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The integrase inhibitor raltegravir has impressive activity in treatment-experienced patients (ACC May 7 2007) and, according to a 24-week analysis, may have similarly potent effects in patients who are treatment naive (ACC Sep 18 2006). Now, 48-week results are available from this same industry-sponsored study.
The trial involved 201 treatment-naive patients, including 30 who participated in an initial 10-day study of raltegravir monotherapy (J Acquir Immune Defic Syndr 2006; 43:509). All were randomized to receive tenofovir and 3TC, plus either efavirenz or one of four doses of raltegravir (100 mg, 200 mg, 400 mg, or 600 mg twice daily). Entry criteria included a viral load ≥5000 copies/mL and a CD4 count ≥100 cells/mm3. At baseline, the mean viral load ranged across treatment arms from 4.6 to 4.8 log copies/mL, and the mean CD4 count ranged from 271 to 338 cells/mm3.
By week 48, approximately 85% of patients in each group had achieved viral loads <50 copies/mL. Viral loads became undetectable more rapidly in patients who received raltegravir at any dose than in those who received efavirenz (P<0.05). CD4-cell responses were similar among treatment arms. Central nervous system side effects and lipid elevations occurred more commonly in those who received efavirenz. Virologic failure occurred in 3% of patients in each group; of the five raltegravir recipients who experienced virologic failure, two had viruses with the N155H amino acid substitution, a mutation known from in vitro experiments to be selected by raltegravir.
Markowitz M et al. Rapid and durable antiretroviral effect of the HIV-1 integrase inhibitor raltegravir as part of combination therapy in treatment-naive patients with HIV-1 infection: Results of a 48-week controlled study. J Acquir Immune Defic Syndr 2007 Aug 30; [e-pub ahead of print].
Comment
These 48-week results confirm that raltegravir is likely to be at least as potent as efavirenz when used in an initial regimen with two NRTIs. The clinical relevance of the faster decline in viral load is unclear, but the observation is certainly remarkable given that efavirenz-based regimens induce a faster HIV RNA decline than do regimens using boosted PIs. Although the authors speculate that patients with raltegravir resistance might have maintained viral loads below baseline because of a reduction in viral fitness due to raltegravir-selected mutations, this phenomenon has previously been well described with NRTI resistance, which was also present in these patients. Given these impressive results overall, we eagerly anticipate the findings of a larger, phase III study of raltegravir versus efavirenz that is already fully enrolled. If that study yields similarly favorable results, the decision about when to consider raltegravir a first-line therapy option will be up to individual clinicians, patients, and various guidelines committees, with the major concern being the absence of long-term safety data.