Peginterferon Ribavirin Treatment Research Articles

Peg-interferon and ribavirin treatment in HIV/HCV co-infected patients in Thailand: efficacy, safety and pharmacokinetics.

In Thailand, 7.2% of HIV patients are co-infected with hepatitis C virus (HCV), and these patients are treated with peg-interferon + ribavirin (PR) for their HCV infection. This study evaluates efficacy and safety of PR treatment and pharmacokinetics of ribavirin in this population. HIV/HCV co-infected Thai patients were treated with PR for 24 or 48 weeks. Sustained virological response 24 weeks after the end of treatment (SVR24) was used to describe efficacy. (laboratory) safety parameters and ribavirin plasma concentrations were evaluated during study visits. Ribavirin concentrations were compared with t-tests for patients with and without anaemia (haemoglobin <10 g/dl) and SVR24. A total of 101 HIV/HCV co-infected patients were included; 88% were male (n = 88), and 46% were infected with genotype 3. The median (IQR) start dose was 14.28 mg/kg/day. SVR24 rate was 56%. All patients reported at least one (serious) adverse event, of which 28% of patients developed anaemia. Seven patients discontinued treatment due to toxicity issues. Geometric mean (IQR) ribavirin concentration was 1.81 (1.42-2.32) mg/l at week 8 of treatment. At week 8, patients with and without anaemia and SVR had ribavirin concentrations of 2.29 and 1.63 mg/l and 1.91 and 1.74 mg/l, respectively. PR treatment has comparable response rates and toxicity profile in Thai HIV/HCV co-infected patients as in Western HIV/HCV patients. However, ribavirin plasma concentrations were comparable with previously published studies in HIV/HCV co-infected patients, but both, just as SVR rate, were lower than in mono-infected patients.

High post-treatment absolute monocyte count predicted hepatocellular carcinoma risk in HCV patients who failed peginterferon/ribavirin therapy.

Salient studies have investigated the association between host inflammatory response and cancer. This study was conducted to test the hypothesis that peripheral absolute monocyte counts (AMC) could impart an increased risk of hepatocellular carcinoma (HCC) development in hepatitis C virus (HCV)-infected patients after a failed peginterferon/ribavirin (PR) combination therapy. A total of 723 chronic HCV-infected patients were treated with PR, of which 183 (25.3%) patients did not achieve a sustained virological response (non-SVR). Post-treatment AMC values were measured at 6months after end of PR treatment. Fifteen (2.8%) of 540 patients with an SVR developed HCC during a median follow-up period of 41.4months, and 14 (7.7%) of 183 non-SVR patients developed HCC during a median follow-up of 36.8months (log rank test for SVR vs. non-SVR, P = 0.002). Cox regression analysis revealed that post-treatment AFP level (HR 1.070; 95% CI = 1.024-1.119, P = 0.003) and post-treatment aspartate aminotransferase (AST)-to-platelet ratio index (APRI) ≥0.5 (HR 4.401; 95% CI = 1.463-13.233, P = 0.008) were independent variables associated with HCC development for SVR patients. For non-SVR patients, diabetes (HR 5.750; 95% CI = 1.387-23.841, P = 0.016), post treatment AMC ≥370mm(-3) (HR 5.805; 95% CI = 1.268-26.573, P = 0.023), and post-treatment APRI ≥1.5 (HR 10.905; 95% CI = 2.493-47.697, P = 0.002) were independent risks associated with HCC. In conclusion, post-treatment AMC has a role in prognostication of HCC development in HCV-infected patients who failed to achieve an SVR after PR combination therapy.

The relationships between IFNL4 genotype, intrahepatic interferon-stimulated gene expression and interferon treatment response differs in HCV-1 compared with HCV-3.

The biological mechanism underlying the association between IFNL4/IFNL3 polymorphism and peginterferon/ribavirin (PR) response in HCV-1 is thought to involve differential intrahepatic interferon-stimulated gene expression. HCV-3 is more sensitive to PR, but there are no studies of the association between IFNL4 polymorphism, PR treatment response and liver interferon-stimulated gene expression in HCV-3. We evaluated the association between IFNL4/IFNL3 genotypes, PR treatment outcomes and intrahepatic interferon-stimulated gene expression, according to HCV genotype. HCV-1 and HCV-3 patients who received PR therapy were identified. IFNL3 (rs12979860) and IFNL4 genotype (rs368234815) were determined. A second cohort with stored liver specimens was identified. Expression of ISGs was measured by rt-PCR. Two hundred and fifty-nine patients were identified: 55% HCV-1, 45% HCV-3. IFNL4 genotype frequency was TT/TT 44%, TT/ΔG 42% andΔG/ΔG 14%. Linkage disequilibrium with IFNL3 genotype was high (r(2) = 0.98). The association between IFNL4 genotype and PR response was attenuated in HCV-3 vs. HCV-1 (HCV-3: SVR 89% vs. 76% vs. 72% for TT/TT vs. TT/ΔG vs. ΔG/ΔG, P = 0.09; HCV-1: SVR: 82% vs. 29% vs. 24%, P < 0.001). Intrahepatic ISG expression was evaluated in 92 patients; 61% HCV-1. The association between IFNL4 genotype and liver ISG expression was significantly different for HCV-3 vs. HCV-1 (P-value for interaction = 0.046), with levels of interferon-stimulated gene expression being highest in HCV-1 patients who carried a poor-response IFNL4 genotype. The relationship between IFNL4 genotype and PR treatment response as well as intrahepatic interferon-stimulated gene expression differs between HCV-1 and HCV-3. These data suggest fundamental differences in host-virus interactions according to HCV genotype.

Efficacy of lead‐in silibinin and subsequent triple therapy in difficult‐to‐treat HIV/hepatitis C virus‐coinfected patients

The efficacy of current hepatitis C virus (HCV) triple therapy, including a protease inhibitor, is limited in HIV/HCV-coinfected patients with advanced liver fibrosis and nonresponse to previous peginterferon-ribavirin. These patients have a low chance (only 30%) of achieving a sustained virological response (SVR) during triple therapy and cannot wait for next-generation anti-HCV drugs. In a pilot study, we investigated the efficacy of a lead-in therapy with silibinin before triple therapy in difficult-to-treat patients. Inclusion criteria were HIV/HCV coinfection with advanced liver fibrosis and documented failure of previous peginterferon-ribavirin treatment. Intervention was lead-in therapy with intravenous silibinin 20 mg/kg/day for 14 days. Subsequently, peginterferon-ribavirin combined with telaprevir was initiated for 12 weeks, followed by peginterferon-ribavirin dual therapy until week 48 after initiation of triple therapy. The outcome measurements were HCV RNA after silibinin lead-in, at weeks 2, 4 and 12 of triple therapy, and SVR at week 24 after the end of treatment. We examined six HIV/HCV-coinfected patients (four infected with genotype 1a). All had fibrosis grade METAVIR ≥F3 and were on fully suppressive antiretroviral therapy. Mean HCV RNA decline after silibinin therapy was 2.6 log10 IU/mL (range 2-3 log10 IU/mL). Five of the six patients were virologically suppressed at weeks 2 and 4, and all six at week 12 of triple therapy. One experienced a viral breakthrough thereafter. Four of five patients (80%) showed an SVR 24. One patient had an SVR 12 but has not yet reached week 24. A lead-in with silibinin before triple therapy is highly effective and increases the probability of HCV treatment success in difficult-to-treat HIV/HCV-coinfected patients with advanced liver fibrosis and previous failure of peginterferon-ribavirin.

CP-065 Effectiveness in genotypes 1B, 1A in patients with hepatitis C virus infection treated with telaprevir-based treatment

BackgroundHepatitis C virus genotype 1a (HCV-1a) is a predictor of poor response to peginterferon-ribavirin treatment, which has been associated with a lower resistance barrier, compared to HCV genotype 1b (HCV-1b).Variations...

CP-066 Interleukin-28B polymophism as a predictor of response to telaprevir-based regimens in patients with hepatitis C virus genotype 1 infection

BackgroundInterleukin-28B genetic polymorphism is a key predictor of response to peginterferon-ribavirin treatment in hepatitis C virus (HCV) genotype 1 infection (HCVg1i), CC interleukin-28B genotype (IL28Bg) being highly predictive of efficacy....

SVR12 is higher than SVR24 in treatment-na&amp;iuml;ve hepatitis C genotype 1 patients treated with peginterferon plus ribavirin

BackgroundRandomized clinical trials (RCTs) of interventions for the hepatitis C virus have historically used sustained virological response (SVR) at 24 weeks after treatment (SVR24) as the key effect measure. However, recent RCTs investigating the efficacy of new direct acting agents (DAAs) have used SVR at 12 weeks after treatment (SVR12). While there is evidence to suggest SVR24 and SVR12 are similar in patients receiving new DAAs, this is unlikely to be true for patients receiving backbone peginterferon-ribavirin control treatment. Establishing the difference between SVR12 and SVR24 for patients receiving peginterferon-ribavirin treatment is therefore necessary to avoid biased interpretations of the benefits of newer DAAs.MethodsWe searched the MEDLINE®, Embase™, and Cochrane CENTRAL for RCTs with a peginterferon-ribavirin arm that used SVR24 and/or SVR12. As no RCTs reported on both, we pooled SVR12 and SVR24 proportions using conventional meta-analysis. Proportions were pooled separately for peginterferon alpha-2a and alpha-2b. Further, a Bayesian meta-regression model was employed to estimate the difference between SVR12 and SVR24.ResultsThirty-five RCTs including a peginterferon arm were identified. Twenty-four trials included a peginterferon alpha-2a plus ribavirin arms, of which 20 reported SVR24 and five reported SVR12. Seventeen trials included a peginterferon alpha-2b plus ribavirin arm, of which 16 reported SVR24 and one reported SVR12. Using Bayesian meta-regression, the pooled SVR12 was 6% higher than SVR24 with peginterferon alpha-2a (53% versus 47%) and 5% higher with peginterferon alpha-2b (45% versus 40%) and 95% credible intervals (CrIs) were only marginally overlapping. The meta-regression also demonstrated a marginally significant relative risk of 1.13 (95% CrI 0.99–1.26) of SVR12 versus SVR24. The conventional pairwise meta-analyses were consistent with these findings.ConclusionConsidering the relatively large difference observed between SVR12 and SVR24, it seems reasonable to insist that future clinical trials report both to allow for complete transparency and clarity in their interpretation.

Sustained virological response based on the week 4 response in hepatitis C virus genotype 1 patients treated with peginterferons α-2a and α-2b, plus ribavirin

It is unclear whether the magnitude of reduction in hepatitis C virus (HCV) RNA between baseline and week 4 of peginterferon-ribavirin treatment influences the probability of achieving a sustained virological response (SVR) in patients without a rapid virological response (RVR). Data of 151 genotype 1 chronic hepatitis C patients treated with 48 weeks of peginterferon α-2a (group 1, n=86) and peginterferon α-2b (group 2, n=65), plus ribavirin, were evaluated retrospectively. Patients of each group were further divided into those who had RVR and those who did not. Patients without an RVR were then subdivided into four discrete categories on the basis of the magnitude of decrease in HCV RNA from baseline to week 4: those with a ≥3 log10 drop, those with a ≥2 log10 but <3 log10 drop, those with a ≥1 log10 but <2 log10 drop, and those with a <1 log10 drop. The proportion of SVR was calculated for each category. Overall, 80 and 88.2% of RVR patients and 41.2 and 39.6% of non-RVR patients achieved an SVR in group 1 and group 2, respectively. Among non-RVR patients, the SVR rates were 75, 50, 16.7, and 11.1% in group 1 (trend test P=0.001) and 63.6, 42.9, 30, and 23.1% in group 2 (trend test P=0.038) in those with a drop in HCV RNA level of ≥3 log10, ≥2 log10, ≥1 log10, and <1 log10 at week 4, respectively. Patients with a ≥3 log10 drop in HCV RNA at week 4 have a high probability of achieving an SVR when treated with either peginterferon α-2a-ribavirin or peginterferon α-2b-ribavirin.

Longitudinal assessment of liver stiffness in patients undergoing antiviral treatment for hepatitis C

Liver stiffness has been suggested as a parameter of fibrosis progression/regression in hepatitis C virus (HCV) patients. To evaluate stiffness before and after peginterferon-ribavirin treatment. Stiffness was prospectively measured in 74 HCV patients, 32 genotypes 1/4 (43.25%) and 42 genotypes 2/3 (56.75%), before, at end of treatment, and after 3 years of follow-up (49 patients). On the same study day, 21 patients underwent liver biopsy. In 55 patients with sustained virological response (74.32%), liver stiffness decreased significantly at end of therapy (6.8±4.9kPa) vs. baseline (9.5±6.9kPa, p=0.04). The decrease vs. baseline was maintained in 30 sustained virological response patients after 3 years follow-up (6.8±4.6kPa vs. 10.8±8.5kPa, p=0.0141). No difference was found at end of treatment vs. baseline (10.1±4.7kPa vs. 9.7±4.2kPa, p=0.825) and after 3 years of follow-up vs. baseline (10.2±3.4kPa vs. 9.7±4.2kPa, p=0.765) in null responders. Similar results were found in relapsers at end of treatment vs. baseline (13.7±7.7kPa vs. 15.2±8.2kPa, p=0.74), and after 3 years of follow-up vs. baseline (16.9±10.0kPa vs. 15.2±8.2kPa, p=0.734). Pre-treatment stiffness >12kPa was significantly associated with no SVR (p<0.025), RR=2.44 (95%C.I. 1.17-5.07). Liver stiffness may be useful to assess long-term antiviral treatment response.

Alanine aminotransferase normalization at week 8 predicts viral response during hepatitis C treatment

To investigate alanine aminotransferase (ALT) and sustained virological response (SVR) in chronic hepatitis C (CHC) during peginterferon-ribavirin treatment. One hundred and fifty-one genotype 1 CHC patients underwent treatment for 48 wk with peginterferon and ribavirin, and were retrospectively divided into two groups as having a rapid virological response (RVR) (Group 1, n = 52) and not having an RVR (Group 2, n = 99). We also subdivided each group into two according to the initial ALT level being high (Group 1h and Group 2h) or normal (Group 1n and Group 2n). HCV RNA and ALT levels were measured at baseline; at 4, 12, 24 and 48 wk during the treatment period; and at 24 wk follow-up. ALT levels were also obtained at 8 wk. According to the results of ALT, patients were enrolled in either the follow-up abnormal or follow-up normalized ALT groups at each interval. Patients with high and normal ALT levels were compared for each interval in terms of SVR. The SVR rates were 83% vs 40% (P = 0.000), 82% vs 84% (P = 0.830), and 37% vs 44% (P = 0.466) when comparing Group 1 with 2, 1h with 1n, and 2h with 2n, respectively. In Group 2h, the SVR rates were 34% vs 40% (P = 0.701), 11% vs 52% (P = 0.004), 12% vs 50% (P = 0.007), 7% vs 50% (P = 0.003), 6% vs 53% (P = 0.001), and 0% vs 64% (P = 0.000) when comparing patients with high and normalized ALT levels at week 4, 8, 12, 24, 48 and 72, respectively. The multiple logistic regression analysis revealed that RVR (OR = 7.05; 95%CI: 3.1-16.05, P = 0.000), complete early virological response (cEVR) (OR = 17.55; 95%CI: 6.32-48.76, P = 0.000), normalization of ALT at 8 wk (OR = 3.04; 95%CI: 1.31-7.06, P = 0.008), and at 12 wk (OR = 4.21; 95%CI: 1.65-10.76, P = 0.002) were identified as independent significant predictive factors for SVR. Normalization of ALT at 8 wk may predict viral response during peginterferon-ribavirin treatment in genotype-1 CHC patients especially without RVR.

Response-Guided Telaprevir Combination Treatment for Hepatitis C Virus Infection

Patients with chronic infection with hepatitis C virus (HCV) genotype 1 often need 48 weeks of peginterferon-ribavirin treatment for a sustained virologic response. We designed a noninferiority trial (noninferiority margin, -10.5%) to compare rates of sustained virologic response among patients receiving two treatment durations. We enrolled patients with chronic infection with HCV genotype 1 who had not previously received treatment. All patients received telaprevir at a dose of 750 mg every 8 hours, peginterferon alfa-2a at a dose of 180 μg per week, and ribavirin at a dose of 1000 to 1200 mg per day, for 12 weeks (T12PR12), followed by peginterferon-ribavirin. Patients who had an extended rapid virologic response (undetectable HCV RNA levels at weeks 4 and 12) were randomly assigned after week 20 to receive the dual therapy for 4 more weeks (T12PR24) or 28 more weeks (T12PR48). Patients without an extended rapid virologic response were assigned to T12PR48. Of the 540 patients, a total of 352 (65%) had an extended rapid virologic response. The overall rate of sustained virologic response was 72%. Among the 322 patients with an extended rapid virologic response who were randomly assigned to a study group, 149 (92%) in the T12PR24 group and 140 (88%) in the T12PR48 group had a sustained virologic response (absolute difference, 4 percentage points; 95% confidence interval, -2 to 11), establishing noninferiority. Adverse events included rash (in 37% of patients, severe in 5%) and anemia (in 39%, severe in 6%). Discontinuation of all the study drugs was based on adverse events in 18% of patients overall, as well as in 1% of patients (all of whom were randomly assigned) in the T12PR24 group and 12% of the patients randomly assigned to the T12PR48 group (P<0.001). In this study, among patients with chronic HCV infection who had not received treatment previously, a regimen of peginterferon-ribavirin for 24 weeks, with telaprevir for the first 12 weeks, was noninferior to the same regimen for 48 weeks in patients with undetectable HCV RNA at weeks 4 and 12, with an extended rapid virologic response achieved in nearly two thirds of patients. (Funded by Vertex Pharmaceuticals and Tibotec; ILLUMINATE ClinicalTrials.gov number, NCT00758043.).

P66 SVR with telaprevir, peginterferon alfa-2A and ribavirin in HCV patients with well-characterised prior null response, partial response, viral breakthrough or relapse after peginterferon+ ribavirin

IntroductionStudy107 is an open-label rollover study of telaprevir (T) with peginterferon+ ribavirin (PR) in genotype-1 HCV patients who did not achieve SVR following PR treatment in telaprevir Phase 2 studies.MethodNull...

Overwhelming diffuse psoriasis during chronic HCV infection, after peginterferon-ribavirin treatment, supported by frequent resort to filgrastim rescue

Overwhelming diffuse psoriasis during chronic HCV infection, after peginterferon-ribavirin treatment, supported by frequent resort to filgrastim rescue

Association of a single nucleotide polymorphism near the interleukin-28B gene with response to hepatitis C therapy in HIV/hepatitis C virus-coinfected patients

Given that peginterferon-ribavirin treatment is poorly tolerated, there is interest in the identification of predictors of response, particularly in HIV/hepatitis C virus (HCV)-coinfected patients that respond less than HCV-monoinfected individuals. A single nucleotide polymorphism (SNP) near the IL28B gene (rs12979860) has been shown to predict treatment response in HCV-monoinfected patients carrying genotype 1. Information is lacking for HIV/HCV-coinfected individuals and/or other HCV genotypes. From 650 HIV/HCV-coinfected patients, we identified those who had completed a course of peginterferon-ribavirin therapy with a validated outcome and available repository DNA. The rs12979860 SNP was examined in a blinded fashion. A total of 164 patients were included in the final IL28B genotyping analysis, 90 (55%) of whom achieved sustained virological response (SVR). HCV genotype distribution was as follows: HCV-1 58%, HCV-3 31% and HCV-4 11%. Overall, the SVR rate was higher in patients with CC than in those CT/TT genotypes: 56 of 75 (75%) versus 34 of 89 (38%) (P < 0.0001). The effect of the SNP was seen in HCV genotypes 1 and 4 but not in HCV genotype 3 carriers. In the multivariable analysis (odds ratio; 95% confidence interval; P value), the rs12979860 CC genotype was a strong predictor of SVR (3.7; 1.6-8.5; 0.002), independent of HCV genotype 3 (8.0; 3.1-21.0; <0.001), serum HCV-RNA less than 600,000 IU/ml (11.9; 3.8-37.4; <0.001) and lack of advanced liver fibrosis (3.5; 1.4-8.9; 0.009). The rs12979860 SNP located near the IL28B gene is associated with HCV treatment response in HIV-infected patients with chronic hepatitis C due to genotypes 1 or 4. Thus, IL28B genotyping should be considered as part of the treatment decision algorithm in this difficult-to-treat population.

Safety and efficacy of peginterferon-ribavirin treatment in hepatitis C patients with heart disease

Safety and efficacy of peginterferon-ribavirin treatment in hepatitis C patients with heart disease

Update on viral hepatitis: 2005

This review aims to provide a concise summary of relevant developments in the treatment and prevention of viral hepatitis based on publications between December 2004 and November 2005. Long-term therapy with lamivudine was shown to reduce the incidence of adverse clinical outcomes in patients with chronic hepatitis B. This benefit was, however, diminished in patients with viral breakthrough. Combination therapy (peginterferon or telbivudine plus lamivudine) decreased the risk of antiviral resistance but did not improve response compared with monotherapy. Entecavir and tenofovir were shown to be effective in suppressing lamivudine-resistant hepatitis B. A shorter duration of peginterferon-ribavirin treatment was shown to be feasible in genotype 2/3 hepatitis C patients. Relapsers to previous standard interferon-based therapy had higher sustained virological response rates than previous non-responders when retreated with peginterferon-ribavirin. Hepatitis C patients with advanced liver disease may achieve sustained virological response with peginterferon-ribavirin treatment, but the complication rate was high. New insights into the management of viral hepatitis have been gained over the past year. The problem of antiviral resistance in chronic hepatitis B is real and treatment options need to keep evolving. Advances have been made in hepatitis C treatment including patients with genotypes 2 or 3 infection and decompensated cirrhosis.