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Very Early HIV Treatment May Delay Disease Progression, Raise CD4 Count

Starting antiretroviral therapy (ART) within the first 6 months after infection may slow immune system decline and raise CD4 T-cell counts, but the benefits may not last after treatment is stopped, according to a pair of studies published in January 17, 2013, New England Journal of Medicine.

Starting antiretroviral therapy (ART) within the first 6 months after infection may slow immune system decline and raise CD4 T-cell counts, but the benefits may not last after treatment is stopped, according to a pair of studies published in January 17, 2013, New England Journal of Medicine.

When to start HIV treatment has long been a contentious issue and recommendations have changed over the years as people with HIV and their clinicians learned more about the effects of HIV and the side effects of drugs used to treat it.

A growing body of evidence indicates that HIV infection causes inflammation and immune system damage long before an individual's CD4 count falls into the danger zone for opportunistic infections, and the latest U.S. treatment guidelines recommend that everyone diagnosed with HIV should be offered ART. But such early treatment may be associated with drawbacks including not-yet-recognized long-term toxicities.

Since the early years of the epidemic researchers have held out hope that starting treatment as soon as possible after initial infection might preserve immune function and potentially eradicate the virus, but research to date has yielded conflicting results.

Primary HIV Infection

As described in the first report, investigators with the SPARTAC trial (which stands for "Short Pulse AntiRetroviral Therapy At HIV seroConversion") aimed to determine whether short-course ART during primary HIV infection could delay disease progression.

The analysis included 366 newly infected adults from 8 countries estimated to be within the first 6 months after HIV infection (median 3 months). A majority (60%) were men, the median age was 32 years, and the median CD4 count at study entry was approximately 560 cells/mm³. About 60% said they had experienced symptoms of acute retroviral infection/seroconversion. People who needed immediate ART due to low CD4 count or clinical symptoms of AIDS were excluded.

Participants were randomly assigned (1:1:1) to receive ART for 48 weeks or 12 weeks, starting within 6 months after seroconversion, or else no treatment (the former standard of care at this stage of disease).

Follow-up continued for a mean 4.2 years. The primary endpoints were reaching a CD4 count less than 350 cells/mm³ -- a previous threshold for treatment initiation -- or starting long-term ART.

Results

• 50% of participants in the 48-week ART arm reached the primary endpoints, compared with 61% in both the 12-week ART group and the standard-of-care group.
• The hazard ratio was 0.63 for 48-week ART versus the standard of care, a significant difference (P=0.01).
• The hazard ratio was 0.93 for 12-week ART versus the standard of care, which did not reach statistical significance (P=0.67).
• 28% of patients in the 48-week ART group saw their CD4 count fall below 350 cells/mm³ compared with 40% both the 12-week ART and standard-of-care groups.
• The proportion of people who started long-term treatment was similar in all 3 groups: 22%, 21%, and 22%, respectively.
• The median time to reach the primary endpoints was 65 weeks longer in the 48-week ART group compared with the standard-of-care group.
• A post hoc analysis found a trend toward a longer interval between ART initiation and the primary endpoints when therapy was started closer to the time of seroconversion.
• 48-week ART was associated with a 0.44 log reduction in HIV viral load at 36 weeks after completing short-course therapy. There were no significant differences between the groups with regard to progression to AIDS, death, or serious adverse events.

"A 48-week course of ART in patients with primary HIV infection delayed disease progression, although not significantly longer than the duration of the treatment," the SPARTAC researchers concluded. "There was no evidence of adverse effects of ART interruption on the clinical outcome."

CD4 Cell Restoration

In the second study, Tuan Le from the Veterans Affairs Research Center for AIDS and HIV-1 Infection looked at the relationship between timing of ART initiation and CD4 cell recovery.

This prospective, observational (non-randomized) cohort study included 468 U.S. adults with acute or early HIV infection. More than 90% were men, most were white, and the median age was 33 years at the time of infection and 35 years at the time of ART initiation.

One group was comprised of 384 participants analyzed while they were not receiving ART; of these, 136 never received treatment during the 48-week observation period. The second group -- which overlapped with the first -- included 213 people who started ART soon after study entry or sometime shortly thereafter (median 4.9 months after estimated infection date); 176 of them were crossovers from the first group.

The researchers analyzed CD4 count trajectories over a 48-month period, including the likelihood ofrecovery to 900 cells/mm³ or more within 48 months while on ART with suppressed viral load.

Results

• Among participants who were not receiving ART, CD4 counts increased spontaneously soon after HIV infection, with a median gain of 495 cells/mm³ over the baseline level.
• CD4 counts reached a peak within approximately 4 months after the estimated date of infection, at a median 763 cells/mm³.
• After this point, however, CD4 counts progressively declined. 
• About 64% of participants who started ART within 4 months after infection experienced CD4 cell recovery to at least 900 cells/mm³, compared with 34% of those who started treatment after 4 months -- a significant difference.
• After adjusting for whether ART initiation occurred when CD4 count was above or below 500 cells/mm³, people who started treatment later had a 65% lower likelihood of reaching at least 900 cells/mm³ and a 56% slower rate of CD4 cell recovery.
• There was no observed association, however, between plasma viral load at the time of ART initiation and CD4 cell recovery.

Based on these findings, the study authors concluded, "A transient, spontaneous restoration of CD4+ T-cell counts occurs in the 4-month time window after HIV-1 infection. Initiation of ART during this period is associated with an enhanced likelihood of recovery of CD4+ counts."

Editorial

In an accompanying editorial, Bruce Walker from the Ragon Institute of MGH, MIT, and Harvard and Martin Hirschfrom Massachusetts General Hospital and Harvard Medical School said that these 2 studies "provide compelling support for early treatment" on the basis of CD4 cell restoration.

"Both provide evidence that greater CD4+ cell recovery is achieved with earlier initiation of therapy during primary infection," they wrote, "but both fall short of defining a clear clinical benefit for such early treatment."

"When resources are severely constrained (e.g., in developing countries)," they continued, "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."

The authors noted that early treatment during acute infection "may offer substantial benefits beyond those to the infected person" by reducing the risk of HIV transmission. But it is difficult to identify people at such early stages of HIV infection. To realize these benefits, "It will be critical to increase HIV testing of patients with symptoms suggestive of possible acute primary infection, as well as to screen asymptomatic persons at high risk for infection, using the most current techniques available for early detection," they wrote.

"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," Walker and Hirsch concluded.

1/24/13

References

S Fidler, K Porter, F Ewings, et al (SPARTAC Trial Investigators). Short-Course Antiretroviral Therapy in Primary HIV Infection. New England Journal of Medicine 368(3):207-217. January 17, 2013.

T Le, EJ Wright, DM Smith, et al. Enhanced CD4+ T-Cell Recovery with Earlier HIV-1 Antiretroviral Therapy. New England Journal of Medicine 368(3):218-230. January 17, 2013.

BD Walker and MS Hirsch. Antiretroviral Therapy in Early HIV Infection (editorial). New England Journal of Medicine 368(3):279-281. January 17, 2013.