Enhanced OI prophylaxis reduces mortality when starting ART late

Polly Clayden, HIV i-Base

Enhanced antimicrobial prophylaxis combined with ART reduced rates of death at both 24 and 48 weeks in HIV positive adults and children with advanced HIV in the REALITY trial. [1]

In sub-Sharan Africa, 20–25% of people with HIV still present for care with 100 CD4 cells/mm3 of less. Among this group, approximately 10% die within the first three months of starting ART, and severe bacterial infections (including tuberculosis and cryptococcus) are often the cause.

The REALITY trial, conducted in Uganda, Zimbabwe, Malawi and Kenya, looked at three strategies to potentially reduce the risk of death: enhanced antimicrobial prophylaxis, adding raltegravir to standard ART, and food supplementation.

It was a factorial open-label trial enrolling adults and children five years of age or older who had not received previous ART and were starting with CD4 count less than 100 cells/mm3.

The primary outcome was death from any cause at 24 weeks. Secondary outcomes included death from any cause at 48 weeks, serious adverse events, grade 4 adverse events, and adverse events leading to modification of ART or other trial drugs; as well as changes in CD4 count or weight, incidence of bacterial infections, adherence and acceptability.

The investigators reported the effect of the enhanced prophylaxis in the 20 July 2017 edition of NEJM in a paper authored by Hakim et al. The evaluation found no evidence of benefits from other factorial randomisations to adding raltegravir or supplementary food (p>0.7).

All participants started ART with two NRTIs and one NNRTI. They were then randomised (1:1 ratio) to start enhanced prophylaxis or standard prophylaxis.

Enhanced prophylaxis included: a single dose (400 mg) of albendazole, five 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 and 800 mg respectively), 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).

Children younger than 13 years of age, received half doses of all drugs except for albendazole. Standard prophylaxis was trimethoprim– sulfamethoxazole alone.

Participants in the enhanced prophylaxis group discontinued fluconazole after 12 weeks and continued trimethoprim–sulfamethoxazole or the fixed dose combination.  Those in the standard prophylaxis group continued trimethoprim–sulfamethoxazole or switched to the fixed-dose combination.

Use of isoniazid–pyridoxine after 12 weeks was according to national guidelines.

The trial included 1805 participants: 1733 adults and 72 children or adolescents (906 enhanced prophylaxis and 899 standard prophylaxis). They were followed for 48 weeks. Overall loss to follow-up was 3.1% (56 participants, 24 in the enhanced and 32 in the standard prophylaxis groups).

Participants were a median age of 36 years; 72 (4.0%) were children and adolescents 5–17 years of age. Median CD4 count was 37 cells/mm3, and 1300 of 1763 (73.7%) had a viral load of at least 100,000 copies/mL. But almost half (47.3%) were asymptomatic or mildly symptomatic (WHO stage 1–2).

At 24 weeks, there were 80 vs 108 (8.9 vs 12.2%) deaths in the enhanced vs standard prophylaxis groups: HR 0.73 (95% CI 0.55 to 0.98), p=0.03). By 48 weeks, there were 98 vs 127 (11.0 vs 14.4%) deaths, respectively: HR 0.76 (95% CI 0.58 to 0.99), p=0.04.

Participants in the enhanced prophylaxis group had significantly lower rates of a new diagnosis of tuberculosis (7.1 vs 10.2%), p=0.02; cryptococcal infection (1 vs 2.6%), p=0.01; candidiasis (1.1 vs 2.6), p=0.02), and new hospitalisation (17 vs 20.7%), p=0.03.

There was also a significantly lower rate of likely IRIS events (as judged by the end-point committee) with enhanced prophylaxis (7.4 vs 12.00%), p=0.001.

But there was no significant difference in the rate of severe bacterial infection between groups (42 vs 33), p=0.32). There were slightly lower rates of serious adverse events and grade 4 adverse events in the enhanced-prophylaxis group, but these were not significant (p=0.08 and p=0.09, respectively).

Rates of viral suppression and adherence to ART were similar in the two groups.

The authors noted that among HIV positive adults and older children with advanced HIV who started ART, the relative rate of death was 27% lower in those who received enhanced prophylaxis than those who received standard prophylaxis. This benefit was maintained through 48 weeks: 24% lower. The number-needed-to-treat to prevent one death was 29.

The cost of enhanced prophylaxis ranged from US $8 to $34 across the trial countries. But drug costs varied by a factor of 10, once again highlighting the importance of ensuring access to medicines at the lowest prices across all countries.

The authors concluded that enhanced prophylaxis is relatively inexpensive, and would be fairly easy to implement at primary health centres, since it only requires screening for clinical symptoms and CD4 testing to identify asymptomatic people with advanced HIV.


Hakim J et al. Enhanced prophylaxis plus antiretroviral therapy for advanced HIV infection in Africa. N Engl J Med 2017;377:233-45.

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