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Less than 1% of people with HIV are considered "elite controllers," meaning their immune system can keep the virus in check long-term without antiretroviral therapy (ART). While they can maintain a low or undetectable viral load and experience very slow CD4 T-cell decline, recent research indicated that elite controllers show evidence that low-level HIV is causing chronic inflammation and immune activation. This raises questions about whether they, like normal progressors, are at higher risk for non-AIDS conditions and whether they might benefit from ART.

Trevor Crowell and colleagues with the HIV Research Networkcompared hospitalization rates and causes between elite controllers and HIV positive people with more typical progression. The elite controllers were significantly more likely to be women and black.

Looking at 34,354 adults in care at 11 sites from 2005 through 2011, the researchers identified 149 eligible elite controllers who had never taken ART (0.4%). They were compared to 4709 people with undetectable viral load on ART, 7998 people with low viral load between 50 and 1000 copies/mL (either on or off ART), and 10,605 people with viral load above 1000 copies/mL (mostly not on ART). All participants were required to have relatively well-preserved immune function with CD4 counts >350 cells/mm³, but elite controllers' average CD4 level were significantly higher (about 775 vs 500 cells/mm³).

Results

• Unadjusted hospitalization rates were 23.3 per 100 person-years among elite controllers compared with 10.5 per 100 person-years among people with viral suppression on ART, 12.6 per 100 person-years among people with low HIV viremia, and 16.9 per 100 person-years among those with high viremia.
• After adjusting for demographic and clinical factors, elite controllers had higher rates of hospitalization due to all causes than people with viral suppression on ART (adjusted incidence rate ratio [IRR] 1.77, or 77% higher risk).
• However, a single elite controller had an unusually large number of hospitalizations due to lung problems; when this individual was excluded, the adjusted IRR fell to 1.56, or 56% higher risk.
• Elite controllers also had higher rates of hospitalization for cardiovascular events (IRR 3.19, or more than 3 times higher risk) and for psychiatric conditions (IRR 3.98, or nearly 4 times higher risk).
• Overall, non-AIDS-defining infections were the most common reason for hospital admissions overall (24.1%), but these were rare among elite controllers (2.7%).
• Among elite controllers, cardiovascular events including chest pain, coronary artery disease, and heart failure were the most common reason for hospitalization (31.1%, vs 13.5% for the study population as a whole).

"Elite controllers are hospitalized more frequently than persons with medically controlled HIV and cardiovascular hospitalizations are an important contributor," the study author concluded.

In an accompanying editorial, Maile Karris and Richard Haubrich from University of California at San Diego asked whether ART for elite controllers is justified or premature.

"On the surface, these findings seem to provide compelling clinical evidence for ART treatment in elite controller despite chronic viral control and high CD4 cell count, and raise questions as to whether immune viral control will be an adequate end point for functional cure strategies," they wrote. "However, potential study limitations, particularly unmeasured confounders...limit our ability to fully interpret these results and may still leave unanswered the clinical question of the need to treat this rare group of HIV immune controllers."

"Interestingly, psychiatric admission rates were higher in elite controller than in the medical control group, a finding that may support a higher rate of comorbid conditions in the elite controller population (including substance abuse)," they noted. "Alternatively, it is possible that elite controllers have higher rates of low-level viral replication and inflammation at anatomic reservoir sites such as the central nervous system, with subsequent development of HIV-associated neurocognitive disorders."

So what advice should be provided to clinicians regarding the merits of initiating ART when faced with the rare elite controller? "Although the current study provides a nudge in the direction favoring therapy, the level of evidence still resides firmly in the category of 'expert opinion'," Karris and Haubrich concluded. "The most cogent decision would be to refer the patient for study until we have better data to formulate stronger recommendations."

B Cell Sanctuary

In a related study published in the January 19 edition of Nature Medicine, Yoshinori Fukazawa and Louis Picker from the Vaccine and Gene Therapy Institute at Oregon Health and Science University examined viral replication among rhesus macaques that were elite controllers or typical progressors.

During chronic infection, HIV and simian immunodeficiency virus (SIV) replication is as much as 10,000-fold lower in elite controllers compared with typical progressors, the study authors noted as background. But still, enough replication persists in tissues of elite controllers to allow viral sequence evolution and trigger excess immune activation.

The researchers found that productive SIV infection in elite controller monkeys -- but not in typical progressors -- is restricted to CD4 follicular helper T cells (TFH cells). This suggests that highly effective SIV-specific CD8 T cells in the elite controllers can clear productive SIV infection from extra-follicular sites. However, the fact that these effective T cells cannot enter B cell follicles prevents them from eliminating productively infected TFH cells therein.

"CD8+ lymphocyte depletion in elite controller monkeys resulted in a dramatic re-distribution of productive SIV infection to non-TFH cells, with restriction of productive infection to TFH cells resuming upon CD8+ T cell recovery," the researchers concluded. "Thus, B cell follicles constitute 'sanctuaries' for persistent SIV replication in the presence of potent anti-viral CD8+ T cell responses, potentially complicating efforts to cure HIV infection with therapeutic vaccination or T cell immunotherapy."

1/29/15

References

TA Crowell, KA Gebo, JN Blankson, et al (HIV Research Network). Hospitalization Rates and Reasons among HIV Elite Controllers and Persons With Medically Controlled HIV Infection. Journal of Infectious Diseases. December 15, 2014 (Epub ahead of print).

MY Karris and RH Haubrich. Editor's Choice: Antiretroviral Therapy in the Elite Controller: Justified or Premature? (Editorial Comment). Journal of Infectious Diseases. December 15, 2014 (Epub ahead of print).

Y Fukazawa, R Lum, AA Okoye, LJ Picker, et al. B cell follicle sanctuary permits persistent productive simian immunodeficiency virus infection in elite controllers. Nature Medicine. January 19, 2015 (Epub ahead of print).