Effectiveness

Raltegravir’s approval for use in antiretroviral-experienced patients was based upon the results from the BENCHMRK 1 and 2 studies that demonstrated a durable anti-HIV effect in patients with limited treatment options. The STARTMRK clinical studies demonstrated the drug's safety and efficacy in treatment-naive patients and in 2009, raltegravir was approved for use as a first-line regimen.

In an early phase II dose-ranging study (Protocol 005) of raltegravir, treatment-experienced patients with documented multiple ARV class resistance and viral load above 5000 copies/ml were randomised to one of three raltegravir doses or placebo added to an optimised background regimen. At 24 weeks, raltegravir at any of the three doses (200mg, 400mg, or 600mg) provided better viral suppression than placebo (over 70% with viral load <400 copies/ml vs 17% in placebo arm) with no dose-related toxicities.¹

BENCHMRK 1 and 2 studies are identical, international phase III studies that examined the efficacy of raltegravir in patients with triple-class resistant HIV. Nearly 700 patients with a median viral load over 50,000 copies/ml were randomised on a 2:1 basis to raltegravir 400mg twice daily or placebo, with a physician-selected optimised treatment background (OTB).

At week 16, using intent-to-treat analysis, the raltegravir arm was found to be superior; 76% of patients had viral load levels below 400 copies/ml vs 42% of those on placebo with OTB. Viral load less than 50 copies/ml was reached by 62% on the raltegravir arm vs 35% of those on placebo. By week 48, those levels were basically unchanged (62 vs 32% respectively). On the basis of these results, raltegravir gained marketing approval in the EU and US.^{2 3}

In treatment-naive patients, the second part of Protocol 004, a dose-ranging phase II study exploring raltegravir’s safety and efficacy, reported durable and potent ARV activity at weeks 24 and 48. The study arms looked at raltegravir vs efavirenz, both against a treatment background of tenofovir and 3TC.⁴

At week 96, raltegravir had a sustained antiretroviral effect, similar in effect to the efavirenz treatment arm. Viral load was suppressed to less than 400 copies/ml in 84% of the patients in each group and less than 50 copies/ml in 83% of those on raltegravir vs 84% on the efavirenz arm. CD4 cell count increases were similar: 221 cells vs 232 cells/mm³ for the raltegravir and efavirenz arms respectively. Raltegravir had a faster initial viral load decline; whether this is of consequence long-term is not known.⁵

The STARTMRK study is a large phase III study with a similar design to Protocol 004. Week 48 results demonstrated the non-inferiority of raltegravir to efavirenz. Viral load below 50 copies/ml in the raltegravir and efavirenz arms respectively were 86% vs 82%, a non-significant difference. In the raltegravir arm, the mean CD4 cell increase was 189 cells/mm³ vs 163 cells/mm³ in the efavirenz arm.⁶