Bani-Sadr, Firouzé MD*; Denoeud, Lise MD*; Morand, Patrice MD, PhD†; Lunel-Fabiani, Françoise MD, PhD‡; Pol, Stanislas MD, PhD§; Cacoub, Patrice MD∥; Perronne, Christian MD, PhD¶; Carrat, Fabrice MD, PhD*; Agence Nationale pour la Recherche contre le SIDA et les hépatites virales HC02-Ribavic Study Team
To the Editor:
HIV coinfection increases the percentage of patients who show hepatitis C virus (HCV) RNA declines of <2 logs at 12 weeks of peginterferon (pegIFN) and ribavirin combination therapy to 29% to 33%.1,2 We wanted to identify baseline host-related or virus-related factors that might predict early virologic failure of pegIFN α-2b plus ribavirin therapy in patients coinfected with HIV and HCV.
The results of the French National Agency for Research on AIDS and Viral Hepatitis (ANRS) HC02-Ribavic Study have been reported elsewhere.1 In brief, 206 of 416 HIV/HCV-coinfected patients who had never received interferon or ribavirin were randomly assigned to receive weekly subcutaneous injections of 1.5 μg/kg of pegIFN α-2b (ViraferonPeg; Schering-Plough, Kenilworth, NJ) plus 800 mg/d of ribavirin for 48 weeks, and 210 patients were randomly assigned to receive thrice-weekly subcutaneous injections of 3 megaunits of interferon α-2b plus 800 mg/d of ribavirin for 48 weeks. Only patients treated with pegIFN α-2b plus ribavirin and who had taken at least 80% of the total prescribed dose regimen were analyzed here. Early virologic responses were defined by undetectable serum HCV RNA in a qualitative polymerase chain reaction (PCR) assay (Amplicor 2.0 HCV Monitor, detection limit of 50 IU/mL; Roche Diagnostics Systems, Pleasanton, CA) or a decrease of more than 2 log10 in serum HCV RNA in a quantitative PCR assay (bDNA3.0, detection limit of 615 IU/mL; Bayer Diagnostics, Tarrytown, NY) at week 12. We used the χ2 test or Fisher exact test to analyze qualitative variables and the Mann-Whitney test to analyze quantitative variables. Logistic regression models were used to test possible associations between nonresponse (outcome variable) and pretreatment characteristics (input variables). Characteristics with P < 0.10 in univariate analysis were included in multivariate models based on a backward elimination procedure. All statistical tests were 2-sided, with a type I error of 5%.
A total of 194 patients received at least 1 dose of pegIFN α-2b plus ribavirin, and 154 of these patients received at least 80% of their study medication during the first 12 weeks of treatment. Fifty-seven patients (37%) did not have an early HCV virologic response; their mean decline in HCV viral load during the first 12 weeks of treatment was 0.6 ± 0.6 log10 IU/mL. We analyzed the clinical and virologic data to identify baseline factors that were predictive of early HCV virologic failure. Univariate analysis identified higher HCV viral load, genotype 1 or 4 infection, abacavir-based antiretroviral therapy, and elevated gamma-glutamyl transferase (GGT) and bilirubin levels (Table 1). In multivariate analysis, elevated baseline HCV viral load, HCV genotype 1 or 4 infection, abacavir-based antiretroviral therapy, and an elevated baseline bilirubin level remained significantly associated with the risk of early HCV virologic failure (see Table 1).
Because HCV genotype 1 or 4 infection was the most influential risk factor for early virologic failure, we repeated the analyses in the subgroup of patients infected by these genotypes. In multivariate analysis, abacavir-based antiretroviral therapy (odds ratio [OR] = 4.15, 95% confidence interval [CI]: 1.14 to 15.13; P = 0.031) and an elevated baseline bilirubin level (OR = 5.2, 95% CI: 1.34 to 20.36; P = 0.017) remained significantly associated with the risk of early virologic failure.
Several patient-related and virus-related factors have been shown to influence the response to optimal interferon-ribavirin combination therapy for HCV infection.1-4 Most studies compared patients with sustained virologic responses and those with virologic relapse or no response. Nonresponders differ from patients who relapse, in whom HCV RNA becomes undetectable during treatment but then reappears on treatment withdrawal. In nonresponder HCV-monoinfected patients, the average drop in HCV viral load at week 12 is 1 log10, with no subsequent decline during continued treatment.3 Our study confirms that a high baseline HCV viral load and HCV genotype 1 or 4 infection are the most important baseline predictors of early virologic failure.
The link found here between the risk of early nonresponse to anti-HCV therapy and abacavir exposure was unexpected and points to a possible role of drug interaction. In multivariate analysis, concomitant treatment with abacavir and pegIFN-ribavirin was associated with an adjusted 4.9-fold increase in the risk of nonresponse to anti-HCV therapy. The only significant differences between abacavir-treated and abacavir-untreated patients were a longer duration of antiretroviral therapy and a higher baseline GGT level in abacavir-treated patients. These factors were considered in multivariate analysis, and therefore cannot explain the effect of abacavir after adjustment. Poor HIV virologic responses were recently reported with triple-nucleoside reverse transcriptase inhibitor (NRTI) regimens consisting of tenofovir plus another purine NRTI (abacavir or didanosine), but there was no evidence of plasma pharmacokinetic or intracellular phosphorylation interactions.5-7
Ribavirin is a purine ribonucleoside analogue used to treat hepatitis. In HIV/HCV-coinfected patients treated for both infections, ribavirin can affect intracellular NRTI levels by inhibiting inosine 5′-monophosphate dehydrogenase. In vitro, the level antagonism on HIV is lower when ribavirin is combined with abacavir rather than with stavudine or zidovudine.8 The potential loss of ribavirin efficacy on HCV during concomitant use of these NRTIs has not previously been reported, however.
The only host factor predictive of early HCV virologic failure in our study was an elevated serum bilirubin level at baseline. The pathophysiology of bilirubin elevation in this setting is not known, although a correlation between serum bilirubin and hepatic fibrosis is well established. Other factors known to have a negative influence on anti-HCV therapeutic outcome, such as older age, higher body mass index, advanced fibrosis or cirrhosis, liver steatosis, and the daily dose of ribavirin (12.2 mg/kg on average in our study), were not associated with early virologic failure in our study.3,4 Only 5 patients were from sub-Saharan Africa, and the possible impact of ethnicity on the virologic response could not therefore be evaluated.
If confirmed, the negative interaction observed here between ribavirin and abacavir on the response to anti-HCV therapy has to be taken into account in clinical practice.
This study received financial support from ANRS Essai HC 02 and SIDACTION. Results are to be presented at the 14th Conference on Retroviruses and Opportunistic Infections (CROI 2007), Los Angeles, CA, February 25-28, 2007.
Firouzé Bani-Sadr, MD*
Lise Denoeud, MD*
Patrice Morand, MD, PhD†
Françoise Lunel-Fabiani, MD, PhD‡
Stanislas Pol, MD, PhD§
Patrice Cacoub, MD∥
Christian Perronne, MD, PhD¶
Fabrice Carrat, MD, PhD*
Agence Nationale pour la Recherche contre le SIDA et les hépatites virales HC02-Ribavic Study Team
*Groupe Hospitalier Universitaire Est Université Paris 6, INSERM U707 Paris, France
†Centre Hospitalier Universitaire Grenoble, France
‡Faculté de medicine Angers, France
§Groupe Hospitalier Universitaire Ouest Université Paris 5, INSERM U370 Paris, France
∥Groupe Hospitalier Universitaire Est Université Paris 6, UMR7087 Paris, France
¶Centre Hospitalier Universitaire Raymond Poincaré Université de Versailles Garches, France
1. Carrat F, Bani-Sadr F, Pol S, et al. Pegylated interferon alfa-2b versus standard interferon alfa-2b, plus ribavirin for chronic hepatitis C in HIV-infected patients: a randomized controlled trial. JAMA
2. Torriani FJ, Rodriguez-Torres M, Rockstroh JK, et al. Peginterferon alfa-2a plus ribavirin for chronic hepatitis C virus infection in HIV-infected patients. N Engl J Med
3. Di Bisceglie AM, Fan X, Chambers T, et al. Pharmacokinetics, pharmacodynamics, and hepatitis C viral kinetics during antiviral therapy: the null responder. J Med Virol
4. Akuta N, Suzuki F, Sezaki H, et al. Predictive factors of virological non-response to interferon-ribavirin combination therapy for patients infected with hepatitis C virus of genotype 1b and high viral load. J Med Virol
5. Gallant JE, Rodriguez AE, Weinberg WG, et al. Early virologic nonresponse to tenofovir, abacavir, and lamivudine in HIV-infected antiretroviral-naive subjects. J Infect Dis
6. Hawkins T, Veikley W, St. Claire RL III, et al. Intracellular pharmacokinetics of tenofovir diphosphate, carbovir triphosphate, and lamivudine triphosphate in patients receiving triple-nucleoside regimens. J Acquir Immune Defic Syndr
7. Kakuda TN, Anderson PL, Becker SL. CD4 cell decline with didanosine and tenofovir and failure of triple nucleoside/nucleotide regimens may be related. AIDS
8. Margot NA, Miller MD. In vitro combination studies of tenofovir and other nucleoside analogues with ribavirin against HIV-1. Antivir Ther
© 2007 Lippincott Williams & Wilkins, Inc.