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Are HIV Non-Progressors Really Very Slow Progressors?

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HIV positive people traditionally classified as long-term non-progressors or viral controllers may in fact progress slowly over time, according to research reported in the February 20, 2012, edition of the open-access journal PLoS ONE. These findings suggest that so-called non-progressors may in fact benefit from antiretroviral therapy and could provide clues to aid in development of immune-based therapies. 

Since the early years of the epidemic researchers have noted that a small proportion of people with HIV seem to be long-term non-progressors (LTNPs) who maintain stable CD4 T-cell counts and do not experience opportunistic illness despite the absence of antiretroviral therapy (ART). An even smaller subset dubbed HIV controllers or "elite controllers" maintain undetectable viral load without treatment.

To learn more about this unusual group, Sundhiya Mandalia and colleagues analyzed medical records from all patients with HIV-1 seen at Chelsea and Westminster Hospital in London between 1988 and 2010. LTNP were defined as individuals who were HIV positive for more than 7 years, ART-naive, had no history of opportunistic illness (defined as any symptomatic manifestation of HIV disease), and had a stable normal CD4 cell count.

The researchers compared people who had a history of stable CD4 counts below normal (< 450 cells/mm3), or those whose levels fell below normal at least once, versus those whose levels always remained within the normal range. Further, within these 2 groups, they identified individuals with HIV RNA consistently below the limit of detection.

Results

  • Out of 14,227 patients in the hospital database, 5417 were diagnosed as HIV positive more than 7 years ago, and among these, 1204 had never been prescribed ART.
  • Within this group, 239 people (20%) had CD4 counts that had consistently remained within the normal range.
  • Patients with stable normal and stable below-normal CD4 counts were similar with regard to sex (both > 90% men) and age (median 40 years), but there were significantly fewer Caucasians in the consistently normal group.
  • The estimated median time to progression (defined as T-cell decline or clinical progression) for the stable normal CD4 group was 6.2 years, significantly longer than the 4.0 years for patients with stable below-normal counts (P < 0.001).
  • Among the 1204 long-term positive, ART-naive patients, 312 (26%) were consistently asymptomatic.
  • Within this group, 110 (35%) maintained CD4 counts within the normal range; these patients had an estimated median time to progression of 9.1 years, compared with 7.3 years for those whose CD4 count fell below normal at least once.
  • 258 (83%) of the 312 ART-naive asymptomatic patients had unstable or declining CD4 counts, of whom 95 (37%) had counts consistently within the normal range; the estimated median time to progression for this group was 5.8 years -- similar to the 4.6 years for the 163 patients (63%) with a history of below-normal CD4 counts.
  • 50 ART-naive patients were found to have long-term stable CD4 cell counts.
  • Within this group, 13 were classified as LTNPs with CD4 counts consistently in the normal range, while the remaining 37 had at least 1 below-normal measurement.
  • 1 of the 13 LTNPs (8%), and 3 of the 37 with at least 1 low CD4 count, met the viral load criteria to be classified as HIV controllers.

Based on these findings, the investigators determined that few HIV positive people in this and other studies are LTNPs or HIV controllers. Out of all current HIV patients seen at their hospital, 13 (0.2%) met the LTNP criteria, including 3 controllers (0.05%).

"This study suggests that by using varying selection criteria, disease progression is very likely in the majority of people living with HIV-1," they wrote. "The patients who had not progressed within the study period are likely to do so, as demonstrated in the analysis of individuals found to have long-term stable low CD4 T-cell counts compared to those with unstable CD4 T-cell counts."

They raised the possibility that "many more" people living with HIV may actually be LTNPs or HIV controllers, "but due to the absence of clinical manifestations of disease these individuals have not yet attended an HIV-1 testing facility and consequently have not been diagnosed as HIV-1 positive."

Researchers should develop universal definitions of these patient groups, they recommended, to facilitate comparison across populations.

"Studying patients at the extreme of this distribution may enable discovery of correlates of HIV-1 positive disease progression, leading to identification of targets to be manipulated by novel therapeutic approaches, with the ultimate goal of inducing delayed disease progression, retarding ART initiation and alleviating pill burden and toxicity," the authors elaborated in their discussion.

"Large cohorts of well-defined HIV-1 positive patients will be essential for future investigation of genetic associations with HIV-1 control and delayed disease progression," they continued, "as the unique immunological and virological responses demonstrated by LTNP and [HIV controllers] may provide clues towards both the change in disease status of these patients over time, and provide insights for HIV-1 preventive or therapeutic vaccine development."

Investigator affiliations: Department of Medicine, Imperial College London, Chelsea and Westminster Hospital, London, UK; London School of Hygiene and Tropical Medicine, London, UK.

2/24/12

Reference

S Mandalia, SJ Westrop, EJ Beck, et al. Are Long-Term Non-Progressors Very Slow Progressors? Insights from the Chelsea and Westminster HIV Cohort, 1988-2010. PLoS ONE 7(2):e29844. February 20, 2012.