jurnal luar lagi gizi

Delivered by Publishing Technology to IP 93912629 on Sun 11 Oct 2015 004131Copyright (c) Nevin Scrimshaw International Nutrition Foundation All rights reserved

Food and Nutrition Bulletin vol 31 no 4 (supplement) copy 2010 The United Nations University S313

Role of nutrition in HIV infection Review of evidence for more effective programming in resource-limited settings

Abstract

Background HIV infection and malnutrition negatively reinforce each other

Objective For program guidance to review evidence on the relationship of HIV infection and malnutrition in adults in resource-limited settings

Results and conclusions Adequate nutritional status supports immunity and physical performance Weight loss caused by low dietary intake (loss of appetite mouth ulcers food insecurity) malabsorption and altered metabolism is common in HIV infection Regaining weight particularly muscle mass requires antiretroviral therapy (ART) treatment of opportunistic infections consumption of a balanced diet physical activity mitiga-tion of side effects and perhaps appetite stimulants and growth hormone Correcting nutritional status becomes more difficult as infection progresses

Studies document widespread micronutrient deficien-cies among HIV-infected people However supplement composition patient characteristics and treatments vary widely across intervention studies Therefore the World Health Organization (WHO) recommends ensur-ing intake of 1 Recommended Nutrient Intake (RNI) of each required micronutrient which may require taking micronutrient supplements

Few studies have assessed the impact of food supple-ments Because the mortality risk in patients receiving ART increases with lower body mass index (BMI) improving the BMI seems important Whether this requires provision of food supplements depends on the patientrsquos diet and food security It appears that start-ing ART improves BMI and that ready-to-use fortified

spreads and fortified-blended foods further increase BMI (the effect is somewhat less with fortified-blended foods) The studies are too small to assess effects on mortality

Once ART has been established and malnutrition treated the nutritional quality of the diet remains impor-tant also because of ARTrsquos long-term metabolic effects (dyslipidemia insulin resistance obesity) Food insecurity should also be addressed if it prevents adequate energy intake and reduces treatment initiation and adherence (due to the opportunity costs of obtaining treatment and mitigating side effects)

Key words Food insecurity HIV infection mal-nutrition micronutrients resource-limited settings weight loss

Introduction

In 2007 there were an estimated 33 million people living with HIV and sub-Saharan Africa accounted for 67 of all people with HIV and 75 of all AIDS deaths [1] The prevalence of HIV in the sub-Saharan Africa region is 6 [2] Although the number of new infec-tions worldwide has stabilized since 2000 the number of people living with HIV has increased because of HIV treatments that are extending survival [1] Antiretrovi-ral therapy (ART) is becoming more readily available across sub-Saharan Africa but the nutritional situa-tion which was already poor is worsening further for certain vulnerable populations in the face of the global economic crisis [3]

Malnutrition occurs in various forms including undernutrition (low weight short stature micronu-trient deficiencies low birthweight and suboptimal breastfeeding practices) as well as overweight and obesity Overweight or obesity may actually co-occur with micronutrient deficiencies in the same person For HIV and other infections low body weight weight loss micronutrient deficiencies and deficiencies of other nutrients that affect the immune system are

Saskia de Pee and Richard D Semba

Saskia de Pee is affiliated with the World Food Programme Rome and the Friedman School of Nutrition Science and Policy Tufts University Boston Massachusetts USA Rich-ard D Semba is affiliated with the Johns Hopkins University School of Medicine Baltimore Maryland USA

Please direct queries to the corresponding author Saskia de Pee Via Cesare Giulio Viola 6870 Parco dersquoMedici 00148 Rome Italy e-mail depeesaskiagmailcom or Saskiadepeewfporg


S314 S de Pee and R D Semba

all important and will be referred to here as ldquomalnutritionrdquo Malnutrition is widespread with stunting (short stat-ure) affecting 190 million or 32 of all children under 5 years of age in developing countries today In Africa 40 of under-fives are affected As this proportion has not changed much over the last decades many of todayrsquos adults adolescents and school-age children are bearing the lifelong consequences of childhood malnutrition [4] Two bil-lion people or one-third of the world population suffer from micronutrient deficiencies Thus for many people HIV infection comes in addition to some form and degree of malnutrition

Malnutrition especially through its negative effects on the immune system further aggra-vates HIV infection by increasing the risk of oppor-tunistic infections and death In turn HIV-infected persons are at higher risk for malnutrition and certain conditions can magnify the risk such as anorexia dif-ficulty swallowing or painful swallowing malabsorp-tion and diarrhea altered metabolism of nutrients increased utilization of nutrients and greater loss of nutrients [5] Furthermore for people on ART a bal-anced diet and a better nutritional status may enhance the effectiveness of antiretroviral drugs improve adherence to treatment reduce the side effects of medications reduce the complications of opportunistic infections and reduce longer-term metabolic compli-cations of ART use (such as dyslipidemia obesity and insulin resistance) For patients who are malnourished treatment of malnutrition is essential in addition to antiretroviral treatment

In 1999 one of the authors published a review on micronutrients and the pathogenesis of HIV infec-tion with the presentation of a model (fig 1) relat-ing micronutrient malnutrition nutritionally related immunosuppression and HIV infection in a vicious cycle [5] In the last decade considerable progress has been made toward understanding the relationship of nutrition with HIV infection

The purpose of this paper is to reviewraquo Knowledge of the interactions between HIV infec-

tion and nutrition including micronutrients macro-nutrients and weight loss

raquo Evidence for suitable interventions for breaking the vicious cycle between malnutrition and HIV infection including nutrition counseling provision of micronutrients andor food supplements ART and pharmaceutical treatment of opportunistic infectionsThe review focuses on resource-limited settings in

particular sub-Saharan Africa where the food security and nutritional status of the population in general are

already compromised and HIV infection prevalence is high in many areas Aspects relating to food security and livelihoods and to tuberculosis coinfection are dealt with in two other papers in this Supplement [6 7] The scope of this paper has been further limited to HIV infection and malnutrition in adults Each subsection starts with a summary of the main points and then presents the evidence for these points and concludes with comments about the available evidence and remaining uncertainties

HIV infection and nutritionmdashthe interaction

The relationship between infection and nutrition has been known since the early 1900s but the role of nutrition in medical practice and public health has changed over time [8] With advances in antibiotics and pharmaceutical treatment and the improvement of diet and nutrition due to improvements in agriculture and standards of living attention to the role of nutri-tion in developed countries dwindled However the role of nutrition in infection was not forgotten and it truly resurfaced in the 1980s and 1990s when its role in reducing child mortality in developing countries was recognized and emphasized [8 9] Thus the role of nutrition in health and disease is widely acknowledged and underlies the interest in the relationship between nutrition and HIV infection

Research into the relationship between HIV infec-tion and nutrition has mainly focused on the role and impact of micronutrients protein special nutrients such as specific amino acid mixtures and food supple-ments (especially in the case of wasting) Here we will first review the evidence for the relationship between micronutrients and HIV infection We then discuss weight loss and wasting because these lead directly into food supplementation which is one of the main activi-ties of the World Food Programme (WFP) Weight

FIG 1 Vicious cycle of micronutrient deficiencies and HIV pathogenesis (from Semba and Tang [5])

Insufficient dietary intakeMalabsorption and diarrhea

Impaired storage and altered metabolism

Micronutrientdeficiencies

Increased HIV replicationProgression of diseaseIncreased morbidity

Increased oxidative stressImmunosuppression


S315Nutrition and HIV infection

loss and wasting are due to a negative energy balance among other causes which is determined by energy needs and energy intake supplied by macronutrients particularly fats and carbohydrates Protein is not dis-cussed separately but is included in the section ldquoImpact of food supplementsrdquo and the World Health Organiza-tion (WHO) intake recommendation is quoted

Micronutrients

Micronutrients are important for immunity growth and psychomotor development because they catalyze many processes in the body and are essential compo-nents of specific tissues For example iron is part of hemoglobin which transports oxygen in the body vitamin A is known as the anti-infective vitamin and a high dose is provided every 6 months to young children as a child survival intervention zinc tablets are recommended as adjunct treatment for children suffering from diarrhea in order to cure the episode faster and reduce the risk of a next episode Because of the essential role of micronutrients in supporting the bodyrsquos functions HIV-infected people very much need to have an adequate micronutrient status In this section we will reviewraquo To what extent micronutrient deficiencies occur

among HIV-infected people as indicated by inad-equate dietary intake or as directly measured by low micronutrient status (ie low levels in the body) from biochemical and other measurements

raquo Whether HIV-infected people have higher micronu-trient needs than non-HIV-infected people

raquo How micronutrient deficiencies affect HIV infection

Prevalence of micronutrient deficiencies among HIV-infected people

Main points

raquo Multiple micronutrient deficiencies are common in people with HIV infection as shown by both inadequate dietary intake of micronutrients and low circulating micronutrient levels

raquo Micronutrient needs appear to be higher among HIV-infected than non-HIV-infected people

Evidence

Micronutrient intake Low intakes of many differ-ent micronutrients have been reported in different groups of HIV-infected adults [10ndash17] Many studies have reported that a large proportion of HIV-infected adults consume less than the Recommended Dietary Allowance (RDA) of many individual micronutrients including vitamin A vitamin C vitamin E thiamine riboflavin vitamin B6 folate iron and zinc The RDA is the level of intake of a nutrient that is considered to

be adequate to meet the nutrient needs of nearly all (97 to 98) healthy persons and it is defined at a level that is 2 SD above what is considered to be the average level of requirement [18] There is some evi-dence that micronutrient intakes at the level of the RDA may be insufficient for HIV-infected individuals since low circulating micronutrient concentrations have been reported in HIV-infected adults with dietary intakes greater than the RDA for various micronutrients [19] Some recent studies have shown that a large propor-tion of HIV-infected individuals whether they are on ART or not also have a low dietary intake of vitamin A vitamin C vitamin E vitamin B6 iron and zinc in relation to the new Dietary Reference Intakes (DRIs) [16] These data are from the United States and are most likely not only applicable to HIV-infected people Given the fact that micronutrient deficiencies are more widespread in developing countries than in developed countries the likelihood of inadequate micronutri-ent intake among HIV-infected people in developing countries at any stage of infection is very high Table 1 summarizes micronutrients for which evidence of low intake has been reported

Micronutrient status Low serum or plasma micro-nutrient concentrations consistent with deficiency have been described in various HIV-infected groups Low serum vitamin A levels considered to indicate deficiency have been described in many different risk groups for HIV including homosexual men [20 21] injection drug users [22 23] adults in Ethiopia [24] pregnant women in Malawi [25 26] pregnant women in Zimbabwe [27] pregnant women in Thailand [28] lactating women in Malawi [29] and children in Uganda [30] Low serum or plasma carotenoid con-centrations are common in HIV-infected individuals [27 28 31ndash34] A high prevalence of vitamin D defi-ciency based on serum or plasma 25-hydroxyvitamin D concentrations has been described in HIV-infected adolescents and adults [35ndash37] Low serum 25-hydrox-yvitamin D levels were associated with increased mother-to-child transmission of HIV [38] Low serum or plasma vitamin E levels have been described in HIV-infected adults [12 20 31 39 40] and in lactating women in South Africa [41]

Low plasma or serum vitamin C concentrations have been reported in homosexual men and injection drug users [20 31 42] heterosexual adults [33] adolescents [43] and children [44] HIV-infected adults have been described with low circulating concentrations of vita-min B6 [20] vitamin B12 [45ndash51] and folate [31 41ndash43

RNI (recommended nutrient intake) is recommended by FAOWHO and is used throughout this paper except where studies have specifically reported on the RDA (recom-mended dietary allowance) which was recommended by the Institute of Medicine for the United States and Canada and was replaced in the mid 1990rsquos by the DRI (dietary reference intakes)



45 52 53] Low serum zinc concentrations have been reported in HIV-infected adults [20 41 54 55] High prevalence rates of iron deficiency and iron-deficiency anemia have been reported in HIV-infected infants in Uganda [56] children [57 58] female injection drug users [59 60] pregnant women in Malawi [61 62] pregnant women and women of childbearing age in Tanzania [63 64] and lactating women in South Africa [41] Low circulating selenium concentrations have been described in HIV-infected adults [65 66]

See table 1 for an overview of micronutrients for which a low status has been reported in HIV-infected people

Comments

raquo Knowledge depends on what we look for only the

micronutrients that are assessed in the serum or diet in a particular study are what we will know some-thing about

raquo The insufficient intake and higher needs among HIV-infected people apply to some micronutrients more than others but knowledge about this is limited

raquo Micronutrient levels in the blood are affected not only by how much of the micronutrient is present in the body but also by infection which increases the levels of some (ferritin which carries iron) and decreases the levels of others (vitamin A zinc) This complicates the interpretation of blood levels of micronutrients

TABLE 1 Documented relationships between micronutrients and HIV infectiona

Micronutrient

Low intake described in

literature

Deficient status

described

Deficiency associated with adverse HIV infection

outcomesRNI for 19-

to 70-yr-olds

Vitamin A microg X X Yes but also with positive outcome in one study

600

Vitamin E mg X X Yes but one study with a negative and one with a

positive outcome

10

Vitamin B1 mg X Yes part of B-complex supplement

14


16

Niacin mg 18Pantothenic acid mg 6Folic acid microg X X 400Vitamin C mg X 75Vitamin B6 mg X X Yes 2Vitamin B12 microg X Yes 6Calcium mg 1000Magnesium mgSelenium microg X YesZinc mg X X Yes 15Iron mg X X 15Iodine microg 150Copper mg 2Phosphorus mg 1000Potassium mg 3500Manganese mgVitamin D microg X 5Vitamin K microgBiotin microg 30Sodium mgChromium microgMolybdenum microgChloride mgCarotenoids microg X Yes

a See text for references to specific evidence



Micronutrient deficiencies affecting HIV infection

Main point

raquo Deficiencies of several micronutrients have been associated with accelerated disease progression increased mother-to-child transmission increased genital shedding of HIV and increased mortality

Evidence

In HIV-infected patients low serum or plasma vitamin A concentrations have been associated with accelerated HIV disease progression [39] higher adult mortality [22] higher infant mortality [67] and child growth failure [68] Higher plasma vitamin A concentrations were associated with lower mortality in children born to HIV-infected women in Tanzania [69] Low serum vitamin A concentrations during pregnancy were asso-ciated with increased mother-to-child transmission of HIV [25] and greater genital shedding of HIV [70] In lactating women low serum vitamin A concentrations were associated with higher HIV load in breastmilk [71] However low serum vitamin A concentrations do not appear to be a risk factor for heterosexual transmission of HIV as shown from a case-control study of women in Tanzania [72] Surprisingly lower serum vitamin A concentrations were associated with a decreased risk of HIV infection among Kenyan men with genital ulcers [73] Low serum or plasma vitamin A concentrations in individuals with HIV infection must be interpreted with caution since vitamin A is a negative acute phase reactant in the serum Clinical trials have subsequently shown that the relationship between circulating vitamin A levels and mother-to-child transmission of HIV and heterosexual transmission of HIV is not a causal association The measurement of acute phase proteins may facilitate the interpretation of serum nutrient concentrations in the presence of inflammation [74]

Low serum β-carotene concentrations were associ-ated with increased risk of HIV infection among adults attending a clinic for sexually transmitted diseases in Pune India [75] In a study of HIV-infected women in Kenya low serum β-carotene concentrations were asso-ciated with markers of HIV disease progression [34]

Higher plasma vitamin E levels prior to HIV sero-conversion were associated with increased mortality in HIV-infected women in Kenya [76] In contrast higher serum vitamin E levels were associated with a nearly one-third lower risk of progression to AIDS in HIV-infected homosexual men [21] High intake of vitamin B6 was associated with improved survival [77] Low serum vitamin B12 concentrations were associated with more rapid progression of HIV disease in homosexual men [45] Use of B-complex vitamins was associated with reduced progression to AIDS in HIV-infected adults in South Africa [78]

In HIV-positive homosexual men low serum zinc

levels were associated with greater HIV disease pro-gression [39 79] Serum or plasma zinc concentra-tions must be interpreted with caution in patients with inflammation as zinc is a negative acute phase reactant in blood

Low serum or plasma selenium concentrations have been associated with accelerated progression of HIV disease among adults [80] and pregnant women in Tanzania [81] and with higher mortality among HIV-infected adults [82] HIV-infected children [83] and children born to HIV-infected mothers in Tanzania [84] Low plasma selenium concentrations were associ-ated with higher mother-to-child transmission of HIV through the intrapartum route [85] Selenium defi-ciency was associated with a higher risk of genital shed-ding of HIV in HIV-infected women in Kenya [86] HIV-infected injection drug users with low serum sele-nium concentrations were at high risk for developing mycobacterial disease over a 2-year period [87] Low plasma selenium concentrations have been described in HIV-infected adults with myopathy (disease of the muscle) compared with those in HIV-infected adults matched by CD4 lymphocyte count who did not have myopathy [88]

Table 1 summarizes micronutrients for which an association between a low status and poor disease outcome has been documented

Comments

raquo For most micronutrients a low status is associated with poor HIV infection outcome

raquo There appear to be two findings one for vitamin A and one for vitamin E that show the opposite that is a high status associated with increased transmis-sion (vitamin A) or increased mortality (vitamin E) However there were many more studies especially for vitamin A showing a negative outcome related to a low vitamin A or E status

raquo Interpretation of causality that is whether a low micronutrient status leads to a poor HIV infection outcome is difficult though because other factors such as opportunistic infections and loss of appetite may co-occur and be related both to progression of the disease and to a low micronutrient status

raquo Micronutrient deficiencies usually occur for a combi-nation of micronutrients as isolated single deficien-cies are more uncommon For each micronutrient a relationship with poor disease outcome may be found but whether this means that these specific individual micronutrients rather than some other micronutrients or even macronutrients cause a poor outcome cannot be concluded Thus studies of interventions that correct micronutrient deficiencies (one or more at a time) are required to determine causality (see section ldquoImpact of micronutrient sup-plementationrdquo below)



Weight loss and wasting

The AIDS wasting syndrome was first described in 1985 in a report from Uganda as ldquoslim diseaserdquo [89] This indicates how closely weight loss and HIV infec-tion are related

Causes and consequences of weight loss in HIV infection

Main points

raquo Wasting (low body mass index [BMI]) and weight loss are common in people with HIV infection

raquo HIV-infected people on ART also suffer from weight loss

raquo Low BMI and weight loss are strong risk factors for HIV disease progression and mortality independ-ently of CD4 lymphocyte count or other indicators of immune system performance

raquo It is especially the loss of metabolically active tissue such as muscle rather than loss of fat mass that is associated with increased risk of adverse outcomes of HIV infection

raquo There are many different HIV-related causes of weight loss including low food intake increased nutritional needs malabsorption and altered metab-olism (fig 2)

raquo Both malnutrition and infections (HIV and others) need to be treated at the same time

Evidence

Indicators of wasting and weight loss According to the Centers for Disease Control and Prevention definition wasting manifesting as at least 10 of body weight lost is an AIDS-defining event However a weight loss of as little as 5 has also been associated with increased morbidity and mortality [90 91] A low BMI that is one below a specific cutoff (usually 185 kgm2 which indicates moderate malnutrition in adults) without information about the initial BMI or weight lost is also strongly related to HIV disease progression and mortality [90ndash99]

Association with adverse outcome The increase in mortality risk with malnutrition varies among studies populations and degrees of severity of malnutrition and according to whether the patient is concurrently receiving ART the risk may be two to six times higher for malnourished (low BMI) than for nonmalnour-ished patients [96 97 100] A number of studies have assessed whether lean body mass (fat-free mass) or bioimpedance measures reflecting the ratio of extracel-lular to intracellular water are more strongly associated with subsequent mortality than BMI or weight loss but this was generally not the case [91 101] However it appears that the loss of lean body mass especially muscle tissue is the main reason for the association between low BMI or weight loss and mortality [102] but that this loss of lean body mass which is more dif-ficult to measure is adequately reflected by BMI as well as by percentage weight loss In addition low BMI or

FIG 2 Relationship between HIV infection and malnutrition

Loss of appetite

Difficulty swallowing

Avoiding diarrhea

Malnutrition

ndash Low BMI

ndash Weight loss

ndash Micronutrient deficiencies

Context in resource-limited settings

ndash Preexisting malnutrition food insecurity low dietary quality

ndash High infection pressure (malaria TB parasitoses

ndash Higher susceptibility to HIV infection

ndash Higher HIV prevalence

ndash Lower epithelial integrity

ndash Risk behavior

Altered metabolism

ndash Increased nutrient needs due to infection

ndash From 10 higher resting energy expenditure when asymptomatic to 30 higher when symptomatic

ndash Increased losses of MNs due to infection

ndash Inefficient nutrient utilization

ndash Changes of hormone production (glucagon insulin cortisol epinephrine) affecting carbohydrate protein far metabolism

ndash Hypogonadism and adrenal insufficiency

Malabsorption (fat carbohydrates MNs)

ndash Gut functioning

ndash Diarrhea

HIV infection and opportunistic infections

Poverty food insecurity

Low food intake (MNs energy)

Affecting progressionand outcome



weight loss usually also reflects a poor micronutrient status

It is important to note that the increased mortality risk associated with low BMI and weight loss is inde-pendent of CD4 lymphocyte count [102ndash104] even in patients who are on ART [96] Weight loss of approxi-mately 35 of ideal weight irrespective of the cause is strongly predictive of death [102] ART facilitates immune recovery and reduces the risk of losing weight and reducing BMI but weight loss still occurs among a substantial proportion of patients [99 104 105] For example in the Nutrition for Healthy Living Cohort from Boston 335 of patients on ART (156466) who did not report wasting at the time of enrollment met one or more criteria for wasting during follow-up (note that follow-up was done every 6 months and that total length of follow-up varied) Criteria for wasting included lost more than 10 of body weight over serial 6-monthly visits (18) lost more than 5 of body weight in 6 months and that loss was sustained for 1 year (21) or BMI fell below 20 kgm2 (8) at any time during the follow-up Furthermore a total of 58 of all patients (289497) lost more than 15 kg between any two study visits (the average loss among them was 4 kg) [98] Of the 29 of patients who developed wasting some time during the follow-up since diagnosis of HIV nearly two-thirds developed wasting for the first time after starting ART [91] Although this US cohort has different characteristics than HIV-infected populations in for example sub-Saharan Africa similar findings were reported from India [105] which shows that people on ART can also experience weight loss

Causes of weight loss in HIV infection There are multiple causes of weight loss during HIV infection (fig 2) and many of these causes can act simultane-ously [106ndash110]

Reduced food intake often due to loss of appetite can result in a negative energy balance especially when energy needs are increased at the same time Resting energy expenditure is increased by approxi-mately 10 among asymptomatic HIV-infected people However total energy expenditure which consists of energy expenditure during rest digestion (ie after consumption of a meal) and physical activity has not been found to be increased in asymptomatic people [111] at least in developed countries This means that energy expenditure during digestion andor physical activity is reduced and that reduced intake rather than increased energy expenditure primarily drives weight loss During symptomatic infection energy needs are increased by 20 to 30 in adults and 50 to 100 in children with weight loss and infection also hin-ders efficient utilization of nutrients postabsorption However increasing intake during infection to meet the increased energy needs and to try to mitigate the inefficient utilization of nutrients is often difficult due to lack of appetite mouth sores loss or change of taste

andor difficulty swallowing Therefore increasing food consumption during convalescence (ie after illness) is very important Food insecurity is also an important factor affecting food intake either because of an absolute lack of food or because of inability to modify or adjust the diet with more palatable and more frequent meals in order to mitigate the side effects of HIV infection or of medication (such as nausea and diarrhea)

Malabsorption (ie not absorbing nutrients very well as they pass through the gut) due to HIV infection and opportunistic infections especially fat malabsorption can also contribute to a negative energy balance

Inflammation associated with the acute phase response and infection can lead to muscle and tissue catabolism loss of nutrients anorexia and inefficient utilization of nutrients (table 2) [103] HIV infection can affect production of hormones such as glucagon insulin epinephrine (adrenaline) and cortisol which are involved in the metabolism of carbohydrates pro-teins and fat and elevated levels of these hormones contribute to weight loss and the wasting syndrome [112] Hypogonadism and adrenal insufficiency can also be induced by HIV infection and result in meta-bolic changes that can lead to weight loss [113] In developing countries additional factors that can contribute to wasting and weight loss in people with HIV are malaria intestinal parasitoses tuberculosis specific micronutrient deficiencies and low dietary intake of essential amino acids [114] Animal-source foods generally are richer in essential nutrients such as essential amino acids and specific vitamins (eg vitamins B6 B12 and D) and bioavailability of minerals (especially iron and zinc) is higher in animal-source

TABLE 2 Metabolic alterations during sepsis

ProteinIncreased urinary nitrogen lossIncreased protein turnoverDecreased skeletal muscle protein synthesisIncreased skeletal muscle breakdownIncreased hepatic protein synthesis

LipidHypertriglyceridemiaIncreased hepatic de novo fatty acid synthesisIncreased hepatic triglyceride esterificationIncreased very-low-density lipoprotein productionDecreased peripheral lipoprotein lipase activityIncreased adipocyte triglyceride lipase

CarbohydrateHyperglycemiaInsulin resistanceIncreased peripheral glucose utilizationIncreased gluconeogenesis

Source Babameto and Kotler [103]



than in plant-source foods [115]Patterns of weight loss In general there are two

distinct patterns of weight loss in patients with more advanced HIV disease episodes of severe acute weight loss and episodes of chronic unremitting progres-sive weight loss [108] The former is usually related to infection and the accompanying cachexia (tissue breakdown) needs to be resolved by treating the infection(s) in addition to ensuring adequate nutrition whereas the latter is mainly due to a negative energy balance that needs to be resolved by increasing nutri-ent intake [103] through provision of more palatable or more energy-dense foods possibly augmented with appetite stimulants However the two processes are not mutually exclusive and the dynamic interaction with nutritional status means that malnutrition and infec-tion need to be treated concurrently

Comment

raquo Because weight loss can be due to many factors and also occurs among patients receiving ART (albeit among a smaller proportion of patients and usually more slowly) its treatment and prevention have to address different factors simultaneously and take the specific circumstances of the individual patient into account

HIV infection and nutritionmdashreview of nutrition interventions

Because of the associations found between micronu-trient deficiencies and disease progression as well as weight loss or wasting and HIV infection outcome the evidence for the impact of micronutrient and food interventions on HIV infection outcome is reviewed below

Impact of micronutrient supplementation

Main points

raquo High-dose vitamin A supplementation of HIV-pos-itive children under 5 years of age has been shown to reduce morbidity and mortality

raquo Vitamin A supplementation of mothers (10000 IUday during pregnancy or a single high dose of 400000 IU after delivery) does not seem to reduce mother-to-child HIV transmission

raquo An adverse effect of supplementation during preg-nancy and lactation on mother-to-child transmis-sion was observed when vitamin A (5000 IUday) was combined with high-doses of β-carotene (30 mgday) It is unknown whether this effect is due to β-carotene vitamin A or both

raquo The outcomes of supplementation with single nutri-ents (vitamin E selenium zinc and iron) are not yet conclusive

raquo Multimicronutrient supplementation has shown some positive results (slower disease progression reduced mother-to-child transmission) but because the composition of supplements as well as the results varied widely between studies it is not possible to conclude what the optimum amount for each micro-nutrient and for different target groups would be

raquo Based on the available knowledge WHOrsquos current advice is to ensure intake of 1 RNI for all micronu-trients The Academy of Sciences of South Africa recommends an intake of 1 to 2 RNI because needs may be higher during HIV infection (increased uti-lization as well as increased losses)

raquo There is no reason based on currently available evidence to withhold public health interventions with micronutrients from HIV-infected people such as supplementation of children under 5 years of age and lactating women shortly after delivery with high-dose vitamin A capsules and supplementation of pregnant women with ironndashfolic acid tablets

Evidence

Vitamin A for children Periodic high-dose vitamin A supplementation was shown to reduce diarrheal mor-bidity among children born to HIV-infected mothers in South Africa [116] A study conducted in Tanzania showed that children who received high-dose vitamin A supplementation upon admission to the hospital with pneumonia and at 4 and 8 months after discharge had lower mortality than those who received placebo A post hoc analysis was conducted with stored serum samples to identify children who were HIV infected Vitamin A supplementation reduced mortality by 63 in the subset of HIV-infected children [117] and reduced the morbidity from some infectious diseases [118 119] Vitamin A supplementation did not increase the antibody response in HIV-infected children given influenza vaccination but it reduced the postvaccina-tion increase in HIV load [120] In a randomized double-blind placebo-controlled trial of vitamin A for HIV-infected children in Uganda vitamin A sup-plementation reduced mortality by 46 [121]

Vitamin A for pregnant andor lactating women In Malawi HIV-infected women who received daily vita-min A supplementation with 3 mg retinol equivalents (RE) (10000 IU) from 18 to 28 weeks of gestation until delivery had infants with higher birthweight better neonatal growth and greater hemoglobin con-centrations but there was no effect of vitamin A on mother-to-child transmission of HIV [122] High-dose (400000 IU) vitamin A supplementation of HIV-infected mothers in Zimbabwe during the postpartum period had no effect on mother-to-child transmis-sion of HIV [123] and no effect on HIV incidence in women during the postpartum period [124] In the same trial postpartum vitamin A supplementation of HIV-infected mothers and vitamin A supplementation



of HIV-infected neonates had no impact on anemia in the infants [125] Daily vitamin A supplementation with 10000 IU had no impact on genital shedding of HIV among HIV-infected women of childbearing age in Kenya [126]

β-Carotenemdashmegadoses Clinical trials have been conducted using megadoses of β-carotene alone or in combination with small doses of vitamin A for HIV-infected pregnant women and adults In this review these studies are considered separately from the trials of vitamin A alone since β-carotene especially at nonphysiological megadoses has been shown to have pharmacological and physiological effects that are distinct from those of vitamin A β-Carotene can be cleaved either centrally which leads to formation of vitamin A or excentrically which gives rise to a variety of aldehyde alcohol and epoxide metabo-lites and the function if any of these metabolites is largely unknown Concern was raised beginning in the mid-1990s about the use of megadose β-carotene for HIV-infected adults since megadose β-carotene sup-plementation was shown to increase the risk of death cancer and cardiovascular disease in large trials for the prevention of cancer and cardiovascular disease In the Alpha-Tocopherol Beta-Carotene Cancer Prevention Trial β-carotene 20 mgday increased the risk of lung cancer [127 128] and of first-time nonfatal myocardial infarction among male smokers [129] In the Beta-Car-otene and Retinol Efficacy Trial β-carotene 30 mgday plus vitamin A 25000 IU increased the risk of lung cancer among present and former smokers and work-ers exposed to asbestos [130] Megadose β-carotene increases serum levels of β-carotene to levels 5 to 12 times higher than normal physiological levels At high doses β-carotene has prooxidant effects [131] and in humans β-carotene 30 mgday has been shown to decrease the activity of leukocyte superoxide dismutase and to lower levels of serum glutathione peroxidase two important components of antioxidant defenses [132] Excentric cleavage products of β-carotene which are generated at high levels with megadose β-carotene supplementation have been shown to impair mito-chondrial function [133]

Megadose β-carotene 180 mgday did not have any apparent benefit for HIV-infected adults who were already taking multivitamins [134] β-Carotene 180 mgday had no effect on CD4 lymphocyte counts or plasma HIV load after supplementation for 4 weeks [135] In South Africa HIV-infected pregnant women who received β-carotene 30 mgday plus vitamin A 10000 IUday during the third trimester were less likely to have a preterm delivery but no effect was seen on mother-to-child transmission of HIV or birthweight [136] In Tanzania a clinical trial utilizing a 2 times 2 factorial design was conducted in pregnant women to determine whether β-carotene 30 mgday plus vitamin A 5000 IUday multivitamins or both from 12 to 27

weeks of gestation through delivery and postpartum would affect various clinical outcomes Women who received β-carotene and vitamin A had an increased risk of mother-to-child transmission of HIV [137] and higher shedding of HIV in the genital tract at 36 weeks of gestation [138] Supplementation with a natu-ral carotenoid mixture that contained an equivalent of β-carotene 72 mgday did not significantly affect mortality in HIV-infected adults who were receiving multivitamins [139]

Vitamin E Vitamin E supplementation 800 mgday had no significant impact on CD4 lymphocyte count or HIV load [140] but improved lymphocyte viability [141] Supplementation with vitamin E 800 mgday plus vitamin C 1 gday reduced oxidative stress and HIV load in HIV-infected adults [142] In a small trial supplementation with vitamins A C and E reduced oxidative damage to DNA and lipid peroxidation in HIV-infected adults [143] A combination of vitamins C and E plus N-acetyl-cysteine had no effect on CD4 lymphocyte count or HIV load in an uncontrolled study involving 10 HIV-infected adults [144]

Selenium In an uncontrolled trial daily selenium supplementation for 2 months had no impact on CD4 lymphocyte count in 12 HIV-infected adults [80] Selenium supplementation increased levels of antioxi-dant enzymes in HIV-infected adults compared with placebo [145] In HIV-infected ART-naive adults selenium supplementation for 24 weeks had no signifi-cant impact on CD4 lymphocyte counts or HIV load [146] A controlled trial in the United States involving HIV-infected injection drug users on highly active antiretroviral therapy (HAART) dual- or mono-drug therapy or no ART selenium supplementation for 2 years reduced HIV-related hospital admissions and slowed the decline of CD4 lymphocyte counts [147] In a controlled trial conducted in the United States involv-ing HIV-infected adults on various ART regimens or no therapy selenium supplementation for 9 months had an apparent effect on CD4 lymphocyte counts and HIV load when results were presented using a complex structural equation model [148] In this trial the loss to follow-up was greater than 30 changes in ART during the trial were not described and the results were not presented showing CD4 lymphocyte count and HIV load by treatment group at 9 months [149ndash151] In Tanzania 915 HIV-infected pregnant women received either selenium or placebo from 12 to 27 weeks of gestation until 6 months after delivery Selenium supplementation reduced diarrheal morbid-ity during pregnancy but had no impact on hemoglobin concentrations or birth outcome Mortality after 6 weeks postpartum was lower among children born to women receiving selenium than among those whose mothers received placebo [152 153]

Zinc In a controlled trial involving 400 HIV-infected pregnant women zinc supplementation from 12 to 27



weeks of gestation through 6 weeks after delivery had no impact on pregnancy outcome [154] HIV load or mother-to-child transmission of HIV [155] Daily zinc supplementation had no impact on the duration of diarrhea in HIV-infected adults with 7 or more days of diarrhea [156] Zinc supplementation had no impact on the antibody response to pneumococcal vaccine in HIV-infected injection drug users in the United States [157]

Iron Although iron deficiency and iron-deficiency anemia are common especially in HIV-infected women and children concern has been raised that iron supple-mentation could accelerate HIV disease progression since iron is a prooxidant [158] A post hoc analysis of 45 HIV-infected adults in Kenya who participated in a clinical trial in which they received 60 mg of either elemental iron or placebo twice weekly for 4 months showed that iron supplementation had no impact on HIV load [159] A randomized placebo-controlled clinical trial involving 320 HIV-negative and 138 HIV-positive female injection drug users with hepatitis C infection in Baltimore Maryland USA showed that daily supplementation with 18 mg of iron reduced anemia and had no impact on plasma HIV load or plasma hepatitis C load [160]

Multimicronutrients The largest multimicronutrient supplementation study was conducted among preg-nant women in Tanzania as mentioned above The multivitamin arm of the study included daily doses of thiamine (20 mg) riboflavin (20 mg) vitamin B6 (25 mg) vitamin B12 (50 μg) niacin (100 mg) vitamin C (500 mg) vitamin E (30 mg) and folic acid (08 mg) and the women continued with supplementation for more than 2 years postpartum Women who received multivitamins had a reduced risk of fetal death low birthweight and severe preterm birth as well as higher CD4 and CD8 lymphocyte counts [161] Women who received multivitamins had greater weight gain in the third trimester of pregnancy than women who did not receive multivitamins [162] There was no impact of multivitamins on mother-to-child transmission of HIV [163] Children born to HIV-positive mothers who were receiving multivitamins had higher CD4 lymphocyte counts a lower risk of diarrhea [164] better ponderal growth [165] and a lower risk of anemia [166] Women who received multivitamins had slower progression of HIV disease maintained higher CD4 lymphocyte counts and had higher hemoglobin concentrations than women in the placebo group [166 167] Multivitamins were also protective against wast-ing [168]

Other trials of multimicronutrient supplementa-tion among HIV-infected adults have had mixed results In Zambia micronutrient supplementation (vitamin A vitamin C vitamin E selenium and zinc) had no impact on morbidity or mortality among HIV-infected adults with persistent diarrhea [169]

A community-based trial was conducted in Zambia involving 500 adults of whom approximately 40 were HIV infected and the intervention consisted of daily multimicronutrients (β-carotene vitamin C vitamin D vitamin E vitamin B6 vitamin B12 thiamine ribo-flavin folate iron zinc copper selenium and iodine) Overall multimicronutrients reduced the severity but not the incidence of diarrhea Among HIV-infected adults multimicronutrients reduced mortality [170] In Thailand multimicronutrient supplementation in doses above the RNI for 48 weeks had no overall impact on CD4 lymphocyte count HIV load or mortality During follow-up 5 of the participants died and 16 were lost to follow-up [171] In Kenya greater genital shedding of HIV was found in HIV-infected non-pregnant women who received multivitamins than in those receiving placebo [172] A small trial conducted in the United States showed that HIV-infected adults on HAART who received micronutrient supplementa-tion for 12 weeks had higher CD4 lymphocyte counts [173] An uncontrolled study in Australia involving 66 HIV-infected men showed that an antioxidant regimen (β-carotene vitamins C and E selenium and coenzyme Q10) for 12 weeks improved some biomarkers of anti-oxidant defenses but had no effect on HIV load [174]

Comments

raquo Several studies with micronutrient supplements have been conducted However the choice of micronutri-ents (often a combination) and the amounts of each micronutrient provided (ranging from a few to many times the RNI) varied considerably

raquo Furthermore the patientsrsquo stage of HIV disease as well as their treatment and diet varied widely which would affect the impact of micronutrients These many differences make it very difficult to draw firm conclusions about the impact of micro-nutrient supplementation especially for individual micronutrients

raquo Common sense dictates that a balanced diet that contains all nutrients in the recommended amounts including micronutrients should be consumed particularly by people who are vulnerable such as HIV-infected people in order to support the body and immune system In areas where micronutri-ent deficiencies are widely prevalent HIV-infected people may need an intake somewhat above the RNI to correct these deficiencies in addition to meeting normal bodily needs

raquo Some of the studies with micronutrients have pro-vided levels of micronutrients that are much higher than those that are typically consumed in the diet These are basically pharmaceutical interventions the results of which cannot be used to recommend dietary changes because such levels could not be provided by a normal balanced diet



Interventions to prevent or treat weight loss

In principle the aim of nutrition interventions for HIV-infected people is straightforward to reduce mortality risk by increasing or maintaining body weight (ie preventing halting or recovering weight loss) and to support the immune system and body performance by providing access to adequate nutrition in conjunc-tion with infection control However because weight loss is affected by many interrelated factors (as shown in fig 2) it is more complex than one might initially think Also management of weight and nutritional status becomes more and more complex as HIV infec-tion progresses Therefore nutrition interventions should start as early as possible and should include nutrition assessment education and counseling aug-mented with supplements and pharmaceutical prepara-tions when required

Here we will first review the management of weight loss in settings where access to food and to ART is not constrained followed by a review of current recommendations and practices in resource-limited settings and then review studies that provided food supplements both in resource-limited and in resource-adequate settings in order to assess how these results can inform HIV care and treatment in resource-constrained settings

Current recommendations and practice in resource-adequate settings

Main points

raquo Ensuring adequate nutrition is an essential com-ponent of HIV infection control in addition to ART and treatment of opportunistic infections and should start as early as possible

raquo Even in the era of ART weight loss and wasting are not uncommon among HIV-infected people and need to be managed by a combination of approaches

raquo To regain muscle tissue a combination of infection control adequate nutrition and exercise is required and where necessary hormonal treatment can be added

raquo Treating malnutrition in HIV-infected people such as wasting requires more than just ensuring access to appropriate foods that supply required nutrients The management of weight loss in resource-adequate settings combinesndash nutrition assessment education and counseling

and where necessary appetite stimulants or spe-cific nutritional supplements

ndash pharmaceutical treatment of HIV opportunis-tic infections and side effects of infection or of treatment

ndash exercise and where required hormonal treatment to rebuild muscle tissue

raquo ART reduces the risk of weight loss and may increase appetite but it also has side effects and long-term metabolic effects (dyslipidemia insulin resistance and obesity) that require dietary management

Evidence

Current treatment practices for weight loss The earlier optimal nutrition is ensured after the diagnosis of HIV infection the better because maintaining nutritional status during asymptomatic HIV infection is associ-ated with fewer complications than reversing weight loss during acute infection and it slows HIV disease progression by maintaining a good nutritional status [103 104 112] However even during acute infec-tion it appears possible to reverse the catabolic state (breakdown of tissue) by providing complete nutri-tional supplements either orally or enterally leading to increased lean body mass in HIV-infected patients [102 175] as well as in tuberculosis patients [176] The composition of such a ldquocomplete nutritional supple-mentrdquo (Ensure Plus) is shown in table 3 Among the foods currently used for treating malnutrition in food assistance programs the composition of ready-to-use therapeutic food (RUTF) compares best to that of a complete nutritional supplement

In resource-adequate settings the current advice for managing weight loss is to assess the following causes as possible entry points for intervention food intake to ensure adequacy (affected by anorexia nausea vomit-ing diarrhea and oral or esophageal lesions as well as psychosocial aspects) comorbidities as they lead to weight loss and thus need to be treated (gastrointesti-nal disease opportunistic infections malignancies) hypogonadism adrenal insufficiency hyperlactatemia or lactic acidosis as they affect metabolism and med-ication-related side effects that may require change of the medication plan [113] Grinspoon and Mulligan for the Department of Health and Human Services Working Group on the Prevention and Treatment of Wasting and Weight Loss concluded in their 2003 review ldquoEvidence now demonstrates that nutritional counseling and support appetite stimulants progres-sive resistance training and anabolic hormones can reverse weight loss and increase lean body mass in HIV-infected patientsrdquo [113]

In 2004 Wanke and Kotler published collabora-tive recommendations on the approach to diagnosis and treatment of HIV wasting using an algorithm of management of HIV wasting (fig 3) It is important to note that this algorithm applies to patients who are on ART and basically focuses on treating factors that affect intake absorption or utilization of nutrients (appetite psychological factors gastrointestinal side effects etc) but not much on nutrient intake itself

Although both sets of recommendations pertain largely to patients in developed countries their con-clusions are important as we consider approaches to



and management of weight loss among HIV-infected people in resource-limited settingsraquo Even in the era of ART weight loss and wasting are

frequently seen and need to be managed by a com-bination of approaches

raquo Ensuring adequate nutrition is an essential compo-nent of HIV infection control in addition to ART

raquo Exercise is also important in particular to regain muscle tissue

raquo Because of the multifactorial etiology of weight loss pharmacological therapies may be required for reversing weight loss in addition to ART good

nutrition and exercise Pharmacological therapies for control of weight loss

Pharmacological therapies that may be used to try to reverse weight loss where other measures do not work well enough can include appetite stimulants as well as anabolic steroids Megestrol is a potent appetite stimulant with glucocorticoid-like activity leading to preferential accumulation of fat mass Anabolic steroids have been found to increase lean body mass These include natural testosterone esters for hypogonadal men as testosterone promotes the maintenance of lean body mass [112] However a Cochrane review

TABLE 3 Nutrient composition of a variety of food supplements provided to HIV patients suffering from malnutrition and the absolute amount of nutrients provided by these foods when providing 1600 kcaldaya

Ingredient

Composition per 100 g of product

RNIFor 1600

kcal

Intake when 1600 kcal of product is consumed

UL 19-70

Ensure Plus (mL)

Plumpyrsquo nut

Supple-mentary Plumpy

RUF- Valid RUFS-PPB CSB

CSB-USDA

Ensure Plus

Plumpyrsquo nut 92 g


92 g RUF-Valid RUFS-PPB CSBCSB-

USDA

Total quantity g (or mL) 100 1000 1000 100 1000 1000 1000 10600 2944 2944 2980 2891 4413 4260Energy kcal 151 5435 5435 5362 5551 3636 3760 2600 1600 16006 16000 16000 15979 16048 16048 16018Protein g 57 136 136 123 145 134 172 48 30 604 400 400 367 419 590 733Fat g 47 358 358 gt 35 371 70 69 498 1053 1053 gt 35 1074 309 294

MicronutrientsVitamin A microg 160 9130 9130 8169 2898 2781 8710 600 600 16960 26880 26880 24344 8378 12272 37105 3000Vitamin E mg 12 200 200 182 212 87 87 10 10 127 589 589 542 614 384 371 1000Vitamin B1 mg 0138 06 06 06 04 03 05 14 14 15 18 18 18 13 15 23 mdashVitamin B2 mg 018 18 18 17 05 02 05 16 16 19 53 53 51 15 09 20 mdashNiacin mg 255 53 53 48 57 35 62 18 18 270 156 156 143 165 153 265 35Pantothenic acid mg 074 31 31 28 34 6 6 78 91 91 83 145Folic acid microg 26 2098 2098 1917 1633 409 1796 400 400 2756 6176 6176 5713 4720 1805 7651 600Vitamin C mg 64 533 533 483 367 70 400 75 75 678 1568 1568 1439 1062 307 1704 1000Vitamin B6 mg 021 06 06 05 05 03 05 2 2 22 18 18 15 15 12 21 100Vitamin B12 microg 021 18 18 16 06 01 10 6 6 22 54 54 48 17 06 43 mdashCalcium mg 128 3000 3000 3041 3388 690 8310 1000 1000 13568 8832 8832 9062 9794 3044 35401Magnesium mg 277 920 920 980 1337 1738 2936 2707 2707 2832 5900 7404Selenium microg 55 300 300 318 59 60 583 883 883 920 260 256 400Zinc mg 17 140 140 124 33 21 50 15 15 180 413 413 370 94 94 213 45Iron mg 162 115 115 105 33 43 175 15 15 172 339 339 313 94 189 745 45Iodine microg 17 1000 1000 927 570 150 150 1802 2944 2944 2762 2428 1100Copper mg 021 17 17 17 04 08 09 2 2 22 51 51 51 11 34 38 10Phosphorus mg 117 3000 3000 351 2857 2807 2060 1000 1000 12402 8832 8832 10460 8260 12390 8776Potassium mg 170 11109 5554 9356 11755 4545 6340 3500 3500 18020 32704 16352 27881 33984 20060 27008Manganese mg 055 07 58 30Vitamin D microg 064 163 163 146 20 16 49 5 5 68 480 480 435 59 71 209 50Vitamin K microg 210 210 mdash 618 618Biotin microg 15 652 595 mdash 30 30 1590 1920 1920 1773Sodium mg 106 73 11236 311Chromium microg 47 498Molybdenum microg 12 1272Chloride mg 115 12190

CSB corn-soya blend RNI recommended nutrient intake RUF ready-to-use food RUFS ready-to-use fortified spread UL 19-70 upper limit for adults aged 19 to 70 yearsa Ensure Plus is a commercial product that was used by Berneis et al [175] Supplementary Plumpy and Plumpyrsquonut are commercial products

produced by Nutriset France for treating moderate and severe malnutrition respectively and their composition is comparable to that of



concluded that the impact of anabolic steroids in HIV-infected people is limited and that side effects include liver dysfunction and hypogonadism [177] Moreover their use in women is currently not recommended Growth hormone increases lean body mass in HIV-infected patients with wasting and promotes lean tissue retention in those with secondary infections However side effects include increased blood glucose arthralgia myalgia and peripheral edema [178] Therefore the use of growth hormone should be carefully considered and monitored

Because micronutrient deficiencies also reduce

appetite it will be worth assessing whether micronutri-ent supplements increase appetite among HIV patients in resource-limited settings and hence contribute to reversing weight loss Adults in a refugee camp in Kenya reported an increased appetite when using a micronutrient powder (World Food Programme unpublished observation) The micronutrient powder for home fortification is distributed to all people in the camps aged 6 months and older and contains 16 micronutrients at a level of 1 RNI for 1- to 3-year-old children but with reduced iron and zinc content because of malaria endemicity Improved appetite was


Ingredient


RNIFor 1600

kcal


UL 19-70

Ensure Plus (mL)

Plumpyrsquo nut



CSB-USDA

Ensure Plus




USDA



F100 RUF-Valid is the fortified spread used in the study by Bahwere et al [197] RUFS-PPB refers to the product used by Ndekha and colleagues [196 207] and van Oosterhout et al [208] CSB is the product used by the latter investiga-tors CSB-USDA refers to the content of the CSB donated by the US Agency for International Development (USAID)



recently reported among HIV-infected children aged 6 to 24 months not on ART who received micronutrient supplements [179]

ART in relation to weight loss appetite and weight gain ART impacts positively on nutritional status because of immune reconstitution (ie strengthening of the immune system) which in turn reduces oppor-tunistic infections The reduction in opportunistic infections especially those contributing to diarrhea and malabsorption helps to reduce weight loss and in many cases leads to a gain in weight [180] Evidence from Kenya and Cambodia showed that weight gain in adults after 3 months of ART was highly predictive of survival [181] In addition to reducing the risk of weight loss ART may increase metabolic demand [94] and concurrently increase appetite In fact increased

appetite as an effect of ART is mentioned as one of the reasons to stop or not to start ART for food-insecure patients in resource-limited settings ART can also increase weight but this may be due to increased fat mass rather than increased lean body mass

Because fat mass may increase more than fat-free mass in patients receiving ART (see fig 4 for a descrip-tion of the two distinct components of weight gain) especially in nonwasted patients care should be taken to prevent the development of obesity insulin resist-ance and dyslipidemia once a target weight has been achieved This is particularly important in the longer term because ART is a lifelong treatment

Furthermore most of the drugs used for ART or to treat HIV-related infections interact with food uti-lization or absorption Thus some need to be taken

FIG 3 Algorithm for management of HIV wasting in resource-adequate settings (from Wanke and Kotler [104])

Prior to initiating therapies for HIV wasting

ndash Assess HIV control and adjust therapy if warranted

ndash Treat factors with the potential to impair energy intake and expenditure

ndash Opportunistic infections and malignancies

ndash Depression or other psychosocial problems

ndash GI side effects from antiretroviral therapies

If wasting persists offer therapies targeted at HIV wasting

ndash Growth hormone (only therapy FDA-approved)

ndash Testosterone

ndash Anabolic steroids

If wasting persists prescribe nutritional counseling with or without appetite stimulants

After initiating therapy for HIV wasting monitor response in regard to both weight and energy

FIG 4 Components of weight gain

Fat-free mass mdash required for bodily functions requires

ndash Consuming correct nutrients that build up the tissues

ndash Exercise (to grow muscles)

ndash Ability to build tissues (anabolic instead of catabolic states)

Fat mass mdash constitutes the bodyrsquos energy reserves and insulation

ndash More easily built on positive energy balance because it doesnrsquot require many different nutrients

ndash However too much associated with

ndash Increased triglyceride level

ndash Insulin resistance (diabetes)

ndash Overweightobesity

Weight gain



with food and others without food and some specific foodndashdrug interactions need to be avoided or enabled Food and Nutrition Technical Assistance (FANTA) has published a very good guide on these interactions [182] which also stresses the point that managing food and drug interactions requires food security

Comment

raquo The management of HIV infection in resource-adequate settings includes nutrition assessment education and counseling treatment and prevention of weight loss mitigation of side effects of infection and management of short- and long-term effects of medication However current guidance for manag-ing weight loss is not very specific about what nutri-tion advice is to be given

Current recommendations and practice in resource-limited settings

As mentioned above ensuring adequate nutrition is an essential component of HIV infection con-trol Whereas nutrition assessment education and counseling is the primary intervention for ensuring adequate nutrition in resource-adequate settings with use of appetite stimulants and supplements of specific nutrients when required food insecurity is a major obstacle for nutritional management of HIV infection in resource-limited settings affecting both dietary quality and quantity [183] as well as treatment initiation and adherence [184] Recent evidence from the urban poor in San Francisco and British Columbia shows that food-insecure patients on ART are at higher risk for incomplete HIV RNA suppression [185] as well as death [186] This association with food insecurity may be related to undernutrition poorer adherence to ART and effects of food on the pharmacokinetics of antitretroviral medication as well as psychological factors Furthermore malnutrition is widely prevalent in resource-limited settings thus many HIV-infected people were already malnourished and often also food insecure before contracting HIV infection Current recommendations for HIV-infected people in resource-limited settings focus on advice for a balanced diet and for treatment of moderate or severe wasting

Main points

raquo Nutrition management of HIV infection and of ART is important

raquo Advice for HIV infection management in resource-limited settings is in principle not different from that in resource-adequate settings but the context is very different with regard to nutritional status stage of HIV infection opportunistic infections (malaria tuberculosis etc) and resources available at the household health system and public services levels

raquo Pre-existing malnutrition complicates the formula-tion of appropriate dietary advice (prevention and treatment of malnutrition at the same time) and food insecurity limits the extent to which dietary advice can be implemented

raquo There are no specific guidelines for treating malnu-trition in HIV-infected adults WHO guidelines for treating wasted adults are used instead

raquo It is worth assessing whether micronutrient sup-plementation in resource-limited settings stimulates appetite among HIV-infected people suffering from anorexia

raquo It is not known whether the upper limits for intake of micronutrients for adults in general are also safe for HIV-infected people who may also be malnour-ished but the current practice of using RUTF with a composition comparable to that of F100 suggests that it is assumed safe

Evidence

Dietary advice and constraints in resource-limited set-tings The way in which weight loss has been managed in resource-adequate settings shows that it is a complex matter requiring more than just an adequate diet which in itself is already difficult for many people in resource-limited settings Furthermore particularly in the context of HIV infection experts do not agree entirely on what constitutes optimal nutrition or on how it is best provided [187] The latter is also due to the fact that evidence on the impact of nutrition interventions among HIV-infected people is scanty However the authors are of the opinion that the lack of evidence is also related to difficulties with conceptual-izing the relationship and appropriately designing and interpreting macronutrient intervention studies

Since nutrition among people in developing coun-tries is also closely related to food security and poverty nutrition interventions for HIV-infected people in developing countries include nutrition assessment education and counseling targeted nutrition supple-ments and establishing linkages with food security and livelihood programs [188 189] Many patients already suffer from malnutrition before HIV-related weight loss and wasting occur

Dietary guidelines from WHO for HIV-infected people are summarized in table 4 [187 190 191] and several documents provide guidance [187 190ndash194] According to these guidelines HIV-infected people should consume the same proportions of energy from protein (12 to 15) fat and carbohydrates as are recommended for people who do not have HIV infec-tion increase total energy intake of adults by 10 to 30 depending on clinical status and consume 1 Recommended Nutrient Intake (RNI) of each required vitamin and mineral However there are no estab-lished therapeutic guidelines for the management of weight loss and wasting in HIV-infected patients The



Working Group on the Prevention and Treatment of Wasting and Weight Loss has proposed some guid-ance in this regard [113] (reviewed above) which is largely relevant for resource-adequate settings WHO guidelines for treatment of malnutrition in any adult irrespective of HIV infection status are also being applied to malnourished HIV-infected people

Protein is one of the three macronutrients in the diet and is among other functions required for building muscle tissue which is the main component of lean body mass Losing body protein or muscle tissue affects the body in several ways and rebuilding it requires not only an adequate protein intake but also appropriate utilization by the body a process that is negatively affected by active infection (see also fig 2) Hsu and colleagues described this process very succinctly ldquoLoss of body protein plays a key role in reducing immunity delaying tissue repair and slowing recovery after opportunistic infection Recovering it requires a combination of improved infection control increased food availability including items which are palatable for those with anorexia and compassionate care and supportrdquo [195]

It is important to note that the ldquoCurrent recommen-dations and practice in resource-adequate settingsrdquo described above also apply to resource-limited settings Thus dietary management of ART is very important because of foodndashdrug interactions side effects that affect appetite and digestion and metabolic alterations related to long-term ART use

Applying guidance for treating malnutrition to HIV-infected people There are nutrient intake

recommendations for severely malnourished adults and for HIV-infected people but recommendations for the latter do not distinguish between malnourished and nonmalnourished patients The recommendations for HIV-infected people are to consume the same propor-tions of energy from protein fat and carbohydrates as noninfected people but to increase total energy intake and to consume vitamins and minerals at the level of 1 RNI In case of severe malnutrition HIV-infected people need to be referred to the recommendations for severely malnourished adults which are formulated without taking HIV status into account Severely mal-nourished adults who are recommended to consume F100 or a nutritionally equivalent product such as an RUTF (eg Plumpyrsquonut) have an intake of micronu-trients that is several times higher than the RNI (table 3) but good results in the treatment of malnutrition in HIV-infected people are reported [196 197] This sug-gests that nutrient intakes up to a few times higher than 1 RNI do not harm malnourished HIV-infected people and could actually benefit them The higher fat content of RUTF enables a greater energy intake per amount of food consumed which is important for malnourished people who need to gain weight However high fat intake may be difficult in cases of fat malabsorption

For moderately malnourished adults nutrient intake is not specified in the WHO guidance instead exam-ples of foods that can be provided are given which may result in micronutrient intake levels below 1 RNI For example cornndashsoya blend (CSB) which is very often given contains a limited number of micronutrients and provides at average intake levels less than 1 RNI for

TABLE 4 WHO guidance for nutritional management of HIV infection and malnutrition among adults

With regard to nutrition assessmentMeasure weight weight change height BMI MUACAssess appetite difficulty swallowing nausea diarrhea drugndashfood interaction effectsAssess household food security

With regard to malnutritionMild to moderately malnourished adults (BMI lt 185 kgm2) regardless of HIV status should receive supplementary

feeding Usually fortified blended foods such as CSB are provided but compressed bars or biscuits and lipid-based nutrient supplements (pastes) may also be used

Severely malnourished adults (BMI lt 16 kgm2) should receive a therapeutic food nutritionally equivalent to F100 For initial treatment of severely malnourished adults aged 19 to 75 years energy intake should be 40 kcalkgday for initial treatment of those aged 15 to 18 years energy intake should be 50 kcalkgday [212]

With regard to dietary intake [191 194]Energy intake in asymptomatic HIV infection should be increased by 10During infection the aim should be to reach the maximum achievable intake of 20 to 30 above normal intake

during the recovery phase intake should be increased to the maximum extent possiblePercentage of energy from protein and from fat should not be changed compared with that for persons in the HIV-

negative stateHowever as energy intake is increased the absolute amounts of protein and fat are also increasedIntake of 1 RNI of vitamins and minerals is recommended even though this may not be enough to correct nutritional

deficiencies in HIV-infected people but the lack of safe upper limits for HIV-infected people precludes recommend-ing higher intakes

BMI body mass index CSB cornndashsoya blend MUAC mid-upper-arm circumference RNI recommended nutrient intakeSource World Health Organization [187]



several of these (table 3) Thus without an additional micronutrient supplement moderately malnourished adults who receive supplementary feeding in the form of CSB which is usually added to a predominantly staple-food-based diet do not meet the micronutrient intake of 1 RNI that is recommended for HIV-infected people When other foods are used for supplementary feeding such as ready-to-use foods derived from RUTF micronutrient intake is more comparable to that of people treated for severe malnutrition because those foods have higher micronutrient specifications

Are F100 and its equivalents appropriate for treating malnourished HIV-positive adults It is important to note that F100 and RUTF were developed for treating severe acute malnutrition (SAM) in children and that the vitamin and mineral contents were set in propor-tion to energy (ie per 1000 kcal) rather than in absolute amounts required per day such as is the case with the RNI The rationale to set these contents per 1000 kcal is that the nutrients provided are required for rebuilding tissues (fat-free mass and fat mass) and to replenish depleted stores and these needs are higher for a person with a larger body that also requires more energy The amount of energy recommended per kilogram of body weight is lower for adults than for children (40 kcalkg for 19- to 75-year-olds versus 75 kcalkg for 7- to 10-year-olds) However a 40-kg adult who consumes enough RUTF to provide 1600 kcalday [197 198] would consume 34 g of iron 45 g of zinc 2688 RE of vitamin A etc (see intake from Plumpyrsquonut in table 3) These intakes and those of several other micronutrients would be well above the RNI but those of other micronutrients would be below the RNI

For some nutrients such as those required to con-stitute new tissue (phosphorus calcium magnesium etc) the higher intakes may be good but for nutrients that are essential to bodily functions and immunity (such as iron vitamin A etc) the requirement includ-ing an allowance to replenish repleted stores may not increase linearly with energy needs Within the range of body weight encountered among children suffer-ing from SAM the difference in absolute amount of nutrients consumed is within relatively small limits However when the amount of food consumed is increased to cover malnourished adults weighing up to 50 kg the absolute amount of certain micronutrients consumed becomes much higher But still at an intake of 1600 kcalday from RUTF all nutrient intakes would remain below the upper limits (ULs) of intake set for adults aged 19 to 70 years ULs are levels that should not be consistently exceeded but they have a generous safety margin so that intakes slightly over these levels

Note that these are macrominerals which are not typi-cally included in micronutrient preparations because of the larger amounts that are required per day ie hundreds of milligrams rather than quantities ranging from tenths to tens of milligrams

are not immediately harmful especially when they are only taken for a limited period of time However it is not known whether these ULs also apply to HIV-infected people

For moderately malnourished children nutrient intake levels have recently been proposed [199] that are between the RNI for their age group and the higher amounts given to children suffering from SAM Such guidance is also needed for HIV-infected people suf-fering from malnutrition in order to bridge the gap between current advice for nutrient intakes among HIV-infected people (ie increased energy intake and 1 RNIday of micronutrients) and the guidance for treat-ing moderate and severe malnutrition among adults which is also used for treating HIV-infected adults

Comments

raquo In principle HIV infection does not require differ-ent treatment in resource-limited settings However a higher prevalence of malnutrition later detection of the infection and limited resources present many different challenges that are unique to the manage-ment of HIV infection in resource-limited settings

raquo Lack of evidence for the applicability of both the RNIs and ULs of intake for HIV-infected people who may also suffer from some degree of malnutri-tion means that intake levels and guidance for non-HIV-infected people with or without moderate or severe malnutrition are also applied to HIV-infected people

Impact of food supplements

Because implementing dietary advice is not always possible and weight loss may occur even when it is followed and because there are many hypotheses with regard to specific nutrients that may have beneficial impacts several studies have assessed the impact of nutritional supplements Some of these studies have provided very specific nutrients to nonmalnourished HIV-infected people who have been consuming an apparently adequate diet and who may have suffered some degree of weight loss whereas others were conducted among severely malnourished people and provided highly nutritious foods as a total replacement of the patientsrsquo diet

Figure 5 shows the aspects and context that should be considered when comparing the results of studies of food supplements for HIV-infected people the characteristics of the patients among whom the study is conducted (age sex and physiological status nutri-tional status and HIV infection stage whether using ART basic diet before provision of food supplements) the ingredients and nutrient content of the food sup-plement the diet of patients while they are consuming the supplement (how much did the basic diet change in terms of nutrient content) and the treatment of HIV



disease during the course of the studyBelow we review food supplementation studies

conducted in resource-adequate and resource-limited settings and compare the nutrient contents of various food supplements

Main points

raquo The design of studies using food supplements varies widely with regard to supplements used charac-teristics of patients (HIV stage nutritional status age sex physiological status) treatment provided and basic diet Therefore findings obtained in one context are of limited value in another context

raquo The nutrients consumed whether from a home diet supplements or both need to be of the right kind and combination for regeneration of tissue in par-ticular muscle Increasing the fat content to increase the energy density of foods provided to severely malnourished patients is justified (except when fat malabsorption is a problem) but this should not be continued once weight lost has been recovered in order to avoid unfavorable triglyceride levels over-weight etc

raquo There is some evidence from resource-adequate set-tings that supplementation with specific nutrients can increase fat-free mass and reduce viral load

raquo The few studies with food supplements conducted in resource-limited settings focused on treating malnutrition and assessed its impact on HIV infec-tion outcome It is important to note that most of these people had advanced HIV disease in which case treatment of malnutrition is a complex task

that should be done in combination with treating HIV and other infections The foods provided were more-or-less commonly available commodities ie CSB and ready-to-use spreads

raquo Consumption of ready-to-use spreads resulted in faster weight gain than consumption of CSB and consumption of CSB resulted in greater weight gain than consumption of no food supplement in one study but not in another The better result with spreads may be related to their nutritional value higher energy density and ingredients as well as to their ease of use and possibly less sharing in the family

raquo Compared with no food supplements the spreads or CSB did not improve HIV disease progression or other indexes of HIV infection However adherence to ART was substantially better among patients who received food supplements

raquo The studies were too small to assess whether faster weight gain during the first few months of ART among moderately and severely malnourished patients receiving spreads than among those receiv-ing CSB has survival benefits

raquo When severe-to-moderate malnutrition has been

Note that this is different from the third main point where impact is reported from very specific nutrients that were added to an otherwise quite balanced diet consumed by HIV patients in resource-adequate settings This is very different from studying malnourished people with advanced HIV disease in resource-limited settings and CSB cannot be compared with a balanced diet supplemented with very specific nutrients

FIG 5 Factors affecting the impact of a food intervention on malnutrition and HIV disease outcome

Total food and nutrient intake

ndash What information and counseling is provided to the patient

ndash How much of the food supplement does the patient consume per day and for how long

ndash What else does the patient consumeTreatment adherence and progression of HIV-disease during the study period

Characteristics of food supplement

ndash Content of supplement

ndash Nutrients macro- and micronutrients protein quality essential amino acids essential fatty acids

ndash Anti-nutrients

ndash Energy density

ndash Amount provided per day

ndash Form of the food (palatability preparation required)

ndash Ingredients

ndash Packaging

ndash In what setting is the food provided (clinic community)

Starting point of patients and context

ndash Baseline nutritional status

ndash Target group (children women men etc)

ndash Food security situation

ndash Basic diet to which food supplement is added

ndash HIV-disease stage

ndash ART (yesno) and other treatment received

Impact of food intervention on malnutrition and HIV-disease (mortality viral load CD4 count)



treated nutritional quality of the diet still needs to be ensured by providing dietary advice and possibly also a complementary food supplement containing specific high-quality nutrients Such a complementary food supplement can range from a low-dose spread (45 gday such as Plumpyrsquodoz) to a micronutrient powder that provides only additional vitamins and minerals It is important to take both a qualitative and a quantitative approach when coun-seling patients or designing programs to improve nutrient intake Nutrient intake from the diet with or without specific fortified commodities needs to be estimated and compared with the RNI and gaps or grossly higher intakes need to be adjusted Where food insecurity prevents an adequate energy intake and hence reduces treatment adherence household food security needs to be improved as well

Evidence

Food supplementation studies in resource-adequate settings Three reviews have recently been published about nutritional intervention studies for HIV-infected people The Cochrane review by Mahlungulu and col-leagues aimed to evaluate the effectiveness of various macronutrient interventions such as a balanced diet a high-protein high-carbohydrate diet or a high-fat diet all given orally in reducing morbidity and mor-tality in adults and children living with HIV [200] Randomized controlled trials published before 2007 that evaluated the effectiveness of macronutrient inter-ventions compared with no nutritional supplements or placebo in the management of HIV infection in adults and children were eligible for inclusion in the review

It should be noted that providing a ldquoplacebordquo in a food intervention in the sense of providing a similar commodity without nutritional value is not possible Therefore in this context placebo usually refers to a commodity of the same macronutrient composition but without the specific tasteless nutrient that is being studied Such an approach can be chosen when specific often tasteless nutrients are studied but not when studying the impact of supplying macronutrients for which there is no placebo

Eight trials from developed countries with a total of 486 participants met the inclusion criteria The Cochrane review concluded that based on these stud-ies no firm conclusions can be drawn about the effects of macronutrient supplementation on morbidity and mortality in HIV-infected people With regard to the limited availability of suitable evidence the review concluded ldquoThere is an urgent need for high-quality adequately powered randomized controlled trials investigating the effectiveness of clearly specified macronutrient interventions in reducing morbidity and mortality in HIV-infected individuals living in devel-oping countries Interventions should be well-defined and targeted at specific target populations defined by

age (adults and children) CD4 lymphocyte count HIV load treatment status (presence and absence of treatment type of ART) and baseline nutritional status (undernourished adequately nourished or over-nourished)rdquo [200]

The Academy of Science of South Africa (ASSAf) having reviewed the same studies as well as studies and reports available from resource-limited settings concluded that there was limited evidence from ran-domized placebo-controlled trials that macronutri-ent supplementation is of benefit in HIV-infected individuals and that there was preliminary evidence that specific dietary supplements such as amino acid mixtures increase body weight and reduce HIV viral load [201ndash203] They also concluded that supplementa-tion with medium-chain triglycerides is more effective than supplementation with long-chain triglycerides in reducing HIV-associated intestinal dysfunction and fat malabsorption

Koethe and colleagues reviewed the evidence sup-porting macronutrient supplementation for HIV-infected adults in both resource-adequate and resource-limited settings [204] According to the authors nine trials from resource-adequate settings demonstrated improved energy and protein intake among patients given macronutrient supplements compared with that among patients given placebos or no supplements but no uniform improvement in body weight fat mass or fat-free mass only one study reported improved CD4 lymphocyte counts compared with the control group However these studies were conducted among food-secure patients The lowest mean BMI in any of the studies was 196 kgm2 The supplements provided in these studies were very specialized nutrition supplementsmdashsuch as medium-chain triglycerides L-glutamine and antioxidants an amino acid mixture with arginine glutamine and β-hydroxy-β-methylbutyrate a supplement with whey protein etcmdashand in most studies the control group received nutrition education and in some studies also an isonitrogenous formulation (ie with comparable protein content) Thus these studies basically exam-ined whether providing specific nutrients important for tissue reconstitution leads to increased body weight lean tissue mass and fat mass and found mixed results Replacement of part of the basic diet by the supple-ments appears to have been limited because of the specialized nature of the supplements

Food supplementation studies in resource-limited settings The two studies reviewed by Koethe and colleagues that were conducted in resource-limited settings were very different from those conducted in resource-adequate settings In the study by Cantrell and colleagues in Zambia among people starting ART one group of patients as part of treatment adher-ence counseling received CSB and a food ration for the household and the other group received no food



assistance [205] Compared with the basic diet before enrollment in the program the CSB received is likely to have improved energy intake among patients from food-insecure households as well as protein content and quality and micronutrient intake However it is widely recognized that the nutritional value of CSB is not adequate for treating moderate malnutrition among young children [206] and some of the reasons for this would also apply to its ability to meet the nutrient needs of malnourished HIV-infected people ie low energy density a limited content and bioavail-ability of micronutrients a lack of animal-source foods and a high antinutrient content The study found no significant differences between the intervention and control groups in weight gain (54 kg in the interven-tion group and 51 kg in the control group at 6 months 63 kg in the intervention group and 54 kg in the con-trol group at 12 months) or CD4 lymphocyte count However medication possession ratio (a measure of timeliness of clinic visits to receive refills calculated as 100ndash100 x [number of days late total number of days on treatment] where counting of number of days late started from the 4th day after the scheduled visit day) of 95 was 70 and 48 in the intervention and control groups respectively Thus the intervention most likely primarily addressed food insecurity and potentially mitigated side effects of ART treatment leading to increased treatment adherence It is also important to note that the group that did not receive food also gained more than 5 kg since starting ART which may primarily be the effect of stabilization of HIV infection due to ART

A study by Ndekha and colleagues compared two groups of patients with BMI under 185 kgm2 who were starting ART one group received a ready-to-use fortified spread (RUFS) and the other received CSB The composition of both supplements is shown in table 3 each provided approximately 50 of required energy needs [196] After 35 months of supplementa-tion there was a greater increase in BMI and fat-free body mass in the RUFS group (n = 245) than in the CSB group (n = 246) 22 versus 17 kgm2 and 29 versus 22 kg respectively Mortality rates did not differ (27 and 26 respectively) and CD4 lymphocyte count HIV load adherence to ART and quality of

Different formulations of CSB are currently available (according to WFP or US Agency for International Develop-ment [USAID] specifications) and WFP has recently revised its specifications However the main change WFP has made to CSB for general use is an improvement of micronutrient content The special CSB that is made available for moder-ately malnourished children under 5 years of age and for blanket feeding of children aged 6ndash23 months also includes milk powder oil and sugar to increase nutritional value and energy content and has tighter microbiologic limits As the special CSB becomes available it will first be provided to the special target groups of children mentioned above See de Pee and Bloem [206] for further details

life were also not different The reasons for the greater improvement in nutritional status in the RUFS group may be the composition of the supplement (higher energy density and higher nutritional value) and its use (it may have been shared less because it was ready-to-eat) In another paper [207] the authors assessed the outcome among the same patients 3 and 9 months after the 35-month supplementation period ended At 3 months the BMI did not differ between the two groups (n = 162 and n = 174 in the RUFS and the con-trol group respectively) at 12 months the 05 kgm2 difference that was observed at the end of the supple-mentation period (190 vs 185 kgm2 respectively p = 001) was observed again (203 vs 198 kgm2 respectively p = 22) but due to greater variation the difference was not significant any more The authors also compared their results after 35 months of food supplementation and 3 months later with historical data from patients who received ART but no food sup-plements [208] They concluded that patients receiving RUFS or CSB during ART had improved nutritional recovery (increased BMI after 14 weeks) as compared with those receiving no food supplement and that the effect was superior with RUFS However the food sup-plementation was stopped at 14 weeks and at 26 weeks the significant difference in BMI no longer existed The authors suggested that longer supplementation with food might have been required by these patients There was no difference with regard to hospitalizations and survival but the groups involved in the study were small (n = 104 for no food supplement n = 244 for RUFS and n = 245 for CSB) As was also found in the study by Cantrell et al [205] treatment adherence was better in the groups receiving supplements than in the group not receiving supplement (lt 1 in the supple-mented groups vs 9 in the nonsupplemented group stopped ART after 24 weeks)

Preliminary results of a randomized trial in Kenya that provided either nutrition counseling or nutrition counseling and enhanced CSB (with additional whey powder oil sugar and adjusted micronutrient premix) to patients receiving ART as well as to patients before the initiation of ART found that BMI increased in all groups but more among those that also received enhanced CSB The difference between groups receiv-ing and those not receiving enhanced CSB was larger among the pre-ART clients and BMI improvement was larger among people enrolled while on ART than among the pre-ART clients Six months after enroll-ment approximately 45 of the clients in the CSB group and approximately 55 in the nutrition coun-seling group were lost to follow-up (status unknown)

Unpublished observations from FANTA and the Kenya Medical Research Institute (KEMRI) presented at the International Conference of Nutrition in Bangkok October 2009



Two descriptive studies of food supplementation in resource-limited settings have also been reported In Malawi patients were followed for 6 months before food supplementation and also for 12 months after a food supplementation program had started [209] None of the patients received ART because the study was conducted in 200304 before ART became available free of charge The foods provided to families consisted of Likuni Phala (a locally produced fortified CSB) maize beans and oil BMI increased by 007 kgm2 in 100 days (not a statistically significant increase) among those not receiving supplementary food and by 046 to 049 kgm2 among those receiving supplementary food (p lt 05) The difference between the two periods ie before food supplementation started and when food was supplemented was almost significant (p = 08) Survival was higher among patients who also received oil a commodity that was introduced later in the program Because the patients were enrolled with advanced disease and did not receive ART the impact of food supplementation appears to have been limited but the higher survival among those who received oil as part of the ration is interesting However it should be noted that treatment was not randomized but rather was changed over time and that use of the food sup-plements was not monitored In fact very few studies have monitored the actual use of food supplements

A study in Malawi followed 60 patients with advanced HIV disease (25 with WHO stage 3 and 75 with WHO stage 4) 50 of whom had a BMI lt 16 kgm2 and 19 of whom had a BMI of 16 to lt 17 kgm2 and 133 of whom had started ART 1 or 2 months before they started to receive supplementary food [197] The patients received 500 gday of a locally made chickpea-sesame RUTF for 3 months (composition shown in table 3) The average consumption was 300 gday pro-viding 1590 kcalday After 3 months the mean weight gain was 25 kg and patient mobility had improved to such an extent that they were now able to come to the clinic to enroll in ART (Steve Collins personal com-munication) This weight gain is higher than that in Bangwe Malawi among patients receiving staples and fortified blended food (FBF) [209] and comparable to that among patients receiving fortified spread in the study by Ndekha and colleagues [196]

Composition of food supplements providedmdashspreads versus FBFs Table 3 compares the composition of dif-ferent foods that are provided to HIV-infected people including those used in the studies reviewed here The main things to note are the followingraquo The food supplements vary considerably in macro-

and micronutrient content both between ready-to-use spreads and CSB and within these two groups of foods

raquo The spreads have a much higher energy density due to a larger amount of fat and thus require consump-tion of a smaller amount in order to achieve the same

energy intakeraquo The zinc and iron contents of one of the spreads

(RUFS-PPB) were adjusted to be comparable to those of the CSB used in their study [196 207 208] and their levels were hence more comparable to the RNIs On the basis of the available studies it appears that in

settings of high food insecurity RUFS results in faster weight gain than CSB when provided to malnourished adults who have developed AIDS This finding is consistent with findings among moderately wasted children [210] and may be due both to the composition of the food (variety quality and relative proportions of macro- and micronutrients higher energy density and lower content of antinutrients) and to its use (less likely to be shared with other family members because it is ready to eat and more easily accepted as being a therapeutic food to be consumed exclusively by the patient) This faster improvement of nutritional status may be particularly of value among severely to moder-ately malnourished patients who are at increased risk for death However the cost of the spreads is approxi-mately three times higher than that of an FBF provid-ing the same amount of energy and it will therefore be worthwhile to assess whether it is possible to sustain the weight rapidly regained during a few months of RUFS consumption by continuing supplementation with an FBF and to calculate the cost-effectiveness of first using RUFS rather than FBF

As mentioned before nutrition education should always be part of HIV infection control Furthermore the composition of the diet and the nutritional status of the patient and its changes during treatment should guide the selection of a food supplement if any

Extrapolating results from studies conducted in one setting to another setting The design of studies using food supplements varies widely not only with regard to the supplements used but also the characteristics of the patients (HIV stage nutritional status age sex physiological status) the ART and other treatment they receive and their basic diet All these factors need to be taken into account when interpreting results and when considering the applicability of results of studies with particular foods conducted in a certain context to a different group of HIV-infected people in another context

Particular caution is necessary when extrapolating from studies conducted in resource-adequate settings and applying them to resource-limited settings [211] In general the impact of a nutritional intervention depends on nutritional status at the start which is usu-ally much better among patients in resource-adequate settings than among patients in resource-limited set-tings In resource-adequate settings the largest groups at risk for HIV are injection drug users and men having sex with men (MSM) This situation is different from that in sub-Saharan Africa where HIV affects men women and children The medication taken



in resource-adequate settings both ART (except for first-line treatment) and medication to treat second-ary infections is different from that used in resource-limited settings There are also substantial differences with regard to the composition of the experimental and control interventions the basic diet and ability to put the dietary advice in practice disease stage and treat-ment status of the participants [211]

Comments

raquo It is important to be specific about the nutrient content of foods that are provided because ldquonutri-tion providedrdquo depends entirely on macro- and micronutrient content protein quality antinutrients energy density etc Furthermore food supplements are usually consumed at home where they may be shared or mixed with family foods before consump-tion by the patient and rather than supplementing they may partly replace some of the patientrsquos usual diet Thus in order to assess the impact of the pro-vision of a certain food it is important to assess the total nutrient intake of the patient before and during supplementation Only when the resulting diet is of a good quality and quantity can it realistically be expected to make a difference to nutritional status and outcome

raquo In order to assess the quantity of different nutrients provided by a certain diet what foods would need to be added to increase nutrient content to required levels or whether adding a micronutrient supple-ment would be a more cost-effective solution linear programming can be used

raquo Whether ingested nutrients are used appropriately by the body depends not only on the kind combina-tion and quantity of nutrients but also on the bodyrsquos metabolic state and whether the patient is on ART

raquo A substantial amount of weight lost during infection or when there is a negative energy balance consists of lean tissue especially muscle thus it is important that weight gained consist of both lean tissue and fat mass

raquo In order to decide whether and what nutritional support to provide to which HIV-infected people we need to consider not only the therapeutic advantages of one supplement over another (or no supplement) and the way the supplements are used by patients in a particular context (which also depends on the messages that are provided to the patients about the supplements and their use as well as on the packag-ing of the product) but also how they can be deliv-ered and the financial and opportunity costs [212] Investigators need to recognize these questions and apply rigorous and ethical methodologies to help answer them

Discussion

The main points at the start of each subsection have summarized currently available evidence and where available current consensus Here we discuss the two different conceptual approaches to the relationship between nutrition and HIV infection and how this affects the way evidence is gathered and interpreted and programs in resource-limited settings are designed and we identify questions that need to be resolved urgently

The Academy of Sciences of South Africa stated in its 2007 report ldquoIt is clear that malnutrition per se is a condition that impacts negatively on health on so many levels that a justification to feed malnourished people on the basis of their increased risk of any single disease is only a small part of the rationalerdquo [201] This statement highlights very well the two different concepts that are being applied to nutrition in HIVAIDS a medical point of view versus a more holistic humanitarian assistance point of view

The medical approach examines the impact on disease outcome of specific (micro)nutrient supple-ments according to the same methodology that is used to assess the impact of medication and treatment protocols ie comparing the results obtained in the intervention group with those obtained in a group that receives an otherwise unchanged diet or a placebo sup-plement Because of the inclusion of a group receiving placebo or otherwise unchanged diet for comparison these trials usually use highly specific supplements that provide only a limited amount of energy Experts favor-ing a more holistic humanitarian assistance point of view treat malnutrition with an energy- and nutrient-rich food because of the many negative consequences of malnutrition for health and not primarily because of how this affects the outcome of a specific disease such as HIV However detailed knowledge of nutrition and its interaction with HIV infection is required in order to treat malnutrition in the most effective way affecting both outcomes Furthermore because treating malnutrition and providing food supplements is part of the individual medical treatment plan for HIV infec-tion and most financing for HIV programs aims to improve HIV disease control and outcome the benefit of nutritional support for HIV disease outcome needs to be clear

However as mentioned in the section ldquoHIV infec-tion and nutrition ndash review of nutrition interventionsrdquo gathering evidence of the impact of food interventions using the same approach as that used for medication is not possible because there is no placebo for macro-nutrient supplements and the net intervention is the actual change of the patientrsquos diet due to the receipt of the food supplement but not equal to the nutrient content of the supplement This change of diet is highly



context specific Thus the primary question should be not ldquoWhat food needs to be providedrdquo but ldquoWhat should be the daily intake of all essential nutrients and how can that be achievedrdquo In resource-limited set-tings food interventions for HIV-infected people have primarily focused on treating the malnourished (BMI lt 185 kgm2) where possible in conjunction with ART and used food commodities that were readily available such as ready-to-use spreads and FBFs such as CSB The recent publications on these food interventions have taken a predominantly medical approach and have not taken a close enough look at what specific nutrients were consumed and in what quantity

Furthermore people consume foods rather than nutrients and food consumption is affected by food security and cultural customs and beliefs as well as by feelings of discomfort (nausea) and physical problems (mouth ulcers diarrhea etc) which necessitates a more holistic multidisciplinary approach to the issue of nutrition and HIV infection At present much of the guidance for clinical practice and for HIV control programs in resource-limited settings is based on a combination of the medical and the more holistic humanitarian assistance approach Hsu and colleagues in their review of evidence for the relationship between macronutrients and HIVAIDS concluded ldquoIt seems reasonable to assume that nutritional interventions in HIVAIDS will enhance defense against infection pro-mote recovery and improve quality of life and survival despite the lack of properly conducted trialsrdquo [195]

Many questions remain about the nutrient intake that should be achieved by HIV-infected people WHO recommends on the basis of available evidence that micronutrient intake should be at the level of 1 RNI and it can be argued that intakes should be between 1 and 2 times the RNI where micronutrient deficien-cies are widely prevalent [201] and higher intakes are provided when treating severe malnutrition whether people are HIV infected or not For macronutrient intake guidelines for the proportions of energy from protein (12 to 15) fat and carbohydrates are not different from those for noninfected people but total energy intake should be increased (by 10 in asymp-tomatic adults 20 to 30 in symptomatic adults and 50 to 100 in symptomatic children with weight loss) which will also increase the absolute amounts of protein carbohydrates and fat consumed In case of wasting or weight loss or inability to consume the required amount of energy due to the required volume a greater proportion of energy can be derived from fat and sugar but the amount of saturated and trans-fatty acids should remain low to avoid unfavorable health effects in the longer term and the patient should be able to tolerate the higher fat and sugar levels The latter is most important during long-term ART use when the risks of insulin resistance dyslipidemia and overweight need to be carefully managed

Adequate and upper limits of nutrient intakes for HIV-infected people at different stages of infection and with different nutritional status should urgently be established This can then inform the formulation of dietary advice food commodities complementary food supplements and micronutrient supplements for addition to predominantly staple-based diets The utilization and impact of these commodities should be assessed in studies that take program realities into account when designing the optimal treatment and its delivery for the intervention group and compare the impact in this group to that in a group that receives prevailing treatment and support in compliance with ethical criteria In case prevailing treatment does not provide for a good comparison group the use of his-torical data can be considered

Unresolved questions with regard to nutritional guid-ance for HIV-infected people include the followingraquo Should different nutrient intakes (including both

macro- and micronutrients) and supportive meas-ures be recommended for patients at different stages of HIV infection and with different nutritional status

raquo Which nutrients including specific amino acids micronutrients macrominerals etc are most essen-tial to regain weight lost especially lean body mass and in what amounts

raquo Could supplementation with micronutrients in amounts of 1 RNIday increase appetite and when combined with ART and a balanced diet support regaining lean body mass

raquo What constitutes an optimal nutrient intake for patients with chronic diarrhea or gastrointestinal infection

raquo What are optimal energy and protein intake levels during metabolic stress Is substrate use impaired and can excess energy and protein be harmful

raquo What are safe ULs for nutrient intakes in HIV-infected people with different degrees of malnutri-tion and in those with no malnutrition

raquo Related to the above is the high intake of micronutri-ents by malnourished HIV-infected adults receiving RUTF-type products safe or should the vitamin and mineral contents be revised for use among adults

raquo What effect does nutritional intervention early in HIV infection have on preventing opportunistic infections and slowing disease progression

raquo What impact can be expected on disease progression and mortality from different nutrition interventions at different stages of disease Is the impact greater with earlier intervention

raquo To what extent is wasting in HIV-infected people in resource-limited settings due to food insecurity or to HIV disease itself (reduced food intake due to lack of appetite and other discomforts and increased energy requirement due to symptomatic disease)



Conclusions

The relationship between infection and nutrition has been known since the early 1900s but the role of nutri-tion in medical practice and public health has changed over time [8] With the advancement of antibiotics and pharmaceutical treatment and the improvement of diet and nutrition due to improvements in agriculture and standards of living attention to the role of nutri-tion in developed countries dwindled However the role of nutrition in infection was not forgotten and it truly resurfaced in the 1980s and 1990s when its role in reducing child mortality in developing countries was recognized and emphasized [8 9] Thus the role of nutrition in health and disease is now widely acknowledged and its importance for HIV infection control recognized However proving its worth at dif-ferent stages of HIV infection and under widely varying circumstances and deciding what nutrition to provide when and to whom remains very challenging

Treating malnutrition including micronutrient malnutrition in HIV infection is more complicated than preventing a deterioration of nutritional status and preventing a deterioration of nutritional status also slows progression of disease Therefore nutrition assessment education and counseling should start immediately after the diagnosis of HIV infection Whether the nutrition advice can be put into practice however depends on availability of and access to food including animal-source and plant-source foods Where ingredients for a balanced diet are not avail-able or accessible due to food insecurity and poverty provision of food supplements may be considered Providing cash or other livelihood support can also be considered but it is important that this results not only

in increased caloric intake but also in improvement of the nutritional quality of the diet

Good nutrition is of benefit to HIV-infected people and malnutrition such as wasting or weight loss is a clear indication that people are not coping very well in their battle against HIV disease progression When HIV infection is diagnosed at a relatively late stage and patients are malnourished food supplements are required for those who cannot acquire appropriate foods themselves At any time optimal food supple-ments should be provided together with ART and treatment of opportunistic infections and side effects

In summary the evidence as reviewed in this paper shows that raquo The relationship between nutrition and HIV infec-

tion is very complex and is modified by factors such as nutritional status including wasting or weight loss and micronutrient deficiencies HIV disease stage other physiological factors and diet

raquo The management of HIV disease requires a combi-nation of medical treatment nutrition assessment education and counseling food supplements where necessary and ongoing monitoring of outcome and adjustment of medical treatment and nutrition management

Acknowledgments

We thank the following people for their input and review Martin Bloem Nils Grede Tony Castleman Andrew Thorne-Lyman Mark Manary Eduardo Vil-lamor Pamela Fergusson Ian Darnton-Hill Annmarie Isler Francesca Erdelmann Tina van den Briel Mutinta Hambayi Mary Njoroge and Joris van Hees

References

1 Joint United Nations Programme on HIVAIDS (UNAIDS) 2008 Report on the global AIDSHIV epi-demic Geneva UNAIDS 2008

2 Quinn TC HIV epidemiology and the effects of antiviral therapy on long-term consequences AIDS 200822(suppl 3)S7ndash12

3 Sztam KA Fawzi WW Duggan C Macronutrient sup-plementation and food prices in HIV treatment J Nutr 2010140213ndash23

4 Victora CG Adair L Fall C Hallal P Martorell R Rich-ter L Sachdev HS Maternal and child undernutrition consequences for adult health and human capital Lancet 2008371340ndash57

5 Semba RD Tang AM Micronutrients and the pathogen-esis of human immunodeficiency virus infection Br J Nutr 199981181ndash9

6 Semba RD Darnton-Hill I de Pee S Addressing tuber-culosis in the context of malnutrition and HIV coinfec-tion Food Nutr Bull 201031(Suppl)S345ndashS364

7 Frega R Duffy F Rawat R Grede N Food inse-curity in the context of HIVAIDS a framework for a new era of programming Food Nutr Bull 201031(Suppl)S292ndashS312

8 Semba RD Nutrition and development a historical perspective In Semba RD Bloem MW eds Nutrition and health in developing countries 2nd ed Totowa NJ USA Humana Press 20081ndash31

9 Schroeder DG Malnutrition In Semba RD Bloem MW eds Nutrition and health in developing countries 2nd ed Totowa NJ USA Humana Press 2008341ndash76

10 Abrams B Duncan D Hertz-Picciotto I A prospective study of dietary intake and acquired immune deficiency syndrome in HIV-seropositive homosexual men J Acquir Immune Defic Syndr 19936949ndash58

11 Tang AM Graham NMH Kirby AJ McCall AD Wil-lett WC Saah AJ Dietary micronutrient intake and risk progression to acquired immunodeficiency syndrome (AIDS) in human immunodeficiency virus type 1



(HIV-1)-infected homosexual men Am J Epidemiol 19931381ndash15

12 Baum M Cassetti L Bonvehi P Shor-Posner G Lu Y Sau-berlich H Inadequate dietary intake and altered nutritional status in early HIV-1 infection Nutrition 19941016ndash20

13 Luder E Godfrey E Godbold J Simpson DM Assess-ment of nutritional clinical and immunologic status of HIV-infected inner-city patients with multiple risk factors J Am Diet Assoc 199595655ndash60

14 Smit E Graham NMH Tang A Flynn C Solomon L Vlahov D Dietary intake of community-based HIV-1 seropositive and seronegative injecting drug users Nutri-tion 199612496ndash501

15 Kim JH Spiegelman D Rimm E Gorbach SL The cor-relates of dietary intake among HIV-positive adults Am J Clin Nutr 200174852ndash61

16 Woods MN Spiegelman D Knox TA Forrester JE Connors JL Skinner SC Silva M Kim JH Gorbach SL Nutrient intake and body weight in a large HIV cohort that includes women and minorities J Am Diet Assoc 2002102203ndash11

17 Wig N Bhatt SP Sakhuja A Srivastava S Agarwal S Dietary adequacy in Asian Indians with HIV AIDS Care 200820370ndash5

18 Food and Nutrition Board Institute of Medicine Dietary reference intakes Applications in dietary assessment Washington DC National Academy Press 2000

19 Baum MK Shor-Posner G Bonvehi P Cassetti I Lu Y Mantero-Atienza E Beach RS Sauberlich HE Influence of HIV-infection on vitamin status and requirements Ann N Y Acad Sci 1992669165ndash73

20 Beach RS Mantero-Atienza E Shor-Posner G Javier JJ Szapocznik J Morgan R Sauberlich HE Cornwell PE Eisdorfer C Baum MK Specific nutrient abnormalities in asymptomatic HIV-1 infection AIDS 19926701ndash8

21 Tang AM Graham NM Semba RD Saah AJ Associa-tion between serum vitamin A and E levels and HIV-1 disease progression AIDS 199711613ndash20

22 Semba RD Graham NM Caiaffa WT Margolick JB Clement L Vlahov D Increased mortality associated with vitamin A deficiency during human immunode-ficiency virus type 1 infection Arch Intern Med 1993 1532149ndash54

23 Semba RD Caiaffa WT Graham NM Cohn S Vlahov D Vitamin A deficiency and wasting as predictors of mortality in human immunodeficiency virus-infected injection drug users J Infect Dis 19951711196ndash202

24 Kassu A Andualem B Van Nhien N Nakamori M Nishikawa T Yamamoto S Ota F Vitamin A deficiency in patients with diarrhea and HIV infection in Ethiopia Asia Pac J Clin Nutr 200716(suppl 1)323ndash8

25 Semba RD Miotti PG Chiphangwi JD Saah AJ Canner JK Dallabetta GA Hoover DR Maternal vitamin A deficiency and mother-to-child transmission of HIV-1 Lancet 19943431593ndash7

26 Semba RD Kumwenda N Taha TE Mtimavalye L Broadhead R Miotti PG Eisinger W Hoover D Chiphangwi JD Plasma and breast milk vitamin A as indicators of vitamin A status in pregnant women Int J Vitam Nutr Res 200070271ndash7

27 Friis H Gomo E Koestel P Ndhlovu P Nyazema N Krarup H Michaelsen KF HIV and other predictors of serum beta-carotene and retinol in pregnancy a

cross-sectional study in Zimbabwe Am J Clin Nutr 2001731058ndash65

28 Phuapradit W Chaturachinda K Taneepanichskul S Sirivarasry J Khupulsup K Lerdvuthisopon N Serum vitamin A and beta-carotene levels in pregnant women infected with human immunodeficiency virus-1 Obstet Gynecol 199687564ndash7

29 Dancheck B Nussenblatt V Ricks MO Kumwenda N Neville MC Moncrief DT Taha TE Semba RD Breast milk retinol concentrations are not associated with systemic inflammation among breast-feeding women in Malawi J Nutr 2005135223ndash6

30 Melikian G Mmiro F Ndugwa C Perry R Jackson JB Garrett E Tielsch J Semba RD Relation of vitamin A and carotenoid status to growth failure and mortality among Ugandan infants with human immunodeficiency virus Nutrition 200117567ndash72

31 Bogden JD Baker H Frank O Perez G Kemp F Bruen-ing K Louria D Micronutrient status and human immunodeficiency virus (HIV) infection Ann N Y Acad Sci 1990587189ndash95

32 Ullrich R Schneider T Heise W Schmidt W Averdunk R Riecken EO Zeitz M Serum carotene deficiency in HIV-infected patients Berlin DiarrhoeaWasting Syn-drome Study Group AIDS 19948661ndash5

33 Skurnick JH Bogden JD Baker H Kemp FW Sheffet A Quattrone G Louria DB Micronutrient profiles in HIV-1-infected heterosexual adults J Acquir Immune Defic Syndr Hum Retrovirol 19961275ndash83

34 Baeten JM McClelland RS Wener MH Bankson DD Lavreys L Mandaliya K Bwayo JJ Kreiss JK Relation-ship between markers of HIV-1 disease progression and serum beta-carotene concentrations in Kenyan women Int J STD AIDS 200718202ndash6

35 Stephensen CB Marquis GS Kruzich LA Douglas SD Aldrovandi GM Wilson CM Vitamin D status in adolescents and young adults with HIV infection Am J Clin Nutr 2006831135ndash41

36 Van Den Bout-Van Den Beukel CJ Fievez L Michels M Sweep FC Hermus AR Bosch ME Burger DM Bravenboer B Koopmans PP Van Der Ven AJ Vitamin D deficiency among HIV type 1-infected individuals in the Netherlands effects of antiretroviral therapy AIDS Res Hum Retroviruses 2008241375ndash82

37 Rodriacuteguez M Daniels B Gunawardene S Robbins GK High frequency of vitamin D deficiency in ambulatory HIV-positive patients AIDS Res Hum Retroviruses 2009259ndash14

38 Mehta S Hunter DJ Mugusi FM Spiegelman D Manji KP Giovannucci EL Hertzmark E Msamanga GI Fawzi WW Perinatal outcomes including mother-to-child transmission of HIV and child mortality and their association with maternal vitamin D status in Tanzania J Infect Dis 20092001022ndash30

39 Baum MK Shor-Posner G Lu Y Rosner B Sauberlich HE Fletcher MA Szapocznik J Eisdorfer C Buring JE Hennekens CH Micronutrients and HIV-1 disease progression AIDS 199591051ndash6

40 Jordao Junior AA Silveira S Figueiredo JF Vannucchi H Urinary excretion and plasma vitamin E levels in patients with AIDS Nutrition 199814423ndash6

41 Papathakis PC Rollins NC Chantry CJ Bennish ML Brown KH Micronutrient status during lactation



in HIV-infected and HIV-uninfected South African women during the first 6 mo after delivery Am J Clin Nutr 200785182ndash92

42 Coodley G Girard DE Vitamins and minerals in HIV infection J Gen Intern Med 19916472ndash9

43 Stephensen CB Marquis GS Jacob RA Kruzich LA Douglas SD Wilson CM Vitamins C and E in adoles-cents and young adults with HIV infection Am J Clin Nutr 200683870ndash9

44 Srinivas A Dias BF Antioxidants in HIV positive chil-dren Indian J Pediatr 200875347ndash50

45 Tang AM Graham NM Chandra RK Saah AJ Low serum vitamin B-12 concentrations are associated with faster human immunodeficiency virus type 1 (HIV-1) disease progression J Nutr 1997127345ndash51

46 Burkes RL Cohen H Krailo M Sinow RM Carmel R Low serum cobalamin levels occur frequently in the acquired immune deficiency syndrome and related disorders Eur J Haematol 198738141ndash7

47 Boudes P Zittoun J Sobel A Folate vitamin B12 and HIV infection Lancet 19903351401ndash2

48 Remacha AF Montagud M Cadafalch J Riera A Mar-tino R Gimferrer E Vitamin B12 transport proteins in patients with HIV-1 infection and AIDS Haematologica 19937884ndash8

49 Rule SA Hooker M Costello C Luck W Hoffbrand AV Serum vitamin B12 and transcobalamin levels in early HIV disease Am J Hematol 199447167ndash71

50 Paltiel O Falutz J Veilleux M Rosenblatt DS Gordon K Clinical correlates of subnormal vitamin B12 levels in patients infected with the human immunodeficiency virus Am J Hematol 199549318ndash22

51 Hepburn MJ Dyal K Runser LA Barfield RL Hepburn LM Fraser SL Low serum vitamin B12 levels in an outpatient HIV-infected population Int J STD AIDS 200415127ndash33

52 Friis H Gomo E Koestel P Ndhlovu P Nyazema N Krarup H Michaelsen KF HIV and other predictors of serum folate serum ferritin and hemoglobin in preg-nancy a cross-sectional study in Zimbabwe Am J Clin Nutr 2001731066ndash73

53 Castro L Goldani LZ Iron folate and vitamin B12 parameters in HIV-1 infected patients with anaemia in southern Brazil Trop Doct 20093983ndash5

54 Koch J Neal EA Schlott MJ Garcia-Shelton YL Chan MF Weaver KE Cello JP Zinc levels and infec-tions in hospitalized patients with AIDS Nutrition 199612515ndash8

55 Wellinghausen N Kern WV Joumlchle W Kern P Zinc serum level in human immunodeficiency virus-infected patients in relation to immunological status Biol Trace Elem Res 200073139ndash49

56 Totin D Ndugwa C Mmiro F Perry RT Jackson JB Semba RD Iron deficiency anemia is highly prevalent among human immunodeficiency virus-infected and uninfected infants in Uganda J Nutr 2002132324ndash9

57 Castaldo A Tarallo L Palomba E Albano F Russo S Zuin G Buffardi F Guarino A Iron deficiency and intestinal malabsorption in HIV disease J Pediatr Gas-troenterol Nutr 199622359ndash63

58 Ray A Ndugwa C Mmirot F Ricks MO Semba RD Soluble transferrin receptor as an indicator of iron deficiency in HIV-infected infants Ann Trop Paediatr

20072711ndash6 59 Semba RD Shah N Strathdee SA Vlahov D High

prevalence of iron deficiency and anemia among female injection drug users with and without HIV infection J Acquir Immune Defic Syndr 200229142ndash4

60 Dancheck B Tang AM Thomas AM Smit E Vlahov D Semba RD Injection drug use is an independent risk factor for iron deficiency and iron deficiency anemia among HIV-seropositive and HIV-seronegative women J Acquir Immune Defic Syndr 200540198ndash201

61 Semba RD Kumwenda N Hoover DR Taha TE Mtimavalye L Broadhead R Eisinger W Miotti PG Chiphangwi JD Assessment of iron status using plasma transferrin receptor in pregnant women with and with-out human immunodeficiency virus in Malawi Eur J Clin Nutr 200054872ndash7

62 Semba RD Taha TE Kumwenda N Mtimavalye L Broadhead R Miotti PG Chiphangwi JD Iron status and indicators of human immunodeficiency virus dis-ease severity among pregnant women in Malawi Clin Infect Dis 2001321496ndash9

63 Antelman G Msamanga GI Spiegelman D Urassa EJ Narh R Hunter DJ Fawzi WW Nutritional factors and infectious disease contribute to anemia among pregnant women with human immunodeficiency virus in Tanza-nia J Nutr 20001301950ndash7

64 Kupka R Msamanga GI Mugusi F Petraro P Hunter DJ Fawzi WW Iron status is an important cause of anemia in HIV-infected Tanzanian women but is not related to accelerated HIV disease progression J Nutr 20071372317ndash23

65 Dworkin BM Rosenthal WS Wormser GP Weiss L Selenium deficiency in the acquired immunode-ficiency syndrome JPEN J Parenter Enteral Nutr 198610405ndash7

66 Mantero-Atienza E Beach RS Gavancho MC Morgan R Shor-Posner G Fordyce-Baum MK Selenium status of HIV-1 infected individuals JPEN J Parenter Enteral Nutr 199115693ndash4

67 Semba RD Miotti PG Chiphangwi JD Liomba G Yang LP Saah AJ Dallabetta GA Hoover DR Infant mortality and maternal vitamin A deficiency during human immunodeficiency virus infection Clin Infect Dis 199521966ndash72

68 Semba RD Miotti P Chiphangwi JD Henderson R Dallabetta G Yang LP Hoover D Maternal vitamin A deficiency and child growth failure during human immunodeficiency virus infection J Acquir Immune Defic Syndr Hum Retrovirol 199714219ndash22

69 Chatterjee A Bosch RJ Hunter DJ Manji K Msamanga GI Fawzi WW Vitamin A and vitamin B-12 concen-trations in relation to morbidity and mortality among children born to HIV-infected women J Trop Pediatr 20105627ndash35

70 John GC Nduati RW Mbori-Ngacha D Overbaugh J Welch M Richardson BA Ndinya-Achola J Bwayo J Krieger J Onyango F Kreiss JK Genital shedding of human immunodeficiency virus type 1 DNA during pregnancy association with immunosuppression abnormal cervical or vaginal discharge and severe vitamin A deficiency J Infect Dis 199717557ndash62

71 Nduati RW John GC Richardson BA Overbaugh J Welch M Ndinya-Achola J Moses S Holmes K



Onyango F Kreiss JK Human immunodeficiency virus type 1-infected cells in breast milk association with immunosuppression and vitamin A deficiency J Infect Dis 19951721461ndash8

72 Villamor E Kapiga SH Fawzi WW Vitamin A serosta-tus and heterosexual transmission of HIV case-control study in Tanzania and review of the evidence Int J Vitam Nutr Res 20067681ndash5

73 MacDonald KS Malonza I Chen DK Nagelkerke NJ Nasio JM Ndinya-Achola J Bwayo JJ Sitar DS Aoki FY Plummer FA Vitamin A and risk of HIV-1 serocon-version among Kenyan men with genital ulcers AIDS 200115635ndash9

74 Thurnham DI Mburu AS Mwaniki DL Muniu EM Alumasa F de Wagt A Using plasma acute-phase pro-tein concentrations to interpret nutritional biomarkers in apparently healthy HIV-1-seropositive Kenyan adults Br J Nutr 2008100174ndash82

75 Mehendale SM Shepherd ME Brookmeyer RS Semba RD Divekar AD Gangakhedkar RR Joshi S Risbud AR Paranjape RS Gadkari DA Bollinger RC Low carotenoid concentration and the risk of HIV serocon-version in Pune India J Acquir Immune Defic Syndr 200126352ndash9

76 Graham SM Baeten JM Richardson BA Bankson DD Lavreys L Ndinya-Achola JO Mandaliya K Overbaugh J McClelland RS Higher pre-infection vitamin E levels are associated with higher mortality in HIV-1-infected Kenyan women a prospective study BMC Infect Dis 2007763

77 Tang AM Graham NMH Saah AJ Effects of micronutri-ent intake on survival in human immunodeficiency virus type 1 infection Am J Epidemiol 19961431244ndash56

78 Kanter AS Spencer DC Steinberg MH Soltysik R Yarnold PR Graham NM Supplemental vitamin B and progression to AIDS and death in black South African patients infected with HIV J Acquir Immune Defic Syndr 199921252ndash3

79 Graham NM Sorensen D Odaka N Brookmeyer R Chan D Willett WC Morris JS Saah AJ Relationship of serum copper and zinc levels to HIV-1 seropositivity and progression to AIDS J Acquir Immune Defic Syndr 19914976ndash80

80 Cirelli A Ciardi M de Simone C Sorice F Giordano R Ciaralli L Costantini S Serum selenium concentration and disease progress in patients with HIV infection Clin Biochem 199124211ndash4

81 Kupka R Msamanga GI Spiegelman D Morris S Mugusi F Hunter DJ Fawzi WW Selenium status is associated with accelerated HIV disease progression among HIV-1-infected pregnant women in Tanzania J Nutr 20041342556ndash60

82 Baum MK Shor-Posner G Lai S Zhang G Lai H Fletcher MA Sauberlich H Page JB High risk of HIV-related mortality is associated with selenium deficiency J Acquir Immune Defic Syndr Hum Retrovirol 199715370ndash4

83 Campa A Shor-Posner G Indacochea F Zhang G Lai H Asthana D Scott GB Baum MK Mortality risk in selenium-deficient HIV-positive children J Acquir Immune Defic Syndr Hum Retrovirol 199920508ndash13

84 Kupka R Msamanga GI Spiegelman D Rifai N Hunter DJ Fawzi WW Selenium levels in relation to morbidity and mortality among children born to HIV-infected

mothers Eur J Clin Nutr 2005591250ndash8 85 Kupka R Garland M Msamanga G Spiegelman D

Hunter D Fawzi W Selenium status pregnancy out-comes and mother-to-child transmission of HIV-1 J Acquir Immune Defic Syndr 200539203ndash10

86 Baeten JM Mostad SB Hughes MP Overbaugh J Bankson DD Mandaliya K Ndinya-Achola JO Bwayo JJ Kreiss JK Selenium deficiency is associated with shedding of HIV-1-infected cells in the female genital tract J Acquir Immune Defic Syndr 200126360ndash4

87 Shor-Posner G Miguez MJ Pineda LM Rodriguez A Ruiz P Castillo G Burbano X Lecusay R Baum M Impact of selenium status on the pathogenesis of myco-bacterial disease in HIV-1-infected drug users during the era of highly active antiretroviral therapy J Acquir Immune Defic Syndr 200229169ndash73

88 Chariot P Dubreuil-Lemaire ML Zhou JY Lamia B Dume L Larcher B Monnet I Levy Y Astier A Gher-ardi R Muscle involvement in human immunodefi-ciency virus-infected patients is associated with marked selenium deficiency Muscle Nerve 199720385ndash9

89 Serwadda D Mugerwa RD Sewankambo NK Lwegaba A Carswell JW Kirya GB Bayley AC Downing RG Tedder RS Clayden SA Dalgleish AG Slim disease a new disease in Uganda and its association with HTLV-III infection Lancet 19852849ndash52

90 Wheeler DA Gibert CL Launer CA Muurahainen N Elion RA Abrams DI Bartsch GE Weight loss as a predictor of survival and disease progression in HIV infection Terry Beirn Community Programs for Clini-cal Research on AIDS J Acquir Immune Defic Syndr Hum Retrovirol 19981880ndash5

91 Tang AM Forrester J Spiegelman D Knox TA Tchetgen E Gorbach SL Weight loss and survival in HIV-positive patients in the era of highly active antiretroviral therapy J Acquir Immune Defic Syndr 200231230ndash6

92 Jerene D Endale A Hailu Y Lindtjoslashrn B Predictors of early death in a cohort of Ethiopian patients treated with HAART BMC Infect Dis 20066136

93 Malvy E Thiebaut R Marimoutou C Dabis F Weight loss and body mass index as predictors of HIV disease progression to AIDS in adults Aquitaine cohort France 1985ndash1997 J Am Coll Nutr 200120609ndash15

94 Mangili A Murman DH Zampini AM Wanke CA Nutrition and HIV infection review of weight loss and wasting in the era of highly active antiretroviral therapy from the nutrition for healthy living cohort Clin Infect Dis 200642836ndash42

95 Severe P Leger P Charles M Noel F Bonhomme G Bois G George E Kenel-Pierre S Wright PF Gulick R Johnson WD Jr Pape JW Fitzgerald DW Antiretroviral therapy in a thousand patients with AIDS in Haiti N Engl J Med 20053532325ndash34

96 Paton NI Sangeetha S Earnest A Bellamy R The impact of malnutrition on survival and CD4 count response in HIV-infected patients starting antiretroviral therapy HIV Med 20067323ndash30

97 van der Sande MA Schim van der Loeff MF Aveika AA Sabally S Togun T Sarge-Njie R Alabi AS Jaye A Corrah T Whittle HC Body mass index at time of HIV diagnosis a strong and independent predictor of sur-vival J Acquir Immune Defic Syndr 2004371288ndash94

98 Wanke CA Silva M Knox TA Forrester J Speigelman D



Gorbach SL Weight loss and wasting remain common complications in individuals infected with human immunodeficiency virus in the era of highly active antiretroviral therapy Clin Infect Dis 200031803ndash5

99 Tang AM Jacobson DL Spiegelman D Knox TA Wanke C Increasing risk of 5 or greater unintentional weight loss in a cohort of HIV-infected patients 1995 to 2003 J Acquir Immune Defic Syndr 20054070ndash6

100 Zachariah R Fitzgerald M Massaquoi M Pasulani O Arnould L Makombe S Harries AD Risk factors for high early mortality in patients on antiretroviral treatment in a rural district of Malawi AIDS 2006 202355ndash60

101 Schwenk A Beisenherz A Romer K Kremer G Salzberger B Elia M Phase angle from bioelectrical impedance analysis remains an independent predictive marker in HIV-infected patients in the era of highly active antiretroviral treatment Am J Clin Nutr 2000 72496ndash501

102 Kotler DP Tierney AR Wang J Pierson RNJ Magnitude of body-cell-mass depletion and the timing of death from wasting in AIDS Am J Clin Nutr 198950444ndash7

103 Babameto G Kotler DP Malnutrition in HIV infection Gastroenterol Clin North Am 199726393ndash415

104 Wanke C Kotler D The approach to diagnosis and treat-ment of HIV wasting J Acquir Immune Defic Syndr 200437S284ndash8

105 Saghayam S Kumarasamy N Cecelia AJ Solomon S Mayer K Wanke C Weight and body shape change in a treatment-naiumlve population after 6 months of nevirap-ine-based generic highly active antiretroviral therapy in South India Clin Infect Dis 200744295ndash300

106 Grunfeld C Pang M Shimizu L Shigenaga JK Jensen P Feingold KR Resting energy expenditure caloric intake and short-term weight change in human immunodefi-ciency virus infection and the acquired immunodefi-ciency syndrome Am J Clin Nutr 199255455ndash60

107 Grunfeld C What causes wasting in AIDS N Engl J Med 1995333123ndash4

108 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 199358417ndash26

109 Macallan DC Wasting in HIV infection and AIDS J Nutr 1999129238Sndash42S

110 Macallan DC Nutrition and immune function in human immunodeficiency virus infection Proc Nutr Soc 199958743ndash8

111 Macallan DC Noble C Baldwin C Jebb SA Prentice AM Coward WA Sawyer MB McManus TJ Griffin GE Energy expenditure and wasting in human immunode-ficiency virus infection N Engl J Med 199533383ndash8

112 Young J HIV and medical nutrition therapy J Am Diet Assoc 199710S161ndash7

113 Grinspoon S Mulligan K Weight loss and wasting in patients infected with human immunodeficiency virus Clin Infect Dis 200336S69ndash78

114 Villamor E Manji K Fawzi WW Human Immunodefi-ciency virus infection In Semba RD Bloem MW eds Nutrition and health in developing countries 2nd ed Totowa NJ USA Humana Press 2008307ndash39

115 Michaelsen KF Hoppe C Roos N Kaestel P Stougaard M Lauritzen L Moslashlgaard C Girma T Friis H Choice

of foods and ingredients for moderately malnourished children 6 months to 5 years of age Food Nutr Bull 200930S344ndash405

116 Coutsoudis A Bobat RA Coovadia HM Kuhn L Tsai WY Stein ZA The effects of vitamin A supplementa-tion on the morbidity of children born to HIV-infected women Am J Public Health 1995851076ndash81

117 Fawzi WW Mbise RL Hertzmark E Fataki MR Her-rera MG Ndossi G Spiegelman D A randomized trial of vitamin A supplements in relation to mortality among human immunodeficiency virus-infected and uninfected children in Tanzania Pediatr Infect Dis J 199918127ndash33

118 Fawzi WW Mbise R Spiegelman D Fataki M Hertz-mark E Ndossi G Vitamin A supplements and diarrheal and respiratory tract infections among children in Dar es Salaam Tanzania J Pediatr 2000137660ndash7

119 Villamor E Mbise R Spiegelman D Hertzmark E Fataki M Peterson KE Ndossi G Fawzi WW Vitamin A supplements ameliorate the adverse effect of HIV-1 malaria and diarrheal infections on child growth Pedi-atrics 2002109E6

120 Hanekom WA Yogev R Heald LM Edwards KM Hussey GD Chadwick EG Effect of vitamin A therapy on serologic responses and viral load changes after influ-enza vaccination in children infected with the human immunodeficiency virus J Pediatr 2000136550ndash2

121 Semba RD Ndugwa C Perry RT Clark TD Jackson JB Melikian G Tielsch J Mmiro F Effect of periodic vitamin A supplementation on mortality and morbid-ity of human immunodeficiency virus-infected chil-dren in Uganda a controlled clinical trial Nutrition 20052125ndash31

122 Kumwenda N Miotti PG Taha TE Broadhead R Biggar RJ Jackson JB Melikian G Semba RD Antena-tal vitamin A supplementation increases birth weight and decreases anemia among infants born to human immunodeficiency virus-infected women in Malawi Clin Infect Dis 200235618ndash24

123 Humphrey JH Iliff PJ Marinda ET Mutasa K Moulton LH Chidawanyika H Ward BJ Nathoo KJ Malaba LC Zijenah LS Zvandasara P Ntozini R Mzengeza F Mahomva AI Ruff AJ Mbizvo MT Zunguza CD ZVITAMBO Study Group Effects of a single large dose of vitamin A given during the postpartum period to HIV-positive women and their infants on child HIV infection HIV-free survival and mortality J Infect Dis 2006193860ndash71

124 Humphrey JH Hargrove JW Malaba LC Iliff PJ Moulton LH Mutasa K Zvandasara P Nathoo KJ Mzengeza F Chidawanyika H Zijenah LS Ward BJ ZVITAMBO Study Group HIV incidence among post-partum women in Zimbabwe risk factors and the effect of vitamin A supplementation AIDS 2006201437ndash46

125 Miller MF Stoltzfus RJ Iliff PJ Malaba LC Mbuya NV Zimbabwe Vitamin A for Mothers and Babies Project (ZVITAMBO) Study Group Humphrey JH Effect of maternal and neonatal vitamin A supplementation and other postnatal factors on anemia in Zimbabwean infants a prospective randomized study Am J Clin Nutr 200684212ndash22

126 Baeten JM McClelland RS Overbaugh J Richardson BA Emery S Lavreys L Mandaliya K Bankson DD



Ndinya-Achola JO Bwayo JJ Kreiss JK Vitamin A sup-plementation and human immunodeficiency virus type 1 shedding in women results of a randomized clinical trial J Infect Dis 20021851187ndash91

127 Alpha-Tocopherol Beta Carotene Cancer Prevention Study Group The effect of vitamin E and β carotene on the incidence of lung cancer and other cancers in male smokers N Engl J Med 19943301029ndash35

128 Albanes D Heinonen OP Taylor PR Virtamo J Edwards BK Rautalahti M Hartman AM Palmgren J Freedman LS Haapakoski J Barrett MJ Pietinen P Malila N Tala E Liippo K Salomaa ER Tangrea JA Teppo L Askin FB Taskinen E Erozan Y Greenwald P Huttunen JK α-Tocopherol and β-carotene supplements and lung cancer incidence in the Alpha-Tocopherol Beta-Carotene Cancer Prevention Study effects of base-line characteristics and study compliance J Natl Cancer Inst 1996881560ndash70

129 Toumlrnwall ME Virtamo J Korhonen PA Virtanen MJ Taylor PR Albanes D Huttunen JK Effect of α-tocopherol and β-carotene supplementation on coro-nary heart disease during the 6-year post-trial follow-up in the ATBC study Eur Heart J 2004251171ndash8

130 Omenn GS Goodman GE Thornquist MD Balmes J Cullen MR Glass A Keogh JP Meyskens FL Val-anis B Williams JH Barnhart S Hammar S Effects of a combination of beta carotene and vitamin A on lung cancer and cardiovascular disease N Engl J Med 19963341150ndash5

131 Palozza P Prooxidant actions of carotenoids in biologic systems Nutr Rev 199856257ndash65

132 McGill CR Green NR Meadows MC Gropper SS Beta-carotene supplementation decreases leukocyte superoxide dismutase activity and serum glutathione peroxidase concentration in humans J Nutr Biochem 200314656ndash62

133 Siems W Wiswedel I Salerno C Crifograve C Augustin W Schild L Langhans CD Sommerburg O β-Carotene breakdown products may impair mitochondrial func-tions mdash potential side effects of high-dose β-carotene supplementation J Nutr Biochem 200516385ndash97

134 Coodley GO Coodley MK Lusk R Green TR Bakke AC Wilson D Wachenheim D Sexton G Salveson C Beta-carotene in HIV infection an extended evaluation AIDS 199610967ndash73

135 Nimmagadda AP Burri BJ Neidlinger T OlsquoBrien WA Goetz MB Effect of oral beta-carotene supplementation on plasma human immunodeficiency virus (HIV) RNA levels and CD4+ cell counts in HIV-infected patients Clin Infect Dis 1998271311ndash3

136 Coutsoudis A Pillay K Spooner E Kuhn L Coovadia HM Randomized trial testing the effect of vitamin A supplementation on pregnancy outcomes and early mother-to-child HIV-1 transmission in Durban South Africa South African Vitamin A Study Group AIDS 1999131517ndash24

137 Fawzi WW Msamanga GI Hunter D Renjifo B Antel-man G Bang H Manji K Kapiga S Mwakagile D Essex M Spiegelman D Randomized trial of vitamin supplements in relation to transmission of HIV-1 through breastfeeding and early child mortality AIDS 2002161935ndash44

138 Fawzi W Msamanga G Antelman G Xu C Hertzmark

E Spiegelman D Hunter D Anderson D Effect of pre-natal vitamin supplementation on lower-genital levels of HIV type 1 and interleukin type 1 beta at 36 weeks of gestation Clin Infect Dis 200438716ndash22

139 Austin J Singhal N Voigt R Smaill F Gill MJ Walmsley S Salit I Gilmour J Schlech WF 3rd Choudhri S Rach-lis A Cohen J Trottier S Toma E Phillips P Ford PM Woods R Singer J Zarowny DP Cameron DW CTN 091CRIT Cartenoids Study Group A community ran-domized controlled clinical trial of mixed carotenoids and micronutrient supplementation of patients with acquired immunodeficiency syndrome Eur J Clin Nutr 2006601266ndash76

140 Spada C Treitinger A Reis M Masokawa IY Verdi JC Luiz MC Silveira MV Oliveira OV Michelon CM Avila-Juacutenior S Gil DO Ostrowsky S An evaluation of antiretroviral therapy associated with alpha-tocopherol supplementation in HIV-infected patients Clin Chem Lab Med 200240456ndash9

141 de Souza Juacutenior O Treitinger A Baggio GL Michelon C Verdi JC Cunha J Ferreira SI Spada C Alpha-tocopherol as an antiretroviral therapy supplement for HIV-1-infected patients for increased lymphocyte viability Clin Chem Lab Med 20053376ndash82

142 Allard JP Aghdassi E Chau J Tam C Kovacs CM Salit IE Walmsley SL Effects of vitamin E and C supplemen-tation on oxidative stress and viral load in HIV-infected subjects AIDS 1998121653ndash9

143 Jaruga P Jaruga B Gackowski D Olczak A Halota W Pawlowska M Olinski R Supplementation with antioxi-dant vitamins prevents oxidative modification of DNA in lymphocytes of HIV-infected patients Free Radic Biol Med 200232414ndash20

144 McComsey G Southwell H Gripshover B Salata R Valdez H Effect of antioxidants on glucose metabolism and plasma lipids in HIV-infected subjects with lipoat-rophy J Acquir Immune Defic Syndr 200433605ndash7

145 Delmas-Beauvieux MC Peuchant E Couchouron A Constans J Sergeant C Simonoff M Pellegrin JL Leng B Conri C Clerc M The enzymatic antioxidant system in blood and glutathione status in human immunode-ficiency virus (HIV)-infected patients effects of sup-plementation with selenium or beta-carotene Am J Clin Nutr 199664101ndash7

146 Look MP Rockstroh JK Rao GS Barton S Lemoch H Kaiser R Kupfer B Sudhop T Spengler U Sauerbruch T Sodium selenite and N-acetylcysteine in antiretroviral-naive HIV-1-infected patients a randomized controlled pilot study Eur J Clin Invest 199828389ndash97

147 Burbano X Miguez-Burbano MJ McCollister K Zhang G Rodriguez A Ruiz P Lecusay R Shor-Posner G Impact of a selenium chemoprevention clinical trial on hospital admissions of HIV-infected participants HIV Clin Trials 20023483ndash91

148 Hurwitz BE Klaus JR Llabre MM Gonzalez A Law-rence PJ Maher KJ Greeson JM Baum MK Shor-Posner G Skyler JS Schneiderman N Suppression of human immunodeficiency virus type 1 viral load with selenium supplementation a randomized controlled trial Arch Intern Med 2007167148ndash54

149 Ross DA Cousens S Wedner SH Sismanidis C Does selenium supplementation slow progression of HIV Potentially misleading presentation of the results of a



trial Arch Intern Med 20071671555ndash6 150 Passaretti C Gupta A Selenium and HIV-1 hype or

hope Arch Intern Med 20071672530ndash1 151 Dillon DM Stapleton JT Selenium effects on

HIV RNA and CD4 cell counts Arch Intern Med 2007671556ndash7

152 Kupka R Mugusi F Aboud S Msamanga GI Finkelstein JL Spiegelman D Fawzi WW Randomized double-blind placebo-controlled trial of selenium supplements among HIV-infected pregnant women in Tanzania effects on maternal and child outcomes Am J Clin Nutr 2008871802ndash8

153 Kupka R Mugusi F Aboud S Hertzmark E Spiegelman D Fawzi WW Effect of selenium supplements on hemo-globin concentration and morbidity among HIV-1-in-fected Tanzanian women Clin Infect Dis 2009481475ndash8

154 Fawzi WW Villamor E Msamanga GI Antelman G Aboud S Urassa W Hunter D A trial of zinc supple-ments in relation to pregnancy outcomes hematologic indicators and T-cell counts among HIV-1 infected women in Tanzania Am J Clin Nutr 200581161ndash7

155 Villamor E Aboud S Koulinska IN Kupka R Urassa W Chaplin B Msamanga G Fawzi WW Zinc supplemen-tation to HIV-1-infected pregnant women effects on maternal anthropometry viral load and early mother-to-child transmission Eur J Clin Nutr 200660862ndash9

156 Caacutercamo C Hooton T Weiss NS Gilman R Wener MH Chavez V Meneses R Echevarria J Vidal M Holmes KK Randomized controlled trial of zinc supplementa-tion for persistent diarrhea in adults with HIV-1 infec-tion J Acquir Immune Defic Syndr 200643197ndash201

157 Deloria-Knoll M Steinhoff M Semba RD Nelson K Vlahov D Meinert CL Effect of zinc and vitamin A sup-plementation on antibody responses to a pneumococcal conjugate vaccine in HIV-positive injection drug users a randomized trial Vaccine 2006241670ndash9

158 Clark TD Semba RD Iron supplementation during human immunodeficiency virus infection a double-edged sword Med Hypotheses 200157476ndash9

159 Olsen A Mwaniki D Krarup H Friis H Low-dose iron supplementation does not increase HIV-1 load J Acquir Immune Defic Syndr 200436637ndash8

160 Semba RD Ricketts EP Mehta S Netski D Thomas D Kirk G Wu AW Vlahov D Effect of micronutrients and iron supplementation on hemoglobin iron status and plasma hepatitis C and HIV RNA levels in female injection drug users a controlled clinical trial J Acquir Immune Defic Syndr 200745298ndash303

161 Fawzi WW Msamanga GI Spiegelman D Urassa EJ McGrath N Mwakagile D Antelman G Mbise R Her-rera G Kapiga S Willett W Hunter DJ Randomised trial of effects of vitamin supplements on pregnancy outcomes and T cell counts in HIV-1-infected women in Tanzania Lancet 19983511477ndash82

162 Villamor E Msamanga G Spiegelman D Antelman G Peterson KE Hunter DJ Fawzi WW Effect of multivita-min and vitamin A supplements on weight gain during pregnancy among HIV-1-infected women Am J Clin Nutr 2002761082ndash90

163 Fawzi WW Msamanga G Hunter D Urassa E Renjifo B Mwakagile D Hertzmark E Coley J Garland M Kapiga S Antelman G Essex M Spiegelman D Randomized trial of vitamin supplements in relation to vertical

transmission of HIV-1 in Tanzania J Acquir Immune Defic Syndr 200023246ndash54

164 Fawzi WW Msamanga GI Wei R Spiegelman D Antelman G Villamor E Manji K Hunter D Effect of providing vitamin supplements to human immu-nodeficiency virus-infected lactating mothers on the childlsquos morbidity and CD4+ cell counts Clin Infect Dis 2003361053ndash62

165 Villamor E Saathoff E Bosch RJ Hertzmark E Baylin A Manji K Msamanga G Hunter DJ Fawzi WW Vitamin supplementation of HIV-infected women improves post-natal child growth Am J Clin Nutr 200581880ndash8

166 Fawzi WW Msamanga GI Kupka R Spiegelman D Villamor E Mugusi F Wei R Hunter D Multivitamin supplementation improves hematologic status in HIV-infected women and their children in Tanzania Am J Clin Nutr 2007851335ndash43

167 Fawzi WW Msamanga GI Spiegelman D Wei R Kapiga S Villamor E Mwakagile D Mugusi F Hertzmark E Essex M Hunter DJ A randomized trial of multivitamin supplements and HIV disease progression and mortality N Engl J Med 200435123ndash32

168 Villamor E Saathoff E Manji K Msamanga G Hunter DJ Fawzi WW Vitamin supplements socioeconomic status and morbidity events as predictors of wasting in HIV-infected women from Tanzania Am J Clin Nutr 200582857ndash65

169 Kelly P Musonda R Kafwembe E Kaetano L Keane E Farthing M Micronutrient supplementation in the AIDS diarrhoea-wasting syndrome in Zambia a rand-omized controlled trial AIDS 199913495ndash500

170 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 lim-ited effects on intestinal infectious disease and mortality in a Zambian population of mixed HIV status a cluster randomized trial Am J Clin Nutr 2008881010ndash7

171 Jiamton S Pepin J Suttent R Filteau S Mahakkanukrauh B Hanshaoworakul W Chaisilwattana P Suthipinit-tharm 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 2003172461ndash9

172 McClelland RS Baeten JM Overbaugh J Richardson BA Mandaliya K Emery S Lavreys L Ndinya-Achola JO Bankson DD Bwayo JJ Kreiss JK Micronutrient supplementation increases genital tract shedding of HIV-1 in women results of a randomized trial J Acquir Immune Defic Syndr 2004371657ndash63

173 Kaiser JD Campa AM Ondercin JP Leoung GS Pless RF Baum MK Micronutrient supplementation increases CD4 count in HIV-infected individuals on highly active antiretroviral therapy a prospective double-blinded placebo-controlled trial J Acquir Immune Defic Syndr 200642523ndash8

174 Batterham M Gold J Naidoo D Lux O Sadler S Bridle S Ewing M Oliver C A preliminary open label dose comparison using an antioxidant regiment to determine the effect on viral load and oxidative stress in men with HIVAIDS Eur J Clin Nutr 200155107ndash14

175 Berneis K Battegay M Bassetti S Nuesch R Leisibach A Bilz S Keller U Nutritional supplements combined with dietary counseling diminish whole body protein



catabolism in HIV-infected patients Eur J Clin Invest 20003087ndash94

176 Paton NI Chua Y-K Earnest A Chee CBE Randomized controlled trial of nutritional supplementation in patients with newly diagnosed tuberculosis and wasting Am J Clin Nutr 200480460ndash5

177 Johns KKJ Beddall MJ Corrin RC Anabolic steroids for the treatment of weight loss in HIV-infected individuals Cochrane Database Syst Rev 20054CD005483

178 Gelato MM McNurlan M Freedland E Role of recom-binant human growth hormone in HIV-associated wasting and cachexia pathophysiology and rationale for treatment Clin Ther 2007292269ndash88

179 Mda S van Raaij JMA MacIntyre UE de Villiers FPR Kok FJ Improved appetite after multi-micronutrient supplementation for six months in HIV-infected South African children Appetite 201054150ndash5

180 Shikuma CM Zacklin R Sattler F Mildvan D Nyang-weso P Alston B Evans S Mulligan K Changes in weight and lean body mass during highly active antiret-roviral therapy Clin Infect Dis 2004391223ndash30

181 Madec Y Szumilin E Genevier C Ferradini L Balkan S Pujades M Fontanet A Weight gain at 3 months of antiretroviral therapy is strongly associated with sur-vival evidence from two developing countries AIDS 200923853ndash61

182 Castleman T Seumo-Fosso E Cogill B Food and nutri-tion implications of antiretroviral therapy in resource limited settings Food and Nutrition Technical Assist-ance (FANTA) Technical Note No 7 Washington DC FANTA 2004

183 Ivers LC Cullen KA Freedberg KA Block S Coates J Webb P HIVAIDS undernutrition and food insecu-rity Clin Infect Dis 2009491096ndash102

184 Weiser SD Tuller DM Frongillo EA Senkungu J Muki-ibi N Bangsberg DR Food insecurity as a barrier to sustained antiretroviral therapy adherence in Uganda PLoS ONE 20105(4)e10340 Available at httpwwwncbinlmnihgovpmcarticlesPMC2860981pdfpone0010340pdf Accessed 22 September 2010

185 Weiser SD Frongillo EA Ragland K Hogg RS Riley ED Bangsberg DR Food insecurity is associated with incomplete HIV RNA suppression among homeless and marginally housed HIV-infected individuals in San Francisco J Gen Intern Med 20092414ndash20

186 Weiser SD Fernandes KA Brandson EK Lima VD Anema A Bangsberg DR Montaner JS Hogg RS The association between food insecurity and mortality among HIV-infected individuals on HAART J Acquir Immune Defic Syndr 20093342ndash9

187 World Health Organization Essential prevention and care interventions for adults and adolescents living with HIV in resource-limited settings Geneva WHO 2008

188 Piwoz E Nutrition and HIVAIDS evidence gaps and priority actions Washington DC US Agency for International Development 2004

189 Greenaway K GAIN Working Paper Series No 2 food by prescription a landscape paper Geneva GAIN UNAIDS WFP 2009 Available at httpwwwgain-healthorgsitesdefaultfilesWorking20Paper202pdf Accessed 19 August 2010

190 World Health Organization Nutrient requirements for

people living with HIVAIDS Report of a technical consultation Geneva WHO 2003

191 World Health Organization Management of severe malnutrition A manual for physicians and other senior health workers Geneva WHO 1999

192 World Health Organization Department of Nutrition for Health and Development Executive summary of a scientific review Consultation on nutrition and HIVAIDS in Africa evidence lessons and recommenda-tions for action Durban South Africa 10ndash13 April 2005 Available from httpwwwwhointentitynutritiontopicsExecutive20Summary20WHOpdf Accessed 14 September 2010

193 Food and Nutrition Technical Assistance HIVAIDS a guide for nutritional care and support 2nd ed Wash-ington DC FANTA Academy for Educational Develop-ment 2004

194 Department of Health Directorate Nutrition National guidelines on nutrition for people living with HIV AIDS TB and other chronic debilitating conditions Pre-toria South Africa Department of Health 20061ndash77

195 Hsu JW-C Pencharz PB Macallan D Tomkins A Macronutrients and HIVAIDS a review of current evidence Consultation on Nutrition and HIVAIDS in Africa evidence lessons and recommendations for action Durban South Africa 10ndash13 April 2005 Geneva World Health Organization Available from httpwwwwhointentitynutritiontopicsPaper20Number20120-20Macronutrientspdf Accessed 14 September 2010

196 Ndekha M van Oosterhout JJ Zijlstra E Manary M Saloojee H Manary M Supplementary feeding with either ready-to-use fortified spread or corn-soy blend in wasted adults starting antiretroviral therapy in Malawi randomized investigator blinded controlled trial BMJ 2009338b1867

197 Bahwere P Sadler K Collins S Acceptability and effectiveness of chickpea sesame-based ready-to-use therapeutic food in malnourished HIV-positive adults Patient Prefer Adherence 2009367ndash75

198 Dibari F A qualitative investigation of Plumpynutreg consumption and access in adults enrolled in an MoHMSF HIV programme in Kenya 2008 Available at httpwwwvalidinternationalorgdemoreportsHIV08051520MSF20-20abstractpdf Accessed 19 August 2010

199 Golden MH Proposed recommended nutrient densities for moderately malnourished children Food Nutr Bull 200930S267ndash343

200 Mahlungulu SSN Grobler L Visser MME Volmink J Nutritional interventions for reducing morbidity and mortality in people with HIV Cochrane Database Syst Rev 20073CD004536

201 Academy of Sciences of South Africa (ASSAf) HIVAIDS TB and nutrition Scientific inquiry into the nutritional influences on human immunity with spe-cial reference to HIV infection and active TB in South Africa 2007 ASSAf Pretoria South Africa Available at wwwassaforgza Accessed 19 August 2010

202 Karsegard VL Raguso CA Genton L Hirschel B Pichard C L-Ornithine alpha-ketoglutarate in HIV infection effects of muscle gastrointestinal and immune functions Nutrition 200420515ndash20



203 Shabert JK Winslow C Lacey JM Wilmore DW Glutamine-antioxidant supplementation increases body cell mass in AIDS patients with weight loss a randomized double-blind controlled trial Nutrition 199915860ndash4

204 Koethe JR Chi BH Megazinni KM Heimburger DC Stringer JSA Macronutrient supplementation for mal-nourished HIV-infected adults a review of the evidence in resource-adequate and resource-constrained settings Clin Infect Dis 200949787ndash98

205 Cantrell RA Sinkala M Megazinni K Lawson-Marriott S Washington S Chi BH Tambatamba-Chapula B Levy J Stringer EM Mulenga L Stringer JS A pilot study of food supplementation to improve adherence to antiret-roviral therapy among food-insecure adults in Lusaka Zambia J Acquir Immune Defic Syndr 200849190ndash5

206 de Pee S Bloem MW Current and potential role of specially formulated foods and food supplements for preventing malnutrition among 6ndash23 months old and treating moderate malnutrition among 6ndash59 months old children Background paper prepared for WHO UNICEF WFP UNHCR informal consultation on the management of moderate malnutrition in under-5 children Food Nutr Bull 200930S434ndash63

207 Ndekha M van Oosterhout JJG 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 2009141ndash5

208 van Oosterhout JJ Ndekha MJ Moore E Kumwenda JJ Zijlstra EE Manary M The benefit of supplementary feeding for wasted Malawian adults initiating ART AIDS Care 201022737ndash42

209 Bowie C Kalilani L Marsh R Misiri H Cleary P Bowie C An assessment of food supplementation to chronically sick patients receiving home based care in Bangwe Malawi a descriptive study Nutr J 200512 doi1011861475-2891-4-12 Available at httpwwwnutritionj comcontent4112 Accessed 22 September 2010

210 Matilsky DK Maleta K Castleman T Manary MJ Supplementary feeding with fortified spreads results in higher recovery rates than with a cornsoy blend in moderately wasted children J Nutr 2009139773ndash8

211 Piwoz EG Preble EA HIVAIDS and nutrition a review of the literature and recommendations for nutritional care and support in Sub-Saharan Africa Washington DC US Agency for International Development 2000

212 Rollins N Food supplements and HIV More is not necessarily better BMJ 20093381282ndash3



all important and will be referred to here as ldquomalnutritionrdquo Malnutrition is widespread with stunting (short stat-ure) affecting 190 million or 32 of all children under 5 years of age in developing countries today In Africa 40 of under-fives are affected As this proportion has not changed much over the last decades many of todayrsquos adults adolescents and school-age children are bearing the lifelong consequences of childhood malnutrition [4] Two bil-lion people or one-third of the world population suffer from micronutrient deficiencies Thus for many people HIV infection comes in addition to some form and degree of malnutrition

Malnutrition especially through its negative effects on the immune system further aggra-vates HIV infection by increasing the risk of oppor-tunistic infections and death In turn HIV-infected persons are at higher risk for malnutrition and certain conditions can magnify the risk such as anorexia dif-ficulty swallowing or painful swallowing malabsorp-tion and diarrhea altered metabolism of nutrients increased utilization of nutrients and greater loss of nutrients [5] Furthermore for people on ART a bal-anced diet and a better nutritional status may enhance the effectiveness of antiretroviral drugs improve adherence to treatment reduce the side effects of medications reduce the complications of opportunistic infections and reduce longer-term metabolic compli-cations of ART use (such as dyslipidemia obesity and insulin resistance) For patients who are malnourished treatment of malnutrition is essential in addition to antiretroviral treatment

In 1999 one of the authors published a review on micronutrients and the pathogenesis of HIV infec-tion with the presentation of a model (fig 1) relat-ing micronutrient malnutrition nutritionally related immunosuppression and HIV infection in a vicious cycle [5] In the last decade considerable progress has been made toward understanding the relationship of nutrition with HIV infection

The purpose of this paper is to reviewraquo Knowledge of the interactions between HIV infec-

tion and nutrition including micronutrients macro-nutrients and weight loss

raquo Evidence for suitable interventions for breaking the vicious cycle between malnutrition and HIV infection including nutrition counseling provision of micronutrients andor food supplements ART and pharmaceutical treatment of opportunistic infectionsThe review focuses on resource-limited settings in

particular sub-Saharan Africa where the food security and nutritional status of the population in general are

already compromised and HIV infection prevalence is high in many areas Aspects relating to food security and livelihoods and to tuberculosis coinfection are dealt with in two other papers in this Supplement [6 7] The scope of this paper has been further limited to HIV infection and malnutrition in adults Each subsection starts with a summary of the main points and then presents the evidence for these points and concludes with comments about the available evidence and remaining uncertainties

HIV infection and nutritionmdashthe interaction

The relationship between infection and nutrition has been known since the early 1900s but the role of nutrition in medical practice and public health has changed over time [8] With advances in antibiotics and pharmaceutical treatment and the improvement of diet and nutrition due to improvements in agriculture and standards of living attention to the role of nutri-tion in developed countries dwindled However the role of nutrition in infection was not forgotten and it truly resurfaced in the 1980s and 1990s when its role in reducing child mortality in developing countries was recognized and emphasized [8 9] Thus the role of nutrition in health and disease is widely acknowledged and underlies the interest in the relationship between nutrition and HIV infection

Research into the relationship between HIV infec-tion and nutrition has mainly focused on the role and impact of micronutrients protein special nutrients such as specific amino acid mixtures and food supple-ments (especially in the case of wasting) Here we will first review the evidence for the relationship between micronutrients and HIV infection We then discuss weight loss and wasting because these lead directly into food supplementation which is one of the main activi-ties of the World Food Programme (WFP) Weight

FIG 1 Vicious cycle of micronutrient deficiencies and HIV pathogenesis (from Semba and Tang [5])

Insufficient dietary intakeMalabsorption and diarrhea

Impaired storage and altered metabolism

Micronutrientdeficiencies

Increased HIV replicationProgression of diseaseIncreased morbidity

Increased oxidative stressImmunosuppression




Micronutrients






Main points



Evidence










Comments






Micronutrient


literature

Deficient status

described


outcomesRNI for 19-

to 70-yr-olds


600


positive outcome

10


14


16






Main point


Evidence








Comments










Main points







Evidence




Loss of appetite


Avoiding diarrhea

Malnutrition

ndash Low BMI

ndash Weight loss








ndash Risk behavior

Altered metabolism









ndash Diarrhea























Comment





Main points








Evidence



















Comments











Main points









Evidence















Ingredient


RNIFor 1600

kcal


UL 19-70

Ensure Plus (mL)

Plumpyrsquo nut



CSB-USDA

Ensure Plus




USDA











Ingredient


RNIFor 1600

kcal


UL 19-70

Ensure Plus (mL)

Plumpyrsquo nut



CSB-USDA

Ensure Plus




USDA




















ndash Testosterone















Weight gain




Comment




Main points







Evidence






























Comments










Main points























ndash Ingredients

ndash Packaging













Evidence
































Comments






Discussion
























Conclusions








Acknowledgments


References























































































































































































































































Micronutrients






Main points



Evidence










Comments






Micronutrient


literature

Deficient status

described


outcomesRNI for 19-

to 70-yr-olds


600


positive outcome

10


14


16






Main point


Evidence








Comments










Main points







Evidence




Loss of appetite


Avoiding diarrhea

Malnutrition

ndash Low BMI

ndash Weight loss








ndash Risk behavior

Altered metabolism









ndash Diarrhea























Comment





Main points








Evidence



















Comments











Main points









Evidence















Ingredient


RNIFor 1600

kcal


UL 19-70

Ensure Plus (mL)

Plumpyrsquo nut



CSB-USDA

Ensure Plus




USDA











Ingredient


RNIFor 1600

kcal


UL 19-70

Ensure Plus (mL)

Plumpyrsquo nut



CSB-USDA

Ensure Plus




USDA




















ndash Testosterone















Weight gain




Comment




Main points







Evidence






























Comments










Main points























ndash Ingredients

ndash Packaging













Evidence
































Comments






Discussion
























Conclusions








Acknowledgments


References
























































































































































































































































Comments






Micronutrient


literature

Deficient status

described


outcomesRNI for 19-

to 70-yr-olds


600


positive outcome

10


14


16






Main point


Evidence








Comments










Main points







Evidence




Loss of appetite


Avoiding diarrhea

Malnutrition

ndash Low BMI

ndash Weight loss








ndash Risk behavior

Altered metabolism









ndash Diarrhea























Comment





Main points








Evidence



















Comments











Main points









Evidence















Ingredient


RNIFor 1600

kcal


UL 19-70

Ensure Plus (mL)

Plumpyrsquo nut



CSB-USDA

Ensure Plus




USDA











Ingredient


RNIFor 1600

kcal


UL 19-70

Ensure Plus (mL)

Plumpyrsquo nut



CSB-USDA

Ensure Plus




USDA




















ndash Testosterone















Weight gain




Comment




Main points







Evidence






























Comments










Main points























ndash Ingredients

ndash Packaging













Evidence
































Comments






Discussion
























Conclusions








Acknowledgments


References























































































































































































































































Main point


Evidence








Comments










Main points







Evidence




Loss of appetite


Avoiding diarrhea

Malnutrition

ndash Low BMI

ndash Weight loss








ndash Risk behavior

Altered metabolism









ndash Diarrhea























Comment





Main points








Evidence



















Comments











Main points









Evidence















Ingredient


RNIFor 1600

kcal


UL 19-70

Ensure Plus (mL)

Plumpyrsquo nut



CSB-USDA

Ensure Plus




USDA











Ingredient


RNIFor 1600

kcal


UL 19-70

Ensure Plus (mL)

Plumpyrsquo nut



CSB-USDA

Ensure Plus




USDA




















ndash Testosterone















Weight gain




Comment




Main points







Evidence






























Comments










Main points























ndash Ingredients

ndash Packaging













Evidence
































Comments






Discussion
























Conclusions








Acknowledgments


References

























































































































































































































































Main points







Evidence




Loss of appetite


Avoiding diarrhea

Malnutrition

ndash Low BMI

ndash Weight loss








ndash Risk behavior

Altered metabolism









ndash Diarrhea























Comment





Main points








Evidence



















Comments











Main points









Evidence















Ingredient


RNIFor 1600

kcal


UL 19-70

Ensure Plus (mL)

Plumpyrsquo nut



CSB-USDA

Ensure Plus




USDA











Ingredient


RNIFor 1600

kcal


UL 19-70

Ensure Plus (mL)

Plumpyrsquo nut



CSB-USDA

Ensure Plus




USDA




















ndash Testosterone















Weight gain




Comment




Main points







Evidence






























Comments










Main points























ndash Ingredients

ndash Packaging













Evidence
































Comments






Discussion
























Conclusions








Acknowledgments


References






































































































































































































































































Comment





Main points








Evidence



















Comments











Main points









Evidence















Ingredient


RNIFor 1600

kcal


UL 19-70

Ensure Plus (mL)

Plumpyrsquo nut



CSB-USDA

Ensure Plus




USDA











Ingredient


RNIFor 1600

kcal


UL 19-70

Ensure Plus (mL)

Plumpyrsquo nut



CSB-USDA

Ensure Plus




USDA




















ndash Testosterone















Weight gain




Comment




Main points







Evidence






























Comments










Main points























ndash Ingredients

ndash Packaging













Evidence
































Comments






Discussion
























Conclusions








Acknowledgments


References




































































































































































































































































Comments











Main points









Evidence















Ingredient


RNIFor 1600

kcal


UL 19-70

Ensure Plus (mL)

Plumpyrsquo nut



CSB-USDA

Ensure Plus




USDA











Ingredient


RNIFor 1600

kcal


UL 19-70

Ensure Plus (mL)

Plumpyrsquo nut



CSB-USDA

Ensure Plus




USDA




















ndash Testosterone















Weight gain




Comment




Main points







Evidence






























Comments










Main points























ndash Ingredients

ndash Packaging













Evidence
































Comments






Discussion
























Conclusions








Acknowledgments


References


























































































































































































































































Main points









Evidence















Ingredient


RNIFor 1600

kcal


UL 19-70

Ensure Plus (mL)

Plumpyrsquo nut



CSB-USDA

Ensure Plus




USDA











Ingredient


RNIFor 1600

kcal


UL 19-70

Ensure Plus (mL)

Plumpyrsquo nut



CSB-USDA

Ensure Plus




USDA




















ndash Testosterone















Weight gain




Comment




Main points







Evidence






























Comments










Main points























ndash Ingredients

ndash Packaging













Evidence
































Comments






Discussion
























Conclusions








Acknowledgments


References






























































































































































































































































Ingredient


RNIFor 1600

kcal


UL 19-70

Ensure Plus (mL)

Plumpyrsquo nut



CSB-USDA

Ensure Plus




USDA











Ingredient


RNIFor 1600

kcal


UL 19-70

Ensure Plus (mL)

Plumpyrsquo nut



CSB-USDA

Ensure Plus




USDA




















ndash Testosterone















Weight gain




Comment




Main points







Evidence






























Comments










Main points























ndash Ingredients

ndash Packaging













Evidence
































Comments






Discussion
























Conclusions








Acknowledgments


References


























































































































































































































































Ingredient


RNIFor 1600

kcal


UL 19-70

Ensure Plus (mL)

Plumpyrsquo nut



CSB-USDA

Ensure Plus




USDA




















ndash Testosterone















Weight gain




Comment




Main points







Evidence






























Comments










Main points























ndash Ingredients

ndash Packaging













Evidence
































Comments






Discussion
























Conclusions








Acknowledgments


References




































































































































































































































































ndash Testosterone















Weight gain




Comment




Main points







Evidence






























Comments










Main points























ndash Ingredients

ndash Packaging













Evidence
































Comments






Discussion
























Conclusions








Acknowledgments


References























































































































































































































































Comment




Main points







Evidence






























Comments










Main points























ndash Ingredients

ndash Packaging













Evidence
































Comments






Discussion
























Conclusions








Acknowledgments


References














































































































































































































































































Comments










Main points























ndash Ingredients

ndash Packaging













Evidence
































Comments






Discussion
























Conclusions








Acknowledgments


References
























































































































































































































































Main points























ndash Ingredients

ndash Packaging













Evidence
































Comments






Discussion
























Conclusions








Acknowledgments


References























































































































































































































































Evidence
































Comments






Discussion
























Conclusions








Acknowledgments


References












































































































































































































































































Comments






Discussion
























Conclusions








Acknowledgments


References







































































































































































































































































Conclusions








Acknowledgments


References




















































































































































































































































jurnal luar lagi gizi

Documents