July 24, 2007
The lead agent in the integrase inhibitor drug class, raltegravir (RAL, MK-0518) has demonstrated potent antiretroviral activity in phase 2 and 3 clinical trials conducted in both treatment-naive1 and treatment-experienced individuals2 when combined with other active antiretrovirals.
In addition, findings from phase 2 studies indicate that raltegravir produces more rapid viral load reductions than comparator regimens.3 These findings are intriguing considering that previous studies on viral decay kinetics have established that HIV-1 RNA suppression undergoes biphasic decay. The first phase occurs quickly (half-life: 1.5 days) and is thought to lead to the loss of productively infected cells, whereas the second phase occurs more slowly (half-life: 14.0 days) and theoretically causes the loss of long-lived infected cells.
To better investigate the impact of raltegravir on viral decay kinetics, data were used from a two-part phase 2 study4 that was performed in treatment-naive individuals with a baseline viral load above 5,000 copies/mL and a CD4+ cell count above 100 cells/mm3.
In the first dose-finding monotherapy portion of the study, raltegravir was administered at one of four different doses -- 600, 400, 200 or 100 mg twice daily -- and was compared with placebo over nine days (n = 8 for each treatment group). After day nine, raltegravir-treated patients added tenofovir (TDF, Viread) and lamivudine (3TC, Epivir) to their regimen, and the placebo group commenced efavirenz (EFV, Sustiva, Stocrin) with tenofovir and lamivudine, thus rolling over to the second combination-therapy portion of the trial. In addition, a further 30 patients in each group commenced therapy at this time.
Monotherapy with raltegravir yielded similar first-phase viral decay kinetics for all doses, with a mean half-life of 1.2 days. In the second portion of the study, the rate of virologic suppression was significantly higher during the first weeks of combination therapy in the raltegravir-treated group. For example, patients who received combination therapy with raltegravir were significantly more likely to have undetectable HIV-1 RNA (less than 50 copies/mL) at day 15 compared with those who received combination therapy with efavirenz (30% or greater vs. 11%; P In addition, the median second-phase viral levels for the raltegravir groups were significantly reduced by an additional 70% relative to the efavirenz group (P These observations challenge the current hypothesis that second-phase virus originates from long-lived infected cells. Using mathematical modeling, the authors suggested two alternative hypotheses to explain the observed differential effects of raltegravir on viral dynamics.
The first hypothesis suggests that second-phase virus arises from cells newly infected by long-lived infected cells, whereas the second hypothesis suggests that second-phase virus arises from activation of latently infected cells with unintegrated HIV DNA. According to the first hypothesis, raltegravir is thought to be highly effective at blocking infection of new cells by long-lived cells, whereas other antiretrovirals are not as effective.
According to the second hypothesis, raltegravir is thought to block the integration of fully transcribed HIV-1 DNA into the host genome, whereas the anti-HIV mechanisms carried out by other antiretrovirals are unable to block this step.
Further study of the effect of raltegravir on viral decay are planned to better understand the observations from this study.
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