Studies Support Early Initiation of Antiretroviral Therapy in HIV

January 16, 2013

NEW YORK (Reuters Health) Jan 16 - Two new studies on the timing of antiretroviral therapy (ART) for HIV infection provide "compelling" support for starting treatment early, based on evidence that it helps restore CD4 T-cells in peripheral blood.

That's according to an editorial accompanying the studies in the January 17 issue of the New England Journal of Medicine.

Both studies "provide evidence that greater CD4+ cell recovery is achieved with earlier initiation of therapy during primary infection, but both fall short of defining a clear clinical benefit for such early treatment," Dr. Bruce Walker and Dr. Martin Hirsch from Massachusetts General Hospital and Harvard Medical School, Boston write in their editorial.

In an observational cohort with acute or early HIV-1 infection, Dr. Tuan Le, from the Veterans Affairs Research Center for AIDS and HIV-1 Infection in San Antonio, Texas and colleagues determined the trajectory of CD4 counts over 48 months in partially overlapping study sets. Study set one included 384 patients during the time window in which they were not receiving ART, and study set two included 213 patients who received ART soon after study entry or sometime thereafter and had a suppressed plasma HIV viral load.

The investigators saw a transient and partial restoration of CD4 counts during the first four months after the estimated date of HIV infection in untreated patients, and they say treatment initiated during this early period enhanced CD4 T-cell recovery.

Roughly two-thirds of those treated within four months after infection reached the primary CD4 T-cell end point of 900 or more cells/mm3 in peripheral blood within 48 months. In contrast, only about one third of those whose initial treatment was delayed beyond four months recovered CD4 cell numbers to a similar degree.

Also, the likelihood of reaching the primary end point was lower and the rate of recovery was slower in those who initiated treatment more than four months after the estimated date of first infection.

In the second paper, the Short Pulse Anti-Retroviral Therapy at Seroconversion (SPARTAC) trialists report the effect of short-course ART on CD4 cell decline in 366 HIV-infected patients who were randomly allocated to 12 or 48 weeks of highly active ART or to no treatment, with average follow-up of 4.2 years.

The study was specifically designed to determine whether short-term ART during primary HIV infection can lengthen the time until patients reach a CD4 count less than 350 or require long-term ART. The trial included patients in whom seroconversion had occurred within six months prior to randomization.

A 48-week course of ART during primary HIV infection did delay disease progression and the consequent need for long-term ART, although the delay was not significantly longer than the duration of initial treatment, the research team reported. There was no benefit of 12-week ART given during primary HIV infection, however.

Specifically, the primary end point (CD4 count of less than 350 or long-term ART initiation) was reached in 50% of the 48-week ART group, as compared with 61% in each of the 12-week ART and no ART groups. The average hazard ratio was 0.63 for 48-week ART and 0.93 for 12-week ART, compared with no ART.

The proportion of patients who had a CD4 count of less than 350 was 28% in the 48-week ART group, 40% in the 12-week group, and 40% in the no ART group.

A post hoc analysis showed a trend (p=0.09) toward greater delay to the primary end point among participants in the 48-week ART group who were treated earlier. There was no evidence of adverse effects of ART interruption on the clinical outcome, the researchers say.

In their editorial, Drs. Walker and Hirsch note that both studies support the current Department of Health and Human Services and International Antiviral Society-USA guidelines for resource-rich settings, "which suggest ART for nearly everyone who is HIV-infected, regardless of the stage of infection."

"The question of when to initiate ART," they acknowledge, "remains a difficult one, particularly in resource-limited settings."

These two studies, they say, provide strong supportive evidence suggesting a benefit for early therapy. "Future studies of treatment even earlier in the course of infection may show additional benefits, and a population of such patients will be an important study group for eventual studies aimed at 'cure' of infection."

"When resources are severely constrained (e.g., in developing countries), the bar for proving benefit deserves to be higher, and treatment emphasis should still be on saving the maximum number of lives by treating a greater number of patients at later stages of disease," they conclude.

The study by Le et al was funded by the National Institute of Allergy and Infectious diseases and others. The SPARTAC trial was funded by the Wellcome Trust. A complete list of author disclosures can be found at NEJM.org.

SOURCES: http://bit.ly/UtEpgd, http://bit.ly/UtEpgd, and http://bit.ly/UtEpgd,

N Engl J Med 2013;368:207-230,280-281.

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