The dose-response relationship of peginterferon alfa-2a and ribavirin in the treatment of patients coinfected with HIV-HCV.

PURPOSE: The relationship between peginterferon/ribavirin exposure and the probability of achieving a sustained virologic response (SVR) in HIV-HCV coinfected patients is not well described. We conducted a retrospective analysis of HIV-HCV coinfected patients randomized to 48 weeks of treatment with peginterferon alfa-2a (40 kD) 180 µg/week and ribavirin 800 mg/day in the multinational APRICOT study to define optimal exposure thresholds. METHOD: Actual drug exposure was estimated in 287 patients, taking into consideration dose reductions for adverse events or laboratory abnormalities. RESULTS: SVR overall and SVR in those completing treatment was, respectively, 29% and 37% among HCV genotype-1 patients and 59% and 68% among genotype non-1 patients. No patients with ≤40% exposure to ribavirin achieved an SVR. Receiver operating characteristic analysis identified that threshold exposures to both drugs of >75% (genotype-1) and >60% (genotype non-1) are associated with SVR. An existing generalized additive model populated with data from HCV monoinfected patients was updated to predict an overall SVR of 37% if genotype-1 patients received ribavirin 1000 or 1200 mg/day but at the cost of a higher incidence of anemia (23%). CONCLUSION: Completion of scheduled treatment and exceeding certain thresholds for exposure to peginterferon alfa 2a (40 kD) and ribavirin is associated with higher SVR rates.

Baseline factors prognostic of sustained virological response in patients with HIV-hepatitis C virus co-infection.

OBJECTIVE: To identify baseline characteristics predictive of a sustained virological response (SVR) in patients with HIV-hepatitis C virus (HCV) co-infection treated with interferon-based therapy. DESIGN/METHODS: A stepwise multiple logistic regression analysis was used to explore the prognostic factors associated with SVR [undetectable HCV-RNA (< 50 IU/ml) at the end of untreated follow-up in week 72]. RESULTS: In all patients (n = 853), in addition to the HCV therapy received, the factors most predictive of SVR were baseline HCV-RNA [< or = versus > 400 000 IU/ml; odds ratio (OR) 4.77; 95% confidence interval (CI) 3.15-7.22; P < 0.0001] and HCV genotype (OR 2.87; 95% CI 2.00-4.12; P < 0.0001). HIV treatment (with a protease inhibitor or non-nucleoside reverse transcriptase inhibitor; P = 0.034), race (P = 0.027), and body mass index (P = 0.039) were also weak predictors of HCV treatment response. CONCLUSIONS: In the AIDS PEGASYS Ribavirin International Co-infection Trial (APRICOT), the predictors of SVR among HIV-HCV co-infected patients treated with peginterferon alfa-2a plus ribavirin were similar to those in patients with HCV mono-infection. The HCV genotype and pretreatment HCV-RNA level had the greatest influence on SVR.

Peginterferon Alfa-2a plus ribavirin for chronic hepatitis C virus infection in HIV-infected patients.

BACKGROUND: Hepatitis C virus (HCV) infection is highly prevalent and is associated with substantial morbidity and mortality among persons infected with the human immunodeficiency virus (HIV). We compared the efficacy and safety of pegylated interferon alfa-2a (peginterferon alfa-2a) plus either ribavirin or placebo with those of interferon alfa-2a plus ribavirin for the treatment of chronic HCV infection in patients who were also infected with HIV. METHODS: A total of 868 persons who were infected with both HIV and HCV and who had not previously been treated with interferon or ribavirin were randomly assigned to receive one of three regimens: peginterferon alfa-2a (180 microg per week) plus ribavirin (800 mg per day), peginterferon alfa-2a plus placebo, or interferon alfa-2a (3 million IU three times a week) plus ribavirin. Patients were treated for 48 weeks and followed for an additional 24 weeks. The primary end point was a sustained virologic response (defined as a serum HCV RNA level below 50 IU per milliliter at the end of follow-up, at week 72). RESULTS: The overall rate of sustained virologic response was significantly higher among the recipients of peginterferon alfa-2a plus ribavirin than among those assigned to interferon alfa-2a plus ribavirin (40 percent vs. 12 percent, P<0.001), or peginterferon alfa-2a plus placebo (40 percent vs. 20 percent, P<0.001). Among patients infected with HCV genotype 1, the rates of sustained virologic response were 29 percent with peginterferon alfa-2a plus ribavirin, 14 percent with peginterferon alfa-2a plus placebo, and 7 percent with interferon alfa-2a plus ribavirin. The corresponding rates among patients infected with HCV genotype 2 or 3 were 62 percent, 36 percent, and 20 percent. Neutropenia and thrombocytopenia were more common among patients treated with regimens that contained peginterferon alfa-2a, and anemia was more common among patients treated with regimens containing ribavirin. CONCLUSIONS: Among patients infected with both HIV and HCV, the combination of peginterferon alfa-2a plus ribavirin was significantly more effective than either interferon alfa-2a plus ribavirin or peginterferon alfa-2a monotherapy.

Cost-effectiveness of peginterferon alfa-2a (40kDa) plus ribavirin in patients with HIV and hepatitis C virus co-infection.

BACKGROUND: A multinational trial (APRICOT) showed that peginterferon alfa-2a (40kDa) plus ribavirin is efficacious for treatment of HIV-HCV co-infection. The cost-effectiveness of treating these patients with peginterferon alfa-2a/ribavirin has yet to be explored from a US societal perspective. OBJECTIVE: To predict the cost-effectiveness of peginterferon alfa-2a/ribavirin with interferon/ribavirin (IFN/RBV) or no treatment in HIV-HCV co-infected patients. STUDY DESIGN: A Markov model was constructed with liver progression estimates based on published literature. Sustained virological response and baseline characteristics of the reference case were based on APRICOT. Quality of life and costs in 2004 US dollars (US$) were based on literature estimates and discounted at 3%. RESULTS: Peginterferon alfa-2a/ribavirin compared with IFN/RBV or no treatment is predicted to increase quality-adjusted life-years (QALYs) by 0.73 and 0.94 years, respectively, in HCV-genotype-1 patients. The incremental cost-effectiveness ratio of peginterferon alfa-2a/ribavirin compared with IFN/RBV and no treatment for all patients is respectively US$ 2,082 and 5,187/QALY gained. CONCLUSIONS: Anti-HCV treatment is predicted to decrease the risk of cirrhosis and increase quality-adjusted survival of HIV-HCV co-infected patients compared with IFN/RBV and no treatment. Peginterferon alfa-2a/ribavirin's cost per QALY gained relative to these options falls within the cost-effectiveness level of many health technologies commonly adopted in the US.

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.

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.

Hepatitis C virus (HCV) and human immunodeficiency virus (HIV) dynamics during HCV treatment in HCV/HIV coinfection.

We studied hepatitis C virus (HCV) and human immunodeficiency virus (HIV) dynamics in 10 coinfected subjects in a trial of pegylated interferon-alpha2a (PEG-IFN) alone or combined with ribavirin (RBV), compared with IFN plus RBV for the treatment of HCV. Five subjects, 4 of whom were treated with PEG-IFN, achieved a sustained virological response, although it was delayed by >/=1 week in 3 subjects. The median treatment efficacy in blocking virion production was 99.7% in the PEG-IFN group and 60% with standard IFN. In 2 patients with detectable HIV loads before starting HCV study drugs, we observed a 1-log decrease in HIV RNA load. The estimated HCV virion half-life was longer in the HIV-coinfected subjects, which suggests that coinfection may contribute to a slower clearance of HCV. Although the early viral kinetics of coinfected subjects treated with PEG-IFN or IFN differ from those of singly infected subjects, the treatment response seems unaffected.