HIV: Earlier Therapy May Be Better

Larry Hand

November 25, 2014

Starting antiretroviral therapy (ART) within 12 months of the estimated dates of seroconversion (EDS) in patients infected with HIV may help more patients achieve normalization of CD4+ T-cells than starting ART based on T-cell count alone, according to an article published online November 24 in JAMA Internal Medicine.

Jason F. Okulicz, MD, from the Infectious Disease Clinical Research Program, Uniformed Services University of Health Sciences, Bethesda, Maryland, and colleagues analyzed the records of 1119 patients infected with HIV-1 in the US Military Natural History Study (NHS), a large cohort of individuals who mostly have identified EDS. The vast majority of the cohort were male (95.3%), with a median age of 31 years at ART initiation.

The researchers defined normal CD4+ counts for adults not infected with HIV using data from three sources, including the US National Health and Examination Survey; measurements from the University of California, San Diego, HIV Neurobehavioral Research Center; and an update to their own literature survey.

Median CD4+ counts in the uninfected groups ranged from 904 to 988 cells/μL.

Among the NHS cohort, 26.1% of patients initiated ART within 12 months of EDS and 57.6% of patients started ART within 12 months of enrolling in the study.

Overall, 30.9% participants achieved CD4+ normalization, with a greater likelihood among those who started therapy earlier. Specifically, of participants who initiated ART within 12 months of EDS, 38.4% achieved normal CD4+ T-cell counts ≥900 cells/µL) compared with 28.3% of those who initiated ART later than 12 months after EDS (P = .001).

In addition, participants who had CD4+ T-cell counts of 500 cells/μL or higher at study entry or at ART initiation experienced significantly increased CD4+ normalization rates compared with other participants who had lower counts at study entry or at ART initiation and who started ART at lower counts (P = .001, for both comparisons).

Earlier ART also correlated with better clinical outcomes. Participants initiating ART within 12 months of EDS had almost half the risk for AIDS compared with those who initiated ART later (7.8% vs 15.3%; P = .002).

In general, the authors note that the benefits of therapy were additive with respect to starting therapy within 12 months of EDS and while CD4+ cell count remained high. "[A]mong participants with study entry CD4+counts of less than 500 cells/μL, earlier ART did not substantially improve CD4+ normalization rates, whereas it did so among participants with entry CD4+ counts of 500 cells/μL or more," they write.

"These data indicate that it was not the numeric CD4+ value at ART initiation per se, but rather the duration of the untreated infection that is associated with CD4+ normalization," the researchers write.

Traditionally, early or late ART initiation has been defined as initiating before or after CD4+ counts go below a certain level, such as 500 cells/μL, they explain.

Clinical Implications

They write that the study results have four broad clinical implications: normalization of CD4+ counts may be a significant therapeutic target, adjunctive therapies that target functional gaps in immune reconstitution are needed, the CD4+ normalization capacity is retained if duration of untreated infection is short and ART initiation is at 500 cells/μL or more, and a shorter duration of untreated HIV infection led to improved immunological and clinical outcomes.

They caution, however, that their findings might not be generalizable to HIV-infected women or older adults or to patients other than those with the HIV-1 subtype.

"[T]here is a narrow time window after acquiring HIV infection within which commencement of ART favors CD4+ normalization," they conclude. "Achieving CD4+ normalization is an imminently feasible therapeutic goal, provided ART is started within 12 months of the EDS at higher CD4+ counts (≥500 cells/μL)."

Clinically Important Endpoints Measured

"This is an important study because the investigators used as primary end points measures of immune function that should be the goal of antiretroviral therapy: full restoration of immune function," Timothy W. Schacker, MD, from the Department of Medicine at the University of Minnesota, Minneapolis, writes in an invited commentary. "Historically, many of the sentinel studies used to make policy decisions on when and how to treat HIV infection used end points such as suppression of virus replication in peripheral blood, increases in peripheral blood CD4+ T-cell count, or progression to a diagnosis of AIDS."

He adds, however, that it is unrealistic to expect to identify patients with 12 months of infection in parts of the world where HIV is most present.

Nevertheless, the researchers "have provided the clearest signal to date that we will not restore immunity with the drugs we have available."

He concludes, "We need better formulations of antiretroviral drugs that fully suppress virus replication in tissues. However, we also need adjunctive therapies that eliminate the causes of persistent immune activation and restore lymphoid tissues to their normal anatomy and function."

This research was supported by the Veterans Affairs research Center for AIDS and HIV Infection, the National Institutes of Health, the Doris Duke Charitable Foundation, the Elizabeth Glaser Pediatric AIDS Foundation, Burroughs Wellcome, the Max and Minnie Tomerlin Voelcker Fund, the National Health and Medical Research Council of Australia, the National Institute of Allergy and Infectious Diseases, and the Department of Defense. Five coauthors have reported various relationships with pharmaceutical companies; no other coauthors or the commentator have disclosed any relevant financial relationships.

JAMA Intern Med. Published online November 24, 2014. Article abstract, Editorial extract

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