Those with very low CD4 counts have highest mortality risk after starting Tx

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Mortality in people with a low CD4 cell count at the time of HIV diagnosis is associated with a group of risk factors including a high number of symptoms, weight loss, poor mobility, self-care issues and some abnormal laboratory findings, investigators report. The study led by Ann Sarah Walker at the Medical Research Council Trials Unit at University College London, found that questions about fever, vomiting, weight loss, mobility and the ability to wash and dress oneself identified people in especially high need of same-day treatment initiation.

The study involved people in sub-Saharan Africa who had a CD4 cell count below 100 cells/mm3 at the time of their HIV diagnosis. There was a high mortality rate during the first 48 weeks of antiretroviral therapy (ART) and the researchers identified several groups of clinical and laboratory features that were associated with the greatest risk of mortality.

Treatment guidelines now recommend ART for all people, irrespective of CD4 cell count. But between a fifth and a quarter of people in sub-Saharan Africa have severe immune suppression at the time of their HIV diagnosis and should be prioritised for rapid treatment initiation and other interventions to prevent opportunistic infections. Any delay may be fatal; approximately 10% of people with very low CD4 cell counts die within three months of starting ART. In the absence of CD4 cell counts, or if laboratory test results are delayed, healthcare workers need to know who is in especially urgent need of antiretroviral treatment and other preventive treatment.

Investigators from the Reduction in EArly MortaLITY (REALITY) trial wanted to see if mortality during the first 48 weeks of ART was associated with specific groups of clinical and laboratory characteristics in people who were also severely immuno-suppressed at the time of their HIV diagnosis.

The REALITY study was a prospective clinical study of ART and enhanced antimicrobial prophylaxis in adults and children aged five years and over. The participants were recruited at eight centres in Kenya, Malawi, Uganda and Zimbabwe. All had a CD4 cell count below 100 cells/mm3 at the time of diagnosis and started immediate ART. Half the participants were randomised to also receive enhanced antimicrobial prophylaxis and ART that included the addition of raltegravir as a fourth drug for the first 12 weeks of treatment.

The primary analysis of the study showed that enhanced microbial prophylaxis significantly reduced the risk of death after starting antiretroviral treatment. In this analysis, individuals were assessed at baseline for risk factors potentially associated with an increased mortality risk, such as weight, grip strength and body mass, social factors including self-care, symptoms and laboratory abnormalities. The investigators conducted an analysis to see if clusters of specific risk factors were especially associated with mortality risk, independent of CD4 cell count.

During follow-up, a total of 203 people (12%) died. Mortality was independently associated with older age (p = 0.002), lower CD4 cell count (p < 0.001), lower albumin (p = 0.001), lower haemoglobin (p = 0.01), weaker grip strength (p = 0.03), moderate or severe weight loss (p = 0.04), mobility problems (p = 0.005), fever (p = 0.001), vomiting (p = 0.02) and problems with self-care (p = 0.003).

Taking enhanced antimicrobial prophylaxis was associated with reduced mortality risk (p = 0.02). Outcomes did not differ according to the use of raltegravir.

Several phenotypes – groupings of risk factors – were associated with higher mortality risk.

The highest mortality rate (25%) was associated with a median CD4 cell count of 28 cells/mm3, a high burden of symptoms, weight loss, poor mobility and low albumin and haemoglobin.

The next highest mortality rate (11%) was observed in people with a grouping of risk factors including a median CD4 cell count of 43 cells/mm3, weight loss, and also blood test results indicating underlying inflammation or infections, such as high white blood cell count, and abnormal platelet and neutrophil counts.

A third group of individuals with a 10% mortality rate had a median CD4 cell count of 27 cells/mm3 but had a low burden of symptoms and maintained fat mass and body weight. Mortality in the rate in the remaining people was between 4 and 6%.

“Rather than late presenters being a homogenous group, we identified 5 phenotypes, with several prognostic factors varying substantially across groups, as did mortality,” write the authors. “Screening patients with low CD4 counts at baseline for significant weight loss, a small cluster of symptoms (fever and vomiting), impaired activities of daily living, and a simple assessment of grip strength might identify those at highest risk of death.” Patients with these characteristics should then be prioritised for same-day ART and enhanced antimicrobial prophylaxis, recommend the investigators.

Abstract
Background: Severely immunocompromised human immunodeficiency virus (HIV)–infected individuals have high mortality shortly after starting antiretroviral therapy (ART). We investigated predictors of early mortality and “late presenter” phenotypes.
Methods: The Reduction of EArly MortaLITY (REALITY) trial enrolled ART-naive adults and children ≥5 years of age with CD4 counts <100 cells/µL initiating ART in Uganda, Zimbabwe, Malawi, and Kenya. Baseline predictors of mortality through 48 weeks were identified using Cox regression with backwards elimination (exit P > .1).
Results: Among 1711 included participants, 203 (12%) died. Mortality was independently higher with older age; lower CD4 count, albumin, hemoglobin, and grip strength; presence of World Health Organization stage 3/4 weight loss, fever, or vomiting; and problems with mobility or self-care at baseline (all P < .04). Receiving enhanced antimicrobial prophylaxis independently reduced mortality (P = .02). Of five late-presenter phenotypes, Group 1 (n = 355) had highest mortality (25%; median CD4 count, 28 cells/µL), with high symptom burden, weight loss, poor mobility, and low albumin and hemoglobin. Group 2 (n = 394; 11% mortality; 43 cells/µL) also had weight loss, with high white cell, platelet, and neutrophil counts suggesting underlying inflammation/infection. Group 3 (n = 218; 10% mortality) had low CD4 counts (27 cells/µL), but low symptom burden and maintained fat mass. The remaining groups had 4%–6% mortality.
Conclusions: Clinical and laboratory features identified groups with highest mortality following ART initiation. A screening tool could identify patients with low CD4 counts for prioritizing same-day ART initiation, enhanced prophylaxis, and intensive follow-up.

Authors
Abraham Siika, Leanne McCabe, Mutsa Bwakura-Dangarembizi, Cissy KityoJane Mallewa, Jay Berkley, Kath Maitland, Anna Griffiths, Keith Baleeta, Shepherd Mudzingwa, James Abach, Kusum Nathoo, Margaret J Thomason, Andrew J Prendergast, Ann Sarah Walker, Diana M Gibb, REALITY Trial Team

Aidsmap material
Clinical Infectious Diseases abstract


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