Journal of Antimicrobial Chemotherapy (2006) 57, 815–818

doi:10.1093/jac/dkl068

Advance Access publication 23 March 2006

Management of chronic hepatitis B and C inHIV-coinfected patients

Vincent Soriano*, Pablo Barreiro and Marina Nunez

Department of Infectious Diseases, Hospital Carlos III, Calle Sinesio Delgado 10, 28029 Madrid, Spain

One-third of HIV-infected individuals worldwide suffer from chronic hepatitis C virus (HCV) infection, butchronic hepatitis C affects more than 75% of HIV-positive subjects infected parenterally, such as haemo-philiacs and intravenousdrugusers. Chronic hepatitisBvirus (HBV) infection, on theother hand, occurs in10% of HIV-infected persons, coinfection being more prevalent in Southeast Asia. There are two mainreasons for considering HCV and HBV therapy as a priority in HIV-coinfected patients: first, the morerapid liver disease progression seen in this population, leading to end-stage liver disease complications,including hepatocellular carcinoma, at younger ages; and second, the higher risk of developing hepato-toxicity following the initiationof antiretroviral therapy in subjectswithunderlyingchronichepatitis than inHIV-monoinfected individuals. As highly active antiretroviral therapy (HAART) has dramatically improvedthe prognosis of thosewith HIV disease, the consequences of associated illnesses such as hepatitis B andC, which are currently among the leading causes of hospital admission and death in the HIV-infectedpopulation, have become more relevant. Therefore, the adequate management of viral hepatitis shouldnow be considered a priority in HIV-coinfected patients. Several guidelines have recently been released inresponse to thisdemand. In this article,wediscuss themostcritical issueshighlighted in thesedocuments.

Keywords: HIV, HBV, HCV, interferon, antiretroviral therapy, lamivudine, tenofovir, liver

Introduction

HIV, hepatitis B virus (HBV) and hepatitis C virus (HCV) sharesimilar routes of transmission, with sexual, parenteral and peri-natal transmission being the most frequent modes of acquiringthese infections. In contrast, exposure to these viruses is followedby an immune response which differs markedly in its ability toclear the infection. Clearance is maximal for adults exposed toHBV, much lower for HCV and negligible (or non-existent) forHIV. Taking into consideration these two facts, it comes as nosurprise that there is a high worldwide prevalence of coinfectionwith these agents. Figure 1 shows the estimated burden of thepopulation currently living with each of these viruses and thenumber of coinfected persons.

Hepatitis C

One-third of HIV-infected individuals worldwide suffer fromchronic hepatitis C, but HCV affects more than 75% of HIV-positive subjects infected parenterally, such as haemophiliacs andintravenous drug users.1 End-stage liver disease complicationshave emerged as one of the leading causes of hospital admissionand death in HIV-infected patients in developed countries, wherethe use of highly active antiretroviral therapy (HAART) has

halted the progression of HIV-associated immunodeficiency.As a result, classical opportunistic infections are now only rarelyseen in HIV-infected individuals in regular clinical care, whereasliver complications due to viral hepatitis coinfections havebecome more evident.2–4 In the past few years, severalguidelines5,6 and reviews7–10 have highlighted this problemand have provided recommendations about how best to managepatients coinfected with HIV and HCV.

Screening for HCV antibodies is key to an effective strategyagainst hepatitis C, and should be mandatory for all HIV-infectedindividuals. HCV-seropositive subjects should be tested forserum HCV RNA. Around 15% will have cleared HCV spontan-eously. For the rest, quantitative serum HCV RNA measurementusing sensitive tests (lower limit of detection in 10–50 IU/mL)and HCV genotyping should be performed before consideringany therapeutic intervention against HCV.

The treatment of choice for hepatitis C is a combination ofpegylated interferon and ribavirin. Unfortunately, HCV therapyis associated with poorer response and a higher incidence ofside effects in HIV/HCV-coinfected patients than in HCV-monoinfected individuals.11,12 However, recent studies suggestthat when adequate HCV therapy is administered (using higherdoses of ribavirin than in earlier trials, with satisfactory drugcompliance and for at least 12 months irrespective of the

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*Corresponding author. Tel: +34-91-4532500; Fax: +34-91-7336614; E-mail: vsoriano@dragonet.es.............................................................................................................................................................................................................................................................................................................................................................................................................................

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HCV genotype), and to the most appropriate candidates (exclud-ing active intravenous drug users, alcoholics and subjects withvery low CD4 counts), treatment response rates may improvesignificantly in HIV/HCV-coinfected patients and can approachwhat is achieved in HCV-monoinfected individuals.13–18 The bestcoinfected responders are individuals with the following profile:infection with HCV genotypes 2 or 3, low HCV viral load, nocirrhosis, age less than 40 years, elevated ALT concentrations,preserved CD4 counts and low or undetectable plasma HIV RNA.Using the data already available from HCV monoinfection, it istime to design trials in coinfected patients in which therapy istailored on the basis of individual characteristics. As an example,using variables such as baseline HCV RNA, genotype and week 4virological clearance, patients could be allowed to completedifferent lengths of therapy (see Figure 2) in an attempt tobalance efficacy and tolerance of the medication.

Treatment should be considered early in antiretroviral-naivecoinfected patients with stable HIV infection. In patients alreadyon antiretroviral therapy, HCV therapy should not be admin-istered before ensuring that didanosine is not taken, given theincreased risk of mitochondrial toxicities (i.e. pancreatitis and

lactic acidosis). If possible, zidovudine should be avoided aswell, given the higher risk of anaemia. Treatment adherence iskey to maximizing the chances of success, and side effects of theHCV medication should be managed expertly before discontinu-ing HCV therapy.

The histological information obtained using either non-inva-sive procedures (FibroScan, Fibro-test, etc.)19–21 or liver biopsy isuseful but these tests should not be considered mandatory beforeprescribing HCV therapy.22 Progression of liver fibrosis tocirrhosis and hepatocellular carcinoma occurs more rapidly23,24

and liver toxicity following initiation of HAART is more fre-quent25,26 in HCV/HIV-coinfected patients. Thus, virologicalrather than histological findings justify the provision of therapyin this population.22 In patients with evidence of more advancedliver fibrosis, HCV therapy should be considered a real priority.However, patients with decompensated cirrhosis should not betreated with interferon, given the serious risk of liver failure. Onthe other hand, in patients with CD4 counts <200 cells/mm3 and/or plasma HIV RNA >100 000 copies/mL, it is advisable tosuppress HIV replication and increase the CD4 counts beforebeginning HCV therapy, as the APRICOT trial showed thatside effects of the HCV medication occurred more often inpatients with lower CD4 counts.11

Individuals with a history of neuropsychiatric disorders shouldbe seen by an experienced psychiatrist before being considered ascandidates for HCV therapy. The psychiatrist may advise aboutthe possibility of interferon-based therapy and/or the usefulnessof any co-medication. In patients with mild depression, prophy-lactic treatment with anti-depressant drugs has proven benefit.10

Subjects who consume a great deal of alcohol and/or are addictedto illegal drugs generally should not be considered suitable forHCV treatment, and medical efforts should concentrate ondetoxification.

In summary, liver disease associated with HCV is a growingproblem in HIV-positive individuals. The relatively low efficacyof the current medication and its low tolerability should promptthe discovery of new drugs with a direct antiviral activity againstHCV. In contrast to antiretroviral drugs, which need to be usedindefinitely against HIV, the biology of HCV (which fortunatelyis not integrated into cellular DNA) provides the chance forlimited treatment duration. This opportunity should be muchappreciated by both coinfected patients and their doctors.Thus, the provision of HCV treatment should be encouragedwithout unnecessary delay in the absence of clear contraindica-tion in the coinfected population. A further recent stimulus for thetherapeutic intervention is the demonstration of a lack of clinicalprogression of liver disease in HIV-infected individuals whocleared HCV with therapy: their hepatitis C is cured!27

Hepatitis B

Approximately 10% of the HIV-infected population worldwidesuffers from chronic hepatitis B (Figure 1). This figure mayapproach 20% in Southeast Asia, whereas it is�5% inNorth Amer-ica and Western Europe. Unlike with HCV, infection with HBV isnot eradicable and the main goal of therapy is to suppress HBVreplication as much as possible and for as long as possible. Thistranslates into histological and clinical benefit. Guidelines for theadequate management of chronic hepatitis B in HIV-coinfectedindividuals have recently been released,6,28,29 and several reviews30

Pos

Neg

High

Pos

NegLow

1,4

Pos

NegHigh

Pos

NegLow2,3

NegativeHCV-RNAweek 4

BaselineHCV-RNA

HCV genotype

10–15%

55–65%

25–30%

Length HCV therapy

6 mo

12 mo

18 mo

Figure 2. Preferred treatment duration of HCV therapy taking into account

different patient characteristics. Percentages represent estimates of the number

of HIV/HCV-coinfected patients in each category in the PRESCO trial.16

HCV

HBV

HIV

4

40

350

12

175

1

0.5

Figure 1. Estimated number (in millions) of subjects infected with HIV, HBV

and HCV worldwide.

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have updated the knowledge on this topic, providing usefulinformation about how to manage HBV/HIV-coinfected patients.

Four drugs have been approved so far for the treatment ofchronic hepatitis B: interferon alpha (standard or pegylated),lamivudine, adefovir and, more recently, entecavir. However,other drugs with anti-HBV activity such as tenofovir and emtricit-abine are already approved for the treatment of HIV infection andtherefore are frequently used in coinfected patients as anti-HBVagents. In ACTG A5127, the efficacy and safety of tenofovir andadefovir were prospectively compared in 52 HBV/HIV-coinfectedindividuals, 75% of whom had already failed on lamivudine.31 At48 weeks, the mean reduction in serum HBV DNA was 3.2 logs inthe adefovir arm and 4.4 logs in the tenofovir arm. The study waspowered only to show the non-inferiority of tenofovir with respectto adefovir, but the results support the general belief that tenofovir300 mg/day is much more potent than adefovir 10 mg/day againstHBV. The widespread use of tenofovir in HBV/HIV-coinfectedpatients has demonstrated that HBV can become resistant totenofovir, although this seems to occur very slowly.32

The prescription of treatment for chronic hepatitis B and thedrug of choice are still controversial and may vary in differentsituations. Four main variables should guide the selection ofpatients to be treated for HBV and of the drug(s) of choice:transaminase levels, serum HBV DNA viral loads, presence ofserum HBV e antigen (HBeAg) and liver fibrosis staging. Giventhat chronic hepatitis B patients with elevated transaminase levelstend to have liver damage, they should generally be consideredprimary candidates for treatment (Figure 3), especially in thecontext of HIV coinfection, since HBV-related liver damagetends to progress faster in HIV-coinfected patients than inHBV-monoinfected patients.33,34 While HBeAg-positive chronichepatitis B patients tend to show better responses to interferontherapy provided for 6–12 months, HBeAg-negative individualsshould preferentially be treated with nucleoside/nucleotideanalogues (Figure 4). In HBV/HIV-coinfected patients, aproblem arises when no antiretroviral therapy is required butHBV therapy is considered to be necessary. Although someauthors have favoured the prescription of adefovir monotherapyin this situation, concern about the selection of the K65R resist-ance mutation in HIV has precluded this treatment in some cases.Recent data, however, suggest that this risk is negligible.35 In thisspecific situation, drugs such as entecavir or in the futuretelbivudine or clevudine, which are potent anti-HBV agents lack-ing any HIV activity, will likely be the first choice. The 24 weekresults of the ETV-038 trial were presented at the 2005 Confer-ence on Retroviruses and Opportunistic Infections.36 Thistrial assessed prospectively the efficacy and safety of entecavir1.0 mg/day against a placebo in 68 HBV/HIV-coinfected indi-viduals, all of whom had failed prior lamivudine therapy. Thevirological response was significantly better in the entecavir arm.Even though entecavir acts in patients with lamivudine-resistantHBV, some cross-resistance between these two drugs exists, andtherefore the greatest efficacy of entecavir will be obtained inpatients without prior exposure to lamivudine.

In summary, substantial progress has been made in the treat-ment of hepatitis B in HIV-positive individuals in recent years.This subset of patients, who typically show more rapid and severeliver damage, now have more treatment options that can be moreeasily administered and have fewer adverse effects. The achieve-ment and maintenance of HBV suppression (despite the lackof eradication) by judicious use of current HBV therapies will

permit prevention of liver complications in most HBV/HIV-coinfected patients.

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NoFibrosis Yes

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