To cure HIV, we need to get rid of latently infected cells which are indistinguishable from uninfected cells. We need to determine where these cells are, and what strategies need to be deployed to remove them. Although current antiretroviral therapies (ARTs) are very good, some agents do not penetrate all tissues, and there are concerns about the brain, lymph node tissue, and genitourinary tract where the HIV reservoir is thought to be enhanced.
Within trial design, the most clinically important outcome for clinicians and patients is viral control, off therapy. However, to do this it is critical to determine what is being measured and there are obvious concerns with asking patients to interrupt their ART.
Strategic approaches to cure HIV include pushing viral reservoir levels to below an arbitrary threshold by initiating early ART after acute infection. Another method is through enhancing HIV specific T-cell immunity in PLWH in therapy, or by recovering an exhausted immune system – an approach which has been very successful in treating cancer. However, study results have been inconclusive.
In an attempt to reduce the size of the HIV reservoir, the HIV Kick and Kill approach uses a latency reversing agent combined with some form of HIV-specific immune response which then kills the latently activated cells. The RIVER trial compared controls who entered with ART alone with people who had vaccine and vorinostat, and findings revealed no significant difference in total HIV DNA or in viral outgrowth by the study arm.
Next-generation broadly neutralising antibodies (bnAbs) are currently under investigation and with half-lives of up to 3-6 months these could also be explored for prevention as well as treatment. Importantly, these have a completely different mechanism from ART.
Q: "What is the evidence so far that bnAbs are not only antivirals?"
A: “There is evidence of something called a vaccinal effect and it’s uncertain actually how this works, and exactly how important it is in terms of remission. It may well be that the Fc portion of the antibody is in some way binding to antigen-presenting cells, facilitating antibody-dependent cellular killing of cells that are expressing viral proteins.”