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Antiviral Therapy 14:155–164 Review The pathogenesis of liver disease in the setting of HIV–hepatitis B virus coinfection David M Iser1,2 and Sharon R Lewin2,3* Department of Medicine, The University of Melbourne, St Vincent’s Hospital, Melbourne, Victoria, Australia Infectious Diseases Unit, The Alfred Hospital, Melbourne, Victoria, Australia 3 Department of Medicine, Monash University, Melbourne, Victoria, Australia 1 2 *Corresponding author: E-mail: [email protected] There are many potential reasons for increased liverrelated 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. Introduction Approximately 370 million people worldwide are infected with the hepatitis B virus (HBV) and approximately 40 million with HIV (6% and 0.6% of the world population, respectively) [1]. Areas endemic for HBV, such as sub-Saharan Africa and Asia, also have a high prevalence of HIV. Approximately 5–10% of individuals with HIV are coinfected with HBV [2], but this could be as high as 20% in parts of Africa [3]. The presence of HIV has important effects on the natural history of HBV. Individuals with HIV–HBV coinfection clear acute HBV less frequently, seroconvert from hepatitis B e antigen (HBeAg) to hepatitis B e antibody less frequently [4], have higher HBV DNA levels [5], lower levels of alanine aminotransferase (ALT) and milder necroinflammatory activity on histology than those with HBV alone [5]. Progression to cirrhosis, however, seems to be more rapid and more common and liver-related mortality is higher in HIV– HBV coinfection than with either infection alone [6]. In this article we review the current understanding of how these two viruses interact (Figure 1) and highlight areas where we believe further research is needed. Viral factors HIV in vivo studies There are numerous studies demonstrating evidence for the presence of HIV within liver tissue (reviewed in [7]). © 2009 International Medical Press 1359-6535 (print) 2040-2058 (online) Lewin.indd 155 HIV capsid antigen (p24) has been demonstrated within Kupffer cells by immunohistochemistry in liver from HIV-positive individuals [8,9]. In addition, HIV DNA was detected by PCR and HIV RNA detected by in situ hybridization in liver obtained from HIV-infected individuals following percutaneous biopsy, surgical biopsy and autopsy. HIV RNA was detected in Kupffer cells and other sinusoidal cells, portal mononuclear inflammatory cells and hepatocytes [9,10]. In one study that measured HIV DNA in liver samples from individuals coinfected with HBV, the authors observed a trend towards higher amounts of HIV in liver from individuals who were also HBV-infected compared with those without HBV infection, although this difference did not reach statistical significance [9]. HIV in vitro studies In vitro studies of HIV infection of liver cells support the in vivo findings (Table 1). HIV infection of primary human Kupffer [11,12] and primary endothelial cells has been demonstrated in vitro [13]. A number of studies have demonstrated HIV infection of hepatoma cell lines as models for primary hepatocytes. These studies have included cell lines such as Huh-7, Hep3B, CZHC/8571, PLC/PRF/5 (Alexander cells) and hepatoblastoma-derived HepG2 [14]. Infection was confirmed by detecting reverse transcriptase or p24 in culture supernatant, in situ hybridization for messenger 155 3/4/09 11:16:03 DM Iser & SR Lewin Figure 1. Pathogenesis of liver disease in HIV–HBV coinfection HBV HSC activation • High viral load • Mutations Drug resistance (L173V+L180M+M204V) • Inflammation • Hepatic fibrosis Unique (-1G) Intrahepatic HIV • KC HC • HC Gut • HSC • Mucosal Portal vein • EC CD4+ T-cells • Microbial trafficking • LPS burden EC HSC KC Immune system Hepatocyte Clinical factors damage • HBV-specific CD4+ and CD8+ T-cells • CD4+/CD8+ T-cell ratio • HAART • NK cell activity • Alcohol • TLR-2 expression (HBeAg) • Other medication Potential factors leading to the progression of liver disease in HIV–hepatitis B virus (HBV) coinfection. HIV-infected cells are indicated in red. EC, endothelial cells; HAART, highly-active antiretroviral therapy; HBeAg, hepatitis B e antigen; HC, hepatocytes; HSC, hepatic stellate cells; KC, Kupffer cells; LPS, lipopolysaccharide (from bacterial cell walls); NK, natural killer; TLR, Toll-like receptor. RNA and radioimmunoassay for HIV type-1 antigens. Virions were also seen under electron microscopy. Infection was thought to be CD4-independent, as all five cell lines were negative for CD4 receptors by immunofluorescence, for CD4 messenger RNA by slot-blot hybridization and because infection was demonstrated despite the presence of soluble CD4 or anti-CD4 monoclonal antibody. In another study, HepG2 cells were found to express CD4 and could be infected with HIV [15]. PLC/ PRF/5, CZHC/8571 and Hep3B constitutively express hepatitis B surface antigen (HBsAg) and might therefore be useful models for investigating coinfection of HIV and HBV in vitro. A recent study from the Mayo Clinic demonstrated the presence of CXCR4 on human hepatocytes and proposed that HIV might cause hepatocyte apoptosis by signalling through CXCR4 without actually infecting the cell [16]. Although HIV usually gains entry to target cells via CD4 receptors in conjunction with either coreceptor CXCR4 or CCR5, there are a number of other coreceptors that can be employed. These include CCR3, CCR2b, CCR8, 156 Lewin.indd 156 Apj, Strl33, Gpr1, Gpr15, CXCR1, ChemR23 or RDC1 [17]. It is not clear whether these alternative receptors are found on hepatocytes or other liver cells. HIV infection of CD4 hepatic cells might occur via receptormediated endocytosis or via alternative receptors. Such mechanisms have been proposed for HIV infection of astrocytes, which are also CD4-negative [18]. HIV infection of hepatic stellate cells (HSCs) has also recently been reported, using both primary HSCs and the LX-2 cell line [19]. Primary HSCs and LX-2 cells express CD4 receptors and the HIV coreceptors CCR5 and CXCR4 [19–21]. However, HIV infection of HSCs appeared to be independent of CD4, and was reduced in the presence of endocytosis blockers, chlorpromazine and NH4Cl [19]. HSCs infected with HIV or exposed to gp120 showed increased activation and fibrogenesis, as measured by a-smooth muscle actin (α-SMA) and collagen production, and increased levels of monocyte chemotactic protein-1 (MCP-1). These findings could provide an explanation for the increased fibrosis seen in HIV–HBV-coinfected individuals [5]. © 2009 International Medical Press 3/4/09 11:16:04 Liver disease pathogenesis in HIV–HBV coinfection Hepatitis B virus mutations HBV itself is not usually pathogenic [22]; however, a form of fulminant hepatitis called fibrosing cholestatic hepatitis (FCH) has been described in the posttransplant setting and in HIV–HBV coinfection [23]. In HBV-monoinfected individuals, FCH is characterized by extremely high levels of HBV DNA, high levels of expression of hepatitis B core antigen and HBsAg in hepatocytes and mild inflammatory activity [24]. However, despite extremely high HBV DNA levels seen in HIV–HBV coinfection [5], only a single case of FCH has been reported [23]. The preservation of residual antiHBV immune pressure, even in advanced AIDS, might be enough to prevent the occurrence of FCH [25]. A novel -1G deletion mutant was reported recently in HIV–HBV-coinfected individuals, which might be associated with altered HBV pathogenesis by two proposed mechanisms [26]. Firstly, the mutation led to a premature stop codon and truncation of the HBV precore and core genes, and might be associated with increased replication, as described in HBV-monoinfected individuals following renal transplant [27]. Secondly, the stop codon occurred within a known major histocompatibility complex (MHC) class II-restricted epitope, and might therefore represent an escape mutation. However, it remains unclear why immune escape would occur in the setting of immunosuppression and an impaired HBV-specific CD4+ T-cell response [28]. In addition to the -1G mutation, a number of other mutations were identified in the core/precore and polymerase genes, hepatitis B X protein (HBx) and regulatory sequences [26]. Some of these mutations, such as core mutation cI59V, were detected exclusively in HIV–HBV-coinfected individuals, whereas cL60I was also found in HBV-monoinfected individuals. Both these mutations occurred in the same CD4+ T-cell epitope as the -1G mutation, and might also be related to immune escape. In individuals on long-term immunosuppression following liver transplant, complex mutations in the core promoter, core gene and pre-S region have been described [29]. Deletions in the core gene can enhance replication at the level of pregenomic encapsidation or reverse transcription when in the presence of an adequate supply of wild-type core protein [30]. Deletions in the pre-S region might be associated with accumulation in the hepatocytes of surface protein via alteration in transcriptional regulation [31]. This has been shown to be associated with increased hepatocyte destruction in transgenic mice, either via direct toxicity or via immune or cytokine mediated injury. It is possible that similar mutations that lead to increased hepatocyte destruction might occur in HIV–HBV coinfection, although to date this has not been demonstrated. Hepatitis B virus drug resistance Highly active antiretroviral therapy (HAART) that targets HBV in HIV–HBV coinfection can promote the selection of isolates with mutations in the HBV polymerase [25]. Lamivudine resistance in HIV–HBV coinfection is extremely common with >90% of individuals developing resistance after 4 years of treatment [32]. This is in contrast to the infrequent emergence of HBV resistance to tenofovir [33]. Following prolonged treatment with lamivudine, a triple HBV polymerase mutant (rtL173V+rtL180M+ rtM204V) has been described in both HBV-monoinfected and HIV–HBV-coinfected individuals [34]. This combination of mutations might have significant public health implications, as it has reduced binding to hepatitis B surface antibody (HBsAb) and therefore could potentially act as a vaccine escape mutation [35]. A high prevalence (17%) of this triple HBV mutant was found in HBV viraemic individuals coinfected with HIV who had received lamivudine for prolonged periods [32]. A number of studies in HBV monoinfection have shown that drug resistance can be prevented with combination therapy [36,37]. Combination therapy with adefovir and lamivudine for lamivudine-resistant HBV was associated with low rates of the adefovir-resistant mutation rtA181V (4% after 4 years) Table 1. Evidence that HIV is able to infect liver cells from in vitro studies using either primary human cells or liver-derived cell lines Affected cells Method of HIV detection Mechanism Primary liver cells Kupffer cells RT in SN, EM, IF CD4-dependent Endothelial cells RT and p24 in SN, EM, IF SN infective to T-cell line CD4-dependent Hepatic stellate cells RT and p24 in SN CD4-independent Hepatocytes Effect of gp120 only (no infection) CXCR4-mediated Liver-derived cell lines Hepatoma (Huh7, Hep3B and Alexander cells) RT and p24 in SN, mRNA (in situ hybridization), RIA CD4-independent Hepatoblastoma (HepG2 cells) p24 in SN CD4-dependent Stellate cell lines (LX-2 cells) RT, p24 CD4-independent Reference [11,12] [13] [19] [16] [14] [15] [19] EM, electron microscopy; IF, immunofluorescence; mRNA, messenger RNA; RIA, radioimmunoassay; RT, reverse transcriptase; SN, supernatant. Antiviral Therapy 14.2 Lewin.indd 157 157 3/4/09 11:16:04 DM Iser & SR Lewin and no virological breakthrough over a median of 42 months in 145 individuals [37]. Adefovir resistance has been reported at much higher rates (22% after 2 years) in individuals treated with adefovir monotherapy for lamivudine-resistant HBV [38]. A recent randomized study of lamivudine, tenofovir or lamivudine plus tenofovir in 36 HIV–HBV-coinfected individuals initiating HAART demonstrated significantly higher rates of drug resistance and persistent viraemia at 48 weeks in individuals receiving lamivudine alone compared with individuals receiving tenofovir either alone or in combination with lamivudine [39]. HBV resistance to tenofovir remains rare as reported from a number of retrospective studies of HIV–HBVcoinfected cohorts (summarized in [40]). A potential unique tenofovir-resistant mutation, rtA194T, was described in only one patient from these cohorts, in association with two lamivudine-resistant mutations, rtL180M and rtM204V [41]. Small numbers of patients in many of these cohorts have experienced persistent HBV viraemia or significant rebounds in HBV DNA despite adherence to tenofovir and without any detectable tenofovir-resistant mutations [33,40]. HIV and HBV interactions in vitro Very few studies have examined the direct effects of HIV on HBV replication or vice versa. HBx has been shown to enhance transcription of the HIV long terminal repeat in Jurkat T-cells [42]. This interaction is probably mediated via the HIV κB-like transcriptional enhancer sequence in the long terminal repeat [43], or alternatively via an interaction with the HIV tat gene [44]. Some effects of accessory HIV proteins on HBV promoter/enhancer elements have been found, but none have been able to explain increased HBV replication. Pseudotyped viruses containing full-length HIV and combinations of large (L), medium (M) and small (S) HBsAg were created by cotransfecting 293T cells. Infectivity was assessed on primary human hepatocytes as well as cell lines (HepG2 cells and HuH7 cells) [45]. HIV (L, M and S) infected primary hepatocytes but none of the cell lines, whereas HIV (S), which lacks the pre-S1 domain, did not infect primary hepatocytes. This finding implies that HBsAg might potentially facilitate HIV entry of primary hepatocytes. Immune factors Anti-hepatitis B virus response The likelihood of a successful immune response to infection with HBV varies depending on age at the time of infection. Clearance of HBV DNA and seroconversion from HBsAg to HBsAb is much more likely in adulthood than childhood [46]. HBsAg seroconversion is significantly less likely in the presence of 158 Lewin.indd 158 HIV coinfection [47]. Immune factors necessary for successful clearance of acute HBV are not completely understood, but involve both cellular and humoural arms of the adaptive immune response, as well as the innate immune response (reviewed in [48]). Innate immune response The earliest response to HBV is likely to depend on the innate immune system, including Toll-like receptors (TLRs) and the release of interferon (IFN)-γ and IFN-β from hepatocytes [48–50]. These cytokines recruit antigen-presenting cells, such as Kupffer cells, which might induce hepatic injury during HBV infection via expression of Fas ligand [51]. Natural killer (NK) cells (CD3and CD56+) and NK T-cells (CD3+ and CD56+) are also recruited, and might be important in the initial anti-HBV response [52]. These components of the innate immune response are important prior to an effective adaptive immune response [48]. Reduced NK-cell-mediated cytotoxicity has been reported in HIV infection, as well as in acute HBV infection in both HIV-positive and HIVnegative individuals [53]. Conversely, markedly increased NK-cell-mediated cytotoxicity was seen in one individual who died of fulminant hepatic failure from acute HBV infection in the setting of AIDS [53]. Altered TLR expression and function might also be important in response to HIV and HBV infection. TLR expression and function is significantly altered by HIV infection [54], which might be important in immune activation and response to other pathogens, including HBV. In HBV, decreased TLR-2 expression on hepatocytes, Kupffer cells and peripheral monocytes has been described in individuals with HBeAg-positive chronic hepatitis B (CHB) compared with HBeAg-negative and uninfected controls [49]. Decreased TLR-2 expression and function (tumour necrosis factor [TNF]-α production) were confirmed in an in vitro model, whereas no change was observed in TLR-4 expression. Both TLR-2 and TLR-4 expression in peripheral monocytes were decreased in another cohort of individuals with CHB, compared with uninfected controls [55]. Together, the findings support a role for TLR in mediating HBV immune tolerance and pathogenesis. HBV might also affect maturation and function of myeloid dendritic cells (mDCs). Both HBV virions and HBsAg might reduce mDC maturation, T-cell stimulation and interleukin (IL)-12 production [56]. Similar findings have been reported in other dendritic cell (DC) subsets [57]. However, not all studies have found a difference in mDC number, phenotype or function in CHB. DCs do not appear to support active replication of HBV [58]. By contrast, DCs in various tissues are an important target of HIV and facilitate dissemination of infection to T-cell populations [59]. Specific alterations © 2009 International Medical Press 3/4/09 11:16:05 Liver disease pathogenesis in HIV–HBV coinfection in TLRs or in DC number or function in HIV–HBV coinfection have not been reported to date. Adaptive immune response The adaptive immune response to HBV infection includes HBV-specific CD8+ cytotoxic T-lymphocytes (CTLs) and the production of non-cytolytic cytokines such as IFN-γ, TNF-α and IFN-α/β [48,60,61]. HBV-specific T-cell responses as well as non-HBV-specific T-cells are both important [62]. An effective CTL response to HBV needs to be both multispecific, where a number of different HBV epitopes can be recognised, and polyclonal, meaning multiple T-cell receptors are able to bind a given HBV peptide–MHC complex [63,64]. HBV-specific CTL responses are reduced in HIVpositive individuals with natural immunity to HBV, compared with HIV-negative individuals with resolved HBV infection [65]. The HBV-specific CD4+ T-cell response is also significantly diminished in HIV–HBV coinfection compared with HBV-monoinfection [28]. Interestingly, in some individuals with chronic HBV infection who acquire acute HIV infection, there is a surprising decrease in HBV DNA and HBeAg loss, possibly because of HIVinduced non-cytolytic cytokine release [66]. An increase in both HBV-specific CD4+ and CD8+ T-cell responses occurs after treatment with HAART [67]. The initial immune response to acute HIV infection involves effector cells of both the innate and adaptive immune responses, namely NK cells and HIV-specific CD8+ T-cells [68]. The CD8+ T-cell response is particularly important, as it has been shown to exert selective pressure driving mutations in key HIV-specific CD8+ T-cell epitopes [69]. HIV antibodies are also produced by the humoural arm of the adaptive response, although their exact role is unclear. Host genetic factors are important determinants of immunological control of HIV, particularly human leukocyte antigen (HLA) molecules. For example, specific HLA alleles might be associated with increased immunological control (HLA-B57 and HLA-B27) or poorer outcome (HLA-B35 and HLA-B22) [70]. Immune restoration disease Following the initiation of HAART in individuals with low CD4+ T-cell counts (<100 cells/µl), approximately 10–30% of individuals present with a new opportunistic infection or worsening clinical symptoms of an already established infection [71], a condition that is often referred to as immune restoration disease (IRD). Hepatotoxicity (grade 3 or 4 transaminitis) after HAART occurs more frequently in HIV-infected individuals with either HBV or hepatitis C virus (HCV) coinfection [72,73]. The aetiology of abnormal ALT levels or hepatic flare following the initiation of HAART is often multifactorial, and includes Antiviral Therapy 14.2 Lewin.indd 159 worsening of underlying liver disease, antiretroviral hepatotoxicity, other medications and opportunistic infections, as well as IRD [74,75]. The pathogenesis of HBV-related IRD is currently unclear, but is possibly secondary to restoration of the anti-HBV adaptive immune response often associated with HBeAg seroconversion or a fall in HBV DNA [25,67,76]. Hepatic flare has also been reported without any changes in HBV markers or DNA, and even an increase in HBV DNA following HAART has been described [76,77]. A recent report demonstrated increased levels of CXCL10, MCP-1 and sCD30, cytokines and chemokines associated with T-cell and NK recruitment to the liver, in individuals with HBV-related IRD [75]. Important clinical risk factors for HBV-related IRD are a high baseline HBV DNA level, high ALT, low baseline CD4+ T-cell count and a rapid rise in CD4+ T-cell count [76]. The risk of mortality or significant morbidity appears to be higher in those with underlying advanced liver disease [76]. HBV-related IRD might also occur in the setting of occult HBV, particularly in individuals who are HBsAg- and HBsAb-negative but hepatitis B core antibody-positive [78]. Hepatic factors Apoptosis Apoptosis of liver cells, including hepatocytes and HSCs, is central to the process of hepatic inflammation that leads to fibrosis. Apoptosis might be the result of inflammation and fibrosis, but could also augment these processes [79]. Two apoptotic pathways have been described: the extrinsic pathway via death receptors (Fas, TNF receptor 1 and TNF-related apoptosis-inducing ligand [TRAIL] receptors 1 and 2) and the intrinsic pathway via intracellular organelles. The intracellular domains of activated death receptors interact with initiator caspases (such as caspase 8) [80] converging with the intrinsic pathway via caspase 3 [79]. Intracellular processes leading to apoptosis include changes in the endoplasmic reticulum, nuclear DNA changes and mitochondrial dysfunction. This might be a mechanism by which HIV or HAART could increase hepatic apoptosis [81]. Activation of TRAIL receptors causes apoptosis by the extrinsic pathway, as described earlier. An increase in membrane-bound TRAIL associated with CD4+ and CD8+ T-cells was found in peripheral blood from individuals with HBV compared with healthy controls, and this correlated with disease activity (ALT levels and liver histology) [82]. Recombinant human TRAIL caused massive and rapid apoptosis and cell death to >60% of human primary hepatocytes exposed for 10 h [80]. Virally infected cells, but not uninfected cells, were susceptible to TRAIL-mediated cytotoxicity in vitro [83]. TRAIL was also found at high levels in NK 159 3/4/09 11:16:05 DM Iser & SR Lewin cells in the blood and liver of individuals with HBV and spontaneous hepatic flare [84]. The extrinsic pathway appears important for T-cell mediated cytotoxicity, whereby all T-cell cytotoxicity appears to be facilitated by either the Fas or perforin pathways [85]. Altered T-cell numbers and a reduced CD4/CD8 ratio in the setting of HIV infection could cause increased hepatic apoptosis. Changes in apoptosis in HIV–HBV coinfection might be a crucial key to explaining increased hepatic fibrosis; however, direct evidence of this is lacking. Fibrogenesis mediated by hepatic stellate cells The major effector cells producing fibrosis are HSCs [79]. HSCs can undergo transformation from a quiescent state to a myofibroblast. Once activated, HSCs are important in the formation of the extracellular matrix and collagen, as well as producing proinflammatory cytokines and phagocytosing apoptotic bodies, which are themselves fibrogenic [86]. HSCs can undergo apoptosis either spontaneously, which is uncommon in vivo [87], or via the death receptors, Fas [88] and TRAIL receptor 2 [89]. Although a reduction in HSC numbers is important in the resolution of liver disease, the expression of death ligands, such as Fas, can be both proinflammatory and profibrogenic [90]. HSCs can also increase inflammation via the expression of MCP-1, intracellular adhesion molecule-1 macrophage inflammatory protein-2 and the complement pathway [91]. HSC activation also leads to upregulation of TLR-4, which is associated with the release of proinflammatory cytokines, such as IL-8 and MCP-1, via nuclear factor-κB [92]. This might explain how bacterial cell wall products, such as lipopolysaccharide (LPS) and lipoteichoic acid cause HSCs to release cytokines, such as IL-6 and MCP-1, and induce accelerated fibrosis [93]. In addition, HBx has a direct effect on HSC activation, leading to increased production of matrix metalloproteinase-2, tissue growth factor (TGF)-β, collagen-1 and α-SMA [94]. HSC activation might also depend on interaction with different T-cell subpopulations [91]. Evidence from a murine model suggests that CD8+ T-cells contribute to more HSC activation than CD4+ T-cells or whole splenic lymphocytes [95]. This might be relevant to HIV–HBV coinfection, where the number of CD8+ T-cells is increased relative to CD4+ T-cells, compared with HBV monoinfection. NK cells also interact with HSCs and might reduce HSC cell numbers by inducing HSC apoptosis [91]. Subsets of NK cells are susceptible to HIV infection and NK cells have reduced cytolytic activity and cytokine production in HIV infection [96]. NK cell suppression of HSC activity might therefore be reduced in HIV–HBV coinfection compared with HBV monoinfection. 160 Lewin.indd 160 Microbial translocation, increased lipopolysaccharide and generalized inflammatory response All venous drainage from the gut flows via the portal system to the liver, which is therefore a site of significant microbial traffic. Blood cultures performed at regular intervals immediately following percutaneous liver biopsy have demonstrated subclinical transient bacteraemia with Gram-negative organisms [97]. Following HIV infection, there is a profound loss of CD4+ T-cells, DCs, NK cells and macrophages from gut-associated lymphoid tissue [98–100]. CCR5+ CD4+ T-cells are significantly depleted, and there is associated T-cell activation and collagen formation within lymph nodes [98]. This damage to gut mucosal defence might lead to increased circulating microbial products, as measured by both LPS from bacterial cell walls and soluble CD14 (sCD14) from LPS-stimulated monocytes, and contribute to HIV-related systemic immune activation [99]. This increased microbial burden might cause immune dysregulation and increased CD4+ T-cell loss via TLR activation [101]. Partial improvement in levels of LPS and sCD14 has been demonstrated following HAART, suggesting an improvement in mucosal immunity and reduction in microbial translocation [99]. Bacterial endotoxaemia has also been described in other clinical settings, including decompensated cardiac failure, septic shock and a range of liver diseases including alcoholic liver disease and cirrhosis [102]. In addition to increased levels of endotoxin in cirrhotic individuals, derangements in pro- and anti-inflammatory cytokines might lead to relative endotoxin tolerance and increased susceptibility to bacterial infection [103]. Individuals with acute (hepatitis A and B) and chronic (hepatitis B and C) viral hepatitis were found to have increased sCD14, which was postulated to contribute to increased immune activation [104]. In HIV–HBV coinfection, it is possible that immune activation might be increased by the synergistic effect of both viruses, as recently demonstrated in HIV– HCV coinfection [105]. Microbial translocation was increased in individuals with HIV–HCV coinfection and the presence of cirrhosis was related to levels of LPS, LPS binding protein, sCD14, Aleuria aurantia lectin and endotoxin core antibodies [105]. Similar data from individuals with HIV–HBV coinfection are lacking. Other factors The initiation of HAART in individuals with HIV is associated with significantly increased ALT levels in up to 10% of cases [106], and higher rates might be seen in individuals with HIV–HBV coinfection [72]. Possible mechanisms for hepatotoxicity secondary to HAART include cumulative dose-related liver injury with drugs such as nevirapine [107], hypersensitivity reactions to © 2009 International Medical Press 3/4/09 11:16:05 Liver disease pathogenesis in HIV–HBV coinfection nevirapine or abacavir [108] or mitochondrial damage from drugs less commonly used now, such as didanosine, zidovudine or stavudine [109]. Several protease inhibitors (including the recently licensed darunavir) and a new non-nucleoside reverse transcriptase inhibitor, etravirine, have also been associated with increased hepatotoxicity in HIV–HBV-coinfected patients, although the mechanism of this is not currently understood [110]. The new classes of antiretrovirals, including the integrase inhibitor, raltegravir, and CCR5 antagonist, maraviroc, have not been associated with enhanced hepatotoxicity in the setting of HIV-hepatitis coinfection, although larger long-term studies of these newer agents are required [111,112]. Cirrhosis has been reported in 1% of HIV-positive individuals in the absence of coinfection with viral hepatitis compared with approximately 6% in those coinfected with HBV [113]. In addition, HIV monoinfection has been associated with portal hypertension without the presence of advanced fibrosis, but with various histological findings, including nodular regenerative hyperplasia [114], microvesicular steatosis or perisinusoidal fibrosis. Prolonged use of HAART agents, such as didanosine, might lead to mitochondrial toxicity or microvascular changes via portal endothelial cell toxicity, resulting in these histological changes [114]. Mitochondrial toxicity might cause direct hepatocellular apoptosis or necrosis or indirect damage via reactive oxygen species, lipid peroxidation and inflammatory cytokines such as TNF-α, TGF-β and Fas ligand [115]. These processes are also important in steatohepatitis, which might be present in HIV, either because of alcoholic or non-alcoholic steatohepatitis [115,116]. Conclusions The explanation for increased liver-related mortality in HIV–HBV coinfection compared with either infection alone is likely to be complex, involving both viruses and the immune response to each virus. HIV infects multiple cells in the liver both in vivo and in vitro. Therefore, there is an opportunity for HIV to 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 CD4+ or CD8+ T-cell immune response in the setting of HIV is likely to be important. The role of microbial translocation and immune activation, together with reduced NK cell activity and increased hepatocyte apoptosis causing increased HSC activation, will be important areas for future study. Acknowledgements DMI is a recipient of a postgraduate scholarship from the National Health and Medical Research Council Antiviral Therapy 14.2 Lewin.indd 161 (NHMRC; Australia). SRL is an NHMRC practitioner fellow and receives funding from the NHMRC, Alfred Foundation (Australia) and National Institutes of Health (1 R01 AI060449; USA). Disclosure statement The authors declare no competing interests. References 1. Alter MJ. Epidemiology of viral hepatitis and HIV coinfection. J Hepatol 2006; 44:S6–S9. 2. Konopnicki D, Mocroft A, de Wit S, et al. 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