In order to measure the success of a cure for HIV or a non-antiretroviral therapy (any of the antibody studies that are underway, for instance), researchers must first take research study participants off of their antiretroviral regimen to test whether the experimental treatment is working. But most of what we know about viral load rebound and CD4 drops when people stop taking medications was learned with much older regimens. Do newer, better-tolerated medications also keep viral load low and CD4 counts higher, for longer periods than older regimens?
The procedure for taking a person living with HIV off of their treatment regimen when they’re enrolled in a clinical trial is known as analytic treatment interruption (ATI). Study participants who stop taking antiretroviral therapy (ART) are carefully monitored for viral rebound and are put back on their medication as soon as they meet certain criteria. Again, the practice is done so that researchers can determine how well an experimental treatment is working, by looking at how soon after ATI participants meet the criteria and need to restart ART.
Scientists from the National Institute for Allergy and Infectious Diseases at the National Institutes of Health (NIH) questioned whether the older data might distort results of research looking for HIV cures. They conducted a new study, published in June’s Journal of Infectious Diseases, to determine the time between ATI and treatment restart for participants who had only ever taken modern ART regimens. The goal of the study was both to find benchmark data that could help other scientists in future research and to see if the time between treatment interruption and restart was different with modern ART.
Researchers enrolled 22 participants who had initiated modern ART during the chronic phase of infection and had undetectable viral loads for multiple years (median 7.7 years). Participants were monitored closely and put back on ART as soon as they met one of the following criteria: a viral load of over 1,000 copies/mL for four or more weeks, a decrease in CD4+ T cells, any HIV-related illness, or pregnancy. The researchers continued to monitor patients for up to a year following reinitiation of ART.
The median time to restart ART was nearly five weeks. Half of participants needed to restart ART because of low CD4+ T-cell counts, eight restarted because of sustained increased viral load, and two restarted as a result of HIV-related thrombocytopenia (low platelet count). One participant restarted ART before meeting the restart criteria.
The relatively short time between participants discontinuing ART and meeting the criteria for needing to go back on it suggests that modern regimens do not alter the rate of viral rebound when compared to older medications. These findings highlight both the need for ART adherence and the ultimate need to find new therapies.
Baseline data on time between ATI and treatment restart is important, especially for studies that don’t have control groups. Much of the existing data on ATI, however, comes from a patchwork of old studies that includes participants who had been on a variety of ART therapies, including earlier formulations, and may have developed resistance to older ART regimens. Moreover, the studies were varied in terms of how long they followed participants and the criteria used for restarting treatment.
“Given the vast majority of our study participants experienced a rapid viral rebound shortly after ATI, modern antiretroviral drug regimens may not offer additional benefits, such as enhancement of immune-mediated virologic control, beyond their remarkable antiretroviral activities against HIV, which underscores the importance of the development of therapeutic strategies aimed at achieving durable virologic remission in the absence of ART,” the authors write.
The results of this study show that ATI is a safe and effective method for evaluating new, ART-free, HIV remission strategies and provide useful information for researchers studying experimental treatments.