BOSTON — The increased risk of disease progression, AIDS, and death associated with structured treatment interruptions in HIV-positive patients is diminished but not fully reversed when continuous therapy is resumed, according to the final results of the largest HIV therapy trial to date.
A treatment strategy that includes interruptions in antiretroviral therapy (ART) guided by patients' CD4 cell counts was deemed detrimental in 2006 by investigators in the Strategies for Management of Antiretroviral Therapies (SMART) trial. The trial was halted and all patients were encouraged to resume therapy, based on interim data showing that patients who used ART only when their CD4 cell counts fell below a threshold had higher rates of AIDS-related opportunistic illnesses, serious nonopportunistic events, and all-cause mortality than patients who stayed on continuous therapy.
“Following the recommendation to reinitiate antiretroviral therapy for patients in the treatment interruption group, the risk of opportunistic disease or death was significantly reduced, but the [risk reduction] was less than complete,” Dr. Wafaa El-Sadr of New York's Harlem Hospital Center reported at the 15th Conference on Retroviruses and Opportunistic Infections. Patients who resumed treatment and were on continuous therapy for at least 85% of the 18 months following study modification reaped the most benefit from treatment reinitiation, she said.
The SMART trial enrolled 5,472 HIV-positive adults with CD4 cell counts of at least 350 cells/mm
Before the study was modified, patients in the conservation arm had spent 36% of the trial on treatment, with a median of three treatment interruptions over an 18-month period, while patients in the viral suppression arm spent 94% of the time on treatment, Dr. El-Sadr noted.
At the time of modification, 35% of the conservation patients and 82% of the suppression patients had an undetectable viral load (less than 400 copies/mL), and the respective median CD4 counts were 425 and 625 cells/mm
After the study modification, patients who had been in the conservation group spent 71% of the follow-up time on treatment, compared with 91% in the suppression group, Dr. El-Sadr said. At the end of the study, 83% and 95% of the conservation and suppression patients, respectively, were on treatment, she said.
With respect to CD4 cells, the percentage of time the conservation group spent with counts lower than 350 cells/mm
Before the study was altered, the outcome rates of opportunistic disease or death per 100 person-years were 3.4 in the conservation arm and 1.4 in the suppression arm. The respective rates per 100 person-years for death due to any cause and a composite outcome of serious cardiovascular, kidney, and liver events were 1.5 and 1.8 in the conservation arm, compared with 0.8 and 1.1 in the suppression group.
At final follow-up, the rates for all three outcomes declined significantly in the conservation arm and remained stable in the suppression arm. For example, the rate per 100 person-years of opportunistic disease or death among those who reinitiated treatment was 2.1, compared with 1.4 for the suppression group. The rates per 100 person-years of death from any cause and of composite serious events were 1.3 and 1.1 in the conservation group, vs. 0.9 and 0.9 in the suppression group, she said.
Patients who had developed a nonfatal opportunistic disease or cardiovascular disease and those who had a renal or liver event prior to study modification had a nearly sixfold increased risk of death after the study was altered, she reported.
The “less than full” risk reversal following treatment reinitiation in the drug conservation group could be a consequence of a lower average CD4 cell count and the increased number of patients with detectable viral load, which was likely associated with a failure to resume continuous therapy as recommended, Dr. El-Sadr said. The findings, she said, support the recommendation against antiretroviral therapy interruption based on CD4 cell threshold.