1. This study demonstrated that second-line antiretroviral therapy consisting of a protease inhibitor with two nucleoside reverse-transcriptase inhibitors was efficacious in achieving good HIV control.
2. There were no significant differences in the rates of adverse events when compared with other regimens that do not include nucleoside reverse-transcriptase inhibitors.
Evidence Rating Level: 1 (Excellent)
Study Rundown: In resource-limited settings, the common first-line approach to treating human immunodeficiency virus (HIV) involves using two nucleoside reverse-transcriptase inhibitors (NRTIs) and one non-NRTI (NNRTI). The typical second-line regimen currently used in these settings consists of a boosted protease inhibitor (PI) and two NRTIs. While some evidence exists to support this regimen, there is growing concern about cross-resistance, given that NRTIs form the backbone of both lines of therapy. Moreover, there is concern about the risk of toxicity associated with NRTIs.
The purpose of this trial was to explore the efficacy of three different second-line regimens. The first of these was the currently recommended combination of a PI and two NRTIs. The second was a regimen consisting of a boosted PI and raltegravir, an integrase inhibitor. It was proposed that using two completely new classes of medications as second-line therapy would sufficiently address resistance selected for by first-line therapy, while causing fewer toxic adverse effects. The last regimen consisted of a PI alone (with no NRTIs). It was thought that this would be non-inferior to the standard regimen currently being used, while being less toxic and less complex.
In summary, this study demonstrated that using NRTIs with a PI as second-line therapy was efficacious when compared with other regimens involving raltegravir or PI monotherapy. The rates of adverse events were not significantly different between the three groups. Notably, viral loads were less often controlled in the group treated using PI monotherapy.
In-Depth [randomized controlled trial]: This study was conducted at 14 centres in 5 sub-Saharan African countries. Patients were eligible if they were HIV-infected, >12 years of age, had received first-line therapy consisting of two NRTIs and one NNRTI continuously for >12 months, had not previously been treated with a PI, had missed no more than 3 days of treatment during the preceding month, and had virologic, immunologic, or clinical treatment failure (i.e., viral load >400 copies/mL). Patients were randomized 1:1:1 into three treatment arms: 1) the NRTI group (i.e., a boosted PI with two or three NRTIs), 2) the raltegravir group (i.e., a PI with raltegravir), and 3) the monotherapy group (i.e., a PI alone after 12 weeks of raltegravir as induction therapy). Randomization was stratified according to study centre and CD4+ counts. The primary composite endpoint was defined as no new World Health Organization stage 4 events (other than esophageal candidiasis or mucosal herpes simplex virus infection) or death, a CD4+ count >250 cells/mm3, and a viral load <10,000 copes/mL (or ≥10,000 copies/mL without PI resistance mutations) at week 96.
A total of 1,277 patients underwent randomization. The primary endpoint was achieved in 60% of patients in the NRTI group, 64% of patients in the raltegravir group, and 55% of patients in the monotherapy group. Patients in the raltegravir group had a nonsignificant increase in the rate of the primary endpoint when compared to the NRTI group (p=0.21, superiority not demonstrated). Those in the monotherapy group experienced a nonsignificant reduction in the primary endpoint, as compared with the NRTI group (non-inferiority not demonstrated). There were no significant differences between the three groups in survival rates at week 96 (p=0.73). The percentage of patients achieving viral loads <400 copies/mL was 86% in the NRTI group, 86% in the raltegravir group (p=0.97 for NRTI vs. raltegravir), and 61% for the monotherapy group (p<0.001 for NRTI vs. monotherapy). There were no significant differences between the three groups in the rates of serious adverse events.
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