Hepatitis C and HIV: genotype 1 is not a lost cause, report Spanish doctors

Spanish researchers have reported the best ever response to pegylated interferon and ribavirin in people coinfected with HIV and hepatitis C genotype 1 (the most difficult to treat variant). In a randomised study given fast track publication in the September 3^rd edition of AIDS, the Barcelona group report that almost half the genotype 1 patients who received pegylated interferon showed a sustained response to treatment.

The rate of sustained virological response seen in patients infected with hepatitis C subtype 1 was strikingly higher in this study using PegIntron (pegylated interferon alpha-2b, produced by Schering Plough) than in the recently published APRICOT study using Pegasys (pegylated interferon alpha-2a, produced by Roche), or in the RIBAVIC study (which used PegIntron).

In the APRICOT study participants received a standard dose of pegylated interferon, and the sustained virologic response rate 24 weeks after stopping treatment was 29% in the genotype 1 group. In the Ribavic study, which also used a standard dose of pegylated interferon, the sustained virologic response was 15% in the genotype 1 group.

The authors of the Spanish study cannot directly explain the higher response rate in the genotype 1 group, but do note that a low discontinuation rate due to dose adjustment may have helped. They also highlight the contribution of an experienced multidisciplinary team: all the patients in this study were recruited at one treatment centre.

Study results

Between spring 2001 and autumn 2002 investigators in Barcelona recruited 95 HIV-positive patients coinfected with hepatitis C virus to a randomised, single centre, prospective study. The study was designed to determine the efficacy and safety of a hepatitis C treatment regimen consisting of a weight adjusted once-weekly injection of pegylated interferon alpha-2b against a weight adjusted dose of standard interferon alpha-2b three times a week, both with a weight adjusted daily dose of ribavirin.

The duration of treatment was determined by the hepatitis C virus genotype. Patients who were infected with genotypes 1 and 4, which are harder to treat, received 48 weeks of therapy, and individuals infected with the easier to treat genotypes 2 and 3 received 24 weeks of treatment.

The primary endpoint of the study was the proportion of patients in each arm with a sustained virological response to therapy 24 weeks after the cessation of treatment. Individuals with detectable hepatitis C virus or who discontinued treatment were considered failures. Secondary endpoints included virological response at the end of treatment, and sustained biological response, defined as normal alanine aminotransferease (ALT) levels 24 weeks after the cessation of treatment. Data were also gathered on side-effects which were graded as mild, moderate, severe and life-threatening.

At baseline, all the patients had a detectable hepatitis C viral load, an ALT level at least one and a half times the upper limit of normal, and liver fibrosis proved by liver biopsy. Over two-thirds of patients (68%) were male, the mean age was 40 years, 80% had a history of injecting drug use, and the mean duration of hepatitis C virus infection was 17 years.

The overwhelming majority of patients (94%) were taking antiretroviral therapy for their HIV infection, the mean CD4 cell count being 570 cells/mm³ and mean HIV viral load was 199 copies/ml.

Overall, 34% of patients achieved a sustained virological response 24 weeks after finishing hepatitis C virus treatment. However, the proportion of patients achieving a sustained response was significantly higher amongst individuals treated with pegylated interferon than standard interferon (44% versus 21%, p = 0.017).

The efficacy of pegylated interferon versus standard interferon was most striking for patients infected with hepatitis C genotypes 1 or 4. In total, 38% of these patients treated with pegylated interferon achieved a sustained virological response compared to only 7% of individuals receiving interferon (p = 0.007). For hepatitis C genotypes 2 and 3 the rates of sustained virological response were similar for pegylated interferon and standard interferon (53% versus 47%, p = 0.730).

Individuals with a low hepatitis C viral load (below 80,000 IU/ml) were more likely to achieve a sustained virological response (49% versus 22%, p = 0.007).

Overall, 45% of patients had a sustained biological response, and although there was a trend for patients treated with pegylated interferon to be more likely to have maintained normal ALT values 24 weeks after completing treatment (53% versus 33%), this did not reach statistical significance (p = 0.079).

In univariate analysis, hepatitis C genotypes 2 or 3 (p = 0.011), a baseline hepatitis C viral load below 80,000 IU/ml (p = 0.008), and treatment with pegylated interferon were all significantly associated with an increased chance of achieving a sustained virological response. In multivariate analysis only hepatitis C genotypes 2 or 3 (p = 0.006), and treatment with pegylated interferon (p = 0.025) remained significant.

The side-effect profiles of pegylated interferon and standard interferon were similar. A total of 27% of patients developed anaemia (31% pegylated interferon versus 23% interferon), the most common haematogical side-effect. Depression was diagnosed in 43% of patients (37% pegylated interferon versus 51% interferon), and nine patients developed mitochondrial toxicity, one experiencing symptoms of weight loss, abdominal pain, nausea and vomiting. There patient stopped both his HIV and hepatitis C treatment and completely recovered.

In total 15 patients withdrew from the study due to side-effects, nine from the pegylated interferon arm. Flu-like symptoms were the main reason for study discontinuation (nine patients)

Hepatitis C treatment did not adversely effect HIV disease, however mean CD4 cell count fell from a baseline of 560 cells/mm³ to 330 cells/mm³, but CD4 cell percentage remained unchanged. Even though 19 patients experienced a fall in their CD4 cell count to below 200 cells/mm³, none developed an AIDS-defining opportunistic infection. HIV viral load did not change significantly during the study.

“In our study pegylated interferon and ribavirin was significantly more effective than interferon and ribavirin for the treatment of chronic hepatitis C in HIV coinfected patients,” comment the investigators. They add, “the benefit of pegylated interferon versus interferon regimen was most apparent for patients with genotype 1, the subgroup that is most common and the most difficult to treat.”

Depression and mitochondrial toxicity were highlighted by the investigators with concern. “We recommend close assessment of psychiatric symptoms during the first weeks after initiating interferon-based therapy in HIV-HCV coinfected patients. Early treatment of these side-effects with antidepressants would help to avoid early dropout from therapy.”

Regarding mitochondrial toxicities the investigators write, “in our series mitochondrial toxicity occurred in 12% of patients; although most cases were asymptomatic, concomitant use of ribavirin plus [antiretroviral therapy regimens] containing nucleoside analogues such as ddI or d4T, should be cautioned against or not recommended.”