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JAIDS Journal of Acquired Immune Deficiency Syndromes:
doi: 10.1097/QAI.0b013e3181b62858
Letters to the Editor

Ribavirin Plasma Concentration Predicts Sustained Virological Response to Peginterferon Alfa 2a Plus Ribavirin in Previously Treated HCV-HIV–Coinfected Patients

Breilh, Dominique PhD*; Djabarouti, Sarah PhD*; Trimoulet, Pascale PharmD†; Bail, Brigitte Le MD, PhD‡; Dupon, Michel MD§; Ragnaud, Jean-Marie MD§; Fleury, Hervé MD, PhD†; Saux, Marie-Claude PharmD, PhD*; Thiébaut, Rodolphe PhD‖; Chêne, Geneviève MD, PhD¶; Neau, Didier PhD, MD§

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*Laboratoire de Pharmacocinétique et Pharmacie Clinique, CHU and Université Victor Segalen, Hôpital Haut-Lévêque, Pessac, France; †Laboratoire de Virologie, CHU and Université Victor Segalen, Hôpital Pellegrin, Bordeaux, France; ‡Laboratoire d'Anatomie Pathologique, CHU, Hôpital Pellegrin, Bordeaux, France; §Fédération des Maladies Infectieuses et Tropicales, CHU, Hôpital Pellegrin, Bordeaux, France; ‖INSERM, U897 & CIC-EC7, ISPED, Université Victor Segalen, Bordeaux, France; ¶CHU Bordeaux, Unité de Soutien Méthodologique à la Recherche Clinique et Epidémiologique, Bordeaux, France

Supported by Produits Roche

To the Editors:

Treatment combining peginterferon alfa plus ribavirin is proposed to treat hepatitis C virus (HCV) infection in HIV-infected patients.1 In a clinical trial, sustained virological response (SVR) was obtained in 29% and 62% of patients infected with HCV genotypes 1 and 2 or 3, respectively.2 Factors explaining these lower SVR rates in comparison with HCV-monoinfected patients remain to be determined. Because of potential toxicity, patients received low dosage of ribavirin (400 mg twice a day),2 in part contributing to low SVR. Indeed, studies have demonstrated a relationship between ribavirin exposure and anti-HCV therapy efficiency in HCV monoinfected3 and HIV-coinfected patients4 previously untreated for their hepatitis C. In this study, we assessed the impact of ribavirin plasma levels on SVR in patients previously treated for their hepatitis C without HCV clearance and receiving peginterferon alfa plus ribavirin as retreatment.

HIV-1-infected patients aged 18-65 years with chronic hepatitis C previously treated without virological response were eligible for the study. They had previously received a first anti-HCV treatment as follows without virological response: (1) interferon alfa alone at least 3 MU 3 times per week for at least 12 weeks; (2) interferon alfa at least 3 MU 3 times per week and ribavirin at least 600 mg per day during a minimal duration of 24 weeks. They had a CD4 cell count >200 cells per microliter and a plasma HIV RNA level <10,000 copies per milliliter (Versant HIV-1 RNA 3.0 Assay; Bayer Corporation, Berkeley, CA; cutoff 50 copies/mL), with or without antiretroviral therapy. Patients received pegylated interferon alfa-2a (Pegasys, Produit Roche, 180 μg subcutaneously once a week; Neuilly-sur-Seine, France) and ribavirin (Copegus, Produit Roche, 800, 1000, or 1200 mg twice per day for a bodyweight <65 kg, between 65 kg and 85 kg, and ≥85 kg, respectively) for 48 weeks. HCV genotype was determined at the beginning of the study (TruGene 5′NC HCV Genotyping Assay; Bayer Diagnostics, Tarrytown, NY). The plasma HCV load (Cobas Amplicor HCV Monitor 2.0; Roche Diagnostics, Meylan, France, cutoff 600 IU/mL) was measured before and at weeks 4 and 12 of the treatment. SVR was defined as plasma HCV RNA undetectability 24 weeks after the end of the treatment, nonresponse if HCV RNA was detectable at this time.

The ribavirin concentration was measured on stored frozen plasma from blood samples taken 2 and 12 weeks after treatment initiation and collected before the next dose of ribavirin. Samples were processed in the 2 hours after blood sampling and were kept frozen at −80°C. Ribavirin concentrations were measured using an automated solid phase extraction process and a validated high-performance liquid chromatography-ultraviolet assay adapted from previously published methods5,6 at weeks 2 and 12 after treatment initiation. Association between trough plasma concentration of ribavirin (RBV C0) at these times and SVR was determined according to the best cutoff.

Analysis of HCV treatment efficiency was conducted on an intention-to-treat basis. The value of efficacy cutoff was evaluated by considering the median, the first, and third quartiles of the concentration of ribavirin, respectively. To compare the proportions of patients who achieved a SVR, a χ2 or a Fisher exact test was used. For each comparison, patients were divided in 2 groups after the observed plasma RBV C0 (≤ or >cutoff). For each series of experiments, the variability of ribavirin concentration was estimated by determination of the relative standard deviation.

Seventeen patients {14 males, median age 39 [interquartile range (IQR)] (28-44)} were included in the study. The median CD4 T-lymphocyte count was 609/μL (IQR 302-1140) at the initiation of anti-HCV therapy. All the patients received an antiretroviral treatment, 12 had an undetectable HIV RNA level. Eleven patients were infected with HCV genotype 1, 3 with genotype 2 or 3, and 3 with genotype 4. Eleven had previously been treated with standard interferon alfa alone, the others having received standard interferon alfa plus ribavirin. The median baseline HCV level was 6.44 (IQR: 5.77-6.73) log10 IU/mL. Concerning the fibrosis score, 6 patients were F1 or F2, the others F3 or F4 (METAVIR score). SVR was achieved in 7 patients (41.2%; 95% confidence interval: 18.4 to 67.1), 5 of them being infected with genotype 1. At week 2, median ribavirin plasma concentration was 0.9 [IQR 0.9-1.8] μg/mL. It was significantly higher in patients achieving a SVR than in nonresponders (P = 10−7) (Fig. 1A). An optimal cutoff value of 1.8 μg/mL was obtained with a sensibility of 57%, a specificity of 100%, a positive predictive value of 100%, and a negative predictive value negative predictive value of 77%. Similarly, at week 12, median ribavirin plasma concentration was 0.8 (IQR 0.7-0.8) μg/mL. It was also demonstrated to be higher in patients obtaining a SVR (P = 10−7) (Fig. 1B). An optimal cutoff of 1.9 μg/mL was determined with a sensibility of 100%, a specificity of 90%, a positive predictive value of 88%, and a negative predictive value of 100%. No relationship was observed between ribavirin plasma concentration and changes in hemoglobin level during the follow-up period.

Figure 1
Figure 1
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In this study, a relationship between plama RBV C0 and efficiency of anti-HCV treatment was demonstrated in HIV-coinfected patients previously treated without virological response. Our study was conducted in patients who had previously received suboptimal anti-HCV schedules without virological response. Data concerning the efficiency of a retreatment including pegylated interferon and ribavirin in such HIV-coinfected patients are lacking. A SVR response was observed in 3 of 24 patients (13%), non responders to a previous treatment with standard interferon and ribavirin.7 More recently, 16 among 54 patients (30%) who failed to a former interferon-based therapy (non responders or relapsers) achieved a SVR.8 In our study, a SVR was observed in 40% of cases, which confirms the interest of anti-HCV retreatment in this population. As in HCV alone-infected patients, adequate exposure to ribavirin is crucial to optimize virological response to anti-HCV therapy in HIV-coinfected patients, in whom the immune effects of interferon may be altered.1 Previous studies have been performed in patients never treated for their hepatitis C. Rendon et al9 demonstrated a correlation of plasma ribavirin level with an early virological response (weeks 4 and 12) and the occurrence of anemia. A ribavirin concentration cutoff of 2700 ng/mL could predict early virological response with 70% sensitivity and 49% specificity. An association between ribavirin concentration and SVR was also found in 2 studies in patients infected by HCV genotype 1 or 4, with a ribavirin cutoff of 1600 ng/mL and 2300 ng/mL, respectively.4,10 Ribavirin concentration correlated also with hemoglobin decrease.4 To our knowledge, the present study is the first one investigating patients previously treated for their HCV infection. Our results confirm a correlation between SVR and ribavirin concentration with a cutoff close to those previously described, although we were not able to demonstrate a correlation with the occurrence of side effects and particularly anaemia.

In summary, trough plasma concentration of ribavirin must be monitored during anti-HCV therapy in previously treated patient, as described in naive patients. Adjustment of dosage of ribavirin according to a ribavirin concentration determined shortly after initiation of anti-HCV therapy could be crucial to obtain a SVR.

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ACKNOWLEDGMENT

We thank Christel Duprat for technical assistance.

Dominique Breilh, PharmD, PhD*

Sarah Djabarouti, PharmD, PhD*

Pascale Trimoulet, PharmD†

Brigitte Le Bail, MD, PhD‡

Michel Dupon, MD§

Jean-Marie Ragnaud, MD§

Hervé Fleury, MD, PhD†

Marie-Claude Saux, PharmD, PhD*

Rodolphe Thiébaut, PhD‖

Geneviève Chêne, MD, PhD¶

Didier Neau, MD, PhD§

*Laboratoire de Pharmacocinétique et Pharmacie Clinique, EA 2968, CHU and Université Victor Segalen, Hôpital Haut-Lévêque, Pessac, France

†Laboratoire de Virologie, EA 2968, CHU and Université Victor Segalen, Hôpital Pellegrin, Bordeaux, France

‡Laboratoire d'Anatomie Pathologique, CHU, Hôpital Pellegrin, Bordeaux, France

§Fédération des Maladies Infectieuses et Tropicales, CHU, Hôpital Pellegrin, Bordeaux, France

‖INSERM, U897 & CIC-EC7, ISPED, Université Victor Segalen, Bordeaux, France

¶CHU Bordeaux, Unité de Soutien Méthodologique à la Recherche Clinique et Epidémiologique, Bordeaux, France

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REFERENCES

1. Soriano V, Puoti M, Sulkowski M, et al. Care of patients coinfected with HIV and hepatitis C virus: 2007 updated recommendations from the HCV-HIV International Panel. AIDS. 2007;21:1073-1089.

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. 2004;351:438-450.

3. Loustaud-Ratti V, Alain S, Rousseau A, et al. Ribavirin exposure after the first dose is predictive of sustained virological response in chronic hepatitis C. Hepatology. 2008;47:1453-1461.

4. Aguilar Marucco D, Gonzalez de Requena D, Bonora S, et al. The use of ribavirin concentration to predict sustained virological response and haematological toxicity in HIV/HCV-co-infected patients treated with ribavirin and pegylated interferon. J Antimicrob Chemother. 2008;61:919-924.

5. Svensson JO, Bruchfeld A, Schvarcz R, et al. Determination of ribavirin in serum using highly selective solid-phase extraction and high-performance liquid chromatography. Ther Drug Monit. 2000;22:215-218.

6. Loregian A, Scarpa MC, Pagni S, et al. Measurement of ribavirin and evaluation of its stability in human plasma by high-performance liquid chromatography with UV detection. J Chromatogr B Analyt Technol Biomed Life Sci. 2007;856:358-364.

7. Myers RP, Benhamou Y, Bochet M, et al. Pegylated interferon alpha 2b and ribavirin in HIV/hepatitis C virus-co-infected non-responders and relapsers to IFN-based therapy. AIDS. 2004;18:75-79.

8. Crespo M, Mira JA, Pineda J, et al. Efficacy of pegylated interferon and ribavirin for retreatment of chronic HCV infection in HIV co-infected patients failing a previous standard interferon-based regimen. J Antimicrob Chemother. 2008;62:793-796.

9. Rendon AL, Nunez M, Romero M, et al. Early monitoring of ribavirin plasma concentrations may predict anemia and early virologic response in HIV/hepatitis C virus coinfected patients. J Acquir Immune Defic Syndr. 2005;39:401-405.

10. Nicot F, Legrand-Abravanel F, Lafont T, et al. Serum concentrations of ribavirin and pegylated interferon and viral responses in patients infected with HIV and HCV. J Med Virol. 2008;80:1523-1529.

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© 2009 Lippincott Williams & Wilkins, Inc.

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