Be careful if using fosamprenavir/ritonavir for PEP, and did HCV mean that PEP for HIV failed?

In a letter to the January 11^th edition of AIDS, doctors from Lille, France, report a high incidence of severe liver toxicities in individuals prescribed a post-exposure prophylaxis (PEP) regimen that includes the protease inhibitor fosamprenavir (Telzir)/ritonavir. The doctors caution against the use of fosamprenavir/ritonavir as part of PEP.

A second letter in the same edition of AIDS is also concerned with PEP. Italian doctors report a case of concomitant HIV and hepatitis C seroconversion in an individual prescribed unsuccessful PEP. The investigators also believe that the patient experienced an unusually late HIV seroconversion, and they speculate that this, and the apparent failure of PEP, was due to an interaction between HIV and hepatitis C.

Liver toxicities in Lille

In France, PEP is provided to individuals after potential occupational or occupational exposure to HIV. Current guidelines recommend the use of two nucleoside reverse transcriptase inhibitors and a protease inhibitor for four weeks.

Until January 2006 doctors in Lille prescribed a PEP regimen consisting of AZT/3TC (Combivir) with the protease inhibitor, nelfinavir (Viracept). However, in early 2006, a decision was taken to replace nelfinavir with fosamprenavir/ritonavir.

Between January and March 2006 a total of 26 patients (22 for sexual exposure) were prescribed the fosamprenavir/ritonavir, Combivir regimen before a high incidence of side-effects lead physicians to discontinue the use of this regimen for PEP.

Of the 26 patients who received this regimen, seven (27%) reported nausea, vomiting and abdominal pain. In addition, three patients reported rash a median of ten days after the initiation of PEP, leading one patient to discontinue therapy. Two patients developed mild liver toxicities (grade 1 and grade 2) 14 and 28 days after starting PEP, and there were two instances of severe liver toxicity.

The first case of severe liver toxicity (grade 4) involved a 22 year-old woman. After eight days of PEP she presented with nausea, vomiting and abdominal pain. Blood tests performed at day 14 showed elevated ALT and AST levels and that the patient was negative not infected with either hepatitis B or hepatitis C. Other than PEP, the patient was taking oral contraceptives and the antibiotic, vibramycin. The decision was taken to stop PEP, and liver function had returned to normal within six weeks. An HIV test performed four months after PEP was initiated was negative.

The second case of grade 4 liver toxicity involved a 29 year-old man. After nine days of PEP, he presented with a generalised blotchy red rash. Once again, ALT and AST levels were elevated. At the time of presentation the patient was found to be uninfected with HIV, hepatitis B and hepatitis C. Once again, PEP was stopped, the rash regressed and the patient’s liver function returned to normal within six weeks.

“The high incidence of severe liver toxicity in our cohort was unexpected” write the investigators, particularly as a low incidence of liver toxicities was observed in fosamprenavir/ritonavir clinical trials in both HIV-negative and HIV-positive individuals.

“In our experience, PEP for HIV infection with Combivir with a fosamprenavir/ritonavir combination was found to be associated with a high incidence of severe liver toxicity. The results need further confirmation: however, in the meantime, we recommend caution when prescribing this regimen for PEP”, conclude the authors.

PEP, HIV, hepatitis C and late seroconversion

A second letter in the same edition of AIDS was also concerned with PEP. It reported concomitant seroconversion with HIV and hepatitis C in a gay man. The HIV seroconversion occurred unusually late - seven months after exposure to HIV and the use of PEP.

In December 2003, a 24 year-old gay man was prescribed PEP consisting of Combivir and indinavir (Crixivan) for four weeks following receptive unprotected anal sex with an HIV-positive man. Initial HIV and hepatitis C tests were both negative.

In March 2004, however, the patient was diagnosed with hepatitis C virus. An HIV test at this time, and again two months later was negative.

However, despite claiming that he had been adherent to his course of PEP, and denying any further HIV risk behaviour, the man tested HIV-positive in July 2004. At the time of HIV diagnosis, his viral load was a little under 9,000 copies/ml and his CD4 cell count was 540 cells/mm³.

The authors provide some possible explanation for these unusual events. They note that animal models suggest the PEP is likely to be most effective is provided within 24 hours of exposure to HIV. However, their patient only sought treatment 30 hours after his HIV exposure. They also speculate that hepatitis C could have delayed HIV seroconversion and that PEP could have failed because of an interaction between the two viruses. They conclude, “in the case of sexual or professional exposure to both viruses a prolonged follow-up is recommended to cover a risk of late seroconversion.”