Today, a presentation by Ricardo Diaz at the ongoing virtual International AIDS Conference (AIDS 2020) caused a major splash in the media by reporting that one out of 30 participants in a clinical trial conducted in Brazil has experienced a lack of viral load rebound for a little over a year (64.7 weeks) after interrupting antiretroviral therapy (ART).
The trial was launched in 2015 and involved a complex design in which 30 participants with HIV were divided into six groups of five people each. One group continued on a standard ART regimen and served as controls, while the other five groups received the following additional interventions:
- Group 2: Dolutegravir and the CCR5 inhibitor maraviroc (which has been reported to also exert HIV latency-reversing effects)
- Group 3: Dolutegravir, maraviroc and nicotinamide (a water-soluble form of vitamin B3 that may have HIV latency-reversing activity)
- Group 4: Dolutegravir, maraviroc and auranofin (an antiproliferative drug)
- Group 5: Dolutegravir and a dendritic cell therapeutic vaccine
- Group 6: Dolutegravir, a dendritic cell therapeutic vaccine, auranofin and nicotinamide
Results from the trial have been presented on a number of previous occasions, including at AIDS 2018, CROI 2019, and the 2019 HIV Persistence Workshop (see abstract OP 8.6 in the abstract book and the report from NATAP toward the base of this page). Results from participants who received auranofin were also the subject of a published paper last year. Overall, declines in HIV DNA levels (a surrogate measure of the HIV reservoir) were found to be greatest among recipients of the multiple interventions in group six.
The original study design did not include an analytical treatment interruption (ATI), but the protocol was later revised and 25 of the participants underwent an ATI approximately 2.5 years after the end of the 48-week study period (during which the interventions were administered).
The presentation at last year's HIV Persistence Workshop reported that two participants in group six and one in group three displayed undetectable HIV viral loads after the ATI. However, after around 16 weeks the two people from group six showed evidence of viral load rebound and restarted ART.
The remaining participant from group three was the subject of today's AIDS 2020 presentation. The individual was diagnosed with HIV infection in October 2012 and started ART two months later. According to an article by Jon Cohen in Science, they estimate the date of HIV acquisition to be around June 2012 (the last previous HIV negative test result was in 2010). Viral load at ART initiation was relatively low: 20,221 copies/mL.
At the time of entry into the trial in September 2015, viral load was undetectable and the CD4 count 720. Two very low level transient viral load blips occurred while receiving the study interventions but otherwise undetectable levels have been maintained while on ART.
HIV DNA was detectable in rectal tissue and blood samples at the end of the 48-week intervention period. Measurements of blood HIV DNA levels subsequently showed a decline during treatment with regular ART regimens, eventually becoming undetectable immediately prior to the ATI which was initiated in March 2019.
After the ATI, viral load did not rebound and has remained undetectable ever since (the last available measurement at the time of the presentation was from June 22, 2020). Slides showing CD4 count and CD4:CD8 ratio over time indicated a notable decline shortly after the ATI, which is surprising given the apparent lack of viral load rebound in the blood, but no further longitudinal data on these measures was reported.
HIV antibody levels evaluated by the Abbott ARCHITECT antigen/antibody combination assay have declined throughout follow up, with the exception of one possible slight increase immediately after the ATI. Results of a rapid HIV antibody test are now negative (in some media reports this has been mistakenly represented as indicating that no HIV antibodies are detectable, which is not accurate).
The case appears encouraging for HIV cure research, with the caveat that late rebounds in viral load have occurred in some previous examples of HIV remission. Importantly, it's unclear as yet whether the interventions received during the trial contributed to the outcome; the person may have started ART fairly soon after HIV acquisition and there have been other case reports of early-treated individuals containing viral load for variable periods after ART interruptions.
Notably, of the other 29 study participants, nine received nicotinamide and 14 received dolutegravir and maraviroc. Although it's unclear whether all of these other participants were among those that underwent ATI, no additional examples of similarly prolonged absence of viral load rebound were observed. This appears to argue against a strong effect of these interventions. Additionally, HIV DNA levels continued to decline long after the cessation of the interventions in the participant who has not rebounded.
Emphasizing the uncertainty about the role of the study drugs is important given that nicotinamide is available over-the-counter as a supplement. At the current time, there is no evidence to suggest that adding dolutegravir, maraviroc and nicotinamide to ART regimens would lead to similar outcomes in other people with HIV.
Further analyses will hopefully shed light on how viral load rebound has so far been prevented, and whether the interventions contributed in some way. Information on HIV-specific T cell responses and the individual's HLA type could be particularly helpful. The Associated Press article on the research includes the welcome news that Diaz will receive support to conduct a larger 60-person trial, so more robust results should be forthcoming.
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