A randomized phase 2b study of peginterferon lambda-1a for the treatment of chronic HCV infection.

BACKGROUND & AIMS: Peginterferon lambda-1a (Lambda) is a type-III interferon with similar antiviral activity to alfa interferons but with a diminished extrahepatic receptor distribution, reducing the risk for extrahepatic adverse events. METHODS: This was a randomized, blinded, actively-controlled, multicentre phase 2b dose-ranging study in patients chronically infected with HCV genotypes 1-4. Treatment-naive patients received Lambda (120/180/240 µg) or peginterferon alfa-2a (alfa; 180 µg) once-weekly with ribavirin for 24 (genotypes [GT] 2,3) or 48 (GT1,4) weeks. RESULTS: Rates of undetectable HCV-RNA at week 12 (complete early virologic response [cEVR]; primary end point) were significantly higher in GT1,4 patients receiving Lambda vs. alfa (170/304, 56% vs. 38/103, 37%); with similar cEVR rates for GT2,3 (80/88, 91% vs. 26/30, 87%). Rates of undetectable HCV-RNA at week 4 were significantly higher on 180 µg (15/102, 15% GT1,4; 22/29, 76% GT2,3) and 240 µg (17/104, 16% GT1,4; 20/30, 67% GT2,3) Lambda than alfa (6/103, 6% GT1,4; 9/30, 30% GT2,3). Sustained virologic responses (post-treatment week 24) were comparable between Lambda and alfa for GT1,4 (37-46% Lambda; 37% alfa) and GT2,3 (60-76% Lambda; 53% alfa). Aminotransferase and/or bilirubin elevations were the primary dose-limiting abnormalities for Lambda; a sponsor-mandated 240 to 180 µg dose reduction was therefore implemented. Serious adverse events were comparable (3-13% Lambda; 3-7% alfa). Grade 3-4 haemoglobin, neutrophil, and platelet reductions were lower on Lambda than alfa. Among alfa patients, 28/133 (21%) had peginterferon and 31/133 (23%) had ribavirin dose reductions for haematologic abnormalities vs. 0/392 and 8/392 (2%) on Lambda. Lambda demonstrated fewer musculoskeletal (16-28% vs. 47-63%) and influenza-like events (8-23% vs. 40-46%) than alfa. CONCLUSION: Lambda was associated with improved or similar rates of virologic response with fewer extrahepatic adverse events than alfa in chronic HCV infection.

Outcomes of treatment for hepatitis C virus infection by primary care providers.

BACKGROUND: The Extension for Community Healthcare Outcomes (ECHO) model was developed to improve access to care for underserved populations with complex health problems such as hepatitis C virus (HCV) infection. With the use of video-conferencing technology, the ECHO program trains primary care providers to treat complex diseases. METHODS: We conducted a prospective cohort study comparing treatment for HCV infection at the University of New Mexico (UNM) HCV clinic with treatment by primary care clinicians at 21 ECHO sites in rural areas and prisons in New Mexico. A total of 407 patients with chronic HCV infection who had received no previous treatment for the infection were enrolled. The primary end point was a sustained virologic response. RESULTS: A total of 57.5% of the patients treated at the UNM HCV clinic (84 of 146 patients) and 58.2% of those treated at ECHO sites (152 of 261 patients) had a sustained viral response (difference in rates between sites, 0.7 percentage points; 95% confidence interval, -9.2 to 10.7; P=0.89). Among patients with HCV genotype 1 infection, the rate of sustained viral response was 45.8% (38 of 83 patients) at the UNM HCV clinic and 49.7% (73 of 147 patients) at ECHO sites (P=0.57). Serious adverse events occurred in 13.7% of the patients at the UNM HCV clinic and in 6.9% of the patients at ECHO sites. CONCLUSIONS: The results of this study show that the ECHO model is an effective way to treat HCV infection in underserved communities. Implementation of this model would allow other states and nations to treat a greater number of patients infected with HCV than they are currently able to treat. (Funded by the Agency for Healthcare Research and Quality and others.).

Viral clearance is associated with improved insulin resistance in genotype 1 chronic hepatitis C but not genotype 2/3.

OBJECTIVES: Genotype-specific associations between hepatitis C virus (HCV) and insulin resistance (IR) have been described, but a causal relationship remains unclear. This study investigated the association between a sustained virological response (SVR) and IR after chronic HCV therapy. METHODS: 2255 treatment-naive patients with chronic HCV genotype 1 or 2/3 were enrolled in two phase 3 trials of albinterferon alpha-2b versus pegylated interferon alpha-2a for 48 or 24 weeks, respectively. IR was measured before treatment and 12 weeks after treatment using homeostasis model assessment (HOMA)-IR. RESULTS: Paired HOMA-IR measurements were available in 1038 non-diabetic patients (497 with genotype 1; 541 with genotype 2/3). At baseline the prevalence of HOMA-IR >3 was greater in patients with genotype 1 than 2/3 (33% vs 27%; p=0.048). There was a significant reduction in the prevalence of IR in patients with genotype 1 achieving SVR (δ 10%; p<0.001), but not in genotype 1 non-responders or those with genotype 2/3. Multivariate analysis indicated that SVR was associated with a significant reduction in mean HOMA-IR in patients with genotype 1 (p=0.004), but not in those with genotype 2/3, which was independent of body mass index, alanine transaminase, γ-glutamyl transpeptidase and lipid level changes. CONCLUSIONS: SVR is associated with a reduction in HOMA-IR in patients with HCV genotype 1 but not in those with genotype 2/3. Genotype 1 may have a direct effect on the development of IR, independent of host metabolic factors, and may be partially reversed by viral eradication.

Response to therapy with pegylated interferon and ribavirin for chronic hepatitis C in hispanics compared to non-Hispanic whites.

OBJECTIVES: Ethnicity has been shown to play an important role in hepatitis C virus (HCV) treatment response. However, few studies have examined the treatment response of Hispanics to combination therapy with pegylated interferon and ribavirin. The aim of this study was to compare the treatment responses of Hispanics and non-Hispanic whites (NHW) treated with pegylated interferon and ribavirin for chronic HCV. METHODS: A retrospective review was conducted of all treatment-naive Hispanics and NHW with HCV who were treated at the University of New Mexico Hospital or Albuquerque VA Medical Center between October 2001 and January 2007. Genotype 1 patients received 48 weeks of therapy with pegylated interferon and ribavirin; genotype 2 and 3 patients received 24 weeks of treatment. RESULTS: A total of 396 patients were included in the analysis, consisting of 179 Hispanics and 217 NHW. Overall, fewer Hispanics completed therapy compared with NHW (64.8% vs. 80.2%, P<0.001). In genotype 1 patients, early virologic response (EVR), end-of-treatment response (ETR), and sustained virologic response (SVR) did not differ significantly between the two ethnic groups. In genotype 2 and 3 patients, Hispanics had similar EVR compared with NHW (81.3% vs. 88.2%, P=0.25), but lower ETR (64.1% vs. 83.1%, P=0.01) and SVR (45.3% vs. 75.3%, P<0.001). After correcting for patients who prematurely discontinued therapy, genotype 2 and 3 Hispanics continued to have a reduced SVR compared with NHW (65.9% vs. 87.3%, P=0.014). The attenuated SVR in Hispanics was because of a higher relapse rate after achieving ETR compared with NHW (25% vs. 7.5%, P=0.02). CONCLUSIONS: Hispanics with genotype 2 and 3 HCV infection treated with pegylated interferon and ribavirin are less likely to achieve SVR compared with NHW. The lower rate of SVR in Hispanic patients is, in part, because of an increased rate of relapse after ETR.

Peginterferon alfa-2a does not alter the pharmacokinetics of methadone in patients with chronic hepatitis C undergoing methadone maintenance therapy.

OBJECTIVE: Our objective was to quantify the pharmacokinetics of methadone and the pharmacokinetics and pharmacodynamics of peginterferon alfa-2a (40 kd) in patients with chronic hepatitis C undergoing methadone maintenance therapy. METHODS: Adults with chronic hepatitis C who had been receiving a consistent methadone maintenance regimen for at least 3 months were eligible for this open-label, multicenter, nonrandomized drug interaction study. All patients received 180 microg subcutaneous peginterferon alfa-2a once weekly for 4 weeks and continued their methadone regimen. Serial blood samples were collected at baseline and immediately before and for up to 168 hours after study drug administration for the purposes of quantifying methadone and peginterferon alfa-2a serum concentrations, measuring serum 2',5'-oligoadenylate synthetase activity, and determining hepatitis C virus ribonucleic acid levels. RESULTS: Twenty-four patients were enrolled. Methadone exposure, as measured by maximum serum concentration (C(max)) and area under the concentration-time curve (AUC) normalized to a 100-mg/d dose, after 4 doses of peginterferon alfa-2a increased by 10% to 15% when compared with baseline. The week 4/baseline ratio of the mean C(max) was 1.11 (90% confidence interval [CI], 1.02-1.22), and for AUC from time 0 to 24 hours, the week 4/baseline ratio was 1.15 (90% CI, 1.08-1.23). The mean accumulation ratios (week 4/first dose) for C(max) and AUC from time 0 to 168 hours of peginterferon alfa-2a were 2.1 and 2.3, respectively. CONCLUSIONS: Peginterferon alfa-2a does not appreciably alter the pharmacokinetics of methadone.

Virological response and safety outcomes in therapy-nai ve patients treated for chronic hepatitis C with taribavirin or ribavirin in combination with pegylated interferon alfa-2a: a randomized, phase 2 study.

BACKGROUND/AIMS: Pegylated interferon plus ribavirin can cause dose-limiting anemia. Taribavirin, a ribavirin prodrug, has shown a lower incidence of anemia. We sought to determine the efficacy and safety of taribavirin vs. ribavirin combined with pegylated interferon in patients with chronic hepatitis C (CHC). METHODS: This phase 2 open-label study randomized 180 patients with CHC to receive pegylated interferon alfa-2a 180 microg/week plus taribavirin 800, 1200 or 1600 mg QD or ribavirin 1000 or 1200 mg QD. Efficacy variables included proportions of patients with undetectable serum HCV RNA levels at end of treatment and after a 24-week follow-up. RESULTS: The proportions of patients with undetectable HCV RNA at 12 weeks did not differ significantly between taribavirin (38%, 42%, and 49% for the 800, 1200, and 1600 mg groups) and ribavirin (49%). The highest proportion of patients with undetectable HCV RNA at end of treatment and at follow-up occurred in both the taribavirin 1200mg QD (63% and 37%) and ribavirin groups (62% and 44%). SVR rates were 23%, 37% and 29% for taribavirin and 44% for ribavirin. Fewer patients on any dose of taribavirin had severe anemia (hemoglobin <10 g/dL) than on ribavirin (6/135 [4%] vs. 12/45 [27%]). CONCLUSIONS: Given with interferon, taribavirin produced SVR rates comparable to those of ribavirin, with a lower occurrence of anemia.

Treatment of chronic hepatitis C patients with persistently normal alanine aminotransferase levels with the combination of peginterferon alpha-2a (40 kDa) plus ribavirin: impact on health-related quality of life.

BACKGROUND: Peginterferon alpha-2a (40 kDa) plus ribavirin is equally effective in chronic hepatitis C patients with normal or elevated alanine aminotransferase (ALT) values. This analysis, in patients with normal ALT levels, compared health-related quality of life (HRQoL) measurements between untreated control patients and treated patients grouped by virological response. HRQoL in the present population was also compared with HRQoL in patients with elevated ALT levels, observed in a previous study. METHODS: A total of 491 patients with persistently normal ALT levels were randomized to peginterferon alpha-2a (40 kDa)/ribavirin for 24 (group A) or 48 weeks (group B) or no treatment for 72 weeks (group C). Quality of life was assessed with valid instruments (self-administered Short Form (SF)-36 Health Survey and Fatigue Severity Scale). RESULTS: In groups A and B, patients with sustained virological responses after combination therapy had significantly better quality of life and less fatigue than patients without sustained responses. Differences were significant for five SF-36 domains, the SF-36 Physical Component score and both Fatigue Severity Scale scores. Viral clearance was not observed in any untreated patients (group C). Comparison with data from elevated ALT patients revealed little difference in baseline quality of life, although normal ALT patients had significantly higher scores related to mental health than elevated ALT patients. CONCLUSIONS: Eradication of HCV with peginterferon alpha-2a (40 kDa) plus ribavirin is associated with better quality of life and less fatigue in normal ALT patients. These patient benefits, coupled with the high probability of eradicating HCV, should be considered in making decisions about treating this population.