Raltegravir

Initial vs Subsequent Therapy

Current adult and adolescent treatment guidelines of the U.S. Department of Health and Human Services include the combination of raltegravir plus either tenofovir DF or tenofovir alafenamide (TAF) with either emtricitabine or lamivudine among the "Recommended Initial Regimens in Certain Clinical Situations."

In initial therapy, a randomized double-blind noninferiority comparison of raltegravir (400 mg BID) and efavirenz, each in combination with tenofovir DF + emtricitabine, found similar rates of virologic suppression to <50 copies/mL at 48 weeks: 86% in the raltegravir arm and 82% in the efavirenz group.(2) CD4 increases also were similar in the two groups: 189 cells/µL and 163 cells/µL, respectively.

In treatment-naive individuals, raltegravir (400 mg BID) was compared with darunavir + ritonavir and with atazanavir + ritonavir; each was given in combination with tenofovir DF/emtricitabine. At week 96 (the primary endpoint), by intention to treat (snapshot) analysis, the rate of virologic suppression to <50 copies/mL was 80% in the raltegravir group, 73% in the darunavir + ritonavir group, and 63% in the atazanavir + ritonavir group; the difference with each comparator was statistically significant. The differences in efficacy were driven primarily by higher rates of adverse effects in the comparator groups. Mean increases in CD4 cell counts were similar in all treatment groups.(3)

Also in initial therapy, a randomized double-blind study compared raltegravir (400 mg BID) and dolutegravir, each given in combination with investigator-selected nucleoside analogues, either tenofovir DF + emtricitabine or abacavir + lamivudine. At 48 weeks, by snapshot analysis, 85% of the raltegravir group and 88% of the dolutegravir group achieved HIV RNA suppression to <50 copies/mL; this difference was not statistically significant. In subjects with HIV RNA >100,000 copies/mL at baseline, HIV RNA suppression rates were 75% and 82%, respectively. The median CD4 increase was 230 cells/µL in each group.(4)

A randomized double-blind study in initial therapy compared raltegravir 1,200 mg once daily with raltegravir 400 mg BID; each was given with once-daily tenofovir DF/emtricitabine. At 48 weeks, rates of virologic suppression to <40 copies/mL were virtually the same, 89% in the once-daily group and 88% in the twice-daily group; rates of adverse events also were similar.(5)

In treatment-experienced patients with resistance to at least 2 classes of antiretrovirals but no previous exposure to integrase inhibitors, a randomized controlled study compared raltegravir and dolutegravir (50 mg once daily) each in combination with other antiretrovirals as selected by investigators (background regimens were required to include at least 1 agent with full activity against HIV). At 48 weeks, higher rates of virologic failure were seen in the raltegravir group: 64% of patients in the raltegravir group and 71% of patients in the dolutegravir group had HIV RNA levels of <50 copies/mL (p = .03). Mean CD4 count increases were 153 and 162 cells/µL cells/µL, respectively.(6)

In treatment-experienced patients with resistance to 3 classes of antiretrovirals (nucleoside analogues, nonnucleoside reverse transcriptase inhibitors, and protease inhibitors) and ongoing viral replication, 2 Phase III studies (described above in "Approval") compared raltegravir with placebo, each given in combination with an optimized background regimen. In combined analysis, the groups that received raltegravir had higher rates of virologic suppression at 24 and 48 weeks than the groups that received placebo (at 48 weeks, HIV RNA was <400 copies/mL in 73% of raltegravir recipients vs 37% of placebo recipients, and <50 copies/mL in 62% vs 33%, respectively).(1) These differences were statistically significant (p < .001). Virologic suppression was closely correlated with having at least 1 active agent in the background antiretroviral regimen, and the inclusion of enfuvirtide or darunavir in the regimen of those without previous exposure to these drugs substantially improved the rates of virologic response. In the raltegravir treatment groups, the mean increase in CD4 count was higher than in the placebo group (109 cells/µL vs 45 cells/µL at 48 weeks; p < .001).(1),(7)

A smaller Phase II randomized controlled trial, also involving patients with advanced HIV disease, extensive treatment experience, and resistance to at least 1 agent in each of 3 classes, compared 3 dosages of raltegravir (200 mg, 400 mg, and 600 mg, administered twice daily) with placebo. All participants were also given an optimized background regimen (tipranavir and darunavir were not available for use). At 24 weeks, by intention-to-treat analysis, the proportion of patients with HIV RNA levels of <50 copies/mL was 56-67% in the raltegravir groups and 13% in the placebo group (p < .0001 for comparison of each raltegravir dose with placebo). All participants were continued on open-label raltegravir (at the 400 mg twice daily dosage) to 48 weeks; at this time point, the proportion with HIV RNA levels of <50 copies/mL was 46-64%. As in the Phase III studies, the presence of other active antiretroviral agents (including enfuvirtide) in the background regimen substantially increased the rates of virologic suppression. The raltegravir groups had greater increases in CD4 cell counts at 24 weeks (60-102 cells/µL) than the placebo group (8),(9)