July 29, 2009
The immune systems of untreated HIV-infected individuals appear to deteriorate faster than previously thought, according to preliminary results of a small clinical trial. This finding suggests that clinicians may need to monitor people with recent HIV infection as closely as they monitor people with more advanced disease, the study investigators postulate.
Known as the SETPOINT study, or A5217, the trial was designed to compare the point at which the amount of HIV in the blood levels off in two groups of people with recent HIV infection: those who receive a 36-week course of antiretroviral therapy (ART), and those who receive no therapy until they meet immunologic, virologic or clinical criteria for starting ART. The amount of HIV in the blood is thought to reach a plateau, known as the viral setpoint, and remain there for years after infection. The level of this setpoint is thought to influence the severity of the course of HIV disease. The SETPOINT investigators wanted to learn whether early treatment lowers the viral setpoint.
In the final analysis, the difference in viral setpoint between the two groups could not be statistically evaluated because too few viral setpoints were directly measured. However, the study investigators discovered that those who did not receive the 36-week course of ART progressed to the point of needing continuous ART more quickly than anticipated. The median CD4+ T cell count in the deferral group at study entry was 556 cells per cubic millimeter (mm3). Since it is commonly thought that people with untreated HIV infection lose approximately 60 CD4+ T cells/mm3 per year, and since U.S. guidelines recommend starting ART when the CD4+ T cell count drops below 350 cells/mm3, the study team expected at least two to three years would elapse before members of the deferral group would need treatment. Thus, it was surprising that 20 of 39 members of the deferral group needed treatment within one and a half years. Close observation of a larger population of individuals with recent HIV infection will be necessary to validate this finding, which could have implications for future clinical trial design and public health policy.
The SETPOINT study has been conducted by the Acute Infection and Early Disease Research Program and the AIDS Clinical Trials Group, both funded by the National Institute of Allergy and Infectious Diseases (NIAID), part of the National Institutes of Health. The principal investigator is Christine Hogan, M.D., an assistant professor at the Medical College of Wisconsin and an adjunct assistant professor of clinical medicine at Columbia University.
The trial has been stopped ahead of schedule because, during a routine interim review, an independent data and safety monitoring board (DSMB) determined that the early treatment group had a superior outcome largely driven by HIV disease progression in the deferral group. The DSMB also found that more than half of the deferral group needed to initiate continuous ART before the viral setpoint could be measured at 72 weeks. As a result, the trial was unable to demonstrate a meaningful difference in measured viral setpoints between the two groups.
The DSMB recommended ending the SETPOINT trial early because continuing it would not likely change the outcome or yield additional clinically useful information. The DSMB also recommended that study staff offer antiretroviral drugs for up to 36 weeks to anyone in the early treatment group who had not yet completed his or her 36-week course of medication. NIAID concurred with these recommendations.
The study team is working with the participants who started ART during the trial and their physicians to ensure a smooth transition to clinical care outside the study. The team also is providing ART for up to 36 weeks to volunteers in the early treatment group who have not finished their 36-week course of therapy and wish to complete it.