There are many potential reasons for increased liver-related mortality in HIV–hepatitis B virus (HBV) coinfection compared with either infection alone. HIV infects multiple cells in the liver and might potentially alter the life cycle of HBV, although evidence to date is limited. Unique mutations in HBV have been defined in HIV–HBV-coinfected individuals and might directly alter pathogenesis. In addition, an impaired HBV- specific T-cell immune response is likely to be important. The roles of microbial translocation, immune activation and increased hepatic stellate cell activation will be important areas for future study.
References
1.
AlterM.J.Epidemiology of viral hepatitis and HIV coinfection.J Hepatol2006; 44: S6–S9.
2.
KonopnickiD., MocroftA., de WitS.Hepatitis B and HIV: prevalence, AIDS progression, response to highly active antiretroviral therapy and increased mortality in the EuroSIDA cohort.AIDS2005; 19: 593–601.
3.
FeldJ.J., OcamaP., RonaldA.The liver in HIV in Africa.Antivir Ther2005; 10: 953–965.
4.
GilsonR.J., HawkinsA.E., BeechamM.R.Interactions between HIV and hepatitis B virus in homosexual men: effects on the natural history of infection.AIDS1997; 11: 597–606.
5.
ColinJ.F., Cazals–HatemD., LoriotM.A.Influence of human immunodeficiency virus infection on chronic hepatitis B in homosexual men.Hepatology1999; 29: 1306–1310.
6.
ThioC.L., SeabergE.C., SkolaskyR.Jr.. HIV-1, hepatitis B virus, and risk of liver-related mortality in the Multicentre Cohort Study (MACS).Lancet2002; 360: 1921–1926.
7.
BlackardJ.T., ShermanK.E.HCV/HIV coinfection: time to re-evaluate the role of HIV in the liver?J Viral Hepat2008; 15: 323–330.
8.
HoussetC., LamasE., BrechotC.Detection of HIV1 RNA and p24 antigen in HIV1-infected liver cells.Res Virol1990; 141: 153–159.
9.
CaoY.Z., DieterichD., ThomasP.A., HuangY.X., MirabileM., HoD.D.Identification and quantitation of HIV-1 in the liver of patients with AIDS.AIDS1992; 6: 65–70.
10.
HoussetC., LamasE., CourgnaudV.Presence of HIV-1 in human parenchymal and non-parenchymal liver cells in vivo.J Hepatol1993; 19: 252–258.
11.
SchmittM.P., SteffanA.M., GendraultJ.L.Multiplication of human immunodeficiency virus in primary cultures of human Kupffer cells: possible role of liver macrophage infection in the pathophysiology of AIDS.Res Virol1990; 141: 143–152.
12.
GendraultJ.L., SteffanA.M., SchmittM.P., JaeckD., AubertinA.M., KirnA.Interaction of cultured human Kupffer cells with HIV-infected CEM cells: an electron microscope study.Pathobiology1991; 59: 223–226.
13.
SteffanA.M., LafonM.E., GendraultJ.L.Primary cultures of endothelial cells from the human liver sinusoid are permissive for human immunodeficiency virus type I.Proc Natl Acad Sci U S A1992; 89: 1582–1586.
14.
CaoY.Z., Friedman-KienA.E., HuangY.X.CD4-independent, productive human immunodeficiency virus type 1 infection of hepatoma cell lines in vitro.J Virol1990; 64: 2553–2559.
15.
BanerjeeR., SperberK., PizzellaT., MayerL.Inhibition of HIV-1 productive infection in hepatoblastoma HepG2 cells by recombinant tumor necrosis factor-alpha.AIDS1992; 6: 1127–1131.
16.
VlahakisS.R., Villasis-KeeverA., GomezT.S., BrenG.D., PayaC.V.Human immunodeficiency virus-induced apoptosis of human hepatocytes via CXCR4.J Infect Dis2003; 188: 1455–1460.
17.
BergerE.A., MurphyP.M., FarberJ.M.Chemokine receptors as HIV-1 coreceptors: roles in viral entry, tropism, and disease.Annu Rev Immunol1999; 17: 657–700.
18.
GorryP.R., OngC., ThorpeJ.Astrocyte infection by HIV-1: mechanisms of restricted virus replication, and role in the pathogenesis of HIV-1-associated dementia.Curr HIV Res2003; 1: 463–473.
19.
TuyamaA., HongF., SchecterA.HIV entry and replication in stellate cells promotes cellular activation and fibrogenesis: implications for hepatic fibrosis in HIV/ HCV coinfection.15th Conference on Retroviruses and Opportunistic Infections. 3–6 February 2008, Boston, MA, USA. Abstract 57.
20.
SchwabeR.F., BatallerR., BrennerD.A.Human hepatic stellate cells express CCR5 and RANTES to induce proliferation and migration.Am J Physiol Gastrointest Liver Physiol2003; 285: G949–G958.
21.
HongF., TuyamaA., AgarwalR.Autocrine signalling by SDF-1alpha through its receptor, CXCR4, mediates hepatic stellate cell activation in vivo and in vitro.58th Annual Meeting of the American Association for the Study of Liver Diseases. 2–6 November 2007, Boston, MA, USA. Abstract 1400.
22.
RapicettaM., FerrariC., LevreroM.Viral determinants and host immune responses in the pathogenesis of HBV infection.J Med Virol2002; 67: 454–457.
23.
FangJ.W., WrightT.L., LauJ. Y.. Fibrosing cholestatic hepatitis in patient with HIV and hepatitis B.Lancet1993; 342: 1175.
24.
ThungS.N.Histological findings in recurrent HBV.Liver Transpl2006; 12: S50–S53.
25.
PuotiM., TortiC., BrunoR., FiliceG., CarosiG.Natural history of chronic hepatitis B in co-infected patients.J Hepatol2006; 44: S65–S70.
26.
RevillP.A., LittlejohnM., AyresA.Identification of a novel hepatitis B virus precore/core deletion mutant in HIV/hepatitis B virus co-infected individuals.AIDS2007; 21: 1701–1710.
27.
GuntherS., BaginskiS., KisselH.Accumulation and persistence of hepatitis B virus core gene deletion mutants in renal transplant patients are associated with end-stage liver disease.Hepatology1996; 24: 751–758.
28.
ChangJ.J., WightmanF., BartholomeuszA.Reduced hepatitis B virus (HBV)-specific CD4+ T-cell responses in human immunodeficiency virus type 1-HBV-coinfected individuals receiving HBV-active antiretroviral therapy.J Virol2005; 79: 3038–3051.
29.
PreikschatP., GuntherS., ReinholdS.Complex HBV populations with mutations in core promoter, C gene, and pre-S region are associated with development of cirrhosis in long-term renal transplant recipients.Hepatology2002; 35: 466–477.
30.
MarschenzS., EndresA.S., BrinckmannA.Functional analysis of complex hepatitis B virus variants associated with development of liver cirrhosis.Gastroenterology2006; 131: 765–780.
31.
ChisariF.V., FilippiP., BurasJ.Structural and pathological effects of synthesis of hepatitis B virus large envelope polypeptide in transgenic mice.Proc Natl Acad Sci U S A1987; 84: 6909–6913.
32.
MatthewsG.V., BartholomeuszA., LocarniniS.Characteristics of drug resistant HBV in an international collaborative study of HIV–HBV-infected individuals on extended lamivudine therapy.AIDS2006; 20: 863–870.
33.
BenhamouY., FleuryH., TrimouletP.Anti-hepatitis B virus efficacy of tenofovir disoproxil fumarate in HIV-infected patients.Hepatology2006; 43: 548–555.
34.
SheldonJ., RamosB., Garcia-SamaniegoJ.Selection of hepatitis B virus (HBV) vaccine escape mutants in HBV-infected and HBV/HCV-coinfected patients failing antiretroviral drugs with anti-HBV activity.J Acquir Immune Defic Syndr2007; 46: 279–282.
35.
DelaneyW.E.IV, YangH., WestlandC.E.The hepatitis B virus polymerase mutation rtV173L is selected during lamivudine therapy and enhances viral replication in vitro.J Virol2003; 77: 11833–11841.
36.
YatsujiH., SuzukiF., SezakiH.Low risk of adefovir resistance in lamivudine-resistant chronic hepatitis B patients treated with adefovir plus lamivudine combination therapy: two-year follow-up.J Hepatol2008; 48: 923–931.
37.
LamperticoP., ViganoM., ManentiE., IavaroneM., SablonE., ColomboM.Low resistance to adefovir combined with lamivudine: a 3-year study of 145 lamivudine-resistant hepatitis B patients.Gastroenterology2007; 133: 1445–1451.
38.
FungS.K., ChaeH.B., FontanaR.J.Virological response and resistance to adefovir in patients with chronic hepatitis B.J Hepatol2006; 44: 283–290.
39.
MatthewsG.V., AvihingsanonA., LewinS.R.A randomized trial of combination hepatitis B therapy in HIV/ HBV coinfected antiretroviral naive individuals in Thailand.Hepatology2008; 48: 1062–1069.
40.
AudsleyJ., ArrifinN., YuenL.Prolonged use of tenofovir in HIV/hepatitis B virus (HBV)-coinfected individuals does not lead to HBV polymerase mutations and is associated with persistence of lamivudine HBV polymerase mutations.HIV Med2009; in press.
41.
SheldonJ., CaminoN., RodesB.Selection of hepatitis B virus polymerase mutations in HIV-coinfected patients treated with tenofovir.Antivir Ther2005; 10: 727–734.
42.
SetoE., YenT.S., PeterlinB.M., OuJ-H. Trans-activation of the human immunodeficiency virus long terminal repeat by the hepatitis B virus X protein.Proc Natl Acad Sci U S A1988; 85: 8286–8290.
43.
TwuJ-S, ChuK., RobinsonW.S.Hepatitis B virus X gene activates kappa B-like enhancer sequences in the long terminal repeat of human immunodeficiency virus 1.Proc Natl Acad Sci U S A1989; 86: 5168–5172.
44.
TwuJ-S, RobinsonW.Hepatitis B virus X gene can transactivate heterologous viral sequences.Proc Natl Acad Sci U S A1989; 86: 2046–2050.
45.
ChaiN., ChangH.E., NicolasE., GudimaS., ChangJ., TaylorJ.Assembly of hepatitis B virus envelope proteins onto a lentivirus pseudotype that infects primary human hepatocytes.J Virol2007; 81: 10897–10904.
46.
GanemD., PrinceA.M.Hepatitis B virus infection – natural history and clinical consequences.N Engl J Med2004; 350: 1118–1129.
47.
PirothL., SeneD., PolS.Epidemiology, diagnosis and treatment of chronic he patitis B in HIV-infected patients (EPIB 2005 STUDY).AIDS2007; 21: 1323–1331.
48.
ChangJ.J., LewinS.R.Immunopathogenesis of hepatitis B virus infection.Immunol Cell Biol2007; 85: 16–23.
49.
VisvanathanK., SkinnerN.A., ThompsonA.J.Regulation of Toll-like receptor-2 expression in chronic hepatitis B by the precore protein.Hepatology2007; 45: 102–110.
50.
IsogawaM., RobekM.D., FuruichiY., ChisariF. V.. Toll-like receptor signalling inhibits hepatitis B virus replication in vivo.J Virol2005; 79: 7269–7272.
51.
TangT.J., KwekkeboomJ., LamanJ.D.The role of intrahepatic immune effector cells in inflammatory liver injury and viral control during chronic hepatitis B infection.J Viral Hepat2003; 10: 159–167.
52.
KakimiK., GuidottiL.G., KoezukaY., ChisariF. V.. Natural killer T cell activation inhibits hepatitis B virus replication in vivo.J Exp Med2000; 192: 921–930.
53.
MorsicaG., TascaS., BiswasP.Natural killer-cell cytotoxicity in HIV-positive and HIV-negative patients with and without severe course of hepatitis B virus infection.Scand J Immunol2005; 62: 318–324.
54.
LesterR.T., YaoX.D., BallT.B.Toll-like receptor expression and responsiveness are increased in viraemic HIV-1 infection.AIDS2008; 22: 685–694.
55.
ChenZ., ChengY., XuY.Expression profiles and function of Toll-like receptors 2 and 4 in peripheral blood mononuclear cells of chronic hepatitis B patients.Clin Immunol2008; 128: 400–408.
56.
Op den BrouwM.L., BindaR.S., van RoosmalenM.H.Hepatitis B virus surface antigen impairs myeloid dendritic cell function: a possible immune escape mechanism of hepatitis B virus.Immunology2009; 126: 280–289.
57.
van der MolenR.G., SprengersD., BindaR.S.Functional impairment of myeloid and plasmacytoid dendritic cells of patients with chronic hepatitis B.Hepatology2004; 40: 738–746.
58.
UntergasserA., ZedlerU., LangenkampA.Dendritic cells take up viral antigens but do not support the early steps of hepatitis B virus infection.Hepatology2006; 43: 539–547.
59.
CameronP.U., LoweM.G., SotzikF., CoughlanA.F., CroweS.M., ShortmanK.The interaction of macrophage and non-macrophage tropic isolates of HIV-1 with thymic and tonsillar dendritic cells in vitro.J Exp Med1996; 183: 1851–1856.
60.
GuidottiL.G., IshikawaT., HobbsM.V., MatzkeB., SchreiberR., ChisariF. V.. Intracellular inactivation of the hepatitis B virus by cytotoxic T lymphocytes.Immunity1996; 4: 25–36.
61.
ThimmeR., WielandS., SteigerC.CD8(+) T cells mediate viral clearance and disease pathogenesis during acute hepatitis B virus infection.J Virol2003; 77: 68–76.
62.
VierlingJ.M.The immunology of hepatitis B.Clin Liver Dis2007; 11: 727–759.
63.
MainiM.K., BertolettiA.How can the cellular immune response control hepatitis B virus replication?J Viral Hepat2000; 7: 321–326.
64.
RehermannB., FerrariC., PasquinelliC., ChisariF.V.The hepatitis B virus persists for decades after patients’ recovery from acute viral hepatitis despite active maintenance of a cytotoxic T-lymphocyte response.Nat Med1996; 2: 1104–1108.
65.
LascarR.M., LopesA.R., GilsonR.J.Effect of HIV infection and antiretroviral therapy on hepatitis B virus (HBV)-specific T cell responses in patients who have resolved HBV infection.J Infect Dis2005; 191: 1169–1179.
66.
ThioC.L., NetskiD.M., MyungJ., SeabergE.C., ThomasD.L.Changes in hepatitis B virus DNA levels with acute HIV infection.Clin Infect Dis2004; 38: 1024–1029.
67.
LascarR.M., GilsonR.J., LopesA.R., BertolettiA., MainiM.K.Reconstitution of hepatitis B virus (HBV)-specific T cell responses with treatment of human immunodeficiency virus/ HBV coinfection.J Infect Dis2003; 188: 1815–1819.
68.
AlterG., TeigenN., AhernR.Evolution of innate and adaptive effector cell functions during acute HIV-1 infection.J Infect Dis2007; 195: 1452–1460.
69.
AllenT.M., AltfeldM., GeerS.C.Selective escape from CD8+ T-cell responses represents a major driving force of human immunodeficiency virus type 1 (HIV-1) sequence diversity and reveals constraints on HIV-1 evolution.J Virol2005; 79: 13239–13249.
70.
NolanD., GaudieriS., MallalS.Host genetics and viral infections: immunology taught by viruses, virology taught by the immune system.Curr Opin Immunol2006; 18: 413–421.
71.
FrenchM.A.Disorders of immune reconstitution in patients with HIV infection responding to antiretroviral therapy.Curr HIV/AIDS Rep2007; 4: 16–21.
72.
SulkowskiM.S., ThomasD.L., ChaissonR.E., MooreR.D.Hepatotoxicity associated with antiretroviral therapy in adults infected with human immunodeficiency virus and the role of hepatitis C or B virus infection.JAMA2000; 283: 74–80.
73.
den BrinkerM., WitF.W., Wertheim-van DillenP.M.Hepatitis B and C virus coinfection and the risk for hepatotoxicity of highly active antiretroviral therapy in HIV-1 infection.AIDS2000; 14: 2895–2902.
74.
BenhamouY.Hepatitis B in the HIV-coinfected patient.J Acquir Immune Defic Syndr2007; 45: S57–S65.
75.
CraneM., MatthewsG., LewinS.Hepatitis virus immune restoration disease of the liver.J Infect Dis2009; in press.
76.
DrakeA., MijchA., SasadeuszJ.Immune reconstitution hepatitis in HIV and hepatitis B coinfection, despite lamivudine therapy as part of HAART.Clin Infect Dis2004; 39: 129–132.
77.
AsmuthD.M., BuschM.P., LaycockM.E.Hepatitis B and C viral load changes following initiation of highly active antiretroviral therapy (HAART) in patients with advanced HIV infection.Antiviral Res2004; 63: 123–131.
78.
FilippiniP., CoppolaN., PisapiaR.Impact of occult hepatitis B virus infection in HIV patients naive for antiretroviral therapy.AIDS2006; 20: 1253–1260.
79.
CanbayA., FriedmanS., GoresG.J.Apoptosis: the nexus of liver injury and fibrosis.Hepatology2004; 39: 273–278.
80.
JoM., KimT.H., SeolD.W.Apoptosis induced in normal human hepatocytes by tumor necrosis factor-related apoptosis-inducing ligand.Nat Med2000; 6: 564–567.
81.
PerryS.W., NormanJ.P., LitzburgA., ZhangD., DewhurstS., GelbardH.A.HIV-1 transactivator of transcription protein induces mitochondrial hyperpolarization and synaptic stress leading to apoptosis.J Immunol2005; 174: 4333–4344.
82.
ChenG.Y., HeJ.Q., LuG.C.Association between TRAIL expression on peripheral blood lymphocytes and liver damage in chronic hepatitis B.World J Gastroenterol2005; 11: 4090–4093.
83.
SatoK., HidaS., TakayanagiH.Antiviral response by natural killer cells through TRAIL gene induction by IFN-alpha/beta.Eur J Immunol2001; 31: 3138–3146.
84.
DunnC., BrunettoM., ReynoldsG.Cytokines induced during chronic hepatitis B virus infection promote a pathway for NK cell-mediated liver damage.J Exp Med2007; 204: 667–680.
85.
KagiD., VignauxF., LedermannB.Fas and perforin pathways as major mechanisms of T cell-mediated cytotoxicity.Science1994; 265: 528–530.
86.
CanbayA., TaimrP., TorokN., HiguchiH., FriedmanS., GoresG.J.Apoptotic body engulfment by a human stellate cell line is profibrogenic.Lab Invest2003; 83: 655–663.
87.
FriedmanS.L.Molecular regulation of hepatic fibrosis, an integrated cellular response to tissue injury.J Biol Chem2000; 275: 2247–2250.
88.
SaileB., KnittelT., MatthesN., SchottP., RamadoriG.CD95/ CD95L-mediated apoptosis of the hepatic stellate cell. A mechanism terminating uncontrolled hepatic stellate cell proliferation during hepatic tissue repair.Am J Pathol1997; 151: 1265–1272.
89.
TaimrP., HiguchiH., KocovaE., RippeR.A., FriedmanS., GoresG.J.Activated stellate cells express the TRAIL receptor-2/death receptor-5 and undergo TRAIL-mediated apoptosis.Hepatology2003; 37: 87–95.
90.
CanbayA., HiguchiH., BronkS.F., TaniaiM., SeboT.J., GoresG.J.Fas enhances fibrogenesis in the bile duct ligated mouse: a link between apoptosis and fibrosis.Gastroenterology2002; 123: 1323–1330.
91.
FriedmanS.L.Hepatic stellate cells: protean, multifunctional, and enigmatic cells of the liver.Physiol Rev2008; 88: 125–172.
92.
PaikY.H., SchwabeR.F., BatallerR., RussoM.P., JobinC., BrennerD.A.Toll-like receptor 4 mediates inflammatory signalling by bacterial lipopolysaccharide in human hepatic stellate cells.Hepatology2003; 37: 1043–1055.
93.
BrunP., CastagliuoloI., PinzaniM., PaluG., MartinesD.Exposure to bacterial cell wall products triggers an inflammatory phenotype in hepatic stellate cells.Am J Physiol Gastrointest Liver Physiol2005; 289: G571–G578.
94.
Martin-VilchezS., Sanz-CamenoP., Rodriguez-MunozY.The hepatitis B virus X protein induces paracrine activation of human hepatic stellate cells.Hepatology2008; 47: 1872–1883.
95.
SafadiR., OhtaM., AlvarezC.E.Immune stimulation of hepatic fibrogenesis by CD8 cells and attenuation by transgenic interleukin-10 from hepatocytes.Gastroenterology2004; 127: 870–882.
96.
FauciA.S., MavilioD., KottililS.NK cells in HIV infection: paradigm for protection or targets for ambush.Nat Rev Immunol2005; 5: 835–843.
97.
Le FrockJ.L., EllisC.A., TurchikJ.B., ZawackiJ.K., WeinsteinL.Transient bacteremia associated with percutaneous liver biopsy.J Infect Dis1975; 131: S104–S107.
98.
BrenchleyJ.M., SchackerT.W., RuffL.E.CD4+ T cell depletion during all stages of HIV disease occurs predominantly in the gastrointestinal tract.J Exp Med2004; 200: 749–759.
99.
BrenchleyJ.M., PriceD.A., SchackerT.W.Microbial translocation is a cause of systemic immune activation in chronic HIV infection.Nat Med2006; 12: 1365–1371.
100.
MelaC.M., SteelA., LindsayJ., GazzardB.G., GotchF.M., GoodierM.R.Depletion of natural killer cells in the colonic lamina propria of viraemic HIV-1-infected individuals.AIDS2007; 21: 2177–2182.
101.
FunderburgN., LucianoA.A., JiangW., RodriguezB., SiegS.E., LedermanM.M.Toll-like receptor ligands induce human T cell activation and death, a model for HIV pathogenesis.PLoS ONE2008; 3: e1915.
102.
CireraI., BauerT.M., NavasaM.Bacterial translocation of enteric organisms in patients with cirrhosis.J Hepatol2001; 34: 32–37.
103.
von BaehrV., DockeW.D., PlauthM.Mechanisms of endotoxin tolerance in patients with alcoholic liver cirrhosis: role of interleukin 10, interleukin 1 receptor antagonist, and soluble tumour necrosis factor receptors as well as effector cell desensitization.Gut2000; 47: 281–287.
104.
OesterreicherC., PfeffelF., PetermannD., MullerC.Increased in vitro production and serum levels of the soluble lipopolysaccharide receptor sCD14 in liver disease.J Hepatol1995; 23: 396–402.
105.
BalagopalA., PhilpF.H., AstemborskiJ.Human immunodeficiency virus-related microbial translocation and progression of hepatitis C.Gastroenterology2008; 135: 226–233.
106.
SorianoV., PuotiM., BonaciniM.Care of patients with chronic hepatitis B and HIV coinfection: recommendations from an HIV-HBV International Panel.AIDS2005; 19: 221–240.
107.
SulkowskiM.S., ThomasD.L., MehtaS.H., ChaissonR.E., MooreR.D.Hepatotoxicity associated with nevirapine or efavirenz-containing antiretroviral therapy: role of hepatitis C and B infections.Hepatology2002; 35: 182–189.
108.
Gonzalez de RequenaD., NunezM., Jimenez-NacherI., SorianoV.Liver toxicity caused by nevirapine.AIDS2002; 16: 290–291.
109.
WalkerU.A., BauerleJ., LagunoM.Depletion of mitochondrial DNA in liver under antiretroviral therapy with didanosine, stavudine, or zalcitabine.Hepatology2004; 39: 311–317.
110.
RachlisA., ClotetB., BaxterJ., MurphyR., LefebvreE.Safety, tolerability, and efficacy of darunavir (TMC114) with low-dose ritonavir in treatment-experienced, hepatitis B or C co-infected patients in POWER 1 and 3.HIV Clin Trials2007; 8: 213–220.
111.
SteigbigelR., CooperD., KumarP.Raltegravir with optimized background therapy for resistant HIV-1 infection.N Engl J Med2008; 359: 339–354.
112.
GulickR.M., LalezariJ., GoodrichJ.Maraviroc for previously treated patients with R5 HIV-1 infection.N Engl J Med2008; 359: 1429–1441.
113.
CastellaresC., BarreiroP., Martin-CarboneroL.Liver cirrhosis in HIV-infected patients: prevalence, aetiology and clinical outcome.J Viral Hepat2008; 15: 165–172.
114.
MaidaI., Garcia-GascoP., SotgiuG.Antiretroviral-associated portal hypertension: a new clinical condition? Prevalence, predictors and outcome.Antivir Ther2008; 13: 103–107.
115.
BegricheK., IgoudjilA., PessayreD., FromentyB.Mitochondrial dysfunction in NASH: causes, consequences and possible means to prevent it.Mitochondrion2006; 6: 1–28.
116.
KresinaT.F., FlexnerC.W., SinclairJ.Alcohol use and HIV pharmacotherapy.AIDS Res Hum Retroviruses2002; 18: 757–770.
