Effects on mortality of a nutritional intervention for malnourished HIV-infected adults referred for antiretroviral therapy: a randomised controlled trial

BMC Medicine

Paul Kelly²  Henrik Friis⁷  Douglas C Heimburger¹  Daniel Yilma³  Natasha Larke⁴  Daniela Manno⁴  Jeremiah Kidola⁵  Denna Michael⁵  John Changalucha⁵  John R Koethe¹  Joshua Siame⁶  Molly Chisenga⁶  Andrea M Rehman⁴  Susannah Woodd⁴  Lackson Kasonka⁶  George PrayGod⁵  Suzanne Filteau⁴ 

[1] Vanderbilt Institute of Global Health, Vanderbilt University School of Medicine, 2525 West End Avenue, Nashville, TN, USA;Barts & The London School of Medicine, Queen Mary University of London, 4 Newark Street, London, UK;Jimma University Specialised Hospital, Jimma, Ethiopia;Faculty of Epidemiology and Population Health, London School of Hygiene and Tropical Medicine, Keppel Street, London WC1E 7HT, UK;Mwanza Research Centre, National Institute for Medical Research, Isamilo road, Mwanza, Tanzania;University Teaching Hospital, Nationalist Road, Lusaka, Zambia;University of Copenhagen, Copenhagen, Rolighedsvej 30, Frederiksberg, DK-1958, Denmark

关键词: Micronutrients;    Malnutrition;    HIV;    Electrolytes;    Body mass index;    Antiretroviral therapy;   

Others  :  1109730
DOI  :  10.1186/s12916-014-0253-8

 received in 2014-10-10, accepted in 2014-12-10,  发布年份 2015

【 摘 要 】

Background

Malnourished HIV-infected African adults are at high risk of early mortality after starting antiretroviral therapy (ART). We hypothesized that short-course, high-dose vitamin and mineral supplementation in lipid nutritional supplements would decrease mortality.

Methods

The study was an individually-randomised phase III trial conducted in ART clinics in Mwanza, Tanzania, and Lusaka, Zambia. Participants were 1,815 ART-naïve non-pregnant adults with body mass index (BMI) <18.5 kg/m² who were referred for ART based on CD4 count <350 cells/μL or WHO stage 3 or 4 disease. The intervention was a lipid-based nutritional supplement either without (LNS) or with additional vitamins and minerals (LNS-VM), beginning prior to ART initiation; supplement amounts were 30 g/day (150 kcal) from recruitment until 2 weeks after starting ART and 250 g/day (1,400 kcal) from weeks 2 to 6 after starting ART. The primary outcome was mortality between recruitment and 12 weeks of ART. Secondary outcomes were serious adverse events (SAEs) and abnormal electrolytes throughout, and BMI and CD4 count at 12 weeks ART.

Results

Follow-up for the primary outcome was 91%. Median adherence was 66%. There were 181 deaths in the LNS group (83.7/100 person-years) and 184 (82.6/100 person-years) in the LNS-VM group (rate ratio (RR), 0.99; 95% CI, 0.80–1.21; P = 0.89). The intervention did not affect SAEs or BMI, but decreased the incidence of low serum phosphate (RR, 0.73; 95% CI, 0.55–0.97; P = 0.03) and increased the incidence of high serum potassium (RR, 1.60; 95% CI, 1.19–2.15; P = 0.002) and phosphate (RR, 1.23; 95% CI, 1.10–1.37; P <0.001). Mean CD4 count at 12 weeks post-ART was 25 cells/μL (95% CI, 4–46) higher in the LNS-VM compared to the LNS arm (P = 0.02).

Conclusions

High-dose vitamin and mineral supplementation in LNS, compared to LNS alone, did not decrease mortality or clinical SAEs in malnourished African adults initiating ART, but improved CD4 count. The higher frequency of elevated serum potassium and phosphate levels suggests high-level electrolyte supplementation for all patients is inadvisable but the addition of micronutrient supplements to ART may provide clinical benefits in these patients.

Trial registration

PACTR201106000300631 webcite, registered on 1^st June 2011.

【 授权许可】

   
2015 Filteau et al.; licensee BioMed Central.

【 图 表 】

Figure 1.

Figure 2.

Figure 3.

【 参考文献 】

• [1]Lawn SD, Harries AD, Anglaret X, Myer L, Wood R: Early mortality among adults accessing antiretroviral treatment programmes in sub-Saharan Africa. AIDS. 2008, 22:1897-908.
• [2]Stringer JS, Zulu I, Levy J, Stringer EM, Mwango A, Chi BH, Mtonga V, Reid S, Cantrell RA, Bulterys M, Saag MS, Marlink RG, Mwainga A, Ellerbrock TV, Sinkala M: Rapid scale-up of antiretroviral therapy at primary care sites in Zambia: feasibility and early outcomes. JAMA. 2006, 296:782-93.
• [3]Koethe JR, Lukusa A, Giganti MJ, Chi BH, Nyirenda CK, Limbada MI, Banda Y, Stringer JS: Association between weight gain and clinical outcomes among malnourished adults initiating antiretroviral therapy in Lusaka. Zambia. J Acquir Immune Defic Syndr. 2010, 53:507-13.
• [4]Liu E, Spiegelman D, Semu H, Hawkins C, Chalamilla G, Aveika A, Nyamsangia S, Mehta S, Mtasiwa D, Fawzi W: Nutritional status and mortality among HIV-infected patients receiving antiretroviral therapy in Tanzania. J Infect Dis. 2011, 204:282-90.
• [5]Hsu J, Pencharz P, Macallan D, Tomkins A: Macronutrients and HIV/AIDS: A Review of Current Evidence. World Health Organization, Geneva; 2005.
• [6]Macallan DC, Noble C, Baldwin C, Foskett M, McManus T, Griffin GE: Prospective analysis of patterns of weight change in stage IV human immunodeficiency virus infection. Am J Clin Nutr. 1993, 58:417-24.
• [7]Ashworth A, Khanum S, Jackson A, Schofield C: Guidelines for the Inpatient Treatment of Severely Malnourished Children. World Health Organization, Geneva; 2003.
• [8]Heimburger DC, Koethe JR, Nyirenda C, Bosire C, Chiasera JM, Blevins M, Munoz AJ, Shepherd BE, Potter D, Zulu I, Chisembele-Taylor A, Chi BH, Stringer JS, Kabagambe EK: Serum phosphate predicts early mortality in adults starting antiretroviral therapy in Lusaka, Zambia: a prospective cohort study. PLoS One. 2010, 5:e10687.
• [9]Koethe JR, Blevins M, Nyirenda C, Kabagambe EK, Shepherd BE, Wester CW, Zulu I, Chiasera JM, Mulenga LB, Mwango A, Heimburger DC: Nutrition and inflammation serum biomarkers are associated with 12-week mortality among malnourished adults initiating antiretroviral therapy in Zambia. J Int AIDS Soc. 2011, 14:19. BioMed Central Full Text
• [10]Prentice A: Iron metabolism, malaria and other infections: what is all the fuss about? J Nutr. 2008, 138:2537-41.
• [11]Collins S, Myatt M, Golden B: Dietary treatment of severe malnutrition in adults. Am J Clin Nutr. 1998, 68:193-9.
• [12]Academy of Science of South Africa: HIV/AIDS, TB and Nutrition. Academy of Science of South Africa, Pretoria, SA; 2007.
• [13]Grobler 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
• [14]Ndekha 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:b1867.
• [15]Ndekha M, van Oosterhout JJ, Saloojee H, Pettifor J, Manary M: Nutritional status of Malawian adults on antiretroviral therapy 1 year after supplementary feeding in the first 3 months of therapy. Trop Med Int Health. 2009, 14:1059-63.
• [16]Olsen MFAA, Kæstel P, Tesfaye M, Yilma D, Girma T, Wells JCK, Ritz C, Mølgaard C, Michaelsen KF, Zerfu D, Brage S, Andersen AB, Friis H: Effects of nutritional supplementation for HIV patients starting antiretroviral treatment: randomised controlled trial in Ethiopia. BMJ. 2014, 348:g3187.
• [17]Kelly P, Katubulushi M, Todd J, Banda R, Yambayamba V, Fwoloshi M, Zulu I, Kafwembe E, Yavwa F, Sanderson IR, Tomkins A: Micronutrient supplementation has limited effects on intestinal infectious disease and mortality in a Zambian population of mixed HIV status: a cluster randomized trial. Am J Clin Nutr. 2008, 88:1010-7.
• [18]Irlam JH, Visser MM, Rollins NN, Siegfried N: Micronutrient supplementation in children and adults with HIV infection. Cochrane Database Syst Rev. 2010., 12
• [19]Gibson R, Kafwembe E, Mwanza S, Gosset L, Bailey K, Mullen A, Baisley K, Filteau S: A micronutrient-fortified food enhances iron and selenium status of Zambian infants but has limited efficacy on zinc. J Nutr. 2011, 141:935-43.
• [20]Gitau R, Makasa M, Kasonka L, Sinkala M, Chintu C, Tomkins A, Filteau S: Maternal micronutrient status and decreased growth of Zambian infants born during and after the maize price increases resulting from the Southern African drought of 2001–2002. Pub Health Nutr. 2005, 8:837-43.
• [21]PrayGod G, Range N, Faurholt-Jepsen D, Jeremiah K, Faurholt-Jepsen M, Aabye MG, Jensen L, Jensen AV, Grewal HM, Magnussen P, Changalucha J, Andersen AB, Friss H: Daily multi-micronutrient supplementation during tuberculosis treatment increases weight and grip strength among HIV-uninfected but not HIV-infected patients in Mwanza. Tanzania. J Nutr. 2011, 141:685-91.
• [22]Marston M, Michael D, Wringe A, Isingo R, Clark BD, Jonas A, Mngara J, Kalongoji S, Mbaga J, Changalucha J, Todd J, Zaba B, Urassa M: The impact of antiretroviral therapy on adult mortality in rural Tanzania. Trop Med Int Health. 2012, 17:e58-65.
• [23]Zambian Central Statistical Office, Tropical Diseases Research Centre, University of Zambia, Macro International Inc.: Zambia Demographic and Health Survey 2007. CSO and Macro International Inc, Calverton, MA; 2009.
• [24]Hebie M, Jungjohann S, Praygod G, Filteau S: Acceptability of different lipid-based nutrient supplements for adults with HIV. Afr J Food Agricul Nutr Devel 2013, 13(1):7254-72.
• [25]Jiamton S, Pepin J, Suttent R, Filteau S, Mahakkanukrauh B, Hanshaoworakul W, Chaisilwattana P, Suthipinittharm P, Shetty P, Jaffar S: A randomized trial of the impact of multiple micronutrient supplementation on mortality among HIV-infected individuals living in Bangkok. AIDS. 2003, 17:2461-9.
• [26]Friis H: Micronutrient interventions and HIV infection: a review of current evidence. Trop Med Int Health. 2006, 11:1849-57.
• [27]Golden M: Proposed nutrient requirements of moderately malnourished populations of children. Food Nutr Bull. 2009, 30:S267-342.
• [28]UK Department of Health: Dietary Reference Values for Food Energy and Nutrients for the UK. Department of Health, London; 1991.
• [29]Lawn SD, Little F, Bekker LG, Kaplan R, Campbel E, Orrell C, Wood R: Changing mortality risk associated with CD4 cell response to antiretroviral therapy in South Africa. AIDS. 2009, 23:335-42.
• [30]US National Institutes of Health Division of AIDS. Division of AIDS Table for Grading the Severity of Adult and Pediatric Adverse Events. 2009. http://rsc.tech-res.com/document/safetyandpharmacovigilance/table_for_grading_severity_of_adult_pediatric_adverse_events.pdf.
• [31]Tietz N: Clinical Guide to Laboratory Tests. 3rd edition. WB Saunders, Philadelphia; 1995.
• [32]Isanaka S, Mugusi F, Hawkins C, Spiegelman D, Okuma J, Aboud S, Guerino C, Fawzi WW: 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, 308:1535-44.
• [33]Schoenfeld D: Partial residuals for the proportional hazards regression model. Biometrika. 1982, 69:239-41.
• [34]Filmer D, Pritchett L: Estimating wealth effects without expenditure data – or tears: an application to educational enrolments in states of India. Demography. 2001, 38:115-32.
• [35]Koethe JR, Limbada MI, Giganti MJ, Nyirenda CK, Mulenga L, Wester CW, Chi BH, Stringer JS: Early immunologic response and subsequent survival among malnourished adults receiving antiretroviral therapy in Urban Zambia. AIDS. 2010, 24:2117-21.