Higher doses of ribavirin increases response rate to HCV treatment in coinfected patients: results from PRESCO study
6 December 2006. Related: Conference reports, Hepatitis coinfection, HIV 8th Glasgow 2006.
Simon Collins, HIV i-Base
An oral presentation of the results from the PRESCO trial by Vincent Soriano was one of the most interesting late-breaker presentations in Glasgow. PRESCO used higher doses of ribavirin with pegylated interferon alfa-2a (180μg/week) in HCV coinfected patients, and was also designed to look at longer duration of HCV treatment.
This was a prospective, multicenter, open-label trial, in 389 patients with CD4 >300 cells/mm3 and elevated aminotransferases who were HCV-treatment naive. Ribavirin was dosed at 1000 mg daily for people weighing <75 Kg; and 1200 mg daily if >75 kg. People with HCV genotypes 1 and 4 were treated for 48 or 72 weeks, and patients with HCV genotypes 2 and 3 were treated for 24 or 48 weeks.
Baseline characteristics included 75% male, median age 40, median CD4 count 456 cells/mm3, 74% on HAART (nearly all suppressed <50 copies/mL). Baseline HCV parameters included 28% patients with F3/F4 stage fibrosis and 67% with HCV RNA >500,000 IU/mL. HCV genotype was 49% G1/12% G4 and 1% G2/38% G3. Exclusion criteria included active drug addiction, alcohol abuse, decompensated liver cirrhosis, hepatitis B virus infection, or treatment with ddI. AZT use was actively discouraged to minimise ribarvin-related toxicity.
Sustained virological response rates (SVR) were significantly higher in patients with G2/3 compared to G1/4, and were approaching moninfection rates (see Table 1). The 44% (174/389) discontinuation rates were largely due to virological failure, mainly at week 24 (66/174) and voluntary withdrawal (64/174). 32 people discontinued treatment due to serious events and 12 were lost to follow-up.
Table 1: Response rates by genotype and duration of treatment
| n | ETR | SVR | short | long | |
|---|---|---|---|---|---|
| Overall | 389 | 67% | 50% | ||
| G1/4 | 237 | 53% | 30% | 31% | 53% |
| G2/3 | 152 | 90% | 72% | 67% | 82% |
These rates were higher than achieved previously in the APRICOT study using 800mg ribavirin, and were the same as those seen in the HCV moninfection FRIED study using weight-based RBV for genotype 1 and 3, and gave an improved for genotype 4 (G2 data was not shown).
45/101 patients allocated to the extended therapy arms refused to continue therapy after completing the standard treatment period (data from ICAAC poster).
However, voluntary discontinuations were higher in the extended arms, especially in G1/G4 patients (80% vs 8% in patients using treatment for 72 weeks rather than 48 weeks). In G2/G3 patients, discontinuation rates were 16% and 4% in the 48 week and 24 week treatment arms respectively. This significantly reduces the power of the study to look at the effect of duration of treatment.
Despite rates of voluntary discontinuations, tolerability was reported as good, and this was largely explained by low use of AZT. 15% and 22% of patients reduced their interferon and ribavirin doses respectively.
The impact of ribavirin exposure on SVR was analysed in a sub-group of patients and median levels of 2.8 ug/mL were found in 21 non-responders compared to 3.3 ug/mL in 42 responders. The range of RBV concentrations significantly overlapped though the trend to higher RBV levels and SVR was statistically significant (p=0.01).
Infection with HCV-2/3 (RR 2.48; 1.45-4.24; p=0.001), lower baseline HCV-RNA (RR 2.61: 1.54-4.43, p<0.0001), and HCV-RNA <50 IU/ml at week 12 (RR 4.97: 2.71-9.11, p<0.0001) were independent predictors of SVR in the multivariate analysis. Extended treatment duration was not (RR 1.78: 0.83-3.81, p=0.14).
Comment
In general, the PRESCO trial is encouraging, demonstrating that ribavirin doses higher than 800mg can be used safely in HIV-coinfected patients, and that this may have contributed to higher success rate. As in mono-infected patients, the dose of ribavirin is an important determinant of SVRs. However, about 75% of the patients only had fibrosis stage F0-2 (Metavir), which may also have contributed to the better success rate.
The findings that show a superiority of the extended treatment arms are remarkable considering the high proportion of patients (45%) who never entered the extended treatment period. Only 45 many people completed 72 weeks of treatment in the G1/4 arm and only 24 achieved SVR, and the 80% is quite a stunning non-completion rate. Although extending the duration to 72 week in difficult to treat patients has been a useful strategy in monoinfection, as this study shows, tolerability may be a limiting issue for many patients. Nevertheless, for motivated individual patients with slow reduction in viral load this may be a useful strategy.
This study also starts to add weight to the fact that in some G2/3 patients shorter duration of therapy may suffice.
The dose-reduction rate of 22% due to ribavirin is still on the high side despite no AZT use. EPO use is not mentioned but is a useful adjunct to minimise symptomatic anaemia.
However, despite the additional burden of toxicity, this approach should be investigated further, in particular, in patients with slow viral response or high viral load. Both these characteristics frequently observed in coinfected patients.
Treatment of HCV in HIV co-infected patients is moving towards the concept of individualised therapy, where in the future the duration of therapy with pegIFN and ribavirin will be determined by baseline host and viral characteristics and early viral kinetics.
Reference:
Nuñez M, Miralles C, Berdún MA et l. The PRESCO trial: role of extended duration of therapy with pegylated interferon alfa-2a plus weight- based ribavirin dose in 389 HCV/HIV co-infected patients. 8th International Congress on Drug Therapy in HIV Infection, 12-16 November 2006, Glasgow. Oral abstract PL13.1.