Complete Early Response to Pegylated Interferon/ribavirin Predicts Sustained Response in HIV-HCV Coinfected Patients: SLAM-C

By Liz Highleyman

HIV-HCV coinfected patients tend to respond less well to interferon-based therapy for chronic hepatitis C than individuals with HCV alone. Some studies have suggested that coinfected patients may respond more slowly, and therefore might benefit from longer treatment.

At the 16th Conference on Retroviruses and Opportunistic Infections (CROI 2009) this week in Montreal, Raymond Chung from Massachusetts General Hospital presented the latest results from the SLAM-C study (Sustained Long-term Antiviral Maintenance with Pegylated Interferon in HCV/HIV Coinfected Patients; aka ACTG A5178), focusing on early responders.

The SLAM-C trial consisted of 3 steps. In step 1, 329 HIV-HCV coinfected participants were treated with 180 mcg/week pegylated interferon alfa-2a (Pegasys) plus 1000-1200 mg/day weight-based ribavirin for 12 weeks.

In step 2, participants who achieved early virological response (EVR) -- at least a 2 log decrease or undetectable (< 600 IU/mL) HCV viral load at week 12 --continued to receive pegylated interferon/ribavirin for a total duration of 72 weeks (the standard duration for coinfected patients is 48 weeks regardless of genotype), while non-responders stopped ribavirin and continued on pegylated interferon monotherapy at the same dose. Results for the non-responders in step 2 were reported at CROI 2008, essentially showing no benefit from maintenance therapy.

The present analysis focused on the 183 participants (56% or the original cohort) who achieved partial or complete EVR. About three-quarters were classified as having complete EVR (HCV RNA < 600 IU/mL), with the rest were classified as having partial EVR (at least a 2 log decrease in HIV RNA, but still > 600 IU/mL).

In step 3, 169 early responders opted to continue combination therapy through 72 weeks (most of those who declined to continue did so due to treatment side effects). Sustained virological response (SVR) data -- continued undetectable HCV viral load 24 weeks after completion of treatment -- were available for 146 patients.

In the continuing combination therapy group, 89% were men, the median age was 48 years, 52% were white, 29% were African-American, and 14% were Hispanic. The proportion of blacks decreased from the initial cohort, reflecting the fact that black patients as a group respond less well to interferon-based therapy.

A majority of patients (78%) had hard-to-treat HCV genotypes 1 or 4, 29% were interferon-experienced, and 9% had cirrhosis. Participants generally had well-controlled HIV disease; 89% were on HAART, 86% had HIV RNA < 50 copies/mL, and the median CD4 count was about 300 cells/mm3 (a drop from nearly 500 cells/mm3 in the initial cohort).

Results

Overall, 51% of patients who achieved EVR went on to achieve SVR.

The SVR rate among patients who completed 72 weeks of therapy was 63%.

Consistent with other studies, the SVR rate was 82% for patients with HCV genotype 2 or 3, compared with 42% for those with genotypes 1 or 4.

Previously treated patients had an SVR rate of 60%, compared with 30% for interferon treatment-naive individuals.

Patients who had achieved complete EVR were nearly 4 times more likely to achieve SVR than partial early responders (62% vs 17%, respectively; P < 0.0001).

African-Americans had a lower overall SVR rate than non-black patients, again consistent with other studies (38% vs 57%, respectively).

However, among complete early responders, SVR rates no longer differed according to race/ethnicity, at 69% for Hispanics, 65% for whites, and 54% for African-Americans (P = non-significant).

35% of participant discontinued therapy before 72 weeks.

The most common adverse events were recognized interferon or ribavirin side-effects including muscle aches, depression, and blood cell deficiencies (growth factors were permitted).

A majority of early treatment discontinuations and dose reductions occurred during the final 24 weeks of treatment -- that is, the extension beyond the standard-of-care duration.

Based on these findings, the investigators concluded that patients who obtain complete EVR "do very well," whereas those with partial EVR have "very limited responses."

"While premature discontinuation was frequent," they added, "two thirds completed therapy, with a high rate of SVR."

In discussing these results, Chung stated that failure to achieve complete HCV clearance by week 12 will identify most patients who will not achieve SVR, allowing likely non-responders to avoid additional futile therapy.

"These data suggest that complete EVR should be utilized in the guidance of [HIV-HCV coinfected] subjects," the researchers recommended, "particularly when extended treatment regimens are used."

2/13/09

Reference
R Chung, T Umbleja, A Butt, and others. SLAM-C (ACTG A5178): Role of early virologic response in extended therapy with PEG-interferon and weight-based ribavirin in HCV/HIV co-infection. 16th Conference on Retroviruses and Opportunistic Infections (CROI 2009). Montreal, Canada. February 8-11, 2009. Abstract 103LB.