The High Price of HIV Elite Control

Study Reveals That Elite Controllers Have Poorer Health Outcomes

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Among people living with HIV, elite controllers have long been considered charmed, able to naturally control HIV infection without the use of antiretroviral drugs. It is estimated that as many as one in 200 HIV-infected people might be classified as an elite controller (EC), and their ability to maintain low-to-undetectable viral loads has placed them at the very heart of HIV research.

Yet, while many ECs are able to allay disease progression for ten years or more, increasing evidence has shown that they may not be able to do so indefinitely.

Meanwhile, other studies have concluded that HIV elite control may come at a price, with many ECs experiencing poorer health outcomes than those on active therapy.

Study Design and Results

A six-year study from researchers at the John Hopkins University School of Medicine investigated hospital admissions between the EC and non-EC populations in 11 U.S. clinics from 2005-2011.

Of the 23,461 patients included in the cohort, 149 were identified as ECs (0.64%). Patients included in the study had to have had a CD4 count of at least 350 cells/mL at the time of enrolment, while non-EC participants had to have been on antiretroviral therapy (ART) for a minimum of one year.

For the purpose of the study, elite control was defined having had three consecutive undetectable viral loads (under 50 copies/mL) for a minimum of one year without ART.  The average CD4 count of the EC group was 788 cells/mL, while non-ECs had a CD4 count average of over 500 cells/mL.

Among the findings:

  • After adjustments for demographics and clinical factors, ECs were seen to have more than twice the hospitalizations of non-ECs (22.3 per 100 patient years versus 10.5 per 100 patient years).
  • Even non-ECs with viral loads under 1000 copies/mL had better outcomes than ECs, with 22% fewer hospitalizations over the six-year period.
  • When compared to non-ECs with undetectable viral loads, the results were even more profound, with ECs logging 77% more hospital admissions compared to non-ECs.

Cardiovascular disease (CVD) and psychiatric disorders were two conditions most noted in the EC population. In fact, CVD hospitalizations were seen to be highest among ECs without exception—as much a three times higher—even when compared to non-ECs with viral loads over 1,000 copies/mL.

Similarly, ECs had a four-fold increase in psychiatric admissions over the same period, higher again than even non-ECs with viral loads or 1,000 copies/mL or more.

Explaining the Results

It has long been established that the persistent chronic inflammation associated with HIV increases the risk of comorbid conditions like CVD and other non-HIV-related illnesses (including diabetes and cancer). Inflammatory proteins are certainly among the key causes for the premature hardening and narrowing of arteries (atherosclerosis) in people with HIV, while early infiltration of HIV in the brain can often result in adverse, even profound changes to the central nervous system.

Antiretroviral therapy appears to significantly reduce the incidence of these conditions by suppressing viral activity, ideally to undetectable levels, thereby reducing the inflammatory response associated with infection (even during the so-called "latent" stages of infections when viral activity is low).

This suggests that the slower disease progression may, in fact, may have far greater consequences in the long run if inflammation is allowed to go unchecked.

Other factors may also explain the disparity in health outcomes. According to the study, ECs tended to monitor their disease far less than their non-EC counterparts, presumably because they were "well" insofar as HIV monitoring was concerned. It is possible that non-HIV-related comorbidities were largely overlooked, including preventative measures meant to lower risk (e.g., smoking cessation, lipid screening).

Impact on HIV Research

While the factors to elite control remain central to HIV/AIDS research, including vaccine development and the so-called "functional cure," the long-term consequence of untreated disease may ultimately blunt expectations. Is it enough to replicate these controls in an HIV-infected population—as we saw with Timothy Brown, the "Berlin Patient" presumably cured of HIV—if it leaves those patients open to premature illness or death as a result of non-HIV-related conditions?

Clearly, the public is ever eager to embrace an age where HIV drugs are no longer needed on a daily basis and where issues of adherence are no longer the mantra of informed care. But until we have a better understanding of the long-term health outcomes of the elite controller, researchers may need to step back and focus more on issues relating to inflammation and HIV immune activation before any such curative strategy can be confidently established.

Sources:

Crowell, T.; Gebo, K.; Blankson, J.; et al. "Hospitalization Rates and Reasons among HIV Elite Controllers and Persons With Medically Controlled HIV." Clinical Infectious Diseases. December 15, 2014; doi: 10.1093/infdis/jiu809.

Olson, A.; Meyer, L.; Prins, M.; et al. "An Evaluation of HIV Elite Controller Definitions within a Large Seroconverter Cohort Collaboration." PLoS|One. January 28, 2014; DOI:10.1371/journal.pone.0086719.

Fitchenbaum, C. "Inflammation Markers Associated With Coronary Heart Disease in Person with HIV Infection."  Current Infectious Diseases Report. February 1, 2011; 13(1):94-101.

Spudich, S. and González-Sanches, F. "HIV-1-Related Central Nervous System Disease: Current Issues in Pathogenesis, Diagnosis, and Treatment." Cold Spring Harbor Perspectives in Medicine. June 2012, 2(6):a007120.

Hütter, G.; Nowak, D.; Mossner, M.; et al. "Long-Term Control of HIV by CCR5 Delta32/Delta32 Stem-Cell Transplantation." New England Journal of Medicine. February 12, 2009; 360:692-698.

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