Early Antiretroviral Therapy Initiation Does Not Lead to HIV Functional Cure

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Starting antiretroviral therapy (ART) during the earliest phase of HIV infection may not be enough to prevent formation of viral reservoirs and enable cure or long-term ART-free HIV remission, according to a case study of 2 patients published in PLoS Medicine.¹ “HIV relapsed despite initiation of ART at one of the earliest stages of acute HIV infection possible. Near complete loss of detectable HIV in blood and tissues did not lead to indefinite ART-free HIV remission,” wrote first author Timothy Henrich, MD, of University of California San Francisco, and colleagues.

One of the patients is the first documented case of an adult started on ART at one of the earliest opportunities after seroconversion. Other cases have been followed to see if some people can achieve functional “cure” for HIV. The Mississippi baby, a well-known example, tested positive for HIV at birth, was started on ART, and had undetectable HIV levels after a 5-month treatment interruption. Yet, at about age 4, HIV re-emerged. Other examples include 2 adult patients, one of which may harbor a genetic mutation associated with HIV nonprogression; the other underwent stem cell transplantation from a donor with a genetic mutation that prevents HIV entry into cells. In both patients, HIV levels have remained undetectable or extremely low off ART.

The problem with achieving cure or remission is the persistence of viral reservoirs in memory CD4+ T cells in the blood or in tissues, which form a source of viral rebound upon ART discontinuation. To see whether very early initiation of ART can decrease viral reservoirs and prevent establishment of lifelong infection, doctors studied 2 individuals recruited from a pre-exposure prophylaxis (PrEP) program at the University of California San Francisco. Both patients initially tested negative for HIV, were started on 2-drug PrEP regimens, and then converted to standard 4-drug ART regimens after confirmed HIV infection.

Patient A was a 54-year-old man who was started on ART 10 days after HIV seroconversion, with peak plasma HIV RNA of 220 copies/mL. Viremia was fully suppressed on ART, with no detectable HIV from the ileum, rectum, lymph nodes, bone marrow, CSF, circulating CD4+ T cells, and plasma.

As part of the study, Patient A underwent treatment interruption after 32 weeks of being on ART. After stopping therapy, he remained without viremia for 7.4 months, after which he rebounded with HIV RNA of 36 copies/mL. Within 6 days, his viral load increased to 59,805 copies/mL, and ART was re-started. Rebound plasma HIV sequences were the same as those during acute infection. Mathematical modeling revealed that the latent reservoir size in Patient A was about 200 cells before treatment interruption. Researchers estimated that about 1% of people with a similar HIV burden might be able to achieve lifelong ART-free remission.

Patient B was a 31-year-old man who was started on ART about 12 days after seroconversion, with peak plasma HIV RNA of 3343 copies/mL. No HIV was detected in tissue samples. However, low-level HIV RNA or DNA were intermittently found in his blood and CD4+ Tcells, and he did not undergo treatment interruption.

Experiments in mice showed that 1 out of 10 mice that received CD4+ cells from patient A developed very low level HIV viremia (201 copies/mL). Three out of 8 mice that received CD4+ cells from Patient B developed HIV viremia (1000, 5000, and 11,000 copies/mL).

The researchers hypothesized that if a true “curative window” of opportunity exists, it may be very small. For example, monkeys who are started on ART within 2 days of receiving SIV infection can prevent infection, while those started 3 days after receiving SIV experience viral rebound after discontinuing ART.^2,3 Henrich and colleagues concluded “. . . , although HIV persisted indefinitely in both of these PrEP cases, a continuum may exist across PrEP, postexposure prophylaxis, and early ART strategies. Further investigation in larger cohorts of individuals treated extremely early following HIV infection is warranted.” A limitation of the study was the very small sample size because of the rarity of individuals who present with very early HIV infection.

Take Home Points
• ART started at the earliest stage of acute HIV infection did not prevent formation of latent viral reservoirs, nor did it prevent HIV rebound upon treatment discontinuation
• Viremia was fully suppressed for 2 years in Patient A but rebounded 7.4 months after treatment discontinuation
• Low-levels of HIV RNA or DNA were intermittently found in Patient B’s blood and CD4+ Tcells, and he did not undergo treatment interruption
• Mathematical modeling suggests that the latent reservoir size in Patient A was about 200 cells before treatment interruption; it is surmised that about 1% of people with a similar HIV burden may be able to achieve lifelong ART-free remission
• Larger studies are needed to determine whether a “curative window” exists during which extremely early ART initiation can prevent lifelong infection

References:

1. Henrich TJ, Hatano H, Bacon O, et al. HIV-1 persistence following extremely early initiation of antiretroviral therapy (ART) during acute HIV-1 infection: an observational study. PLoS Med. 2017;14:e1002417.
2. Lifson JD, Piatak M Jr, Cline An, et al. Transient early post-inoculation anti-retroviral treatment facilitates controlled infection with sparing of CA4+ T cells in gut-associated lymphoid tissues in SIVmas239-infected rhesus macaques, but not resistance to rechallenge. J Med Primatol. 2003;32:201-210.
3. Whitney JB, Hill AL, Barouch DH. Rapid seeding of the viral reservoir prior to SIV viraemia in rhesus monkeys. Nature. 2014;512:74-77.