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.”