Service of Internal Medicine, Unit of Infectious Diseases, Hospital Universitario de Valme, Seville, Spain
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Abstract |
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Keywords: HCV , HIV , AIDS , antiretroviral therapy , liver disease
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Introduction |
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Chronic hepatitis C (CHC) induces necrosis and inflammation of the liver, which appear to be responsible for the associated fibrogenesis. Mortality caused by this disease results predominantly from the development of progressive liver fibrosis, which ultimately leads to decompensated liver cirrhosis.
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Incidence of liver fibrosis in HIV/HCV-coinfected patients |
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Effects of HAART on HCV-related disease |
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Liver toxicity associated with antiretroviral drugs |
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It has been proposed that immune reconstitution may lead to an enhancement of liver injury caused by HAART in coinfected patients, due to a more vigorous immune response. However, a number of prospective studies have questioned this hypothesis.1 Antiretroviral drug-related hepatotoxicity has been found to be associated with the degree of CD4 cell recovery in some studies.9 However, a greater CD4 cell gain may be a marker of better adherence to HAART, which also increases the risk of liver toxicity appearing. Other factors that increase the risk of HAART-related hepatotoxicity in coinfected patients are alcohol consumption, infection with hepatitis B virus and higher baseline aminotransferase levels.1,912
Nucleoside reverse transcriptase inhibitors, such as zidovudine, didanosine or stavudine, may cause mitochondrial dysfunction, leading to lactic acidosis and steatohepatitis, which may result in liver failure.
In addition to the unconjugated hyperbilirubinaemia associated with indinavir and atazanavir therapy, protease inhibitors also cause elevations in hepatic aminotransferases. As many as 30% of patients prescribed full-dose ritonavir show a grade 3 or 4 change in levels of AST and/or ALT, i.e. an increase > 5 times the upper ULN or > 3.5 times the baseline level, if they were abnormal.13 Reduced doses of ritonavir cause increases in the aminotransferase levels less frequently. This incidence is also lower for the remaining protease inhibitors, with frequencies ranging from 1% to 9.5%.13
A grade 3 or 4 change in the values of AST and/or ALT occurs in 1015% of patients after starting nevirapine. This incidence ranges from 4% to 8% in individuals prescribed efavirenz.9,10,12 Although the evidence is conflicting, symptomatic liver disease seems to be more frequently associated with nevirapine than with efavirenz or the protease inhibitors. Thus, about 5% of patients undergoing nevirapine therapy develop symptomatic hepatic events. Cases of fulminant liver failure have been reported in HIV-infected patients on nevirapine therapy, including pregnant women receiving multiple doses for the prevention of mother-to-child HIV transmission.10 Likewise, health-care workers taking nevirapine for post-exposure prophylaxis after occupational HIV exposures have developed life-threatening hepatotoxicity.14 Nevertheless, fulminant hepatic failure or severe decompensations of chronic liver disease are uncommon.
During the first few weeks of therapy including non-nucleoside reverse transcriptase inhibitors (NNRTIs), liver injury may appear in the setting of a hypersensitivity reaction to these drugs, along with rash and fever. However, from half to two-thirds of liver toxicity cases emerge after 3 months on treatment.9,11,12 Moreover, the risk of NNRTI-related hepatotoxicity increases steadily over time during the first year of therapy.9,11,12
The pathogenic mechanism for liver toxicity associated with NNRTIs is not known. At least with nevirapine, it is unlikely that the same mechanism underlies all cases. Hepatitis cases appearing along with rash and hypereosinophilia are due to a hypersensitivity reaction. The remaining cases, specifically those occurring later in the course of the therapy, are more probably due to a cumulative effect of nevirapine.12 In HIV/HCV-coinfected patients, plasma nevirapine levels have been reported to be associated with the risk of hepatotoxicity.10 Whether high plasma nevirapine levels are the cause of liver toxicity or a mere consequence of liver dysfunction remains to be elucidated.
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Effects of antiretroviral drugs on liver fibrosis progression |
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A number of retrospective studies have been carried out to explore ways to overcome these problems. The FPR has been used to assess the speed of fibrosis development. However, this parameter might be fallacious, due to a lack of linear progression of fibrosis and to mistakes in the estimation of HCV infection date. Associations between individual drugs, drug classes or combinations and the FPR or the fibrosis stage have been analysed in these studies.
In a study of 152 HIV/HCV-coinfected patients in our unit, 31% of patients who had been treated with protease inhibitors had fibrosis F3 or F4, while this degree of fibrosis was seen in 49% of patients who were protease inhibitor naive. In addition, therapy with the protease inhibitors was associated with a lower FPR than therapy with nevirapine or efavirenz. Conversely, a history of nevirapine therapy was associated with higher FPR. Moreover, more patients among nevirapine recipients than among nevirapine-naive individuals showed advanced liver fibrosis (56% versus 36%, P=0.04). The prevalence of advanced fibrosis was greater in patients exposed to this drug for longer than 1 year. The levels of ALT had increased 2.5-fold from baseline in 27% of patients on protease inhibitors and in 76% of individuals who had received nevirapine. Efavirenz tended to be associated with a low FPR, but this association did not reach statistical significance. No other association with individual drugs or drug classes was detected in this study. According to these results, protease inhibitor-based combinations seem to protect against the progression of fibrosis, whereas nevirapine as the backbone of HAART is associated with faster liver fibrosis development. This effect of nevirapine seems to be cumulative and parallels ALT increases during therapy, which suggests that it is a consequence of the toxic effect of this drug on the liver. The different impact on the progression of liver fibrosis observed with these drugs is striking, given that they cause similar rates of liver toxicity. However, the reported frequencies of hepatotoxicity were estimated on the basis of the development of grade 3 or 4 changes in aminotransferases. It should be pointed out that AST and ALT remain less than 1.25 times the ULN or the baseline level in only 20% of nevirapine recipients. This rate is higher than that observed in patients on efavirenz9 or protease inhibitors.13 It is conceivable that this low-grade liver injury may lead to an enhancement of fibrosis progression.
Other studies addressing the impact of antiviral therapy on the progression of liver fibrosis have yielded conflicting results. Antiretroviral therapy, considered as a whole, was not associated with the severity of liver fibrosis in two studies.4,5 A longer time on antiretroviral therapy correlated with lower degrees of liver fibrosis in another Spanish study.15 Benhamou et al.16 also found protease inhibitors to be a protective factor against the progression of liver fibrosis. No relationship between NNRTI therapy and the severity of liver fibrosis was found in a European collaborative study.5 However, the effect of nevirapine could have been underestimated as nevirapine was grouped with efavirenz in the latter study. These conflicting results may reflect differences in analytic approach, patient populations and in the rate of use of specific antiretroviral drugs and combinations. In addition, a low statistical power may have accounted for the failure to detect some associations.
Long-term prospective studies are necessary to establish definitely the impact of antiretroviral drugs on the progression of HCV-related liver disease. The end points of these studies should be clinical, such as the emergence of liver failure or liver-related death.
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Patient management |
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HCV infection should be treated with pegylated interferon plus ribavirin, if there is no contraindication. Although the hypothesis is untested, it seems plausible that a sustained virological response leads to a reduction in the risk for liver injury due to HAART.
Other factors that are associated with advanced liver fibrosis independently of HAART should be eliminated. Hence, alcohol consumption must be avoided. HBV infection, if present, should be treated.
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Acknowledgements |
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References |
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