Background:  After more than a decade of highly effective ART, there is no consensus on optimal timing of its initiation in the setting of acute opportunistic infections.

Methods:  A5164 was a randomized phase IV strategy trial of immediate ART given within 14 days of starting acute opportunistic infections treatment vs deferred ART given after acute opportunistic infections treatment is completed (at least 4 weeks after randomization). Randomization was stratified by opportunistic infections and CD4 (< or ≥50 cells/mm³). Patients with tuberculosis were excluded. Study drugs included lopinavir/ritonavir (LPV/r), stavudine (d4T), and tenofovir/emtricitabine (TDF/FTC), but clinicians were free to use any standard ART. The primary week 48 endpoint was an ordered categorical variable of: death/AIDS progression; no progression, HIV viral load ≥50; or no progression, viral load <50 copies/mL.

Results:  We randomized 282 subjects, 141 per arm. Subjects were 85% men, 37% black, 36% Hispanic, and 23% white with a median age of 38 years. Entry median CD4 count was 29 cells/mm³, and log₁₀ viral load was 5.07 copies/mL. Entry opportunistic infections included Pneumocystic carinii pneumonia (PCP) 63%, cryptococcal meningitis 13%, pneumonia 10%. Immediate and deferred arms started ART a median of 12 and 45 days, respectively, after treatment for the opportunistic infection had started. There were no significant differences in initial ART regimens. Each arm had 18 subjects for whom "no endpoint information" was coded as endpoint. There was no statistically significant difference in the primary endpoint: 14% vs 24%, 38% vs 31%, and 48% vs 45% in immediate vs deferred arm, respectively. Both arms achieved similar CD4 and viral load by week 24. Importantly, the immediate arm had: fewer deaths/AIDS progressions (p =0.035), longer time to death/AIDS progression (stratified HR = 0.53, p = 0.02), and shorter time to achieving an increase in CD4 counts to >50 and >100 (median 8.1 vs 3.9 weeks and 11.8 vs 4.2 weeks), respectively. There was a trend of earlier ART changes in the immediate arm (p = 0.15), but no significant differences in grade 3 or 4 adverse events, adherence, hospitalizations, or immune reconstitution inflammatory syndrome (8 immediate vs 12 deferred).

Conclusions:  Although there was no significant difference between immediate and deferred ART in the primary endpoint that includes both clinical and virological response, immediate ART reduced death/AIDS progression over 48 weeks. This randomized strategy trial suggests that, absent contraindications, consideration should be given to early use of ART in HIV-infected patients presenting with an acute opportunistic infections.