Perspective from Wafaa El-Sadr, MD, MPH
July 19, 2017
3 min read

Enhanced antibiotic prophylaxis lowers death rate in patients with advanced HIV

Perspective from Wafaa El-Sadr, MD, MPH
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In sub-Saharan African patients with advanced HIV who were starting ART for the first time, enhanced antimicrobial prophylaxis reduced the rate of death by 27% after 24 weeks compared with standard prophylaxis, according to partial study findings published in The New England Journal of Medicine.

The results are from the Reduction of Early Mortality in HIV-Infected Adults and Children Starting Antiretroviral Therapy (REALITY) trial, which is being conducted in eight urban or peri-urban areas of Kenya, Malawi, Uganda and Zimbabwe.

Around 20% to 25% of patients with HIV in sub-Saharan Africa present for care with severe immunosuppression, and approximately 10% of these patients die within 3 months of initiating ART, primarily from severe bacterial infection, tuberculosis and cryptococcal infection, according to James Hakim, FRCP, of the University of Zimbabwe Clinical Research Center, and colleagues.

For the REALITY trial, Hakim and colleagues randomly assigned ART-naive patients with low CD4 counts to receive enhanced antimicrobial prophylaxis or standard prophylaxis, adjunctive raltegravir or no raltegravir and supplementary food or no supplementary food. The findings published today included only the effects of the enhanced antimicrobial prophylaxis.

“Current guidelines recommend ruling out tuberculosis and cryptococcal meningitis before the initiation of ART, along with the use of trimethoprim-sulfamethoxazole and isoniazid prophylaxis,” they wrote. “The risk of death increases markedly with decreasing CD4 counts and body mass index ... in both adults and children, which suggests the need for additional interventions aimed at preventing infection, accelerating immune recovery (through rapid viral-load reduction), and improving nutritional status.”

From June 2013 through April 2015, Hakim and colleagues enrolled 1,805 HIV-infected adults and children aged 5 years and older who were starting ART for the first time and had CD4 counts lower than 100 cells/mm3. Patients were followed for 48 weeks. They received either enhanced prophylaxis — continuous TMP-SMX plus at least 12 weeks of isoniazid-pyridoxine and TMP-SMX in a single fixed-dose combination tablet, 12 weeks of fluconazole, 5 days of azithromycin and a single dose of albendazole — or standard prophylaxis of TMP-SMX alone. The median baseline CD4 count was 37 cells/mm3, but 47.3% of patients were either asymptomatic or mildly symptomatic, according to the study.

Compared with standard prophylaxis, enhanced antibiotic treatment reduced rates of death by 27% at 24 weeks and 24% at 48 weeks without compromising viral suppression or increasing toxic effects, Hakim and colleagues reported. Specifically, 80 patients (8.9%) in the enhanced prophylaxis arm and 108 patients (12.2%) on standard treatment died in the first 24 weeks, with an HR of 0.73 (95% CI, 0.55 to 0.98). By 48 weeks, 98 patients (11%) on enhanced prophylaxis and 127 (14.4%) who received standard treatment died, with an HR of 0.76 (95% CI, 0.58 to 0.99).


In secondary outcomes measures at 48 weeks, patients in the enhanced-prophylaxis group also experienced significantly lower rates of WHO stage 3 or 4 events or death (19.8% vs. 24.9%), TB (7.1% vs. 10.2%), cryptococcal infection (1.0% vs. 2.6%), candidiasis (1.1% vs. 2.6%) and new hospitalization (17% vs. 20.7%), but there was no significant difference in the rate of severe bacterial infection (4.6% vs. 3.7%) between the two groups. Additionally, there was marginal evidence of a lower rate of serious adverse events and grade 4 adverse events in the enhanced-prophylaxis group, whereas rates of HIV viral suppression and adherence to ART were similar in the two groups, according to Hakim and colleagues.

“In conclusion,” they wrote, “we found a survival benefit for multicomponent enhanced antimicrobial prophylaxis in adults and older children with advanced HIV infection who were initiating ART with a CD4 count of fewer than 100 cells/mm3 — a group that represents a substantial proportion of those starting treatment who are at increased risk for early death.

“The enhanced prophylaxis is relatively inexpensive, has a low pill burden and an acceptable side effect profile and would be easy to implement at primary health centers since it relies only on screening for clinical symptoms and testing of CD4 counts to identify asymptomatic patients with advanced HIV infection.” – by Gerard Gallagher


Hakim J, et al. N Engl J Med. 2017;doi:10.1056/NEJMoa1615822.

Disclosure: Please see the study for a list of all authors’ relevant financial disclosures.