Role of nutrition in HIV infection: Review of evidence

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

Saskia de Pee and Richard D. Semba 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, mitigation of side effects, and perhaps appetite stimulants and growth hormone. Correcting nutritional status becomes more difficult as infection progresses. Studies document widespread micronutrient deficiencies among HIV-infected people. However, supplement composition, patient characteristics, and treatments vary widely across intervention studies. Therefore, the World Health Organization (WHO) recommends ensuring 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 supplements. 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 patient’s diet and food security. It appears that starting ART improves BMI and that ready-to-use fortified 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; Richard 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, 68/70, Parco de’Medici, 00148 Rome, Italy; e-mail: [email protected] or Saskia. [email protected].

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 important, also because of ART’s 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 infections worldwide has stabilized since 2000, the number of people living with HIV has increased because of HIV treatments that are extending survival [1]. Antiretroviral therapy (ART) is becoming more readily available across sub-Saharan Africa, but the nutritional situation, 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, micronutrient 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

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Insufficient dietary intake all important and will be referred to Malabsorption and diarrhea here as “malnutrition.” Malnutrition is Impaired storage and altered metabolism widespread, with stunting (short stature) affecting 190 million, or 32%, of all children under 5 years of age in developing countries today. In Africa, Increased HIV replication Micronutrient 40% of under-fives are affected. As this Progression of disease deficiencies proportion has not changed much over Increased morbidity the last decades, many of today’s adults, adolescents, and school-age children are bearing the lifelong consequences of childhood malnutrition [4]. Two bilIncreased oxidative stress lion people, or one-third of the world Immunosuppression population, suffer from micronutrient deficiencies. Thus, for many people HIV FIG. 1. Vicious cycle of micronutrient deficiencies and HIV pathogenesis infection comes in addition to some form (from Semba and Tang [5]) and degree of malnutrition. Malnutrition, especially through its negative effects on the immune system, further aggra- already compromised and HIV infection prevalence is vates HIV infection by increasing the risk of oppor- high in many areas. Aspects relating to food security tunistic infections and death. In turn, HIV-infected and livelihoods and to tuberculosis coinfection are persons are at higher risk for malnutrition, and certain dealt with in two other papers in this Supplement conditions can magnify the risk, such as anorexia, dif- [6, 7]. The scope of this paper has been further limited ficulty swallowing or painful swallowing, malabsorp- to HIV infection and malnutrition in adults. Each tion and diarrhea, altered metabolism of nutrients, subsection starts with a summary of the main points increased utilization of nutrients, and greater loss of and then presents the evidence for these points and nutrients [5]. Furthermore, for people on ART, a bal- concludes with comments about the available evidence anced diet and a better nutritional status may enhance and remaining uncertainties. the effectiveness of antiretroviral drugs, improve adherence to treatment, reduce the side effects of medications, reduce the complications of opportunistic HIV infection and nutrition—the interaction infections, and reduce longer-term metabolic complications of ART use (such as dyslipidemia, obesity, and The relationship between infection and nutrition insulin resistance). For patients who are malnourished, has been known since the early 1900s, but the role of treatment of malnutrition is essential in addition to nutrition in medical practice and public health has antiretroviral treatment. changed over time [8]. With advances in antibiotics In 1999, one of the authors published a review on and pharmaceutical treatment, and the improvement of micronutrients and the pathogenesis of HIV infec- diet and nutrition due to improvements in agriculture tion, with the presentation of a model (fig. 1) relat- and standards of living, attention to the role of nutriing micronutrient malnutrition, nutritionally related tion in developed countries dwindled. However, the immunosuppression, and HIV infection in a vicious role of nutrition in infection was not forgotten, and it cycle [5]. In the last decade, considerable progress has truly resurfaced in the 1980s and 1990s, when its role been made toward understanding the relationship of in reducing child mortality in developing countries was nutrition with HIV infection. recognized and emphasized [8, 9]. Thus, the role of The purpose of this paper is to review: nutrition in health and disease is widely acknowledged » Knowledge of the interactions between HIV infec- and underlies the interest in the relationship between tion and nutrition, including micronutrients, macro- nutrition and HIV infection. nutrients, and weight loss; Research into the relationship between HIV infec» Evidence for suitable interventions for breaking tion and nutrition has mainly focused on the role and the vicious cycle between malnutrition and HIV impact of micronutrients, protein, special nutrients infection, including nutrition counseling, provision such as specific amino acid mixtures, and food suppleof micronutrients and/or food supplements, ART, ments (especially in the case of wasting). Here, we will and pharmaceutical treatment of opportunistic first review the evidence for the relationship between infections micronutrients and HIV infection. We then discuss The review focuses on resource-limited settings, in weight loss and wasting, because these lead directly into particular sub-Saharan Africa, where the food security food supplementation, which is one of the main activiand nutritional status of the population in general are ties of the World Food Programme (WFP). Weight Delivered by Publishing Technology to: Guest User IP: 162.218.208.135 on: Wed, 08 Oct 2014 11:30:49 Copyright (c) Nevin Scrimshaw International Nutrition Foundation. All rights reserved.

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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 discussed separately, but is included in the section “Impact of food supplements,” and the World Health Organization (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 components 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 body’s functions, HIV-infected people very much need to have an adequate micronutrient status. In this section we will review: » To what extent micronutrient deficiencies occur among HIV-infected people, as indicated by inadequate dietary intake or as directly measured by low micronutrient status (i.e., low levels in the body) from biochemical and other measurements; » Whether HIV-infected people have higher micronutrient needs than non-HIV-infected people; » How micronutrient deficiencies affect HIV infection. Prevalence of micronutrient deficiencies among HIVinfected people Main points

» Multiple micronutrient deficiencies are common in people with HIV infection, as shown by both inadequate dietary intake of micronutrients and low circulating micronutrient levels. » Micronutrient needs appear to be higher among HIV-infected than non-HIV-infected people Evidence

Micronutrient intake. Low intakes of many different micronutrients have been reported in different groups of HIV-infected adults [10–17]. 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 evidence 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 proportion 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 micronutrient 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 micronutrient 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 concentrations are common in HIV-infected individuals [27, 28, 31–34]. A high prevalence of vitamin D deficiency, based on serum or plasma 25-hydroxyvitamin D concentrations, has been described in HIV-infected adolescents and adults [35–37]. Low serum 25-hydroxyvitamin 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 vitamin B6 [20], vitamin B12 [45–51], and folate [31, 41–43, *RNI (recommended nutrient intake) is recommended by FAO/WHO and is used throughout this paper, except where studies have specifically reported on the RDA (recommended dietary allowance), which was recommended by the Institute of Medicine for the United States and Canada, and was replaced in the mid 1990’s by the DRI (dietary reference intakes).

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TABLE 1. Documented relationships between micronutrients and HIV infectiona

Micronutrient

Low intake described in literature

Deficient status described

Deficiency associated with adverse HIV infection outcomes

Vitamin A, µg

X

X

Vitamin E, mg

X

X

Vitamin B1, mg

X

Vitamin B2, mg

X

Yes, but also with positive outcome in one study Yes, but one study with a negative and one with a positive outcome Yes, part of B-complex supplement Yes, part of B-complex supplement

Niacin, mg Pantothenic acid, mg Folic acid, µg Vitamin C, mg Vitamin B6, mg Vitamin B12, µg Calcium, mg Magnesium, mg Selenium, µg Zinc, mg Iron, mg Iodine, µg Copper, mg Phosphorus, mg Potassium, mg Manganese, mg Vitamin D, µg Vitamin K, µg Biotin, µg Sodium, mg Chromium, µg Molybdenum, µg Chloride, mg Carotenoids, µg

X X X

X X

X X X

Yes Yes

X X X

Yes Yes

X

RNI for 19to 70-yr-olds 600 10 1.4 1.6 18 6 400 75 2 6 1,000

15 15 150 2 1,000 3,500 5 30

X

Yes

a. See text for references to specific evidence.

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

micronutrients that are assessed in the serum or diet in a particular study are what we will know something about. » The insufficient intake and higher needs among HIV-infected people apply to some micronutrients more than others, but knowledge about this is limited. » 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.

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Micronutrient deficiencies affecting HIV infection Main point

» 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 associated 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 associated 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 associated with markers of HIV disease progression [34]. Higher plasma vitamin E levels prior to HIV seroconversion 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 HIVinfected 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 progression [39, 79]. Serum or plasma zinc concentrations 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 HIVinfected adults [82], HIV-infected children [83], and children born to HIV-infected mothers in Tanzania [84]. Low plasma selenium concentrations were associated with higher mother-to-child transmission of HIV through the intrapartum route [85]. Selenium deficiency was associated with a higher risk of genital shedding of HIV in HIV-infected women in Kenya [86]. HIV-infected injection drug users with low serum selenium 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

» For most micronutrients, a low status is associated with poor HIV infection outcome. » 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 transmission (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. » 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. » Micronutrient deficiencies usually occur for a combination of micronutrients, as isolated single deficiencies 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 “Impact of micronutrient supplementation” below).

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Evidence

Weight loss and wasting The AIDS wasting syndrome was first described in 1985 in a report from Uganda as “slim disease” [89]. This indicates how closely weight loss and HIV infection are related. Causes and consequences of weight loss in HIV infection Main points

» Wasting (low body mass index [BMI]) and weight loss are common in people with HIV infection. » HIV-infected people on ART also suffer from weight loss. » Low BMI and weight loss are strong risk factors for HIV disease progression and mortality, independently of CD4 lymphocyte count or other indicators of immune system performance. » 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. » There are many different HIV-related causes of weight loss, including low food intake, increased nutritional needs, malabsorption, and altered metabolism (fig. 2). » Both malnutrition and infections (HIV and others) need to be treated at the same time.

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 18.5 kg/m2, 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 [90–99]. 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 nonmalnourished patients [96, 97, 100]. A number of studies have assessed whether lean body mass (fat-free mass) or bioimpedance measures reflecting the ratio of extracellular 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 difficult to measure, is adequately reflected by BMI as well as by percentage weight loss. In addition, low BMI or

Loss of appetite Poverty, food insecurity

Difficulty swallowing Avoiding diarrhea

Malabsorption (fat, carbohydrates, MNs): – Gut functioning – Diarrhea

Low food intake (MNs, energy)

Malnutrition: – Low BMI – Weight loss

Affecting progression and outcome

HIV infection and opportunistic infections

– Micronutrient deficiencies Altered metabolism: Context in resource-limited settings: – Preexisting malnutrition, food insecurity, low dietary quality

– Increased nutrient needs due to infection – From 10% higher resting energy expenditure when asymptomatic to 30% higher when symptomatic – Increased losses of MNs due to infection

– High infection pressure (malaria, TB, parasitoses

– Inefficient nutrient utilization

– Higher susceptibility to HIV infection:

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

– Higher HIV prevalence – Lower epithelial integrity

– Hypogonadism and adrenal insufficiency

– Risk behavior

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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 independent of CD4 lymphocyte count [102–104], even in patients who are on ART [96]. Weight loss of approximately 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, 33.5% of patients on ART (156/466), 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 kg/m2 (8%) at any time during the follow-up. Furthermore, a total of 58% of all patients (289/497) lost more than 1.5 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 simultaneously [106–110]. 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 approximately 10% among asymptomatic HIV-infected people. However, total energy expenditure, which consists of energy expenditure during rest, digestion (i.e., 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 and/or 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 hinders 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,

and/or difficulty swallowing. Therefore, increasing food consumption during convalescence (i.e., 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 (i.e., 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, proteins, 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 metabolic 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 (e.g., vitamins B6, B12, and D), and bioavailability of minerals (especially iron and zinc) is higher in animal-source TABLE 2. Metabolic alterations during sepsis Protein Increased urinary nitrogen loss Increased protein turnover Decreased skeletal muscle protein synthesis Increased skeletal muscle breakdown Increased hepatic protein synthesis Lipid Hypertriglyceridemia Increased hepatic de novo fatty acid synthesis Increased hepatic triglyceride esterification Increased very-low-density lipoprotein production Decreased peripheral lipoprotein lipase activity Increased adipocyte triglyceride lipase Carbohydrate Hyperglycemia Insulin resistance Increased peripheral glucose utilization Increased gluconeogenesis Source: Babameto and Kotler [103].

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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, progressive 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 nutrient 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 infection need to be treated concurrently. Comment

» 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 nutrition—review of nutrition interventions Because of the associations found between micronutrient 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

» High-dose vitamin A supplementation of HIV-positive children under 5 years of age has been shown to reduce morbidity and mortality » Vitamin A supplementation of mothers (10,000 IU/day during pregnancy or a single high dose of 400,000 IU after delivery) does not seem to reduce mother-to-child HIV transmission. » An adverse effect of supplementation during pregnancy and lactation on mother-to-child transmission was observed when vitamin A (5,000 IU/ day) was combined with high-doses of β-carotene (30 mg/day). It is unknown whether this effect is due to β-carotene, vitamin A, or both. » The outcomes of supplementation with single nutrients (vitamin E, selenium, zinc, and iron) are not yet conclusive.

» 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 micronutrient, and for different target groups, would be. » Based on the available knowledge, WHO’s current advice is to ensure intake of 1 RNI for all micronutrients. The Academy of Sciences of South Africa recommends an intake of 1 to 2 RNI, because needs may be higher during HIV infection (increased utilization as well as increased losses). » 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 iron–folic acid tablets. Evidence

Vitamin A for children. Periodic high-dose vitamin A supplementation was shown to reduce diarrheal morbidity 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 postvaccination increase in HIV load [120]. In a randomized, double-blind, placebo-controlled trial of vitamin A for HIV-infected children in Uganda, vitamin A supplementation reduced mortality by 46% [121]. Vitamin A for pregnant and/or lactating women. In Malawi, HIV-infected women who received daily vitamin A supplementation with 3 mg retinol equivalents (RE) (10,000 IU) from 18 to 28 weeks of gestation until delivery had infants with higher birthweight, better neonatal growth, and greater hemoglobin concentrations, but there was no effect of vitamin A on mother-to-child transmission of HIV [122]. High-dose (400,000 IU) vitamin A supplementation of HIVinfected mothers in Zimbabwe during the postpartum period had no effect on mother-to-child transmission 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

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of HIV-infected neonates had no impact on anemia in the infants [125]. Daily vitamin A supplementation with 10,000 IU had no impact on genital shedding of HIV among HIV-infected women of childbearing age in Kenya [126]. β-Carotene—megadoses. 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 metabolites, 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 supplementation 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 mg/day, increased the risk of lung cancer [127, 128] and of first-time, nonfatal myocardial infarction among male smokers [129]. In the Beta-Carotene and Retinol Efficacy Trial, β-carotene, 30 mg/day, plus vitamin A, 25,000 IU, increased the risk of lung cancer among present and former smokers and workers 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 mg/day, 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 mitochondrial function [133]. Megadose β-carotene, 180 mg/day, did not have any apparent benefit for HIV-infected adults who were already taking multivitamins [134]. β-Carotene, 180 mg/day, 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 mg/day, plus vitamin A, 10,000 IU/day, 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 × 2 factorial design was conducted in pregnant women to determine whether β-carotene, 30 mg/day, plus vitamin A, 5,000 IU/day, 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 natural carotenoid mixture that contained an equivalent of β-carotene, 72 mg/day, did not significantly affect mortality in HIV-infected adults who were receiving multivitamins [139]. Vitamin E. Vitamin E supplementation, 800 mg/day, had no significant impact on CD4 lymphocyte count or HIV load [140] but improved lymphocyte viability [141]. Supplementation with vitamin E, 800 mg/day, plus vitamin C, 1 g/day, 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 antioxidant enzymes in HIV-infected adults compared with placebo [145]. In HIV-infected, ART-naive adults, selenium supplementation for 24 weeks had no significant 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 involving 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 [149–151]. 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 morbidity 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

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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 supplementation 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 HIVpositive 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 pregnant 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 (0.8 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 wasting [168]. Other trials of multimicronutrient supplementation 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, riboflavin, 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, nonpregnant 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 supplementation 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 antioxidant defenses but had no effect on HIV load [174]. Comments

» Several studies with micronutrient supplements have been conducted. However, the choice of micronutrients (often a combination) and the amounts of each micronutrient provided (ranging from a few to many times the RNI) varied considerably. » Furthermore, the patients’ 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 micronutrient supplementation, especially for individual micronutrients. » 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 micronutrient 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. » Some of the studies with micronutrients have provided 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.

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Interventions to prevent or treat weight loss

In principle, the aim of nutrition interventions for HIVinfected people is straightforward: to reduce mortality risk by increasing or maintaining body weight (i.e., preventing, halting, or recovering weight loss) and to support the immune system and body performance by providing access to adequate nutrition in conjunction 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 infection progresses. Therefore, nutrition interventions should start as early as possible and should include nutrition assessment, education, and counseling, augmented with supplements and pharmaceutical preparations 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 resourceadequate settings, in order to assess how these results can inform HIV care and treatment in resourceconstrained settings. Current recommendations and practice in resourceadequate settings Main points

» Ensuring adequate nutrition is an essential component of HIV infection control, in addition to ART and treatment of opportunistic infections, and should start as early as possible » 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. » To regain muscle tissue, a combination of infection control, adequate nutrition, and exercise is required, and where necessary hormonal treatment can be added. » 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 combines – nutrition assessment, education, and counseling and, where necessary, appetite stimulants or specific nutritional supplements; – pharmaceutical treatment of HIV, opportunistic infections, and side effects of infection or of treatment; – exercise and, where required, hormonal treatment to rebuild muscle tissue.

» 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 associated 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 infection, it appears possible to reverse the catabolic state (breakdown of tissue) by providing complete nutritional 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 “complete nutritional supplement” (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, vomiting, diarrhea, and oral or esophageal lesions, as well as psychosocial aspects), comorbidities as they lead to weight loss and thus need to be treated (gastrointestinal disease, opportunistic infections, malignancies), hypogonadism, adrenal insufficiency, hyperlactatemia or lactic acidosis as they affect metabolism, and medication-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 “Evidence now demonstrates that nutritional counseling and support, appetite stimulants, progressive resistance training, and anabolic hormones can reverse weight loss and increase lean body mass in HIV-infected patients” [113]. In 2004, Wanke and Kotler published collaborative 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 conclusions are important as we consider approaches to

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TABLE 3. Nutrient composition of a variety of food supplements provided to HIV patients suffering from malnutrition, and Composition per 100 g of product

Ingredient Total quantity, g (or mL) Energy, kcal Protein, g Fat, g Micronutrients Vitamin A, µg Vitamin E, mg Vitamin B1, mg Vitamin B2, mg Niacin, mg Pantothenic acid, mg Folic acid, µg Vitamin C, mg Vitamin B6, mg Vitamin B12, µg Calcium, mg Magnesium, mg Selenium, µg Zinc, mg Iron, mg Iodine, µg Copper, mg Phosphorus, mg Potassium, mg Manganese, mg Vitamin D, µg Vitamin K, µg Biotin, µg Sodium, mg Chromium, µg Molybdenum, µg Chloride, mg

Ensure Plus (mL)

Plumpy’ nut

Supplementary Plumpy

RUFValid

RUFS-PPB

CSB

CSBUSDA

100 151 5.7 4.7

100.0 543.5 13.6 35.8

100.0 543.5 13.6 35.8

100 536.2 12.3 > 35

100.0 555.1 14.5 37.1

100.0 363.6 13.4 7.0

100.0 376.0 17.2 6.9

160 1.2 0.138 0.18 2.55 0.74 26 6.4 0.21 0.21 128 27.7 5.5 1.7 1.62 17 0.21 117 170 0.55 0.64

913.0 20.0 0.6 1.8 5.3 3.1 209.8 53.3 0.6 1.8 300.0 92.0 30.0 14.0 11.5 100.0 1.7 300.0 1,110.9

913.0 20.0 0.6 1.8 5.3 3.1 209.8 53.3 0.6 1.8 300.0 92.0 30.0 14.0 11.5 100.0 1.7 300.0 555.4

816.9 18.2 0.6 1.7 4.8 2.8 191.7 48.3 0.5 1.6 304.1

289.8 21.2 0.4 0.5 5.7

278.1 8.7 0.3 0.2 3.5

12.4 10.5 92.7 1.7 351 935.6

163.3 36.7 0.5 0.6 338.8 98.0 31.8 3.3 3.3

40.9 7.0 0.3 0.1 69.0 133.7 5.9 2.1 4.3

0.4 285.7 1,175.5

0.8 280.7 454.5

16.3 21.0 65.2

16.3 21.0

14.6

2.0

1.6

871.0 8.7 0.5 0.5 6.2 3.4 179.6 40.0 0.5 1.0 831.0 173.8 6.0 5.0 17.5 57.0 0.9 206.0 634.0 0.7 4.9 — — 7.3

15 106 4.7 12 115

59.5

RNI 2,600 48

600 10 1.4 1.6 18 6 400 75 2 6 1,000

15 15 150 2 1,000 3,500 5 30

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 years a. Ensure Plus is a commercial product that was used by Berneis et al. [175]. Supplementary Plumpy and Plumpy’nut are commercial products produced by Nutriset France for treating moderate and severe malnutrition, respectively, and their composition is comparable to that of

and management of weight loss among HIV-infected people in resource-limited settings: » Even in the era of ART, weight loss and wasting are frequently seen and need to be managed by a combination of approaches. » Ensuring adequate nutrition is an essential component of HIV infection control in addition to ART. » Exercise is also important, in particular to regain muscle tissue. » 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

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the absolute amount of nutrients provided by these foods when providing 1,600 kcal/daya Intake when 1,600 kcal of product is consumed Supplementary Plumpy, 92 g RUF-Valid RUFS-PPB

For 1,600 kcal

Ensure Plus

Plumpy’ nut, 92 g

1,600 30

1,060.0 1,600.6 60.4 49.8

294.4 1,600.0 40.0 105.3

294.4 1,600.0 40.0 105.3

298.0 1,597.9 36.7 > 35

1,696.0 12.7 1.5 1.9 27.0 7.8 275.6 67.8 2.2 2.2 1,356.8 293.6 58.3 18.0 17.2 180.2 2.2 1,240.2 1,802.0 5.8 6.8

2,688.0 58.9 1.8 5.3 15.6 9.1 617.6 156.8 1.8 5.4 883.2 270.7 88.3 41.3 33.9 294.4 5.1 883.2 3,270.4

2,688.0 58.9 1.8 5.3 15.6 9.1 617.6 156.8 1.8 5.4 883.2 270.7 88.3 41.3 33.9 294.4 5.1 883.2 1,635.2

2,434.4 54.2 1.8 5.1 14.3 8.3 571.3 143.9 1.5 4.8 906.2

48.0 61.8 192.0

48.0 61.8 192.0

600 10 1.4 1.6 18 6 400 75 2 6 1,000

15 15 150 2 1,000 3,500 5 30

159.0 1,123.6 49.8 127.2 1,219.0

CSB

CSBUSDA

289.1 1,604.8 41.9 107.4

441.3 1,604.8 59.0 30.9

426.0 1,601.8 73.3 29.4

837.8 61.4 1.3 1.5 16.5

1,227.2 38.4 1.5 0.9 15.3

37.0 31.3 276.2 5.1 1,046.0 2,788.1

472.0 106.2 1.5 1.7 979.4 283.2 92.0 9.4 9.4

180.5 30.7 1.2 0.6 304.4 590.0 26.0 9.4 18.9

1.1 826.0 3,398.4

3.4 1,239.0 2,006.0

43.5

5.9

7.1

3,710.5 37.1 2.3 2.0 26.5 14.5 765.1 170.4 2.1 4.3 3,540.1 740.4 25.6 21.3 74.5 242.8 3.8 877.6 2,700.8 3.0 20.9

177.3

UL 19-70

3,000 1,000 — — 35 600 1,000 100 —

400 45 45 1,100 10

50

31.1

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 investigators. CSB-USDA refers to the content of the CSB donated by the US Agency for International Development (USAID).

concluded that the impact of anabolic steroids in HIVinfected 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 HIVinfected 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 micronutrient 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-yearold children, but with reduced iron and zinc content because of malaria endemicity. Improved appetite was

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S. de Pee and R. D. Semba Prior to initiating therapies for HIV wasting: – Assess HIV control and adjust therapy if warranted – Treat factors with the potential to impair energy intake and expenditure – Opportunistic infections and malignancies – Depression or other psychosocial problems – GI side effects from antiretroviral therapies

If wasting persists, prescribe nutritional counseling with or without appetite stimulants

If wasting persists, offer therapies targeted at HIV wasting: – Growth hormone (only therapy FDA-approved) – Testosterone – Anabolic steroids

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

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

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 (i.e., strengthening of the immune system), which in turn reduces opportunistic 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 description of the two distinct components of weight gain), especially in nonwasted patients, care should be taken to prevent the development of obesity, insulin resistance, 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 utilization or absorption. Thus, some need to be taken

Weight gain

Fat-free mass — required for bodily functions, requires: – Consuming correct nutrients that build up the tissues – Exercise (to grow muscles) – Ability to build tissues (anabolic instead of catabolic states)

Fat mass — constitutes the body’s energy reserves and insulation: – More easily built on positive energy balance, because it doesn’t require many different nutrients – However, too much associated with: – Increased triglyceride level – Insulin resistance (diabetes) – Overweight/obesity

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with food and others without food, and some specific food–drug 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

» The management of HIV infection in resourceadequate 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 managing weight loss is not very specific about what nutrition advice is to be given. Current recommendations and practice in resourcelimited settings

As mentioned above, ensuring adequate nutrition is an essential component of HIV infection control. 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 resourcelimited settings focus on advice for a balanced diet and for treatment of moderate or severe wasting. Main points

» Nutrition management of HIV infection and of ART is important. » Advice for HIV infection management in resourcelimited 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.

» Pre-existing malnutrition complicates the formulation 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. » There are no specific guidelines for treating malnutrition in HIV-infected adults. WHO guidelines for treating wasted adults are used instead. » It is worth assessing whether micronutrient supplementation in resource-limited settings stimulates appetite among HIV-infected people suffering from anorexia. » 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 malnourished, 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 settings. 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 conceptualizing the relationship and appropriately designing and interpreting macronutrient intervention studies. Since nutrition among people in developing countries 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 supplements, 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, 190–194]. 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 infection; 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 established therapeutic guidelines for the management of weight loss and wasting in HIV-infected patients. The

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TABLE 4. WHO guidance for nutritional management of HIV infection and malnutrition among adults With regard to nutrition assessment Measure weight, weight change, height, BMI, MUAC Assess appetite, difficulty swallowing, nausea, diarrhea, drug–food interaction effects Assess household food security With regard to malnutrition Mild to moderately malnourished adults (BMI < 18.5 kg/m2), 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 < 16 kg/m2) 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 kcal/kg/day; for initial treatment of those aged 15 to 18 years, energy intake should be 50 kcal/kg/day [212] With regard to dietary intake [191, 194] Energy intake in asymptomatic HIV infection should be increased by 10% During 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 possible Percentage of energy from protein and from fat should not be changed compared with that for persons in the HIVnegative state. However, as energy intake is increased, the absolute amounts of protein and fat are also increased Intake 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 recommending higher intakes BMI, body mass index; CSB, corn–soya blend; MUAC, mid-upper-arm circumference; RNI, recommended nutrient intake Source: World Health Organization [187].

Working Group on the Prevention and Treatment of Wasting and Weight Loss has proposed some guidance 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: “Loss 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 support” [195]. It is important to note that the “Current recommendations and practice in resource-adequate settings” described above also apply to resource-limited settings. Thus, dietary management of ART is very important because of food–drug 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 proportions 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 malnourished adults who are recommended to consume F100 or a nutritionally equivalent product such as an RUTF (e.g., Plumpy’nut) have an intake of micronutrients 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 suggests 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, examples of foods that can be provided are given, which may result in micronutrient intake levels below 1 RNI. For example, corn–soya blend (CSB), which is very often given, contains a limited number of micronutrients and provides, at average intake levels, less than 1 RNI for

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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 proportion to energy (i.e., per 1,000 kcal), rather than in absolute amounts required per day, such as is the case with the RNI. The rationale to set these contents per 1,000 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 kcal/kg for 19- to 75-year-olds versus 75 kcal/kg for 7- to 10-year-olds). However, a 40-kg adult who consumes enough RUTF to provide 1,600 kcal/day [197, 198] would consume 34 g of iron, 45 g of zinc, 2,688 RE of vitamin A, etc. (see intake from Plumpy’nut 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 constitute 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, including an allowance to replenish repleted stores, may not increase linearly with energy needs. Within the range of body weight encountered among children suffering 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 1,600 kcal/day 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 typically included in micronutrient preparations because of the larger amounts that are required per day, i.e., 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 HIVinfected 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 suffering from malnutrition, in order to bridge the gap between current advice for nutrient intakes among HIV-infected people (i.e., increased energy intake and 1 RNI/day of micronutrients) and the guidance for treating moderate and severe malnutrition among adults, which is also used for treating HIV-infected adults. Comments

» In principle, HIV infection does not require different 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 management of HIV infection in resource-limited settings. » 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 malnutrition, means that intake levels and guidance for nonHIV-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 patients’ 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; nutritional status and HIV infection stage; whether using ART; basic diet before provision of food supplements), the ingredients and nutrient content of the food supplement, 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

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Characteristics of food supplement – Content of supplement – Nutrients: macro- and micronutrients, protein quality, essential amino acids, essential fatty acids – Anti-nutrients – Energy density – Amount provided per day

Starting point of patients and context: – Baseline nutritional status – Target group (children, women, men, etc.) – Food security situation – Basic diet to which food supplement is added – HIV-disease stage – ART (yes/no) and other treatment received

– Form of the food (palatability, preparation required) – Ingredients – Packaging – In what setting is the food provided (clinic, community)?

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

Total food and nutrient intake: – What information and counseling is provided to the patient? – How much of the food supplement does the patient consume, per day and for how long? – What else does the patient consume?

Treatment adherence and progression of HIV-disease during the study period

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

disease during the course of the study. Below we review food supplementation studies conducted in resource-adequate and resource-limited settings and compare the nutrient contents of various food supplements. Main points

» The design of studies using food supplements varies widely with regard to supplements used, characteristics 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. » 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 particular 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, overweight, etc. » There is some evidence from resource-adequate settings that supplementation with specific nutrients can increase fat-free mass and reduce viral load. » The few studies with food supplements conducted in resource-limited settings focused on treating malnutrition and assessed its impact on HIV infection 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, i.e., CSB and ready-to-use spreads. » 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. » 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. » 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 receiving CSB has survival benefits. » 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.

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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 g/day, such as Plumpy’doz) to a micronutrient powder that provides only additional vitamins and minerals. It is important to take both a qualitative and a quantitative approach when counseling 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 colleagues 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 mortality in adults and children living with HIV [200]. Randomized, controlled trials published before 2007 that evaluated the effectiveness of macronutrient interventions 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 “placebo” 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 studies, 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: “There 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 developing 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 overnourished)” [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 randomized, placebo-controlled trials that macronutrient 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 [201–203]. They also concluded that supplementation 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 supporting macronutrient supplementation for HIVinfected 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 19.6 kg/m2. The supplements provided in these studies were very specialized nutrition supplements—such as mediumchain triglycerides, L-glutamine, and antioxidants; an amino acid mixture with arginine, glutamine, and β-hydroxy-β-methylbutyrate; a supplement with whey protein, etc.—and in most studies the control group received nutrition education and in some studies also an isonitrogenous formulation (i.e., with comparable protein content). Thus, these studies basically examined 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 supplements 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 adherence counseling, received CSB and a food ration for the household, and the other group received no food

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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: i.e., low energy density, a limited content and bioavailability 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 (5.4 kg in the intervention group and 5.1 kg in the control group at 6 months; 6.3 kg in the intervention group and 5.4 kg in the control group at 12 months) or CD4 lymphocyte count. However, medication possession ratio (a measure of timeliness of clinic visits to receive refills, calculated as 100%–100% 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 18.5 kg/m2 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 3.5 months of supplementation, 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): 2.2 versus 1.7 kg/m2 and 2.9 versus 2.2 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 Development [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 moderately malnourished children under 5 years of age and for blanket feeding of children aged 6–23 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 readyto-eat). In another paper [207], the authors assessed the outcome among the same patients 3 and 9 months after the 3.5-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 control group, respectively); at 12 months, the 0.5 kg/m2 difference that was observed at the end of the supplementation period (19.0 vs. 18.5 kg/m2, respectively; p = .001) was observed again (20.3 vs. 19.8 kg/m2, respectively; p = .22), but due to greater variation, the difference was not significant any more. The authors also compared their results after 3.5 months of food supplementation and 3 months later with historical data from patients who received ART but no food supplements [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 supplementation 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 (< 1% in the supplemented 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 receiving 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 enrollment, approximately 45% of the clients in the CSB group and approximately 55% in the nutrition counseling 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.

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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 2003/04, 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 0.07 kg/m2 in 100 days (not a statistically significant increase) among those not receiving supplementary food and by 0.46 to 0.49 kg/m2 among those receiving supplementary food (p < .05). The difference between the two periods, i.e., 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 supplements 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 < 16 kg/m2 and 19% of whom had a BMI of 16 to < 17 kg/m2, and 13.3% of whom had started ART 1 or 2 months before they started to receive supplementary food [197]. The patients received 500 g/day of a locally made chickpeasesame RUTF for 3 months (composition shown in table 3). The average consumption was 300 g/day, providing 1,590 kcal/day. After 3 months, the mean weight gain was 2.5 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 communication). 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 provided—spreads versus FBFs. Table 3 compares the composition of different foods that are provided to HIV-infected people, including those used in the studies reviewed here. The main things to note are the following: » The food supplements vary considerably in macroand micronutrient content both between ready-touse spreads and CSB and within these two groups of foods. » The spreads have a much higher energy density due to a larger amount of fat and thus require consumption of a smaller amount in order to achieve the same

energy intake. » 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 moderately malnourished patients who are at increased risk for death. However, the cost of the spreads is approximately three times higher than that of an FBF providing 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 usually much better among patients in resource-adequate settings than among patients in resource-limited settings. 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

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in resource-adequate settings, both ART (except for first-line treatment) and medication to treat secondary infections, is different from that used in resourcelimited 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 treatment status of the participants [211]. Comments

» It is important to be specific about the nutrient content of foods that are provided, because “nutrition provided” 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 consumption by the patient, and rather than supplementing they may partly replace some of the patient’s usual diet. Thus, in order to assess the impact of the provision 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. » 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 supplement would be a more cost-effective solution, linear programming can be used. » Whether ingested nutrients are used appropriately by the body depends not only on the kind, combination, and quantity of nutrients, but also on the body’s metabolic state and whether the patient is on ART. » 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. » 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 packaging of the product), but also how they can be delivered 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 “It 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 rationale” [201]. This statement highlights very well the two different concepts that are being applied to nutrition in HIV/ AIDS, 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 supplements according to the same methodology that is used to assess the impact of medication and treatment protocols, i.e., comparing the results obtained in the intervention group with those obtained in a group that receives an otherwise unchanged diet or a placebo supplement. 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 favoring a more holistic, humanitarian assistance point of view treat malnutrition with an energy- and nutrientrich 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 infection, 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 “HIV infection and nutrition – review of nutrition interventions” 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 macronutrient supplements, and the net intervention is the actual change of the patient’s 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

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context specific. Thus, the primary question should be not “What food needs to be provided?” but “What should be the daily intake of all essential nutrients and how can that be achieved?” In resource-limited settings, food interventions for HIV-infected people have primarily focused on treating the malnourished (BMI < 18.5 kg/m2), 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 HIV/AIDS, concluded “It seems reasonable to assume that nutritional interventions in HIV/AIDS will enhance defense against infection, promote recovery and improve quality of life and survival despite the lack of properly conducted trials” [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 deficiencies 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 asymptomatic 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 historical data can be considered. Unresolved questions with regard to nutritional guidance for HIV-infected people include the following: » Should different nutrient intakes (including both macro- and micronutrients) and supportive measures be recommended for patients at different stages of HIV infection and with different nutritional status? » Which nutrients, including specific amino acids, micronutrients, macrominerals, etc., are most essential to regain weight lost, especially lean body mass, and in what amounts? » Could supplementation with micronutrients in amounts of 1 RNI/day increase appetite and, when combined with ART and a balanced diet, support regaining lean body mass? » What constitutes an optimal nutrient intake for patients with chronic diarrhea or gastrointestinal infection? » What are optimal energy and protein intake levels during metabolic stress? Is substrate use impaired and can excess energy and protein be harmful? » What are safe ULs for nutrient intakes in HIVinfected people with different degrees of malnutrition and in those with no malnutrition? » Related to the above, is the high intake of micronutrients by malnourished HIV-infected adults receiving RUTF-type products safe, or should the vitamin and mineral contents be revised for use among adults? » What effect does nutritional intervention early in HIV infection have on preventing opportunistic infections and slowing disease progression? » 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? » 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)?

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Conclusions 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 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 nutrition 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 different 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 available 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 supplements 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: » The relationship between nutrition and HIV infection 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. » The management of HIV disease requires a combination 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 Villamor, Pamela Fergusson, Ian Darnton-Hill, Annmarie Isler, Francesca Erdelmann, Tina van den Briel, Mutinta Hambayi, Mary Njoroge, and Joris van Hees.

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