On January 18th, the National Institute of Allergy and Infectious Diseases announced that enrollment into a large international clinical trial comparing continuous anti-HIV therapy with episodic drug treatment guided by T-cell counts had been stopped. All that was reported at that time was that patients receiving episodic therapy (which included structured treatment interruptions, or STIs) had twice the risk of disease progression (meaning the development of AIDS or death) compared to those in the continuous therapy group. At the 13th Conference on Retroviruses and Opportunistic Infections, held in Denver earlier this week, a more detailed review of the study results were reported.
The Strategies for Management of anti-HIV Therapy (SMART) trial originally intended to enroll 6,000 HIV-positive patients with T-cell counts above 350, who were either on treatment or had not yet started therapy. The patients were randomized to one of two groups: 1) a continuous treatment group, in which treatment would be continued indefinitely; or 2) an episodic treatment group, in which treatment would be delayed or discontinued until the T-cell count falls below 250, followed by treatment until the T-cell count is back above 350, followed by another treatment discontinuation until the T-cell count again falls below 250 (and so on).
The researchers conducting SMART suggested that episodic treatment would enable patients to keep their T-cell counts high enough to keep them healthy while at the same time reducing the amount of time on treatment to help reduce the risk of side effects.
On January 10th, when the study's data safety and monitoring board recommended halting the study, the 5472 patients enrolled in the study had been followed for approximately 14 months (the study was supposed to take approximately nine years). While the study is technically still being conducted, no new patients are being enrolled and patients in the episodic treatment group – especially those who had tried and failed other anti-HIV drugs in the past – were advised to restart treatment and to remain on therapy.
Dr. Wafaa El-Sadr, Chief of the Infectious Disease Division at Harlem Hospital in New York and a leading SMART researcher, presented the data at the conference. She reported that there were 164 "events" during the 14 weeks of study follow up. These events were defined as either death or the development of a serious AIDS-related condition or another serious complication (such as a potential side effect).
In the continuous treatment group, there were 47 events. In the episodic treatment group, there were 117 events. In other words, 3.7% of the patients in the episodic treatment group had an event, compared to 1.5% of the patients in the continuous treatment group. More specifically, 1.7% of patients in the episodic treatment group died during the follow-up period, compared to 0.9% of patients in the continuous treatment group. As for progression to AIDS, this occurred in 0.9% of patients in the episodic treatment group, compared to 0.6% of patients in the continuous treatment group. Esophageal candidiasis was the most common AIDS-related sign of disease progression among the patients in the episodic treatment group.
While the SMART researchers were hoping that episodic therapy would be associated with fewer complications believed to be associated with treatment – including heart attacks, stroke, serious coronary artery disease, kidney problems, and liver damage – they actually found fewer complications in the continuous treatment group. According to Dr. El-Sadr's report, 2.1% of patients in the episodic treatment group experienced a serious complication, compared to 1.4% of patients in the continuous treatment group.
Many structured treatment interruption studies have documented that the lowest a patient's T-cells have ever been (the T-cell "nadir"), the more likely it is that someone will progress while off treatment. This, however, did not turn out to be the case in SMART; patients with both low and high T-cell nadirs experienced "events" during the study. What's more, patients who had viral loads below 400 at the time of stopping therapy were more likely to have an event than those who stopped therapy with higher viral loads.
SMART's conclusion, based on the data presented thus far, is hard to deny: episodic therapy, using a T-cell count of higher than 350 as a stopping point and a T-cell count of lower than 250 as a restarting point, is inferior to continuous treatment – the current standard-of-care.
Making sense of the SMART data will undoubtedly be tricky. One reason why patients in the episodic treatment group may have done so poorly is because of the low T-cell count used to restart treatment. For example, in another study reported at the conference (the Staccato trial, conducted in parts of Europe and Thailand), patients doing episodic treatment – in which treatment was restarted when their T-cell counts fell below 350 – were no more likely to die or experience an AIDS-related complication, compared to those who remained on continuous therapy. What's more, a third episodic treatment study reported at the conference (the Trivacan study, conducted in Cote d'Ivoire), mirrored the results of SMART; it, too, used a T-cell count of 250 to restart patients on treatment.
Another factor to consider is that a sizeable number of patients in SMART had a history of an AIDS diagnosis (24%) and many (95%) had tried and failed other treatments in the past. In other words, conducted the same study with patients who had a healthier history and newer to anti-HIV treatment may have yielded different results.
While the preliminary results from the SMART trial (and the Trivacan study) suggest that using T-cell counts to guide episodic treatment may not be such a good idea, the results of the Staccato trial suggest that it may be possible after all. But without additional studies – and it's not clear if such studies will be conducted again – it's not likely that T-cell-guided episodic treatment will be a standardized treatment approach in the near future.