CROI 2013: Can HIV Elite Controllers Benefit from Antiretroviral Treatment?

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Elite controllers -- people who naturally maintain undetectable viral load without antiretroviral therapy (ART) -- experienced decreased levels of HIV genetic material and reductions in markers of inflammation and immune activation after starting experimental treatment, according to study findings presented at the 20th Conference on Retroviruses and Opportunistic Infections (CROI 2013) last week in Atlanta.

Elite controllers have undetectable viral load according to standard HIV RNA tests, but ultrasensitive assays can almost always detect low-level virus. While this group generally does not experience overt disease progression or the expected decline in CD4 T-cells, researchers have attempted to determine whether this low-level virus is truly benign or causes subtle immune system changes that may in fact be detrimental.

Even low-level HIV may be enough to trigger chronic inflammation and persistent immune activation, which a growing body of evidence has linked to non-AIDS conditions such as cardiovascular disease and neurocognitive impairment in an aging HIV population.

Effects of Low-level HIV

Joyce Sanchez and colleagues from the University of Minnesota and University of California at San Francisco (UCSF) looked at gut-associated lymphoid tissue (GALT), from 5 different groups: HIV negative people, untreated HIV controllers with viral load <2000 copies/mL -- about half of them being elite controllers with <75 copies/mL -- untreated non-controllers, immunological non-responders on ART who suppressed viral load but did not achieve expected CD4 cell gains, and responders on ART with viral load <75 copies/mL and CD4 count > 500 cells/mm3.

The researchers looked at indicators of chronic inflammation including collagen deposition and fibrosis in lymphoid tissue in the gut. They found that all groups of people with HIV -- including controllers -- had higher levels of collagen in rectal tissue samples. Despite undetectable viral load according to standard tests, a small number of controllers (less than 5%), about one-quarter of immunological non-responders, and more than 40% of responders showed evidence of low-level virus production.

Only a single individual had normal lymphoid architecture, normal collagen levels, no HIV RNA in lymph nodes or gut tissue, and normal CD4 cell levels: the "Berlin Patient," Timothy Brown, who appears to be cured of HIV after undergoing bone marrow stem cell transplants to treat leukemia from a donor with CD4 cells naturally resistant to HIV (CCR5-delta-32).

"The observation that HIV RNA expression is often detected in these tissues even among controllers and among ART suppressed patients suggests that persistent virus production may contribute to inflammation and immune activation that ultimately leads to tissue fibrosis," the researchers concluded. "Strategies to fully suppress virus replication in tissues may result in reversal of inflammatory damage and more complete reconstitution of immunity."

Treating Elite Controllers

Hiroyu Hatano and Steven Deeks from UCSF colleagues conducted an exploratory study of ART given to a small cohort of elite controllers.

Although these 16 patients had been living with HIV for a median of 10 years, their median viral load was only 77 copies/mL and their median CD4 count was a near-normal 600 cells/mm3. All were treated for 24 weeks with raltegravir (Isentress) plus tenofovir/emtricitabine (the drugs in Truvada) -- a standard-of-care ART regimen for people starting HIV treatment for the first time.

The researchers saw a significant decrease in plasma HIV RNA using ultrasensitive assays after participants started treatment. There was also a trend toward decreased levels of cell-associated HIV RNA and proviral DNA in gut tissue, although the changes did not reach statistical significance. Although they did not see significant CD4 cell gains, markers of T-cell activation and abnormal function in the blood and gut decrease significantly.

In response to a question at an accompany press about the downsides of ART for elite controllers who can get along without treatment, Hatano said that the UCSF patients are "highly motivated" regarding research involvement, did not experience adverse events during this short observation period, and "a majority chose on their own to continue ART after the follow-up period."

3/15/13

References

J Sanchez, P Hunt, J Jessurun, et al. Persistent Abnormalities of Lymphoid Structures in HIV Viremic Controllers. 20th Conference on Retroviruses and Opportunistic Infections (CROI 2013). Atlanta, March 3-6, 2013. Abstract 74.

H Hatano, S Yukl, A Ferre, S Deeks, et al. Prospective ART of Asymptomatic HIV+ Controllers. 20th Conference on Retroviruses and Opportunistic Infections (CROI 2013). Atlanta, March 3-6, 2013. Abstract 75LB.