Patients starting antiretroviral therapy (ART) for acquired immunodeficiency syndrome (AIDS) in sub-Saharan Africa have high rates of mortality in the initial weeks of treatment. We assessed the association of serum phosphate with early mortality among HIV-infected adults with severe malnutrition and/or advanced immunosuppression.
An observational cohort of 142 HIV-infected adults initiating ART in Lusaka, Zambia with body mass index (BMI) <16 kg/m2 or CD4+ lymphocyte count <50 cells/µL, or both, was followed prospectively during the first 12 weeks of ART. Detailed health and dietary intake history, review of systems, physical examination, serum metabolic panel including phosphate, and serum ferritin and high-sensitivity C-reactive protein (hsCRP) were monitored. The primary outcome was mortality. Baseline serum phosphate was a significant predictor of mortality; participants alive at 12 weeks had a median value of 1.30 mmol/L (interquartile range [IQR]: 1.04, 1.43), compared to 1.06 mmol/L (IQR: 0.89, 1.27) among those who died (p<0.01). Each 0.1 mmol/L increase in baseline phosphate was associated with an incremental decrease in mortality (AHR 0.83; 95% CI 0.72 to 0.95). The association was independent of other metabolic parameters and known risk factors for early ART-associated mortality in sub-Saharan Africa. While participant attrition represented a limitation, it was consistent with local program experience.
Low serum phosphate at ART initiation was an independent predictor of early mortality among HIV patients starting ART with severe malnutrition or advanced immunosuppression. This may represent a physiologic phenomenon similar to refeeding syndrome, and may lead to therapeutic interventions that could reduce mortality.
Citation: Heimburger DC, Koethe JR, Nyirenda C, Bosire C, Chiasera JM, Blevins M, et al. (2010) Serum Phosphate Predicts Early Mortality in Adults Starting Antiretroviral Therapy in Lusaka, Zambia: A Prospective Cohort Study. PLoS ONE 5(5): e10687. https://doi.org/10.1371/journal.pone.0010687
Editor: Robert J. Wilkinson, Institute of Infectious Diseases and Molecular Medicine, South Africa
Received: February 21, 2010; Accepted: April 19, 2010; Published: May 18, 2010
Copyright: © 2010 Heimburger et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Funding: This project was supported by Award Number R21 AI076430 from the National Institute of Allergy and Infectious Diseases, US National Institutes of Health. The study was also supported by the University of Alabama at Birmingham Center for AIDS Research; the Fogarty International Clinical Research Scholars Program; and the Fulbright Scholars Program, United States Department of State. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Competing interests: The authors have declared that no competing interests exist.
Access to antiretroviral therapy (ART) for acquired immunodeficiency syndrome (AIDS) in sub-Saharan Africa has expanded rapidly since 2003, but mortality, especially in the first month after initiating treatment, remains high , , . The etiology is likely multifactorial, but several analyses from the region have identified low body mass index (BMI) and low CD4+ lymphocyte count as powerful predictors of death shortly after starting ART , , , .
HIV-associated wasting, defined as a 10% or greater decrease from usual body weight, with concomitant chronic diarrhea or chronic weakness and fever, was recognized as a significant prognostic factor in HIV infection early in the epidemic , . In areas where food is scarce, wasting may be accelerated by unbalanced or inadequate energy intake, leading to multiple metabolic abnormalities rarely seen in resource-rich settings. Rapid weight loss or prolonged fasting can deplete serum phosphate stores, leading to a state of hypophosphatemia and the potential for refeeding syndrome to develop upon increased nutrient intake . This potentially lethal condition is classically defined by electrolyte and fluid shifts following a reversal from catabolism and fat oxidation to the metabolism of exogenous carbohydrate , and predisposes to cardiovascular, respiratory and neurologic sequelae, among others , . Rapid improvements in appetite and activity level reported by patients starting ART in sub-Saharan Africa, ,  where dietary staples are often high in carbohydrate (e.g., maize meal and green banana) , , could conspire to produce a refeeding-like syndrome, especially in patients with severe wasting.
We hypothesized that metabolic abnormalities at the intersection of advanced HIV disease and malnutrition are transiently exacerbated by the introduction of ART and could explain some of the excess early mortality observed in developing countries. Among these could be the refeeding syndrome or a variant of it. We conducted a prospective cohort study to assess the association of serum phosphate levels with early mortality among HIV-infected individuals with severe malnutrition and/or advanced immunosuppression in Lusaka, Zambia.
Materials and Methods
This study enrolled HIV-infected adults initiating ART in a public sector primary care clinic located in the Chawama neighborhood of Lusaka, Zambia. Chawama is a high-density residential area with an estimated population of 56,300 in 2000 . The neighborhood encompasses a range of housing, from planned developments of modern units connected to municipal electricity, water, and sewer systems to crowded, unplanned developments of mud or concrete block structures without electrification. The ART program at Chawama clinic began in March 2006 as part of the Zambian national program for HIV care and treatment , . When our study enrollment began in November 2006, 1539 patients were enrolled in care at Chawama clinic and 874 were receiving ART.
The primary study endpoint was all-cause mortality in the first 12 weeks of ART. Baseline phosphate concentration was the main exposure variable. Serum phosphate, dietary intake, and calculated energy intake at one week were secondary outcomes, in addition to receipt of phosphate supplementation at any time during the study.
Individuals were eligible for the study if they qualified for ART according to national guidelines in place at the time (i.e., WHO stage 4 disease, a CD4+ lymphocyte count <200 cells/µL, or WHO stage 3 disease and a CD4+ lymphocyte count <350 cells/µL) and were intending to start therapy the same day; had a BMI<16 kg/m2 or a CD4+ lymphocyte count <50 cells/µL; intended to remain in the area for the duration of study; agreed to adhere to the additional study visits and laboratory testing requirements; and agreed to be contacted in the event of a missed study visit.
Study design and procedures
Individuals who met the study eligibility criteria and provided written informed consent were enrolled on the day of ART initiation. At each study visit, participants were evaluated by a research nurse and a clinical officer (similar to a physician assistant in the US and Europe), and additional evaluation was performed by a supervising physician as needed. The initial visit included a detailed health and 24-hour dietary intake history, review of systems, physical examination, and laboratory testing (serum metabolic panel including phosphate, and serum ferritin and high-sensitivity C-reactive protein (hsCRP)). The first-line ART regimen was selected from the national program formulary: a non-nucleoside reverse transcriptase inhibitor (NNRTI; efavirenz [EFV] or nevirapine [NVP]), in combination with two nucleoside reverse transcriptase inhibitors (NRTIs; lamivudine [3TC] with either zidovudine [ZDV] or stavudine [d4T]). In July 2007, tenofovir with emtricitabine (TDF/FTC) was introduced as the first line NRTI combination by the national program, and study participants enrolled after this time received the new agents . Patients on treatment prior to July 2007 remained on the original regimen, except in cases of treatment failure or toxicity.
Subsequent study visits occurred after 1, 2, 4, 8, and 12 weeks of ART. At each visit, the symptom assessment, physical examination, and metabolic panel were repeated; 24-hour dietary intake recall was repeated after 1, 4, and 12 weeks. Nutrient intake was computed using Nutrition Data System for Research (NDS-R®, Minneapolis, Minnesota, USA; www.ncc.umn.edu). Using the 2005 Zambian Nutrition Commission composition data , we matched consumed foods to the NDS-R database food and nutrient content and added recipes of frequently consumed foods to the database. Zambian foods not in the database were substituted with similar foods in the database using recommended tolerance guidelines.
When deficiencies of phosphate were detected, we intervened according to a predetermined algorithm based on serum level. Participants whose levels were 0.65–0.86 mmol/L were counseled to increase their intake of phosphorus-containing foods and provided a World Food Programme macronutrient supplement ration; those whose levels were 0.5–0.64 mmol/L also received oral phosphate supplementation, typically in 7-day allotments, while those with levels <0.5 mmol/L were additionally treated with intravenous phosphate supplementation. Intervention typically occurred at least 7 days after the serum collection due to time required for assay completion and reporting of results to the study clinic.
If a participant missed a study visit, study staff first attempted to contact the individual or a designated representative by mobile phone. If the participant could not be contacted, community outreach teams attempted to locate the patient or a relative using housing locator forms completed at enrollment in HIV care . If the participant could not be located or credible information on vital status could not be obtained from relatives or the community, the participant was classified as lost to follow-up.
The study protocol and informed consent documents were approved by the University of Zambia Research Ethics Committee (Lusaka, Zambia), and the Institutional Review Boards at the University of Alabama at Birmingham (Birmingham, Alabama, USA) and Vanderbilt University (Nashville, Tennessee, USA).
CD4+ lymphocyte counts were performed using a Beckman Coulter Epics XL-MCL flow cytometer (Beckman Coulter, Inc., Fullerton, CA, USA), and hemogram or complete blood count with differential using a Horiba ABX Pentra 80 (Horiba ABX Diagnostics Inc., Montpellier, France). Routine and study-specific chemistry assays were measured using a Roche COBAS Integra 400+ (Roche Diagnostics, Basel, Switzerland) or a Pointe 180 Chemistry Analyzer (Pointe Scientific, Canton, MI, USA).
We compared differences between survivors and non-survivors with the Wilcoxon rank sum test for continuous variables and the chi-square test for categorical variables. We used Cox proportional hazards regression to determine whether baseline phosphate concentration was associated with mortality and adjusted for potential confounders: sex, age, and baseline hemoglobin , . We modeled the relationship between the log-hazard of death and baseline phosphate by first assuming linearity (primary analysis) and then relaxing this assumption using restricted cubic splines with 3 knots. Linearity was assessed using a likelihood ratio test. In the primary analysis, a participant was censored at the last study visit date if vital status at 12 weeks was unknown (i.e., lost to follow-up). A second multivariable regression modeled the relationship between time to death or loss to follow-up and the same predictors.
We accounted for missing values of baseline variables with multiple imputation techniques . In multiple imputation, known baseline participant characteristics are used to predict a series of plausible values for those that are missing. We repeated this process 25 times and performed Cox proportional hazard regression on each imputed data set, producing multiple analysis results. We report the average estimates from these multiple calculations. R-software 2.9.2 (www.r-project.org) was used for data analyses.
Between 6 November 2006 and 12 November 2007, 142 participants were enrolled. Figure 1 describes the study visit schedule and the status of the cohort at each visit. Thirty-two (23%) participants met only the BMI criterion for participation, 83 (58%) met only the CD4+ lymphocyte criterion, and 27 (19%) met both. Twenty-five participants died over the 12-week follow-up period (mortality rate 87.4 per 100 person-years of follow-up); 10 (40%) participants died within four weeks of starting ART, although none died in the first week. Thirty-three participants (23%) were lost to follow-up; the median follow-up time for those lost was 58 days (interquartile range [IQR]: 45, 71).
Table 1 shows the baseline demographics of the cohort. Participants were predominantly female (61%), consistent with trends seen in the Lusaka HIV care program . The median CD4+ lymphocyte count (34 cells/µL) and BMI (16.4 kg/m2) were low, with narrow IQRs. There were no clinically meaningful differences between sexes in BMI, CD4+ lymphocyte count, hemoglobin, or baseline median serum chemistries (data not shown). First-line ART regimens differed significantly between the sexes: 25% of males received efavirenz-containing regimens compared to 15% of females, while 47% of males received zidovudine-containing regimens compared to 18% of females (p<0.01).
We found no significant differences in baseline demographic and medical descriptors, or serum chemistries, between participants alive at 12 weeks versus those lost to follow-up, with the exception of age (Table 2). We also compared participants lost to follow-up with those not lost to follow-up (i.e., known to be alive or dead at 12 weeks) and found no significant differences in baseline descriptors or serum chemistries, with the exception of age (30 versus 34 years; p<0.01) and serum glucose (3.6 versus 4.0 mmol/L; p = 0.03 [data not shown]).
Baseline serum phosphate was significantly higher among participants alive at 12 weeks (median 1.30 mmol/L; IQR: 1.04, 1.43), compared to those who died (median 1.06 mmol/L; IQR: 0.89, 1.27; p<0.01). Other measured electrolytes were not significantly associated with mortality (Table 2). Overall, 44 (31%) participants had phosphate levels <0.87 mmol/L at some point during the study, and received at least dietary counseling. Seventeen (12%) had levels <0.65 mmol/L at some point, 7 (5%) of which occurred on ≥2 visits despite phosphate supplementation. By week 12, 7 (8%) survivors compared to 5 (20%) deceased participants and 1 (3%) lost participant had received phosphate supplementation orally only (12 persons) or intravenously and orally (1 person) on at least one occasion. One participant met criteria for intravenous supplementation at week 4 (serum phosphate 0.47 mmol/L) but died 8 days later without returning to the clinic. Of those supplemented, 5 (42%) had baseline phosphate levels <0.87 mmol/L; these participants' median (IQR) time to supplementation was 14 (13, 21) days and their median (IQR) duration on supplementation was 7 (7, 7) days. Seven (58%) supplemented participants had baseline phosphate levels ≥0.87 mmol/L but required supplementation after subsequent visits. These participants' median (IQR) time to supplementation was 29 (20.5, 61) days and their median (IQR) duration on supplementation was 6 (6, 7) days. Mortality did not statistically differ by phosphate supplementation (p = 0.20).
At baseline there were no significant differences in appetite or dietary intake of survivors compared to non-survivors (p>0.05). However, after one week of ART, appetite and intakes of carbohydrate and total energy were significantly lower in non-survivors than in survivors (p<0.01).
After adjusting for sex, age, CD4+ lymphocyte count, BMI, and baseline hemoglobin, low baseline serum phosphate was associated with an increased risk of death within 12 weeks of ART initiation (p = 0.008, Table 3). For each 0.1 mmol/L increase in baseline phosphate, the estimated hazard of death decreased 17% (adjusted hazard ratio (AHR) 0.83; 95% CI 0.72 to 0.95). BMI, CD4+ lymphocyte count, and hemoglobin were not significant predictors of mortality in this model. In secondary analyses that adjusted for significant variables in Table 2 (i.e., albumin, ferritin, and hsCRP) baseline phosphate remained a significant predictor of mortality (p<0.05; data not shown).
There was insufficient evidence to conclude that the relationship between baseline serum phosphate and the log-hazard of death was non-linear (p = 0.27), although baseline phosphate remained a good predictor of mortality in secondary analyses that relaxed the linearity assumption (p = 0.05; data not shown). Baseline phosphate was not associated with an increased risk of death or loss to follow-up (AHR = 0.98 compared to patients who were active and alive, 95% CI 0.90 to 1.06). While the absolute phosphate change from baseline to week one trended toward statistical significance (p = 0.07), the percentage decrease (14.9% [alive] versus 9.0% [deceased]) did not (p = 0.21). Additionally, median week one phosphate values did not differ significantly between alive (1.06) and subsequently deceased (1.07) participants.
In this observational cohort of HIV-infected persons with severe malnutrition, advanced immunosuppression, or both, a low serum phosphate at ART initiation predicted lower survival probability at 12 weeks. The increased hazard of death conferred by low serum phosphate was independent of other metabolic parameters, hsCRP, and known risk factors for early ART-associated mortality in sub-Saharan Africa, including low BMI, CD4+ lymphocyte count and hemoglobin.
Our findings may represent a variant of the refeeding syndrome associated with advanced HIV disease, in which low pre-ART serum phosphate is insufficient to maintain homeostasis in response to metabolic changes accompanying treatment initiation. The increased appetite and capacity for physical activity often reported by patients starting ART could reflect a burst of phosphate-dependent cellular respiration and ATP generation in response to reduced systemic inflammation and HIV-1 viral replication , . This is but one speculative hypothesis for our findings, and further research into the metabolic consequences of ART in advanced HIV infection is warranted. The lower appetite and dietary intake among non-survivors after one week of ART may indicate overall worsening of their condition and suggests that the phosphate-mortality interaction did not strictly represent refeeding.
The lack of association between week one phosphate and subsequent mortality suggests that acute electrolyte derangements were not a proximate cause of death in most instances. However, 10 deaths (40%) occurred in the second through fourth weeks of ART. This timing is consistent with reports of refeeding syndrome deaths among starving prisoners liberated from internment after World War II , , but it could also be consistent with immune reconstitution inflammatory syndrome (IRIS). At least one study participant exhibited findings consistent with classic refeeding syndrome: a 34-year-old male with severe hypophosphatemia developed anasarca after 6 weeks of ART despite oral and intravenous phosphorus supplementation. It resolved after 2 weeks of further supplementation and administration of a low-dose diuretic .
Baseline serum phosphate retained significance as a predictor of survival independent of renal function, acid-base status, albumin, ferritin and hsCRP. Significantly higher baseline levels of ferritin and hsCRP, both markers of systemic inflammation, among non-survivors may indicate a greater burden of undiagnosed opportunistic infections or an exaggerated response to HIV-1 viremia. The presence or absence of occult co-infections could not be adequately explored in this study because of limited diagnostic capabilities in the study setting, which was representative of public-sector clinics in Lusaka Zambia. Further prospective studies to characterize the etiology and epidemiology of occult infections in severely immunocompromised HIV-infected adults using advanced diagnostic modalities are needed to explore this.
Thirteen participants received phosphate supplementation because of low serum levels. While supplementation was not significantly associated with survival, we cannot conclude that it had no effect without an appropriate comparison group. Rather, because we were ethically obligated to provide supplementation to all participants with low phosphate levels, supplementation was essentially a marker for hypophosphatemia. To the extent that supplementation may have reduced mortality, it would bias our results toward the null hypothesis of observing no mortality difference between those with low serum phosphate and those with normal phosphate.
The observational design of our study prevents us from concluding a causal relationship between low serum phosphate and mortality. The study was also limited by participant attrition, but the number of lost participants was not atypical. The observed loss rates are similar to reports from other programmatic cohorts in sub-Saharan Africa, and previous analyses of the Zambian ART program have reported a similar lost to follow-up rate prior to 6 months among low BMI patients , . Except for slight differences in median age and serum glucose, those who were lost to follow-up did not differ substantially when compared to either survivors or all participants not lost to follow-up.
Relative homogeneity of known markers of advanced HIV among study participants, indicated by narrow interquartile ranges (Table 1), likely contributed to the finding that BMI, CD4+ count, and hemoglobin were not significant predictors of mortality. The independence of baseline serum phosphate as a predictor of mortality is bolstered by our study inclusion criteria, which limited the potential impact of known confounders.
In this observational cohort study, serum phosphate at ART initiation was an independent predictor of mortality among patients with advanced HIV disease. This may represent a physiologic phenomenon similar to the refeeding syndrome. A randomized prospective trial of phosphate repletion among patients with low BMIs or low serum levels, either through electrolyte or nutritional supplementation, is warranted to address causality and explore the therapeutic implications of these findings.
The authors wish to acknowledge and thank Jiatao Ye, Mary Lauren Neel, Laura Nahm, and Megan Brennard (University of Alabama at Birmingham) for their contributions to data management, and Ronald Cantrell and Andrew Westfall (Centre for Infectious Disease Research in Zambia) for their assistance in data acquisition. The content of this article is solely the responsibility of the authors and does not necessarily represent the official views of the National Institute of Allergy and Infectious Diseases or the National Institutes of Health.
Conceived and designed the experiments: DCH CB DP IZ EKK. Performed the experiments: DCH CN CB JMC DP IZ ACT BHC JSAS EKK. Analyzed the data: DCH JRK CB MB AJM BES EKK. Contributed reagents/materials/analysis tools: DCH JMC. Wrote the paper: DCH JRK CN CB JMC MB AJM BES DP IZ ACT BHC JSAS EKK.
- 1. Braitstein P, Brinkhof MW, Dabis F, Schechter M, Boulle A, et al. (2006) Mortality of HIV-1-infected patients in the first year of antiretroviral therapy: comparison between low-income and high-income countries. Lancet 367: 817–824.P. BraitsteinMW BrinkhofF. DabisM. SchechterA. Boulle2006Mortality of HIV-1-infected patients in the first year of antiretroviral therapy: comparison between low-income and high-income countries.Lancet367817824
- 2. UNAIDS (2008. Available at:http://www.unaids.org/en/KnowledgeCentre/HIVData/GlobalReport/2008/2008_Global_report.asp) Report on the global AIDS epidemic. Geneva: Joint United Nations Programme on HIV/AIDS. Accessed April 8, 2010. UNAIDS (2008. Available at:http://www.unaids.org/en/KnowledgeCentre/HIVData/GlobalReport/2008/2008_Global_report.asp) Report on the global AIDS epidemic. Geneva: Joint United Nations Programme on HIV/AIDS. Accessed April 8, 2010.
- 3. Stringer JS, Zulu I, Levy J, Stringer EM, Mwango A, et al. (2006) Rapid scale-up of antiretroviral therapy at primary care sites in Zambia: feasibility and early outcomes. JAMA 296: 782–793.JS StringerI. ZuluJ. LevyEM StringerA. Mwango2006Rapid scale-up of antiretroviral therapy at primary care sites in Zambia: feasibility and early outcomes.JAMA296782793
- 4. Lawn SD, Myer L, Orrell C, Bekker LG, Wood R (2005) Early mortality among adults accessing a community-based antiretroviral service in South Africa: implications for programme design. AIDS 19: 2141–2148.SD LawnL. MyerC. OrrellLG BekkerR. Wood2005Early mortality among adults accessing a community-based antiretroviral service in South Africa: implications for programme design.AIDS1921412148
- 5. Jerene D, Endale A, Hailu Y, Lindtjorn B (2006) Predictors of early death in a cohort of Ethiopian patients treated with HAART. BMC Infect Dis 6: 136.D. JereneA. EndaleY. HailuB. Lindtjorn2006Predictors of early death in a cohort of Ethiopian patients treated with HAART.BMC Infect Dis6136
- 6. Johannessen A, Naman E, Ngowi BJ, Sandvik L, Matee MI, et al. (2008) Predictors of mortality in HIV-infected patients starting antiretroviral therapy in a rural hospital in Tanzania. BMC Infect Dis 8: 52.A. JohannessenE. NamanBJ NgowiL. SandvikMI Matee2008Predictors of mortality in HIV-infected patients starting antiretroviral therapy in a rural hospital in Tanzania.BMC Infect Dis852
- 7. Zachariah R, Fitzgerald M, Massaquoi M, Pasulani O, Arnould L, et al. (2006) Risk factors for high early mortality in patients on antiretroviral treatment in a rural district of Malawi. AIDS 20: 2355–2360.R. ZachariahM. FitzgeraldM. MassaquoiO. PasulaniL. Arnould2006Risk factors for high early mortality in patients on antiretroviral treatment in a rural district of Malawi.AIDS2023552360
- 8. Centers for Disease Control and Prevention (1987) Revision of the CDC surveillance case definition for acquired immunodeficiency syndrome. Council of State and Territorial Epidemiologists; AIDS Program, Center for Infectious Diseases. MMWR Morb Mortal Wkly Rep 36: Suppl 11S–15S.Centers for Disease Control and Prevention1987Revision of the CDC surveillance case definition for acquired immunodeficiency syndrome. Council of State and Territorial Epidemiologists; AIDS Program, Center for Infectious Diseases.MMWR Morb Mortal Wkly Rep36Suppl 11S15S
- 9. Kotler DP, Tierney AR, Wang J, Pierson RN Jr (1989) Magnitude of body-cell-mass depletion and the timing of death from wasting in AIDS. Am J Clin Nutr 50: 444–447.DP KotlerAR TierneyJ. WangRN Pierson Jr1989Magnitude of body-cell-mass depletion and the timing of death from wasting in AIDS.Am J Clin Nutr50444447
- 10. Heimburger D, Ard J, editors. (2006) Handbook of Clinical Nutrition. Philadelphia: Mosby Elsevier. D. HeimburgerJ. Ard2006Handbook of Clinical Nutrition.PhiladelphiaMosby Elsevier
- 11. Knochel JP (1977) The pathophysiology and clinical characteristics of severe hypophosphatemia. Arch Intern Med 137: 203–220.JP Knochel1977The pathophysiology and clinical characteristics of severe hypophosphatemia.Arch Intern Med137203220
- 12. Kohn MR, Golden NH, Shenker IR (1998) Cardiac arrest and delirium: presentations of the refeeding syndrome in severely malnourished adolescents with anorexia nervosa. J Adolesc Health 22: 239–243.MR KohnNH GoldenIR Shenker1998Cardiac arrest and delirium: presentations of the refeeding syndrome in severely malnourished adolescents with anorexia nervosa.J Adolesc Health22239243
- 13. Boateng AA, Sriram K, Meguid MM, Crook MA (2010) Refeeding syndrome: Treatment considerations based on collective analysis of literature case reports. Nutrition 26: 156–167.AA BoatengK. SriramMM MeguidMA Crook2010Refeeding syndrome: Treatment considerations based on collective analysis of literature case reports.Nutrition26156167
- 14. Au JT, Kayitenkore K, Shutes E, Karita E, Peters PJ, et al. (2006) Access to adequate nutrition is a major potential obstacle to antiretroviral adherence among HIV-infected individuals in Rwanda. AIDS 20: 2116–2118.JT AuK. KayitenkoreE. ShutesE. KaritaPJ Peters2006Access to adequate nutrition is a major potential obstacle to antiretroviral adherence among HIV-infected individuals in Rwanda.AIDS2021162118
- 15. Hardon AP, Akurut D, Comoro C, Ekezie C, Irunde HF, et al. (2007) Hunger, waiting time and transport costs: time to confront challenges to ART adherence in Africa. AIDS Care 19: 658–665.AP HardonD. AkurutC. ComoroC. EkezieHF Irunde2007Hunger, waiting time and transport costs: time to confront challenges to ART adherence in Africa.AIDS Care19658665
- 16. Muranga FI, Sampath H, Marlett JA, Ntambi JM (2007) Impact of processing technique on the apparent bioavailability of cooking banana (matooke) starch. African Journal of Biochemistry Research 1: 72–77.FI MurangaH. SampathJA MarlettJM Ntambi2007Impact of processing technique on the apparent bioavailability of cooking banana (matooke) starch.African Journal of Biochemistry Research17277
- 17. United States Agency for International Development Food Commodity Fact Sheets, Updated January 2006. Available at http://www.usaid.gov/our_work/humanitarian_assistance/ffp/crg/sec2.htm. Accessed April 8, 2010. United States Agency for International Development Food Commodity Fact Sheets, Updated January 2006. Available at http://www.usaid.gov/our_work/humanitarian_assistance/ffp/crg/sec2.htm. Accessed April 8, 2010.
- 18. Central Statistical Office Zambia (2002) Preliminary Report - Census 2000. Central Statistical Office Zambia2002Preliminary Report - Census 2000.Central Statistical Office, Lusaka, Zambia. Central Statistical Office, Lusaka, Zambia.
- 19. Bolton-Moore C, Mubiana-Mbewe M, Cantrell RA, Chintu N, Stringer EM, et al. (2007) Clinical outcomes and CD4 cell response in children receiving antiretroviral therapy at primary health care facilities in Zambia. JAMA 298: 1888–1899.C. Bolton-MooreM. Mubiana-MbeweRA CantrellN. ChintuEM Stringer2007Clinical outcomes and CD4 cell response in children receiving antiretroviral therapy at primary health care facilities in Zambia.JAMA29818881899
- 20. Chi BH, Mwango A, Giganti M, Mulenga LB, Tambatamba-Chapula B, et al. (2009) Early Clinical and Programmatic Outcomes with Tenofovir-Based Antiretroviral Therapy in Zambia. J Acquir Immune Defic Syndr, Epub ahead of print Dec 2009.BH ChiA. MwangoM. GigantiLB MulengaB. Tambatamba-Chapula2009Early Clinical and Programmatic Outcomes with Tenofovir-Based Antiretroviral Therapy in Zambia.J Acquir Immune Defic Syndr, Epub ahead of print Dec2009
- 21. Nyirenda DB, Musukwa M, Mugode RH, Shindano J (2005) Revised food composition table of Zambia. Zambia Ministry of Health. DB NyirendaM. MusukwaRH MugodeJ. Shindano2005Revised food composition table of Zambia.Zambia Ministry of Health
- 22. Krebs DW, Chi BH, Mulenga Y, Morris M, Cantrell RA, et al. (2008) Community-based follow-up for late patients enrolled in a district-wide programme for antiretroviral therapy in Lusaka, Zambia. AIDS Care 20: 311–317.DW KrebsBH ChiY. MulengaM. MorrisRA Cantrell2008Community-based follow-up for late patients enrolled in a district-wide programme for antiretroviral therapy in Lusaka, Zambia.AIDS Care20311317
- 23. Marazzi MC, Liotta G, Germano P, Guidotti G, Altan AD, et al. (2008) Excessive early mortality in the first year of treatment in HIV type 1-infected patients initiating antiretroviral therapy in resource-limited settings. AIDS Res Hum Retroviruses 24: 555–560.MC MarazziG. LiottaP. GermanoG. GuidottiAD Altan2008Excessive early mortality in the first year of treatment in HIV type 1-infected patients initiating antiretroviral therapy in resource-limited settings.AIDS Res Hum Retroviruses24555560
- 24. Lawn SD, Harries AD, Anglaret X, Myer L, Wood R (2008) Early mortality among adults accessing antiretroviral treatment programmes in sub-Saharan Africa. AIDS 22: 1897–1908.SD LawnAD HarriesX. AnglaretL. MyerR. Wood2008Early mortality among adults accessing antiretroviral treatment programmes in sub-Saharan Africa.AIDS2218971908
- 25. Little RJA, Rubin DB (1987) Statistical Analysis with Missing Data. New York: Wiley. RJA LittleDB Rubin1987Statistical Analysis with Missing Data.New YorkWiley
- 26. Brozek J, Chapman CB, Keys A (1948) Drastic food restriction; effect on cardiovascular dynamics in normotensive and hypertensive conditions. J Am Med Assoc 137: 1569–1574.J. BrozekCB ChapmanA. Keys1948Drastic food restriction; effect on cardiovascular dynamics in normotensive and hypertensive conditions.J Am Med Assoc13715691574
- 27. Schnitker MA, Mattman PE, Bliss TL (1951) A clinical study of malnutrition in Japanese prisoners of war. Ann Intern Med 35: 69–96.MA SchnitkerPE MattmanTL Bliss1951A clinical study of malnutrition in Japanese prisoners of war.Ann Intern Med356996
- 28. Nyirenda C ZI, Kabagambe EK, Bagchi S, Potter D, Bosire C, Krishnasami Z, Heimburger DC (2009) Acute hypophosphatemia and hypokalemia in a patient starting antiretroviral therapy in Zambia – a new context for refeeding syndrome? ZI Nyirenda CEK KabagambeS. BagchiD. PotterC. BosireZ. KrishnasamiDC Heimburger2009Acute hypophosphatemia and hypokalemia in a patient starting antiretroviral therapy in Zambia – a new context for refeeding syndrome?A case report. BMJ Case Reports, 3 April 2009. A case report. BMJ Case Reports, 3 April 2009.
- 29. Rosen S, Fox MP, Gill CJ (2007) Patient retention in antiretroviral therapy programs in sub-Saharan Africa: a systematic review. PLoS Med 4: e298.S. RosenMP FoxCJ Gill2007Patient retention in antiretroviral therapy programs in sub-Saharan Africa: a systematic review.PLoS Med4e298
- 30. Koethe JR, Lukusa A, Giganti MJ, Chi BH, Nyirenda CK, et al. (2010) Association between weight gain and clinical outcomes among malnourished adults initiating antiretroviral therapy in Lusaka, Zambia. J Acquir Immune Defic Syndr 53: 507–513.JR KoetheA. LukusaMJ GigantiBH ChiCK Nyirenda2010Association between weight gain and clinical outcomes among malnourished adults initiating antiretroviral therapy in Lusaka, Zambia.J Acquir Immune Defic Syndr53507513
- 31. Fauci AS, Braunwald E, Kasper DL, Hauser SL, Longo DL, et al., editors. (2008) Harrison's Principles of Internal Medicine (17th ed). New York: McGraw-Hill Medical. AS FauciE. BraunwaldDL KasperSL HauserDL Longo2008Harrison's Principles of Internal Medicine (17th ed).New YorkMcGraw-Hill Medical