753 patients infected with HIV who were antiretroviral naive were screened and 602 patients entered the study. Intervention Patients were randomized to receive either tenofovir DF (n=299) or stavudine (n=303), with placebo, in combination with lamivudine and efavirenz. Main Outcome Measure Proportion of patients with HIV RNA levels of less than 400 copies/mL at week 48. Results In the primary intent-to-treat analysis in which patients with missing data or who added or switched antiretroviral medications before week 48 were considered as failures, the proportion of patients with HIV RNA of less than 400 copies/mL at week 48 was 239 (80%) of 299 in patients receiving tenofovir DF and 253 (84%) of 301 in patients receiving stavudine (95% confidence interval, −10.4% to 1.5%), exceeding the predefined −10% limit for equivalence. However, equivalence was demonstrated in the secondary analyses (HIV RNA Ͻ50 copies/ mL) at week 48 and through 144 weeks. Virologic failure was associated most frequently with efavirenz and lamivudine resistance. Through 144 weeks, the K65R mutation emerged in 8 and 2 patients in the tenofovir DF and stavudine groups, respectively (P = .06). A more favorable mean change from baseline in fasting lipid profile was noted in the tenofovir DF group at week 144: for triglyceride levels (+1 mg/dL for tenofovir DF [n=170] vs +134 mg/dL for stavudine [n=162], PϽ.001), total cholesterol (+30 mg/dL [n=170] vs +58 mg/dL [n=162], PϽ.001), direct lowdensity lipoprotein cholesterol (+14 mg/dL [n = 169] vs +26 mg/dL [n = 161], PϽ.001), and high-density lipoprotein cholesterol (+9 mg/dL [n=168] vs +6 mg/dL [n = 154], P = .003). Investigator-reported lipodystrophy was less common in the tenofovir DF group compared with the stavudine group (9 [3%] of 299 vs 58 [19%] of 301, PϽ.001). The number of bone fractures and the renal safety profile were similar between the 2 groups. Conclusions Through 144 weeks, the combination of tenofovir DF, lamivudine, and efavirenz was highly effective and comparable with stavudine, lamivudine, and efavirenz in antiretroviral-naive patients. However, tenofovir DF appeared to be associated with better lipid profiles and less lipodystrophy.

Integrase is essential for human immunodeficiency virus-type 1 (HIV-1) replication; however, potent inhibition of the isolated enzyme in biochemical assays has not readily translated into antiviral activity in a manner consistent with inhibition of integration. In this report, we describe diketo acid inhibitors of HIV-1 integrase that manifest antiviral activity as a consequence of their effect on integration. The antiviral activity of these compounds is due exclusively to inhibition of one of the two catalytic functions of integrase, strand transfer.

In HIV-infected patients with limited treatment options, raltegravir plus optimized background therapy provided better viral suppression than optimized background therapy alone for at least 48 weeks. (ClinicalTrials.gov numbers, NCT00293267 and NCT00293254.)

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