Martin-Carbonero, Luz; Soriano, Vincent
Department of Infectious Diseases, Hospital Carlos III, Madrid, Spain.
Liver steatosis is a common finding in patients with visceral obesity, hyperlipidaemia, elevated alcohol consumption and hyperglycaemia [1]. It is also frequently reported in patients with chronic hepatitis C virus (HCV) infection [2-4], particularly among those infected with HCV genotype 3 [3]. The mechanisms underlying the development of parenchymal steatosis in the liver of HCV-infected individuals are largely unknown, although it has been postulated that HCV core protein expression within the mitochondria could alter the double membrane structure, causing an impairment of lipid oxidation in hepatocytes. Ultimately, this phenomenon will result in the accumulation of fatty acids in the liver [5]. Hepatic steatosis accelerates the evolution of chronic HCV infection and has been associated with more severe liver inflammation and fibrosis [6,7]. Moreover, it has also been associated with poorer response to interferon-based therapies [8].
The clinical relevance of liver steatosis in the HIV-infected population is largely unknown. However, much concern exists, particularly following reports of severe hepatic steatosis and lactic acidosis in patients exposed to nucleoside analogue reverse transcriptase inhibitors (NRTI), mainly resulting from mitochondrial damage [9-11]. Moreover, many factors well known to be associated with liver steatosis, such as alcohol abuse, hyperlipidaemia, hyperglycaemia, visceral obesity and HCV infection, are highly prevalent among HIV-infected individuals. However, the harmful consequences of fatty liver disease in HIV-infected individuals only recently has attracted attention [12].
The real prevalence and clinical impact of liver steatosis among HIV-positive patients taking antiretroviral therapy is unknown. In this issue of the journal, Sulkowski et al. [13] have reported the rate of liver steatosis and its predictors in 112 HIV-HCV-coinfected patients with extensive prior antiretroviral therapy experience. Surprisingly, only 5% of patients showed significant liver steatosis in the liver biopsy, considered as fatty deposition in > 30% of hepatocytes. Moreover, 60% of patients did not show any liver steatosis at all. This low rate of liver steatosis is similar to that reported for HCV-monoinfected individuals [2-4] and, therefore, questions the presumed contribution of antiretroviral therapy and/or HIV itself on the development of fatty liver disease. It should be noted, however, that some particular features of the study population might have influence the author's results. For example, most patients were African-Americans (94%), and all but one were infected with HCV genotype 1. It is now well known that blacks have a lower prevalance of hepatic steatosis than whites, for unclear reasons [14], and that HCV genotype 3 is more freuently associated to lives steatosis than other HCV genotypes [3]. However, another recent report has found similar relatively low rates of liver steatosis in a different HIV-infected population [15]. More interestingly, in both studies, patients with hepatic steatosis had more sever liver fibrosis than those without it.
Sulkowski et al. [13] explored the independent predictors of liver steatosis. They found that it was significantly associated with the Caucasian ethnicity, overweight, hyperglycaemia and prior exposure to stavudine. A trend towards an association with exposure to protease inhibitors was equally noticed.
Inhibition of mitochondrial DNA polymerase gamma by NRTI has been associated with an impairment in mitochondrial function, accumulation of non-sterified fatty acids within intracellular vesicles, and increased production of lactate [16]. Side effects owing to mitochondrial toxicity are more frequent with certain NRTI than with others, and they may be more common when the drugs are taken in combination [17,18]. For example, myopathy has been mainly associated with zidovudine therapy, while peripheral neuropathy or pancreatitis has been particularly linked to didanosine and/or stavudine use. In their population, Sulkowski et al. [13] found that exposure to stavudine was associated with liver steatosis: nearly 90% of their patients with hepatic steatosis had been exposed to stavudine; conversely, none of those never exposed to the drug had liver steatosis. It should be kept in mind, however, that only 4 out of 112 individuals in their series had never received stavudine, while > 75% had been treated with stavudine and protease inhibitors. However, current or past exposure to stavudine did not seem to correlate with liver steatosis at the time of the liver biopsy. If stavudine plays a role in fat accumulation, it would be expected that some amelioration would occur upon discontinuation, as has been demonstrated with other factors causing fatty liver disease [19]. The same argument could be made for the other antiretroviral drugs. More than one-quarter of subjects were not taking antiretroviral therapy at the time the liver biopsy was performed, and these patients did not have less fat accumulation than the other subjects. Clearly, the involvement of stavudine and other antiretroviral agents in liver steatosis should be further examined in longitudinal studies and in larger populations before considering avoidance of their use in HIV-HCV-coinfected patients in an attempt to prevent liver steatosis.
Any potential deleterious impact of highly active antiretroviral therapy (HAART) on liver function, mainly among patients coinfected with HIV and HCV, should be balanced with the growing evidence supporting a beneficial effect of HAART on liver disease progression in this population [20,21]. The faster progression of HCV-related liver fibrosis classically seen in HIV-coinfected patients seems to be somewhat halted when patients are successfully treated with HAART [22,23]. Accordingly, many experts feel that the presence of chronic HCV infection should favour the early prescription of antiretroviral therapy in HIV-infected individuals [24,25], given the negative effect of immunodeficiency on HCV-related liver fibrosis [26]. In this respect, the report by Sulkowski et al. represents a note of caution and highlights that, depending of the antiretroviral drugs in use, the positive effects of HAART over HCV-related liver disease might be overshadowed by the development of drug-associated liver toxicities [27]. The recent experience with nevirapine confirms this concern [28,29]. Therefore, a closer look is warranted, and studies assessing the potential harmful effects of different antiretroviral agents on the liver are welcome and should be encouraged.
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