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The integrase inhibitor raltegravir alters viral decay kinetics of HIV, significantly reducing the second phase and challenging current hypotheses of viral replication
Presented by John M Murray, Australia.
Murray J.M.1, Emery S.1, Kelleher A.1, Law M.1, Hazuda D.2, Nguyen B.-Y.2, Teppler H.2, Cooper D.A.1
1National Centre in HIV Epidemiology and Clinical Research, Sydney, Australia, 2Merck Research Laboratories, North Wales, United States
Objectives: HIV-integrase inhibitors are a new class of antiretroviral drugs that target a crucial process in the life cycle of HIV. Results from a phase II trial with the integrase inhibitor MK-0518 (raltegravir) allowed us to assess its impact on viral decay kinetics.
Methods: Patients were antiretroviral treatment naïve with baseline HIV RNA ³5,000 copies/ml and CD4+ T cell counts ³ 100 cells/mm3. Part 1 compared monotherapy raltegravir at 4 different doses (600, 400, 200, 100mg bid.) with placebo over 9 days (n=8 for each group). In Part 2, patients were randomized to one of the four dosages of raltegravir or to efavirenz (EFV), in addition to tenofovir and lamivudine for 48 weeks (n³38 each group). No adjustments were made to values for multiple testing. Mathematical models were simulated in Matlab.
Results: Monotherapy with raltegravir yielded similar first phase decay for all doses, with a mean half-life of 1.2 days. Combination therapy including raltegravir was more likely to achieve undetectable HIV RNA (<50 copies/ml), than EFV by the second time point at day 15 (p£0.047, Fisher Exact), at day 29 (p£0.003), and at day 57 (p£0.006). Median second phase viral levels for the raltegravir groups were significantly reduced by 70% over the EFV group (p<0.0001 Wilcoxon Rank Sum). Mathematical modeling produced two hypotheses to explain the observed differential effects of raltegravir on viral dynamics: 1) that second phase virus arises from cells newly infected by long-lived infected cells, or 2) that it arises from activation of latently infected cells with full-length unintegrated HIV DNA.
Conclusions: Intervention with raltegravir results in a different decay curve producing a more extensive first phase and significant reduction in the second phase. This observation challenges the current hypothesis that second phase virus originates from infected long-lived cells.
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