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Earlier Antiretroviral Therapy Lowers Risk of Progression to AIDS and Related Conditions

Starting antiretroviral therapy (ART) at higher CD4 cell levels can significantly reduce the risk of AIDS-related clinical events, especially tuberculosis, as well as dramatically reducing the likelihood of HIV sexual transmission, according to findings from the HPTN 052 study published in the April 2014 issue of Lancet Infectious Diseases.

Current U.S. antiretroviral treatment guidelines recommend that all people diagnosed with HIV should consider starting ART regardless of CD4 T-cell count, while the latest World Health Organization (WHO) global guidelines call for treatment starting at a CD4 count of 500 cells/mm³.

HIV Prevention Trials Network (HPTN) Study 052 is best known for showing that when HIV positive partners in serodiscordant heterosexual couples started ART immediately upon diagnosis rather than waiting for their CD4 count to fall, sexual transmission was reduced by 96%, supporting the concept of "treatment as prevention." But some advocates have raised concerns about pressuring HIV positive people who are still in relatively good health to start treatment earlier for the sake of others.

In parallel with the HPTN 052 transmission analysis, Beatriz Grinsztejn from Instituto de Pesquisa Clinica Evandro Chagas in Rio de Janeiro and colleagues looked at outcomes among the HIV positive partners in the study. Data from this analysis -- first presented at the 2011 International AIDS Society Conference on HIV Pathogenesis, Treatment and Prevention -- were hailed as the first evidence from a randomized clinical trial showing the benefits of earlier treatment for people with HIV themselves.

HPTN 052 enrolled 1763 HIV serodiscordant couples in 9 low- and middle-income countries in Africa, Asia, and South America. The HIV positive partners were about evenly divided between men and women, and most were in the 26-40 year age range. At enrollment the positive partners had CD4 counts between 350 and 550 cells/mm³.

HIV positive partners were randomly assigned (1:1) to either start combination ART immediately upon enrollment or wait until either their CD4 count fell below 250 cells/mm³ or they developed AIDS-related symptoms. The median CD4 count at the time of ART initiation was 442 cells/mm³ in the immediate treatment arm and 230 cells/mm³ in the delayed arm.

The researchers looked at primary AIDS clinical events including WHO stage 4 HIV disease, tuberculosis (TB), and severe bacterial infections, as well as serious medical conditions unrelated to AIDS including cardiovascular disease, liver disease, end-stage kidney disease, non-AIDS malignancies, and diabetes mellitus. They also analyzed various secondary outcomes including WHO stage 2 or 3 (symptomatic) HIV disease, malaria, liver or kidney dysfunction, lipodystrophy, hypertension, blood cell deficiencies, and non-opportunistic infections. The median follow-up period was approximately 2 years.

Results

• Overall, 498 primary or secondary AIDS and non-AIDS outcomes occurred in the early ART group, compared with 585 in the delayed treatment group -- incidence rates of 24.9 vs 29.2 per 100 person year, respectively, a statistically significant difference (p=0.025).
• Primary clinical events occurred in 57 participants (6%) assigned to early ART versus 77 people (9%) in the delayed arm -- a hazard ratio (HR) of 0.73, or a 27% risk reduction, which did not reach statistical significance (p=0.074).
• New-onset AIDS events occurred in 40 participants (5%) assigned to early ART and 61 people (7%) in the delayed arm -- HR 0.64, or a 36% reduction, which was significant (p=0.031).
• The largest reduction was seen for tuberculosis, observed in 17 people (2%) in the immediate ART arm and 34 people (4%) in the delayed arm -- HR 0.49, or a 51% reduction, also significant (p=0.018).
• Serious non-AIDS-related events were uncommon in both groups (12 vs 9 events, respectively).
• Secondary outcomes occurred with similar frequency, in about one-third of participants in both the immediate and delayed ART groups.
• 11 participants in the early ART group and 15 in the delayed treatment group died during follow-up.
• A majority of primary and secondary events occurred among people with higher CD4 counts, at a median of 353 and 502 cells/mm³, respectively, in the immediate and delayed arms.

"Early initiation of antiretroviral treatment delayed the time to AIDS events and decreased the incidence of primary and secondary outcomes," the study authors concluded. "The clinical benefits recorded, combined with the striking reduction in HIV-1 transmission risk previously reported, provides strong support for earlier initiation of antiretroviral treatment."

Even though the differences seen in this study were small, the researchers noted, the results suggest that earlier ART could reduce morbidity for millions of people with HIV worldwide.

5/12/14

References

B Grinsztejn, MC Hosseinipour, HJ Ribaudo, et al (HPTN 052 Study Team). Effects of early versus delayed initiation of antiretroviral treatment on clinical outcomes of HIV-1 infection: results from the phase 3 HPTN 052 randomised controlled trial. Lancet Infectious Diseases 14(4):281-290. April 2014.

S Nolan and E Wood. End of the debate about antiretroviral treatment initiation (Comment). Lancet Infectious Diseases 14(4):258-259. April 2014.