Fayez M. Hamzeh

Peginterferon Alfa-2a and Ribavirin in Latino and Non-Latino Whites with Hepatitis C

BACKGROUND Race has been shown to be a factor in the response to therapy for hepatitis C virus (HCV) infection, and limited data suggest that ethnic group may be as well; however, Latinos and other ethnic subpopulations have been underrepresented in clinical trials. We evaluated the effect of Latino ethnic background on the response to treatment with peginterferon alfa-2a and ribavirin in patients infected with HCV genotype 1 who had not been treated previously. METHODS In a multicenter, open-label, nonrandomized, prospective study, 269 Latino and 300 non-Latino whites with HCV infection received peginterferon alfa-2a, at a dose of 180 microg per week, and ribavirin, at a dose of 1000 or 1200 mg per day, for 48 weeks, and were followed through 72 weeks. The primary end point was a sustained virologic response. We enrolled Latinos whose parents and grandparents spoke Spanish as their primary language; nonwhite Latinos were excluded. RESULTS Baseline characteristics were similar in the Latino and non-Latino groups, although higher proportions of Latino patients were 40 years of age or younger, had a body-mass index (BMI, the weight in kilograms divided by the square of the height in meters) of more than 27 or more than 30, and had cirrhosis. The rate of sustained virologic response was higher among non-Latino whites than among Latinos (49% vs. 34%, P<0.001). The absence of HCV RNA in serum was more frequent in non-Latino whites at week 4 (P=0.045) and throughout the treatment period (P<0.001 for all other comparisons). Latino or non-Latino background was an independent predictor of the rate of sustained virologic response in an analysis adjusted for baseline differences in BMI, cirrhosis, and other characteristics. Adherence to treatment did not differ significantly between the two groups. The numbers of patients with adverse events and dose modifications were similar in the two groups, but fewer Latino patients discontinued therapy because of adverse events. CONCLUSIONS Treatment with peginterferon alfa-2a and ribavirin for 48 weeks resulted in rates of sustained virologic response among patients infected with HCV genotype 1 that were lower among Latino whites than among non-Latino whites. Strategies to improve the sustained virologic response in Latinos are needed. (ClinicalTrials.gov number, NCT00107653.)

Early virologic response after peginterferon alpha‐2a plus ribavirin or peginterferon alpha‐2b plus ribavirin treatment in patients with chronic hepatitis C*

Abstract  Patients infected with hepatitis C virus (HCV) genotype 1 and with serum HCV RNA concentrations over 800 000 IU/mL have relatively low rates of virologic response to pegylated interferons. The 2 forms of pegylated interferon have different pharmacokinetic profiles, and pilot studies comparing them have yielded varying results. We compared the virologic response to 12 weeks of treatment with peginterferon alpha‐2a plus ribavirin vs peginterferon alpha‐2b plus ribavirin in 380 patients who were infected with HCV genotype 1 and had high viral loads.

Factors associated with rapid and early virologic response to peginterferon alfa-2a/ribavirin treatment in HCV genotype 1 patients representative of the general chronic hepatitis C population

Summary.  Rapid virologic response (RVR) and complete early virologic response (cEVR) are associated with sustained virologic response to hepatitis C virus (HCV) therapy. We retrospectively examined baseline and on‐treatment factors associated with RVR (HCV RNA undetectable at week 4) and cEVR (HCV RNA undetectable at week 12, regardless of week 4 response). The analysis comprised 1550 HCV genotype‐1 patients from five clinical trials, including three enriched with difficult‐to‐treat populations, randomized to peginterferon alfa‐2a 180 μg/week plus ribavirin 1000–1200 mg/day. Overall, 15.6% achieved RVR and 54.0% achieved cEVR. Baseline factors predictive of RVR were serum HCV RNA ≤ 400 000 IU/mL (OR: 7.34; P < 0.0001), alanine aminotransferase >3 ×  ULN (OR: 2.01; P < 0.0001), non‐cirrhotic status (OR: 1.92; P = 0.0087), age ≤ 40 years (OR: 1.56; P = 0.0085), white non‐Latino ethnicity (OR: 1.41; P = 0.0666) and individual study (P < 0.0001). These factors plus body mass index ≤ 27 kg/m2 were predictive of cEVR. After adjusting for these factors, mean on‐treatment ribavirin dose >13 mg/kg/day was predictive of RVR (OR: 1.69; P = 0.005) and cEVR (OR: 1.24; P = 0.09), whereas peginterferon alfa‐2a dose reduction was not. Greater decreases in haematologic parameters were observed in patients who achieved cEVR compared with patients who did not. In conclusion, several baseline and on‐treatment factors were associated with RVR and cEVR to peginterferon alfa‐2a plus ribavirin in difficult‐to‐treat HCV genotype‐1 patients, providing important prognostic information on the antiviral response in a patient cohort that is reflective of the general chronic hepatitis C population.

535 Virologic and Metabolic Responses in Chronic Hepatitis C (CHC) Patients With Insulin Resistance (IR) Treated With Pioglitazone and Peginterferon Alfa-2a Plus Ribavirin

Background In CHC patients with IR, improving insulin sensitivity may increase the response to anti-HCV therapy. The Sensitize study is designed to compare virologic and metabolic responses in CHC patients with IR who were randomized to receive peginterferon alfa-2a plus ribavirin (PEG-2a/RBV) alone or PEG-2a/RBV plus pioglitazone (PIO). Methods This is a multicenter, randomized, open-label study designed to treat 240 CHC patients with HCV genotype 1 and IR. Patients stratified by homeostasis model assessment score (HOMA) of >2- 3×ULN (22% vs 15%), and had HCV RNA ≥800,000 IU/mL (83% vs 77%). Glycemic variables were similar between arms. In the control arm vs PIO arm, the median log10 changes in HCV RNA from baseline to Wks 4 and 12 of anti-HCV therapy were -2.1 vs -2.0 IU/mL and -4.2 vs -4.0 IU/mL; the proportion of patients achieving undetectable HCV RNA (<28 IU/mL) at Wk 4 was 16% (11/70) vs 8% (5/59), and at Wk 12 was 54% (36/67) vs 49% (19/39). Median changes in HOMA score, insulin, and glucose concentrations from baseline to Wk 12 of anti-HCV therapy were -0.5, -10.5 pmol/L, and -0.2 mmol/L in the control arm vs -1.2, -37.5 pmol/L, and -0.4 mmol/L in the PIO arm, respectively. Median change in adiponectin levels was greater in the PIO arm vs the control arm (10.0 vs 0 μg/ mL). No clinically relevant changes in lipid variables were observed in the PIO arm. Four patients (5%) in the control arm and 5 (6%) in the PIO arm withdrew due to adverse events while 26 (34%) controls and 31 (39%) treated with PIO withdrew for non-safety reasons. Conclusions Improvements in several glycemic variables with PIO treatment prior to and during anti-HCV therapy may not improve virologic responses in CHC patients with IR treated for 12 weeks. This ongoing study will determine whether this trend extends over the long-term.