Mark Sulkowski, M.D.
The Hopkins HIV Report - November 1998

Protease Inhibitor Associated Hepatotoxicity: Role of HCV? Hepatitis C Viremia and Disease Activity: Impact of HAART and HIV Co-infection HCV and HIV Co-infection: Clinical Outcomes

Protease Inhibitor Associated Hepatotoxicity: Role of HCV?

Anecdotal reports have suggested an increased risk of drug-induced hepatotoxicity (DIH) during antiretroviral therapy in the setting of chronic HCV infection, and several presentations at ICAAC examined this possible interaction.

Hsiao and colleagues performed a retrospective, cross-sectional study evaluating the serum alanine transaminase level (ALT) among HIV and HCV co-infected patients receiving antiretroviral therapy for at least 2 months [H-23]. The study cohort consisted of 324 patients taking either nelfinavir (N=55), indinavir (N=37), or no protease inhibitor (N=80). Forty-two percent of patients were co-infected with HCV. The investigators found that HCV-infected patients receiving nelfinavir had higher serum ALT levels compared to HCV-negative patients receiving nelfinavir, indinavir, or no protease inhibitor. However, the authors did not have pre-treatment serum ALT levels on any patients, and the study design does not permit any firm conclusions regarding the role of HCV-infection in the development of DIH.

Piroth and coworkers reported the results of a prospective study describing the reasons for discontinuation of protease inhibitor therapy among a cohort of 309 patients, of whom 81 were HCV infected [I-60]. The investigators reported that drug-induced hepatitis was observed in 12 patients (3.8%); nine of the 12 cases occurred in HCV-infected patients receiving ritonavir. Hepatotoxicity was seen in 9 (12.7%) of 71 ritonavir treated and 1 (1.3%) of 153 indinavir treated patients. The authors suggest that DIH is associated with ritonavir use and coinfection with HCV. These results are in agreement with those of another study presented at ICAAC, which also suggests that ritonavir and viral hepatitis are associated with DIH [H-116].

Orenstein and colleagues described 5 patients followed at the VA Medical Center in Richmond, Virginia who developed DIH, defined as a serum ALT or AST level >3 x ULN [I-63]. The investigators found that the liver abnormalities were reversible with discontinuation of the drugs. Four of the 5 patients received ritonavir-containing antiretroviral regimens, emphasizing the greater potential for hepatotoxicity during ritonavir therapy.

Dieterich and colleagues presented results from the CHORUS observational database, which has prospectively collected clinical and laboratory data on 3459 HIV-infected patients since August 1997 [H-115]. The researchers presented data on 74 individuals who received protease inhibitor therapy and had pre-treatment and follow-up liver enzymes available. Ten of 74 (14%) of these individuals were chronically infected with HCV or HBV. They found that patients with chronic viral hepatitis had higher serum ALT level during therapy than non-infected individuals. Due to the small number of patients, the authors were not able to address which drugs were associated with hepatotoxicity.

Finally, our group from Johns Hopkins presented findings from a prospective, cohort study conducted at the Johns Hopkins Moore Clinic which examined the incidence of DIH following the initiation of antiretroviral therapy and the role of chronic viral hepatitis in its development [H-116]. We followed 253 patients who received PI-containing therapy and 128 patients who received dual nucleoside analog therapy between January 1996 and January 1998. Changes in serum liver enzymes during treatment were categorized according to standard toxicity scales, grade 0-4, with severe hepatotoxicity defined as a grade 3 or 4 change (>5 x ULN or >3.5 x an abnormal baseline value).

During antiretroviral therapy, 31 (10.4%) of 298 patients developed severe toxicity. The greatest risk of hepatotoxicity was observed with ritonavir-containing regimens. Fifteen (30%) of 50 patients taking ritonavir experienced DIH compared to 11 (6.8%) of 161 of patients taking non-ritonavir PI therapy and 5 (5.6%) of 87 patients taking dual nucleoside analog therapy. Ritonavir use was associated with a 6-fold increased risk of severe hepatotoxicity compared to nelfinavir, indinavir, saquinavir, and nucleoside analogs. Severe toxicity due to ritonavir was independent of HCV status, while severe toxicity due to non-ritonavir regimens was associated with chronic viral hepatitis. Among those not taking ritonavir, 13 of 16 episodes of severe hepatotoxicity were observed among patients with chronic viral hepatitis. In addition, 8 of 10 episodes of severe hyper-bilirubinemia also occurred among patients with chronic viral hepatitis.

This study suggests that ritonavir is associated with a greater risk of severe hepatotoxicity independent of HCV status, and that chronic viral hepatitis may increase the risk of hepatoxicity associated with non-ritonavir containing regimens. However, it should be noted that almost 90% of patients with HCV infection did not develop significant hepatotoxicity during treatment, suggesting that HCV-infected individuals are still good candidates for PI therapy.

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Recently published reports suggest that hepatitis C viremia may increase after the initiation of highly active antiretroviral therapy. Increases in serum transaminases have been attributed to concurrent increases in CD8 cell counts and an immune-mediated lysis of HCV-infected cells [Rutschmann OT, et al. J Infect Dis 1998; 177:783-5]. However, others have not found any significant change in plasma HCV RNA levels after the initiation of HAART [Zylbererg H, et al. Clin Infect Dis 1998; 26:1104-6]. Several papers presented at ICAAC examined the impact of HAART and immune reconstitution on HCV RNA levels during therapy.

Perez-Cano and colleagues reported that despite significant reductions in HIV RNA levels and increases in CD4 cell counts during antiretroviral therapy, HCV RNA levels increased during the first 3 months of treatment [H-27]. The authors followed 30 co-infected patients and found a 0.17 log increase in HCV RNA at 3 months post-treatment (P value not given), which was followed by a 0.34 log decrease after 12 months on therapy. These results are consistent with those of Rutschmann and colleagues and suggest the possible role of immune-mediated events occurring shortly after initiation of therapy.

However, two other studies presented at ICAAC contradicted these findings. In a well-designed study, Mendel and coworkers reported no increase in HCV RNA levels among 43 HIV/HCV co-infected patients receiving PI-based antiretroviral therapy [H-28]. In addition, Verdon et al examined HCV RNA, CD4 and CD8 counts during antiretroviral therapy. They analyzed frozen specimens from 27 patients and found no significant change from pre-treatment levels in HCV RNA at 3 and 6 months. In addition, there was no correlation of HCV RNA levels and either CD4 or CD8 cell counts [H-111].

In summary, while there may be an increase in HCV RNA within the first 3 months of HAART, these studies suggest that antiretroviral therapy and immune reconstitution have no long-term impact on the level of HCV replication.

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Monga presented the findings of a retrospective, cohort study performed at the VA Medical Center in Houston [H-118]. They examined the records and laboratory data of 142 patients with HIV and HCV co-infection and 195 patients with HIV alone. They found HCV-infected patients had higher serum ALT and AST levels and lower albumin levels than patients in the HCV negative cohort, but there was no evidence of an impact of PI therapy. The most interesting finding in this study was the prevalence of liver-related disease among co-infected persons. Decompensated liver disease and/or hepatocellular carcinoma was found in 6% of the HCV cohort compared to no cases in the HCV negative group (P=.0008) and was often diagnosed among patients with CD4 cell counts >50 cells/mm³.

This study highlights the increasing clinical recognition that hepatitis C virus infection leads to significant liver-related morbidity and mortality among HIV-infected persons and emphasizes the urgent need for more effective and aggressive anti-HCV therapy for co-infected individuals.

Mark Sulkowski, M.D. is an Assistant Professor of Medicine at the Johns Hopkins University School of Medicine

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©1998. The Johns Hopkins University AIDS Service, Division of Infectious Diseases. Permission to use and reproduce portions of this newsletter is hereby granted provided that author and publication are fully credited and both copyright and permission notice appear with reprinted material. Inquiries may be directed to Sharon McAvinue, Managing Editor. Website: Johns Hopkins AIDS Service.

The original of this article can be found at http://hopkins-aids.edu/publications/report/nov98_5.html