Severe liver toxicity in postexposure prophylaxis for HIV infection with a zidovudine, lamivudine and fosamprenavir/ritonavir regimen

In France, post-exposure prophylaxis (PEP) is provided to patients after HIV occupational or sexual exposure. Current guidelines recommend the use of combined antiretroviral therapy (i.e. two nucleoside reverse-transcriptase inhibitors and one protease inhibitor) for 4 weeks [1]. After January, 2006, in the Infectious Disease Department of Lille University at Tourcoing Hospital, France, in the absence of genotypic resistance mutations to antiretroviral drugs in source patients, PEP provided to patients exposed to HIV was changed from zidovudine/lamivudine (combivir) 300 mg/150 mg twice a day, and nelfinavir (1250 mg twice a day) to combivir and fosamprenavir/ritonavir (700/100 mg twice a day). From January 2006 to March 2006, 26 patients were prescribed this regimen, 22 of whom were sexually and four occupationally exposed to HIV, respectively. On 31 March 2006, it was decided to stop the use of this combination for PEP because of the occurrence of an unexpectedly high incidence of side effects. Of the 26 patients prescribed combivir and fosamprenavir/ritonavir, seven patients (26.9%) reported nausea, vomiting or abdominal pain (i.e. grade 1–2 toxicity); none of these events resulted in PEP interruption. Three patients (11.5%) reported rash (i.e. grade 2 toxicity) a median of 10 days after treatment initiation, among whom one discontinued fosamprenavir/ritonavir. One patient (3.8%) developed grade 1 and one patient (3.8%) grade 2 liver toxicity, 28 days and 14 days after treatment initiation, respectively. Two patients (7.7%) reported grade 4 liver toxicity with alanine aminotransferase (ALT) levels above 10 times normal values. The first patient with severe liver toxicity was a 22-year-old woman who started on PEP after being raped. At day 8 of treatment, she presented with nausea, vomiting and abdominal pain. Blood tests performed at day 14 showed an ALT elevation of 517 IU/l, and an aspartate aminotransferase elevation of 148 IU/l. This patient, previously vaccinated against hepatitis B virus with antibody to hepatitis B surface antigen greater than 10 IU/l, had a negative hepatitis C virus RNA, and a negative P24 antigenemia at the time of the occurrence of liver toxicity. Her HIV enzyme-linked immunosorbent assay remained negative 4 months after her potential exposure to HIV. Besides hormonal contraceptive agents, started several months before HIV exposure, she was started on vibramycin after being raped. PEP was interrupted and was followed by a substantial decrease and a normalization of transaminase levels at weeks 2 and 6 of treatment interruption, respectively. The second patient was a 29-year-old man, who had a sexual exposure to HIV and presented at day 9 of treatment with a pruriginous generalized maculopapular rash with buccal mucosal touch. Erythema multiforme was diagnosed. Blood tests were performed and showed ALT and aspartate aminotransferase elevations of 958 IU/l and 413 IU/l, respectively. HIV and hepatitis C virus RNA, hepatitis B surface antigen, and core antibody were negative at the time of the occurrence of hepatic cytolysis. After treatment interruption, the rash regressed and the transaminase levels were normalized within 6 weeks. A high incidence of severe liver toxicity has been reported with nevirapine in the PEP setting [2,3]. It has therefore been recommended that the use of this drug in PEP should be restricted [2]. In contrast, liver toxicity has been found to be rare and mild to moderate with PEP regimens including two nucleoside reverse-transcriptase inhibitors and a protease inhibitor [2,4] (Table 1) [5–8]. The high incidence of severe liver toxicity observed in our cohort was unexpected considering that severe transaminase elevations have rarely been observed in healthy patients while receiving the standard regimen of fosamprenavir/ritonavir 700/100 mg twice a day, or in HIV-infected patients during phase III randomized trials conducted to assess the efficacy and safety of fosamprenavir administered twice a day [9] or once a day [10]. In the Neat trial, grade 3 and 4 ALT increases were observed in 6% of patients, predominantly in patients co-infected with hepatitis B or C [9]. In the Solo trial, grade 3 and 4 ALT increases were observed in 3% of the patients without co-infection with hepatitis B or C [10]. However, the frequency of transaminase elevations observed with the higher dosage regimens has recently led to the premature termination of one study designed to evaluate high-dose combinations of fosamprenavir/ritonavir in healthy adults (grade 1–3 in 32% of patients on fosamprenavir/ritonavir 1400/200 mg twice a day, and in 12% of patients on fosamprenavir/ritonavir 1400/100 mg twice a day) [11].Table 1: Incidence of liver toxicity reported in the medical literature with postexposure prophylaxis regimens including protease inhibitors or nucleoside reverse transcriptase inhibitors.In our experience, PEP for HIV infection with a combivir and fosamprenavir/ritonavir combination was found to be associated with a high incidence of severe liver toxicity. These results need further confirmation; however, in the meanwhile, we recommend caution when prescribing this regimen for PEP. The findings in this study do not apply to the use of fosamprenavir/ritonavir in other settings.