Causes and Timing of Mortality and Morbidity Among Late Presenters Starting Antiretroviral Therapy in the REALITY Trial

Overview

Journal Clin Infect Dis

Publisher Oxford University Press

Specialty Infectious Diseases

Date 2018 Mar 8

PMID 29514234

Citations 23

Authors

Frank A Post

Alexander J Szubert

Andrew J Prendergast

Victoria Johnston

Hermione Lyall

Felicity Fitzgerald

Victor Musiime

Godfrey Musoro

Priscilla Chepkorir

Clara Agutu

Jane Mallewa

Chathurika Rajapakse

Helen Wilkes

James Hakim

Peter Mugyenyi

A Sarah Walker

Diana M Gibb

Sarah L Pett

Affiliations

Soon will be listed here.

Abstract

Background: In sub-Saharan Africa, 20%-25% of people starting antiretroviral therapy (ART) have severe immunosuppression; approximately 10% die within 3 months. In the Reduction of EArly mortaLITY (REALITY) randomized trial, a broad enhanced anti-infection prophylaxis bundle reduced mortality vs cotrimoxazole. We investigate the contribution and timing of different causes of mortality/morbidity.

Methods: Participants started ART with a CD4 count <100 cells/µL; enhanced prophylaxis comprised cotrimoxazole plus 12 weeks of isoniazid + fluconazole, single-dose albendazole, and 5 days of azithromycin. A blinded committee adjudicated events and causes of death as (non-mutually exclusively) tuberculosis, cryptococcosis, severe bacterial infection (SBI), other potentially azithromycin-responsive infections, other events, and unknown.

Results: Median pre-ART CD4 count was 37 cells/µL. Among 1805 participants, 225 (12.7%) died by week 48. Fatal/nonfatal events occurred early (median 4 weeks); rates then declined exponentially. One hundred fifty-four deaths had single and 71 had multiple causes, including tuberculosis in 4.5% participants, cryptococcosis in 1.1%, SBI in 1.9%, other potentially azithromycin-responsive infections in 1.3%, other events in 3.6%, and unknown in 5.0%. Enhanced prophylaxis reduced deaths from cryptococcosis and unknown causes (P < .05) but not tuberculosis, SBI, potentially azithromycin-responsive infections, or other causes (P > .3); and reduced nonfatal/fatal tuberculosis and cryptococcosis (P < .05), but not SBI, other potentially azithromycin-responsive infections, or other events (P > .2).

Conclusions: Enhanced prophylaxis reduced mortality from cryptococcosis and unknown causes and nonfatal tuberculosis and cryptococcosis. High early incidence of fatal/nonfatal events highlights the need for starting enhanced-prophylaxis with ART in advanced disease.

Clinical Trials Registration: ISRCTN43622374.

Citing Articles

Prevalence, Predictors, and Outcomes of HIV Care in HIV-Positive Clients Entering HIV Care With Advanced HIV Disease in Sub-Saharan Africa 2010-2022: Systematic Review and Meta-Analysis.

Haumba S, Arora S, Williams V, Maseko T, Mafukidze A, Ojoo S Health Sci Rep. 2024; 7(12):e70285.

PMID: 39720238 PMC: 11667100. DOI: 10.1002/hsr2.70285.

Implementation of the advanced HIV disease package of care using a public health approach: lessons from Nigeria.

Eigege W, Agbaji O, Otubu N, Abudiore O, Sowale O, Levy-Braide B BMC Public Health. 2024; 24(1):3366.

PMID: 39627726 PMC: 11613670. DOI: 10.1186/s12889-024-20841-x.

Biomarkers of mortality in adults and adolescents with advanced HIV in sub-Saharan Africa.

Riitho V, Connon R, Gwela A, Namusanje J, Nhema R, Siika A Nat Commun. 2024; 15(1):5492.

PMID: 38944653 PMC: 11214617. DOI: 10.1038/s41467-024-49317-7.

Advanced HIV disease in Homa Bay County, Kenya: Characteristics of newly-diagnosed and antiretroviral therapy-experienced clients.

Masaba R, Herrera N, Siamba S, Ouma M, Okal C, Mayi A Medicine (Baltimore). 2023; 102(51):e36716.

PMID: 38134082 PMC: 10735128. DOI: 10.1097/MD.0000000000036716.

Clinical characteristics and morbidity among hospitalized adults with advanced HIV disease in Uganda during 'test and treat' era.

Tugume L, Semitala F, Owachi D, Kagimu E, Kamya M, Meya D PLOS Glob Public Health. 2023; 3(10):e0002457.

PMID: 37851597 PMC: 10584089. DOI: 10.1371/journal.pgph.0002457.

References

Siika A, McCabe L, Bwakura-Dangarembizi M, Kityo C, Mallewa J, Berkley J . Late Presentation With HIV in Africa: Phenotypes, Risk, and Risk Stratification in the REALITY Trial. Clin Infect Dis. 2018; 66(suppl_2):S140-S146. PMC: 5850547. DOI: 10.1093/cid/cix1142. View

French M, Price P, Stone S . Immune restoration disease after antiretroviral therapy. AIDS. 2004; 18(12):1615-27. DOI: 10.1097/01.aids.0000131375.21070.06. View

Muller M, Wandel S, Colebunders R, Attia S, Furrer H, Egger M . Immune reconstitution inflammatory syndrome in patients starting antiretroviral therapy for HIV infection: a systematic review and meta-analysis. Lancet Infect Dis. 2010; 10(4):251-61. PMC: 4183458. DOI: 10.1016/S1473-3099(10)70026-8. View

Schreibman T, Friedland G . Use of total lymphocyte count for monitoring response to antiretroviral therapy. Clin Infect Dis. 2003; 38(2):257-62. DOI: 10.1086/380792. View

Walker A, Prendergast A, Mugyenyi P, Munderi P, Hakim J, Kekitiinwa A . Mortality in the year following antiretroviral therapy initiation in HIV-infected adults and children in Uganda and Zimbabwe. Clin Infect Dis. 2012; 55(12):1707-18. PMC: 3501336. DOI: 10.1093/cid/cis797. View

Cornell M, Grimsrud A, Fairall L, Fox M, Van Cutsem G, Giddy J . Temporal changes in programme outcomes among adult patients initiating antiretroviral therapy across South Africa, 2002-2007. AIDS. 2010; 24(14):2263-70. PMC: 2948209. DOI: 10.1097/QAD.0b013e32833d45c5. View

Avila D, Althoff K, Mugglin C, Wools-Kaloustian K, Koller M, Dabis F . Immunodeficiency at the start of combination antiretroviral therapy in low-, middle-, and high-income countries. J Acquir Immune Defic Syndr. 2014; 65(1):e8-16. PMC: 3894575. DOI: 10.1097/QAI.0b013e3182a39979. View

Boulle A, Schomaker M, May M, Hogg R, Shepherd B, Monge S . Mortality in patients with HIV-1 infection starting antiretroviral therapy in South Africa, Europe, or North America: a collaborative analysis of prospective studies. PLoS Med. 2014; 11(9):e1001718. PMC: 4159124. DOI: 10.1371/journal.pmed.1001718. View

Prendergast A, Szubert A, Berejena C, Pimundu G, Pala P, Shonhai A . Baseline Inflammatory Biomarkers Identify Subgroups of HIV-Infected African Children With Differing Responses to Antiretroviral Therapy. J Infect Dis. 2016; 214(2):226-36. PMC: 4918830. DOI: 10.1093/infdis/jiw148. View

10.

Ledwaba L, Tavel J, Khabo P, Maja P, Qin J, Sangweni P . Pre-ART levels of inflammation and coagulation markers are strong predictors of death in a South African cohort with advanced HIV disease. PLoS One. 2012; 7(3):e24243. PMC: 3308955. DOI: 10.1371/journal.pone.0024243. View

11.

Hakim J, Musiime V, Szubert A, Mallewa J, Siika A, Agutu C . Enhanced Prophylaxis plus Antiretroviral Therapy for Advanced HIV Infection in Africa. N Engl J Med. 2017; 377(3):233-245. PMC: 5603269. DOI: 10.1056/NEJMoa1615822. View

12.

Gupta A, Nadkarni G, Yang W, Chandrasekhar A, Gupte N, Bisson G . Early mortality in adults initiating antiretroviral therapy (ART) in low- and middle-income countries (LMIC): a systematic review and meta-analysis. PLoS One. 2012; 6(12):e28691. PMC: 3248405. DOI: 10.1371/journal.pone.0028691. View

13.

Musicha P, Cornick J, Bar-Zeev N, French N, Masesa C, Denis B . Trends in antimicrobial resistance in bloodstream infection isolates at a large urban hospital in Malawi (1998-2016): a surveillance study. Lancet Infect Dis. 2017; 17(10):1042-1052. PMC: 5610140. DOI: 10.1016/S1473-3099(17)30394-8. View

14.

Kuller L, Tracy R, Belloso W, De Wit S, Drummond F, Lane H . Inflammatory and coagulation biomarkers and mortality in patients with HIV infection. PLoS Med. 2008; 5(10):e203. PMC: 2570418. DOI: 10.1371/journal.pmed.0050203. View

15.

Post F, Wood R, Maartens G . CD4 and total lymphocyte counts as predictors of HIV disease progression. QJM. 1996; 89(7):505-8. DOI: 10.1093/qjmed/89.7.505. View

16.

Meintjes G, Lawn S, Scano F, Maartens G, French M, Worodria W . Tuberculosis-associated immune reconstitution inflammatory syndrome: case definitions for use in resource-limited settings. Lancet Infect Dis. 2008; 8(8):516-23. PMC: 2804035. DOI: 10.1016/S1473-3099(08)70184-1. View