Clinical Trial Result Information
Protocol number
NR15961
Title of Study
APRICOT study. A Randomized, Partially Blinded, Multicenter, Phase III, 3-Arm Study Evaluating the Efficacy and Safety of Peginterferon alfa-2a (40KD) Monotherapy Versus Combination Therapy of Peginterferon alfa-2a (40KD) With Ribavirin Versus Combination Therapy of Interferon alfa-2a (IFN alfa-2a) With Ribavirin for 48 Weeks and 24 Weeks of Follow-up in Patients With Chronic Hepatitis C (CHC) Co-infected With Human Immunodeficiency Virus (HIV)
Sponsor
F Hoffman-La Roche Ltd
Company division
Pharmaceutical
Product name
PEGASYS
Generic name
peginterferon alfa-2a (40KD)
Therapeutic area
Hepatitis C, Chronic
Clinical study summary
This international, multicenter, randomized, parallel-group, partially blinded, active- and placebo-controlled study evaluated the efficacy and safety of peginterferon alfa-2a (40KD) (PEGASYS), PEGASYS + ribavirin, and IFN alfa-2a + ribavirin in patients co-infected with hepatitis C virus (HCV) and HIV.
Study center(s)
A total of 95 centers in the United States, Canada, South America, Europe, and Australia.
Phase of development
III
Objectives
Primary: To compare the effect of PEGASYS, PEGASYS + ribavirin, and IFN alfa-2a + ribavirin on the clearance of HCV viremia 24 weeks after treatment end (sustained virologic response (SVR)).
Secondary: (1) To compare the efficacy of the 3 therapy arms on the reduction of HCV viremia after up to 48 weeks of treatment; (2) To compare the safety of the 3 therapy arms; (3) To compare the effect of the 3 therapy arms on HIV-1 infection (HIV-1 RNA, CD4+ cell count, and AIDS-defining adverse events); (4) To compare the treatment arms in terms of quality of life (QOL) and fatigue severity, as measured by the Short Form 36 (SF-36) of the Medical Outcome Study and the Fatigue Severity Scale (FSS); (5) To monitor serum alanine aminotransferase (ALT) levels during and after therapy.
Methodology
Patients were randomized 1:1:1 to treatment with PEGASYS, PEGASYS + ribavirin, or IFN alfa-2a + ribavirin. Patients in all treatment groups were treated for 48 weeks and then followed for a 24-week treatment-free period. During treatment and follow-up, patients’ disease status was assessed by monitoring HCV RNA titers. Liver biopsies were performed within 15 months before the start of the study and in some patients at the end of the 24-week follow-up period. Patients completed QOL (SF-36 and FSS) questionnaires before, and at intervals during, the study. Patients were assessed for safety, which included serum ALT levels, HIV RNA titers, and CD4+ and CD8+ cell counts, at all study visits during treatment (48 weeks) and follow-up (Week 72).
Number of patients (planned/analyzed)
840 planned; 868 randomized; 860 treated.
Diagnosis and main criteria for inclusion
Male and female outpatients >=18 years of age with serologically and histologically proven CHC, elevated ALT levels, detectable HCV RNA, serologic evidence of HIV-1 infection, a CD4+ cell count of >=100 cells/µL, and stable HIV disease with or without antiretroviral therapy.
Test product, dose and mode of administration or test procedure
PEGASYS, 180 µg/sc/once weekly. Ribavirin 800 mg/po/day, in split doses.
Duration of treatment
48 weeks + 24 weeks of untreated follow-up
Reference therapy, dose and mode of administration or reference procedure
IFN alfa-2a, 3 MIU/sc/tiw
Criteria for evaluation (efficacy, safety)
Primary efficacy parameters: SVR defined as undetectable HCV RNA (<50 IU/mL) based on a single negative HCV RNA measurement at the end of the untreated follow-up period.
Secondary efficacy parameters: (1) SVR based on 2 consecutive negative HCV RNA measurements (<50 IU/mL) >=21 days apart at the end of the untreated follow-up period; (2) virologic response at Weeks 4, 12, 24, 36, and 48; (3) histologic response; (4) maintenance of virologic response at the end of the 24-week untreated follow-up period.
QOL parameters: QOL scores, as measured by the SF-36 and FSS questionnaires.
Safety parameters: Clinical adverse events, AIDS-defining events, laboratory test results, HIV RNA titers, CD4+ cell counts, CD8+ cell counts, and vital signs.
Statistical methods
Primary analysis population: All intent-to-treat patients.
Efficacy: Hypothesis testing, and odds ratio and 97.5% confidence intervals given for pairwise treatment comparisons of SVR. Categorical variables were analyzed using the Cochran-Mantel-Haenszel test.
Safety: Descriptive statistics were used to summarize safety parameters by treatment group.
Summary (efficacy, safety, other results)
Efficacy - Sustained virologic response (SVR) was highest in patients receiving PEGASYS + ribavirin (40%) and was statistically superior to the SVR in patients receiving IFN alfa-2a + ribavirin (12%; odds ratio, 5.40; P<0.0001) or PEGASYS monotherapy (20%; odds ratio, 2.89; P<0.0001). SVR in patients receiving PEGASYS monotherapy was significantly higher than in patients receiving IFN alfa-2a + ribavirin (20% vs 12%; P=0.008).
Virologic response at the end of treatment was higher in patients receiving PEGASYS + ribavirin (47%) than in patients receiving IFN alfa-2a + ribavirin (14%) or PEGASYS monotherapy (31%). The percentage of patients who maintained their response at the end of the 24-week follow-up period was higher in the combination therapy groups (75% in each of PEGASYS plus ribavirin, and IFN alfa-2a + ribavirin groups) than in the PEGASYS monotherapy group (54%).
The highest SVR in the PEGASYS + ribavirin group was achieved by patients infected with either genotype 2 or 3 (59 of 95 patients; 62%), and SVR in these patients did not appear to be dependent on baseline viral titer. In contrast, in patients in the PEGASYS + ribavirin group infected with genotype 1, SVR was dependent on baseline viral titer, and patients with a low baseline viral titer had a higher SVR than patients with a high baseline viral titer (61% vs 18%). Similarly, the percentage of patients who maintained their virologic response at the end of treatment in the PEGASYS + ribavirin group was higher in patients infected with genotypes 2 and 3 (84%) than in patients infected with genotype 1 (69%). In patients infected with genotype 4, the highest SVR was achieved by patients treated with PEGASYS + ribavirin (38%). In all 3 treatment groups, patients infected with genotype 1 had a lower SVR than patients infected with genotype non-1.
Histologic response (mainly improvement in necroinflammatory scores) was highest in the group receiving PEGASYS + ribavirin (57% of patients with paired liver biopsies). In the 3 treatment groups, histologic improvement was also seen in patients who did not achieve a SVR. Between 30% and 43% of patients with paired liver biopsies who did not achieve a SVR achieved a histologic response, with the histologic response being highest in the PEGASYS + ribavirin group (43%).
Patients who did not achieve an early virologic response by Week 12 were highly unlikely to achieve an SVR (negative predictive value of 98%–100%), regardless of treatment group or HCV genotype.
QOL - QOL results obtained from the SF-36 and FSS questionnaires demonstrated that QOL and tolerability of HCV treatment was similar in patients receiving PEGASYS + ribavirin and IFN alfa-2a + ribavirin. Quality of life has been shown to be improved in patients with HIV-HCV coinfection who achieve an SVR after treatment with PEGASYS + ribavirin.
Safety - The safety profile of PEGASYS + ribavirin was generally similar to that of IFN alfa-2a + ribavirin. The frequency of serious adverse events was similar in the PEGASYS + ribavirin (17%) and IFN alfa-2a + ribavirin (15%) groups and slightly higher in the PEGASYS monotherapy group (21%). A similar percentage of patients in the 3 treatment groups (15%–16%) withdrew from treatment for safety reasons. The percentage of patients who required modifications of either their interferon or their ribavirin dose was higher in the PEGASYS + ribavirin group (39% and 37%, respectively) than in the IFN alfa-2a + ribavirin group (16% and 28%, respectively). The occurrence of AIDS-defining events was uncommon, and the incidence (1%) was the same in all 3 treatment groups.
Serious infections (4% PEGASYS + ribavirin; 7% IFN alfa-2a + ribavirin; 7% PEGASYS monotherapy) were the most common serious adverse events. The most common serious infection was pneumonia (2, 5, and 6 patients, respectively). Except for 1 patient, these serious infections were not associated with a concomitant decrease in neutrophil count to <0.5 x 109/L.
A higher percentage of patients in the PEGASYS + ribavirin and PEGASYS monotherapy groups had neutropenia (11%, and 13%, respectively) and anemia (4% and 3%, respectively) than in the IFN alfa-2a + ribavirin group (<1% and 1%, respectively); the majority of these patients were clinically managed by temporary or permanent dose reduction of study drug or treatment with growth factors.
A higher percentage of patients in the PEGASYS + ribavirin and the PEGASYS monotherapy groups (13% in both groups) had hypertriglyceridemia at some time during treatment or follow-up than in the IFN alfa-2a + ribavirin group (8%), but none of these patients was withdrawn from treatment prematurely nor were any of the events associated with serious adverse events such as pancreatitis. Almost half of the patients in each treatment group were concomitantly taking antiretroviral protease inhibitors (PIs) for their HIV infection. It is not known how much these PIs contributed to triglyceride elevations.
The overall incidences of pancreatitis, lactic acidosis, symptomatic hyperlactatemia, and AIDS-defining events were low and occurred with similar frequencies in the 3 treatment groups. HIV RNA titers remained stable during the study, decreasing slightly during HCV treatment in patients with detectable HIV RNA titers at baseline, and remaining undetectable in the majority of patients with undetectable HIV RNA titers at baseline. Total lymphocyte, CD4+, and CD8+ cell counts decreased from baseline during the 48-week treatment period in all 3 treatment groups and returned to baseline levels following completion of the 48-week treatment. CD4+ %, however, did not change or increased slightly during treatment for HCV. In the 3 treatment groups evaluated in this study, treatment for HCV did not have an adverse impact on the effect of HIV antiretroviral therapy on HIV viral titers.
A total of 7 patients (<1%) experienced elevated serum ALT activity during treatment and follow-up (2 patients in the PEGASYS + ribavirin group and 5 patients in the PEGASYS monotherapy group) resulting in dose modification or premature withdrawal from study treatment. Elevation of serum ALT activity in these 7 patients was not associated with hepatic decompensation.
A total of 12 patients died, including 3 who died beyond the 24 week post-treatment follow-up period, with a similar frequency among the 3 treatment groups.Of these 12 patients, 7 were patients with cirrhosis and 6 of the 7 died of hepatic decompensation. The overall incidence of hepatic decompensation in this study was infrequent and occurred in a similar proportion of patients in the 3 treatment groups (4–5 patients in each group). All patients who had hepatic decompensation had cirrhosis, and many had evidence of hepatic dysfunction at baseline as reflected by high Child-Pugh scores. Treatment with PEGASYS + ribavirin was not associated with an increased risk of hepatic decompensation relative to treatment with PEGASYS monotherapy or IFN alfa-2a + ribavirin.
With the exception of hepatic decompensation and thrombocytopenia, which occurred more frequently in the cirrhotic population than in the overall population, the adverse event profile in the cirrhotic population was similar to that of the overall population.
Conclusions
A sustained virologic response was achieved by 40% of patients with HIV/HCV co-infection who were treated with PEGASYS + ribavirin; this was significantly higher than the SVR of 12% achieved by patients treated with IFN alfa-2a + ribavirin. The SVR of 20% achieved by patients treated with PEGASYS monotherapy was also significantly higher than that achieved with IFN alfa-2a + ribavirin, suggesting that PEGASYS monotherapy can be considered an alternative treatment for patients who cannot tolerate ribavirin.
The adverse event profile of PEGASYS + ribavirin was generally similar to that of IFN alfa-2a + ribavirin, as was the overall tolerability of treatment for HCV as measured by QOL assessments during the study. Although neutropenia, thrombocytopenia, and anemia were more common in the PEGASYS–treated groups than in the IFN alfa-2a + ribavirin group, these abnormalities were managed successfully with dose reductions in the majority of patients and only rarely led to treatment discontinuation.
No evidence was seen suggesting a negative impact on HIV viremia during treatment for HCV.
The results of this trial demonstrate that PEGASYS + ribavirin has a favorable benefit-to-risk ratio in patients with HIV/HCV co-infection and that a substantial proportion of this patient population is likely to benefit from treatment with this combination.
Publications (references, if available)
Torriani F, Rodriguez-Torres M, Rockstroh J et al. Peginterferon Alfa-2a plus Ribavirin for Chronic Hepatitis C Virus Infection in HIV-Infected Patients. NEJM 351: 438-450 (2004).
Date of report
4/29/2004
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