therapies for hiv and viral hepatitis coinfection

9
Review 10.1586/14787210.3.1.81 © 2005 Future Drugs Ltd ISSN 1478-7210 81 www.future-drugs.com Therapies for HIV and viral hepatitis coinfection Curtis L Cooper The Ottawa Hospital – General Campus, Room G12, 501 Smyth Road, Ottawa, Ontario, K1H 8L6, Canada Tel.: +1 613 737 8924 Fax: +1 613 737 8164 [email protected] KEYWORDS: alcohol, hepatitis B virus, hepatitis C virus, highly active antiretroviral therapy, HIV, pegylated interferon, substance abuse The natural history of chronic viral hepatitis is altered by HIV coinfection. Liver fibrosis rates and clinical features of liver disease develop more rapidly. Although HIV–hepatitis C virus coinfected subjects may progress more rapidly to AIDS, this is probably explained by comorbid illness, substance abuse and socioeconomic circumstances. Safe and virologically active treatment of HIV–hepatitis B virus coinfection can be concurrently achieved by the use of highly active antiretroviral therapy regimens containing lamivudine and/or tenofovir. In most cases, highly active antiretroviral therapy represents the most beneficial initial pharmaceutical intervention for HIV–hepatitis C virus coinfection. Hepatitis C virus antiviral therapy should, in most cases, be reserved for those achieving HIV RNA suppression and immune restoration from highly active antiretroviral therapy or with nadir CD4 T-lymphocytes above 350 cells/μl. Expert Rev. Anti Infect. Ther. 3(1), 81–89 (2005) The worldwide prevalence of HIV, hepatitis B (HBV) and C virus (HCV) infection is high, and the distribution of cases overlaps (TABLE 1) [1–4]. It is not surprising that these chronic virus infections are often found concurrently in the same host. Approximately a quarter of HIV- infected individuals are HCV seropositive [5]. Among intravenous drug users with HIV, this rate is at least 50% and up to 90% in some regions [6]. The prevalence of HBV coinfection is approximately 5% but variable depending on location. Given this high prevalence, chronic viral hepatitis is expected to impact the morbid- ity, mortality and treatment decisions made in HIV-seropositive individuals for the foreseeable future. This article serves to review the natural history of HIV–HCV and HIV–HBV coinfec- tion and discuss relevant treatment issues. Issues specific to the management of patients with sub- stance abuse issues are considered. Priority issues requiring additional research are discussed. Characteristics of chronic viral hepatitis in HIV infection Spontaneous HCV clearance occurs at a fre- quency of 15 to 40% in immunocompetent hosts. In contrast, clearance occurs in less than 10% of HIV-infected subjects following acute HCV infection [7]. Similarly, chronic HBV fol- lowing acute infection occurs more frequently in HIV-seropositive individuals [8]. Higher HBV DNA levels and positive serologic mark- ers of HBV replication (Hepatitis B e antigen [HBeAg]) reveal that HBV is more active in HIV–HBV coinfection [9]. The characteristics of chronic HCV infection are also modified by coinfection with HIV. It is well documented that HCV RNA levels are higher in HIV–HCV coinfection [10,11]. Some [12,13], but not all [10,11] reports demonstrate a small, inverse correlation between HCV RNA viral load and absolute CD4 + T-lymphocyte count. The clinical rele- vance of increased HCV RNA is unclear, as plasma and intrahepatic HCV RNA levels corre- late weakly with the amount of hepatic fibrosis found on liver biopsy [11,14]. This information is consistent with the concept that long-term liver injury is immune mediated and does not result from direct viral cytotoxicity. It remains unclear why the rate of hepatic fibrosis is accelerated in those with HIV, an immune compromising dis- ease, if fibrosis is wholly immune mediated. Clearly, further study of the pathogenesis of HCV in HIV infection is required. CONTENTS Characteristics of chronic viral hepatitis in HIV infection Effect of chronic viral hepatitis on HIV progression Antiretroviral therapy in HIV–chronic viral hepatitis coinfection Antiviral therapy in HIV–chronic viral hepatitis coinfection Which virus should be treated first? Influence of alcohol & other substances of abuse on therapeutic outcome Research priorities Expert opinion Five-year view Key issues References Affiliation For reprint orders, please contact [email protected]

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Page 1: Therapies for HIV and viral hepatitis coinfection

Review

10.1586/14787210.3.1.81 © 2005 Future Drugs Ltd ISSN 1478-7210 81www.future-drugs.com

Therapies for HIV and viral hepatitis coinfectionCurtis L Cooper

The Ottawa Hospital – General Campus, Room G12, 501 Smyth Road, Ottawa, Ontario,K1H 8L6, CanadaTel.: +1 613 737 8924Fax: +1 613 737 [email protected]

KEYWORDS: alcohol, hepatitis B virus, hepatitis C virus, highly active antiretroviral therapy,HIV, pegylated interferon,substance abuse

The natural history of chronic viral hepatitis is altered by HIV coinfection. Liver fibrosis rates and clinical features of liver disease develop more rapidly. Although HIV–hepatitis C virus coinfected subjects may progress more rapidly to AIDS, this is probably explained by comorbid illness, substance abuse and socioeconomic circumstances. Safe and virologically active treatment of HIV–hepatitis B virus coinfection can be concurrently achieved by the use of highly active antiretroviral therapy regimens containing lamivudine and/or tenofovir. In most cases, highly active antiretroviral therapy represents the most beneficial initial pharmaceutical intervention for HIV–hepatitis C virus coinfection. Hepatitis C virus antiviral therapy should, in most cases, be reserved for those achieving HIV RNA suppression and immune restoration from highly active antiretroviral therapy or with nadir CD4 T-lymphocytes above 350 cells/µl.

Expert Rev. Anti Infect. Ther. 3(1), 81–89 (2005)

The worldwide prevalence of HIV, hepatitis B(HBV) and C virus (HCV) infection is high,and the distribution of cases overlaps (TABLE 1)

[1–4]. It is not surprising that these chronic virusinfections are often found concurrently in thesame host. Approximately a quarter of HIV-infected individuals are HCV seropositive [5].Among intravenous drug users with HIV, thisrate is at least 50% and up to 90% in someregions [6]. The prevalence of HBV coinfection isapproximately 5% but variable depending onlocation. Given this high prevalence, chronicviral hepatitis is expected to impact the morbid-ity, mortality and treatment decisions made inHIV-seropositive individuals for the foreseeablefuture. This article serves to review the naturalhistory of HIV–HCV and HIV–HBV coinfec-tion and discuss relevant treatment issues. Issuesspecific to the management of patients with sub-stance abuse issues are considered. Priority issuesrequiring additional research are discussed.

Characteristics of chronic viral hepatitis inHIV infectionSpontaneous HCV clearance occurs at a fre-quency of 15 to 40% in immunocompetenthosts. In contrast, clearance occurs in less than

10% of HIV-infected subjects following acuteHCV infection [7]. Similarly, chronic HBV fol-lowing acute infection occurs more frequentlyin HIV-seropositive individuals [8]. HigherHBV DNA levels and positive serologic mark-ers of HBV replication (Hepatitis B e antigen[HBeAg]) reveal that HBV is more active inHIV–HBV coinfection [9]. The characteristics ofchronic HCV infection are also modified bycoinfection with HIV. It is well documented thatHCV RNA levels are higher in HIV–HCVcoinfection [10,11]. Some [12,13], but not all [10,11]

reports demonstrate a small, inverse correlationbetween HCV RNA viral load and absoluteCD4+ T-lymphocyte count. The clinical rele-vance of increased HCV RNA is unclear, asplasma and intrahepatic HCV RNA levels corre-late weakly with the amount of hepatic fibrosisfound on liver biopsy [11,14]. This information isconsistent with the concept that long-term liverinjury is immune mediated and does not resultfrom direct viral cytotoxicity. It remains unclearwhy the rate of hepatic fibrosis is accelerated inthose with HIV, an immune compromising dis-ease, if fibrosis is wholly immune mediated.Clearly, further study of the pathogenesis ofHCV in HIV infection is required.

CONTENTS

Characteristics of chronic viral hepatitis in HIV infection

Effect of chronic viral hepatitis on HIV progression

Antiretroviral therapy in HIV–chronic viralhepatitis coinfection

Antiviral therapy in HIV–chronic viralhepatitis coinfection

Which virus should be treated first?

Influence of alcohol & other substances of abuse on therapeutic outcome

Research priorities

Expert opinion

Five-year view

Key issues

References

Affiliation

For reprint orders, please contact [email protected]

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82 Expert Rev. Anti Infect. Ther. 3(1), (2005)

HCV-induced liver fibrosis is more frequently observed and ofa more advanced stage in HIV–HCV [7,15–21] and HIV–HBV [22]

coinfection. In a study by Benhamou and colleagues, fibrosisprogression rates where calculated by dividing the Metavir fibro-sis stage by the estimated duration of HCV infection [16]. Theestimated median duration of HCV infection prior to cirrhosiswas 26 years (range: 22 to 34) in HIV–HCV coinfected patientsand 38 years (range: 32 to 47) in HIV-seronegative individuals.Immunodeficiency (CD4 < 200 cells/µl) and alcohol consump-tion greater that 50 g per week were independently associatedwith rapid progression to cirrhosis. Overall, these results indicatea deleterious influence of HIV on the natural progression ofHCV infection. There is a paucity of studies evaluating the effectof HIV on the rate of hepatic fibrosis in chronic HBV infection,but it is generally believed to accelerate this process [8,22,23].

Progression to clinically evident liver disease is accelerated inHIV–HCV coinfected individuals [24,25]. In one of these stud-ies, 81 HIV–HCV coinfected hemophiliacs infected between1978 and 1985 were assessed for persistent bilirubin elevation(>21 µmol/l), ultrasound demonstrated ascites, hepaticencephalopathy, histologic evidence of cirrhosis or hepato-cellular carcinoma and esophageal or gastric varies [10]. Alterna-tive etiologies for liver disease, including opportunistic infec-tions, malignancies and alcohol, were ruled out prior toattributing these end points to chronic HCV infection. Theestimated time between HCV infection and any of these endpoints was a mean 17.2 years. A total of 27% (22 out of 28)met at least one of these criteria compared with 5.7% (three outof 53) in a matched HCV mono-infected cohort. The oddsratio for progression to at least one of these clinical measures ofliver disease was 7.4 (95% confidence interval: 2.2 to 22.5).

Effect of chronic viral hepatitis on HIV progressionThe influence of HCV on the natural course of HIV infection isless pronounced [26–29]. In a cohort of over 3000 subjects, HCVseropositivity and active-injection drug use were identified as pre-dictors of progression to an AIDS-defining event or death. Incontrast, no difference in progression to AIDS or death, evenwhen adjusted for exposure to highly active antiretroviral therapy(HAART) and HIV suppression, was identified in another large,well-described cohort [29]. Confounders and selection bias con-tribute to these discrepancies. Confounders include alcohol, sub-stance abuse, nutritional status, socioeconomic status, antiretro-viral adherence, extent of prior antiretroviral exposure and degreeof virologic suppression. These factors are often poorly describedand not controlled for in these analyses.

CD4 T-cell count recovery following initiation of HAARTin HIV–HCV coinfection may be blunted in comparison withHCV seronegative individuals [26,30]. CD4 T-lymphocytecount increase from baseline at 6, 12 and 18 months wassmaller in HIV–HCV coinfected subjects when comparedwith HIV mono-infected individuals [26]. These populationswere well matched for the duration of HIV infection, age, sexand baseline CD4 T-lymphocyte count. Other key potentialconfounders were not considered.

It is plausible that HCV may influence HIV disease andblunt immune restoration following the initiation of HAART.Immune activation induced by HCV may accelerate CD4T-lymphocyte depletion in subjects not receiving HAART [31].In addition, the immune-deactivating effects of HAART couldbe negated by persistent HCV replication with subsequentblunting of immune recovery and continued depletion ofimmune reserve. Although HCV infection does not produce aclinically recognized state of immune deficiency, chronic infec-tion may induce subtle deficits in immune function. It is note-worthy that antibody concentrations following vaccination forhepatitis A and B are lower in HCV-infected patients than inHCV-seronegative individuals [32,33]. This impairment ofimmune function may at least partially explain the reducedCD4 T-lymphocyte recovery observed in HAART-treatedHIV–HCV coinfected subjects. Direct HCV pathogenicity onlymphocytes may contribute to lower proliferation of CD4T-lymphocytes. HCV envelope protein (E2) binds to theCD81 cellular receptor [34], and HCV has been detected in anumber of cells including monocytes, macrophages, B-cells, aswell as CD4 and CD8 T-lymphocytes [35–37].

Overall, the influence of HCV infection on the naturalhistory of HIV is far less striking than that of HIV on HCV.Although there may be subtle effects on the progression toAIDS and death, as well as on immune restoration followingthe initiation of HAART, these effects cannot be accuratelyquantified without accounting for potential key confounders.

Antiretroviral therapy in HIV–chronic viral hepatitis coinfectionThe characteristics of HCV infection are altered by antiretro-viral therapy. An initial increase in HCV RNA levels occursfollowing the initiation of therapy [38]. This is often associatedwith an increase in liver enzyme levels [38,39]. In those achiev-ing maximal virologic suppression and remaining on therapyfor at least 12 months, plasma [38] and intrahepatic [40,41]

HCV RNA levels often fall below those of baseline. This isdependent on the pretreatment CD4 T-lymphocyte count [42]

and alcohol consumption [38]. With long-term adherence tovirologically potent HAART, liver enzyme levels generallyremain similar to baseline levels [38]. In fact, levels may fall

Table 1. HIV and hepatitis C and B viruses.

HIV Hepatitis B Hepatitis C

Virus type Retrovirus Hepadnavirus Flavivirus

Genetic material RNA DNA RNA

Prevalence (million)

Worldwide 40 400 170

Western Europe 0.58 17 8.9

USA 1 1.25 4

Annual deaths (USA) 15000 6000 8000–10000

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below baseline in subjects with high pretreatment levels [43,44].Liver fibrosis and inflammation activity scores are lower andcalculated fibrosis rates slower in HIV–HCV coinfected sub-jects receiving protease inhibitor-based HAART regimens thanin those receiving nucleoside analogs or no therapy [17,45].These positive changes in virologic, enzymatic and histologicmeasures may result from the restoration of HCV-specific cell-mediated immune function achieved with potent and durableHAART. Despite rare cases of flares in HCV disease followingthe initiation of HAART due to immune reconstitution syn-drome and/or drug toxicity [46], the weight of evidence indi-cates that antiretroviral therapy has a marked beneficial effecton HCV laboratory measures and disease progression inHIV–HCV coinfected individuals [47,48].

There is ongoing debate as to whether certain antiretroviralclasses and specific drugs within these classes should be prefer-entially used in HIV–viral hepatitis coinfection to optimizetherapy and to avoid hepatotoxicity. In the case of HIV–HBVcoinfection, HAART regimens containing the nucleosidereverse transcriptase inhibitors (NRTIs) lamivudine and/or ten-ofovir are ideal, given that these drugs infrequently cause hepa-totoxicity and possess virologic activity against both HIV andHBV [49]. Hepatic steatosis and fulminant hepatitis are rarecomplications of HIV NRTI treatment [50–53]. It is unclearwhether subclinical forms of NRTI-induced hepatic steatosisinfluence the amount of inflammation and rate of fibrosis accu-mulation found within the parenchyma of the liver in thosewith chronic viral hepatitis. Lactic acidosis and pancreatitis arealso occasionally observed and are slightly more common withregimens containing stavudine and didanosine, respectively[54,55]. Women and the obese may also be at a greater risk ofNRTI mitochondrial toxicity. These toxicities are mediated byNRTI inhibition of mitochondrial DNA polymerase [56].Unfortunately, it is difficult to predict who will develop severemanifestations of this toxicity. The frequency and severity ofthese adverse events may be increased with the coadministra-tion of ribavirin, which is used in combination with interferonfor HCV drug therapy [51,52]. Didanosine should be substitutedfor another antiretroviral prior to initiating ribavirin. Carefulmonitoring of liver enzymes (and serum lactate in those withclinical symptoms suggestive of mitochondrial toxicity[i.e., anorexia, fatigue, nausea and shortness of breath]) is war-ranted for all HIV–HCV coinfected individuals managed withNRTI-containing HAART and ribavirin.

Protease inhibitors are often cited as being particularlyhepatotoxic in those with chronic viral hepatitis [44,57,58]. Thisis usually manifested as acute, asymptomatic liver enzyme ele-vation occurring soon after the initiation of protease inhibi-tor-containing antiretroviral therapy. It is generally self-lim-ited and is probably immune mediated in nature. Thisphenomenon is generally not a result of direct drug-relatedhepatocyte injury, although it must be acknowledged thatliver enzyme elevation following the initiation of HAART isnot well understood. Full-dose ritonavir (600 mg twice daily)has been implicated as being particularly hepatotoxic [58].

This dosing is no longer prescribed. The incidence of liverenzyme elevation greater than threefold the upper limit ofnormal with low-dose ritonavir-boosted HAART regimens(100–200 mg twice daily), which is the current standard ofcare for HIV infection, is between 5 and 10% [59–61], and sim-ilar to that of other protease inhibitor-based HAART regi-mens [39]. The risk is greater with chronic viral hepatitis coin-fection and in those with advanced stages of liver fibrosis.Although careful observation is advised, most HIV–viral hep-atitis coinfection patients initiating protease inhibitor-containing regimens do not experience treatment-limitingtransaminitis or overt liver toxicity [39,62], achieve desirablevirologic suppression and realize immunologic restoration [45].

The relative incidence of transaminitis between the non-NRTIs (NNRTIs) is controversial. Prospective evaluation ofefavirenz and nevirapine-containing HAART in treatment-naive subjects demonstrated a 2 to 4% incidence of trans-aminitis [63]. Other nonrandomized assessments suggest thatthe incidence of transaminitis may be higher in HBV and/orHCV seropositive individuals treated with nevirapine-contain-ing regimens and that new episodes of transaminitis occurbeyond the initial 3 months of therapy [58,64]. An early nevira-pine hypersensitivity syndrome consisting of fever, rash andtransaminitis is well described but infrequently observed [58,65].The risk of this is greatest in females and in those with higherCD4 T-cell counts. It is important to note that the occurrenceof clinically symptomatic hepatotoxicity is rare with the use ofnevirapine [64] and efavirenz [63]. Given the low frequency ofclinically relevant hepatotoxicity with both protease inhibitorsand NNRTIs, the selection of protease inhibitor versus NNRTIin HIV–viral hepatitis should be primarily based on virologicpotency and anticipated extrahepatic toxicities.

Hepatotoxicity has not been recognized as a frequent sideeffect with the HIV fusion inhibitor enfuvirtide [66,67]. Addi-tional research will determine if this class of antiretrovirals willbecome a liver-friendly and virologically potent treatmentoption in HIV–viral hepatitis coinfected individuals.

Antiviral therapy in HIV–chronic viral hepatitis coinfectionThe current overall success rate in achieving a sustained virologicresponse (SVR) with interferon–ribavirin-based regimens inHIV–HCV coinfected patients is no more than 30 to 40%[45,68–73]. With pegylated forms of interferon plus ribavirin, thereported virologic response rates were 29% in genotype-1-infected subjects receiving optimal clinical care in hospital-based research clinics [71,73]. Other key studies report a lowerSVR (15%) in genotype 1 recipients of pegylated interferon andribavirin. Possible explanations for the discrepancies between tri-als are listed in TABLE 2. SVR for genotype 2- and 3-infected sub-jects range between 40 and 60% following 48 weeks of therapy.This is well below the rates reported for HCV mono-infectedindividuals receiving 24 weeks of treatment [74,75]. These reducedSVR results occur even in those on virologically potent HAARTwith relatively high CD4 T-lymphocyte counts [45]. One caveatto this statement is that CD4 T-lymphocyte count at the time of

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therapy, as opposed to nadir count, is reported in these studies.Nadir CD4 T-lymphocyte count may be an important predictorof achieving a SVR and should be reported in future studies.

The constitutional and cognitive toxicities related to interferonand ribavirin therapy are not inconsequential [76] but in gen-eral are not substantially more plentiful or severe inHIV–HCV coinfection. Owing to the high prevalence ofcomorbid illnesses in the HIV infected population, interferonand/or ribavirin use is often contraindicated. These comor-bidities include psychiatric illness, cytopenias and uncon-trolled substance abuse. Although the risk of the additive tox-icities of HAART and HCV antiviral therapy is often cited asa concern regarding the concurrent use of these therapies,severe adverse interactions are rare and can usually be avoidedby careful laboratory monitoring and avoidance of certaincombinations of medications. The risk of pancreatitis withthe combination of didanosine and ribavirin preclude com-bined use [51,52]. As both zidovudine and ribavirin can causeanemia, careful attention to this measure is warranted if coad-ministered. Erythropoetin may be a valuable supportive adju-vant to current HCV drug therapies [76]. Ribavirin may alterthe drug levels of several NRTIs [77]. These in vitro findingsare not clinically significant, as increased treatment sideeffects or loss of HIV virologic suppression have not beenreported in NRTI-treated subjects initiating ribavirin. HCVdrug therapy may actually increase the potency of antiretroviral

therapy as interferon possesses HIV antiviral activity [78].Although CD4 T-lymphocyte count declines in approxi-mately half of HIV seropositive individuals treated with inter-feron and ribavirin, this is not associated with increasedoccurrence of opportunistic infection. CD4 T-lymphocytecount rapidly returns to pretreatment levels once HCV therapyhas been completed.

There are few circumstances in which interferon would bepreferable to lamivudine and/or tenofovir for HBV treatment.The rates of transaminase normalization, reduction of HBV DNAto undetectable levels, loss of HBeAg, and the development ofanti-HBeAg are similar for interferon, lamivudine and tenofovir[79–83]. An advantage of tenofovir over lamivudine is the slowerevolution of drug resistance and the efficacy of tenofovir inHBV-infected individuals with lamivudine-resistant HBV [83,84].

Interferon may slow or reverse hepatic fibrosis resultingfrom both HBV and HCV infection. Although several studiesare currently evaluating the benefits of long-term, low-doseinterferon for those not achieving sustained virologicresponse, this intervention is still considered experimental forHCV treatment [85–87].

Which virus should be treated first?In the case of HIV–HBV coinfection, both viruses can be treatedsimultaneously. Obviously, monotherapy with lamivudine ortenofovir directed against HBV is not recommended inHIV–HBV coinfection. The best strategy for HIV–HCVcoinfection is more contentious. All would agree that treatmentshould be individualized. For those with CD4 T-lymphocytecounts below 350 cells/µl, HAART usually represents the mostbeneficial initial pharmaceutical treatment intervention. Thelower the CD4 T-lymphocyte count, the more imperative it is totreat HIV infection first. HAART often controls HIV disease, isgenerally associated with lower toxicity than HCV interferon-based regimens, is likely to slow HCV disease progression, infre-quently causes clinically relevant hepatotoxicity, and creates animmunologic milieu that may optimize the effects of HCV drugtherapy. Antiviral therapy for HCV infrequently achieves a SVRin HIV–HCV coinfected subjects and is associated with multipletoxicities. This should not be taken as a statement against inter-feron-based treatment in HIV–HCV coinfected patients. Afterall, a quarter SVR is not inconsequential. However, when consid-ering treatment options, it is important to identify where the bestreturn lies. This is usually with HAART. In cases in which theCD4 T-lymphocyte count has never fallen below 350 cells/µl,the strategy of first treating HCV and then HIV in order to avoidthe combined toxicities of coadministration of these medicationsis reasonable. There are few published data describing the SVRrates associated with this therapeutic strategy.

Influence of alcohol & other substances of abuse on therapeutic outcomeAlcohol accelerates the rate of hepatic fibrosis both in HCVmono-infected subjects as well as in HIV–HBV and –HCVcoinfected individuals [16,17]. The estimated median time to

Table 2. Key differences in the major HIV–hepatits C virus coinfection studies.

RIBAVIC APRICOT ACTGA5071

SVR results

Genotype 1 15% 29% 14%

Nongenotype 1 43% 62% 73%

Differences between studiesPegylated interferon α2b α2a α2a

Genotype 1 proportion 59% 61% 77%

Stage 3/4 fibrosis 22/18% NR/15% NR/10%

Discontinuation rates 38% 15% 12%

Dose reduction frequency and amount

NR NR NR

Use of growth factors No Yes Yes

Trial sites Community Academic Community

Alcohol use NR NR NR

Active substance use NR NR NR

White race 80% 50%

ACTG: AIDS Clinical Trial Group; APRICOT: AIDS Pegasys Ribavirin International COinfection Trial; NR: Not reported; RIBAVIC: RIBARVarin In Combination study; SVR: Sustained virologic response.

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cirrhosis in HIV-seropositive individuals consuming greaterthan 50 g of alcohol per day with CD4 T-lymphocyte countsbelow 200 cells/µl was 16 years [16,17]. In contrast, the esti-mated median time to cirrhosis in a similar subject consum-ing less than 50 g of alcohol per day is approximately 5 yearslonger. Alcohol consumption impairs the efficacy of inter-feron-based HCV therapy [88,89]. HCV RNA rise, andremains elevated, following the initiation of antiretroviraltherapy in individuals consuming more than 50 g of alcoholper day, despite achieving virologic suppression of HIV [38].In contrast, an initial increase in HCV RNA, followed by asubsequent decline to below baseline levels by 12 months isoften observed in individuals achieving sustained virologicsuppression and not consuming excess alcohol. This may beclinically relevant, as it is consistent with other work suggest-ing that alcohol blunts the restoration of HCV-specificimmunity following the initiation of HAART [90]. Addition-ally, as baseline HCV RNA level predicts the likelihood ofSVR with HCV interferon-based therapies, the influence ofalcohol on HCV RNA in HAART-treated HIV–HCV coin-fected subjects may be relevant. In the author’s clinic, alcoholconsumption has been identified as an important factor pre-dicting the likelihood of remaining on HAART once initi-ated in HIV–HCV coinfected patients (FIGURE 1). In contrastwith other drug-based interventions for HCV, alcohol cessa-tion is associated with little or no toxicity. Although ongoingcontrolled alcohol (or other substance abuse) should notpreclude HIV and HCV drug therapy [91], cessation of drugsof abuse and alcohol use should be emphasized as a highlybeneficial therapeutic intervention.

Research prioritiesThe complex interactions between HIV, viral hepatitis, HIVantiretrovirals, HCV and HBV antivirals and alcohol remainunclear. At the basic-science level, further study of the effect ofalcohol on immune restoration following the initiation ofHAART is warranted. Investigation of why HIV–HCV coin-fected patients infrequently achieve sustained virologic clear-ance with interferon-based HCV treatment may be useful forimproving treatment responses or, at the very least, identifyingthose more likely to achieve positive results with therapy. Pro-spective, well-designed clinical studies into the safety and effec-tiveness of HAART in the HIV–chronic viral hepatitis coin-fected population are required to alleviate concerns pertainingto antiretroviral hepatotoxicity; factors predicting increasedlikelihood of this adverse event need to be identified. Long-term liver injury resulting from uninterrupted NRTI use withconcurrent mitochondrial DNA polymerase inhibition is aconcern. Nucleoside-sparing HAART regimens should be eval-uated in coinfected populations. Studies of CD4 T-lymphocyterecovery following HAART therapy that control for confound-ers such as substance abuse, nutritional status and socio-economic environment will elucidate whether blunted immunerecovery following HAART in HIV–HCV coinfected popula-tions is a direct result of HCV. Investigation and validation of

treatment strategies that will improve HAART and viral hepatitisdrug therapy adherence are required to ensure that individualswho abuse substances derive the maximum benefits possiblewith current HIV and viral hepatitis therapies. Given the wide-spread use of medicinal marijuana in this population, quantifi-cation of the benefits and negative consequences of regular,long-term use is mandatory. Rigorous evaluation of the safety,purported benefits and effect on quality of life are required forthe many alternative and herbal remedies available to thoseliving with HIV and chronic viral hepatitis.

Expert opinionAs a first intervention, alcohol cessation must be emphasized.Liver injury will be reduced, HCV RNA levels will fall, andimproved response to HAART and HCV drug therapy will berealized. This intervention requires sustained commitment toalcohol cessation programs and patience. HAART usually rep-resents the next most beneficial intervention. HAART oftencontrols HIV disease, is generally associated with less toxicitythan HCV interferon-based regimens, may indirectly slowHCV progression, infrequently causes clinically relevanthepatotoxicity, and creates an immunologic milieu that mayoptimize the effects of HCV drug therapy. Antiviral therapy forHCV infrequently achieves a SVR in HIV–HCV coinfectedsubjects. Although potentially organ and life saving, it should,in most cases, be reserved for those abstaining from alcohol andachieving HIV RNA suppression and immune restoration fromHAART, or for those whose nadir CD4 T-lymphocyte countsare above 350 cells/µl.

Months on HAART therapy806040200

Pat

ient

sre

mai

ning

onH

AA

RT

1.0

0.8

0.6

0.4

0.2

0.0

Alcohol <50 g/day

Alcohol ≥50 g/day

Figure1. Influence of excess alcohol consumption on the likelihood of remaining on HAART.HAART: Highly active antiretroviral therapy.

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Five-year viewHIV–HCV coinfection management will change with thearrival of alternative HCV therapies. Several HCV-specificprotease inhibitors and NS5 RNA polymerase inhibitors arecurrently in preclinical development and under Phase I/IIclinical investigation [92–96]. Early human studies demonstraterapid and sizable HCV RNA reduction with both HCV anti-viral classes. If these agents are proven to be effective, safe andbetter tolerated than interferon–ribavirin-based HCV drugtherapy, then more liberal use of HCV treatment inHIV–HCV coinfection is predicted. Concurrent use of bothHAART and these new HCV medications would be anoption for more patients. The rapid evolution of HCV drug

resistance with HCV protease inhibitor and HCV polymeraseinhibitor monotherapy is likely to occur. Therefore, combina-tion HCV drug therapy is likely to become the standard ofcare. It is possible that one of these newer agents will replaceribavirin, thereby reducing therapeutic toxicity, avoiding thepotential interactions between HIV nucleosides and ribavi-rin, and potentially increasing sustained virologic responserates. With the arrival of entecavir [97], the ability to treatHBV without producing HIV drug resistance (i.e., lamivu-dine monotherapy in HIV–HBV coinfection) will be real-ized. Immune modulators including cytosine phospho-guanine oligodeoxynucleotides may have a role in thetreatment of chronic viral hepatitis [98,99].

Key issues

• A quarter of HIV-infected individuals are hepatitis C virus (HCV) seropositive and 5% are hepatitis B virus (HBV) coinfected. This prevalence varies widely between clinics depending on cliental characteristics.

• Viral loads are higher, and liver-fibrosis rates accelerated in HIV-seropositive patients with viral hepatitis coinfection.• Most HIV-infected patients with viral hepatitis coinfection do not experience large liver enzyme elevations following the initiation of

HIV antiretroviral therapy. It is rare that subjects will develop clinically symptomatic liver toxicity necessitating interruption in combination antiretroviral treatment.

• Potent and durable combination antiretroviral therapy may reduce HCV RNA and liver enzyme levels from baseline and slowliver-fibrosis rates.

• Sustained virologic response with pegylated interferon and ribavirin is diminished with HIV infection but can be achieved in 25 to 50% of HIV–HCV coinfected individuals depending on genotype and other patient characteristics.

• In general, highly active antiretroviral therapy should be initiated first in those with CD4 counts under 350 cells/µl. HCV drug therapy may be considered first for those with higher CD4 counts.

• Eliminating alcohol consumption may have the largest single impact on the rate of liver fibrosis and long-term prognosis in HIV–HBV and –HCV coinfection.

ReferencesPapers of special note have been highlighted as:• of interest•• of considerable interest

1 HIV/AIDS Surveillance Report. US HIV and AIDS cases reported through December 2002. Centers for Disease Control and Prevention. 14, 1–48 (2002).

2 Alter MJ, Kruszon-Moran D, Nainan OV et al. The prevalence of hepatitis C virus infection in the USA, 1988 through 1994. N. Engl. J. Med. 341(8), 556–562 (1999).

3 Kim WR. The burden of hepatitis C in the United States. Hepatology 36(5 Suppl. 1), S30–S34 (2002).

4 Mahoney FJ. Update on diagnosis, management and prevention of hepatitis B virus infection. Clin. Microbiol. Rev. 12(2), 351–366 (1999).

5 Stubble L, Soriano V, Antunes F. Hepatitis C in the EuroSIDA Cohort of European HIV-infected patients: prevalence and prognostic value. 12th World AIDS Conference. Geneva, Switzerland, 28 June–3 July 1998 (Abstract 22261).

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45 Cooper C, LaRoche A, Kane M, Conto-Cohoon M, Lee C, Garber GE. Evaluation of th benefits of HAART in HIV–HCV coinfected subjects. 43rd Interscience Conference on Antimicrobials and Chemotherapy. Chicago, IL, USA, 14–18 September 2003 (Abstract H-826).

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66 Lalezari JP, Eron JJ, Carlson M et al. A Phase II clinical study of the long-term safety and antiviral activity of enfuvirtide-based antiretroviral therapy. AIDS 17(5), 691–698 (2003).

67 Lalezari JP, Henry K, O’Hearn M et al. Enfuvirtide, an HIV-1 fusion inhibitor, for drug-resistant HIV infection in North and South America. N. Engl. J. Med. 348(22), 2175–2185 (2003).

68 Zylberberg H, Benhamou Y, Lagneaux JL et al. Safety and efficacy of interferon–ribavirin combination therapy in HCV–HIV coinfected subjects: an early report. Gut 47(5), 694–697 (2000).

69 Neau D, Trimoulet P, Winnock M et al. Comparison of 2 regimens that include interferon-α-2a plus ribavirin for treatment of chronic hepatitis C in human immunodeficiency virus-coinfected patients. Clin. Infect. Dis. 36(12), 1564–1571 (2003).

70 Landau A, Batisse D, Piketty C et al. Long-term efficacy of combination therapy with interferon-α 2b and ribavirin for severe chronic hepatitis C in HIV-infected patients. AIDS 15(16), 2149–2155 (2001).

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78 Emilie D, Burgard M, Lascoux-Combe C et al. Early control of HIV replication in primary HIV-1 infection treated with antiretroviral drugs and pegylated IFN-α results from the Primoferon A (ANRS 086) Study. AIDS 15(11), 1435–1437 (2001).

79 Dienstag JL, Schiff ER, Wright TL et al. Lamivudine as initial treatment for chronic hepatitis B in the United States. N. Engl. J. Med. 341(17), 1256–1263 (1999).

80 Schalm SW, Heathcote J, Cianciara J et al. Lamivudine and α-interferon combination treatment of patients with chronic hepatitis B infection: a randomized trial. Gut 46(4), 562–568 (2000).

81 Da Silva LC, Pinho JR, Sitnik R, Da Fonseca LE, Carrilho FJ. Efficacy and tolerability of long-term therapy using high lamivudine doses for the treatment of chronic hepatitis B. J. Gastroenterol. 36(7), 476–485 (2001).

82 Benhamou Y, Bochet M, Thibault V et al. Long-term incidence of hepatitis B virus resistance to lamivudine in human immunodeficiency virus-infected patients. Hepatology 30(5), 1302–1306 (1999).

83 Cooper D, Coakley DF, Sayre J et al. Antihepatitis B virus (HBV) activity of tenofovir disoproxil fumarate (TDF) in lamivudine (LAM) experienced HIV/HBV coinfected patients. XIV International AIDS Conference. Barcelona, Spain, 7–12 July 2002 (Abstract 6015).

84 Bochet M, Tubiana R, Benhamou Y et al. Tenofovir disoproxil fumarate suppresses lamivudine-resistant HBV replication in patiens coinfected with HIV/HBV. 9th Conference on Retroviruses and Opportunistic Infections. Seattle, WA, USA, 24–28 February 2003 (Abstract 675-M).

85 Nishiguchi S, Shiomi S, Nakatani S et al. Prevention of hepatocellular carcinoma in patients with chronic active hepatitis C and cirrhosis. Lancet 357(9251), 196–197 (2001).

86 Shiratori Y, Shiina S, Teratani T et al. Interferon therapy after tumor ablation improves prognosis in patients with hepatocellular carcinoma associated with hepatitis C virus. Ann. Intern. Med. 138(4), 299–306 (2003).

87 Di Bisceglie AM, Dienstag J, Bankovsky H et al. Serum α-fetoprotein (AFP) levels in patients with advanced hepatitis-C-associated liver disease without hepatocellular carcinoma: results from the HALT-C trial. 54th Annual Meeting of the American Association for the Study of Liver Diseases. Boston, MN, USA, 24–28 October 2003 (Abstract 567).

88 Bhattacharya R, Shuhart MC. Hepatitis C and alcohol: interactions, outcomes and implications. J. Clin. Gastroenterol. 36(3), 242–252 (2003).

89 Tabone M, Sidoli L, Laudi C et al. Alcohol abstinence does not offset the strong negative effect of lifetime alcohol consumption on the outcome of interferon therapy. J. Viral Hepat. 9(4), 288–294 (2002).

90 Miguez MJ, Shor-Posner G, Morales G, Rodriguez A, Burbano X. HIV treatment in drug abusers: impact of alcohol use. Addict. Biol. 8(1), 33–37 (2003).

91 Edlin BR. Prevention and treatment of hepatitis C in injection drug users. Hepatology 36(5 Suppl. 1), S210–S219 (2002).

92 Hinrichsen H, Benhamou Y, Reiser M et al. First report on the antiviral efficacy of BILN 2061, a novel oral HCV serine protease inhibitor, in patients with chronic hepatitis C geneotype 1. 55th Annual Meeting of the American Association for the Study of Liver Diseases. Boston, MA, USA, 29 October 2004 (Abstract 567).

93 Benhamou Y, Hinrichsen H, Sentjens R et al. Safety, tolerability and antiviral effect of BILN 2061, a novel HCV serine protease inhibitor,after oral treatment over 2 days in patients with chronic hepatitis C, genotype 1, with advanced liver fibrosis. 55th Annual Meeting of the American Association for the Study of Liver Diseaes. Boston, MA, USA, 29 October 2004 (Abstract 563).

94 Seiwert S, Tan H, Rieger R et al. Discovery and preclinical characterization of novel inhibitors of the HCV NS3/4 protease. 55th Annual Meeting of the American Association for the Study of Liver Diseases. Boston, MA, USA, 29 October 2004 (Abstract LB14).

95 Afdhal N, Godofsky E, Dienstag J et al. Final Phase I/II trial results for NM283, a new polymerase inhibitor for hepatitis C: antivirial efficacy and tolerance in patients with HCV-1 infection, including previous interferon failures. 55th Annual Meeting of the AMerican Association for the Study of Liver Diseases. Boston, MA, USA, 29 October 2004 (Abstract LB03).

96 Chu HM, McNair L, Purdy S. Results of a Phase 1 single-dose escalation study of the hepatitis C protease inhibitor VX-950 in healthy volunteers. 55th Annual Meeting of the American Association for the Study of Liver Diseases. Boston, MA, USA, 29 October 2004 (Abstract LB20).

97 Shouval D, Lai CL, Cheinquer H et al. Entecavir demonstrates superior histologic and virologic efficacy over lamivudine in nucleoside-naive HBEAG (-) chronic hepatitis B: results of Phase III trial ETV-027. 55th Annual Meeting of the American Association for the Study of Liver Diseases. Boston, MA, USA, 29 October 2004 (Abstract LB07).

98 Cooper CL, Davis HL, Morris ML et al. CPG7909, an immunostimulatory TLR9 agonist oligodeoxynucleotide, as adjuvant to Engerix-B HBV vaccine in healthy adults: a double-blind Phase I/II study. J. Clin. Immunol. 24(6), 693–701 (2004).

99 Cooper CL, Davis HL, Morris ML et al. Safe and effective use of CpG as adjuvant for HBV vaccination in HIV infection. 10th Conference on Retroviruses and Opportunistic Infections. Boston, MA, USA, 10–14 February 2003 (Abstract 400).

Affiliation• Curtis L Cooper, MD, FRCPC

Assistant Professor of Medicine, The Ottawa Hospital – General Campus, Room G12,501 Smyth Road, Ottawa, Ontario, K1H 8L6, CanadaTel.: +1 613 737 8924Fax: +1 613 737 [email protected]