A paper published in Nature Medicine on October 28th describes two cases of extended post-treatment control of HIV. The research was led by Jana Blazkova from the laboratory of Tae-Wook Chun at the National Institute of Allergy and Infectious Diseases (NIAID) and an accompanying press release generated several media stories. The two people with HIV were participants in a therapeutic HIV vaccine trial conducted at the National Institutes of Health Clinical Center in Bethesda, Maryland.
Both individuals had initiated antiretroviral therapy (ART) during acute HIV infection and were randomized to the placebo arm of the trial. The protocol included an analytical treatment interruption (ATI), and at the time ART was stopped they had been receiving treatment for 6.7 and 6.5 years, respectively.
One person, referred to as Participant 04 in the paper, experienced an initial viral load rebound to 26,967 copies/ml about two months into the ATI before controlling to undetectable levels for a little over 1.5 years. There were subsequent transient viral load blips to 778 and 1,784 copies/ml after 581 and 875 days, respectively, but control was then maintained for approximately an additional two years.
The researchers analyzed the genetic sequences of the viruses that became detectable during the blips and found that mutations were accumulating over time, indicating ongoing low-level HIV replication. There was also evidence that CD8 T cells targeting HIV had induced escape mutations (the immunological equivalent of drug resistance mutations), suggesting these immune responses were playing a role in the observed post-treatment control of viral load.
Screening for the presence of ART in blood samples was conducted regularly on both participants, and around day 1250 (nearly 3.5 years after ATI) these tests showed that Participant 04 had initiated a suboptimal ART regimen without letting the researchers know. The paper provides no information on whether there was a subsequent switch to effective ART.
Viral load in the second participant (#30) remained almost completely undetectable until after almost four years of follow up (there were only four detectable readings during this period, all at the borderline of the 20 copies/ml detection limit of the test). A significant viral load rebound was detected at day 1,424 and detailed analyses of the virus sequences indicated that superinfection with a different HIV variant had occurred. The participant reportedly confirmed that a potential exposure to HIV had preceded the rise in viral load.
In the case of Participant 30, post-treatment control was associated with potent antibody-mediated neutralization activity against HIV isolates sampled prior to the time of viral load rebound. In contrast, the activity of the antibody response was weak against the emerging HIV variant ascribed to superinfection.
The researchers note that this is an unusual observation, as past reports have primarily linked the phenomenon of post-treatment control to HIV-specific T cell responses. They write that the results “suggest that one of the potential mechanisms by which Participant 30 achieved near complete virologic suppression in vivo, before superinfection, might have involved neutralizing antibodies against HIV.”
In addition to providing clues about possible mechanisms of post-treatment control, the findings potentially raise issues for the conduct of HIV cure research. Firstly, it will be important to try to better understand the reasons why study participants might feel reluctant to disclose the use of ART to researchers. This may be an area where social science can contribute insights to help lessen the risk of the issue arising in future studies.
Secondly, discussions of the potential for HIV transmission during ATI have largely focused on risk to HIV-negative partners of trial participants, but this report emphasizes that the risk of superinfection also needs to be considered and included in the informed consent and counseling process for trials involving ATIs.
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