Multiple concurrent factors make the study of liver function during HIV disease treated with antiretroviral combinations an emerging issue. Although the introduction of highly active antiretroviral therapy (HAART) led to sharp drop of immunodeficiency-related opportunistic infections (including hepatobiliary ones), short- and long-term toxicity of each single antiretroviral agent and their combination may add its effect to the frequently underlying chronic hepatitis B virus (HBV) and/or hepatitis C virus (HCV) infection, and their specific antiviral treatment [1–3].
Following the introduction of HAART as the standard of care of HIV disease, multiple pathogenetic mechanisms have been postulated for the emerging liver damage observed during the course of antiretroviral therapy. A direct or immune-mediated hepatic involvement seems to be caused by non-nucleoside reverse trascriptase inhibitors [4–7], while the administration of nucleoside analogues acts via mitocondrial abnormalities prompting hepatosteatosis, lactic acidosis, and muscle and bone toxicity [2,3,8], while protease inhibitors seem to be the main causes of glucose and lipid abnormalities, which also involve extensively liver metabolic pathways, as demonstrated by an increased tendency to abnormal liver enzymes in patients on protease inhibitor-based HAART, compared with controls without a viral hepatitis co-infection . Moreover, the rapid immune recovery as a result of HAART use may prompt an initially increased production of proinflammatory cytokines, which can lead to a flare-up of a concurrent viral hepatitis, especially in patients who initiated HAART when their immunodeficiency was severe [1,2]. For the debate, a surprising, significant improvement of liver enzymes has been described during HIV–HCV co-infection, apparently thanks to the sole HAART administration .
Furthermore, in countries where an HIV–viral hepatitis co-infection is a common feature due to the prevalence of injecting drug use among risk factors for parenteral viral infection [3,10], more than 50–60% of HIV-infected patients has a concurrent chronic hepatitis, characterized by a slow but progressive evolution until recent years, when effective treatments became available also for HIV co-infected patients. As a consequence, during recent years both morbidity and mortality due to complications of chronic hepatic disease (i.e., liver cirrhosis and hepatocarcinoma), overcome those of HIV-related complications, as clearly demonstrated by several epidemiological studies [3,11,12], although other surveys failed to confirm this phenomenon . A recently published French series regarding HIV–HCV co-infection, demonstrated that a shorted survival was related to a diagnosis of AIDS, a lower CD4 lymphocyte count, anaemia, thrombocytopenia, and persistent changes in transaminases (also due to concurrent drug therapy), as opposed to HCV infection itself . As anticipated, novel and potent pharmacological regimens are now available for an effective treatment of HBV and/or HCV infection, with ribavirin, amantadine, lamivudine, and tenofovir joining new interferon formulations as the standard of care of these chronic infections [1–3,14]. However, the extensive and prolonged use of these drugs has potential interactions with other compounds commonly administered for the management of HIV disease, and may be result in liver toxicity [3,14].
The clinical and immunological stabilization of HIV disease that is possible thanks to the availability of a broad spectrum of antiretroviral compounds, has its caveats in adherence, resistance, and toxicity problems. When HIV disease is associated with a viral hepatitis, other pharmacological treatments are needed concurrently and if substance abuse is still present (including intake of alcohol, heroin, and methadone), the risk of increased drug–drug interactions (drugs may include antimicrobial agents, cardiovascular, gastrointestinal, central nervous system drugs, antineoplastic regimens, anticoagulants, and non-steroidal anti-inflammatory drugs) and of end-organ toxicity is increased significantly, especially because of the central role of liver tissue in drug metabolism [8,15]. In particular, the untoward effects of single antiretroviral agents are still being intensively investigated and evaluated with surveillance programmes; these programmes pay particular attention to dysmetabolism and mithochondrial damage, as these as thought to be the common pathogenetic pathways of a broad spectrum of disorders which are increasingly reported among patients treated for a long period with anti-HIV agents. Some studies underlined a role for nucleoside analogues in causing increasing liver abnormalities in patients suffering from HBV and/or HCV co-infection [1,2,8,16]. Unfortunately, most of these patients have been treated for many years, so that cumulative toxicity has to be taken into account, while the concurrent use of three or four different drugs belonging to two or three different classes of antiretroviral agents makes more difficult the recognition of the role of each single drug in prompting toxicity [2,8,16]. This phenomenon becomes even more complicated when the spectrum of toxicity of the different drugs overlap, and several confounding factors may be present concurrently [15–18].
As a result, most of the available data are still limited by reduced sample size, absence of adequate control populations, and the real difficulty in assessing the role of each specific risk factor, especially when most of them are not independent from other supporting situations; multivariate analyses can be biased by a multitude of problems, which could explain the contradictory results of some published studies. A recent retrospective survey that investigated the incidence and risk factors of severe (grade 4) liver enzyme alteration in patients starting HAART, showed a crude incidence of 6.3%, with independent supporting factors recognized in chronic HBV/HCV disease, greater baseline transaminase levels, recent start of nevirapine- or high-dose ritonavir-containing regimens, and female sex ; the discontinuation of lamivudine proved a particular risk factor in HBV-co-infected subiects.
Coming to the role of non-nucleoside reverse trascriptase inhibitors in promoting increased liver toxicity, this feature seems significantly more frequent compared with that observed with other HAART regimens, but many studies failed in identifying the impact of single drug administration, from multiple co-existing risk factors. Nevirapine hepatic damage can result from a direct drug effect, leading to a long-term, possibly cumulated toxicity [5,12,19], or may occur earlier via a potential immune-mediated mechanism, which could be also responsible for the development of rash and other allergic reactions, which represent the most common untoward effects of this drug, although usually transient and mild in severity [4,6]. A recent study by Martinez et al. including 610 HIV-infected patients treated with nevirapine-containing regimens, underlined the proportionally frequent (12.5%) laboratory hepatotoxicity, but showed a limited number of episodes of acute hepatitis (1.1% of cases only) . A multivariate analysis of risk factors pointed out an independent role for duration of prior antiretroviral administration, concurrent HCV disease, and higher baseline transaminase levels . Another recent survey demonstrated a severe hepatotoxicity in 15.6% and 8% of patients prescribed nevirapine and efavirenz respectively, but 43% and 7.7% of the whole 568-patient cohort was co-infected with HCV and HBV, respectively . The concomitant administration of protease inhibitors seemed to increase the risk of liver toxicity, and interestingly elevated laboratory abnormalities were detected during the first 12 weeks of non-nucleoside reverse trascriptase inhibitor administration in 32% and 50% of cases for nevirapine and efavirenz, respectively  thus underlining a more frequent late hepatotoxicity for nevirapine compared with the other non-nucleoside compounds. In our experience, a low, comparable rate of adverse events was found when comparing first-line nevirapine use with nevirapine adjunct to a multi-drug salvage HAART . When compared with efavirenz, in a recent survey involving more than 1000 HIV-infected patients receiving this last compound, a significant elevation of liver function tests was observed in 0.68% of cases only . A retrospective investigation involving 272 patients treated with non-nucleoside reverse trascriptase inhibitors, detected a negligible 1.1% rate of grade 3–4 transaminase elevation, despite a 9% and 12% frequency of HBV and HCV co-infection, respectively; no difference was found among patients who took nevirapine (52% of evaluated patients), efavirenz (33%), or delavirdine (15%) . Interestingly, nevirapine-associated liver toxicity seems to be related to elevated plasma levels of the drug, and this feature is prompted by chronic HCV disease: in particular, serum drug nevirapine concentrations > 6 μg/ml were associated with a 92% rate of liver toxicity, in a pharmacokinetic study involving 70 HIV-infected patients .
The paper by de Maat et al. in this issue sheds light on an early-onset acute hepatic toxicity apparently prompted by nevirapine, although pre-existing liver abnormalities and the prior and concurrent administration of other drugs does not allow accurate estimation of the role played by nevirapine alone in this setting. The authors stress that strict monitoring should be in place for hepatic toxicity, which can parallel allergic rash such that an increase in liver enzymes may not represent a long-term toxicity that is easily recognized by the standard quarterly laboratory examinations usually performed in HIV-infected patients. Similar clinical features were previously described in a report of four cases of acute hepatitis apparently induced by nevirapine, which occurred shortly after drug initiation in patients with and without a pre-existing liver disease, and resolved promptly upon discontinuation , as well as in the seven cases evaluated by Martinez et al. .
In conclusion, the clinical and therapeutic tasks of clinicians caring for patients with both HIV infection and viral hepatitis are becoming more and more difficult. Starting from a complete knowledge of pharmacokinetic and pharmacodynamic interactions among all involved drugs, and between pharmacotherapy and an altered metabolism, careful attention has to be paid to ensure optimal treatment for chronic viral diseases (HIV, HBV, and HCV) in order to keep morbidity and mortality as low as possible. Case series such as that reported by de Maat et al. may add significantly to our knowledge, pending extensive, controlled studies which are expected to clarify the multiple points of doubt arising in parallel with the availability of effective pharmacological weapons for the management of potentially life-threatening diseases, such as HIV disease and chronic HBV/HCV viral hepatitis. Waiting for a complete pathogenetic insight, frequent and simple laboratory monitoring of short- and long-term markers of drug toxicity is warranted for HIV-infected patients treated with antiretrovirals, especially when other recognized risk factors are of concern.
1. Den Brinker M, Wit FW, Wertheim-van Dillen PM, Jurriaans S, Weel J, van Leeuwen R, et al
. Hepatitis B and C virus co-infection and the risk for hepatotoxicity of highly active antiretroviral therapy in HIV-1 infection. AIDS
2. Sulkowski M, Thomas DL, Chaisson R, Moore RD. Hepatotoxicity associated with antiretroviral therapy in adults infected with human immunodeficiency virus and the role of hepatitis C or B virus infection. JAMA
3. Ensoli F, Sirianni MC. HIV/HCV co-infection: clinical and therapeutic challenges. AIDS
4. Cattelan AM, Erne E, Salatino A, Trevenzoli M, Carretta G, Meneghetti F, et al
. Severe hepatic failure related to nevirapine treatment. Clin Infect Dis
5. Martinez E, Blanco JL, Arnaiz JA, Pérez-Cuevas JB, Mocroft A, Cruceta A, et al
. Hepatotoxicity in HIV-1-infected patients receiving nevirapine-containing antiretroviral therapy. AIDS
6. Piliero PJ, Purdy B. Nevirapine-induced hepatitis: a case series and review of the literature. AIDS Read
7. Sulkowski MS, Thomas DL, Mehta SH, Chaisson RE, Moore RD. Hepatotoxicity associated with nevirapine or efavirenz-containing antiretroviral therapy: role of hepatitis C and B infections. Hepatology
8. Bruno R, Sacchi P, Filice C. Mitochondrial toxicity in HIV-HCV coinfection: it depends on the choice of antiretroviral drugs? Hepatology
9. Diaz B, Martin-Carbonero L, Perez-Olinda M, Soriano V. Normalization of liver enzymes in an HIV-hepatitis C virus co-infected patient after potent antiretroviral therapy. AIDS
10. Rancinan C, Neau D, Saves M, Lawson-Ayayi S, Bonnet F. Mercie P, et al
. Is hepatitis C virus co-infection associated with survival in HIV-infected patients treated by combination antiretroviral therapy? AIDS
11. Cohen MH, French AL, Benning L, Kovacs A, Anastos K, Young M, et al
. Causes of death among women with human immunodeficiency virus infection in the era of combination antiretroviral therapy. Am J Med
12. Soriano V, Martin-Carbonero L, Garcia-Samaniego J, Puoti M. Mortality due to chronic viral liver disease among patients infected with human immunodeficiency virus. Clin Infect Dis
13. Cacoub P, Geffray L, Rosenthal E, Perronne C, Veyssier P, Raguin G. Mortality among human immunodeficiency virus-infected patients with cirrhosis or hepatocellular carcinoma due to hepatitis C virus in French Departments of Internal Medicine/Infectious Diseases, in 1995 and 1997. Clin Infect Dis
14. Bruno R, Sacchi P, Puoti M, Soriano V, Filice G. HCV chronic hepatitis in patients with HIV: clinical management issues. Am J Gastroenterol
15. Kresina TF, Flexner CW, Sinclair J, Correia MA, Stapleton JT, Adeniyi-Jones S, et al
. Alcohol use and HIV pharmacotherapy. AIDS Res Hum Retroviruses
16. Wit FW, Weverling GJ, Weel J, Jurriaans S, Lange JM. Incidence and risk factors for severe hepatotoxicity associated with antiretroviral combination therapy. J Infect Dis
17. Perez-Molina JA. Safety and tolerance of efavirenz in different antiretroviral regimens: results from a national multicenter prospective study in 1,033 HIV-infected patients. HIV Clin Trials
18. Palmon R, Koo BC, Shoultz DA, Dieterich DT. Lack of hepatotoxicity associated with nonnucleoside reverse trascriptase inhibitors. J Acquir Immune Defic Syndr
19. Clarke S, Harrington P, Condon C, Kelleher D, Smith OP, Mulcahy F. Late onset hepatitis and prolonged deterioration in haepatic function associated with nevirapine therapy. Int J STD AIDS
20. Manfredi R, Chiodo F. First-line nevirapine in combination with nucleoside analogues compared with nevirapine added to a salvage HAART. Infection
21. Gonzalez de Requeña D, Nuñez M, Jimenez-Nacher I, Soriano V. Liver toxicity caused by nevirapine. AIDS