French Cohort of HIV+ People Treated Early Appear to Control Virus

A group of French HIV patients who started antiretroviral therapy (ART) during the earliest stage of infection appear to be controlling the virus despite prolonged treatment interruption, according to a recent report in PLoS Pathogens. While the findings do not represent a cure, they may offer insight to help certain people with HIV achieve a "functional cure," or periods off treatment without disease progression.

One of the factors that makes HIV difficult to eradicate is that its DNA remains latent inside resting CD4 T-cells, ready to begin replicating if the cell are activated. Since the early years of ART, some research has suggested that very early treatment might shrink or prevent establishment of viral reservoirs, but more sensitive tests have shown that hidden bits of HIV genetic material remain.

Asier Sáez-Cirión from Institut Pasteur and colleagues first reported findings from the VISCONTI cohort at the July 2012 International AIDS Conference in Washington, DC. At the time they presented data from 12 "post-treatment controllers" -- and the PLoS Pathogens article included 14 -- out of a larger group of 750 people who started combination ART soon after HIV infection, of whom about one-tenth interrupted therapy.

The VISCONTI cohort includes 10 men and 4 women. Most were infected in the late 1990s and sought treatment due to symptoms of acute viral infection, which only occur in a minority of people. They started treatment within about 2 months after infection and remained on treatment for at least 1 year (median 3 years, maximum nearly 8 years). They have since been off ART for 4 to 10 years.

The researchers used sensitive tests to measure residual virus, characterize CD4 cells, and compare immune system characteristics between the post-treatment controllers and a group of untreated "elite controllers" who are naturally able to maintain undetectable HIV RNA without ever receiving ART.

Results

• Post-treatment controllersappear to have maintained HIV suppression, with very low viral load for several years after treatment interruption.
• Once off treatment, post-treatment controllerswere able to maintain an extremely low viral reservoir, and in some cases experienced further HIV decline.
• A higher proportion of post-treatment controllers-- about 15% -- maintained HIV suppression after interruption of early ART compared with the rare elite controllers (<1% of the population).
• Most post-treatment controllerslacked protective HLA B alleles characteristic of spontaneous elite controllers; in fact, they instead carried "risk-associated" HLA variants seldom seen among natural controllers.
• Post-treatment controllershad poorer CD8 T-cell responses against HIV and more severe primary infection than spontaneous controllers.
• Long-lived HIV-infected CD4 T-cells contributed a relatively small proportion of the viral reservoir in post-treatment controllers,due to a low rate of infection of naive T-cells and a "skewed distribution" of resting memory T-cell subsets.

"Our results show that early and prolonged combination ART may allow some individuals with a rather unfavorable background to achieve long-term infection control and may have important implications in the search for a functional HIV cure," the study authors concluded.

However, "the possibility to translate their mechanisms of control to other patients is uncertain," they continued. "We found that [post-treatment controllers] were able, after therapy interruption, to keep, and in some cases further reduce, a weak viral reservoir. This might be related to the low contribution of long-lived cells to the HIV-reservoir in these patients."

Although the French group's conclusions were quite conservative, their publication came on the heels of a report at the Conference on Retroviruses and Opportunistic Infections (CROI 2013) this month in Atlanta about an apparently HIV-infected baby who seems functionally cured after starting combination ART within 2 days after birth.

While these cases all offer clues that may point investigators in the right direction, much more research is needed before even a temporary functional cure is widely available.

3/27/13

Reference

A Sáez-Cirión, C Bacchus, L Hocqueloux, 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 Pathogens 9(3):e1003211. 2013.