The recent case of the London patient—potentially the second known case of an HIV cure—highlights a challenge faced by the cure research field: How do you know when an intervention has resulted in a cure?
To date, the field has used analytic treatment interruption (ATI)—stopping antiretroviral therapy (ART) under the guidance of a doctor—to monitor when, how high, and for how long the virus rebounds. If the virus rebounds, then the question of viral eradication has been answered and the participant can restart ART. But using ATI to determine whether post-treatment control (PTC)—the ability to keep the virus under control in the absence of ART—has been achieved, is a longer and more complex proposition. ATI presents challenges to participants, their partners, and to the researchers seeking to make sense of the data.
In the April issue of AIDS, amfAR-funded scientist Dr. Sharon Lewin of Monash University in Melbourne, Australia, documented nearly two decades of studies using ATI to chart achievements and lessons learned. Analyzing 159 ATI clinical trials conducted between 2000 and 2017, Dr. Lewin and colleagues noted a trend to restart ART as soon as virus was detected in plasma, especially after 2014, when the World Health Organization began recommending universal ART.
Prior to 2014, when CD4 count rather than plasma viral load was used as the main criterion to restart ART, researchers were more likely to delay restarting ART to determine whether an intervention had a post-treatment control effect. The trend toward restarting ART sooner alleviates the concern that a patient will unwittingly transmit HIV to a sexual partner and is generally agreed to be safest for the participant, but it comes at a cost to the researchers’ ability to discover effective interventions.
The challenge of when to restart ART was among the topics discussed by more than 40 scientists and clinicians who convened at the Ragon Institute of MGH, MIT and Harvard in July 2018, including amfAR grantee Dr. Dan Barouch and amfAR vice president and director of research, Dr. Rowena Johnston.
The attendees published their recommendations for researchers and clinicians planning ATI studies in The Lancet HIV, aiming to ensure that study designs maximize the knowledge gained and reduce the risk to trial participants. The group agreed that restarting ART should occur any time a participant requests it or if HIV-related conditions emerge.
However, mitigating the risk of transmitting the virus to a partner during a longer ATI to test for PTC was a more difficult challenge. Participants would require comprehensive counseling, including on the use of condoms or pre-exposure prophylaxis (PrEP), and researchers may need to exclude participants who engage in high-risk behavior. Some studies have begun to routinely test for sexually transmitted infections as one indicator of a participant’s use of condoms during ATI.
Until better predictors of curative success are found, or tests proving the absence of an HIV reservoir are developed, ATI will continue to be the gold standard in HIV cure research. By developing better standards and recommendations that guide current and future ATI studies, the field is ensuring that the progress made is safer for the participant and more valuable to the research community.
Dr. Flores is amfAR's associate director of research.