AT AIDS 2016
DURBAN, SOUTH AFRICA (FRONTLINE MEDICAL NEWS) – Immediate initiation of antiretroviral therapy in asymptomatic treatment-naive HIV-infected adults with a CD4+ cell count greater than 500/mL brings considerably more bang for the buck in selected patient subgroups, according to a secondary analysis from the landmark START trial.
Four subgroups in START stood out as having larger absolute risk reductions and lower numbers-needed-to-treat with a strategy of immediate treatment: patients above age 50, those with a baseline Framingham Risk Score in excess of 10%, individuals whose plasma HIV RNA level exceeds 50,000 copies/mL, and patients with a CD4:CD8 ratio below 0.5, Dr. Jean-Michel Molina reported at the 21st International AIDS Conference.
“These patients might be prioritized for immediate access to ART,” observed Dr. Molina, professor of infectious diseases at the University of Paris-Diderot and head of the infectious diseases department at Saint-Louis Hospital, also in Paris.
The START (Strategic Timing of AntiRetroviral Treatment) study was a major clinical trial conducted in 35 countries. Investigators randomized 4,685 treatment-naive HIV-infected men and women with CD4+ cell counts in the normal range to immediate antiretroviral therapy or to deferral of treatment until their CD4+ cell count dropped to 350 cells/mL. After 3 years of prospective follow-up, the immediate-treatment strategy was associated with a 47% reduction in risk for the primary endpoint, a composite of AIDS, major cardiovascular or other non-AIDS events, and death. The number needed to treat immediately for 1 year in order to prevent one major event was 128 (N Engl J Med. 2015;373:795-807).
The START findings prompted a revision in World Health Organization guidelines, which now recommend universal antiretroviral treatment (ART) in patients with HIV infection regardless of their CD4+ cell count.
But some patients are reluctant to go on lifetime ART, particularly since they still feel normal while in the initial phases of HIV infection. In such cases, these new subgroup data may tip the balance in decision-making. Moreover, the new START findings should help physicians and policy makers in prioritizing access to immediate ART in settings where it isn’t universally available, according to Dr. Molina.
In the prespecified subgroup analysis, patients aged 50 and up at enrollment had a 2.9% incidence of the primary composite endpoint at 3 years if randomized to immediate ART and an 11.7% rate if they were assigned to deferred ART. The number of 50-plus-year-olds needed to treat (NNT) immediately for 1 year in order to prevent one additional case of AIDS, a major non-AIDS event, or death was just 45, compared to NNTs of 151 and 206 in patients aged 30-49 and younger than 30, respectively. Patients aged 50 and older accounted for nearly 12% of the overall study population.
For the roughly 28% of START participants whose baseline CD4:CD8 ratio was less than 0.5, the NNT for immediate rather than deferred therapy was 60, substantially more favorable than the NNTs of 214 in patients with a baseline ratio of 0.5-0.8 and 248 in patients with a CD4:CD8 ratio greater than 0.8. The incidence of the primary endpoint at 3 years of follow-up in patients with a CD4:CD8 ratio of less than 0.5 was 0.5% in the immediate ART group and 6.3% with deferred therapy.
Similarly, patients with a baseline 10-year Framingham Risk Score (FRS) of 10% or higher had an NNT of 69, compared with NNTs of 111 in subjects with an FRS of 1%-9.9% and 276 in those with an FRS of less than 1%. Patients with an FRS of 10% or more had a 2.4% incidence of the primary endpoint at 3 years if assigned to immediate ART and a 10.1% rate with deferred therapy. Patients with an FRS of 10% or more comprised only 9.6% of the study population, Dr. Molina continued.
Patients with a heavy baseline viral load as evidenced by a plasma HIV RNA level of at least 50,000 copies/mL accounted for roughly 22% of the total study sample. Their 3-year rate of the primary outcome was 2.1% with immediate ART and 6.9% with deferred treatment. The NNT was 67, compared to an NNT of 122 in patients with 3,000-49,999 copies/mL and 992 in the one-quarter of START participants with a baseline plasma HIV RNA level of less than 3,000 copies/mL.
Variables that weren’t related to the magnitude of absolute risk reduction and NNT in the START subgroup analysis were race, gender, geographic region, baseline CD4 cell count, and whether an individual resided in a high- or lower-income country.
Several audience members rose to assert that the CD4:CD8 ratio and viral load might very well be redundant predictors measuring the same thing, since they are typically tightly correlated. Dr. Molina replied that the START investigators are planning to conduct a multivariate analysis of the data in the near future, which should provide a definitive answer.
Another audience member expressed surprise at what struck him as a low cardiovascular event rate in the START study, given that HIV infection is known to be associated with accelerated atherosclerosis. Dr. Molina said the explanation for the low number of cardiovascular events lies in the fact that cardiovascular risk is so heavily age-dependent, and START participants were relatively young, with a median age of 36 years.
The START trial was carried out by the International Network for Strategic Initiatives in Global HIV Trials (INSIGHT) with funding provided mainly by the National Institutes of Health. Dr. Molina reported having no financial conflicts of interest.