Participants were randomly assigned to one of three arms: 3 million IU standard interferon-alfa-2a three times weekly plus 800 mcg RBV daily (285 patients); 180 mcg pegylated interferon-alfa-2a (Pegasys, manufactured by Roche) once weekly plus placebo (286 patients); or the same doses of PegIFN plus RBV (289 patients), all for 48 weeks.
Baseline characteristics were similar in the three arms. About 81 percent were male, about 79 percent were white, about 10 percent were black, and the mean age was about 40 years. About 60 percent had genotype 1 HCV, 5 percent had genotype 2, 27 percent had genotype 3, and 7 percent 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 percent had bridging fibrosis or cirrhosis. Subjects had stable HIV disease, with a mean CD4 count of about 530 cells/mm3; about 85 percent were on antiretroviral therapy and 60 percent had an HIV viral load below 50 copies/ml.
In an intent-to-treat analysis, 40 percent of patients treated with PegIFN/RBV 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 percent of those receiving PegIFN monotherapy, and 12 percent of those receiving standard interferon/RBV (P<0.001). Among patients with genotype 2 or 3, the corresponding SVR rates were 62 percent, 36 percent, and 20 percent, while in genotype 1 patients SVR was seen in 29 percent, 14 percent, and 7 percent, respectively. (For patients with HCV alone, SVR rates using PegIFN/RBV are about 80 percent for genotype 2 or 3, and about 45 percent 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 log 10 reduction in HCV RNA by week 12) went on to achieve SVR (a negative predictive value of between 98 percent and 100 percent).
HCV therapy had no detrimental impact on HIV disease progression; in fact, HIV viral load decreased by about 0.7log 10 copies in patients treated with PegIFN. Absolute CD4 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 count or use of antiretroviral therapy.
In terms of safety and tolerability, 39 percent of subjects in the standard interferon/RBV arm, 31 percent in the PegIFN monotherapy group, and 25 percent in the PegIFN/RBV arm discontinued treatment for any reason (P<0.001). The rates of serious adverse events judged to be treatment-related were 5 percent, 10 percent, and 8 percent, respectively. Neutropenia and thrombocytopenia were more common in the arms that included pegylated interferon. The rate of mitochondrial toxicity -- a concern when RBV is combined with certain nucleoside reverse transcriptase inhibitors (NRTIs) -- 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.
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 600 mg to 1,000 mg. 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 percent were male, about half were white, about one third were black, and the mean age was about 44 years. About 78 percent had genotype 1 HCV. Subjects had detectable baseline HCV RNA and 67 percent had elevated serum ALT; the median fibrosis score was 2.0, the median HAI score was 5.0, and about 10 percent had cirrhosis. In this study, too, participants had well-controlled HIV; the median CD4 count was about 475 cells/mm3, about 60 percent had an HIV viral load below 50 copies/ml, and about 86 percent were receiving antiretroviral therapy.
After 48 weeks of treatment, 41 percent of patients in the PegIFN arm and 12 percent in the standard interferon arm showed an end-of-treatment response (P<0.001). By 72 weeks, overall SVR rates were 27 percent in the PegIFN arm and 12 percent in the standard interferon arm (P = 0.03). Among subjects with genotype 2 or 3, SVR rates were 73 percent in the PegIFN arm and 33 percent in the standard interferon arm. For those with genotype 1, the corresponding rates were 14 percent and 6 percent.
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 percent). Upon liver biopsy, about 35 percent of patients in both arms without virological clearance still showed evidence of histological response. Among patients with a virological response, 52 percent showed histological improvement.
As in the previous trial, HCV therapy had no adverse effect on HIV disease progression. Absolute CD4 counts decreased in both treatment groups, but CD4 percentages actually increased. Baseline CD4 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 percent 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 [PegIFN] and [RBV] is superior to the combination of [IFN] and [RBV] 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 IFN therapy even without a virological response "since the goal of treatment is slowing the progression of liver disease rather than eradicating the virus."
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 published in the same issue of the New England Journal of Medicine, Jean-Michel Pawlotsky (University of Paris XII, Créteil, France) discussed the treatment of hepatitis C in "difficult-to-treat" patients including those with HIV.3 The APRICOT and A5071 studies "show that a sustained virologic response can be achieved with pegylated interferon-alfa and [RBV] 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."
Editor's Note: Reprinted with permission from www.aidsmap.com (first e-published August 4, 2004).