Department of Infectious Diseases, University of Torino, Amedeo di Savoia Hospital, Corso Svizzera 164, 10149 Turin, Italy
Keywords: drug monitoring , antiretroviral therapy , liver function tests , protease inhibitors
Sir,
Some degree of hepatotoxicity was associated with the use of protease inhibitors (PIs) soon after their introduction into the antiretroviral market.1 Although under the term hepatotoxicity a variety of heterogeneous conditions of liver damage may be included, here the definition is broadly applied to any form of alteration of liver function tests (LFTs).
The clinical use of lopinavir/ritonavir, as a component of antiretroviral regimens, was found to be associated with an incidence of hepatotoxicity ranging from 1% to 9.5% in clinical trials.1 In this setting, an additional factor contributing to the likelihood of developing hepatotoxicity while on highly active antiretroviral therapy (HAART) is represented by the concomitant presence of HCV infection, which was found to be associated with a 4.7-fold increase in LFT abnormalities in lopinavir/ritonavir intakes compared with HCV-free subjects.2 However, generalization from clinical trial data has limited informative value, since no studies specifically addressed to evaluate lopinavir/ritonavir hepatotoxicity have been carried out in geographical areas with high prevalence rates of HIV/HCV co-infection. Among the possible mechanisms accounting for lopinavir/ritonavir hepatotoxicity in HIV/HCV co-infected patients, a role for higher drug concentrations resulting from reduced cytochrome P450 activity has been suggested. In patients with HIV/HCV co-infection, various degrees of liver function impairment were found to be proportionally associated with higher pharmacokinetic parameters of amprenavir, nelfinavir, indinavir, ritonavir and nevirapine.1,3 In HIV-infected patients with mild to moderate HCV-related liver cirrhosis, Arribas et al.4 found lopinavir and ritonavir area-under-the-curve (AUC) increases of 20% and 148280%, respectively. However, few data are available on the pharmacokinetics of lopinavir/ritonavir in non-cirrhotic HIV/HCV co-infected patients. In an observational, comparative, prospective study at the Department of Infectious Diseases of the University of Torino, in a high prevalence area for HIV/HCV co-infection, 149 treatment-naive HIV-infected patients were consecutively administered an antiretroviral regimen consisting of lopinavir/ritonavir and two nucleoside-nucleotide reverse transcriptase inhibitors.
Seventy-eight patients (52.3%) were HIV+/HCV (group A) and 71 were HIV+/HCV+ (group B). Self-reported poor adherence (<90%), liver cirrhosis and concomitant intake of drugs potentially interfering with the CYP450 enzymic system were the main exclusion criteria. Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) values were measured at 1, 3, 6 and 12 months. Hepatotoxicity was classified according to ALT and AST increases relative to baseline values as follows: mild (<2-fold), moderate (25-fold), and severe (>5-fold). Steady-state lopinavir Ctrough values were obtained at 1, 3, 6 and 12 months. Lopinavir plasma levels were measured by validated HPLC with UV detection. Baseline demographic, virological and immunological characteristics were matched in the two groups [median values (range): age, 41 (2671) years; sex ratio (M/F), 3.51; HIV-RNA (log), 4.85 (1.36.0); LTCD4+/mm3, 202 (3739)]. Baseline AST and ALT values were significantly higher in co-infected patients [median values (range): 44.5 (13206) versus 22 (14176) IU/L (P=0.033); and 54 (17149) versus 25 (9308) IU/L (P<0.0001), respectively].
Cumulative toxicity at 3, 6 and 12 months was significantly higher in co-infected subjects (Table 1).
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In our series, the incidence of LFT increase was significantly higher in HIV/HCV co-infected subjects. A similar finding has recently been reported by Chihrin et al.,5 who identified the duration of treatment with lopinavir/ritonavir as a risk factor associated with grade 3/4 ALT increase (odds ratio: 3.18) in co-infected patients. No patient in our study developed a very severe hepatotoxicity (ALT increase >10-fold) and LFT increase did not have a significant impact on treatment discontinuation. The pharmacokinetics of lopinavir/ritonavir, as assessed by serial measurements of Ctrough, showed no differences in the two groups and no association was found between the concentration of lopinavir and ritonavir and the development of hepatotoxicity. These data confirm the observations by Gonzalez de Requena et al.,6 who found no differences in lopinavir pharmacokinetics between non-cirrhotic HIV/HCV co-infected and HCV-free patients. The authors, however, did not determine the pharmacokinetics of ritonavir, a drug which was repeatedly found to be associated with hepatotoxicity when administered at full dosage (600 mg twice a day).7 Our findings thus indicate that the pharmacokinetics of ritonavir, when given at doses of 100 mg twice a day as booster, are not influenced by the presence of HCV infection in non-cirrhotic patients and that ritonavir is not associated with the development of hepatotoxicity. According to these data, no dosage adjustment is required for lopinavir/ritonavir in non-cirrhotic patients with HIV/HCV co-infection, information of particular value for those settings where the prevalence of subjects carrying this dual condition is high.
References
1 . Sulkowski, M. S. (2004). Drug-induced liver injury associated with antiretroviral therapy that includes HIV-1 protease inhibitors. Clinical Infectious Diseases 38, S907.[CrossRef][ISI][Medline]
2 . Da Silva, B., King, M., Cernohous, P. et al. (2004). Lopinavir/ritonavir safety, tolerability and efficacy in hepatitis C and/or hepatitis B-infected patients: review of clinical trials. In Program and Abstracts of the Fifteenth International AIDS Conference, Bangkok, 2004. Abstract MoPeB3285. International AIDS Society, Geneva, Switzerland. [Abstracts available online at http://www.iasociety.org/ejias/search.asp?].
3 . Almond, L. M., Boffito, M., Hoggard, P. G. et al. (2004). The relationship between nevirapine plasma concentrations and abnormal liver function tests. AIDS Research and Human Retroviruses 20, 71622.[CrossRef][ISI][Medline]
4 . Arribas, J., Pulido, F., Peng, J. et al. (2003). Evaluation of multiple-dose pharmacokinetics of lopinavir/ritonavir (LPV/r) in HIV and HCV co-infected patients with mild or moderate hepatic insufficiency. In Program and Abstracts of the Ninth European AIDS Conference, Warsaw, 2003. Presentation #F2/6. European AIDS Clinical Society, Paris, France. [Also available online at http://www.aegis.org/conferences/eacs2003/].
5 . Chihrin, S., Loutfy, M. R., Raboud, J. et al. (2004). Exposure to lopinavir/ritonavir is a risk factor for grade 3/4 elevation of ALT in HIV and hepatitis B (HBV) or C (HCV) coinfected patients. In Program and Abstracts of the Fifteenth International AIDS Conference, Bangkok, 2004. Abstract MoPeB3281. International AIDS Society, Geneva, Switzerland. [Abstracts available online at http://www.iasociety.org/ejias/search.asp?].
6 . Gonzalez de Requena, D., Nunez, M., Jimenez-Nacher, I. et al. (2004). Liver toxicity of lopinavir/ritonavir-containing regimens in HIV-infected patients with or without hepatitis C virus (HCV) co-infection. AIDS Research and Human Retroviruses 20, 698700.[CrossRef][ISI][Medline]
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Sulkowski, M. S., Thomas, D. L., Chaisson, R. E. et al. (2000). Hepatotoxicity associated with antiretroviral therapy in adults infected with human immunodeficiency virus and the role of hepatitis C or B virus infection. Journal of the American Medical Association 283, 7480.