Nutritional support to reduce mortality in patients with HIV?
Authors: George PrayGod, Henrik Friis, Suzanne Filteau
Journal: The Lancet HIV (2018)

Despite increased access to antiretroviral therapy (ART) in patients with HIV, mortality is very high during the early months of treatment.1Lawn SD Harries AD Anglaret X Myer L Wood R Early mortality among adults accessing antiretroviral treatment programmes in sub-Saharan Africa.AIDS. 2008; 22: 1897-1908Crossref PubMed Scopus (517) Google Scholar Immunosuppression and undernutrition, presenting as either low body mass index (BMI) or micronutrient deficiency, are among the key risk factors for increased mortality.2Woodd SL Kelly P Koethe JR et al.Risk factors for mortality among malnourished HIV-infected adults eligible for antiretroviral therapy.BMC Infect Dis. 2016; 16: 562Crossref PubMed Scopus (12) Google Scholar Several clinical trials have investigated the role of micronutrient and macronutrient supplementation on HIV-related treatment outcomes including mortality, but many have shown no effects or only modest beneficial effects.3Grobler L Siegfried N Visser ME Mahlungulu SS Volmink J Nutritional interventions for reducing morbidity and mortality in people with HIV.Cochrane Database Syst Rev. 2013; 2 (CD004536.)Google Scholar, 4Visser ME Durao S Sinclair D Irlam JH Siegfried N Micronutrient supplementation in adults with HIV infection.Cochrane Database Syst Rev. 2017; 5 (CD003650.)PubMed Google Scholar In The Lancet HIV, Jane Mallewa and colleagues5Mallewa J Szubert AJ Mugyenyi P et al.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.Lancet HIV. 2018; (published online April 10.)http://dx.doi.org/10.1016/S2352-3018(18)30038-9Summary Full Text Full Text PDF PubMed Scopus (11) Google Scholar report the results of a large multicentre clinical trial in HIV clinics in Kenya, Malawi, Uganda, and Zimbabwe in which the researchers tested whether ready-to-use supplementary food (RUSF) reduced mortality in severely immunocompromised patients with HIV starting ART. The investigators randomly assigned 897 adults and children aged at least 5 years to peanut-based RUSF (1000 kcal per day) and 908 to no-RUSF (control) for 12 weeks and followed up for 48 weeks. In both groups, individuals received supplementation with ready-to-use therapeutic food only when severely malnourished (BMI <16–18 kg/m2 or BMI-for-age Z scores <–3 for children). At 24 weeks, there was no effect of the intervention on the primary outcome of mortality (hazard ratio 1·05, 95% CI 0·79–1·40, log-rank p=0·75). However, the RUSF group had greater gains than the control group of weight, BMI, and mid-upper-arm circumference. These findings echo those from three previous large trials: NUSTART, a trial in Tanzania and Zambia that showed vitamin and mineral supplementation had no effect on mortality at 12 weeks after ART initiation, but was associated with an increase in CD4 cell counts;6Team NS Filteau S PrayGod G et al.Effects on mortality of a nutritional intervention for malnourished HIV-infected adults referred for antiretroviral therapy: a randomised controlled trial.BMC Med. 2015; 13: 17Crossref PubMed Scopus (29) Google Scholar a Malawian trial testing 14 weeks of RUSF versus a corn and soy blend for undernourished patients starting ART, which led to increased weight and lean mass but had no effect on mortality;7Ndekha MJ van Oosterhout JJ Zijlstra EE Manary M Saloojee H Manary MJ Supplementary feeding with either ready-to-use fortified spread or corn-soy blend in wasted adults starting antiretroviral therapy in Malawi: randomised, investigator blinded, controlled trial.BMJ. 2009; 338: b1867Crossref PubMed Scopus (81) Google Scholar and a trial of a high-dose multivitamin supplement for 24 months in patients starting ART in Tanzania, which showed no effect on disease progression or mortality.8Isanaka S Mugusi F Hawkins C et al.Effect of high-dose vs standard-dose multivitamin supplementation at the initiation of HAART on HIV disease progression and mortality in Tanzania: a randomized controlled trial.JAMA. 2012; 308: 1535-1544Crossref PubMed Scopus (41) Google Scholar The absence of any effect on survival with RUSF5Mallewa J Szubert AJ Mugyenyi P et al.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.Lancet HIV. 2018; (published online April 10.)http://dx.doi.org/10.1016/S2352-3018(18)30038-9Summary Full Text Full Text PDF PubMed Scopus (11) Google Scholar could be a result of several factors, including inadequate composition and duration of the intervention. However, we believe that one of the most likely reasons is that nutritional supplementation doesn't necessarily achieve its aim if given during illness. RUSF fortified with micronutrients could theoretically mediate mortality reduction by increasing lean mass and immunity and modulating metabolic functions. Although there was a beneficial effect on lean mass in this trial, this benefit might not have been enough to increase survival and this inadequate lean mass, coupled with the absence of effect on CD4 cell counts could have contributed to the overall absence of effect on mortality. Even with supplemental micronutrients and macronutrients in the intervention group, the acute phase response to infection at the beginning of ART might have changed nutrient metabolism and hormonal controls rendering adequate tissue deposition as well as immunity recovery impossible9PrayGod G Blevins M Woodd S et al.A longitudinal study of systemic inflammation and recovery of lean body mass among malnourished HIV-infected adults starting antiretroviral therapy in Tanzania and Zambia.Eur J Clin Nutr. 2016; 70: 499-504Crossref PubMed Scopus (10) Google Scholar. In patients with tuberculosis, a population with inflammation as severe as that in HIV-infected patients, nutritional supplementation did not lead to full nutritional recovery because of impaired anabolism during treatment.10Macallan DC McNurlan MA Kurpad AV et al.Whole body protein metabolism in human pulmonary tuberculosis and undernutrition: evidence for anabolic block in tuberculosis.Clin Sci (Lond). 1998; 94: 321-331Crossref PubMed Scopus (78) Google Scholar, 11Schwenk A Hodgson L Wright A et al.Nutrient partitioning during treatment of tuberculosis: gain in body fat mass but not in protein mass.Am J Clin Nutr. 2004; 79: 1006-1012Crossref PubMed Scopus (42) Google Scholar In Ethiopia, RUSF with micronutrients at a concentration of one reference nutrient intake, compared with unsupplemented HIV-infected patients, was associated with a considerable increase in lean mass in a subgroup of patients with viral suppression,12Olsen MF Abdissa A Kaestel P et al.Effects of nutritional supplementation for HIV patients starting antiretroviral treatment: randomised controlled trial in Ethiopia.BMJ. 2014; 348: g3187Crossref PubMed Scopus (42) Google Scholar but not in those without viral suppression, suggesting that reduction of inflammation might have contributed to the beneficial effects in the viral-suppressed subgroup. Thus, similar mechanisms might underlie the results of Mallewa and colleagues' trial5Mallewa J Szubert AJ Mugyenyi P et al.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.Lancet HIV. 2018; (published online April 10.)http://dx.doi.org/10.1016/S2352-3018(18)30038-9Summary Full Text Full Text PDF PubMed Scopus (11) Google Scholar and previous trials.6Team NS Filteau S PrayGod G et al.Effects on mortality of a nutritional intervention for malnourished HIV-infected adults referred for antiretroviral therapy: a randomised controlled trial.BMC Med. 2015; 13: 17Crossref PubMed Scopus (29) Google Scholar, 7Ndekha MJ van Oosterhout JJ Zijlstra EE Manary M Saloojee H Manary MJ Supplementary feeding with either ready-to-use fortified spread or corn-soy blend in wasted adults starting antiretroviral therapy in Malawi: randomised, investigator blinded, controlled trial.BMJ. 2009; 338: b1867Crossref PubMed Scopus (81) Google Scholar, 8Isanaka S Mugusi F Hawkins C et al.Effect of high-dose vs standard-dose multivitamin supplementation at the initiation of HAART on HIV disease progression and mortality in Tanzania: a randomized controlled trial.JAMA. 2012; 308: 1535-1544Crossref PubMed Scopus (41) Google Scholar In the light of these findings, should nutritional supplementation continue to be encouraged in patients starting ART? The answer is yes, it is crucial that we continue to encourage nutritional support because it might increase lean mass, hasten physical and functional recovery, and improve work capacity and quality of life7Ndekha MJ van Oosterhout JJ Zijlstra EE Manary M Saloojee H Manary MJ Supplementary feeding with either ready-to-use fortified spread or corn-soy blend in wasted adults starting antiretroviral therapy in Malawi: randomised, investigator blinded, controlled trial.BMJ. 2009; 338: b1867Crossref PubMed Scopus (81) Google Scholar, 12Olsen MF Abdissa A Kaestel P et al.Effects of nutritional supplementation for HIV patients starting antiretroviral treatment: randomised controlled trial in Ethiopia.BMJ. 2014; 348: g3187Crossref PubMed Scopus (42) Google Scholar, 13Tesfaye M Kaestel P Olsen MF et al.The effect of nutritional supplementation on quality of life in people living with HIV: a randomised controlled trial.Trop Med Int Health. 2016; 21: 735-742Crossref PubMed Scopus (5) Google Scholar—important attributes in sustaining livelihoods of HIV-infected patients in resource-limited settings. However, two key questions are which patients should receive supplements and when. The evidence from Mallewa and colleagues' study5Mallewa J Szubert AJ Mugyenyi P et al.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.Lancet HIV. 2018; (published online April 10.)http://dx.doi.org/10.1016/S2352-3018(18)30038-9Summary Full Text Full Text PDF PubMed Scopus (11) Google Scholar suggests that low CD4 cell counts should not be used as an indicator for supplementation, while findings from other studies indicate that low BMI could be used as a marker.7Ndekha MJ van Oosterhout JJ Zijlstra EE Manary M Saloojee H Manary MJ Supplementary feeding with either ready-to-use fortified spread or corn-soy blend in wasted adults starting antiretroviral therapy in Malawi: randomised, investigator blinded, controlled trial.BMJ. 2009; 338: b1867Crossref PubMed Scopus (81) Google Scholar, 12Olsen MF Abdissa A Kaestel P et al.Effects of nutritional supplementation for HIV patients starting antiretroviral treatment: randomised controlled trial in Ethiopia.BMJ. 2014; 348: g3187Crossref PubMed Scopus (42) Google Scholar Future studies should investigate the appropriate timing for initiating nutritional support in HIV-infected patients when inflammation has reduced, to help provide a scientific basis for further trials of nutritional interventions in improving health of HIV-infected patients. HF reports research grants from Arla Food for Health and Nutriset. GP and SF declare no competing interests. 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 trialIn 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. Full-Text PDF Open Access