Treatment for HIV/HCV coinfection: three major studies report at CROI

Long-awaited results from three studies of combination therapy for hepatitis C in HIV/HCV-coinfected individuals were presented on Tuesday at the Eleventh Conference on Retroviruses and Opportunistic Infections in San Francisco.

HCV/HIV coinfection is a growing public health concern, as evidenced by the considerable attention devoted to the topic at this year’s meeting. An estimated 30-40% of people with HIV are also infected with HCV, although in some populations the coinfection rate is substantially higher. Past studies have shown that in patients with HCV alone, sustained virological response (SVR) rates using pegylated interferon plus ribavirin are somewhat above 50% overall, about 80% in those with HCV genotypes 2 or 3, and about 45% in those with genotype 1, which is harder to treat. However, lower SVRs have consistently been seen in coinfected patients - about 40-60% in those with genotypes 2 or 3, and less than 25% in those with genotype 1.

APRICOT

Data from APRICOT- the AIDS Pegasys Ribavirin International Co-infection Trial - indicate that higher SVRs can be achieved in certain patients with HIV/HCV coinfection. The largest study of its kind to date, APRICOT included 868 participants in 19 countries. Eligible subjects had quantifiable baseline HCV viral load, elevated ALT, compensated liver disease, CD4 counts of at least 100 cells/mL, and stable HIV disease with or without antiretroviral therapy.

Participants were randomly assigned to one of three arms: 3 million IU standard interferon-alpha-2a three times weekly plus 800 mcg ribavirin daily (285 subjects); 180 mcg pegylated interferon-alpha-2a (Pegasys, manufactured by Roche) once weekly plus placebo (286 subjects); or the same doses of pegylated interferon plus ribavirin (289 subjects), all for 48 weeks. (Eight subjects who discontinued before receiving any therapy were excluded from the analysis.)

Baseline characteristics were similar in the three arms. About 81% were male, about 79% were Caucasian, and the mean age was about 40. About 60% had genotype 1, 5% had genotype 2, 27% had genotype C, and 7% had genotype 4 (40% total non-1). Median HIV viral load was 50 copies/mL, mean CD4 count was above 500 cells/mL, and 85% were on antiretroviral therapy. About 16% had bridging fibrosis or cirrhosis.

SVR was defined as HCV RNA viral load less than 50 IU/mL at the end of a 24-week post-treatment follow-up period. The final, 72-week, results were presented at this conference. Uncharacteristically, interim 12-week data (reflecting early virological response) and 48-week data (reflecting end-of-treatment response) had not previously been released.

Overall, 40% of coinfected patients treated with pegylated interferon/ribavirin achieved SVR, compared with 20% of those receiving pegylated interferon monotherapy and 12% of those receiving standard interferon/ribavirin (corresponding end-of-treatment response rates were 49%, 33%, and 14%). Among subjects with genotypes 2 or 3, the respective SVR rates were 62%, 36%, and 20%, while in genotype 1 patients SVR was seen in 29%, 14%, and 7%, respectively. The higher SVR rates in the pegylated interferon/ribavirin arm compared with the pegylated monotherapy arm suggest that ribavirin may play an important role in preventing HCV relapse. HCV therapy had no negative impact on HIV disease progression, and may even have had a small positive effect.

In terms of safety and tolerability, 39% in the standard interferon/ribavirin arm, 31% in the pegylated interferon monotherapy group, and 25% in the pegylated interferon/ribavirin arm discontinued treatment. Adverse side-effects or laboratory abnormalities were seen in about 15% in all three arms. Serious adverse event rates were 5%, 10%, and 8%, respectively; neutropenia was more common in the two pegylated interferon arms (about 12%).

ACTG A5071

The American ACTG A5071 study also compared standard interferon with pegylated interferon in coinfected individuals. This was the first randomised study looking at the safety and efficacy of standard interferon/ribavirin vs pegylated interferon/ribavirin in patients with HIV/HCV. Final 72-week data were presented at this conference; 48-week results were presented previously (Ninth Conference on Retroviruses and Opportunistic Infections, abstract LB 15, 2002). Eligible participants either had a CD4 count of at least 100 cells/mL, an HIV viral load less than 10,000 copies/mL, and stable antiretroviral therapy for at least 12 weeks, or else were antiretroviral naive and had a CD4 count of at least 300.

A total of 133 participants were randomised to receive either 6 million IU standard interferon-alpha-2a three times weekly for 12 weeks followed by 3 million IU three times weekly for 24 weeks (67 subjects), or 180 mcg pegylated interferon (Pegasys) weekly for 48 weeks (66 subjects). Subjects in both arms received daily ribavirin in escalating doses from 600 mg to 1000 mg. Patients who did not clear HCV by week 24 underwent liver biopsy.

Baseline characteristics were similar in both arms. About 80% were men, about half were African-American, mean CD4 count was above 400 cells/mL, and 75% had HCV genotype 1. The median fibrosis score was 2.0 and the median HAI score was 5.0.

Overall, at week 24, virological response (HCV RNA viral load less than 60 IU/mL) was seen in 44% of patients in the pegylated interferon arm, compared with 15% in the standard interferon arm. After 48 weeks of therapy, 41% and 12%, respectively, showed an end-of-treatment response. Within the pegylated interferon arm, 80% with genotypes other than 1 showed an end-of-treatment response, compared with 29% of genotype 1 patients. By 72 weeks, overall SVR rates were 27% in the pegylated interferon arm and 12% in the standard interferon arm. Notably, while the end-of-treatment and SVR rates were the same in the standard interferon arm, the response rate declined dramatically from week 48 to week 72 in the pegylated interferon arm. By genotype, in the pegylated interferon arm, SVR was 73% in non-1 patients and just 14% in genotype 1 patients; in the standard interferon arm, the corresponding rates were 33% and 6%.

No patient who failed to achieve at least a 2-log reduction in HCV RNA by week 12 went on to achieve SVR (negative predictive value of 100%). Besides non-1 genotype, SVR was also associated with absence of current or past injection drug use and with detectable HIV viral load at study entry.

Histological response was seen in 52% of virological responders and 36% of virological nonresponders who underwent biopsy. Both regimens were generally well tolerated. Incidence of side-effects (flu-like symptoms, depression) was similar in both arms, and 12% in both arms prematurely discontinued therapy.

RIBAVIC

Final 72-week results were also presented from the multicentre French ANRS HC02-RIBAVIC study. This 412-person trial compared standard and pegylated interferon, but unlike the previous studies, used pegylated interferon-alpha-2-b (Peg-Intron, manufactured by Schering-Plough). Eligible subjects had detectable baseline HCV viral load, abnormal liver histology, CD4 counts of at least 200 cells/mL, stable HIV viral load, and stable HIV disease with or without antiretroviral therapy. A total of 412 participants were analysed.

Participants were randomly assigned to receive 3 million IU standard interferon three times weekly (207 subjects) or 1.5 mcg/kg pegylated interferon once weekly (205 subjects). Both arms also received 800 mg ribavirin daily.

Baseline characteristics were similar in both arms; 74% were male, 79% were injection drug users, and the mean age was 40. Mean CD4 count was about 500 cells/mL, 66% had undetectable HIV viral load (less than 400 copies/mL), and 82% were receiving antiretroviral therapy. More than half (58%) had HCV genotypes 1 or 4; 34% had genotype 3; and 8% had other genotypes. Stage F3-F4 fibrosis was detected in about 40%, of whom 17% had persistently normal ALT.

Overall, at 72 weeks, 19% of subjects receiving standard interferon achieved SVR, compared with 27% of those on pegylated interferon, using an intent-to-treat analysis. Considering only those who stayed on therapy (as-treated analysis), the respective response rates were 12 % vs 20% at week 4; 34% vs 41% at week 12; 41% vs 54% at week 24; 34% vs 52% at week 48; and 26% vs 35% at week 72. Among patients with genotype 1, SVR was seen in 5% of the standard interferon arm and 15% of the pegylated interferon arm; among non-1 patients, the corresponding rates were 40% and 45%. Early virological response at week 4 strongly predicted later SVR, while lack of response at week 12 predicted no SVR. Some improvement in liver histology was seen in responders.

In terms of tolerability, about 40% discontinued therapy in both arms and about 30% experienced severe adverse events (including six cases of symptomatic hyperlactatemia). Significant decreases were seen in haemoglobin (a marker for red blood cells) and platelets, but not white blood cells.

Comparing Apricots and Oranges?

It is unclear why the sustained response rate in coinfected patients receiving pegylated interferon/ribavirin was so much higher in APRICOT than the other two trials. In ACTG A5071, while a good end-of-treatment response rate was seen with pegylated interferon, the rate of relapse was high. This may be because the study started patients at a lower dosage of ribavirin, in an attempt to improve tolerability and reduce the drop-out rate. If this is true, it suggests that ribavirin timing may be as important as dose. The RIBAVIC study population was considered harder to treat, with a higher proportion of injection drug users, subjects with persistently normal ALT, and patients with more advanced liver damage - perhaps more reflective of some “real world” coinfected populations. Drop-out rates and rates of severe adverse events were both considerably higher in RIBAVIC than in the other two studies. Also, RIBAVIC used Peg-Intron while the others used Pegasys; it is not yet known whether the two types of pegylated interferon differ in efficacy and tolerability, although a head-to-head comparison trial is underway.

The data from these three studies are inconsistent, and in some senses perplexing. Nevertheless, the impressive results from APRICOT (the highest SVR rate ever seen in the coinfected population), along with the encouraging early response rate seen in ACTG A5071, provides reason for renewed hope for successful treatment of people with HIV/HCV.

Further information on this website

Hepatitis C - overview

Hepatitis C - factsheet

HIV and hepatitis 2003 edition of the booklet in the information for HIV-positive people series. To obtain a copy of the 2004 edition email info@nam.org.uk