Effect of ready-to-use supplementary food on mortality in severely immunocompromised HIV-infected individuals in Africa initiating antiretroviral therapy (REALITY): an open-label, parallel-group, randomised controlled trial

Abstract

Background: In sub-Saharan Africa, severely immunocompromised HIV-infected individuals have a high risk of mortality during the first few months after starting antiretroviral therapy (ART). We hypothesise that universally providing ready-to-use supplementary food (RUSF) would increase early weight gain, thereby reducing early mortality compared with current guidelines recommending ready-to-use therapeutic food (RUTF) for severely malnourished individuals only.

Methods: We did a 2 × 2 × 2 factorial, open-label, parallel-group trial at inpatient and outpatient facilities in eight urban or periurban regional hospitals in Kenya, Malawi, Uganda, and Zimbabwe. Eligible participants were ART-naive adults and children aged at least 5 years with confirmed HIV infection and a CD4 cell count of fewer than 100 cells per μL, who were initiating ART at the facilities. We randomly assigned participants (1:1) to initiate ART either with (RUSF) or without (no-RUSF) 12 weeks' of peanut-based RUSF containing 1000 kcal per day and micronutrients, given as two 92 g packets per day for adults and one packet (500 kcal per day) for children aged 5-12 years, regardless of nutritional status. In both groups, individuals received supplementation with RUTF only when severely malnourished (ie, body-mass index [BMI] <16-18 kg/m² or BMI-for-age Z scores <-3 for children). We did the randomisation with computer-generated, sequentially numbered tables with different block sizes incorporated within an online database. Randomisation was stratified by centre, age, and two other factorial randomisations, to 12 week adjunctive raltegravir and enhanced anti-infection prophylaxis (reported elsewhere). Clinic visits were scheduled at weeks 2, 4, 8, 12, 18, 24, 36, and 48, and included nurse assessment of vital status and symptoms and dispensing of all medication including ART and RUSF. The primary outcome was mortality at week 24, analysed by intention to treat. Secondary outcomes included absolute changes in weight, BMI, and mid-upper-arm circumference (MUAC). Safety was analysed in all randomly assigned participants. Follow-up was 48 weeks. This trial is registered with ClinicalTrials.gov (NCT01825031) and the ISRCTN registry (43622374).

Findings: Between June 18, 2013, and April 10, 2015, we randomly assigned 1805 participants to treatment: 897 to RUSF and 908 to no-RUSF. 56 (3%) were lost-to-follow-up. 96 (10·9%, 95% CI 9·0-13·1) participants allocated to RUSF and 92 (10·3%, 8·5-12·5) to no-RUSF died within 24 weeks (hazard ratio 1·05, 95% CI 0·79-1·40; log-rank p=0·75), with no evidence of interaction with the other randomisations (both p>0·7). Through 48 weeks, adults and adolescents aged 13 years and older in the RUSF group had significantly greater gains in weight, BMI, and MUAC than the no-RUSF group (p=0·004, 0·004, and 0·03, respectively). The most common type of serious adverse event was specific infections, occurring in 90 (10%) of 897 participants assigned RUSF and 87 (10%) of 908 assigned no-RUSF. By week 48, 205 participants had serious adverse events in both groups (p=0·81), and 181 had grade 4 adverse events in the RUSF group compared with 172 in the non-RUSF group (p=0·45).

Interpretation: In severely immunocompromised HIV-infected individuals, providing RUSF universally at ART initiation, compared with providing RUTF to severely malnourished individuals only, improved short-term weight gain but not mortality. A change in policy to provide nutritional supplementation to all severely immunocompromised HIV-infected individuals starting ART is therefore not warranted at present.

Funding: Joint Global Health Trials Scheme (UK Medical Research Council, UK Department for International Development, and Wellcome Trust).

Figure 1

Trial profile ART=antiretroviral therapy. RUSF=ready-to-use supplementary food. RUTF=ready-to-use therapeutic food. *Reasons were not mutually exclusive, therefore total is more than the number of patients not randomly assigned treatment. †Considered too unwell (one patient), not able to comply with trial schedule (one patient), and no further details (one patient). ‡Ten patients ineligible after randomisation (four previously received ART, one RUSF contraindicated [milk allergy]), one 3 months pregnant, one had CD4 count ≥100 cells per μL at screening [38 cells per μL at enrolment], one randomly assigned 7 weeks after screening, two incorrect consent [one aged 14 years gave assent but without caregiver consent at enrolment; one aged 19 years old gave assent but caregiver consent was obtained on the basis of a self-reported age of 16 years at screening]). §Four patients assigned no-RUSF and two assigned RUSF were not formally lost to follow-up (they were seen in the clinic within 91 days of week 48). ¶Time-to-event analyses included all times at-risk from randomisation to the earliest of the event or last clinical follow-up if the event had not occurred (details on adherence to randomised strategy in appendix).

Figure 2

Overall mortality through 48 weeks Dotted vertical line at week 24 when the primary outcome (mortality) was measured. HR=hazard ratio. RUSF=ready-to-use supplementary food.

Figure 3

Changes in weight, BMI, MUAC, and grip strength hrough 48 weeks Data are mean (95% CI). Figure shows changes in (A) weight, (B) body-mass index (BMI), (C) MUAC (mid-upper-arm-circumference), and (D) grip strength. p values compare changes from baseline across randomised groups, and hence adjust for any imbalances at baseline. Weight, BMI, and MUAC were analysed only in those aged ≥13 years at initiation of antiretroviral therapy. RUSF=ready-to-use supplementary food.

Figure 4

Changes in body composition through 48 weeks Data are mean (95% CI) for patients aged ≥13 years at initiation of antiretroviral therapy. Figure shows changes in (A) fat mass and (B) fat-free mass. p values compare changes from baseline across randomly assigned groups and hence adjust for any imbalances at baseline. RUSF=ready-to-use supplementary food.