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Slower Time to AIDS and TB in Immediate-Treatment Arm of HPTN 052
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XIX International AIDS Conference, July 22-27, 2012, Washington, DC
Mark Mascolini
People who started antiretroviral therapy (ART) immediately in the randomized HPTN 052 trial had a significantly slower time to an AIDS disease and to tuberculosis than did people who delayed treatment [1]. The group that started ART immediately--at a CD4 count above 350--also had a lower rate of all new diseases assessed in this 2-year analysis.
HPTN 052 randomized HIV-positive adults with a CD4 count between 350 and 550 to start ART immediately or to wait until their count fell below 250 or they had an AIDS illness [2]. People who started ART immediately had a 96% lower risk of transmitting HIV to their partner in this 1763-couple trial. Study participants who started ART at a higher CD4 count also had a lower risk of AIDS-related complications, especially extrapulmonary tuberculosis, in this initial analysis.
The new analysis looked more closely at clinical outcomes through 2 years of follow-up in this international trial. The study considered long lists of primary clinical events (death, WHO stage 4 HIV disease, tuberculosis, severe bacterial infection, serious cardiovascular/vascular disease, serious liver disease, end-stage renal disease, non-AIDS malignancy, and diabetes mellitus) and secondary clinical events (WHO stage 2 or 3 HIV disease, malaria, renal insufficiency, hepatic transaminitis, lipodystrophy, dyslipidemia, hypertension, peripheral neuropathy, lactic acidosis, and thrombocytopenia).
Follow-up of the 1761 HIV-positive people in this analysis (886 in the immediate-ART arm and 875 in the delayed arm) lasted for a median of 2.1 years (interquartile range [IQR] 1.6 to 2.9). During follow-up, 213 people (24%) in the delayed arm started ART. Median CD4 count when ART began stood at 442 in the immediate-treatment group and 229 in the delayed-treatment group. In this analysis, treated people in the delayed group took ART for a median of 1 year (IQR 0.5 to 1.7).
During that time 134 people (7.6%) experienced at least one clinical event, including 26 deaths and 21 non-AIDS events. Proportions of study participants who had at least one primary event were 6% in the immediate-treatment group and 9% in the delayed-treatment group. People in the delayed arm had a 37% higher risk of a primary event (hazard ratio [HR] 1.37), indicating a strong trend favoring immediate ART (95% confidence interval [CI] 0.97 to 1.93, P = 0.07). Risk of a primary event did not differ by continent, gender, or pretreatment CD4 count above or below 450.
Compared with the immediate-treatment group, the delayed-treatment group had a significantly shorter time to an AIDS-defining disease (P = 0.03) and to tuberculosis (P = 0.02). TB incidence was significantly higher in the delayed group (1.8 per 100 person-years, 95% confidence interval [CI] 1.3 to 2.6, versus 0.8 per 100 person-years, 95% CI 0.5 to 1.3, P = 0.009).
In multivariate analysis, delayed treatment raised the risk of a primary event 39%, but that heightened risk fell just short of statistical significance (95% CI 0.98 to 1.96, P = 0.06). Four variables did independently predict a primary event in this analysis: age 40 or older (HR 2.42, 95% CI 1.17 to 4.98, P = 0.017), each 10-fold higher pretreatment viral load (HR 1.34, 95% CI 1.06 to 1.69, P = 0.013), grade 2 or worse hemoglobin deficiency (HR 2.17, 95% CI 1.10 to 4.27, P = 0.025), and hepatitis B coinfection (HR 1.85, 95% CI 1.03 to 3.31, P = 0.04). An analysis that considered time-updated CD4 count determined that every 50-cell higher count lowered the risk of a primary event 10% (HR 0.90, 95% CI 0.85 to 0.95, P < 0.001).
The most frequent AIDS diagnoses were TB (2% in the immediate arm versus 4% in the delayed arm), serious bacterial infection (2% versus 1%), and a WHO stage 4 event (1% versus 2%). Time to a first AIDS-defining disease was significantly faster in the delayed-treatment arm (P = 0.03).
Secondary events arose in 298 people (34%) in the immediate arm and 317 people (36%) in the delayed arm. Incidence of secondary events was significantly higher in the delayed arm (25 versus 21 per 100 person-years, P = 0.05). Primary event incidence was also higher in the delayed arm, but the difference from the immediate arm was not significant (4.5 versus 3.5 per 100 person-years, P = 0.18).
Incidence of any primary or secondary event was significantly higher in the delayed group (29 versus 25 per 100 person-years, P = 0.02). That meant the risk of any event was 20% lower in the immediate-treatment arm (incidence rate ratio 0.8, P = 0.02). This difference could be traced to conditions directly related to HIV infection, such as TB, herpes virus infection, herpes zoster, Candida, and skin conditions.
New non-AIDS diagnoses were rare in HPTN 052, and rates were similar in the two trial arms: incidence 0.6 per 100 person-years in the immediate arm and 0.4 per 100 person-years in the delayed arm (P = 0.51).
The HPTN 052 team proposed that "the combined treatment and prevention benefits of ART support early initiation" of therapy.
References
1. Grinsztejn B, Hosseinipour M, Swindells S, et al. Effect of early versus delayed initiation of antiretroviral therapy (ART) on clinical outcomes in the HPTN 052 randomized clinical trial. XIX International AIDS Conference. July 22-27, 2012. Abstract THLBB05.
2. Cohen MS, Chen YQ, McCauley M, et al. Prevention of HIV-1 infection with early antiretroviral therapy. N Engl J Med. 201;365:493-505. http://www.nejm.org/doi/full/10.1056/NEJMoa1105243.
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