Induction dosing of peginterferon alfa-2a (40 KD) and/or high-dose ribavirin in genotype 1 CHC patients with difficult-to-treat characteristics: pharmacokinetic and viral kinetic (PK/VK) assessment from PROGRESS.

BACKGROUND/AIMS: PROGRESS randomized chronic hepatitis C genotype 1 patients with a baseline viral load ≥400,000 IU/mL weighing ≥85 kg to regimens of 180 µg/week for 48 weeks or 360 µg/week for 12 weeks followed by 180 µg/week for 36 weeks peginterferon alfa-2a plus ribavirin. This analysis explored pharmacokinetics and early viral kinetics (VK) and evaluates differences between groups. METHODOLOGY: Blood samples for pharmacokinetic and VK analyses were collected from 51 patients enrolled in the PROGRESS study. RESULTS: Mean peginterferon alfa-2a trough concentration at week 12 was 11.7±4.3 ng/mL for 180 µg and 23.4±11.3 ng/mL for 360 µg. Early VK profiles suggested a trend towards an enhanced viral decline in the 360 µg groups with a mean decrease in HCV RNA at 48 hours post first dose of 1.04 log10 (IU/mL) compared with 0.76 log10 (IU/mL) in the 180 µg groups. Mean beta slope increased with dose, ranging from 0.38±0.26 log10 IU/week at 180 µg to 0.52±0.32 log10 IU/week at 360 µg. CONCLUSIONS: Early viral de clines may be enhanced with the 360 µg dose. These data may suggest the utility of high-dose peginterfer on alfa-2a plus direct-acting antivirals (DAA) in select difficult-to-treat populations.

Virological response is associated with decline in hemoglobin concentration during pegylated interferon and ribavirin therapy in hepatitis C virus genotype 1.

UNLABELLED: Anemia may increase the likelihood of achieving a sustained virological response (SVR) during pegylated interferon and ribavirin treatment of hepatitis C virus (HCV) infection. To determine whether hemoglobin decline is associated with SVR, we retrospectively evaluated the CHARIOT study of 871 treatment-naïve HCV genotype 1 patients. Anemia (serum hemoglobin <100 g/L) occurred in 137 (16%) patients, of whom only 14 (10%) received erythropoietin. Hemoglobin decline >30g/L from baseline occurred in 76% of patients overall, including 526 patients who did not become anemic. Virological responses were higher in anemic patients compared with those who did not develop anemia (end of treatment, 80% versus 65%, P = 0.003; SVR, 61% versus 50%, P = 0.02); these differences remained significant when patients receiving erythropoietin were excluded from analysis. SVR was also higher in patients with hemoglobin decline >30 g/L compared with patients without a similar decline. In multiple logistic regression analyses with treatment group and baseline characteristics, the odds ratio for SVR was 1.97 (95% confidence interval, 1.08-3.62) for anemia and 2.17 (95% confidence interval, 1.31-3.62) for hemoglobin decline >30 g/L. Patients who first developed a hemoglobin decline >30 g/L during weeks 5-12 and 13-48 were more likely to achieve SVR than those who first developed such changes in weeks 0-4 or who never experienced them. CONCLUSION: Patients with HCV genotype 1 infection who develop anemia or experience a hemoglobin decline >30 g/L during weeks 5-48 of therapy achieve higher virological responses to pegylated interferon and ribavirin therapy that are unrelated to erythropoietin use.

Impact of high-dose peginterferon alfa-2A on virological response rates in patients with hepatitis C genotype 1: a randomized controlled trial.

UNLABELLED: This study tested the hypothesis that high-dose peginterferon alfa-2a (PEG-IFNalpha-2a) for the first 12 weeks would increase early and sustained virological response (SVR) rates in patients with chronic hepatitis C genotype 1. Eight hundred ninety-six patients were randomized 1:1 to 360 microg (n = 448) or 180 microg (n = 448) PEG-IFNalpha-2a weekly plus ribavirin at 1000-1200 mg/day for 12 weeks, followed by 36 weeks of 180 microg PEG-IFNalpha-2a weekly plus ribavirin at 1000-1200 mg/day with 871 patients evaluable for the intention-to-treat analysis. Virological responses were assessed by TaqMan (limit of detection 15 IU/mL) at week 4, 8, 12, 24, 48 (end of therapy), and 24 weeks following therapy (SVR). Undetectable hepatitis C virus RNA rates were significantly higher among patients receiving high-dose induction therapy at week 4 (36% versus 26%, P < 0.005), week 8 (61% versus 50%, P < 0.005), and week 12 (74% versus 62%, P < 0.005). However, SVR was not significantly different between patients receiving high-dose (53%) and standard (50%) therapy. Significant baseline prognostic factors for SVR included age, sex, race, histological stage, and viral load. SVR was considerably higher among patients with no or minimal fibrosis (64% and 60%, respectively) compared to those with severe fibrosis/cirrhosis (28% and 24%, respectively). The frequency of serious adverse events and drug discontinuations were similar in both groups, whereas PEG-IFN dose modification, weight and appetite reduction, and grade IV neutropenia were significantly higher in the induction arm. CONCLUSION: Induction dosing with 360 microg/week PEG-IFNalpha-2a for 12 weeks was well tolerated and enhanced early virological response but not SVR rates. The high SVR rates in patients with minimal fibrosis highlight the benefit of early treatment in patients with hepatitis C virus genotype 1.

Hepatic steatosis in HIV/HCV co-infected patients: correlates, efficacy and outcomes of anti-HCV therapy: a paired liver biopsy study.

BACKGROUND/AIMS: Hepatic steatosis is caused by the complex interaction of host and viral factors, such as metabolic syndrome (MS), alcoholism and HCV genotype, and in HIV-HCV co-infected patients, antiretroviral therapy may also play a role. A large population of patients from the AIDS Pegasys Ribavirin International Co-infection Trial (APRICOT) had paired liver biopsies interpreted and graded for steatosis along with lipid measurements and anthropometric data. METHODS: We analyzed these patients to determine the prevalence of steatosis, baseline factors associated with steatosis, effect of steatosis in HCV therapy efficacy and the impact of anti-HCV treatment on steatosis. RESULTS: A total of 65/283 (23%) patients with paired biopsies were positive for steatosis. Patients with steatosis were significantly more likely to have HCV genotype 3, bridging fibrosis/cirrhosis, higher HCV RNA levels, increased triglycerides and lower cholesterol levels. The only different body measurement was neck circumference which was greater in patients with steatosis and significantly decreased from baseline during the study. Hip circumference was predictive of steatosis at baseline. CONCLUSIONS: Factors associated to the metabolic syndrome are important in co-infected patients. Treatment outcome affected steatosis in that viral eradication reduced steatosis in genotype 3 patients, but altogether steatosis did not affect efficacy of treatment in any genotype.

Effect of baseline CD4 cell count on the efficacy and safety of peginterferon Alfa-2a (40KD) plus ribavirin in patients with HIV/hepatitis C virus coinfection.

OBJECTIVE: The impact of baseline CD4 status on hepatitis C virus (HCV) treatment response among patients with HIV/HCV coinfection was investigated using data from a randomized study of peginterferon alfa-2a (40KD) + ribavirin (Peg-IFN/RBV). METHODS: Of 860 patients treated with conventional interferon alfa-2a + ribavirin (IFN/RBV), peginterferon alfa-2a (40KD) + placebo (Peg-IFN), or Peg-IFN/RBV for 48 weeks, 857 patients had baseline CD4 data available and were included in the analysis. Efficacy and safety were analyzed according to baseline CD4 status as absolute cell count and proportion of total lymphocytes. RESULTS: Sustained virologic response (SVR) rates were highest with Peg-IFN/RBV across all CD4 strata. With Peg-IFN/RBV, SVR rates were independent of baseline CD4 in genotype 2/3 patients, but in genotype 1 patients, they tended to be higher with higher CD4 or CD4%. Frequencies of adverse events (AEs) and serious AEs were similar among treatment arms and CD4 strata. Withdrawal and dose reduction rates attributable to safety were highest with CD4 <200 cells/muL. CONCLUSIONS: Peg-IFN/RBV could be effective and well tolerated in HIV/HCV-coinfected individuals with stable HIV. With Peg-IFN/RBV, response tended to increase with higher CD4 counts in genotype 1; however, because of the paucity of patients with CD4 <200 cells/muL, these data require corroboration.

Histological response to pegIFNalpha-2a (40KD) plus ribavirin in HIV-hepatitis C virus co-infection.

OBJECTIVE: Paired liver biopsies from patients enrolled in the multinational AIDS PEGASYS Ribavirin International Co-infection Trial were analysed to investigate a possible correlation between virological and histological responses. DESIGN AND METHODS: A total of 860 HIV-hepatitis C virus (HCV)-co-infected patients were randomly assigned to receive pegIFNalpha-2a (40KD) 180 microg/week plus 800 mg daily ribavirin, pegIFNalpha-2a (40KD) plus placebo or conventional IFNalpha-2a 3 MIU three times a week plus ribavirin for 48 weeks. Paired biopsies were obtained from 401 patients and scored locally using the Ishak-modified histological activity index (HAI). The second biopsy was obtained, on average, 26 weeks or more after the end of treatment. Histological response was defined as a 2-point or greater reduction in the HAI score. RESULTS: The histological response rate was significantly higher in patients receiving pegIFNalpha-2a (40KD) plus ribavirin (57%) than in patients receiving pegIFNalpha-2a (40KD) plus placebo (39%; P < 0.017) or IFNalpha-2a plus ribavirin (41%; P = 0.04). Histological response was correlated with virological response, with the histological response rate ranging from 62 to 74% in patients who achieved a sustained virological response (SVR). Histological response was also seen in 32-43% of patients not achieving an SVR. A higher total HAI score was the only prognostic factor for achieving histological response. CONCLUSION: The histological response rate was significantly higher in HIV-HCV-co-infected patients who received pegIFNalpha-2a (40KD) plus ribavirin than in those receiving pegIFNalpha-2a (40KD) plus placebo or IFNalpha-2a plus ribavirin. Histological response was correlated with virological response, although a substantial proportion of patients who did not achieve an SVR experienced histological improvement.

Risk factors for hepatic decompensation in patients with HIV/HCV coinfection and liver cirrhosis during interferon-based therapy.

OBJECTIVE: Hepatic decompensation was reported from two recent trials (APRICOT and RIBAVIC) assessing interferon (IFN)-based treatment of hepatitis C virus (HCV) in HIV/HCV-coinfected patients. This paper identifies risk factors associated with hepatic decompensation in APRICOT. METHODS: APRICOT is a randomized, partially-blinded, controlled trial comparing treatment with peg-IFN alpha-2a 180 microg once weekly plus ribavirin/placebo 400 mg twice daily with IFN alpha-2a 3 million units three times weekly plus ribavirin 400 mg twice daily for 48 weeks in a total of 859 patients. Multiple logistic regression analysis was performed comparing the baseline characteristics of those cirrhotic patients who experienced decompensation with those of the other cirrhotic patients enrolled. RESULTS: Fourteen patients, all cirrhotic, experienced hepatic decompensation during the study. The incidence in the cirrhotic subgroup of the study was 10.4% (14/134). Six of the 14 patients died as a result of hepatic decompensation. The risk factors associated with hepatic decompensation were increased bilirubin, decreased haemoglobin, increased alkaline phosphatase or decreased platelets, and treatment with didanosine. Markers of viral replication, histological activity, cellular immune status or HCV-therapy, treatment with ribavirin and pegylated versus non-pegylated IFN were not associated with hepatic decompensation. CONCLUSIONS: The results from APRICOT indicate that the overall risk of hepatic decompensation in HIV/HCV-coinfected patients without cirrhosis receiving IFN-based treatment is low. In contrast, patients with markers of advanced cirrhosis, despite the absence of a history of hepatic decompensation, should be monitored closely during IFN-based therapy, because they are at risk of hepatic decompensation. Treatment with antiretrovirals such as didanosine may increase the risk further.