By Rowena Johnston, Ph.D., and Jeffrey Laurence, M.D.
Assessing the success of any proposed HIV cure currently requires withdrawing combined antiretroviral therapy (cART) under carefully monitored conditions, commonly referred to as an analytic treatment interruption (ATI). This is done to determine if and when the virus reemerges. But temporarily stopping cART has raised several potential safety concerns, including an increased risk of accelerated heart disease, the emergence of drug-resistant virus, and the irreversible replenishment or increase in size of the HIV reservoir. The critical question surrounding ATI is: How long is too long?
Writing in the August issue of the journal AIDS, amfAR-funded scientist Dr. Felipe Garcia and colleagues at the University of Barcelona explore this issue in the context of an experimental therapeutic HIV vaccine tested in infected individuals who had started cART during the chronic phase of their infection. As such, all had well-established and stable reservoirs of HIV.
At the beginning of the clinical trial, participants had been on cART for a median of three years with normal CD4 counts and undetectable viral loads. To make the vaccine, investigators withdrew cART for 12 weeks in order to allow the virus to reemerge in sufficient quantity to collect samples. The vaccine was made by obtaining immune blood cells known as dendritic cells from the volunteers, briefly exposing (“pulsing”) these cells to the individual’s own virus (collected during the 12-week cART interruption period), then re-injecting the cells into the subjects. cART was then restarted. Forty-eight weeks later, three pulsed dendritic cell immunizations were given, separated by two week intervals. A longer 48-week ATI was then instituted in a subset of subjects.
Whether these immunizations had any impact on reservoir size was not reported in the article. But overall measures of these reservoirs—the amount of HIV DNA integrated into an individual’s CD4+ T cells—were very informative. The researchers tracked changes in the amount of viral DNA during the two ATI periods—the first of 12 weeks, and the second of 48 weeks. The first, shorter duration ATI had no adverse effect on reservoir size.
However, some concerns arose in the subset of individuals who volunteered for the 48-week ATI. Integrated HIV DNA increased modestly at 12 weeks and strongly by 48 weeks, rising to levels seen before the individuals had started cART many years previously. Even two years after cART was reinitiated, integrated HIV DNA levels had not returned to their previous low recorded before the beginning of the trial.
The good news, at least in HIV-infected adults (the authors cautioned that these reservoir changes may be very different in HIV-infected infants or children), is that a short-term interruption in cART, as required to assess a proposed HIV cure, had no long-term detrimental effect on viral reservoir size.
However, the consequences of longer periods off cART, where viral reservoirs did not appear to return to baseline, remain to be elucidated.
Dr. Johnston is amfAR’s vice president and director of research. Dr. Laurence is amfAR’s senior scientific consultant.