Patients with HIV infection have experienced a dramatic improvement in survival since the introduction of highly active antiretroviral therapy (HAART) in 1996 [1–3]. This benefit, however, has permitted that liver-related complications due to chronic viral hepatitis become more and more frequent among patients coinfected with both HIV and hepatitis B (HBV) and/or C (HCV) viruses. End-stage liver disease is now one of the leading causes of hospital admission and death among HIV-positive patients in the developed world [4–10]. The increased mortality due to liver disease has translated into higher mortality rates among HIV/HCV-coinfected patients with respect to HCV- negative, HIV-positive individuals in a recent Canadian cohort . In this issue of the journal, Bonacini and colleagues address the impact of liver mortality on overall survival in HIV-infected patients in South California, confirming the deleterious role of coinfection with hepatitis viruses, although providing new hopes derived from a possible beneficial impact of potent antiretroviral therapy on liver disease outcome in coinfected patients . Contrary to the Canadian study , Bonacini et al. found a higher unadjusted mortality rate among HIV-monoinfected individuals compared to those coinfected with hepatitis viruses. This is most likely due to the more severe immune suppression among HIV-positive patients without chronic hepatitis in their cohort. However, as expected, patients with viral hepatitis had greater liver mortality than those with HIV alone, with liver-related death rates accounting for more than 40% of the total number of deaths in their population .
Bonacini and colleagues  studied a cohort of 472 HIV-positive individuals referred to their clinic for evaluation of abnormal liver tests, and followed between 1993 and 2001. Patients were stratified into four groups according to their hepatitis virus serology: without hepatitis, with HCV co-infection, with HBV co-infection, and with multiple hepatitis viruses. Despite a relatively short follow-up period, patients with chronic hepatitis had greater liver mortality than those with HIV alone. Death rates were comparable between HCV- and HBV-coinfected patients, and highest among those with multiple hepatitis viruses. Their most interesting finding was that HAART and CD4 cell counts > 200 × 106 cells/l were associated with significantly lower liver mortality rates. Referral and misclassification biases most likely introduced in Bonacini's study do not invalidate the value of their findings.
A benefit of HAART on the outcome of liver disease in coinfected patients has been previously highlighted by others. In a recent report from Germany in which mainly hemophiliacs were assessed , a lower liver-related mortality was recognized among HCV/HIV-coinfected patients receiving HAART with respect to those who were untreated. This improved prognosis in HIV/HCV-coinfected subjects conferred by HAART seems to be related to a slower progression of liver fibrosis. At least two studies have demonstrated significantly reduced liver fibrosis stages in patients taking protease inhibitors [14,15]. How does antiretroviral therapy produce this benefit? HAART may reverse the negative effect of HIV infection on the immune system, which is known to accelerate liver fibrosis progression, especially when there is profound immune deficiency [16,17]. The findings from Bonacini's and Qurishi's studies [12,13] suggest that HAART immune restoration mainly drives this benefit on liver damage, ameliorating somewhat the characteristic faster liver fibrosis progression seen in coinfected patients .
On the other hand, liver toxicity of antiretroviral drugs is of growing concern and has multiple mechanisms, including a direct cytopathic effect of drugs such as ritonavir  and nevirapine [15,20] or mitochondrial damage induced by some nucleoside analogs [21–23]. In our opinion, at this time is unclear to what extent hepatotoxicity of antiretroviral drugs may compromise the claimed benefit on chronic viral hepatitis as a result of the immune restoration caused by HIV treatment. The topic is of great interest because it might justify an earlier introduction of antiretroviral therapy in coinfected patients, in an attempt to reduce poor liver outcomes.
Specific HBV T-cell responses have been demonstrated in HBV/HIV-coinfected patients receiving antiretroviral regimens that include drugs such as lamivudine and/or tenofovir, which are active against HBV . Likewise, specific HCV immune responses have been proved to increase following the immune recovery driven by HAART . A recent report has highlighted the pivotal role of cellular immune responses in facilitating HCV clearance . However, the results of studies that assessed HCV viremia after introducing HAART show conflicting results, and overall do not support the theory that HAART produces a decline in plasma HCV RNA titers [27,28]. Nevertheless, plasma HCV load does not exactly correlate with liver disease progression. On the other hand, immune suppression caused by HIV might favor the emergence of HCV variants with increased pathogenicity , and antiretroviral therapy might exert its benefit by containing the emergence of these virulent viral strains. Finally, a recent report has highlighted the role of suppression of HIV replication in slowing liver fibrosis progression in HIV/HCV-coinfected patients . Hypothetically, complete control of HIV replication might diminish the release of cytokines and fibrogenic factors, which account for the accelerated liver fibrosis typically seen in coinfected patients. In support of this argument are prior reports that have demonstrated that HIV may modify the inflammatory response to HCV antigens [31,32]. Clearly, further studies are needed to understand better the mechanisms underlying the positive effect of HAART over liver fibrosis progression in HIV-positive patients with chronic viral hepatitis.
The study by Bonacini and colleagues  makes another intriguing finding. According to their results, anti-HCV therapy also improved survival in HCV/HIV-coinfected patients. Subjects ever receiving interferon-based treatment for their HCV infection showed a trend towards lower liver-related mortality rates compared to those never treated. The small size of the study groups probably precluded this reaching a statistical significant difference in the analyses. In support of their findings, a large Japanese recent study has demonstrated an improvement in survival of HCV-monoinfected patients who reached sustained virological response to interferon treatment by preventing liver-related deaths . Further studies are needed to prove this benefit in the setting of HIV infection. If confirmed, it would strongly reinforce the need for treating chronic hepatitis C in HIV-coinfected patients . Although the results from recent trials using pegylated interferon plus ribavirin has proven the limited efficacy of current anti-HCV therapy in the HIV setting [35–38], there is no doubt that a positive impact on survival would render these treatments even more cost-effective. Moreover, the use of higher doses of ribavirin, the appropriate management of side effects and extending treatment for longer periods in earlier virological responders will probably improve the sustained virological response rates in HCV/HIV-coinfected patients, approaching the results seen in HCV-monoinfected individuals .
HBV coinfection seems to be as deleterious in HIV-positive patients as coinfection by HCV. According to a recent US study, HBV coinfection implies an increase in liver mortality of 12.7-fold in HIV-positive patients, and is more prominent in subjects with low CD4 cell counts . In agreement, Bonacini's data confirm that HBV increases liver mortality as much as HCV in HIV-coinfected patients. The analysis was performed previously in the 1990s, when no treatment or only lamivudine was available for treatment of HBV infection. Given the current availability of new drugs, some of them with activity against both HIV and HBV (e.g., lamivudine, emtricitabine and tenofovir), a decline in HBV-related liver complications should be expected in more recent years .
HIV-positive subjects co-infected with both HCV and HBV have shown a higher risk of dying from liver disease than patients co-infected with HCV or HBV alone . Accordingly, Bonacini et al.  found the highest risk of dying from liver disease among a subset of patients with multiple hepatitis factors. Therefore, these patients should have an especially close follow-up and treatment of their infections must be assessed accurately.
Finally, if HAART exerts such a positive impact on liver damage in HIV-positive patients with chronic viral hepatitis, what are the clinical implications of this observation? Current guidelines for the management of HIV infection recommend initiation of antiretroviral treatment only when the CD4 cell count is below < 200–350 × 106 cells/l, based on available data suggesting that mortality from opportunistic infections significantly increases below that threshold and that immune recovery is quite good even with that delayed initiation of therapy [43,44]. However, there is no evidence that HBV- or HCV-related liver damage is increased significantly only at advanced stages of immune suppression. Probably, the immune deficit correlates linearly with a faster rate of liver fibrosis progression. In this way, Bonacini's results acknowledging that HAART slows liver damage caused by hepatitis viruses may prompt us to re-evaluate whether current HIV guidelines are as applicable to patients coinfected with hepatitis viruses as they are to patients with HIV monoinfection. The appropriateness of starting HAART earlier in infection would be even more so for the many patients with chronic hepatitis C and who have major contraindications for receiving anti-HCV treatment (e.g., neuropsychiatric illnesses)  and for those who have failed to respond to it. Certainly, the side effects of HAART, especially long-term toxicities, must be taken into account and be balanced appropriately. However, when it comes to survival, the benefit conferred by HAART seems to far outweigh the risks associated with its use.
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