Research shows that HIV/HCV co-infected people do not respond as well to hepatitis C treatment as those with HCV alone. However, a number of recent studies in Europe and the United States conducted in individuals with well-controlled HIV disease have produced promising results, including people with hard-to-treat genotype 1.
The largest co-infection study to date, known as APRICOT, included 868 co-infected individuals. In this study, those treated with peginterferon alfa 2a plus ribavirin for 48 weeks had an SVR rate of 40% (29% for genotype 1; 62% for genotypes 2 or 3).14
In the American ACTG 5071 study, which included 133 co-infected people, the SVR rate using the same regimen was 27% (14% for genotype 1; 73% for genotypes 2 or 3).15 This study produced a good end-of-treatment response rate, but many individuals later relapsed.
The French RIBAVIC study, which included 412 co-infected participants, produced a less impressive SVR rate of 27% (15% for genotypes 1 or 4; 44% for genotypes 2 or 3) using peginterferon alfa 2b plus ribavirin.16
A Spanish study of 95 co-infected individuals found an SVR rate of 44% for interferon alfa 2b plus ribavirin (38% for genotype 1; 53% for genotypes 2 or 3). This was the highest response rate yet seen in co-infected individuals with genotype 1.17
In early 2008, results from the SLAM-C study (US AIDS Clinical Trials Group study 5178) indicated that extended maintenance therapy with pegylated interferon does not reduce the rate of liver fibrosis progression in HIV/hepatitis C virus co-infected individuals who do not respond to combination treatment for hepatitis C.18
In the SLAM-C study (US 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 1000-1200 mg/day weight-based ribavirin. 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 hepatitis C therapy was assessed at 12 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 ACTG 5071, which used a lower dose of ribavirin (800mg/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 either to receive maintenance therapy with the same dose of pegylated interferon monotherapy for 72 weeks or to be observed without further 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.
These findings in HIV/hepatitis C co-infected 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 is not yet clear why the SVR rates varied so much among these trials, but there were some important differences in study populations. For example, ACTG 5071 included more people of African descent (about one-third) than APRICOT (about one-tenth), a group that responds less well to treatment. RIBAVIC included patients with more advanced liver disease and more current and past IDUs. Also, the discontinuation rate in this study was high: more than 40%. Taken as a whole, these studies cannot show whether peginterferon alfa 2a (Pegasys) or peginterferon alfa 2b (Viraferon Peg / Peg-Intron) works better.
As is the case for people with HCV alone, higher baseline HCV viral loads tend to predict poorer likelihoods of SVR for co-infected people
– at least for those with HCV genotype 1. A trend has been observed toward better response in people with higher baseline CD4 cell percentages.
Also, as for people with HCV alone, response to treatment at 12 weeks predicts whether or not co-infected individuals will ultimately achieve a sustained virological response.19 20 21 22 Newer studies have suggested that early virological response at eight or even four weeks might be adequately predictive of SVR, at least for certain genotypes,23 but there is not yet a consensus on this in clinical practice.
A major concern for HIV/HCV co-infected people has been the relatively high rate of relapse after clearing HCV.24 25 26 In the APRICOT, ACTG A5071 and RIBAVIC studies, in which participants received 48 weeks of treatment, 10 to 15% of people with an end-of-treatment response relapsed during the subsequent six months. The ACTG 5071 researchers suggested that their high relapse rate may have come about because the study started patients on lower initial doses of ribavirin in order to minimise toxicity. People with higher HCV viral loads are also more likely to experience relapse after initially successful therapy.
Treatment success is clearly dose-dependent. Studies in which doses of either ribavirin or peginterferon were reduced due to treatment toxicity have shown poorer response. Conversely, increases in ribavirin dose have shown better results, albeit with greater toxicity. In the Spanish PRESCO trial, early and sustained responses to daily ribavirin doses of 1000mg in patients who weighed less than 75 kg, and 1200mg in those who weighed more, were superior to those in the APRICOT trial, which used a dose of 800mg. However, extended treatment periods were also used in the adjusted-dose trial, which were associated with better response.27 Increased doses of ribavirin lead to increased likelihood of anaemia, requiring treatment with erythropoietin.
Given their lower response rates, it is reassuring that hepatitis C treatment appears to slow liver disease progression in co-infected individuals, as it does in people with HCV alone.28
People co-infected with HCV genotypes 2 and 3, who had high HCV viral loads at baseline and good responses after four weeks of treatment, had a higher likelihood of sustained SVR if treatment was continued for an additional 20 weeks after the 24-week period. Longer courses did not show additional benefit in treating HCV genotypes 1 or 4.
In co-infected individuals who did not achieve SVR after the first course of treatment, repeating the course of HCV treatment has shown mixed results.
Other factors that may influence response to hepatitis C treatment in co-infected individuals are being identified. Insulin resistance may be an important determinant of poor response; in one study the absence of insulin resistance tripled the likelihood of SVR (OR = 3.3).29 Abacavir use has been associated with poorer rates of SVR; an intracellular interaction between abacavir and ribavirin may be responsible. Nevirapine has been associated with better rates of SVR as compared to lopinavir/ritonavir (Kaletra); whether this is because nevirapine has any direct activity against HCV is not known.30