The dose-response relationship of peginterferon alfa-2a and ribavirin in the treatment of patients coinfected with HIV-HCV.

PURPOSE: The relationship between peginterferon/ribavirin exposure and the probability of achieving a sustained virologic response (SVR) in HIV-HCV coinfected patients is not well described. We conducted a retrospective analysis of HIV-HCV coinfected patients randomized to 48 weeks of treatment with peginterferon alfa-2a (40 kD) 180 µg/week and ribavirin 800 mg/day in the multinational APRICOT study to define optimal exposure thresholds. METHOD: Actual drug exposure was estimated in 287 patients, taking into consideration dose reductions for adverse events or laboratory abnormalities. RESULTS: SVR overall and SVR in those completing treatment was, respectively, 29% and 37% among HCV genotype-1 patients and 59% and 68% among genotype non-1 patients. No patients with ≤40% exposure to ribavirin achieved an SVR. Receiver operating characteristic analysis identified that threshold exposures to both drugs of >75% (genotype-1) and >60% (genotype non-1) are associated with SVR. An existing generalized additive model populated with data from HCV monoinfected patients was updated to predict an overall SVR of 37% if genotype-1 patients received ribavirin 1000 or 1200 mg/day but at the cost of a higher incidence of anemia (23%). CONCLUSION: Completion of scheduled treatment and exceeding certain thresholds for exposure to peginterferon alfa 2a (40 kD) and ribavirin is associated with higher SVR rates.

Low-dose peginterferon alfa-2a is safe and produces a sustained virologic response in patients with chronic hepatitis C and end-stage renal disease.

BACKGROUND & AIMS: Chronic hepatitis C increases mortality of patients with end-stage renal disease (ESRD). Ribavirin is not recommended for patients with renal dysfunction; peginterferon monotherapy is the most appropriate treatment for chronic hepatitis C in such patients. We evaluated the efficacy and safety of 2 dosages of peginterferon alfa-2a (40 kDa) in patients with chronic hepatitis C and ESRD on hemodialysis. METHODS: We performed a randomized, multicenter, open-label clinical study of 85 patients with chronic hepatitis C and ESRD who were receiving hemodialysis at specialist outpatient hepatology clinics. Patients were treated with subcutaneous peginterferon alfa-2a (40 kDa) at dosages of 135 or 90 µg/wk for 48 weeks. RESULTS: The incidences of overall sustained virologic responses (SVRs) (undetectable hepatitis C virus [HCV] RNA [<50 IU/mL] after 24 weeks of untreated follow-up) were 39.5% (15/38) in the 135 µg/wk group and 34.9% (15/43) in the 90 µg/wk group (odds ratio, 1.22; 95% confidence interval, 0.49-3.06; P = .67). Among patients with undetectable HCV RNA at week 12, 60.9% (14/23) of those in the 135 µg/wk group and 87.5% (14/16) of those in the 90 µg/wk group achieved an SVR. Therapy was well-tolerated with no new safety concerns. The most common adverse events (>10% of patients in at least 1 treatment group) included conditions associated with ESRD (anemia and hypertension) and with interferon treatment. CONCLUSIONS: Forty-eight weeks of treatment with low-dose peginterferon alfa-2a (40 kDa) is safe and produces an SVR in 35%-40% of patients with chronic hepatitis C and ESRD on hemodialysis.

A sustained virologic response is durable in patients with chronic hepatitis C treated with peginterferon alfa-2a and ribavirin.

BACKGROUND & AIMS: A sustained virologic response (SVR) to therapy for hepatitis C virus (HCV) infection is defined as the inability to detect HCV RNA 24 weeks after completion of treatment. Although small studies have reported that the SVR is durable and lasts for long periods, it has not been conclusively shown. METHODS: The durability of treatment responses was examined in patients originally enrolled in one of 9 randomized multicenter trials (n = 1343). The study included patients who received pegylated interferon (peginterferon) alfa-2a alone (n = 166) or in combination with ribavirin (n = 1077, including 79 patients with normal alanine aminotransferase levels and 100 patients who were coinfected with human immunodeficiency virus and HCV) and whose serum samples were negative for HCV RNA (<50 IU/mL) at their final assessment. Patients were assessed annually, from the date of last treatment, for a mean of 3.9 years (range, 0.8-7.1 years). RESULTS: Most patients (99.1%) who achieved an SVR had undetectable levels of HCV RNA in serum samples throughout the follow-up period. Serum samples from 0.9% of the patients contained HCV RNA a mean of 1.8 years (range, 1.1-2.9 years) after treatment ended. It is not clear if these patients were reinfected or experienced a relapse. CONCLUSIONS: In a large cohort of patients monitored for the durability of an SVR, the SVR was maintained for almost 4 years after treatment with peginterferon alfa-2a alone or in combination with ribavirin. In patients with chronic hepatitis C infection, the SVR is durable and these patients should be considered as cured.

Identifying hepatitis C virus genotype 2/3 patients who can receive a 16-week abbreviated course of peginterferon alfa-2a (40KD) plus ribavirin.

UNLABELLED: The objective of this analysis was to compare sustained virological response (SVR) and relapse rates in patients with a rapid virological response (RVR, HCV RNA <50 IU/mL at week 4) randomized to 24 or 16 weeks of treatment with peginterferon alfa-2a (40KD) 180 microg/week plus ribavirin 800 mg/day in the multinational ACCELERATE study. The analysis was restricted to patients who received treatment for 80% or more of the planned duration. Of 1309 eligible patients, 863 individuals (65.9%) achieved an RVR and were included in this analysis (458 assigned to 16 weeks and 405 assigned to 24 weeks). The overall SVR rate was significantly higher in patients randomized to 24 weeks of treatment (91% versus 82%; P = 0.0006) and among patients infected with genotype 2 (92% versus 81%; P = 0.0010) but not genotype 3 (90% versus 84%; P = 0.1308). Relapse rates were significantly lower among all patients randomized to 24 weeks of treatment: overall (6% versus 15%, P < 0.0001); in those infected with genotype 2 (5% versus 17%, P = 0.0001), and genotype 3 (7% versus 14%, P = 0.0489). SVR rates in patients with a viral load of 400,000 IU/mL or less randomized to 24 and 16 weeks of treatment were similar, 95% and 91% (P = 0.2012). Significant pretreatment predictors of SVR included assignment to 24 weeks of treatment (P = 0.0006), absence of advanced fibrosis on liver biopsy (P = 0.0032), lower HCV RNA level (P = 0.0017), and lower body weight (P < 0.0001). CONCLUSION: The standard 24-week regimen of peginterferon alfa-2a (40KD) plus ribavirin is significantly more effective than an abbreviated 16-week regimen in genotype 2/3 patients who achieve an RVR. Abbreviated regimens may be considered in patients with a low baseline viral load who achieve an RVR.

Re-treatment of patients with chronic hepatitis C who do not respond to peginterferon-alpha2b: a randomized trial.

BACKGROUND: Many patients with chronic hepatitis C have not responded to therapy with pegylated interferon plus ribavirin. OBJECTIVE: To evaluate use of peginterferon-alpha2a plus ribavirin to re-treat nonresponders to peginterferon-alpha2b plus ribavirin. DESIGN: Randomized, parallel-group trial conducted between September 2003 and February 2007. Patients and researchers were not blinded to intervention assignment. Random assignment was centralized, computer-generated, and stratified by geographic region, hepatitis C virus (HCV) genotype, and histologic diagnosis. SETTING: 106 international centers. PATIENTS: 950 nonresponders to 12 or more weeks of therapy with peginterferon-alpha2b plus ribavirin. INTERVENTION: Peginterferon-alpha2a, 360 microg/wk, for 12 weeks, then 180 microg/wk to complete 72 weeks (group A) or 48 weeks (group B), or peginterferon-alpha2a, 180 microg/wk for 72 weeks (group C) or 48 weeks (group D). All patients received ribavirin, 1000 or 1200 mg/d. MEASUREMENTS: Sustained virologic response (SVR), defined as undetectable (<50 IU/mL) HCV RNA levels 24 weeks after the end of treatment. RESULTS: The SVR rates in groups A (n = 317), B (n = 156), C (n = 156), and D (n = 313) were 16%, 7%, 14%, and 9%, respectively (relative risk [RR] for group A vs. group D [the primary comparison], 1.80 [95% CI, 1.17 to 2.77]; P = 0.006). Extended treatment duration increased SVR rates (16% for 72 weeks [groups A and C] vs. 8% for 48 weeks [groups B and D]; RR, 2.00 [CI, 1.32 to 3.02]; P < 0.001). Complete viral suppression (HCV RNA level <50 IU/mL)at week 12 was achieved in 21% of patients in groups A and B and 13% of those in groups C and D. Rates of SVR were 49% (77 of 157 patients) and 4% (32 of 719 patients) among those with and without complete viral suppression at week 12, respectively. LIMITATION: Nonresponders to peginterferon-alpha2a plus ribavirin were not evaluated. CONCLUSION: Re-treating nonresponders to therapy with peginterferon-alpha2b plus ribavirin for 72 weeks significantly increases SVR rates compared with re-treating them for 48 weeks. The overall SVR rate was low, but patients who are most likely to respond to re-treatment can be identified at week 12. PRIMARY FUNDING SOURCE: Roche.

Efficacy and safety of peginterferon α-2a (40 kD) plus ribavirin among patients with chronic hepatitis C and earlier treatment failure to interferon and ribavirin: an open-label study in central and Eastern Europe.

OBJECTIVE: To assess the safety and efficacy of 48 weeks of re-treatment with peginterferon α-2a (40 kD) plus ribavirin in previously treated hepatitis C virus (HCV) genotype 1 patients. METHODS: HCV genotype 1 patients previously treated with conventional interferon with or without ribavirin were assigned to 48 weeks of treatment with peginterferon α-2a (40 kD; 180 µg/week) plus ribavirin (recommended dose: 1000/1200 mg/day) in this open-label trial conducted in central and Eastern Europe. The primary efficacy endpoint was sustained virological response (SVR, HCV RNA <50 IU/ml) after 24 weeks of untreated follow-up. Early virological response (EVR) was defined as an undetectable HCV RNA or at least 2-log drop at week 12. RESULTS: A total of 154 of the 203 (76%) treatment-experienced genotype 1 patients completed the treatment. Overall, 113 patients (56%) achieved an EVR, 107 (53%) had an end-of-treatment response and 63 patients (31%) achieved an SVR [including 38% (40/105) of those with an earlier breakthrough or relapse and 24% (21/88) of those with earlier nonresponse]. Among patients with an EVR, 47% (53/113) achieved an SVR (positive predictive value=47%), compared with 3% (1/34) of patients without an EVR (negative predictive value=97.1%). Rates of SVR were higher in patients without cirrhosis (54/169, 32%), with a baseline viral load of 800 000 IU/ml or less (29/68, 43%) and younger than 40 years of age (36/77, 47%). CONCLUSION: The combination of peginterferon α-2a (40 kD) plus ribavirin produced an overall SVR rate of 31% in difficult-to-treat genotype 1 patients who had not responded to the previous treatment with conventional interferon plus ribavirin.

Efficacy and safety of peginterferon α-2a (40 KD) plus ribavirin in treatment-naive chronic hepatitis C patients in Central and Eastern Europe.

OBJECTIVE: Assess the safety and efficacy of 24 or 48 weeks of treatment with peginterferon α-2a (40 KD) plus ribavirin in treatment-naive patients with chronic hepatitis C. METHODS: All patients in this open-label multinational study were assigned at the investigator's discretion to receive peginterferon α-2a (40 KD) 180 µg/week plus ribavirin (800 mg/day) for a total of 24 weeks or peginterferon α-2a (40 KD) 180 µg/week plus ribavirin (1000/1200 mg/day) for a total of 48 weeks. Treatment success was defined as sustained virological response [sustained virological response (SVR); hepatitis C virus RNA less than 50 IU/ml after completion of untreated follow-up]. RESULTS: A total of 789 treatment-naive patients were enrolled, of whom 91% (138 of 152) of nongenotype 1 patients and 77% (490 of 637) of genotype 1 patients completed 24 and 48 weeks of treatment, respectively. The overall SVR rate was 58% (459 of 789), and was 70 and 55% in nongenotype 1 and genotype 1 patients, respectively. Age (per 10-year decrement) and baseline hepatitis C virus RNA level (≤ 400 000 vs. >4 00 000 IU/ml) were significantly associated with SVR by multiple logistic regression analysis. The safety profile of peginterferon α-2a (40 KD) plus ribavirin was similar to that reported in pivotal trials, with no new or unexpected safety signals. CONCLUSION: The combination of peginterferon α-2a (40 KD) plus ribavirin was well tolerated and produced an overall SVR rate of 58% in treatment-naive patients. This study confirms that SVR rates achieved in pivotal clinical trials in Western Europe and the USA can be achieved in routine clinical practice in Central and Eastern Europe.