HIV/HCV co-infection: clinical and therapeutic challenges

It is demonstrated that an increased risk of hepatotoxicity in cases of HIV/HCV co-infected patients undergoing antiretroviral regimens containing nucleoside reverse transcriptase inhibitors (NRTI) as well as PI is related to the drugs themselves rather than to the virus.

Abstract

The introduction of highly active antiretroviral therapy, containing at least one protease inhibitor (PI), has led to the prolonged survival of HIV-infected patients. In particular, both morbidity and mortality, caused by opportunistic agent-related diseases, have declined sharply [1,2]. Conversely, other clinically relevant complications, such as lipodystrophy, have emerged [3], raising serious issues relating to both the pathogenesis and clinical management. Another substantial challenge comes from HIV-positive patients co-infected by hepatitis B or hepatitis C virus (HCV). In some populations, approximately half the HIV-infected patients are co-infected by HCV [4]. In this issue of AIDS, Rancinan and colleagues [5] have analysed, prospectively and by the use of several covariates, a group of HIV/HCV co-infected patients undergoing antiretroviral regimens containing nucleoside reverse transcriptase inhibitors (NRTI) as well as PI. The authors demonstrated that an increased risk of hepatotoxicity in these cases is related to the drugs themselves rather than to the virus. The study confirmed evidence, reported from another, retrospective study [6], that NRTI can play a role in this disorder [7]. Several studies have focused on the role and the impact of HCV on liver damage in HIV co-infected patients and, subsequently, on the issue of whether antiretroviral therapies can contribute to such damage. As with other virus-triggered diseases, the liver damage of HCV-infected patients resulted substantially from cytokine-mediated inflammation [8]. The role of PI, as assessed by increased transaminase values, seems to be indirect, by inducing a rapid immune activation, with increased production of inflammatory cytokines, followed by a decline during long-term PI-based therapies. Conversely, a growing body of literature points to a direct hepatotoxic effect of antiretroviral regimens, worsening the liver damage induced by the virus. Moreover, some drugs used to treat HCV infection, such as ribavirin, may add to or synergize with some antiretroviral agents in damaging the liver. HIV infection has to be treated with potent drugs and combined therapy with IFN-α and ribavirin was found to be relevant, sustaining a virological response, and was well tolerated in a group of HIV/HCV co-infected patients [9]. In comparison with other studies, however, the addition of ribavirin did not improve, at 24 weeks follow-up, the virological benefit of monotherapy with IFN-α carried out for one year [10]. Biopsy-confirmed liver damage was found in HIV/HCV co-infected patients treated with combinations of antiretroviral agents containing NRTI and PI, plus IFN-α and ribavirin [11]. Findings of lactic acidosis and asymptomatic hyperlactatemia were also reported in patients undergoing the same therapies for concomitant HCV infection [12]. Some of these drugs induce mitochondrial toxicity by inhibiting mitochondrial γ polymerase [3]. This damages DNA replication, key metabolic pathways and, indirectly, some liver functions. An in-vitro gradient of mitochondrial toxicity has been shown for antiretroviral agents, giving the highest score to some NRTI, including zalcitabine, didanosine and stavudine [13,14]. Complications related to mitochondrial toxicity, such as lipodystrophy and serious adverse reactions to essential drugs, resulting in liver damage, are increasing. The issues for clinicians are many. Drug pharmacokinetics and pharmacodynamics have to be studied and understood. This is especially true when managing drugs that share the same molecular target, such as several antiretroviral agents and some compounds active against HCV. Careful clinical and laboratory monitoring, even with relatively cheap and simple tests such as transaminase level measurements, must be carried out in patients at risk of developing these complications, such as those with HIV/HCV co- infection. Finally, given that both infections have to be treated, because they are life-threatening and have a risk of neoplastic complications, and treatments lead to an increased life expectancy, a choice from among the possible drug combinations has to be made taking into consideration the patients’ risk categories. Finally, attempts to optimize drug regimens should be considered, by addressing prospective studies on the usefulness and appropriateness of therapeutic drug monitoring, which have given preliminary results in the field of PI [15], and by improving and clinically validating laboratory tests exploring mitochondrial toxicity [16]. There is still a long way to go, but the results so far seem promising.