cohort. Grade 3 changes in hemoglobin were observed in 19% of the placebo patients and in 31% of the RG7128 patients. There were no clinically significant changes in hepatic, renal, or other safety laboratory parameters, vital signs, or electrocardiograms. Overall, there was no clinical evidence of any major organ toxicities related to RG7128. One patient in the active treatment group discontinued the study during the 4 week treatment period due to lower-gastrointestinal adverse events. At the time of study discontinuation, this patient had undetectable HCV RNA. RG7128 was generally safe and well-tolerated when administered for 4 weeks in combinations with Pegasus plus Copegus in patients with HCV genotype 1.
Results from the 1500 mg dose cohort (cohort 4) in 25 prior treatment non-responders, or patients who did not achieve an SVR with previous interferon-based therapy, and who were chronically infected with HCV genotypes 2 or 3 indicated:
* Following 4 weeks of treatment with RG7128 1500mg BID with Pegasys plus Copegus (cohort 4), preliminary results indicated patients achieved a mean 5.0 log 10 IU/mL decrease in HCV RNA and 90% (18 of 20) patients achieved RVR.
* Following 4 weeks of treatment with placebo with Pegasys plus Copegus, patients achieved a mean 3.7 log 10 IU/mL decrease in HCV RNA and 60.0% (3 of 5) achieved RVR.
* Safety and tolerability during the 4-week treatment period were similar for RG7128 with Pegasys plus Copegus compared to placebo with Pegasys plus Copegus. There were no serious adverse events reported during the 4-week treatment period, and most of the adverse events reported were of mild to moderate intensity. One subject discontinued RG7128, Pegasys and Copegus due to protocol specified stopping criteria (not treatment-emergent), and ECG changes. Adverse events reported in cohort 4 were similar to those reported in Cohorts 1-3. Grade 3/4 neutropenia was observed in 0% of the 5 placebo patients and in 20% of the 20 RG7128 patients in the active dosing cohort. Grade 3 changes in hemoglobin were observed in 20% of the placebo patients and in 25% of the RG7128 patients. There were no clinically significant changes in hepatic, renal, or other safety laboratory parameters, vital signs, or electrocardiograms. As seen in the patients infected with HCV genotype 1, there was no clinical evidence of any major organ toxicities related to RG7128. RG7128 was generally safe and well-tolerated when administered for 4 weeks in combination with Pegasus plus Copegus in patients with HCV genotypes 2 and 3.
RG7128 is being developed by Pharmasset and Roche through our collaboration to develop nucleoside polymerase inhibitors for the treatment of chronic hepatitis C virus (HCV) infections. RG7128 is a pro-drug of a molecule we discovered named PSI-6130, an oral cytidine nucleoside analog. A pro-drug is a chemically modified form of a molecule designed to enhance the absorption, distribution and metabolic properties of that molecule. PSI-6130 is the active component of RG7128. At low concentrations, PSI-6130 was shown to be an inhibitor of HCV replication, specifically targeting the HCV RNA polymerase.
Phase 2b Trial (ongoing)
On April 24, 2009, Roche and we began dosing in a Phase 2b study with RG7128. The Phase 2b trial is anticipated to enroll about 400 treatment-naive, genotype-1 or genotype-4 HCV-infected patients. The trial will evaluate the dose and duration of treatment of RG7128 in combination with Pegasys plus Copegus. The primary efficacy endpoint of the trial will be the proportion of patients that achieve an SVR. Patients are expected to be enrolled into one of 5 arms:
* 24 weeks of total treatment, with RG7128 500mg BID in combination with Pegasys plus Copegus for 12 weeks, followed by 12 weeks of Pegasys plus Copegus
* 24 weeks of total treatment, with RG7128 1000mg BID in combination with Pegasys plus Copegus for 12 weeks, followed by 12 weeks of Pegasys plus Copegus
* 24 weeks of total treatment, with RG7128 1000mg BID in combination with Pegasys plus Copegus for 8 weeks, followed by a further 16 weeks of Pegasys plus Copegus
* 48 weeks of total treatment, with RG7128 1000mg BID in combination with Pegasys plus Copegus for 12 weeks, followed by a further 36 weeks of Pegasys plus Copegus.
* A control arm with only Pegasys plus Copegus for 48 weeks.
Patients in the 24 week arms will discontinue treatment at week 24 if they achieved an RVR. Patients who do not achieve an RVR will continue on the standard of care, Pegasys plus Copegus, until week 48. Patients are expected to be enrolled as two cohorts, with randomization of the second cohort, of about 300 patients, being initiated based on 12 week safety data of the first 100 patient cohort.
INFORM-1 Trial (ongoing)
On April 25, 2009, Roche, InterMune, Inc., and we announced the first results from our initial study of an interferon-free regimen for the treatment of patients chronically infected with HCV. This study, INFORM-1, combined for the first time in patients two oral, direct acting antiviral drugs, RG7128 and RG7227, an inhibitor of the HCV NS3/4 protease, which is being developed by InterMune, Inc., in collaboration with Roche. INFORM-1 is a randomized, double-blind, ascending dose Phase I trial. Patients receiving the combination of RG7227 and RG7128 for 14 days, without pegylated interferon or ribavirin, experienced a median reduction in HCV RNA of -4.8 to -5.2 log 10 IU/mL in the highest doses tested to date. The addition of RG7128 to RG7227 resulted in sustained HCV RNA reductions over the dosing period, with approximately 63% of patients having levels of virus in their blood below the limit of the quantification of the diagnostic assay (less than 40 IU/mL). Furthermore, 25% of patients in the highest dosage groups were below the limit of detection of the virus in their blood (less than 15 IU/mL) on the 14th day of dosing.
The combination was well tolerated over 14 days, with no treatment-related serious adverse events (SAEs), dose reductions or discontinuations. Pharmacokinetic analysis confirmed that there were no drug-drug interactions between the compounds.
The companies are now exploring combinations of RG7128 dosed twice-daily at 1000mg with RG7227 dosed twice-daily at 600mg and 900mg. In this expanded study, the companies also plan to explore this combination in treatment-experienced patients with HCV, or those who did not achieve SVR with a previous interferon-based treatment.
Phase 1 Studies
During September 2008, we completed the clinical activities in Part 3 of a Phase 1 clinical trial with RG7128 that was initiated by Roche and us in October 2006 under an IND filing. This expanded Phase 1 trial was a multiple center, observer-blinded, randomized and placebo-controlled study designed to investigate the pharmacokinetics, pharmacodynamics, safety, tolerability and food effect of RG7128 in healthy volunteers and in patients chronically infected with HCV genotype 1, 2 or 3. This Phase 1 trial also provided antiviral potency data over 14 and 28 days in patients chronically infected with HCV genotype 1 and following 28 days of treatment in patients chronically-infected with HCV genotypes 2 or 3. This adaptive Phase 1 study was comprised of three parts:
Part 1 was a single ascending dose study conducted in 46 healthy volunteers. The primary objective of Part 1 was to assess the safety, tolerability and pharmacokinetics of RG7128 following single ascending doses under fasting conditions. The secondary objective of Part 1 was to explore the effect of food on the pharmacokinetics of RG7128. Single oral doses of RG7128 were administered to 46 healthy volunteers in five sequential dose groups (500 mg, 1500 mg, 4500 mg, 6000 mg and 9000 mg) and one food effect group (1500 mg). Results from the single ascending dose portion of the study indicated:
* All doses of RG7128 studied (500 mg to 9000 mg) were generally safe and well-tolerated.
* All patients completed the study, and none experienced gastrointestinal adverse events or serious adverse events during the study.
* No hematologic or other safety laboratory abnormalities of clinical significance were noted.
* No maximum tolerated dose was identified.
Part 2 was a multiple ascending dose study conducted in 40 patients chronically infected with HCV genotype 1 who had previously failed interferon therapy. The primary objective of Part 2 was to assess the safety, tolerability and pharmacokinetics of RG7128 after once-daily (“QD”) or twice-daily (“BID”) dosing for 14 days. The secondary objective was to assess antiviral efficacy by measuring the change in HCV RNA. Results from the multiple ascending dose portion of the study indicated:
* RG7128 demonstrated potent, dose-dependent antiviral activity in four patient cohorts (8 active, 2 placebo per cohort) receiving 750 mg or 1500 mg administered either QD or BID for 14 days as monotherapy. The maximum decrease in HCV RNA from baseline was demonstrated in the patient cohort that received 1500 mg BID. RG7128 demonstrated mean HCV RNA decreases from baseline of 0.9 log (87.4% reduction), 1.5 log (96.8% reduction), 2.1 log (99.2% reduction) and 2.7 log (99.8% reduction) in patients receiving 750 mg QD, 1500 mg QD, 750 mg BID and 1500 mg BID, respectively. Based on the mean data, all four dose groups reached nadir values at Day 15. A maximum 4.2 log (99.9% reduction) HCV RNA decrease was demonstrated in a patient following 14 days of monotherapy with 1500 mg BID of RG7128, a value also below the level of detection, which was less than 15 International Units per milliliter (IU/ml).
* There was no evidence of viral rebound in any dose cohort during the 14 days of dosing.
* RG7128 was generally safe and well tolerated over 14 days of treatment of patients chronically infected with HCV genotype 1 who had previously failed interferon therapy. There were no serious adverse events, no adverse events requiring dose modification, and no dose-related gastrointestinal adverse events.
Part 3 was a 4-week study of RG7128 in combination with the current standard of care for chronic HCV infection, Pegasys (pegylated interferon) plus Copegus (ribavirin) in 81 treatment-naïve patients chronically infected with HCV genotype 1, and additionally, in 25 prior treatment non-responders, or patients who did not achieve an SVR with previous interferon-based therapy, who were chronically infected with HCV genotypes 2 or 3. The primary objective of this study was to assess the safety, tolerability, and pharmacokinetics of RG7128 in the clinically-relevant setting of combination therapy with the current standard of care for chronic HCV infection. The secondary objective of Part 3 was to evaluate the short-term change in HCV RNA. The study included three oral dose regimens of RG7128 (500 mg, 1500 mg and 1000 mg—cohorts 1,2 and 3, respectively) in patients chronically infected with HCV genotype 1 and one oral dose regimen of RG7128 (1500 mg—cohort 4) in patients chronically infected with HCV genotypes 2 or 3. All four dose regimens were administered twice-daily with Pegasys plus Copegus for 4 weeks. Dose cohorts 1, 2 and 4 enrolled 25 patients, with 20 patients randomized to receive RG7128 and five patients randomized to receive placebo, and cohort 3 enrolled 31 patients, with 25 patients randomized to receive RG7128 and six patients randomized to receive placebo, all administered in combination with standard of care. After completing four weeks of the triple combination regimen and a follow-up of four weeks of Pegasys plus Copegus, all patients are scheduled to receive up to 40 weeks of open-label standard of care dosing under a separate protocol.
Results from cohorts 1, 2 and 3 in 81 treatment-naïve patients chronically infected with HCV genotype 1 indicated:
* Following 4 weeks of treatment with RG7128 500mg BID with Pegasys plus Copegus (cohort 1), patients achieved a mean 3.8 log10 IU/mL decrease in HCV RNA and 30% (6 of 20) achieved undetectable levels of HCV RNA (<15 IU/ml), or rapid virologic response (“RVR”).
* Following 4 weeks of treatment with RG7128 1500mg BID with Pegasys plus Copegus (cohort 2), patients achieved a mean 5.1 log10 IU/mL decrease in HCV RNA and 85% (17 of 20) achieved RVR.
* Following 4 weeks of treatment with RG7128 1000mg BID with Pegasys plus Copegus (cohort 3), preliminary results indicated patients achieved a mean 5.1 log10 IU/mL decrease in HCV RNA and 88% (22 of 25) patients achieved RVR.
* Following 4 weeks of treatment with placebo with Pegasys plus Copegus, patients achieved a mean 2.9 log10 IU/mL decrease in HCV RNA and 18.75% (3 of 16) achieved RVR.
For cohorts 1, 2 and 3 in treatment-naïve genotype 1 patients, safety and tolerability for the 4-week treatment period were similar for RG7128 with Pegasys plus Copegus compared to placebo with Pegasys plus Copegus. There were no serious adverse events reported during the 4-week treatment periods of triple therapy, and most of the adverse events reported were of mild to moderate intensity. Headache and fatigue were the most frequently reported adverse events in patients who received active RG7128 plus Pegasys plus Copegus, with an overall frequency of 66% and 42% reporting at least one of these events, respectively. These events were also the most frequently reported adverse events in patients who received placebo with Pegasys and Copegus. In general, the adverse events reported were consistent with the clinical safety profile for Pegasys and Copegus, including the frequency and severity of these adverse events, as well as any general body system observations. Grade 3/4 neutropenia was observed in 31% of the placebo patients and in 12% to 30% of the RG7128 patients in each active dosing cohort. Grade 3 changes in hemoglobin were observed in 19% of the placebo patients and in 31% of the RG7128 patients. There were no clinically significant changes in hepatic, renal, or other safety laboratory parameters, vital signs, or electrocardiograms. Overall, there was no clinical evidence of any major organ toxicities related to RG7128. One patient in the active treatment group discontinued the study during the 4 week treatment period due to lower-gastrointestinal adverse events. At the time of study discontinuation, this patient had undetectable HCV RNA. RG7128 was generally safe and well-tolerated when administered for 4 weeks in combinations with Pegasus plus Copegus in patients with HCV genotype 1.
Results from the 1500 mg dose cohort (cohort 4) in 25 prior treatment non-responders, or patients who did not achieve an SVR with previous interferon-based therapy, and who were chronically infected with HCV genotypes 2 or 3 indicated:
* Following 4 weeks of treatment with RG7128 1500mg BID with Pegasys plus Copegus (cohort 4), preliminary results indicated patients achieved a mean 5.0 log 10 IU/mL decrease in HCV RNA and 90% (18 of 20) patients achieved RVR.
* Following 4 weeks of treatment with placebo with Pegasys plus Copegus, patients achieved a mean 3.7 log 10 IU/mL decrease in HCV RNA and 60.0% (3 of 5) achieved RVR.
* Safety and tolerability during the 4-week treatment period were similar for RG7128 with Pegasys plus Copegus compared to placebo with Pegasys plus Copegus. There were no serious adverse events reported during the 4-week treatment period, and most of the adverse events reported were of mild to moderate intensity. One subject discontinued RG7128, Pegasys and Copegus due to protocol specified stopping criteria (not treatment-emergent), and ECG changes. Adverse events reported in cohort 4 were similar to those reported in Cohorts 1-3. Grade 3/4 neutropenia was observed in 0% of the 5 placebo patients and in 20% of the 20 RG7128 patients in the active dosing cohort. Grade 3 changes in hemoglobin were observed in 20% of the placebo patients and in 25% of the RG7128 patients. There were no clinically significant changes in hepatic, renal, or other safety laboratory parameters, vital signs, or electrocardiograms. As seen in the patients infected with HCV genotype 1, there was no clinical evidence of any major organ toxicities related to RG7128. RG7128 was generally safe and well-tolerated when administered for 4 weeks in combination with Pegasus plus Copegus in patients with HCV genotypes 2 and 3.
New directly acting antivirals for hepatitis C: potential for interaction with antiretrovirals
New directly acting antivirals for hepatitis C:
potential for interaction with antiretrovirals
Journal of Antimicrobial Chemotherapy Advance Pub March 2010 65(6):1079-1085
"Eventually, HCV treatment may involve a combination of directly acting STAT-C agents, without the requirement for PEG-IFN or ribavirin treatment. In a manner analogous to HIV therapy, this is likely to comprise a combination of protease and polymerase inhibitors,9 which can achieve suppression of viral replication, and be suitably robust against emergence of resistance. In the more immediate future however, single STAT-C agents will be added to PEG-IFN and ribavirin therapy.....Currently, ARV treatment may be adjusted, as far as is practicable, to enable optimal administration of anti-HCV therapy, without compromising ARV efficacy. This will become increasingly complex to manage with the addition of new STAT-C agents. Figure 2 summarizes known an
Conclusions: As more data become available concerning the metabolism, clearance, drug transporter interaction and toxicities of the STAT-C agents in development, potential DDIs with ARVs may be better anticipated. Many interactions are expected between HIV PIs and NNRTIs, and HCV protease inhibitors. It is unlikely that DDIs will preclude treatment of both conditions concurrently; but accurate characterization of these interactions, and prompt recognition of potential dangers by clinicians is important to ensure the safety and efficacy of treatment.
It is also important to note that although DDIs can be theoretically pre-empted and a basis formed for practical management, therapeutic drug monitoring and assessment of individual patient response are important in the management of complicated regimens, particularly when they involve new agents with relatively little experience in the clinical setting."
Kay Seden1,*, David Back2 and Saye Khoo2
1 NIHR Biomedical Research Centre, Royal Liverpool & Broadgreen University Hospitals Trust, Liverpool, UK 2 Department of Pharmacology and Therapeutics, University of Liverpool, Liverpool, UK
* Corresponding author. Department of Pharmacology, University of Liverpool, Pharmacology Research Laboratories, Block H, First Floor, 70 Pembroke Place, Liverpool L69 3GF, UK. Tel/Fax: +44-151-706-2883; E-mail: kseden@liverpool.ac.uk
Abstract
Recent advances in the development of agents that act specifically to inhibit hepatitis C virus (HCV) are set to fundamentally change the way that patients will be treated. New directly acting anti-HCV agents such as protease and polymerase inhibitors will initially be added to standard of care with pegylated interferon-{alpha} and ribavirin. However, future therapy is likely to constitute combinations of agents which act at distinct stages of viral replication and have differing resistance profiles. While directly acting anti-HCV agents will undoubtedly improve treatment outcomes, the introduction of combination therapy may not be without complications in some patient groups. HIV-positive patients who are receiving antiretrovirals (ARVs) are relatively highly represented among those with HCV infection, and are at high risk of drugÐdrug interactions (DDIs). As combination anti-HCV treatment gradually evolves to resemble anti-HIV therapy, it is essential to consider the increased potential for DDIs in patients receiving combination anti-HCV therapy, and particularly in HCV/HIV-co-infected individuals. Therapeutic drug monitoring is likely to play a role in the clinical management of such interactions.
Introduction
Treatment of hepatitis C virus (HCV) with antivirals aims to achieve a sustained virological response (SVR), which equates to undetectable HCV RNA levels 6 months after completion of therapy. This is associated with reduced progression of liver disease and reduced viral transmission. The standard of care for patients requiring treatment for chronic HCV currently involves a combination of pegylated interferon-{alpha} (PEG-IFN) and ribavirin, with response rates and duration of treatment that vary according to HCV genotype.1,2 Weight-based dosing of ribavirin is associated with better treatment outcomes for certain genotypes.3 Clinical studies have shown that combinations of ribavirin and PEG-IFN can achieve an SVR in only 36%Ð46% of patients with HCV genotype 1 monoinfection, when treated for 48 weeks.1,4
Due to the limited success rates of current treatment and the well documented adverse event profiles of ribavirin and PEG-IFN, there is evident need for novel, directly acting treatments. Specifically targeted antiviral therapy for HCV (STAT-C) represents a new treatment paradigm with improved patient outcomes. There are several STAT-C agents at various stages of clinical development, including protease inhibitors (PIs)5Ð8 and nucleoside/non-nucleoside polymerase inhibitors.9,10 Other agents under investigation include novel analogues of ribavirin,11 modified interferons,12 cyclophilin B,13 {alpha} glucosidase inhibitors,14 oligonucleotides15 and immune modulators.16
In patients co-infected with HIV/HCV, progression to cirrhosis, end-stage liver disease and ultimately death is more rapid.17 HCV viral loads may be higher in co-infected patients than those with monoinfection,17 and treatment outcomes in terms of SVR rates may be worse in co-infected patients, particularly with genotype 1 HCV infection.18 No significant difference in efficacy or safety has been reported in co-infected patients treated with PEG-IFN-2a plus ribavirin or PEG-IFN-2b plus ribavirin.19 HCV-associated liver failure is increasing significantly as a cause of death in HIV-positive patients in the post highly active antiretroviral therapy (HAART) era in developed countries.20 It therefore follows that significant changes in HCV therapy could profoundly improve the treatment outcomes of this patient group. However, the addition of combination therapies, which include novel agents, for patients who are taking antiretroviral (ARV) regimens is unlikely to be without complication; clinically significant drugÐdrug interactions (DDIs) involving ARVs are common, affecting 27% of 159 HIV-infected outpatients in a UK study21 and 23%Ð26% of 220 HIV-infected outpatients in a study in the Netherlands.22
The future of anti-HCV therapy
Every stage of the HCV life cycle potentially represents a target for STAT-C agents,15 meaning that increasing numbers of novel agents and novel classes of agents are likely to emerge, in a manner similar to ARV therapy. Currently in Phase III trials, the NS3/4A PIs telaprevir (VX-950)5,6 and boceprevir (SCH 503034)8 are likely to be the first STAT-C agents licensed. The development of some of the furthest advanced nucleoside analogue NS5B polymerase inhibitors has been halted due to toxicities; however, R7128, a pro-drug of PSI-6130, is currently in Phase II trials. Figure 1 illustrates the location in the HCV genome of drug targets, including the NS3/4A serine protease and the NS5B RNA-dependent RNA polymerase enzymes, which, being essential for viral replication, are primary targets for anti-HCV therapy.
Figure 1. Important targets for STAT-C therapy in the HCV genome. Derived from information in Pawlotsky et al.15 and Chevaliez and Pawlotsky.46
Eventually, HCV treatment may involve a combination of directly acting STAT-C agents, without the requirement for PEG-IFN or ribavirin treatment. In a manner analogous to HIV therapy, this is likely to comprise a combination of protease and polymerase inhibitors,9 which can achieve suppression of viral replication, and be suitably robust against emergence of resistance. In the more immediate future however, single STAT-C agents will be added to PEG-IFN and ribavirin therapy, until there are sufficient effective STAT-C agents licensed with which to afford effective combination therapy with a suitable barrier to resistance. Several studies have confirmed the pivotal role of ribavirin in successful HCV antiviral therapy, despite having little intrinsic antiviral activity. For example, with telaprevir and PEG-IFN, ribavirin was found to increase SVR rates by preventing relapse and emergence of telaprevir resistance.6
To draw another comparison with HIV therapy, it is almost certain that the selection of several agents without overlapping resistance patterns will be required for combination therapy, which will increase both the complexity and risk for DDIs.
ARVs and current anti-HCV treatment: potential for DDIs
As PEG-IFN and ribavirin are expected to remain a fundamental component of anti-HCV treatment in the near future, their potential for interaction with ARVs remains important with the advent of STAT-C agents.
Concomitant administration of abacavir with PEG-IFN and ribavirin has been associated with an increased risk of non-response to anti-HCV therapy,23 and an interaction between abacavir and ribavirin has been suggested. As both drugs are guanosine analogues and have some metabolic pathways in common, an inhibitory competition for phosphorylation is the likely mechanism.24
Combinations of zidovudine with ribavirin and PEG-IFN can lead to increased risk of severe haematological toxicity, including anaemia. The use of zidovudine has been identified as an independent factor contributing to haematological adverse events in patients undergoing ribavirin and PEG-IFN treatment; the combination is not recommended.25
The use of didanosine alongside ribavirin is associated with increased risk of mitochondrial toxicity, which may be attributed to increased exposure to the active metabolite of didanosine, dideoxyadenosine 5'-triphosphate, when didanosine is co-administered with ribavirin.26Ð28 Toxicity may be severe and co-administration is not recommended. Mitochondrial toxicity has also been observed with combinations of stavudine and ribavirin. In vitro data have shown that ribavirin can inhibit phosphorylation of zidovudine and stavudine. The clinical significance is not clear; however, close monitoring of HIV RNA with this combination is recommended.
In relation to HIV PIs, it has been reported that in HIV/HCV-co-infected patients, serum bilirubin increases following initiation of PEG-IFN and ribavirin were 1.9-fold higher in patients taking an atazanavir-containing regimen.29 Hyperbilirubinaemia is, however, a relatively common side effect of atazanavir treatment, for which there are various risk factors irrespective of anti-HCV treatment.30 Atazanavir inhibits UGT1A1, an enzyme involved in bilirubin conjugation; it is important to note that different genotypes of UGT1A1 (notably *6*6, *7*7 and *6*731) have an impact on enzyme activity, and interindividual variability in the frequency and severity of hyperbilirubinaemia has been observed in patients treated with atazanavir.31
With HIV non-nucleoside reverse transcriptase inhibitors (NNRTIs), if patients receive efavirenz alongside PEG-IFN, monitoring of CNS effects is important, as the incidence of depressive symptoms in patients with HIV/HCV co-infection treated with IFN is reportedly high.32
Currently, ARV treatment may be adjusted, as far as is practicable, to enable optimal administration of anti-HCV therapy, without compromising ARV efficacy. This will become increasingly complex to manage with the addition of new STAT-C agents. Figure 2 summarizes known and potential DDIs between ARVs and anti-HCV drugs in current use and the HCV PIs in late stages of development.
Figure 2. A summary of known and anticipated DDIs between antiretrovirals and anti-HCV drugs in current use and the HCV protease inhibitors in Phase III development.
Potential interactions between ARVs and STAT-C agents
As illustrated in Figure 2, few data are currently available to evaluate the potential for DDIs between ARVs and emerging STAT-C agents. Most is known about telaprevir and boceprevir, the HCV PIs which are furthest through the development process.
Although they target serine rather than aspartate proteins, HCV PIs have structural similarities with HIV PIs, and there is evidence to suggest that they share a common route of metabolism.33 In human liver microsomes, the metabolism of telaprevir and boceprevir was substantially inhibited in the presence of relatively low concentrations of ritonavir.33 In addition, on co-dosing either telaprevir or boceprevir with ritonavir in rats, the plasma exposure of both HCV agents was markedly increased. These findings suggest that telaprevir and boceprevir may be primarily or exclusively metabolized by CYP3A. This has implications for co-administration of ARV therapy, as HIV PIs such as lopinavir and darunavir inhibit CYP3A4, whereas the NNRTIs efavirenz, nevirapine and etravirine induce metabolism mediated by this enzyme. Although PIs are able to inhibit CYP3A4, the observed effect may be predominantly due to potent inhibitory action of ritonavir, which is commonly used as a pharmacokinetic enhancer to boost levels of other PIs.
Such interactions, when more comprehensively understood, may not be problematic if appropriately managed. For example, ritonavir could be utilized to dually boost both an HIV PI and an HCV PI. Both ritonavir and newer pharmacokinetic enhancers in development such as GS 935034 could be used to reduce dosing frequency, allowing telaprevir and boceprevir to be dosed less frequently than 8 hourly and thus increasing the likelihood of adherence.33 In addition, there are ongoing studies to develop follow-on compounds of the clinical candidate. For example, systematic structureÐactivity relationship studies of different regions of boceprevir have shown improved potency and improved pharmacokinetics compared with boceprevir in model systems.35
As a result of structural similarities between some nucleoside reverse transcriptase inhibitors (NRTIs) and HCV NS5B nucleoside polymerase inhibitors, competition for clearance pathways cannot be ruled out. For example, R7128 is a cytidine analogue, structurally related to the HIV NRTI cytidine analogues lamivudine and emtricitabine. Although there may be potential for interaction, relevance to the clinical setting remains to be elucidated.
The non-nucleoside polymerase inhibitor GS 9190 has little potential for inhibition or induction of CYP450 enzymes and is not transported by P-glycoprotein (P-gp) in vitro; therefore, interactions via these mechanisms are unlikely.36
Overlapping toxicity profiles and adverse effects also need to be considered when using STAT-C agents alongside ARV therapy. For example, clinical studies have illustrated that anaemia is a relatively common adverse effect experienced by patients receiving telaprevir5,6 or boceprevir37 therapy. The frequency of anaemia was increased in treatment groups receiving telaprevir alongside PEG-IFN and ribavirin, compared with groups receiving PEG-IFN and ribavirin alone.5,6 This may have implications for patients who are taking zidovudine as part of their ARV regimen, as anaemia is a common adverse reaction with zidovudine treatment. Concomitant use of telaprevir or boceprevir with zidovudine could therefore increase the risk of anaemia, particularly when used in combination with ribavirin, which is likely to be the case. Use of ribavirin with zidovudine is currently not recommended by one of the manufacturers of ribavirin,38 due to anaemia risk.
Phase II studies have shown an increased incidence of hyperbilirubinaemia in patients treated with the cyclophilin inhibitor Debio 025 compared with controls.39 This may be due to the inhibition of the multidrug resistance protein 2 (MRP2) transporter by Debio 025,40 resulting in reduced elimination of conjugated bilirubin. As various ARVs are themselves inhibitors of or substrates for MRP2, interactions via this mechanism or UGT1A1, as previously described, cannot be ruled out. It has been suggested that haplotypes of certain genes, such as UGT1A, may be useful predictors of PI-induced hyperbilirubinaemia.41 Genetic diagnostics may be an important application to future HCV, as well as HIV therapies. Interestingly, in the context of co-infection, Debio 025 has also shown inhibitory activity against HIV-1 in vitro.42
Although some Phase II studies of STAT-C agents have reported no significant changes in various laboratory parameters and electrocardiogram readings,5,43 as these new drugs become licensed and clinical experience of their use develops, it is possible that toxicities may emerge, as with ARVs. For example, lipodystrophy with various ARVs,44 mitochondrial toxicity with didanosine28 and, more recently, cardiovascular effects with abacavir.45 It is not inconceivable that STAT-C agents in development could have metabolic or mitochondrial toxicities in common with some ARVs, and future regimens may need to be adapted to minimize risk.
Table 1 lists STAT-C agents in Phase II or III trials and, where data are available, their potential to interact with ARVs.
Conclusions
As more data become available concerning the metabolism, clearance, drug transporter interaction and toxicities of the STAT-C agents in development, potential DDIs with ARVs may be better anticipated. Many interactions are expected between HIV PIs and NNRTIs, and HCV protease inhibitors. It is unlikely that DDIs will preclude treatment of both conditions concurrently; but accurate characterization of these interactions, and prompt recognition of potential dangers by clinicians is important to ensure the safety and efficacy of treatment.
It is also important to note that although DDIs can be theoretically pre-empted and a basis formed for practical management, therapeutic drug monitoring and assessment of individual patient response are important in the management of complicated regimens, particularly when they involve new agents with relatively little experience in the clinical setting.
potential for interaction with antiretrovirals
Journal of Antimicrobial Chemotherapy Advance Pub March 2010 65(6):1079-1085
"Eventually, HCV treatment may involve a combination of directly acting STAT-C agents, without the requirement for PEG-IFN or ribavirin treatment. In a manner analogous to HIV therapy, this is likely to comprise a combination of protease and polymerase inhibitors,9 which can achieve suppression of viral replication, and be suitably robust against emergence of resistance. In the more immediate future however, single STAT-C agents will be added to PEG-IFN and ribavirin therapy.....Currently, ARV treatment may be adjusted, as far as is practicable, to enable optimal administration of anti-HCV therapy, without compromising ARV efficacy. This will become increasingly complex to manage with the addition of new STAT-C agents. Figure 2 summarizes known an
Conclusions: As more data become available concerning the metabolism, clearance, drug transporter interaction and toxicities of the STAT-C agents in development, potential DDIs with ARVs may be better anticipated. Many interactions are expected between HIV PIs and NNRTIs, and HCV protease inhibitors. It is unlikely that DDIs will preclude treatment of both conditions concurrently; but accurate characterization of these interactions, and prompt recognition of potential dangers by clinicians is important to ensure the safety and efficacy of treatment.
It is also important to note that although DDIs can be theoretically pre-empted and a basis formed for practical management, therapeutic drug monitoring and assessment of individual patient response are important in the management of complicated regimens, particularly when they involve new agents with relatively little experience in the clinical setting."
Kay Seden1,*, David Back2 and Saye Khoo2
1 NIHR Biomedical Research Centre, Royal Liverpool & Broadgreen University Hospitals Trust, Liverpool, UK 2 Department of Pharmacology and Therapeutics, University of Liverpool, Liverpool, UK
* Corresponding author. Department of Pharmacology, University of Liverpool, Pharmacology Research Laboratories, Block H, First Floor, 70 Pembroke Place, Liverpool L69 3GF, UK. Tel/Fax: +44-151-706-2883; E-mail: kseden@liverpool.ac.uk
Abstract
Recent advances in the development of agents that act specifically to inhibit hepatitis C virus (HCV) are set to fundamentally change the way that patients will be treated. New directly acting anti-HCV agents such as protease and polymerase inhibitors will initially be added to standard of care with pegylated interferon-{alpha} and ribavirin. However, future therapy is likely to constitute combinations of agents which act at distinct stages of viral replication and have differing resistance profiles. While directly acting anti-HCV agents will undoubtedly improve treatment outcomes, the introduction of combination therapy may not be without complications in some patient groups. HIV-positive patients who are receiving antiretrovirals (ARVs) are relatively highly represented among those with HCV infection, and are at high risk of drugÐdrug interactions (DDIs). As combination anti-HCV treatment gradually evolves to resemble anti-HIV therapy, it is essential to consider the increased potential for DDIs in patients receiving combination anti-HCV therapy, and particularly in HCV/HIV-co-infected individuals. Therapeutic drug monitoring is likely to play a role in the clinical management of such interactions.
Introduction
Treatment of hepatitis C virus (HCV) with antivirals aims to achieve a sustained virological response (SVR), which equates to undetectable HCV RNA levels 6 months after completion of therapy. This is associated with reduced progression of liver disease and reduced viral transmission. The standard of care for patients requiring treatment for chronic HCV currently involves a combination of pegylated interferon-{alpha} (PEG-IFN) and ribavirin, with response rates and duration of treatment that vary according to HCV genotype.1,2 Weight-based dosing of ribavirin is associated with better treatment outcomes for certain genotypes.3 Clinical studies have shown that combinations of ribavirin and PEG-IFN can achieve an SVR in only 36%Ð46% of patients with HCV genotype 1 monoinfection, when treated for 48 weeks.1,4
Due to the limited success rates of current treatment and the well documented adverse event profiles of ribavirin and PEG-IFN, there is evident need for novel, directly acting treatments. Specifically targeted antiviral therapy for HCV (STAT-C) represents a new treatment paradigm with improved patient outcomes. There are several STAT-C agents at various stages of clinical development, including protease inhibitors (PIs)5Ð8 and nucleoside/non-nucleoside polymerase inhibitors.9,10 Other agents under investigation include novel analogues of ribavirin,11 modified interferons,12 cyclophilin B,13 {alpha} glucosidase inhibitors,14 oligonucleotides15 and immune modulators.16
In patients co-infected with HIV/HCV, progression to cirrhosis, end-stage liver disease and ultimately death is more rapid.17 HCV viral loads may be higher in co-infected patients than those with monoinfection,17 and treatment outcomes in terms of SVR rates may be worse in co-infected patients, particularly with genotype 1 HCV infection.18 No significant difference in efficacy or safety has been reported in co-infected patients treated with PEG-IFN-2a plus ribavirin or PEG-IFN-2b plus ribavirin.19 HCV-associated liver failure is increasing significantly as a cause of death in HIV-positive patients in the post highly active antiretroviral therapy (HAART) era in developed countries.20 It therefore follows that significant changes in HCV therapy could profoundly improve the treatment outcomes of this patient group. However, the addition of combination therapies, which include novel agents, for patients who are taking antiretroviral (ARV) regimens is unlikely to be without complication; clinically significant drugÐdrug interactions (DDIs) involving ARVs are common, affecting 27% of 159 HIV-infected outpatients in a UK study21 and 23%Ð26% of 220 HIV-infected outpatients in a study in the Netherlands.22
The future of anti-HCV therapy
Every stage of the HCV life cycle potentially represents a target for STAT-C agents,15 meaning that increasing numbers of novel agents and novel classes of agents are likely to emerge, in a manner similar to ARV therapy. Currently in Phase III trials, the NS3/4A PIs telaprevir (VX-950)5,6 and boceprevir (SCH 503034)8 are likely to be the first STAT-C agents licensed. The development of some of the furthest advanced nucleoside analogue NS5B polymerase inhibitors has been halted due to toxicities; however, R7128, a pro-drug of PSI-6130, is currently in Phase II trials. Figure 1 illustrates the location in the HCV genome of drug targets, including the NS3/4A serine protease and the NS5B RNA-dependent RNA polymerase enzymes, which, being essential for viral replication, are primary targets for anti-HCV therapy.
Figure 1. Important targets for STAT-C therapy in the HCV genome. Derived from information in Pawlotsky et al.15 and Chevaliez and Pawlotsky.46
Eventually, HCV treatment may involve a combination of directly acting STAT-C agents, without the requirement for PEG-IFN or ribavirin treatment. In a manner analogous to HIV therapy, this is likely to comprise a combination of protease and polymerase inhibitors,9 which can achieve suppression of viral replication, and be suitably robust against emergence of resistance. In the more immediate future however, single STAT-C agents will be added to PEG-IFN and ribavirin therapy, until there are sufficient effective STAT-C agents licensed with which to afford effective combination therapy with a suitable barrier to resistance. Several studies have confirmed the pivotal role of ribavirin in successful HCV antiviral therapy, despite having little intrinsic antiviral activity. For example, with telaprevir and PEG-IFN, ribavirin was found to increase SVR rates by preventing relapse and emergence of telaprevir resistance.6
To draw another comparison with HIV therapy, it is almost certain that the selection of several agents without overlapping resistance patterns will be required for combination therapy, which will increase both the complexity and risk for DDIs.
ARVs and current anti-HCV treatment: potential for DDIs
As PEG-IFN and ribavirin are expected to remain a fundamental component of anti-HCV treatment in the near future, their potential for interaction with ARVs remains important with the advent of STAT-C agents.
Concomitant administration of abacavir with PEG-IFN and ribavirin has been associated with an increased risk of non-response to anti-HCV therapy,23 and an interaction between abacavir and ribavirin has been suggested. As both drugs are guanosine analogues and have some metabolic pathways in common, an inhibitory competition for phosphorylation is the likely mechanism.24
Combinations of zidovudine with ribavirin and PEG-IFN can lead to increased risk of severe haematological toxicity, including anaemia. The use of zidovudine has been identified as an independent factor contributing to haematological adverse events in patients undergoing ribavirin and PEG-IFN treatment; the combination is not recommended.25
The use of didanosine alongside ribavirin is associated with increased risk of mitochondrial toxicity, which may be attributed to increased exposure to the active metabolite of didanosine, dideoxyadenosine 5'-triphosphate, when didanosine is co-administered with ribavirin.26Ð28 Toxicity may be severe and co-administration is not recommended. Mitochondrial toxicity has also been observed with combinations of stavudine and ribavirin. In vitro data have shown that ribavirin can inhibit phosphorylation of zidovudine and stavudine. The clinical significance is not clear; however, close monitoring of HIV RNA with this combination is recommended.
In relation to HIV PIs, it has been reported that in HIV/HCV-co-infected patients, serum bilirubin increases following initiation of PEG-IFN and ribavirin were 1.9-fold higher in patients taking an atazanavir-containing regimen.29 Hyperbilirubinaemia is, however, a relatively common side effect of atazanavir treatment, for which there are various risk factors irrespective of anti-HCV treatment.30 Atazanavir inhibits UGT1A1, an enzyme involved in bilirubin conjugation; it is important to note that different genotypes of UGT1A1 (notably *6*6, *7*7 and *6*731) have an impact on enzyme activity, and interindividual variability in the frequency and severity of hyperbilirubinaemia has been observed in patients treated with atazanavir.31
With HIV non-nucleoside reverse transcriptase inhibitors (NNRTIs), if patients receive efavirenz alongside PEG-IFN, monitoring of CNS effects is important, as the incidence of depressive symptoms in patients with HIV/HCV co-infection treated with IFN is reportedly high.32
Currently, ARV treatment may be adjusted, as far as is practicable, to enable optimal administration of anti-HCV therapy, without compromising ARV efficacy. This will become increasingly complex to manage with the addition of new STAT-C agents. Figure 2 summarizes known and potential DDIs between ARVs and anti-HCV drugs in current use and the HCV PIs in late stages of development.
Figure 2. A summary of known and anticipated DDIs between antiretrovirals and anti-HCV drugs in current use and the HCV protease inhibitors in Phase III development.
Potential interactions between ARVs and STAT-C agents
As illustrated in Figure 2, few data are currently available to evaluate the potential for DDIs between ARVs and emerging STAT-C agents. Most is known about telaprevir and boceprevir, the HCV PIs which are furthest through the development process.
Although they target serine rather than aspartate proteins, HCV PIs have structural similarities with HIV PIs, and there is evidence to suggest that they share a common route of metabolism.33 In human liver microsomes, the metabolism of telaprevir and boceprevir was substantially inhibited in the presence of relatively low concentrations of ritonavir.33 In addition, on co-dosing either telaprevir or boceprevir with ritonavir in rats, the plasma exposure of both HCV agents was markedly increased. These findings suggest that telaprevir and boceprevir may be primarily or exclusively metabolized by CYP3A. This has implications for co-administration of ARV therapy, as HIV PIs such as lopinavir and darunavir inhibit CYP3A4, whereas the NNRTIs efavirenz, nevirapine and etravirine induce metabolism mediated by this enzyme. Although PIs are able to inhibit CYP3A4, the observed effect may be predominantly due to potent inhibitory action of ritonavir, which is commonly used as a pharmacokinetic enhancer to boost levels of other PIs.
Such interactions, when more comprehensively understood, may not be problematic if appropriately managed. For example, ritonavir could be utilized to dually boost both an HIV PI and an HCV PI. Both ritonavir and newer pharmacokinetic enhancers in development such as GS 935034 could be used to reduce dosing frequency, allowing telaprevir and boceprevir to be dosed less frequently than 8 hourly and thus increasing the likelihood of adherence.33 In addition, there are ongoing studies to develop follow-on compounds of the clinical candidate. For example, systematic structureÐactivity relationship studies of different regions of boceprevir have shown improved potency and improved pharmacokinetics compared with boceprevir in model systems.35
As a result of structural similarities between some nucleoside reverse transcriptase inhibitors (NRTIs) and HCV NS5B nucleoside polymerase inhibitors, competition for clearance pathways cannot be ruled out. For example, R7128 is a cytidine analogue, structurally related to the HIV NRTI cytidine analogues lamivudine and emtricitabine. Although there may be potential for interaction, relevance to the clinical setting remains to be elucidated.
The non-nucleoside polymerase inhibitor GS 9190 has little potential for inhibition or induction of CYP450 enzymes and is not transported by P-glycoprotein (P-gp) in vitro; therefore, interactions via these mechanisms are unlikely.36
Overlapping toxicity profiles and adverse effects also need to be considered when using STAT-C agents alongside ARV therapy. For example, clinical studies have illustrated that anaemia is a relatively common adverse effect experienced by patients receiving telaprevir5,6 or boceprevir37 therapy. The frequency of anaemia was increased in treatment groups receiving telaprevir alongside PEG-IFN and ribavirin, compared with groups receiving PEG-IFN and ribavirin alone.5,6 This may have implications for patients who are taking zidovudine as part of their ARV regimen, as anaemia is a common adverse reaction with zidovudine treatment. Concomitant use of telaprevir or boceprevir with zidovudine could therefore increase the risk of anaemia, particularly when used in combination with ribavirin, which is likely to be the case. Use of ribavirin with zidovudine is currently not recommended by one of the manufacturers of ribavirin,38 due to anaemia risk.
Phase II studies have shown an increased incidence of hyperbilirubinaemia in patients treated with the cyclophilin inhibitor Debio 025 compared with controls.39 This may be due to the inhibition of the multidrug resistance protein 2 (MRP2) transporter by Debio 025,40 resulting in reduced elimination of conjugated bilirubin. As various ARVs are themselves inhibitors of or substrates for MRP2, interactions via this mechanism or UGT1A1, as previously described, cannot be ruled out. It has been suggested that haplotypes of certain genes, such as UGT1A, may be useful predictors of PI-induced hyperbilirubinaemia.41 Genetic diagnostics may be an important application to future HCV, as well as HIV therapies. Interestingly, in the context of co-infection, Debio 025 has also shown inhibitory activity against HIV-1 in vitro.42
Although some Phase II studies of STAT-C agents have reported no significant changes in various laboratory parameters and electrocardiogram readings,5,43 as these new drugs become licensed and clinical experience of their use develops, it is possible that toxicities may emerge, as with ARVs. For example, lipodystrophy with various ARVs,44 mitochondrial toxicity with didanosine28 and, more recently, cardiovascular effects with abacavir.45 It is not inconceivable that STAT-C agents in development could have metabolic or mitochondrial toxicities in common with some ARVs, and future regimens may need to be adapted to minimize risk.
Table 1 lists STAT-C agents in Phase II or III trials and, where data are available, their potential to interact with ARVs.
Conclusions
As more data become available concerning the metabolism, clearance, drug transporter interaction and toxicities of the STAT-C agents in development, potential DDIs with ARVs may be better anticipated. Many interactions are expected between HIV PIs and NNRTIs, and HCV protease inhibitors. It is unlikely that DDIs will preclude treatment of both conditions concurrently; but accurate characterization of these interactions, and prompt recognition of potential dangers by clinicians is important to ensure the safety and efficacy of treatment.
It is also important to note that although DDIs can be theoretically pre-empted and a basis formed for practical management, therapeutic drug monitoring and assessment of individual patient response are important in the management of complicated regimens, particularly when they involve new agents with relatively little experience in the clinical setting.
Subscribe to:
Posts (Atom)
.JPG)