Is a “cure” unrealistic? Long-term remission or maintenance might be the real target for basic scientists

Editor’s notes: News from the Paris IAS conference [1] about the prospects for a cure for HIV was rather sombre this year.  Anthony Fauci, Director of NIAID presented a special session [2] in which he suggested that a true “cure” that could be widely used was likely to prove impossible, and that we should think more in terms of long-term remission in the absence of ART.  He outlined a vision in which the increasing number of broadly neutralizing antibodies and the discovery of more and more potent antibodies might eventually allow for “maintenance treatment” with subcutaneous antibody injections every few months.

Harper’s commentary [3] lays out some of the amazing steps forward over the past decade in understanding how the reservoir of HIV is formed.  We have all heard of CD4 cells, but a much rarer type of lymphocyte, labelled as CD32, seems to be a key target into which HIV integrates.  This allows scientists to develop new ways to measure the reservoir and also to begin to determine which cells are involved in establishing and maintaining the reservoir that makes HIV so hard to cure.

Montserrat et al. also provide a sobering result.  They showed that as expected the size of the HIV reservoir (as measured by the amount of integrated HIV DNA) falls during long term antiretroviral therapy (ART).  When ART is interrupted, HIV begins to replicate and both viral load and the HIV reservoir rebound.  Now they have shown that when ART is restarted after the planned interruption, HIV replication falls promptly, but the HIV reservoir seems to remain high.  This may mean that interruption of ART (including in trials of possible long-term remission) may lead to resetting the clock and losing some of the benefits of the long period of HIV treatment prior to the interruption.

HIV reservoirs in children have been less studied than those in adults.  So the study by Foster et al. is a useful contribution showing that early ART does lead to a smaller reservoir in children too.  This has implications not only for future attempts to “cure” or induce long term remission. It also reduces the pool of variability of the virus in the child, which may make future HIV treatment more straightforward and perhaps reduce the likelihood of developing resistance.  It ties in somewhat with another excitement from Paris, which was the report of a child who after early ART had now been in remission with undetectable viral load for more than a decade without taking further ART [4].  There was still evidence of viral DNA, so we cannot talk of cure, but understanding how some children (and adults) are able to control HIV replication after treatment provides an important avenue to explore.  Nonetheless, it is crucial to remember that these cases remain very rare, and we should be careful not to encourage false hopes that might lead to people stopping their ART.  This should only be done in the context of a very carefully controlled clinical trial situation where close monitoring is available to restart treatment as soon as the virus rebounds. 

Impact of long-term antiretroviral therapy interruption and resumption on viral reservoir in HIV-1 infected patients.

Montserrat M, Plana M, Guardo AC, Andrés C, Climent N, Gallart T, Leal L,Gatell JM, Sánchez-Palomino S, García F. AIDS. 2017 Aug 24;31(13):1895-1897. doi: 10.1097/QAD.0000000000001560. Epub 2017 Jun 5.

We assessed if the increase on viral reservoir after long-term antiretroviral therapy (ART) interruption (ATI) is reversible upon ART resumption in chronic HIV-1 infected patients. Total HIV-1 DNA increased to pre-ART levels after 48 weeks of ATI to return to pre-ATI levels after 104 weeks of ART resumption. Conversely, integrated HIV-1 DNA remained elevated after ART reinitiation. These data suggest that the increase in reservoir after long-term ART discontinuation might not be reversible at mid-term.

Abstract access [5]

 

Early antiretroviral therapy reduces HIV DNA following perinatal HIV infection.

Foster C, Pace M, Kaye S, Hopkins E, Jones M, Robinson N, Fidler S, Frater J; CHERUB Investigators. AIDS. 2017 Aug 24;31(13):1847-1851. doi: 10.1097/QAD.0000000000001565. Epub 2017 Jun

The impact of antiretroviral therapy (ART) on the size of the HIV reservoir has implications for virological remission in adults, but is not well characterised in perinatally acquired infection (PaHIV). In a prospective observational study of 20 children with PaHIV and sustained viral suppression on ART for >5 years, proviral DNA was significantly higher in deferred (>4 years) versus early (first year of life) ART recipients (p = 0.0062), and correlated with age of initiation (p = 0.13; r = 0.57). No difference was seen in cell-associated viral RNA (p = 0.36). Identifying paediatric populations with smaller reservoirs may inform strategies with potential to induce ART-free remission.

Abstract access [6] 

HIV reservoirs [8], HIV Treatment [9]
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