Abacavir Coadministration Does Not Interfere with the Suppressive Activity of Ribavirin in An HCV Replicon System

Abstract

Background

HCV is a major cause of morbidity and mortality in HIV-coinfected patients. Several observational studies have suggested that HCV response to pegylated interferon and ribavirin is lower in HIV-coinfected patients treated with abacavir. It has been postulated that abacavir could compete with ribavirin to be phosphorylated, leading to a reduction in the active form of the drug (triphosphorylated ribavirin). Here, we studied the effect of abacavir, tenofovir or lamivudine addition on the suppressive activity of ribavirin in an HCV RNA replicon system.

Methods

We used the human hepatoma HuH-7 cell clone 9B containing the HCV genotype 1b replicon I389/ NS3-3’. Cells were treated for 24 h with ribavirin (0, 10 and 50 μM) plus abacavir, tenofovir or lamivudine at doses of 0, 10 and 50 μM and HCV RNA production was quantified by real-time PCR in triplicate assays. Results were expressed as mean ±sd of the HCV RNA produced per cell (log₁₀ IU/cell). Means were compared using the Student's t-test.

Results

Ribavirin treatment produced a dose-dependent suppression of HCV RNA production by the replicon system. Combination of ribavirin and interferon resulted in an additive antiviral activity. The addition of abacavir did not modify the suppressive activity of ribavirin on the replicon HCV RNA expression. Similar results were obtained when ribavirin was used in combination with tenofovir or lamivudine.

Conclusions

In a subgenomic HCV RNA replicon system, the antiviral effect of ribavirin was not modified by the addition of abacavir, tenofovir or lamivudine.

References

Soriano

, Puoti

, Sulkowski

Care of patients coinfected with HIV and hepatitis C virus: 2007 updated recommendations from the HCV-HIV International Panel. AIDS 2007; 21: 1073–1089.

Graham

C.S.

, Baden

L.R.

, Yu

Influence of human immunodeficiency virus infection on the course of hepatitis C virus infection: a meta-analysis. Clin Infect Dis 2001; 33: 562–569.

Sulkowski

M.S.

The HIV-coinfected patient: managing viral hepatitis. J Acquir Immune Defic Syndr 2007; 45 Suppl 2: S36–S37.

Bica

, McGovern

, Dhar

Increasing mortality due to end-stage liver disease in patients with human immunodeficiency virus infection. Clin Infect Dis 2001; 32: 492–497.

Palella

F.J.

Jr. , Delaney

K.M.

, Moorman

A.C.

Declining morbidity and mortality among patients with advanced human immunodeficiency virus infection. HIV Outpatient Study Investigators. N Engl J Med 1998; 338: 853–860.

Weber

, Sabin

C.A.

, Friis-Moller

Liver-related deaths in persons infected with the human immunodeficiency virus: the D:A:D study. Arch Intern Med 2006; 166: 1632–1641.

Alberti

, Clumeck

, Collins

Short statement of the first European Consensus Conference on the treatment of chronic hepatitis B and C in HIV co-infected patients. J Hepatol 2005; 42: 615–624.

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.

10.

Chung

R.T.

, Andersen

, Volberding

Peginterferon alfa-2a plus ribavirin versus interferon alfa-2a plus ribavirin for chronic hepatitis C in HIV-coinfected persons. N Engl J Med 2004; 351: 451–459.

11.

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: F27–F36.

12.

Crespo

, Sauleda

, Esteban

J.I.

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

13.

Laguno

, Cifuentes

, Murillas

Randomized trial comparing pegylated interferon alpha-2b versus pegylated interferon alpha-2a, both plus ribavirin, to treat chronic hepatitis C in human immunodeficiency virus patients. Hepatology 2009; 49: 22–31.

14.

Solà

, Galeras

J.A.

, Montoliu

Poor response to hepatitis C virus (HCV) therapy in HIV- and HCV-coinfected patients is not due to lower adherence to treatment. AIDS Res Hum Retroviruses 2006; 22: 393–400.

15.

Pineda

J.A.

, Mira

J.A.

, Gil

I.L.

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.

16.

Opravil

, Sasadeusz

, Cooper

D.A.

Effect of baseline CD4 cell count on the efficacy and safety of peginterferon alfa-2a (40KD) plus ribavirin in patients with HIV/hepatitis C virus coinfection. J Acquir Immune Defic Syndr 2008; 47: 36–49.

17.

Balzarini

, Lee

C.K.

, Herdewijn

, De

C.E.

Mechanism of the potentiating effect of ribavirin on the activity of 2′,3′-dideoxyinosine against human immunodeficiency virus. J Biol Chem 1991; 266: 21509–21514.

18.

Laguno

, Milinkovic

, de Lazzari

Incidence and risk factors for mitochondrial toxicity in treated HIV/ HCV-coinfected patients. Antivir Ther 2005; 10: 423–429.

19.

Hoggard

P.G.

, Kewn

, Barry

M.G.

, Khoo

S.H.

, Back

D.J.

Effects of drugs on 2′,3′-dideoxy-2′,3′-didehydrothymidine phosphorylation in vitro. Antimicrob Agents Chemother 1997; 41: 1231–1236.

20.

Vogt

M.W.

, Hartshorn

K.L.

, Furman

P.A.

Ribavirin antagonizes the effect of azidothymidine on HIV replication. Science 1987; 235: 1376–1379.

21.

Mira

J.A.

, Lopez-Cortes

L.F.

, Merino

Predictors of severe haematological toxicity secondary to pegylated interferon plus ribavirin treatment in HIV-HCV-coinfected patients. Antivir Ther 2007; 12: 1225–1235.

22.

Bani-Sadr

, Denoeud

, Morand

Early virologic failure in HIV-coinfected hepatitis C patients treated with the peginterferon-ribavirin combination: does abacavir play a role?

J Acquir Immune Defic Syndr 2007; 45: 123–125.

23.

Mira

J.A.

, Lopez-Cortes

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.

24.

Vispo

, Barreiro

, Pineda

J.A.

Low response to pegylated interferon plus ribavirin in HIV-infected patients with chronic hepatitis C treated with abacavir. Antivir Ther 2008; 13: 429–437.

25.

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.

26.

Berenguer

, von Wichmann

, Quereda

Effect of accompanying antiretroviral drugs on virologic response to PEG-IFN and ribavirin in HIV/HCV co-infected patients. GESIDA 36/03 and 50/06 study. 17th Conference of Retroviruses and opportunistic Infections. 16–19 February 2010, San Francisco, CA, USA. Poster 663.

27.

Amorosa

V.K.

, Slim

, Mounzer

The influence of abacavir and other antiretroviral agents on virological response to HCV therapy among antiretroviral-treated HIV-infected patients. Antivir Ther 2010; 15: 91–99.

28.

Laufer

, Laguno

, Perez

Abacavir does not influence the rate of virological response in HIV-HCV-coinfected patients treated with pegylated interferon and weight-adjusted ribavirin. Antivir Ther 2008; 13: 953–957.

29.

Van den Eynde

, Tiraboschi

J.M.

, Tural

Ability of treatment week 12 viral response to predict long-term outcome in genotype 1 hepatitis C virus/HIV coinfected patients. AIDS 2010; 24: 975–982.

30.

Pietschmann

, Lohmann

, Kaul

Persistent and transient replication of full-length hepatitis C virus genomes in cell culture. J Virol 2002; 76: 4008–4021.

31.

Kato

, Date

, Miyamoto

Detection of anti-hepatitis C virus effects of interferon and ribavirin by a sensitive replicon system. J Clin Microbiol 2005; 43: 5679–5684.

32.

Tanabe

, Sakamoto

, Enomoto

Synergistic inhibition of intracellular hepatitis C virus replication by combination of ribavirin and interferon-alpha. J Infect Dis 2004; 189: 1129–1139.

33.

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.

34.

Margot

N.A.

, Miller

M.D.

In vitro combination studies of tenofovir and other nucleoside analogues with ribavirin against HIV-1. Antivir Ther 2005; 10: 343–348.

35.

Moreno

, Quereda

, Moreno

High rate of didanosine-related mitochondrial toxicity in HIV/HCV-coinfected patients receiving ribavirin. Antivir Ther 2004; 9: 133–138.

36.

Bani-Sadr

, Carrat

, Rosenthal

Spontaneous hepatic decompensation in patients coinfected with HIV and hepatitis C virus during interferon–ribavirin combination treatment. Clin Infect Dis 2005; 41: 1806–1809.

37.

Sim

S.M.

, Hoggard

P.G.

, Sales

S.D.

Effect of ribavirin on zidovudine efficacy and toxicity in vitro: a concentration-dependent interaction. AIDS Res Hum Retroviruses 1998; 14: 1661–1667.

38.

Landau

, Batisse

, Piketty

, Jian

, Kazatchkine

M.D.

Lack of interference between ribavirin and nucleosidic analogues in HIV/HCV co-infected individuals undergoing concomitant antiretroviral and anti-HCV combination therapy. AIDS 2000; 14: 1857–1858.

39.

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.

40.

Asahina

, Izumi

, Enomoto

Mutagenic effects of ribavirin and response to interferon/ribavirin combination therapy in chronic hepatitis C. J Hepatol 2005; 43: 623–629.

41.

Lau

J.Y.

, Tam

R.C.

, Liang

T.J.

, Hong

Mechanism of action of ribavirin in the combination treatment of chronic HCV infection. Hepatology 2002; 35: 1002–1009.