No effect of interferon maintenance therapy on fibrosis progression in non-responders
Simon Collins, HIV i-Base
One aspect of HCV management that is informed by little data, is whether continued treatment of virologic non-responders with maintenance peg-IFN therapy can reduce the rate of clinical HCV progression.
This question was addressed in a study presented by Kenneth Sherman and colleagues in a multicentered US study that treated a mixed group of 329 patients (68% naive and 32% refractory to previous treatment) with peg-IFN-alpha-2a plus weight-based ribavirin for 12-18 weeks. Median age was 48 years; 83% male; 43% white, 37% black, non-Hispanic and 15% Hispanic; baseline median HCV viral load was 6.6 log IU; CD4 was 498 cells/mm3; 74% had HIV RNA <50 copies/mL.
Early virologic response (EVR) was defined as achieving undetectable HCV viral load (<600 IU) or 2-log drop at week 12. Patients without an EVR received biopsy and were randomised to peg-IFN 180ug alone or observation for 72 weeks.
Liver biopsies obtained at start and end of therapy were blinded, and read by a single pathologist. The study design required 134 subjects to show whether maintenance treatment produced 0.18 unit/year reduction in the rate of Metavir fibrosis progression.
EVR was observed in 55.6% patients (95%CI 50 to 61%; ITT analysis) and was strongly associated with expected factors (gender, race, degree of fibrosis, AST, absolute neutrophil and heamoglobin levels.
86 patients without EVR were then randomised to peg-IFN vs observation. Median entry Metavir score was 2; 28% had advanced fibrosis (F3, F4).
However, lack of fibrosis progression in both groups, lead to DSMB-recommended early closure of the study, when 62 patients had completed 72 weeks of follow-up, only 45 of who had paired biopsy results for this analysis (24 in the IFN, 21 in observation arm).
Compared to the expected rate of 0.18 units/year, median fibrosis change was 0.0 (Q1,Q3: 0.0, 0.69) in the maintenance groups and 0.0 units/year (Q1,Q3: 0.69, 0.61) in the control group.
The authors concluded that, in contrast to recent reports, this randomised controlled trial failed to identify significant change in hepatic fibrosis among untreated non-early virologic responses over 72 weeks. They also commented that weight-based ribavirin achieved higher levels of EVR (55.6% vs. 41%) than the ACTG 5071 study, which used lower doses of ribavirin, and that race (Causaian>Hispanic>Black) appears to be an important independent factor in early virologic response.
Right from the early registration studies for interferon and ribavirin, investigators had noted a slight reduction in hepatic fibrosis scores and also decreases in activity/inflammation, which drives fibrosis in patients who did not have a virological response to therapy. A question that had been asked was does this therapy have an anti-fibrotic effect over and above its anti-viral effect?
This phenomenon was recently explored in the HALT-C study (AASLD 2007, De Bisceglie et al), where HCV mono-infected patients with Child-Pugh A cirrhosis and previous non-response, were randomised to continue pegIFN-alpha 2a at half-dose (90mg) or placebo over 3.5 years. The end-points were death, de-compensation, HCC or an increase in fibrosis by two points. The results, presented by the authors at AASLD, suggested that for all individual end-points, there was no significant difference between the pegIFN arm and the placebo arm, thus suggesting that in clinical terms, pegIFN maintenance therapy did not prevent progression in cirrhotic patients.
This study, also called the SLAM-C study, included HIV/HCV co-infected patients, 15% of whom had cirrhosis. After a lead in period of treatment with pegIFN and weight-based ribavirin, patients with no EVR were randomised to maintenance therapy with pegIFN 180mcgs/week or no therapy. Liver biopsies were evaluated after 72 weeks. There was no fibrosis progression in either arm. However, there was a greater reduction in inflammatory scores in patients on pegIFN arm. Clearly this begs the question of whether maintenance therapy will help reduce fibrosis progression in non-virological responders. From this study, evidently not, although these were small numbers, therapy and follow-up was only for 72 weeks and that these patients had good CD4 counts and well-controlled HIV disease, and were therefore likely to have slow progression of HCV related fibrosis.
Taking HALT-C and SLAM-C results into account, current evidence does not support pegIFN maintenance in patients with no virological response.
Sherman K, et al. Sustained Long-term Antiviral Maintenance with Pegylated Interferon in HCV/HIV-co-infected Patients: Early Viral Response and Effect on Fibrosis in Treated and Control Subjects.15th CROI, Boston 2008. Abstract 59.