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Hepatitis Viruses & HIV Co-infection: pathogenesis & treatment
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Journal of Hepatology
Volume 41, Issue 1 (July 2004)
Anaïs Vallet-Pichard and Stanislas Pol
é d'Hépatologie et Inserm U-370, Hôpital Necker, 149 Rue de S èvres, 75015 Paris, France
Introduction
Co-infections by hepatotropic viruses and the human immunodeficiency virus (HIV) are frequent given the shared (sexual, mother-to-child and parenteral) routes of transmission. We shall mainly develop the reciprocal interactions between the hepatitis C virus (HCV) and hepatitis B virus (HBV) since they complex diagnostic pathogenic and therapeutic issues. Interactions between HIV and HCV have been widely studied before the introduction of highly active antiretroviral therapies (HAART) but the actual impact of HCV or HBV was limited given the severe morbidity and mortality related to HIV infection. In studies conducted in the 'AIDS era' (pre-HAART), the late consequences of hepatitis virus-related chronic liver disease were indeed overshadowed by extra-hepatic causes of deaths, related to severe immune deficiency, namely opportunistic infections, lymphomas or wasting syndrome and the impact of hepatitis virus infection on mortality of HIV-infected patients was low.
The development of HAART (regimens composed of nucleoside reverse transcriptase inhibitors [NRTIs], protease inhibitors [PIs] and/or non-nucleoside reverse transcriptase inhibitors [NNRTIs]) have resulted in a significant decrease in morbidity and mortality amongst HIV-infected patients: this clear benefit allowed the expression of liver-related complications associated with HCV or HBV chronic infection which is mainly acquired before HIV infection, at least in hemophiliacs and injection drug users (IVDUs). Liver disease is nowadays one of the leading causes of morbidity and mortality in co-infected patients. Several non-exclusive pathogenic processes that include drug-related hepatotoxicities, chronic hepatitis B (HBV) or C (HCV) infection, other liver diseases such as steatosis or non-alcoholic steato-hepatitis (NASH) and other liver diseases that are common in the setting of alcohol or drug abuse explain the increasing rate of liver complications associated with HCV-related liver disease. They account for around 9% of morbidity and 5% of mortality in HIV--HCV co-infected patients with a rise paralleling that observed in the general population, even though it has been suggested that HAART and especially protease inhibitors may decrease the severity of the liver disease and the liver-related mortality.
Prevalence of HCV- or HBV--HIV co-infection
AntiHCV antibodies are frequently detected in HIV-infected patients (around 20%), especially in hemophiliacs and intravenous drug users (around 70--90%) and are usually associated with active infection as assessed by detectable HCV viremia. This prevalence might be underestimated by rare delayed anti-HCV seroconversions and rare seroreversions.
Prevalence of HBV infection in HIV-infected population is high since around 80--90% of HIV infected patients have been exposed to HBV and 10% are HBs antigen (HBsAg) chronic carriers.
Reciprocal interactions between HIV and HCV or HBV
Impact of the hepatitis viruses on the natural history of HIV infection
It has been suggested that co-factors including infections may influence the natural history of HIV. Most of the early studies did not indicate a change in the natural history of HIV infection associated with HCV infection. Later studies have indicated that genotype 1b HCV may worsen the spontaneous evolution of HIV to both AIDS and death in hemophiliacs as well in drug users. Moreover, HCV infection (and active intravenous drug use) has been suggested as an important factor in the morbidity and mortality among HIV-1-infected patients, possibly through impaired CD4-cell recovery in HCV seropositive patients receiving potent antiretroviral therapy. Several different mechanisms potentially explain why HCV may act as a co-factor for HIV disease progression. Non-specific immune stimulation enhancing HIV replication, CD4 T-cell depletion reflecting infection of immune cells by HCV or HAART discontinuation all favor liver disease progression (see below). By contrast, HGV infection, which is common in people with HIV or HCV infection, has been suggested to slow the progression to HIV disease and to significantly improve survival. Most of the studies have not reported a clear impact of HBV infection on HIV immune status defined by the CD4-cell count or spontaneous progression to AIDS even though HBx protein may act as a transcriptional transactivator inducing HIV-1 replication and transcription in synergy with T-cell activation signals potentially contributing to a faster progression to AIDS in HBV/HIV co-infected individuals.
Impact of HIV infection on hepatitis viruses
HIV infection significantly modifies the natural history of HCV or HBV infection
Acute HBV infection in HIV infected-patients is different from that observed in non-HIV-infected patients because: (1) icteric illness is less frequent and hepatitis flares longer; (2) fulminant hepatitis has not been reported and (3) development of the chronic carrier state is higher, ranging from nearly 20 to 90% of HIV-infected patients, as compared to less than 3% in non-HIV-infected patients, with a higher risk if CD4-cell count is low and if there is a simultaneous infection by HIV and HBV.
HIV-related immune deficiency modifies the natural history of chronic HBV infection with: (1) higher HBV DNA levels (related to CDC stage of HIV disease but not to the CD4-cells count) this promotes a high contagion rate and the detection of HBV DNA even in the presence of hepatitis Delta virus super-infection; (2) lower ALT levels and lower rate of spontaneous loss of HBeAg and/or HBsAg and seroconversion to anti-HBe and anti-HBs; (3) the high rate of viral reactivation (30%) but also the potential reappearance of HBsAg in patients who have lost detectable HBV surface antigen. Despite the increasing prevalence of pre-core mutants to 60--90% in HBV-monoinfected population, the rate of HBe positive HIV-infected patients is around 85% in our experience, indicating the high replication of HBV and the higher replicative capacity of the wild as compared to the pre-core mutants HBV strains.
HIV infection increases levels of HCV or HBV viremia and HIV seroconversion increase HCV-RNA titers. This 2- to 8-fold increase results in a significantly increase risk of mother-to-child or sexual transmission of HCV (from a mean of 6 to 20% and from 0 to 3%, respectively). HIV co-infection worsens the histological course of HCV and HBV infection by increasing and accelerating the risk of cirrhosis or leading to rare but lethal fibrosing cholestatic hepatitis which is clearly related to direct cytotoxicity of HCV or HBV. As an example for HCV, the rate of cirrhosis is 2- to 5-fold increased in HIV--HCV co-infected patients as compared to HCV-infected patients and the mean time elapsed between contamination and cirrhosis is significantly reduced, which reflects a significantly increased yearly progression of the fibrosis score in co-infected subjects. Higher rates of cirrhosis in HCV/ or HBV/HIV co-infected patients is associated with low CD4-cell count and result in an increased liver-related mortality.
Virologic interactions and pathological impact
The pathogenesis of HBV- and HCV-related chronic hepatitis is mainly modulated by the immune system: the recognition of viral antigens expressed on the surface of hepatocytes triggers the liver injury resulting in spontaneously resolving acute hepatitis if the cellular CD8 immune response is strong or on the contrary on chronic hepatitis if the CD8 response is poor allowing the persistence of intracellular viruses. A decrease in immune-mediated mechanisms in relation with immune deficiency could theoretically result in a reduced necro-inflammation and in a less severe liver disease. Thus, there is a paradox in the greater severity of HBV- or HCV-related liver disease, including progressive fibrosis despite a minimal inflammatory activity. This suggests that the fibrogenesis process in HIV positive patients reflects both immune-mediated mechanisms and direct cytotoxicity of HBV or HCV as well as a complex interplay between viral proteins which may lead to overproduction of profibrogenic cytokines and probably also reflects various qualitative and quantitative non-exclusive mechanisms.
Fibrosis is mainly dependent on HCV-specific cellular immune responses, particularly HCV-specific cytotoxic T lymphocyte responses. HCV-specific CTLs induce liver injury both through the production of cytokines which are unable to control viral replication. The binding of virus proteins to the cell surface, independent of cell infection and viral replication within the cell may modify the signaling effects; such an 'innocent bystander' effect has been demonstrated in an in vitro model of co-infection: HCV E2 and HIV gp120 proteins act collaboratively to up-regulate Fas-L and induce apoptosis by a novel signaling pathway which may participate in the more rapid progression of hepatic disease in co-infected patients. Among the other co-factors of liver deterioration, a marked decrease in the CD4 cells count may lead to variations in the development of HCV quasi-species, resulting in the selection of HCV quasi-species with increased cytopathogeniaty. Not exclusively, HIV infection may have direct cytopathic effect on liver cells or may modify the pattern of cytokine production leading to production of fibrogenic factors. The absence of a correlation between quantitative viremia and severity of the liver disease which has been suggested in immunocompetent patients is now questioned and several studies reported a significant relation between the quantitative viremia and the severity of the liver disease, namely the extent of fibrosis. We consider that the more severe liver disease, which is observed in all the situations of immune deficiency probably reflect, at least partially, a deleterious impact of increased viremia. This is suggested by: (1) the same epidemiological (gender, duration of infection, age at time of infection, alcohol consumption), genotypic characteristics but higher HCV load and severity of the liver disease in HCV--HIV co-infected as compared to HCV mono-infected patients; (2) the association between the CD4 cell count indicating the immune status and liver histology in some studies; (3) the rare but lethal fibrosing cholestatic hepatitis which clearly reflects direct cytotoxicity of HCV or HBV; (4) a 2-fold higher HCV RNA levels in hemophiliacs who developed liver failure as compared to those who did not. Furthermore, in a recent case control study comparing HIV/HCV co-infected patients and mono-infected patients, we observed, like most authors, more severe liver disease in the former than in the latter with a more rapid speed of progression of fibrosis; in the former, specific anti-HCV immuno-chemistry was more frequent and intrahepatic quantitation of HCV RNA was higher (with a correlation between immuno-chemistry and intra-hepatic HCV RNA) than in HCV-monoinfected patients suggesting a causal relationship between high intrahepatic viral load and the more severe liver disease. High level expression of HBV or HCV proteins may lead to cellular injury: the expression of HCV proteins in cell lines diminishes the proliferative capacity of cells. This risk of direct viral cytotoxicity can be controlled in HBV infection by the use of nucleoside or nucleotide RTIs (lamivudine, adefovir dipivoxyl or tenofovir) that efficiently inhibit the HBV DNA polymerase but not in HCV infection. Indeed, only anecdotal cases of the disappearance of detectable HCV RNA have been described in patients receiving HAART (especially ritonavir). Significant restoration of CD4 and CD8 cell counts rarely decreases HBV or HCV load and there is no significant decrease, as compared to baseline values, in HCV RNA loads after 3, 6, or 9 months of HAART in HCV/HIV-coinfected subjects. These data suggest that HAART does not clearly decrease the incidence of HCV-related liver disease associated with HCV replication.
We previously mentioned that a marked decrease in the CD4 cell count may lead to variations in the pattern of HCV (or HBV) quasi-species, paralleling the potential selection of quasi-species with increased pathogenicity. On the contrary, the enhancement of immunity could be deleterious in diseases that involve immune-mediated mechanisms, such as viral chronic hepatitis, as reported after withdrawal from chemotherapy in HBV- or HCV-infected subjects. The number of liver CD8 T lymphocytes directed against specific HCV antigens correlate with disease activity and it is known that HAART restores the numbers of both CD4 and CD8 cells; this may influence the hepatic deterioration. Since the introduction of HAART, several cases of liver deterioration paralleling the immune restoration in HBV/ or HCV/HIV co-infected patients have been reported but it remains difficult to reliably determine a causal link between immune restoration and the liver deterioration.
Drug-related hepatotoxicity
Each component of HAART may result in drug-related hepatotoxicity. Early recognition and diagnosis of drug-associated hepatic events is necessary for a safe and effective use of HAART. The diagnosis of hepatotoxicity is mainly based on chronological, biochemical and serological criteria. Chronological criteria include the recent introduction of potential hepatotoxic drug (within the last 3 months), the biochemical improvement following drug discontinuation and a relapse of liver abnormalities following a re-challenge (which should be avoided). Other factors are mainly the exclusion of other causes of liver disease: alcoholism, viral infections (HAV, HBV, HCV, HDV, CMV, EBV, HSV, etc.), non-viral induced liver disease (NASH), heart disease and/or concomitant medications. Most HIV-infected patients do not fulfill the semiological and chronological signs that allow one to clearly conclude that drug-related hepatotoxicity is present. Patients are treated with multiple drugs, they may use or abuse alcohol or over-the-counter drugs and HBV or HCV co-infection occurs in up to 30% of cases. In parallel with the typical but rare cases of idiosyncratic hepatitis with nevirapine for example, we cannot exclude overdoses or drug-related toxicities enhanced by an underlying liver disease like HCV infection and favored by the depletion of 'protectors' of the liver. All classes of antiretroviral drugs have been associated with liver enzyme abnormalities, which prevalence is not well defined. Hepatotoxicity related to the use of NRTIs, especially zidovudine, stavudine and didanosine, has been reported and may lead, in exceptional cases, to severe microsteatosis with lactic acidosis. 'Drug-related hepatitis' in association with PIs is more frequent and has been observed in 2--8.5% of PI-treated patients, with an increased risk in patients co-infected with HBV or HCV. Liver toxicity, including fulminant hepatitis, has been recently associated with NNRTIs and pre-existing liver disease increases the relative risk.
In most cases of drug-related hepatitis, apart from fulminant presentations, liver enzyme abnormalities resolved after discontinuation of the drug and did not relapse, for example, after changing the PI. We speculate that drug-related hepatitis may be involved in the deteriorating liver histology, mainly by mechanisms associated with drug-related non-alcoholic steatohepatitis (NASH). HAART withdrawal in relation to hepatotoxicity was less than 5%, without significant differences between the different types of antiretroviral drugs.
Other causes of liver damage in HIV--HCV or HBV-co-infected patients
Paralleling HAART-related hepatotoxicity and HCV-chronic hepatitis, HIV-infected patients may have other risk factors for liver enzyme elevations. These mainly include alcohol consumption, drug or other medication abuse and metabolic syndromes. The impacts of these three last co-factors of liver deterioration have not been clearly analyzed in co-infected patients. The deleterious consequences of alcohol in HCV-monoinfected patients include: (1) increased levels of HCV RNA resolving with alcohol withdrawal; (2) increase in fibrosis progression. In co-infected as well as in mono-infected patients, alcohol withdrawal appears necessary to limit its direct detrimental impact and also to improve immune status. Chronic alcohol consumption is observed in 30% of HIV-infected patients (at least ex-drug abusers) and may result in alcoholic hepatitis leading to hepatic deterioration. Medical counseling supports alcohol abstinence in most patients. Interestingly, alcohol, via its metabolic effects, depletes factors that protect the liver, including glutathione, and may enhance drug-related toxicity. The immunosuppressive properties of chronic alcohol consumption enhances viral replication and the combination of alcohol and viral hepatotropic chronic infection has a synergistic and deleterious impact. In our experience, HIV-infected patients seem to be more sensitive to alcohol toxicity, which may be enhanced, at least partially, by other medications.
Drugs, especially cocaine and methamphetamine, have their own hepatic effects and these are sometimes severe (e.g. fulminant hepatitis with renal failure and rhabdomyolysis).
Finally, abnormal metabolic syndromes may participate in liver deterioration of co-infected patients and include NASH in relation to HAART, abnormal metabolic syndromes (such as diabetes and dyslipidemia) and HAART-related metabolic syndromes. The potential involvement of NASH in liver biochemical abnormalities and pathological deterioration is suggested by the significantly higher frequency in HIV-positive than -negative patients of steatosis, Mallory bodies and neutrophils infiltrates which may be due to the effects of the antiretroviral therapy on the mitochondria. Antiretroviral-associated mitochondrial toxicity involves the inhibition of the mitochondrial DNA polymerase g, an enzyme that is required for mitochondrial replication. NRTIs reduce mitochondrial DNA content and alter mitochondrial morphology in a dose-dependent fashion. The depletion of mitochondrial DNA related to the use of NRTIs, in combination with alcohol-induced alterations of mitochondria, could further impair the cellular respiratory chain and finally enhance the macrovesicular or microvesicular steatosis, and the number of giant mitochondria. This may trigger lipid peroxidation and the release of pro-inflammatory cytokines, inducing fibrosis and apoptosis. Steatosis has been recently recognized as an independent factor associated with fibrosis progression in immunocompetent patients, especially those infected with genotype 3 HCV or who are overweight. Steatosis, in relation to alcohol and antiretroviral therapy but also drug-related metabolic disturbances and lipodystrophy, may participate in the pathological deterioration of HIV-infected patients.
Treatment of HCV infection in HIV-infected patients
The increased risk of cirrhosis in HCV--HIV co-infected patients, the histological deterioration under tritherapy related to the intricacies of the various pathogenic mechanisms, the increase in survival of HIV-infected patients underline the need for reliable anti-HCV antiviral therapies. The therapy is the same as in the general population based on the combination of the pegylated interferon and ribavirin. Therapeutic issues are to precisely delineate: (1) when and who among HIV-positive patients should receive antiviral treatment in order to achieve eradication of HCV infection, thus avoiding histological deterioration; (2) whether anti-HCV or anti-HIV therapy is the priority.
The results of treatment with ribavirin--interferon combination indicate roughly a 2-fold lower rate of sustained virological response in co-infected than in HCV mono-infected patients. At least three multicenter studies have been reported comparing the standard to the pegylated interferon--ribavirin combination in HIV--HCV co-infected naive patients (ACTG, Apricot and Ribavic). The preliminary results suggest that there was: (1) no significant difference of tolerance between the two groups who discontinued the treatment in around 15--30% of cases; (2) a higher efficacy of the pegylated combination; (3) a reduced overall efficacy as compared to the non HIV infected population from 55 to 35% of sustained virological response, ranging from 15 to 50% according to the genotypes 1 and 4 or 2 and 3, respectively; (4) the value of the early viral kinetics (fall in HCV RNA at week 4 or 12) which seems to provide a valuable negative predictive value in co-infected as well as mono-infected patients; (5) no positive or negative effect of the pegylated interferon on the immune status (CD4 cell count and HIV viral load); (6) a significant increased risk of mitochondrial events (pancreatitis, liver failure, lactic acidosis) in patients treated with ribavirin and didanosine and stavudine.
Thus, pegylated interferon and ribavirin treatment of HCV infection in HIV-infected patients is likely to be associated with a 30% rate of sustained response and to reduce the development of liver fibrosis and cirrhosis. The potential benefit associated with the so-called maintenance therapies using interferon alone in non-responders to antiviral treatment is not demonstrated in co-infected patients.
A potential limitation of combination IFN/RBV therapy for anti-HCV therapy is the interference between anti-HCV drugs and anti-HIV drugs. In vitro inhibition of the phosphorylation by ribavirin of HIV reverse transcriptase inhibitor, i.e. zidovudine (AZT), stavudine (d4T) and zalcitabine (ddC) has been reported questioning the potential impairment of the efficacy of antiretroviral nucleoside analogs which does not seem to be clearly modified in vivo. By contrast, ribavirin may positively interfere in vitro with phosphorylation of didanosine (ddI) and the triple combination ddI, ribavirin and interferon is highly synergistic in vitro; recent in vivo studies indicate a positive interaction which increases the side effects of ddI, especially the risk of lactic acidosis, in association with pancreatitis. In case of interference between ribavirin and antiretroviral drugs, a change of this latter is now usually possible with the increasing wide range of anti-HIV therapies. In summary, we recommend the pegylated interferon and ribavirin combination in HCV and HIV co-infected with close monitoring of serum lactate, CD4 and HIV viral load in those patients with a biopsy-proven active or fibrotic liver disease.
Treatment of HBV infection in HIV co-infected patients
The tools
Three treatments are approved for HBV: interferon, lamivudine and adefovir.
Interferon-a was the standard treatment of HBV infection and the development of the pegylated (long lasting) prep might increase its indications since in HBV mono-infected patients pegylated interferon is more efficient than standard interferon leading to one third of HBe seroconversion. Lamivudine (3TC), a nucleosidic reverse transcriptase inhibitor, is a safe and effective treatment against HBV infection in HIV co-infected patients, since controlling both HIV and HBV replication, but its efficacy is limited by emergence of (HIV and) HBV resistance associated with prolonged treatment with rates of resistance of 50 and 90% after 2 and 4 years of treatment, respectively. The same efficacy and resistance will be obtained with emtricitabine.
Adefovir dipivoxil, a nucleotide analogue, is efficient against HBV (wild-type and lamivudine resistant virus) in HIV/HBV co-infected patients and the pattern of resistance is more rare than that with lamivudine since observed in less than 2% of patients after 2 years of therapy in HBV mono-infected patients. Tenofovir, another nucleotidic analogue, is efficient against both HIV and HBV at a once daily dose of 300 mg.
Therapeutic strategies in HBV/HIV co-infected patients
Therapeutic strategies depend on the input on the liver by both HIV and HBV and this has to be evaluated by a liver biopsy or biochemical markers of fibrosis.
Table 1. Therapeutic strategies in HBV/HIV co-infection
According to the liver evaluation(a)
No HAART required
--Pegylated-interferon
--Adefovir
-
-Combination?
HAART required and no anti-HBV treatment required
--To include lamivudine in HAART regimen
--To include tenofovir?
--Combination?
HAART in course and indication for anti-HBV treatment
Controlled HIV and lamivudine resistant HBV
--Adefovir
--Pegylated interferon?
Uncontrolled HIV and lamivudine resistant HBV
--Switch to tenofovir
Controlled HIV and wild-type HBV
--To continue lamivudine with virological follow-up (PCR every 4 months)b
[a] Anti HBV therapies are recommended in patients with a significant fibrosis ( F>1 in the Metavir scoring system).
[b] The occurrence of a lamivudine resistance is suggested by an increase in HBV DNA titer of at least which precedes the clinical or biochemical breakthrough of at least 3 months.
Anti-HBV treatment of first choice
If antiretroviral therapy is necessary, it seems reasonable to include lamivudine (or emtricitabine) in HAART. The indications of tenofovir must be developed. The identification for tenofovir or lamivudine (or emtricitabine)--tenofovir combination is unknown. By contrast, if antiretroviral therapy is not necessary, pegylated interferon could be used in patients with a stable and good immune status; it should be used carefully in patients with extensive fibrosis or cirrhosis, knowing that the rate of durable viral eradication will be probably low: most of studies have suggested a rate of response of 10--30% defined by HBV DNA negativation with low sensitive test. If a nucleos(t)ide anti-HBV monotherapy is preferred, the use of adefovir appears to be less risky than lamivudine alone because there is a lower risk of resistance of both HIV and HBV.
Treatment of lamivudine-resistant HBV
Until recently, Interferon was the only potent treatment but there is little data on the response rate to interferon of lamivudine-resistant HBV. Adefovir reduces significantly the viral multiplication without severe adverse events except cases of increased ALT levels in first 3 months of treatment. Long-term efficacy has not been yet studied, but its benefit is demonstrated for reduction of necro-inflammation and fibrosis. HBe/anti-HBe seroconversion can be observed in 10% of patients and viral multiplication negativation using PCR in 15% of them. Adefovir treatment at this dose of 10 mg/ day is not effective to control HIV viral multiplication. Tenofovir (300 mg daily) may be used combining its activity against HBV and HIV. Whether lamivudine should be continued or a switch of lamivudine to adefovir (or tenofovir) made is not clear. The choice whether to use adefovir or tenofovir will be based on the immune status requiring (tenofovir) or not (adefovir) the modification of the antiretroviral regimen.
Vaccination
HIV and HBV transmission occurs by the same paths. In HIV-infected patients exposed to the risk, vaccination against HBV and HAV will be recommended. The problem of vaccination in HIV positive patient is the increase in the adverse reactions and the decrease in vaccine efficacy. There is also the risk that potential T cells become activated by the vaccination which could increase the viral replication.
In patients with chronic hepatitis B, the hepatitis A vaccination is highly advisable since the risk of fulminant hepatitis associated with the HAV infection may be increased in those with co-infection. Cost-effectiveness studies recommend measurement of IgG anti-HAV prior to vaccination, especially in HIV positive adults. The response to hepatitis A vaccine is very poor when CD4-cell count is lower than 200 mm-3. In summary, it is recommended to vaccine against HAV all HIV positive patients who have negative HAV IgG and CD4-cell count higher than 200 mm-3. This recommendation is also based on the high risk of HAV sexual transmission by anal intercourse in homosexual patients.
By contrast with the high efficacy of HBV vaccine in the general population (95%), the immunogenicity of the standard HBV vaccine is decreased in HIV positive patients to 33--85%, in relation with the CD4-cell count. The response to HBV vaccine can increase by 90% with higher dose of antigen and/or higher number of inoculations (four doses at 0, 1 2 and 6 months with double quantity per dose). Finally, in immunocompromised patients, a loss of protection could be more rapid and frequent than in the general immunocompetent people.
Specific problems in managing co-infection
The use of antiretroviral drugs in patients with HCV or HBV infection
A preexisting biochemical abnormalities of the liver does not clearly modify the use of antiretroviral drugs although the use of abacavir and ritonavir may be difficult. Nucleoside inhibitors of reverse transcriptase are not metabolized by the liver. By contrast, protease inhibitors and non-nucleosidic analogues are mainly metabolized by the cytochrome p-450 3A the activity of which may be modified by a preexisting liver disease. The problem is that these metabolic variations may have positive as well as negative effects (enzymatic induction or inhibition) according to the particular combination of antiretroviral drugs. Also the particular pattern of the liver disease, the presence of a liver failure and in addition nutritional, genetic or hormonal factors: all may preclude specific therapies. That is why, the monitoring of the plasmatic levels of antiretroviral drugs may be valuable in order to limit any overdose which may lead to toxicity including hepatotoxicity, ranging from the mitochondrial toxicity of nucleosides analogues to the hepatocyte toxicity of protease inhibitors. In co-infected patients under HAART, a biochemical follow-up is warranted each month in the first 3 months after introduction of any new antiretroviral drug then each 3 months in order to identify potential drug-related toxicity. An increase in ALT levels (>5-fold the upper normal value, but the kinetic of increase is more important than the absolute values) will result in a switch of the protease inhibitor or the introduction of a NNRTI. A liver biopsy should be discussed case by case if biochemical liver abnormalities persist despite drug discontinuation. Biochemical liver abnormalities occurring after the introduction of a non-nucleosid reverse transcriptase inhibitor may lead to treatment withdrawal, especially if cutaneous signs of hypersensitivity are noted. The interpretation of biochemical liver abnormalities is very difficult always raising the question of drug-related hepatitis and/or superimposed toxic causes (alcohol, cocaine, metamphetamine…) or even a hepatitis of 'immune restoration'. Antiviral therapy may be proposed when drug withdrawal does not result in a biochemical normalisation, suggesting a drug-associated triggering of the viral liver disease.
Temporal place of anti-HCV and anti-HIV therapies
An unsolved question is the temporal place of antiHCV and antiHIV therapies. In clinical practice, most of HIV co-infected patients should be referred to the hepatologist while receiving HAART. In the future, hepatologists, immunologists and infection disease specialists should discuss the priority of both treatments according to the liver histology and the immune status. We speculate that imbalance between the potential advantages (complete eradication of HCV infection resulting in a complete reversibility of HCV-related chronic hepatitis, a decrease in the risks of immune restoration and of drug hepatotoxicity increased by the underlying liver disease) and the inconvenience of therapy (side effects, resolving decrease in the CD4 cell count, absence of antiviral sustained efficacy) that antiHCV therapy will frequently appear as the first line treatment, at least in patients with a CD4 cell count above 350cells/ml. Finally, the cost-effectiveness of the treatment has been recently reported.
Temporal place of anti-HBV and anti-HIV therapies
Pretherapeutic liver biopsy is useful in HBV/HIV co-infected patients given the risk of HAART related-hepatotoxicity and immune restoration hepatitis. Liver biopsy (or potentially biochemical tests as mentioned above) appears necessary to decide on whether to treat or not to treat HBV infection according to the degree of necro-inflammatory activity and fibrosis. If the immune status is good, first treatment will be against HBV in patients with significant fibrosis for decreasing the risk of pathological worsening associated with HAART use or immune restoration. If the immune status requires HAART, the antiretroviral therapy is a priority, and lamivudine or tenofovir must be included in HAART for the simultaneous control of both infections.
The place of liver transplantation in co-infected patients
The place of liver transplantation in co-infected patients remains anecdotal. Preliminary results suggest that liver transplantation is feasible with a survival which does not appear to be so different from that observed in the general population, at least if candidates are transplanted when their HIV status is stable (CD4>100 ml-1 and viral load <50copies/ml). The two major pitfalls of liver transplantation are the recurrence of HCV infection on the allograft, As is the case in the HIV infected population the question is of early antiviral therapies after the recurrence. The interactions between immunosuppressive regimen and HAART, which requires close monitoring of plasma levels of both drugs. HBV/HIV co-infected patients have been usually excluded from liver transplantation. The interaction between immune status and the multiplication of HBV associated with antirejection therapies raise the question of transplantation in these patients. The indications for transplantation are the same, in HBV mono-infected and in HBV/HIV co-infected patients, i.e. small hepatocellular carcinoma, hepatic failure or symptomatic portal hypertension with a controlled HVB replication.
In conclusion, at the era of triple antiretroviral therapy HIV/HCV or HBV co-infection may result in symptomatic liver disease and a risk of hepatic deterioration paralleling immune restoration. Given the lack of impact of triple antiretroviral therapy on HCV load, the potential drug-related hepatitis which may modify the natural history of HCV-related liver disease and the potential efficacy (complete virologic and pathological recovery of HCV infection), the possible diagnosis of HCV and HBV infection has to be considered in any HIV-infected patient using both serological (antiHCV antibodies and HBs Ag) and virological (serum HCV RNA or HBV DNA by PCR) tests. The impact of HCV or HBV infection in HIV-infected patients has to be evaluated either on the basis of liver histology and/or biochemical tests in order to identify patients with severe liver disease who require anti-HCV or -HBV therapy. Progresses in the treatment of HIV and HCV or HBV infections justify the active monitoring of co-infection including diagnosis, evaluation and treatment. This requires a multidisciplinary approach with specialists in ID, immunology and hepatology.
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