Effect of An Induction Period of Pegylated Interferon-α2A and Ribavirin on Early Virological Response in HIV–HCV-Coinfected Patients: Results from the Coral-2 Study

Abstract

Background

It is uncertain whether a 4-week induction period of pegylated interferon and ribavirin increases early virological response (EVR) in HIV-HCV-coinfected patients.

Methods

HIV and HCV genotype 1- and 4-coinfected subjects were randomized to receive pegylated interferon-α2a 270 μg/week plus ribavirin 1,600 mg daily and epoetin-β for 4 weeks, followed by pegylated interferon-α2a at standard dosages plus weight-based ribavirin (WBR) dosage for 8 weeks (induction arm [IA]), or pegylated interferon-α2a plus WBR for 12 weeks (standard therapy arm [SA]). HCV RNA was determined at weeks 0, 1, 2, 3, 4, 8 and 12. Ribavirin plasma trough concentrations were determined at weeks 4 (RBV-C₄) and 12 (RBV-C₁₂).

Results

A total of 67 patients were included; 33 in the SA and 34 in the IA. Overall, 25% received nucleoside reverse transcriptase inhibitor (NRTI)-sparing regimens. More patients achieved an HCV RNA decrease ≥1 log₁₀ at week 4 in the IA than in the SA (62% versus 38%; P=0.017), but EVR rates were similar in the two groups (74% versus 59% in the IA and SA, respectively; P=0.15). Independent predictors of faster HCV RNA decrease at 12 weeks were higher RBV-C₄ and younger age. RBV-C₄ were higher in patients allocated in the IA and in those receiving NRTIs (P=0.039).

Conclusions

A 4-week induction with pegylated interferon-α2a plus ribavirin was associated with a greater decrease in HCV RNA at week 4; however, this did not translate into higher EVR rates. Higher RBV doses and avoidance of NRTI-sparing antiretroviral regimens might improve HCV treatment efficacy.

References

Torriani

F.J.

, Rodriguez-Torres

, Rockstroh

J.K.

Peginterferon alfa-2a plus ribavirin for chronic hepatitis C virus infection in HIV-infected patients. N Engl J Med 2004; 351: 438–450.

Carrat

, Bani-Sadr

, Pol

Pegylated interferon alfa-2b vs standard interferon alfa-2b, plus ribavirin, for chronic hepatitis C in HIV-infected patients: a randomized controlled trial. JAMA 2004; 292: 2839–2848.

Laguno

, Murillas

, Blanco

J.L.

Peginterferon alfa-2b plus ribavirin compared with interferon alfa-2b plus ribavirin for treatment of HIV/HCV co-infected patients. AIDS 2004; 18: 27–36.

Crespo

, Sauleda

, Esteban

J.I.

Peginterferon alpha-2b plus ribavirin vs interferon alpha-2b plus ribavirin for chronic hepatitis C in HIV-HCV/HIV coinfected patients. J Viral Hepat 2007; 14: 228–238.

Fleischer

, Boxwell

, Shermann

K.E.

Nucleoside analogues and mitochondrial toxicity. Clin Infect Dis 2004; 38: e79–e80.

Fuster

, Huertas

J.A.

, Gómez

Baseline factors associated with haematological toxicity that leads to a dosage reduction of pegylated interferon-alpha2a and ribavirin in HIV- and HCV-coinfected patients on HCV antiviral therapy. Antivir Ther 2005; 10: 841–847.

Mira

J.A.

, López-Cortés

L.F.

, Barreiro

Efficacy of pegylated interferon plus ribavirin treatment in HIV/ hepatitis C virus co-infected patients receiving abacavir plus lamivudine or tenofovir plus either lamivudine or emtricitabine as nucleoside analogue backbone. J Antimicrob Chemother 2008; 62: 1365–1373.

Pineda

J.A.

, Mira

J.A.

, Gil Ide

Influence of concomitant antiretroviral therapy on the rate of sustained virological response to pegylated interferon plus ribavirin in hepatitis C virus/HIV-coinfected patients. J Antimicrob Chemother 2007; 60: 1347–1354.

Crespo

, Pou

, Esteban

J.I.

Early monitoring of ribavirin serum concentration is not useful to optimize hepatitis C virus treatment in HIV-coinfected patients. Antivir Ther 2007; 12: 1217–1223.

10.

Breilh

, Djabarouti

, Trimoulet

Ribavirin plasma concentration predicts sustained virological response to peginterferon alfa 2a plus ribavirin in previously treated HCV-HIV-coinfected patients. J Acquir Immune Defic Syndr 2009; 52: 428–430.

11.

Aguilar Marucco

, Gonzalez de Requena

, Bonora

The use of trough 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.

12.

Rendón

A.L.

, Núñez

, Romero

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.

13.

Ballesteros

A.L.

, Franco

, Fuster

Early HCV dynamics on peg-interferon and ribavirin in HIV/HCV co-infection: indications for the investigation of new treatment approaches. AIDS 2004; 18: 59–66.

14.

Pegasys (peginterferon alfa-2a). Package insert 2002. Hoffmann-La Roche, Inc., Nutley, NJ, USA.

15.

Copegus (ribavirin) Package insert 2002. Hoffmann-La Roche, Inc., Nutley, NJ, USA.

16.

Reddy

K.R.

, Shiffman

M.L.

, Rodriguez-Torres

Induction pegylated interferon alfa-2a and high dose ribavirin do not increase SVR in heavy patients with HCV genotype 1 and high viral loads. Gastroenterology 2010; 139: 1972–1983.

17.

Hézode

, Forestier

, Dusheiko

Telaprevir and peginterferon with or without ribavirin for chronic HCV infection. N Engl J Med 2009; 360: 1839–1850.

18.

McHutchison

J.G.

, Everson

G.T.

, Gordon

S.C.

Telaprevir with peginterferon and ribavirin for chronic HCV genotype 1 infection. N Engl J Med 2009; 360: 1827–1838.

19.

Berman

, Kwo

P Y.

Boceprevir, an NS3 protease inhibitor of HCV. Clin Liver Dis 2009; 13: 429–439.

20.

Jen

J.F.

, Glue

, Gupta

, Zambas

, Hajian

Population pharmacokinetic and pharmacodynamic analysis of ribavirin in patients with chronic hepatitis C. Ther Drug Monit 2000; 22: 555–565.

21.

Loustaud-Ratti

, Alain

, Rousseau

Ribavirin exposure after the first dose is predictive of sustained virological response in chronic hepatitis C. Hepatology 2008; 47: 1453–1461.

22.

Lindahl

, Stahle

, Bruchfeld

, Schvarcz

High-dose ribavirin in combination with standard dose peginterferon for treatment of patients with chronic hepatitis C. Hepatology 2005; 41: 275–279.

23.

Morello

, Soriano

, Barreiro

Plasma ribavirin trough concentrations at week 4 predict hepatitis C virus (HCV) relapse in HIV-HCV-coinfected patients treated for chronic hepatitis C. Antimicrob Agents Chemother 2010; 54: 1647–1649.

24.

Labarga

, Vispo

, Barreiro

Rate and predictors of success in the retreatment of chronic hepatitis C virus in HIV/hepatitis C Virus coinfected patients with prior nonresponse or relapse. J Acquir Immune Defic Syndr 2010; 53: 364–368.

25.

Dahari

, Markatou

, Zeremski

Early ribavirin pharmacokinetics, HCV RNA and alanine aminotransferase kinetics in HIV/HCV co-infected patients during treatment with pegylated interferon and ribavirin. J Hepatol 2007; 47: 23–30.

26.

Lopez-Cortes

L.F.

, Valera-Bestard

, Gutierrez-Valencia

Role of pegylated interferon-alpha-2a and ribavirin concentrations in sustained viral response in HCV/HIV-coinfected patients. Clin Pharmacol Ther 2008; 84: 573–580.

27.

Marquet

, Sauvage

F.L.

, Loustaud-Ratti

, Babany

, Rosseau

, Lachatre

Stability of ribavirin concentrations depending on the type of blood collection tube and preanalytical conditions. Ther Drug Monit 2010; 32: 237–241.

28.

Rodriguez-Torres

, Torriani

F.J.

, Soriano

Effect of ribavirin on intracellular and plasma pharmacokinetics of nucleoside reverse transcriptase inhibitors in patients with human immunodeficiency virus-hepatitis C virus coinfection: results of a randomized clinical study. Antimicrob Agents Chemother 2005; 49: 3997–4008.

29.

Ramanathan

, Cheng

, Mittan

, Ebrahimi

, Kearney

B P.

Absence of clinically relevant pharmacokinetic interaction between ribavirin and tenofovir in healthy subjects. J Clin Pharmacol 2006; 46: 559–566.