Final APRICOT and ACTG 5071 HIV/HCV coinfection results published

Eagerly awaited data from two major studies of hepatitis C (HCV) treatment in patients coinfected with HIV were presented at the Conference on Retroviruses and Opportunistic Infections this past February The final results from the APRICOT and ACTG A5071 trials were published in the July 29 edition of the New England Journal of Medicine.

Francesca Torriani, MD, and an international team of colleagues presented data from Roche’s APRICOT, or AIDS Pegasys Ribavirin International Coinfection Trial. The largest study of its kind, APRICOT included 860 HIV/HCV-coinfected participants in 19 countries who were receiving HCV treatment for the first time.

Participants were randomly assigned to one of three arms: 3 million IU standard interferon-alfa-2a three times weekly plus 800 mcg ribavirin daily (285 patients); 180 mcg pegylated interferon-alfa-2a (Pegasys, manufactured by Roche) once weekly plus placebo (286 patients); or the same doses of pegylated interferon plus ribavirin (289 patients), all for 48 weeks.

Baseline characteristics were similar in the three arms. About 81% were male, about 79% were white, about 10% were black, and the mean age was about 40 years. About 60% had genotype 1 HCV, 5% had genotype 2, 27% had genotype 3, and 7% had genotype 4. Participants had detectable baseline HCV RNA and elevated serum ALT. The mean total histological activity index (HAI) score was about 8.0, and about 16% had bridging fibrosis or cirrhosis. Subjects had stable HIV disease, with a mean CD4 cell count of about 530 cells/mm³; about 85% were on antiretroviral therapy and 60% had an HIV viral load below 50 copies/ml.

In an intent-to-treat analysis, 40% of patients treated with pegylated interferon/ribavirin achieved sustained virological responses (SVR), defined as undetectable HCV RNA at the end of a 24-week post-treatment follow-up period, compared with 20% of those receiving pegylated interferon monotherapy, and 12% of those receiving standard interferon/ribavirin (p < 0.001). Among patients with genotype 2 or 3, the corresponding SVR rates were 62%, 36%, and 20%, while in genotype 1 patients SVR was seen in 29%, 14%, and 7%, respectively. (For patients with HCV alone, SVR rates using pegylated interferon/ribavirin are about 80% for genotype 2 or 3 and about 45% for genotype 1).

Among patients with genotype 1, those with a baseline HCV RNA level greater than 800,000 IU/ml were significantly less likely to respond to any regimen than those with lower HCV viral loads (p < 0.001), but this difference was not seen in genotype 2 or 3 patients. Only two patients who failed to achieve an early virological response (at least a 2 log₁₀ reduction in HCV RNA by week 12) went on to achieve SVR (a negative predictive value of 98-100%).

HCV therapy had no detrimental impact on HIV disease progression; in fact, HIV viral load decreased by about 0.7 log₁₀ copies in patients treated with pegylated interferon. Absolute CD4 cell counts decreased in all three arms (interferon reduces white blood cell levels overall), but CD4 percentages remained stable. HCV treatment success rates did not vary by baseline CD4 cell count or use of antiretroviral therapy.

In terms of safety and tolerability, 39% of subjects in the standard interferon/ribavirin arm, 31% in the pegylated interferon monotherapy group, and 25% in the pegylated interferon/ribavirin arm discontinued treatment for any reason (p < 0.001). The rates of serious adverse events judged to be treatment-related were 5%, 10%, and 8%, respectively. Neutropenia and thrombocytopenia were more common in the arms that included pegylated interferon. The rate of mitochondrial toxicity -- a concern when ribavirin is combined with certain nucleoside reverse transcriptase inhibitors – was low in all arms.

“[Our] results demonstrate that the current regimen used for the treatment of chronic hepatitis C alone can also be applied to patients coinfected with HIV and HCV,” the researchers concluded. “Peginterferon alfa-2a plus ribavirin has a favorable risk-to-benefit ratio when used to treat such patients, a substantial proportion of whom are likely to benefit from therapy with this combination.” They recommended that coinfected patients with genotypes 2 or 3 should be treated for 48 weeks, even though 24 weeks is sufficient for genotype 2 or 3 patients with HCV alone.

Raymond Chung, MD, from Massachusetts General Hospital and colleagues published results from AIDS Clinical Trials Group (ACTG) A5071, the first randomised study comparing the safety and efficacy of standard interferon/ribavirin vs pegylated interferon/ribavirin in HIV/HCV-coinfected patients being treated for the first time.

A total of 133 participants were randomly assigned to receive either 6 million IU standard interferon-alfa-2a three times weekly for 12 weeks followed by 3 million IU three times weekly for 36 weeks (67 subjects), or 180µg pegylated interferon-alfa-2a (Pegasys) weekly for 48 weeks (66 subjects). Patients in both arms received daily ribavirin in escalating doses from 600mg to 1000mg. Patients who did not achieve a virological response by week 24 underwent liver biopsy; those who showed histological improvement continued treatment.

Baseline characteristics were similar in both arms. About 82% were male, about half were white, about one third were black, and the mean age was about 44 years. About 78% had genotype 1 HCV. Subjects had detectable baseline HCV RNA and 67% had elevated serum ALT; the median fibrosis score was 2.0, the median HAI score was 5.0, and about 10% had cirrhosis. In this study, too, participants had well controlled HIV; the median CD4 cell count was about 475 cells/mm³, about 60% had an HIV viral load below 50 copies/ml, and about 86% were receiving antiretroviral therapy.

After 48 weeks of treatment, 41% of patients in the pegylated interferon arm and 12% in the standard interferon arm showed an end-of-treatment response (p < 0.001). By 72 weeks, overall SVR rates were 27% in the pegylated interferon arm and 12% in the standard interferon arm (p = 0.03). Among subjects with genotype 2 or 3, SVR rates were 73% in the pegylated interferon arm and 33% in the standard interferon arm. For those with genotype 1, the corresponding rates were 14% and 6%.

Notably, while the end-of-treatment and SVR rates were the same in the standard interferon arm, the response rate declined dramatically during the follow-up period in the pegylated interferon arm; the relapse rate was especially high among patients with genotype 1. No patient who failed to achieve a 2 log reduction in HCV RNA by week 12 went on to achieve SVR (negative predictive value of 100%). Upon liver biopsy, about 35% of patients in both arms without virological clearance still showed evidence of histological response. Among patients with a virological response, 52% showed histological improvement.

As in the previous trial, HCV therapy had no adverse effect on HIV disease progression. Absolute CD4 cell counts decreased in both treatment groups, but CD4 percentages actually increased. Baseline CD4 cell count and use of antiretroviral therapy did not predict the likelihood of HCV treatment success, but having a detectable baseline HIV viral load was associated with SVR.

Both regimens were generally well tolerated; 12% in both arms prematurely discontinued therapy. This rate is similar to those seen in studies of patients with HCV alone using these regimens, but lower than those seen in previous studies of coinfected patients. One patient developed elevated lactic acid (a sign of mitochondrial toxicity), but did not require treatment discontinuation.

“In persons infected with HIV, the combination of peginterferon and ribavirin is superior to the combination of interferon and ribavirin in the treatment of chronic hepatitis C,” the authors concluded. “These regimens may provide clinical benefit even in the absence of virologic clearance.” They recommended that coinfected patients with advanced liver disease should continue interferon therapy even without a virological response, “since the goal of treatment is slowing the progression of liver disease rather than eradicating the virus.”

It is unclear why the pegylated interferon/ribavirin SVR was so much higher in APRICOT (40% overall) than in ACTG A5071 (27% overall). In A5071, although a good end-of-treatment response rate was seen with this regimen, the relapse rate was high. This may be because the study started patients on a lower initial dosage of ribavirin in an attempt to reduce the incidence of treatment-limiting anemia. If so, this suggests that ribavirin timing may be as important as dose. In addition, A5071 included more blacks (about 33%) than APRICOT (about 10%), a group that responds less well to interferon-based HCV therapy.

While the inconsistent results of these two studies are perplexing, and point to the need for further research, the impressive results seen in the APRICOT trial -- the highest SVR rate yet seen in a coinfected population -- provide reason for renewed hope.

In an editorial in the same issue, Jean-Michel Pawlotsky, PhD, discussed the treatment of hepatitis C in “difficult-to-treat” patients including those with HIV. The APRICOT and A5071 studies “show that a sustained virologic response can be achieved with pegylated interferon-alfa and ribavirin therapy in a substantial proportion of coinfected patients,” he wrote. Although SVR rates for coinfected patients remain lower than those for patients with HCV alone, “[t]hese results, together with the poor prognosis for HIV-positive patients with HCV infection, justify broad use of antiviral therapy in the treatment of coinfected patients.”