NIH Researchers Pursuing Sustained ART-Free HIV Remission

Novel and innovative strategies are needed to achieve sustained antiretroviral therapy (ART)-free HIV remission, according to a commentary published in JAMA.
Researchers from the National Institute of Allergy and Infectious Diseases (NIAID) at the National Institutes of Health (NIH) are examining pathways for fully and sustained HIV remission with the goal of eliminating the need for daily ART. However, the researchers noted that treatment approaches must involve minimal risk and manageable adverse effects for individuals with HIV.
In the commentary, the researchers discussed the opportunities and challenges in current HIV research.
Currently, the persistence of HIV reservoirs is a major barrier to achieving sustained ART-free remission, according to the researchers. The presence of such reservoirs, which contain HIV genetic material, can activate new virus particles in resting cells.
“Attempts at achieving sustained treatment-induced virologic remission following analytical treatment interruption of ART have consistently failed and have invariably been followed by rapid rebound of plasma viremia, usually to the original virologic set point, in almost all patients who were studied,” the researchers wrote in the commentary.
They cited 2 pathways that are being pursued: the eradication of replication-competent HIV reservoirs and control of plasma viral rebound without eradication of HIV in the absence of ART.
Although several strategies have attempted to eradicate HIV from an infected individual, only stem cell transplantation from a donor with a specific genetic mutation has been effective, and only in 2 cases. According to the researchers, future research into this pathway must consider the risk-to-benefit ratio, particularly in individuals whose plasma viremia is already well controlled by ART. 
“Any substitution for this currently effective approach must be of minimal risk, inexpensive, and scalable to large number of patients,” they wrote.
Alternatively, sustained virologic remission is another sought after pathway. The researchers noted 2 major strategies being studied: replacement of daily ART with intermittent or continual non-ART intervention and induction of durable immune-mediated control of HIV without further intervention.
“The former strategy could be accomplished either by therapeutic vaccination administered as a single intervention or requiring multiple boosts over a period of years,” the researchers said. There have not been any therapeutic vaccine candidates successful in achieving durable suppression thus far.
Another approach would be passive infusion of a single or combination of anti-HIV broadly neutralizing antibodies (bNAbs), optimally at intervals of several months. According to the researchers, bNAbs have shown promise as a potential replacement of daily ART in prior studies, but future investigations will need to require selection of those bNAbs that have maximal potency and wider breadth.
“The approach with the most likely chance of success is the administration of combinations of bNAbs to achieve ART-free remissions,” the researchers wrote.
The researchers noted that recent studies have also shown that passive infusion of bNAbs during early stages of viral infection in nonhuman primates led to durable suppression of virus replication. This has been referred to as a “vaccinal” effect and the approach is being actively pursued in clinical trials, they wrote.
Overall, the researchers emphasized that these approaches will require novel and innovative strategies to overcome obstacles in HIV treatment.
“Building on the extensive foundation of research in this field and the unprecedented success of combination ART, it is important to continue to explore new pathways to successfully attain an ART-free remission for persons with HIV,” they concluded.
TW Chun, Eisinger RW, Fauci AS. Durable control of HIV infection in the absence of antiretroviral therapy: opportunities and obstacles. JAMA. 2019. doi:10.1001/jama.2019.5397
NIH HIV Experts Prioritize Research to Achieve Sustained ART-Free HIV Remission [news release]. National Institutes of Health. Accessed June 6, 2019.

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