Eradicating HIV: Cures, Functional Cures, and Altered Courses Along the Way

At the recent 20th Conference on Retroviruses and Opportunistic Infections in Atlanta, one of the highlights was the oral presentation, Functional HIV cure after very early ART of an infected infant,¹ by Deborah Persaud concerning the baby that appears to be free of HIV now, as a result of very early initiation of antiretroviral therapy (within 30 hours after birth). If true, this astounding outcome would represent only the second time that an HIV-infected person has been “cured” of HIV, and the first time in a pediatric patient. The only other time involved an adult from Germany (the “Berlin patient”),² who received a bone marrow transplant from an HIV-negative donor who was homozygous for the delta-32 deletion (present in only 1% of the population), which results in a phenotype that is resistant to infection with HIV. That individual has been free of HIV (cured) for at least 3 years.

Even though the title of Dr Persaud’s presentation, which I attended, includes the term “functional cure,” many in the audience typically assign another meaning to that term. For instance, some would say that being “undetectable” (eg, below the limit of quantification, typically less than 40 copies/mL of serum) as a result of 100% adherence to combination antiretroviral therapy (cART) for life qualifies as a functional cure. Others reserve the term to refer to those individuals who have had their likely natural course of HIV progression altered by early initiation of antiretroviral therapy (within 12 weeks of infection), who either cycled on and off cART every 3 months or so for about a year,³ or who had been on long-term cART before stopping.⁴ About 20% of those individuals were observed to have stable CD4⁺ cell counts and HIV RNA levels less than approximately 2000 copies/mL for at least 2 years. The goal of either of these approaches is to alter the natural history of HIV infection, which is characterized by a steady decline in CD4⁺ cell counts, by early initiation of therapy and, in the first case, attempting to “prime,” or stimulate, the host response by reexposure to circulating HIV. I, myself, have tried this approach in a handful of patients and have had similar success in approximately the same number of cases.

There are several problems associated with this early antiretroviral-associated definition of functional cure. First and foremost, it doesn’t work in everyone. Not even one-third of individuals are likely to benefit, at least not if we define benefit as stable CD4⁺ cell counts over time and low levels of viremia. Second, identifying those who have been recently infected has proved to be a significant challenge. Even those individuals who seek medical attention for the acute retroviral syndrome often are sent away with the diagnosis of “non-specific” viral syndrome and are not treated or considered or referred for HIV treatment. Third, we do not know yet how long the individuals who do seem to have a functional cure will be immunologically and virologically stable. Fourth, it is not correct to state, even of the 20% that do seem to be functionally cured, that they are immunologically “normal.”  For instance, those HIV-infected individuals with very low levels of viremia still have measurably higher levels of various circulating pro-inflammatory cytokines. The long-term significance of this phenomenon is unknown; it certainly is conceivable, however, that these individuals may be at greater risk for heart, kidney, and liver disease as a result of greater vascular reactivity in the setting of elevated pro-inflammatory cytokine levels.

Finally, even low levels of viremia increase the risk of transmitting infection, albeit less so than at higher levels of viremia, if risk behavior continues (eg, unprotected sexual intercourse between HIV-discordant couples).

Of course, there have always been “elite controllers,” accounting for about 1% of all HIV-infected individuals. These few have fully functional (ie, infectious) virus, circulating at very low levels (typically less than 400 copies/mL), and absolutely stable CD4⁺ cell counts for decades in the absence of any previous or current antiretroviral therapy. There is no evidence that treating these individuals with antiretroviral therapy is of any benefit. Despite decades of study, we do not know what immunologic and genetic factors explain this phenomenon in the majority of cases. We do know that race, sex, mode of acquisition, age, lifestyle, drugs, alcohol, cigarette smoking, and religious affiliation are not factors.

For now, the best approach for the vast majority of at-risk, or already HIV-infected, persons is to seek medical attention as soon as possible, reduce risk behavior, and take cART, if prescribed, 100% of the time indefinitely. While doing so may not result in a completely “normal” life expectancy and does require lifetime adherence to medications with the concomitant risk of side effects, it is as close as we have at present to a functional cure.

References
1.  Persaud D, Gay H, Ziemniak C, et al. Functional HIV cure after very early ART of an infected infant. 20th Conference on Retroviruses and Opportunistic Infections. Atlanta, Georgia, March 3-6, 2013. Paper #48LB.   

2. Htter G, Schneider T, Thiel E . Transplantation of selected or transgenic blood stem cells-a future treatment for HIV/AIDS? J Int AIDS Soc. 2009;12:10. doi:10.1186/1758-2652-12-10.

3.  Kaufmann DE, Lichterfeld M, Altfeld M, et al. Limited durability of viral control following treated acute HIV infection. PLoS Med. 2004;2:e36. doi:10.1371/journal.pmed.0010036.

4.  Saez-Cirion A, Bacchus C, Hocqueloux L, et al. Post-treatment HIV-1 controllers with a long-term virological remission after the interruption of early initiated antiretroviral therapy. ANRS VISCONTI study. PLoS Pathog. 2013;9:e1003211.