Severe liver toxicity in patients receiving two nucleoside analogues and a non-nucleoside reverse transcriptase inhibitor (South African FTC Study)

I. Sanne from South Africa reported on this study on behalf of the FTC-302 Study Investigators. The use of some antiretroviral agents has been associated with hepatotoxicity. This toxicity has been associated with concomitant chronic viral hepatitis, alcohol use, hypersensitivity reactions and lactic acidosis.

In yesterday's presentation by Pedro Cahn, he reported that the incidence of LFT elevations was low in the old BI study 1090, which compared NVP+AZT/3TC to AZT/3TC in a treatment experienced population, with relatively low CD4s. My recollection from Sanne's talk today was that he suggested the reason Cahn's analysis did not detect a higher rate was because they did not look just at higher grade elevations but included grades 1 & 2 as well. Nonetheless, Sanne was confident in his ffindings. He concluded he saw higher rates of grade 4 liver enzyme elevations, and the increased rates are because women are affected more than men.

FTC-302 is a randomized, placebo-controlled, double-blind study com-paring emtricitabine (FTC) to lamivudine in a background of stavudine (d4T) and either nevirapine (NVP) (screening HIV-1 RNA <100 000 copies/ml) or efavirenz (EFV) (screening HIV-1 RNA > 100 000 copies/ml) in antiretroviral treatment-naÔve HIV-infected patients in the Republic of South Africa.

A total of 468 patients were enrolled (385 in the NVP stratum, 83 in the EFV stratum). Fifty-nine percent of the patients are female; 87% of the patients are black. At the time of this report, all patients on treatment have completed 24 weeks. To date, treatment-emergent Grade 4 elevations in liver enzymes (ALT, AST, alkaline phosphatase, and total bilirubin) have been observed in 36 (9.4%) patients in the NVP stratum and in none of the patients receiving EFV. Of these 36 cases, 33 occurred within the first 4 weeks of therapy; the onset date for the remaining three cases was week 32. Sanne I think also suggested that you have to look for these increases early and possibly in other analyses they looked at later time points.

Of the 36 cases, one was HBsAg positive at screening with no evidence of active hepatitis, and two others had serological evidence of HCV infection. Incidence of grade 4 elevations was comparable between blinded treatment arms (9 versus 10%) and between blacks and non-blacks (9 versus 12%), but in females the incidence was twice that of males (abstract said 12% versus 6%, P =0.05, but I think oral talk said 19 vs 9%). Two patients developed liver failure and died, one of whom was HBsAg positive at screening.

Sanne concluded that in this study, a high incidence of severe liver toxicity was observed, especially in women. Clinically these events were attributed to NVP in combination with d4T and blinded treatment medication. Consistent with recent recommendations, liver enzymes in patients receiving NVP with other antiretrovirals should be monitored closely, particularly during the first 8 weeks of use. The recent European recommendation suggest caution using NVP if a person has HCV.