WASHINGTON – Early use of antiretroviral therapy significantly reduced the incidence of clinical events – including tuberculosis and AIDS-defining events – among HIV positive adults in a large multinational trial.
"Overall, our interpretation was that there is a marked clinical benefit in terms of reduced clinical events by starting antiretroviral therapy early," Dr. Mina C. Hosseinipour said in a press briefing held during the meeting.
The data are the latest from the landmark HIV Prevention Trials Network study number 052 (HPTN 052), which previously had shown that use of antiretroviral therapy (ART) early – when CD4 counts were between 350 and 550 cells/mm3 – in the HIV-positive partners of a total of 1,763 serodiscordant couples reduced the rate of HIV transmission to the uninfected partner by 96%. It also showed that early ART is associated with a longer time to HIV disease progression and preservation of the immune system over 2 years in the patients themselves (N. Engl. J. Med. 2011;365:493-505).
"So, we think that combined with the preventive benefit, the clinical benefit that one can see from earlier antiretroviral therapy does support earlier antiretroviral initiation" when CD4 counts are between 350 and 550 cells per cubic millimeter, said Dr. Hosseinipour, clinical director of the University of North Carolina Project in Lilongwe, Malawi.
The new analysis, including an additional 3 months of follow-up from the earlier report, focused on clinical end points among those randomized to early vs. later (CD4 count less than 250/mm3 or the onset of AIDS) antiretroviral treatment. The data were presented at the conference by Dr. Beatriz Grinsztejn of Instituto de Pesquisa Clinica Evandro Chagas, Manguinhos, Brazil.
At baseline, the 886 participants in the immediate ART group were similar to the 875 participants in the delayed ART group with regard to gender (about 50/50); two-thirds between the ages of 26 and 40 years. Just over half (54%) were from Africa, and slightly less than a third (30%) from Asia. The rest were from South America. Baseline CD4 counts were 428 cells/mm3 for the delayed ART group and 442 cells/mm3 for the immediate group, and baseline HIV-1 RNA level was 4.4 log10 copies/mL in both groups.
During an overall median follow-up of 2.1 years, 24% (213) patients in the delayed arm initiated ART, at a median of 3.8 years to initiation. Median duration of exposure to ART was 1 year, vs. 2 years in the immediate treatment group.
The specified primary clinical events were death, World Health Organization stage 4 events, tuberculosis, severe bacterial infection, and targeted non-AIDS events, including serious cardiovascular/vascular disease, serious liver disease, end stage renal disease, non-AIDS malignancy, and diabetes mellitus.
There were no differences in primary event rates between the two groups during the first year, but by the end of the follow-up period, 9% (77) of the delayed group vs. 6% (57) of the immediate group experienced at least one primary event, for a hazard ratio of 1.37. AIDS-related events occurred in 61 of the 77 delayed-therapy group and 40 of the 57 immediate-therapy group patients. Deaths occurred in 15 and 11, respectively. Non-AIDS events occurred in 9 delayed vs.12 immediate-therapy group patients, including diabetes mellitus in 5 and 4, respectively, Dr. Grinsztejn reported.
There were no significant differences in primary event rates by region, gender, or baseline CD4 count above vs. below 450 cells/mm3, she said.
In a multivariate analysis, factors significantly associated with primary events were age 40 years and older vs. 18-24 years (HR, 2.42), having a greater pretreatment HIV-1 log10 RNA count (1.34/1 log higher), a higher hemoglobin (grade 2 or higher vs. 0/1), and hepatitis B coinfection (1.85 for yes vs. no). In addition, regardless of treatment arm, each 50 CD4 cell higher count was associated with a 10% lower risk of primary events, she reported.
Tuberculosis was significantly more frequent in the delayed treatment group, 4% (34) vs. 2% (17), as were WHO stage 4 events (2% vs. 1%), with chronic herpes simplex being the most common of those (in 8 vs. 2 patients, respectively). Serious bacterial infections were more common among the immediate treatment patients, 2% vs. 1%.
Among the secondary events, herpes zoster, oral candidiasis, and seborrheic dermatitis were the most prevalent, all being more common in the delayed-treatment group, she noted.
Combining all primary and secondary events, the incidence was 29/100 person-years for delayed treatment vs. 25/100 person-years for immediate treatment, a significant difference (P = .02). At the time of primary clinical events, the CD4 count was significantly higher in the immediate-treatment group, compared with the delayed group (502 vs. 351). There was a similar distribution with the secondary events (540 vs. 377). Approximately half of the events in the delayed arm occurred at CD4 cell counts higher than 350, Dr. Grinsztejn noted.