UPDATE on the 3 Nevirapine Studies Reporting on Liver Enzyme Elevations & Clinical Hepatitis from Glasgow AIDS Conference

I spoke with Ian Sanne, the South African investigator who conducted the NVP/EFV 3TC/FTC study, at the December 2000 ACTG meeting. His report from Glasgow is reviewed below. He told me at the ACTG meeting that in fact there was a baseline LFT-ALT level for study participants and it was on average normal, and no significant relationship between baseline LFTs and subsequent grade 3 or 4 elevations could be demonstrated. There were a small number of patients who had mild elevations at baseline. At baseline, 8 of 36 patients with grade 4 elevations had grade 1 AST or ALT, 1 of 36 patients had grade 2 AST, and 4 of 36 had grade 1 alkaline phosphatase and raised bilirubin. The number of patients with hepatitis B (7% HbsAg+) and C (3.5%) was low in the patients who developed toxicity, and there was no evidence of active hepatitis at baseline.

It's been hypothesized by others that maybe there was some sort of interaction between d4T and nevirapine as all study participants received d4T with NVP or EFV and either FTC or 3TC. This doesn't ring true. He said another hypothesis that NVP peak blood levels or some PK parameter may be responsible for the response. As reported below Sanne found that women had more of a problem than men with LFT elevations. In fact, he reported that within the NVP treated patients the incidence was twice as high in females (19% vs 9%). He hypothesized that there could be a PK issue related to black women or women in general distinguished from the PK of men.

Another point of interest he suggested was that in the two other studies below from Cahn & Martinez which did not find a LFT problem related to NVP, they evaluated LFT elevations at month 3 after starting the NVP study regimen. While in Sanne's study they evaluated LFT elevations at week 4. He suggested that by month 3 acute LFT elevations may have been missed. As well, persons with rash and/or acute LFT elevations could have withdrawn from the study and therefore would be missed by subsequent evaluations.

Another pharmacology question relates to the possibility that RTV or IDV could increase blood or intracellular levels of d4T, or that impaired liver function could elevate PI or NNRTI blood levels. This could cause hyper-elevated LFTs in hepatitis infected persons, and so-called hepatic cytolysis or hepatotoxicity.