M. Diago

Peginterferon-alpha2a and ribavirin combination therapy in chronic hepatitis C: a randomized study of treatment duration and ribavirin dose

BACKGROUND Treatment with pegylated interferon (peginterferon) and ribavirin for 48 weeks is more effective than conventional interferon and ribavirin in patients with chronic hepatitis C. OBJECTIVE To assess the efficacy and safety of 24 or 48 weeks of treatment with peginterferon-alpha2a plus a low or standard dose of ribavirin. DESIGN Randomized, double-blind trial. SETTING 99 international centers. PATIENTS 1311 patients with chronic hepatitis C. INTERVENTION Peginterferon-alpha2a, 180 microg/wk, for 24 or 48 weeks plus a low-dose (800 mg/d) or standard weight-based dose (1000 or 1200 mg/d) of ribavirin. MEASUREMENT Sustained virologic response: undetectable HCV RNA concentration at the end of treatment and during 12 to 24 weeks of follow-up. RESULTS Overall and in patients infected with HCV genotype 1, 48 weeks of treatment was statistically superior to 24 weeks and standard-dose ribavirin was statistically superior to low-dose ribavirin. In patients with HCV genotype 1, absolute differences in sustained virologic response rates between 48 and 24 weeks of treatment were 11.2% (95% CI, 3.6% to 18.9%) and 11.9% (CI, 4.7% to 18.9%), respectively, between standard- and low-dose ribavirin. Sustained virologic response rates for peginterferon-alpha2a and standard-dose ribavirin for 48 weeks were 63% (CI, 59% to 68%) overall and 52% (CI, 46% to 58%) in patients with HCV genotype 1. In patients with HCV genotypes 2 or 3, the sustained virologic response rates in the 4 treatment groups were not statistically significantly different. CONCLUSION Treatment with peginterferon-alpha2a and ribavirin may be individualized by genotype. Patients with HCV genotype 1 require treatment for 48 weeks and a standard dose of ribavirin; those with HCV genotypes 2 or 3 seem to be adequately treated with a low dose of ribavirin for 24 weeks.

Telaprevir for retreatment of HCV infection.

BACKGROUND Up to 60% of patients with hepatitis C virus (HCV) genotype 1 infection do not have a sustained virologic response to therapy with peginterferon alfa plus ribavirin. METHODS In this randomized, phase 3 trial, we evaluated the addition of telaprevir to peginterferon alfa-2a plus ribavirin in patients with HCV genotype 1 infection who had no response or a partial response to previous therapy or who had a relapse after an initial response. A total of 663 patients were assigned to one of three groups: the T12PR48 group, which received telaprevir for 12 weeks and peginterferon plus ribavirin for a total of 48 weeks; the lead-in T12PR48 group, which received 4 weeks of peginterferon plus ribavirin followed by 12 weeks of telaprevir and peginterferon plus ribavirin for a total of 48 weeks; and the control group (PR48), which received peginterferon plus ribavirin for 48 weeks. The primary end point was the rate of sustained virologic response, which was defined as undetectable HCV RNA 24 weeks after the last planned dose of a study drug. RESULTS Rates of sustained virologic response were significantly higher in the two telaprevir groups than in the control group among patients who had a previous relapse (83% in the T12PR48 group, 88% in the lead-in T12PR48 group, and 24% in the PR48 group), a partial response (59%, 54%, and 15%, respectively), and no response (29%, 33%, and 5%, respectively) (P<0.001 for all comparisons). Grade 3 adverse events (mainly anemia, neutropenia, and leukopenia) were more frequent in the telaprevir groups than in the control group (37% vs. 22%). CONCLUSIONS Telaprevir combined with peginterferon plus ribavirin significantly improved rates of sustained virologic response in patients with previously treated HCV infection, regardless of whether there was a lead-in phase. (Funded by Tibotec and Vertex Pharmaceuticals; REALIZE ClinicalTrials.gov number, NCT00703118.).

Peginterferon Alfa-2a in Patients with Chronic Hepatitis C

BACKGROUND Covalent attachment of a 40-kd branched-chain polyethylene glycol moiety to interferon alfa-2a results in a compound (peginterferon alfa-2a) that has sustained absorption, a slower rate of clearance, and a longer half-life than unmodified interferon alfa-2a. We compared the clinical effects of a regimen of peginterferon alfa-2a with those of a regimen of interferon alfa-2a in the initial treatment of patients with chronic hepatitis C. METHODS We randomly assigned 531 patients with chronic hepatitis C to receive either 180 microg of peginterferon alfa-2a subcutaneously once per week for 48 weeks (267 patients) or 6 million units of interferon alfa-2a subcutaneously three times per week for 12 weeks, followed by 3 million units three times per week for 36 weeks (264 patients). All the patients were assessed at week 72 for a sustained virologic response, defined as an undetectable level of hepatitis C virus RNA (<100 copies per milliliter). RESULTS In the peginterferon group, 223 of the 267 patients completed treatment and 206 completed follow-up. In the interferon group, 161 of the 264 patients completed treatment and 154 completed follow-up. In an intention-to-treat analysis in which patients who missed the examination at the end of treatment or follow-up were considered not to have had a response at that point, peginterferon alfa-2a was associated with a higher rate of virologic response than was interferon alfa-2a at week 48 (69 percent vs. 28 percent, P=0.001) and at week 72 (39 percent vs. 19 percent, P=0.001). Sustained normalization of serum alanine aminotransferase concentrations at week 72 was also more common in the peginterferon group than in the interferon group (45 percent vs. 25 percent, P=0.001). The two groups were similar with respect to the frequency and severity of adverse events, which were typical of those associated with interferon alfa. CONCLUSIONS In patients with chronic hepatitis C, a regimen of peginterferon alfa-2a given once weekly is more effective than a regimen of interferon alfa-2a given three times weekly.

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.

Predicting response to peginterferon α-2a, lamivudine and the two combined for HBeAg-negative chronic hepatitis B

Objective: In a trial of patients with hepatitis B e antigen (HBeAg)-negative chronic hepatitis B, 24 week post-treatment biochemical and virological response rates with peginterferon α-2a with or without lamivudine were significantly higher than with lamivudine alone. The effect of pre-treatment factors on post-treatment responses was investigated. Methods: Multivariate analyses were performed using available data from 518 patients treated with peginterferon α-2a with or without lamivudine, or with lamivudine alone. A post-treatment response was defined as alanine aminotransferase (ALT) normalisation and hepatitis B virus (HBV) DNA level of <20 000 copies/ml. Results: In logistic regression analyses across all treatment arms, peginterferon α-2a (with or without lamivudine) therapy, younger age, female gender, high baseline ALT, low baseline HBV DNA and HBV genotype were identified as significant predictors of combined response at 24 weeks post-treatment. In the peginterferon α-2a and lamivudine monotherapy arms, patients with genotypes B or C had a higher chance of response than genotype D infected patients (p<0.001), the latter responding better to the combination than to peginterferon α-2a monotherapy (p = 0.015). At 1 year post-treatment, response rates by intention-to-treat analysis were 19.2% for the peginterferon α-2a, 19.0% for the combination, and 10.0% for the lamivudine groups, with genotypes B or C associated with a sustained combined response to peginterferon α-2a with or without lamivudine therapy. Conclusions: Baseline ALT and HBV DNA levels, patient age, gender, and infecting HBV genotype significantly influenced combined response at 24 weeks post-treatment, in patients treated with peginterferon α-2a and/or lamivudine. At 1 year post-treatment HBV genotype was significantly predictive of efficacy for patients treated with peginterferon α-2a with or without lamivudine.

Peginterferon alfa-2b and Ribavirin: Effective in Patients With Hepatitis C Who Failed Interferon alfa/Ribavirin Therapy

BACKGROUND & AIMS Treatment with peginterferon alfa and ribavirin produces a sustained virologic response (SVR) in approximately 60% of hepatitis C virus (HCV)-infected patients. Alternate options are needed for patients who relapse or do not respond to therapy. METHODS This prospective, international, multicenter, open-label study evaluated efficacy and safety of peginterferon alfa-2b (1.5 microg/kg/wk) plus weight-based ribavirin (800-1400 mg/day) in 2333 chronic HCV-infected patients with significant fibrosis/cirrhosis whose previous interferon alfa/ribavirin therapy failed. Patients with undetectable HCV-RNA at treatment week (TW) 12 received 48 weeks of therapy; patients with detectable HCV-RNA at TW12 could enter maintenance studies at TW18; 188 patients with low/detectable HCV-RNA at TW12 continued therapy at the investigators request. RESULTS Overall, 22% of the patients attained SVR (56% with undetectable HCV-RNA and 12% with low/detectable HCV-RNA at TW12). SVR was better in relapsers (38%) than nonresponders (14%), regardless of previous treatment, and in patients previously treated with interferon-alfa/ribavirin (25%) than peginterferon alfa-ribavirin (17%). Predictors of response in patients with undetectable HCV-RNA at TW12 were genotype (2/3 vs 1, respectively; odds ratio [OR] 2.4; P < .0001), fibrosis score (F2 vs F4; OR, 2.2; F3 vs F4; OR, 1.7; P < .0001), and baseline viral load (< or =600,000 vs >600,000 IU/mL; OR, 1.4; P = .0223). These factors plus previous treatment and response were overall predictors of SVR. Safety was similar among fibrosis groups. CONCLUSIONS Peginterferon alfa-2b plus weight-based ribavirin is effective and safe in patients who failed interferon alfa/ribavirin therapy. Genotype, baseline viral load, and fibrosis stage were predictors of response.

Association of pretreatment serum interferon γ inducible protein 10 levels with sustained virological response to peginterferon plus ribavirin therapy in genotype 1 infected patients with chronic hepatitis C

Background: Increased serum and intrahepatic interferon γ inducible protein 10 (IP-10) levels in patients with chronic hepatitis C (CHC) have been described. Aim: To analyse the possible association of serum IP-10 levels with different outcomes to antiviral therapy. Patients: A total of 137 CHC patients treated with peginterferon plus ribavirin. Methods: Serum IP-10 levels were determined by enzyme linked immunosorbent assay before therapy, after 12 weeks of treatment, and 24 weeks after cessation of therapy. Variables significantly associated with a sustained virological response (SVR) on univariate analysis were included in a multivariate logistic regression model. Results: Pretreatment serum IP-10 levels in patients with SVR were significantly lower than in non-responders (NR) (332.4 (222.1) v 476.8 (305.3) pg/ml, respectively; p = 0.004). Serum IP-10 concentrations significantly decreased in patients with SVR (pretreatment: 332.4 (222.1) pg/ml; post-treatment: 170.2 (140.1) pg/ml; p<0.001) but not in NR (pretreatment: 476.8 (305.3) pg/ml; post treatment: 387.3 (268.1) pg/ml; p = 0.06). By multivariate analysis, non-1 genotype (odds ratio (OR) 3.5 (95% confidence interval (CI) 1.1–10.4); p = 0.003) and low viral load at baseline (OR 0.34 (95% CI 0.14–0.79); p = 0.01) were independent predictors of SVR in all patients. When multivariate analysis was restricted to patients with genotype 1, only baseline viral load (OR 0.38 (95% CI 0.155–0.96); p = 0.04) and pretreatment serum IP-10 levels (OR 0.99 (95% CI 0.996–0.999); p = 0.03) were identified as predictive factors of SVR. Conclusion: Pretreatment serum IP-10 behaves as a predictive factor of SVR to peginterferon plus ribavirin therapy in genotype 1 infected patients.

Effect of sustained virological response to treatment on the incidence of abnormal glucose values in chronic hepatitis C

BACKGROUND/AIMS To investigate the effect of sustained virological response (SVR) on impaired fasting glucose (IFG) and/or type 2 diabetes (T2DM); to assess the influence of glucose abnormalities on the SVR rate. METHODS 1059 patients with chronic HCV; normal glucose (< 100 mg/dl) in 734, IFG (between 100 and 125 mg/dl) in 218, and T2DM (126 mg/dl) in 107 cases, were treated with interferon plus ribavirin over 24 or 48 weeks, depending on viral genotype. RESULTS The SVR rate was lower in patients with IFG and/or T2DM than in patients with normal glucose concentrations [143/325 (44%) vs. 432/734 (58.8%); P=0.002]. In the follow-up, abnormal glucose concentrations were observed in 74 of 304 (24.3%) non-responders and in 49 of 430 (11.4%) sustained responders (log-rank: 13.8; P=0.00002). Reverse stepwise logistic regression analysis identified the independent variables predictive of IFG or T2DM development as: sustained response (OR: 0.44; 95%CI=0.20-0.97; P=0.004) and fibrosis stage (OR: 1.46; 95%CI=1.06-2.01;P=0.02). Family history of DM, steatosis, gender, HCV viral load, genotype, triglycerides, cholesterol and BMI did not enter the multivariate analysis equation. CONCLUSIONS SVR reduces the risk of IFG and/or T2DM development in patients with chronic hepatitis C while altered glucose metabolism impairs sustained response to viral treatment.

Treatment of insulin resistance with metformin in naïve genotype 1 chronic hepatitis C patients receiving peginterferon alfa‐2a plus ribavirin

Insulin resistance affects sustained virological response (SVR) in chronic hepatitis C. To know whether adding metformin to standard antiviral treatment improves SVR, we conducted a prospective, multicentered, randomized, double‐blinded, placebo‐controlled trial in 19 Spanish hospitals, including 123 consecutive patients with genotype 1 chronic hepatitis C and insulin resistance. Patients were randomized to receive either metformin (arm A; n = 59) or placebo (arm B; n = 64) in addition to peginterferon alfa‐2a (180 μg/week) and ribavirin (1000–1200 mg/day). The primary end point was SVR, and secondary endpoints were viral clearance at weeks 12, 24, and 48, and changes in the homeostasis model assessment (HOMA) index over the first 24 weeks. There were no differences between arms at baseline. In the intent‐to‐treat analysis, SVR was observed in 53% versus 42% in arm A and arm B, respectively (P = NS). In the subgroup analyses, SVR was higher in females (n = 54) receiving metformin: arm A, 58% (15/26) versus 29% (8/28) arm B (P = 0.03). In the per protocol analysis (PPA; n = 101), SVR was 67% in arm A and 49% in arm B (P = 0.06). Viral decline during the first 12 weeks was greater in females receiving metformin: −4.88 (1.18) versus −4.0 (1.44) (P = 0.021), whereas no differences were seen in males. The triple therapy was well tolerated, but diarrhea was more often seen in arm A (34% versus 11%; P < 0.05). Conclusion: Adding metformin to peginterferon and ribavirin was safe and improved insulin sensitivity. Although the study failed to show a statistically significant difference between arms, it did show an improved SVR in females. (HEPATOLOGY 2009.)

Preliminary investigation of the association of oral lichen planus and hepatitis C

OBJECTIVE The aim of this investigation was to determine if an association exists between hepatitis C virus and oral lichen planus. STUDY DESIGN Three groups of subjects were selected: 505 patients with hepatitis C virus infection (group 1), 100 patients with oral lichen planus (group 2), and a randomly selected control group (age- and gender-matched) of 100 healthy subjects (group 3). The prevalence of oral lichen planus was determined in groups 1 and 3, and the prevalence of hepatitis C virus infection was established in groups 2 and 3. RESULTS The prevalence of oral lichen planus was 3.36% (n = 17) in group 1 and 1% (n = 1) in the control group; the prevalence of hepatitis C virus infection was 23% (n = 23) in group 2, and 5% (n = 5) in the control group. No significant differences were observed in the incidence of oral lichen planus in group 1 between those patients who received interferon and those who did not. The 17 patients in group 1 who manifested oral lichen planus and hepatitis C virus infection simultaneously exhibited a marked tendency to have only reticular lesions (70.6%), with involvement of the buccal mucosa in 88.2% of these patients, the tongue in 29.4%, and the gingiva in 11.8%. Analyzing a randomized subgroup of 143 patients from group 1 (subgroup 1) that was matched by age and gender with groups 2 and 3, we found that the incidence of oral lichen planus in patients with hepatitis C virus infection (subgroup 1) was greater than in the control group (5.59% vs 1%), though this was not statistically significant (chi2 = 0.119; p = 0.06). In contrast, group 2 exhibited a statistically significant higher incidence of hepatitis C virus infection (23%) than the controls (5%; chi2 = 0.259, p = 0.0002). CONCLUSIONS The prevalence of hepatitis C virus infection in patients with oral lichen planus was greater than in the control series. In our opinion this observation warrants the investigation of potential concomitant hepatitis C virus infection in patients with oral lichen planus.