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.)

Although the World Health Organization (WHO) guidelines now recommend universal antiretroviral therapy (ART) regardless of the CD4+ count,13 20 to 25% of patients with human immunodeficiency virus (HIV) infection in sub-Saharan Africa present for care with severe immunosuppression (CD4+ count, <100 cells per cubic millimeter).4 Among these patients, approximately 10% die during the first 3 months after ART initiation.58 Causes of death are multifactorial and similar between adults and older children,7with severe bacterial infection,3,9 tuberculosis,8,10,11 and cryptococcal infection12,13 playing prominent roles. The development or exacerbation of such infections has been linked in part to the immune reconstitution inflammatory syndrome (IRIS) associated with the initiation of ART. Current guidelines recommend ruling out tuberculosis and cryptococcal meningitis before the initiation of ART, along with the use of trimethoprim–sulfamethoxazole and isoniazid prophylaxis.1,14,15 The risk of death increases markedly with decreasing CD4+ counts and body-mass index (BMI, the weight in kilograms divided by the square of the height in meters) in both adults and children,7 which suggests the need for additional interventions aimed at preventing infection, accelerating immune recovery (through rapid viral-load reduction), and improving nutritional status.

One approach to preventing infection in all patients is administering preemptive treatment courses for specific high-burden diseases (e.g., tuberculosis) when ART is initiated.16,17 Another is an antimicrobial prophylaxis package targeting dominant pathogens among patients with advanced HIV infection after the clinical exclusion of active infections. Such a pragmatic approach could be universally provided at low-level health facilities. Possible adverse outcomes include toxicity, antimicrobial resistance, and reduced adherence to the ART regimen because of the need to take additional pills.

In the Reduction of Early Mortality in HIV-Infected Adults and Children Starting Antiretroviral Therapy (REALITY) trial, we compared three interventions — enhanced antimicrobial prophylaxis, additional raltegravir, and food supplementation — to reduce early mortality in adults and older children with a CD4+ count of fewer than 100 cells per cubic millimeter in whom ART was initiated in four sub-Saharan African countries. Here, we report the effect of enhanced antimicrobial prophylaxis only.

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Methods

Trial Enrollment

From June 2013 through April 2015, in eight urban or periurban centers in Uganda, Zimbabwe, Malawi, and Kenya, we enrolled HIV-infected adults and children who were 5 years of age or older, who had not received previous ART, and who had a CD4+ count of fewer than 100 cells per cubic millimeter. Patients were excluded if they were pregnant or breast-feeding, had received single-dose nevirapine to prevent mother-to-child transmission of HIV, or had any contraindications to the trial drugs. Adult patients and guardians provided written informed consent; older children provided additional assent, according to national guidelines. The trial was approved by ethics committees in Uganda, Zimbabwe, Malawi, Kenya, and the United Kingdom.

Trial Design

All the patients initiated ART with two nucleoside reverse-transcriptase inhibitors and one non-nucleoside reverse-transcriptase inhibitor. They were then randomly assigned in a 1:1 ratio to initiate open-label enhanced antimicrobial prophylaxis or standard prophylaxis. Enhanced prophylaxis consisted of a single dose (400 mg) of albendazole, 5 days of azithromycin (500 mg once daily), 12 weeks of fluconazole (100 mg once daily), and 12 weeks of a fixed-dose combination of trimethoprim–sulfamethoxazole (160 mg of trimethoprim and 800 mg of sulfamethoxazole), isoniazid (300 mg), and pyridoxine (25 mg) as a scored once-daily tablet (total, three tablets per day for 1 to 5 days, then two pills per day for 12 weeks). Doses were halved for children younger than 13 years of age, except for albendazole. Standard prophylaxis consisted of trimethoprim–sulfamethoxazole alone.

After 12 weeks, fluconazole was discontinued and trimethoprim–sulfamethoxazole or the fixed-dose combination was continued in the enhanced-prophylaxis group; trimethoprim–sulfamethoxazole was continued or switched to the fixed-dose combination in the standard-prophylaxis group. The use of isoniazid–pyridoxine beyond the 12-week period depended on national guidelines for the use of isoniazid preventive therapy. Screening for active tuberculosis before randomization was performed with the use of a WHO-based symptom checklist (see the Methods section in the Supplementary Appendix, available with the full text of this article at NEJM.org). Sputum samples were examined and chest radiography was performed in centers where such evaluation was possible. Patients who were already receiving antimicrobial treatment or prophylaxis or who needed such therapy were treated regardless of randomization but received other prophylaxis according to randomization.

Randomization was stratified according to trial center, age (<13 years vs. ≥13 years), and other factorial randomizations (12 weeks of additional raltegravir vs. no raltegravir and 12 weeks of additional ready-to-use supplementary food vs. no supplementary food). A computer-generated sequential randomization list with variably sized permuted blocks was prepared by the trial statistician and incorporated securely into the online trial database. The list was concealed until eligibility was confirmed by staff members at the local center, who then performed the randomization.

Patients discontinued their participation in the trial after 48 weeks. At weeks 2, 4, 8, 12, 18, 24, 36, and 48, a nurse reviewed a symptom checklist and asked patients about their adherence to the trial drugs, and a pharmacist dispensed the trial drugs. At weeks 4, 12, 24, 36, and 48, a physician took a medical history and performed a physical examination; laboratory testing that included a full blood count, CD4+ count, and evaluation of kidney and renal function was performed (with testing of kidney and renal function performed only at weeks 4 and 48); and plasma was stored for retrospective evaluation of the HIV viral load. All the nurses and physicians were aware of the trial-group assignments; all testing was performed in a blinded manner. At the physicians’ discretion, antiretroviral drugs could be substituted in cases of drug toxicity; in cases of first-line drug failure, regimens could be switched to second-line regimens, according to WHO guidelines.18

Following the factorial design, all the patients also underwent randomization in a 1:1 ratio to receive 12 weeks of additional raltegravir or no raltegravir and to receive 12 weeks of ready-to-use supplementary food or no routine supplementation. The results of these analyses are not reported here. Full details regarding the trial design and analyses are provided in the protocol, available at NEJM.org.

Trial Oversight

Gilead Sciences, ViiV Healthcare/GlaxoSmithKline, Cipla, and Merck donated the antiretroviral drugs, Cipla donated the prophylaxis drugs, and ready-to-use supplementary food was purchased from Valid International. Representatives of the drug manufacturers had no role in the trial design, data collection, data analysis, or manuscript preparation. All the authors vouch for the completeness and accuracy of the data and all analyses, and for the fidelity of the trial to the protocol.


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