Immediate HAART reduces death and AIDS progression over 48 weeks in patients with acute OIs

Andrew Zalopa from Stanford University and colleagues presented results from ACTG A5164 Phase 4 study which randomised 282 patients to either immediate or deferred use of ARVs in the context of an acute OI diagnosis for which treatment is available (TB was excluded).

Optimal timing of HAART in this context is currently guided more by expert opinion than data from randomised studies, and is difficult due to the advanced illness of study participants.

Patients needed to be treatment-naive, not to have used ARVs in the previous 8 weeks or not to have used treatment for more than one month if used in the past. Deferred treatment was defined as after OI treatment (at least 4 weeks after randomisation). Randomisation was stratified by OI and CD4 (above and below 50 cells/mm3). Patients with tuberculosis were excluded. The primary week 48 endpoint was an ordered categorical variable of three outcomes: death/AIDS progression; no progression, HIV viral load <50copies/mL; or no progression, viral load <50 copies/mL.

Baseline characteristics included median (IQR) CD4 and viral load counts of 29 (10-55) cells/mm3 and 5.07 (4.71-5.63) log copies/mL. Over 90% were treatment-naive. Median age was 38 years; 85% men/15% women; 37% black, 36% Hispanic, and 23% white.

OIs included PCP (63%), cryptococcal meningitis (13%), pneumonia (10%), other OI including cyrptosporidiosis, toxoplasmosis, CMV and MAC (25%). One third of patients were diagnosed with more than one OI within 30 days.

Immediate and deferred arms started ART with a median (IQR) of 12 (9-13) and 45 (41-55) days, respectively, after treatment for the opportunistic infection had started. 10% of the deferred treatment arm did not start HAART. Choice of ARVs was open with 89% and 85% patients in the immediate and deferred arms respectively, starting with a boosted-PI based regimen.

13% patients were lost to follow-up (18 in each arm). Although there was no significant difference in the composite primary endpoint with both arms achieved similar CD4 and viral load by week 24, the immediate arm had significant clinical benefits. Immediate HAART led to fewer deaths/AIDS progressions (n=20 vs 34, p =0.035), longer time to death/AIDS progression (stratified HR = 0.53, 99% CI 0.25-1.09, 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, both p<0.001), 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).

The clinical benefits from immediate treatment were driven by the more rapid increase in CD4 count, which decreased the period of vulnerability to new AIDS-related infections and death.

Comment

It is important that the question of HAART timing has been answered in a randomised study. The acknowledgement of patients for participating in this study, many of whom were already disenfranchised from the US healthcare system, was particularly deserved.

Zolopa A, Andersen J, Komarow L et al. Immediate vs Deferred ART in the Setting of Acute AIDS-related Opportunistic Infection: Final Results of a Randomized Strategy Trial, ACTG A5164. Oral abstract 142.
http://www.retroconference.org/2008/Abstracts/32805.htm