Enhanced Prophylaxis plus Antiretroviral Therapy for Advanced HIV Infection in Africa

Abstract

Background In sub-Saharan Africa, among patients with advanced human immunodeficiency virus (HIV) infection, the rate of death from infection (including tuberculosis and cryptococcus) shortly after the initiation of antiretroviral therapy (ART) is approximately 10%. Methods In this factorial open-label trial conducted in Uganda, Zimbabwe, Malawi, and Kenya, we enrolled HIV-infected adults and children 5 years of age or older who had not received previous ART and were starting ART with a CD4+ count of fewer than 100 cells per cubic millimeter. They underwent simultaneous randomization to receive enhanced antimicrobial prophylaxis or standard prophylaxis, adjunctive raltegravir or no raltegravir, and supplementary food or no supplementary food. Here, we report on the effects of enhanced antimicrobial prophylaxis, which consisted of continuous trimethoprim–sulfamethoxazole plus at least 12 weeks of isoniazid–pyridoxine (coformulated with trimethoprim–sulfamethoxazole in a single fixed-dose combination tablet), 12 weeks of fluconazole, 5 days of azithromycin, and a single dose of albendazole, as compared with standard prophylaxis (trimethoprim–sulfamethoxazole alone). The primary end point was 24-week mortality. Results A total of 1805 patients (1733 adults and 72 children or adolescents) underwent randomization to receive either enhanced prophylaxis (906 patients) or standard prophylaxis (899 patients) and were followed for 48 weeks (loss to follow-up, 3.1%). The median baseline CD4+ count was 37 cells per cubic millimeter, but 854 patients (47.3%) were asymptomatic or mildly symptomatic. In the Kaplan–Meier analysis at 24 weeks, the rate of death with enhanced prophylaxis was lower than that with standard prophylaxis (80 patients [8.9% vs. 108 [12.2%]; hazard ratio, 0.73; 95% confidence interval [CI], 0.55 to 0.98; P=0.03); 98 patients (11.0%) and 127 (14.4%), respectively, had died by 48 weeks (hazard ratio, 0.76; 95% CI, 0.58 to 0.99; P=0.04). Patients in the enhanced-prophylaxis group had significantly lower rates of tuberculosis (P=0.02), cryptococcal infection (P=0.01), oral or esophageal candidiasis (P=0.02), death of unknown cause (P=0.03), and new hospitalization (P=0.03). However, there was no significant between-group difference in the rate of severe bacterial infection (P=0.32). There were nonsignificantly lower rates of serious adverse events and grade 4 adverse events in the enhanced-prophylaxis group (P=0.08 and P=0.09, respectively). Rates of HIV viral suppression and adherence to ART were similar in the two groups. Conclusions Among HIV-infected patients with advanced immunosuppression, enhanced antimicrobial prophylaxis combined with ART resulted in reduced rates of death at both 24 weeks and 48 weeks without compromising viral suppression or increasing toxic effects. (Funded by the Medical Research Council and others; REALITY Current Controlled Trials number, ISRCTN43622374.)

Proportions of CD4 test results indicating advanced HIV disease remain consistently high at primary health care facilities across four high HIV burden countries

“…Health centers and clinics, for example, had proportions of advanced disease of 15% and 16%, respectively, in 2016 with historic proportions above 20% for certain years. Similar to the REALITY trial that showed significant proportions of patients with advanced disease at outpatient wards [8], our data suggests that primary care facilities have high proportions of patients with advanced HIV disease that also require the advanced HIV disease package of care in order to minimize HIV-related morbidity and mortality [6].…”

“…CD4 is recommended to monitor patients at risk for opportunistic infections and to identify patients with advanced HIV disease [3,6,7]. Though clinical acumen can be used to identify patients with advanced HIV disease-defined as patients with a CD4 <200 cells/mm 3 or WHO clinical stage 3 or 4 disease [6]-it has been found to be poorly accurate: up to 50% of patients with advanced disease may be asymptomatic (WHO clinical stage 1 or 2) and thus missed by clinical acumen alone [8].…”

Retention and predictors of attrition among patients who started antiretroviral therapy in Zimbabwe’s National Antiretroviral Therapy Programme between 2012 and 2015

“…Indeed, access to baseline CD4 testing, screening and management of opportunistic (tuberculosis, cryptococcal meningitis) and access to prophylaxis (isoniazid preventive therapy & pre-emptive fluconazole) remains a challenge in the Zimbabwe’s public sector [50, 51]. Recent evidence has also shown that screening, prophylaxis and management of opportunistic diseases (mainly tuberculosis, bacterial sepsis and cryptococcal disease) significantly reduce morbidity and mortality [52, 53]. However, evidence from this enhanced care package is currently being poorly implemented by most ART programmes in low resource setting [54].…”

Incidence of tuberculosis in children on antiretroviral therapy: a retrospective cohort study

“…Therefore, prevention of TB through strengthening of TB diagnostic approaches and implementation of strong preventive strategies to children on ART has been suggested. Notably, newly emerging prophylaxis regimen in the prevention of TB [42] needs to be considered. More emphasis is required for the first 6 months after ART initiation.…”