ART at 350-550 CD4s Cuts Disease Rate 40% in Randomized HPTN 052 Trial
6th IAS Conference on HIV Pathogenesis, Treatment and Prevention, July 17-20, 2011, Rome
Starting antiretroviral therapy (ART) at a CD4 count of 350 to 550 rather than waiting for a count of 250 lowered the risk of serious complications, especially extrapulmonary tuberculosis, by 40% in the randomized HPTN 052 trial, conducted in 5 African countries, Brazil, India, Thailand, and the United States . Earlier ART did not cut the risk of death during this trial, which began in 2005.
HPTN 052 is the first randomized trial to demonstrate that antiretroviral treatment lowers the risk that an HIV-positive person will transmit the virus to an HIV-negative sex partner (reviewed separately by NATAP) [by 96% !] . At the same time, HPTN investigators compared rates of HIV-related complications in people who started ART at a CD4 count between 350 and 550 and those who waited until their count fell below 250. Previous studies addressing the pluses and minuses of starting antiretrovirals at a CD4 count above 350 relied on modeling of observational data. HPTN 052 is the first randomized trial to examine this issue.
HPTN 052 enrolled 1763 HIV-positive people, 54% of them from Africa. Median age of study participants stood at 33 years, and half were women. Everyone had a CD4 count between 350 and 550 when they enrolled, and no one had taken antiretrovirals. Median CD4 count at enrollment was 436 and median viral load about 25,000 copies. Participants made a study visit every 3 months. While 7% of enrollees were taking prophylactic cotrimoxazole, 4% were using isoniazid to prevent TB.
The investigators randomized 886 people to start treatment immediately and 877 to wait until they had consecutive CD4 counts under 250 or an AIDS illness. The primary endpoint for this part of HPTN 052 was a World Health Organization stage 4 event, pulmonary tuberculosis, severe bacterial infection, and/or death.
Through 3304 person-years of follow-up, a study-defined clinical event affected 105 people, 40 in the immediate-ART group and 65 in the delayed-ART group. Those numbers translated into an incidence of 2.4 events per 100 person-years with immediate ART and 4.0 per 100 person-years with delayed ART. The clinical risk was 40% lower in the immediate-ART group (hazard ratio [HR] 0.60, 95% confidence interval [CI] 0.4 to 0.9, P = 0.01).
Extrapulmonary TB explained most of the difference between the immediate group and the delayed group. Three people randomized to immediate ART and 17 randomized to delayed ART got diagnosed with extrapulmonary TB during the trial (P < 0.002). Incidence of extrapulmonary TB was 0.2 per 100 person-years in the immediate arm and 1.0 per 100 person-years in the delayed arm. In contrast, incidence of pulmonary TB was 0.8 per 100 person-years in the immediate arm and 0.9 per 100 person-years in the delayed arm.
Twenty-three people died during HPTN 052, 10 in the immediate arm and 13 in the delayed arm, but this difference lacked statistical significance (HR 0.8, 95% CI 0.3 to 1.8). The HPTN 052 researchers noted that longer follow-up could disclose other complications of delayed therapy.
Notably, 1-year responses to ART differed hardly at all in the immediate arm and the delayed arm . Although the immediate group began treatment at a median CD4 count of 442 and the delayed group at a median count of 225, 90% in the immediate group and 93% in the delayed group had a viral load below 400 copies after 1 year. One-year CD4 gains averaged 158 in the immediate group and 191 in the delayed group. These findings indicate that more time spent with a lower CD4 count in the delayed group--rather than a worse response to ART--explain their higher risk of disease progression. (from Jules: and more time with replicating virus is likely important as well.)
For the clinical advantage conferred by earlier antiretroviral therapy, people in the immediate-ART group did pay a price in toxicity: Adverse events possibly related to ART affected 24% of people in the immediate-treatment group versus 5% in the deferred group. Laboratory abnormalities were recorded in 27% in the immediate-treatment group and 18% in the delayed-treatment group. But severe or life-threatening adverse events affected the same proportion in each group, 14%.
1. Grinsztejn B, Ribaudo H, Cohen MS, et al. Effects of early versus delayed initiation of antiretroviral therapy (ART) on HIV clinical outcomes: results from the HPTN 052 randomized clinical trial. 6th IAS Conference on HIV Pathogenesis, Treatment and Prevention. July 17-20, 2011. Rome. Abstract MOAX0105.
2. Cohen M, Chen Y, McCauley M, et al. Antiretroviral treatment to prevent the sexual transmission of HIV-1: results from the HPTN 052 multinational randomized controlled trial. 6th IAS Conference on HIV Pathogenesis, Treatment and Prevention. July 17-20, 2011. Rome. Abstract MOAX0102.
3. Hosseinipour MC, Wang L, Cohen MS, et al. Immunologic and virologic disease progression and responses to ART across geographic regions: outcomes from HPTN 052 study. 6th IAS Conference on HIV Pathogenesis, Treatment and Prevention. July 17-20, 2011. Rome. Abstract MOAX0104.
According to this late breaker presentation HPTN 052 is the first clinical trial to show that waiting unitil a CD4 of 250 increases risk of disease where as initiating between 350 to 550 decreases this risk.
For the sake of saving time, and already having a great summary from NATAP, which is most likely the Press Release.
I am not closely following every track being one person, NATAP has some great coverage, some of which I will return to when I can sort through all the information presented.