HIV/HCV coinfection: superiority of pegylated interferon plus ribavirin, but lower response rate compared to mono-infected patients, especially for genotype-1

2 April 2004. Related: Conference reports, Hepatitis coinfection, CROI 11 (Retrovirus) 2004.

Simon Collins, HIV i-Base

Coinfection with HIV and hepatitis C presents an increasingly pressing challenge because around 20-50% of patients in European cohorts are coinfected with HCV and are at an increased risk of liver-related mortality. [1]

Three major coinfection trials reported results in oral presentations at the conference, two of which were late breakers, using various approaches to pegylated interferon plus ribavirin. The following article will briefly report on each study. Comments specific to new data in coinfection together with the implications of and differences between the three studies are made together at the end of the article.

Although the baseline characteristics and treatment arms limit cross-study comparisons, they clearly show poorer sustained virological response (SVR) rates to those achieved in mono-infected patients, although this was known prior to final 72-week results. In the UK PEG-interferon + ribavirin is already NICE (National Institute for Clinical Excellence) – approved standard of care for treatment of HCV.

APRICOT

The AIDS PEGASYS Ribavirin International Co-infection Trial (APRICOT) randomised 868 co-infected subjects in 19 countries to 48 weeks of treatment with standard interferon-alpha-2a (IFN) 3-MIU three times a week plus 800 mg/day ribavirin (RBV), peginterferon-alpha-2a (40 kD) 180 µg weekly plus placebo, or peginterferon-alpha-2a 180 µg weekly plus 800 mg/day RBV. PEGASYS is pegylated interferon manufactured by Roche Laboratories. [2]

Eligible subjects had compensated liver disease, a CD count >100 cells/mm3, and stable HIV disease, with or without antiretroviral therapy (ART). The primary endpoint was SVR, defined as HCV RNA <50 IU/mL at the end of 24 weeks of treatment-free follow-up (week 72). Response rates were stratified by geographical region, genotype and CD4 count.

Approximately 285 patients were included in each arm – about 80% men, 20% women, 80% Caucasian, mean age 40 +/-7. Mean CD4 count was > 530 cells/mm3 and only around 5% patients had CD4 counts <200 cells/mm3. Eighty-five percent of patients were on HAART, and 60% had undetectable viral load.

Final week-72 results are presented in Table 1 below.

Table 1: APRICOT trial results

Treatment discontinuations overall occurred in 39%, 31% and 25% of patients in arms A, B and C respectively. Adverse events or lab abnormalities occurred in about 15% of patients in each arm. Serious adverse effects related to the treatment occurred in 5%, 10% and 8% of arms A, B and C. Deaths (treatment related) occurred three (1), five (0) and four (1) in each group. Neutropenia (<0.5 x 109/L) occurred significantly less in the standard interferon arm (<1%) compared to 13% in the PEG/placebo and 11% in the PEG+ribavirin arm.

Median CD4 decreased comparably in each arm over the 48 weeks of treatment and returned to baseline levels by week 72. Over the treatment period, the median HIV viral load reduced by about 0.8 log in both the PEG arms in patients who had detectable viral load at study entry, and returned to baseline during weeks 48-72 off-treatment.

ACTG A5071

ACTG A5071 randomised 133 coinfected patients to peginterferon-alpha-2a (PEG) (180µg weekly for 48 weeks) to interferon (6MIU three times weekly for 12 weeks followed by 3MIU three times weekly for 36 weeks). This study used the Roche PEGASYS formulation. Both arms received ribavirin in a dose-escalation schedule from 600mg/d to 1000mg/d. [3]

Table 2: Treatment response in ACTG A5071 by genotype

Independent predictors of sustained virologic response included receipt of PEG/ribavirin, HCV genotype non-1, no prior injection drug use, and a detectable HIV-1 RNA at entry.

Histologic response was observed in 36% of virologic non-responders and in 52% of virologic responders who underwent liver biopsy. Both regimens were well tolerated. Similar frequencies of flu-like symptoms, depression, and laboratory abnormalities were observed in each arm, and premature discontinuation rates were 12% in each arm.

Failure to achieve >2 log HCV RNA reduction at week 12 uniformly predicted failure to accomplish sustained virologic response (100% negative predictive value). After 12 weeks treatment, 41% (n=43) of patients had either >2 log drop in HCV-RNA or an undetectable HCV-RNA viral load. Among these 43 patients, half went on to achieve SVR at week 72 and half did not. None of the 63 patients who were not responding virologically after 12 weeks of therapy achieved an SVR at week 72.

RIBAVIC

The French ANRS RIBAVIC study compared a 48-week course of the standard (IFN-alpha-2b: 3 MIU x 3/week, n = 207; INF group) to the pegylated (PEG-IFN-alpha-2b: 1.5 µ/kg x 1/w, n = 205) interferon; PEG group) both combined with ribavirin (800mg/d, approximately 12mg/kg/d). Primary endpoint was sustained virologic response (SVR) defined as loss of detectable serum HCV RNA at week 72 of follow-up. PEG Interferon in this study was made by Shering Plough. [4]

The population was similar to the APRICOT study – 40 years old, 74% male, 79% injection drug users [IDU]), 82% on HAART with 66% with controlled HIV viraemia <400 copies/mL. Mean CD4 cell count was 514 +/- 229 cells/mm3. HCV genotypes were 1 or 4 in 58%, 3 in 34%, and others in 8%. Mean HCV viral load at baseline was 5.9 + /- 0.7 logs. Baseline variables at entry were not different between groups.

Patients in RIBAVIC may have had more advanced HCV disease than patients in either ACTG A5071 or APRICOT. The mean pre-treatment Metavir score was A 1.8 + 0.7, F 2.3 + 1.0, 24% of patients had F3 (bridging fibrosis) and 16% F4 (cirrhosis).

Treatment discontinuation occurred in 167 patients (42%; 86 IFN, 81 PEG) and severe adverse events in 127 patients (31%) (64 IFN, 63 PEG), including six cases of symptomatic hyperlactataemia and five of acute pancreatitis.

A decrease was observed at week 12 of treatment, in INF and PEG groups respectively, significant for Hb (-1.4 g/dL vs -1.8, p = 0.002 ) and platelets (-19,000 vs -33,000, p = 0.04), not significant for neutrophils (-692 vs -1071), lymphocytes (-543 vs -662), or CD4 cells (-116 vs -124). A summary of response rates is shown below:

Summary of responses

Virologic response at week 12 predicted SVR with 87% Positive Predictive Value and 87% Negative Predictive Value. SVR varied with genotypes 1 or 4 (11%) vs 3 or others (43%).

Table 3. Summary of Sustained Virologic Responses (SVR) to PEGinterferon in HIV/HCV-coinfected patients

* Escalating dose of ribavirin was used in AACTG 5071.  Patients started at a dose of 600 mg/daily, which was then increased by 200 mg/daily every four weeks for a maximum total of 1,000 mg/day.  Both Apricot and Ribavic used 800 mg/day ribavirin throughout.

** Included patients with HCV genotypes 1 and 4.

Comments

Although HCV-monoinfected patients with an HCV genotype of 1 can expect a 40–45% chance of an SVR using pegylated interferon/ribavirin, HIV/HCV-coinfected patients with genotype-1 are looking at an SVR of 14% (ACTG) to 29% (Apricot). The results in co-infected patients with genotypes 2/3 infections were encouraging with 45% (Ribavic) to 62% (Apricot) SVRs. However, it is important to note that all patients received 48 weeks of therapy. It is likely that, in order to achieve an optimal response, all genotype 2/3 HIV/HCV co-infected patients should receive 48 weeks of treatment with pegylated interferon/ribavirin.

HCV-RNA was associated with treatment outcome in Apricot, but not Ribavic. Analysis, especially for patients with genotype -1 co-infections, by baseline viral loads were not available. It is likely that those with high HCV viral loads (800,000 iu/l) will have poor responses. Although, baseline CD4 counts have been shown to affect response to therapy, patients in both Ribavic and Apricot had median CD4 counts above 500 cells/mm3, and included very few patients with CD4 counts less than 200.

The higher proportion of African Americans in the ACTG study and dose escalation of ribarvirin could also contribute to the poorer response. The high discontinuation rate in Ribavic may also have affected thse trial results.

Although, these three studies show slightly different results, it is difficult to make cross-study comparisions, since the patient populations were different, and in the case of ACTG 5071, a lower starting dose of ribavirin (600mg/day) was employed.

In Ribavic, approximately 40% were Metavir grade F3 (24%, bridging fibrosis) or F4 (16%, cirrhosis). In Apricot, approximately 16% of patients had cirrhosis, and in AACTG 5071, no more than 11% of patients, in either treatment group, had cirrhosis before beginning therapy.

The clinical importance of histologic improvement, even without SVR, is unclear, especially as in HCV-monoinfected patients viral response was associated with histological improvement (Camma et. Al. EASL 2003).

There are two different molecules of pegylated interferon, the 12kD Viraferon-PEG (Schering-Plough) and the 40kD Pegasys (Roche). These two molecules have different pharmacokinetics. The 40kD molecule has a slightly longer half-life and a smaller volume of distribution. Although, studies in singular HCV infection has not shown a significant difference interms of SVRs between these two pegylated interferons, a head-to-head study is underway. In terms of HIV/HCV co-infection (where patients have higher HCV viral loads and, in theory, lower viral-specific immune responses) the pharmacokinetics, and the resultant HCV viral kinetics, may play an important role in determining the optimal dose and length of therapy.

Newer viral life cycle inhibitors are still at least 4-5 years away from approval. Research also needs to address how to optimise the safety and tolerability of treatment for coinfected people – for example, dose adjusting or using EPO to maintain adequate dosing of ribavirin, and possibly extending treatment for longer periods (Apricot and Ribavic treated people with genotype 2/3 for 12 months rather than six, and saw a very low relapse rate). Beyond that, half-dose long-term maintenance therapy with pegylated interferon is being studied as a strategy to reduce further liver damage.

References:

1. Rockstroh J, Mocroft A, Soriano V et al. Influence of Hepatitis C coinfection on HIV disease progression within the EuroSIDA cohort. 9th EACS, Warsaw. 25-29 October 2003. Abstract F12/4.
2. FJ Torriani, Rockstroh J, Rodriguez-Torres M et al. Final results of APRICOT: a randomised, partially blinded, international trial evaluating peginterferon-alfa-2a + ribavirin vs interferon-alfa-2a + ribavirin in the treatment of HCV in HIV/HCV co-infection. 11thCROI 2004, Oral abstract 112.
3. Chung R, Andersen J, Volberding P et al. A randomised, controlled trial of PEG-Interferon-alfa-2a plus ribavirin vs interferon-alfa-2a plus ribavirin for chronic hepatitis C virus infection in HIV-co-infected persons: follow-up results of ACTG A5071. 11thCROI 2004, Oral Abstract 110.
4. Perronne C, Carrat F, Bani-Sadr F et al. Final Results of ANRS HC02-RIBAVIC: A randomised controlled trial of pegylated-interferon-alfa-2b plus ribavirin vs interferon-alfa-2b plus ribavirin for the initial treatment of chronic hepatitis C in HIV co-infected patients. 11thCROI 2004, Oral abstract 117LB.