Jurnal Luar Lagi Gizi

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
patients 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 deMedici,
00148 Rome, Italy; e-mail: depee.saskia@gmail.com or Saskia.
depee@wfp.org.
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 ARTs 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
Food and Nutrition Bulletin, vol. 31, no. 4 (supplement) 2010, The United Nations University.
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Copyright (c) Nevin Scrimshaw International Nutrition Foundation. All rights reserved.
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S. de Pee and R. D. Semba
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 todays 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 nutritionthe 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
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Nutrition and HIV infection
loss and wasting are due to a negative energy balance,

among other causes, which is determined by energy
needs and energy intake supplied by macronutrients,
particularly fats and carbohydrates. Protein is not 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 bodys 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 [1017]. 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, 3134]. 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 [3537]. 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 [4551], and folate [31, 4143,
*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 1990s 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, g
Vitamin E, mg
Vitamin B1, mg
Vitamin B2, mg
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, g
Vitamin C, mg
Vitamin B6, mg
Vitamin B12, g
Calcium, mg
Magnesium, mg
Selenium, g
Zinc, mg
Iron, mg
Iodine, g
Copper, mg
Phosphorus, mg
Potassium, mg
Manganese, mg
Vitamin D, g
Vitamin K, g
Biotin, g
Sodium, mg
Chromium, g
Molybdenum, g
Chloride, mg
Carotenoids, g
X
X
X
X
X
RNI for 19to 70-yr-olds
X
X
X
Yes
Yes
X
X
X
Yes
Yes
600
10
1.4
1.6
18
6
400
75
2
6
1,000
15
15
150
2
1,000
3,500
5
30
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.
Knowledge depends on what we look for; only the

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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 -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 -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 [9099].
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
FIG. 2. Relationship between HIV infection and malnutrition

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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 [102104], 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 [106110].
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 nutritionreview 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 -carotene
(30 mg/day). It is unknown whether this effect is due
to -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, WHOs 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 ironfolic 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
S321
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].
-Carotenemegadoses. Clinical trials have been
conducted using megadoses of -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 -carotene, especially
at nonphysiological megadoses, has been shown to
have pharmacological and physiological effects that
are distinct from those of vitamin A. -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 -carotene for
HIV-infected adults, since megadose -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, -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, -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 -carotene
increases serum levels of -carotene to levels 5 to 12
times higher than normal physiological levels. At high
doses, -carotene has prooxidant effects [131], and in
humans, -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 -carotene, which
are generated at high levels with megadose -carotene
supplementation, have been shown to impair mitochondrial function [133].
Megadose -carotene, 180 mg/day, did not have any
apparent benefit for HIV-infected adults who were
already taking multivitamins [134]. -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 -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 -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 -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 -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
[149151]. 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
S322
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 g), 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 (-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
(-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.
S323
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
S324
TABLE 3. Nutrient composition of a variety of food supplements provided to HIV patients suffering from malnutrition, and
Composition per 100 gof product
Ingredient
Total quantity, g (or mL)
Energy, kcal
Protein, g
Fat, g
Micronutrients
Vitamin A, g
Vitamin E, mg
Vitamin B1, mg
Vitamin B2, mg
Niacin, mg
Pantothenic acid, mg
Folic acid, g
Vitamin C, mg
Vitamin B6, mg
Vitamin B12, g
Calcium, mg
Magnesium, mg
Selenium, g
Zinc, mg
Iron, mg
Iodine, g
Copper, mg
Phosphorus, mg
Potassium, mg
Manganese, mg
Vitamin D, g
Vitamin K, g
Biotin, g
Sodium, mg
Chromium, g
Molybdenum, g
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 Plumpynut 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
S325
the absolute amount of nutrients provided by these foods when providing 1,600 kcal/daya
Intake when 1,600 kcalof 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
S326

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 bodys energy reserves and

insulation:
More easily built on positive energy balance, because
it doesnt require many different nutrients
However, too much associated with:
Increased triglyceride level
Insulin resistance (diabetes)
Overweight/obesity
FIG. 4. Components of weight gain

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with food and others without food, and some specific

fooddrug 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, 190194].
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, drugfood 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, cornsoya 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 fooddrug 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., Plumpynut) 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, cornsoya 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 Plumpynut
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
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
Energy density
Amount provided per day
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 Plumpydoz) 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 [201203]. 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 supplementssuch as mediumchain triglycerides, L-glutamine, and antioxidants;
an amino acid mixture with arginine, glutamine, and
-hydroxy--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 623 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 providedspreads
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
S334
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 patients 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 bodys
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 patients 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
S335
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)?
S336
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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Role of nutrition in HIV infection: Review of evidence

for more effective programming in resource-limited

Saskia de Pee and Richard D. Semba

spreads and fortified-blended foods further increase BMI

Key words: Food insecurity, HIV infection, mal-

nutrition, micronutrients, resource-limited settings,

S. de Pee and R. D. Semba

Insufficient dietary intake

Nutrition and HIV infection

loss and wasting are due to a negative energy balance,

Multiple micronutrient deficiencies are common

be adequate to meet the nutrient needs of nearly all

S. de Pee and R. D. Semba

TABLE 1. Documented relationships between micronutrients and HIV infectiona

Deficiency associated with

Yes, but also with positive

RNI for 19to 70-yr-olds

a. See text for references to specific evidence.

45, 52, 53]. Low serum zinc concentrations have been

micronutrients that are assessed in the serum or diet

Knowledge depends on what we look for; only the

Nutrition and HIV infection

Micronutrient deficiencies affecting HIV infection

Deficiencies of several micronutrients have been

In HIV-infected patients, low serum or plasma vitamin

For most micronutrients, a low status is associated

S. de Pee and R. D. Semba

Weight loss and wasting

Wasting (low body mass index [BMI]) and weight

Indicators of wasting and weight loss. According to the

Malabsorption (fat, carbohydrates, MNs):

Low food intake (MNs, energy)

HIV infection and

Increased nutrient needs due to infection

High infection pressure (malaria, TB,

Inefficient nutrient utilization

Higher susceptibility to HIV infection:

Changes of hormone production (glucagon, insulin, cortisol,

Higher HIV prevalence

Hypogonadism and adrenal insufficiency

FIG. 2. Relationship between HIV infection and malnutrition

Nutrition and HIV infection

weight loss usually also reflects a poor micronutrient

and/or difficulty swallowing. Therefore, increasing

S. de Pee and R. D. Semba

than in plant-source foods [115].

Because weight loss can be due to many factors and

HIV infection and nutritionreview of

Multimicronutrient supplementation has shown

Vitamin A for children. Periodic high-dose vitamin A

Nutrition and HIV infection

of HIV-infected neonates had no impact on anemia in

weeks of gestation through delivery and postpartum

S. de Pee and R. D. Semba

weeks of gestation through 6 weeks after delivery had

A community-based trial was conducted in Zambia

Several studies with micronutrient supplements have

Nutrition and HIV infection

Interventions to prevent or treat weight loss

Ensuring adequate nutrition is an essential component of HIV infection control, in addition to

ART reduces the risk of weight loss and may increase

Current treatment practices for weight loss. The earlier

S. de Pee and R. D. Semba

and management of weight loss among HIV-infected