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Coverage provided by Brian A. Boyle, M.D., J.D.

July 9, 2001

• Evaluation of the Anti-HIV-1 Potency of Several Nucleoside RT Inhibitors in PBL, Macrophages, and MT4 Cells, In Vitro (Poster 248)
  Authored by Hazen, R.; GlaxoSmithKline Research Trial, North Carolina, USA

3TC and FTC In Vitro Potency Is Equivalent in Relevant Cell Lines

In HIV therapy, assessment of drug potency is complex. It involves not only the in vitro potency of the drug, but also the levels of the drug that are tolerable in humans and its effectiveness as demonstrated in clinical trials when combined with other antiretroviral agents in a highly active antiretroviral therapy (HAART) regimen. A previous in vitro study indicated that emtricitabine (FTC) is more potent than lamivudine (3TC). Since FTC and 3TC are very similar chemically, differing only by the addition in FTC of fluorine at the 5 position of the cytosine ring, and share similar metabolic and resistance characteristics, the basis for the in vitro superiority of FTC over 3TC has never been established. Further, clinical studies have failed to show that FTC is more potent than 3TC, and instead have shown that when a part of a HAART regimen, FTC and 3TC are relatively equivalent in potency.

Due to this limited and conflicting data, scientists at GlaxoSmithKline decided to further assess the relative in vitro potency of 3TC and FTC. They obtained peripheral blood lymphocytes (PBL) and monocyte-derived macrophages (MAC) by apheresis of uninfected healthy donors. Once obtained, the PBL were infected with HIV-1IIIB and MAC with HIV-1Ba-L. Virus replication was measured by reverse transcriptase production on day 11 following infection. The T-cell line MT4 was infected with HIV-1IIIB, and HIV-induced cytopathic effect was determined by a propidium iodide stain for DNA.

In PBL and MAC, 3TC and FTC did not differ significantly in potency. In MT4 cells, however, FTC was 3.8-fold more potent that 3TC (p<0.001). Below is a chart showing the relative potency of FTC and 3TC in the three cell lines, with comparison to the potency of zalcitabine (ddC) and zidovudine (ZDV).

These results demonstrate the in vitro equivalence of 3TC and FTC with respect to potency in primary cells (PBL and MAC), and contradict previous claims of increased FTC potency, at least in these cell lines. As demonstrated, however, cell type may play a role in potency, with FTC more potent than 3TC in MT4 cells, and this may be potentially accounted for by differing levels of nucleoside anabolic enzymes, for example, 2'-deoxycytidine kinase, expressed in the cell line, which could affect conversion of the agent to its activated triphosphate form. In essence, given the equivalence of 3TC and FTC in the primary cell lines, these data confirm the existing clinical data that show the relative equivalence of these agents.

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