Extended maintenance therapy with pegylated interferon did not reduce the rate of liver fibrosis progression in HIV/hepatitis C virus coinfected individuals who did not respond to combination treatment for hepatitis C, according to data presented on Monday at the Fifteenth Conference on Retroviruses and Opportunistic Infections in Boston.
HIV positive people with chronic hepatitis C tend to experience more rapid liver fibrosis progression than individuals with hepatitis C alone. Further, HIV/hepatitis C coinfected patients, on average, respond less well to interferon-based therapy than those with only hepatitis C. It has been hypothesised that long-term pegylated interferon maintenance therapy may reduce fibrosis progression in hepatitis C patients who have not responded to, or have relapsed after, combination treatment with pegylated interferon plus ribavirin.
In the SLAM-C study (U.S. AIDS Clinical Trials Group study 5178), 330 HIV/hepatitis C coinfected patients were enrolled, all but one of whom were initially treated with standard anti-hepatitis therapy consisting of 180 mcg once-weekly pegylated interferon alfa-2a (Pegasys) plus 1,000-1,200 mg/day weight-based ribavirin.
Most participants (83%) were male, 43% were white, 37% were black, 15% were Hispanic, and the median age was 48 years. The median hepatitis C viral load was 6.6 log10, 84% had HCV genotype 1, and about one-third had received interferon-based therapy in the past. All had at least mild fibrosis (Metavir stage F1) and 13% had cirrhosis (F4), but none had decompensated liver disease. Most participants had well controlled HIV disease, with a median CD4 cell count of 498 cells/mm3 and three-quarters having undetectable HIV viral load (below 50 copies/ml).
Response to anti-hepatitis C therapy was assessed at twelve weeks. At this point, 56% of patients achieved early virological response (at least a 2 log10 drop in HCV viral load), including 42% with undetectable hepatitis C RNA. This was a higher rate than the 41% seen in an earlier trial, ACTG 5071, which used a lower dose of ribavirin (800 mg/day regardless of weight). Factors significantly associated with early response were HCV genotypes 1 or 4 and white race/ethnicity. Other related factors were male sex, less fibrosis and better liver function (lower ALT level) at baseline, and higher neutrophil and haemoglobin levels.
The remainder of the study participants were classified as non-responders. Although the standard duration of hepatitis treatment is 24 weeks for HCV genotypes 2 and 3 or 48 weeks for genotypes 1 and 4, people who do not experience early virological response by week 12 are unlikely to go on to achieve sustained response.
The 86 non-responders were then randomised to either receive maintenance therapy with the same dose of pegylated interferon monotherapy for 72 weeks or to be observed without further treatment. Compared with the initial group as a whole, the non-responders were more likely to be black (about 53%), to have hepatitis C genotype 1 (91%), and to have received prior interferon treatment (about 42%), and had a lower median CD4 cell count (393 cells/mm3); slightly more than one-quarter had advanced fibrosis or cirrhosis (Metavir stage F3-F4).
Some twelve-week responders who later had detectable HCV at week 36 were allowed to roll back into the maintenance therapy part of the trial. In addition, some non-responder patients who had received similar treatment to this point outside the trial joined at the start of the maintenance monotherapy stage.
The investigators compared the rates of fibrosis in the maintenance therapy and untreated observation groups by analysing liver biopsies obtained at the beginning and end of treatment. In April 2007, the trial’s safety monitoring committee stopped the maintenance therapy stage of the study early after it failed to show any difference in fibrosis progression between treated and untreated patients. In part, this was attributable to an unexpectedly low rate of progression in the observation group. Though enrolment in the trial was halted, observation is ongoing.
Before the maintenance therapy stage was stopped, 62 patients had completed 72 weeks of follow-up, and the investigators had 45 paired biopsies available for assessment. Analysis of these biopsies showed that there was no significant change in fibrosis amongst either patients who received interferon maintenance therapy or the observation group. In fact, the maintenance arm showed a non-significant trend toward worse fibrosis progression.
Necroinflammation remained stable in the interferon maintenance group and worsened significantly in the observation group; however, this did not translate to fibrosis progression.
The researchers concluded that, contrary to some previous reports, this randomized controlled trial “failed to identify significant change” in liver fibrosis among pegylated interferon monotherapy treated or untreated patients over 72 weeks.
During a discussion of the presentation, investigator Kenneth Sherman of the University of Cincinnati in Ohio noted that these findings in HIV/hepatitis C coinfected patients were somewhat similar to recently reported results from the HALT-C trial, which found that long-term, low-dose pegylated interferon did not reduce the rate of fibrosis progression amongst non-responders with hepatitis C monoinfection.
“It’s clear that we don’t fully understand the effects of interferon,” he said. “What seemed obvious—that long-term pegylated interferon would be helpful—may not be the case, which is why we do these studies.”
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 patients. Fifteenth Conference on Retroviruses and Opportunistic Infections, Boston, oral abstract 59, 2008.