The benefits of antiretroviral therapy (ART) during acute and early HIV infection remain unproven, despite several years of investigations into the topic. Studies have yielded conflicting results, with many having too few participants involved to make concrete, universal conclusions. It can also be challenging to identify patients who have been infected within the previous 6 months, making it difficult to conduct randomized trials in this population. As such, national guidelines currently recommend that ART be considered optional for acute and early HIV infection.
Testing Early ART in Recently Infected Patients
In the January 2012 Journal of Infectious Disease, researchers from the AIDS Clinical Trials Group Setpoint Study randomized patients with recent but not acute HIV infection to 36 weeks of ART followed by treatment discontinuation or to no treatment until pre-specified criteria for therapy initiation were met. “We aimed to determine whether early treatment was associated with a durable clinical benefit,” explains Christine M. Hogan, MD, lead author of the study. “To do that, we set out to demonstrate whether treatment during early infection would lower the virologic set point (plasma HIV-1 RNA level)—an independent predictor of clinical outcome—after treatment was discontinued at 72 weeks.”
The primary endpoint in the analysis was a composite of required treatment or retreatment and plasma HIV-1 RNA level at Week 72 for both groups and at Week 36 for the delayed-treatment group. The secondary endpoint was the time to meeting guideline criteria—including CD4 count below 350 cells/mm3, clinical progression, or certain virologic criteria—for starting ART in the delayed-treatment arm or restarting ART after 36 weeks in the immediate-treatment arm.
Unexpected Results from Delayed ART Treatment
“When we designed the study, it was expected that some patients in the delayed-treatment group would need to start treatment,” says Dr. Hogan. “However, a higher-than-anticipated proportion of patients needed to start therapy.”
She explains that the study team expected to use off-treatment viral loads of patients as the endpoint for the study, along with a ranked viral load for those in either group who needed to start treatment according to pre-determined criteria. But when the Data and Safety Monitoring Board (DSMB) of the National Institute of Allergy and Infectious Diseases reviewed preliminary findings, they observed that 50% of patients in the delayed-treatment group had progressed to needing treatment, compared with 10% in the immediate-treatment-group. As a result, the DSMB recommended stopping the study. Dr. Hogan adds that “the board decided that our study team wasn’t going to be able to answer our primary question of what happens to the viral load. Continuing the study was unlikely to provide more information.”
HIV-1 RNA values were observed at Week 72 and/or Week 76 in 67% of the immediate-treatment group and 27.5% of the delayed-treatment group. Levels were similar between groups at both weeks. The point estimate for the average level at Week 36 in the delayed-treatment group was higher than that observed at Week 72 in the immediate-treatment group, but Dr. Hogan warns that this finding should be interpreted with caution because patients who achieved these levels were from a small, select group. “We were unable to make statistically valid conclusions about the virologic setpoint because of the higher-than-anticipated need to start therapy,” she adds. “Participants who needed to start therapy were unable to contribute an observed off-therapy HIV-1 RNA level when the study ended.”
Dr. Hogan and colleagues were able to address the secondary endpoint of their study. They found that the time to meeting eligibility criteria for initiating or reinitiating ART was significantly shorter in the delayed-treatment group than the immediate-treatment group (Figure). “We found that those who started and then stopped treatment experienced an additional delay of about 16 weeks beyond the 36 weeks of treatment,” Dr. Hogan notes. “This suggests that early treatment modestly delayed the subsequent start of long-term therapy. However, durable clinical benefits of this strategy remain unproven.”
Putting Results to Practice with HIV Patients
When clinicians are faced with newly infected patients, Dr. Hogan says the decision to initiate early therapy should be made collaboratively with patients. “There are a number of reasons to believe that it makes sense to initiate immediate treatment from a virologic and immunologic perspective. We must also consider, however, that there are possible pitfalls associated with early treatment, including the development of resistance and increased drug exposure. Based on our study findings, it appears that patients are likely going to need treatment—per current HIV treatment guidelines—earlier than traditionally expected if they choose to forego immediate initiation of ART. Our study adds another piece of information that can be utilized in the decision-making process. In addition, clinicians should actively plan for treatment from the beginning in cases when patients decide to delay therapy. That’s because our results suggest that progression to meeting standard criteria for ART initiation may occur somewhat rapidly, especially with changing treatment paradigms.”
Readings & Resources (click to view)
Hogan CM, De Gruttola V, Sun X, et al; the A5217 Study Team. The setpoint study (ACTG A5217): Effect of immediate versus deferred antiretroviral therapy on virologic set point in recently HIV-1–infected individuals. J Infect Dis. 2011, Dec 15 [Epub ahead of print]. Available at: http://jid.oxfordjournals.org/content/early/2011/12/14/infdis.jir699.full.
Kitahata MM, Gange SJ, Abraham AG, et al. Effect of early versus deferred antiretroviral therapy for HIV on survival. N Engl J Med. 2009;360:1815-1826.
Sterne JA, May M, Costagliola D, et al. Timing of initiation of antiretroviral therapy in AIDS-free HIV-1-infected patients: a collaborative analysis of 18 HIV cohort studies. Lancet. 2009; 373:1352-1363.
Bell SK, Little SJ, Rosenberg ES. Clinical management of acute HIV infection: best practice remains unknown. J Infect Dis. 2010;202(Suppl 2):S278-S288.
Markowitz M, Vesanen M, Tenner-Racz K, et al. The effect of commencing combination antiretroviral therapy soon after human immunodeficiency virus type 1 infection on viral replication and antiviral immune responses. J Infect Dis. 1999;179:527-537.
Ray M, Logan R, Sterne JA, et al. The effect of combined antiretroviral therapy on the overall mortality of HIV-infected individuals. AIDS. 2010;24:123-137.
Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents. Washington, DC: Department of Health and Human Services, 2009:1–161. Available at: http://www.aidsinfo.nih.gov/ContentFiles/AdultandAdolescentGL.pdf. Accessed 20 January 2012.
Thompson MA, Aberg JA, Cahn P, et al. Antiretroviral treatment of adult HIV infection: 2010 recommendations of the International AIDS Society-USA panel. JAMA. 2010;304:321-333.