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Raltegravir Efficacy and Safety After 96 Weeks of Phase 2 Trial
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HIV DART 2008, December 9-12, 2008, Rio Grande, Puerto Rico
Mark Mascolini
Nearly half of heavily pretreated people who took the integrase inhibitor raltegravir for 96 weeks in the phase 2 protocol 005 had a viral load below 50 copies in a noncompleter-equals-failure analysis [1]. Nine of 94 people (9.6%) who continued raltegravir in the trial's open-label phase had a virologic rebound above 50 copies after week 48.
Protocol 005 randomized 178 people with triple-class-resistant virus to 200, 400, or 600 mg of raltegravir twice daily (n = 133) or to placebo plus an optimized background regimen [2]. Study participants had taken antiretrovirals for approximately 9 years before entering this trial, and more than 60% had a genotypic sensitivity score (GSS) of 0, meaning the drugs they combined with raltegravir had little or no predicted activity against HIV. More than 90% of study participants had a GSS and a phenotypic sensitivity score of 0 to protease inhibitors. After a 24-week double-blind comparison of raltegravir and placebo, all study participants could take raltegravir at the 400-mg twice-daily dose.
Ninety-four people who began the trial taking raltegravir continued through 96 weeks. Eight of these 94 (8.5%) dropped out between weeks 48 and 92, 3 because of lack of efficacy, 2 because of adverse events, and 3 for other reasons. From weeks 48 to 96, investigators reported one serious drug-related lab abnormality (decreased platelet count) and one malignancy (anal squamous cell carcinoma) not related to study drugs. A noncompleter-equals-failure analysis determined the following response rates (and 95% confidence intervals) based on the 133 people who began the trial taking raltegravir:
Less than 400 copies:
- Week 48: 68% (59% to 76%)
- Week 96: 55% (46% to 64%)
Less than 50 copies:
- Week 48: 55% (46% to 64%)
- Week 96: 48% (40% to 57%)
Four of 6 people who switched from placebo to 400 mg of raltegravir twice daily after week 24 and continued treatment through week 96 reached a viral load below 50 copies. In a last-observation-carried-forward analysis among people who started the trial on raltegravir, CD4 counts rose an average 96 cells (95% confidence interval 71 to 121) at week 48 and 104 cells (95% confidence interval 76 to 131) at week 96.
Among people who took raltegravir throughout the trial, 32 of 79 (41%) who did not use enfuvirtide in the background regimen and 5 of 14 (36%) who recycled enfuvirtide had a viral load below 50 copies at week 96. In contrast, 26 of 31 people (84%) taking enfuvirtide for the first time with raltegravir had a week-96 load under 50 copies. Of 68 raltegravir takers who had a baseline GSS of 0, 31 (46%) had fewer than 50 copies at week 96, compared with 29 of 50 (58%) who had a baseline GSS of 1 or 2.
Among the 9 people with a rebound above 50 copies after week 48, 4 of the 6 tested for resistance mutations had a signature integrase mutation at position Q148 and 1 had the signature N155H mutation. All these people also had secondary mutations in integrase.
References
1. Gatell J, Nguyen BY, Grinsztejn B, et al. 96-week efficacy and safety of raltegravir in treatment-experienced patients. HIV DART 2008, December 9-12, 2008, Rio Grande, Puerto Rico. Abstract 35.
2. Grinsztejn B, Nguyen BY, Katlama C, et al, Protocol 005 Team. Safety and efficacy of the HIV-1 integrase inhibitor raltegravir (MK-0518) in treatment-experienced patients with multidrug-resistant virus: a phase II randomised controlled trial. Lancet. 2007;369:1261-1269.
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