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HIV Disease and Nutrition

TL Miller, P Graham, J Nebhrajani, G Somarriba, SC Tapia, and D Neri, Miller School of Medicine at the University
of Miami, Miami, FL, USA
2016 Elsevier Ltd. All rights reserved.

Introduction
Human immunodeficiency virus (HIV) infection is a worldwide
problem of great magnitude. The World Health Organization
(WHO) estimates that about 35 million adults and children
were living with HIV in 2013, the majority of whom are in
developing nations. In 2013, HIV and its related complications
were the cause of death in 1.5 million people worldwide. However, the number of individuals infected with and dying from
HIV has been steadily declining in the last 15 years. This trend
reflects the expansion of services to prevent the transmission of
HIV from mother to child, the wider use of antiretroviral therapy
(ART), and the improved prophylactic regimens worldwide. In
developed nations, HIV has become a chronic illness with
highly active antiretroviral therapy or now what is currently
called combination antiretroviral therapy (cART) as the mainstay of treatment. With more individuals living with HIV, the
necessity of appropriate supportive care is paramount.
Clinicians who care for those with HIV should be aware of
potential nutritional and metabolic problems and their consequences. In the past, and currently in some subpopulations,
wasting syndrome is the primary nutritional concern for
HIV-infected individuals. Malnutrition can have additive
destructive effects on the immune system and host defense
mechanisms. T cell-mediated immune responses are targeted
primarily and have been termed the nutritionally acquired
immune deficiency syndrome. It has been long thought that
aggressive nutritional rehabilitation can combat and potentially reverse these effects. However, as we approach 20 years
since the advent of cART, expanding cardiometabolic and
related nutritional issues often prevails that can also alter
immune responses and produce additional comorbidities.
Knowledge and implementation of effective nutritional therapies are important to improve medical outcomes and quality of
life. The problem of malnutrition in patients with the acquired
immunodeficiency syndrome (AIDS) is multifactorial, and
proper nutritional support will replenish body cell mass in
these patients, which is associated with functional improvement. With appropriate combinations of ART, nutritional and
other supportive care, many HIV-infected individuals are now
able to lead relatively normal lives.

HIV and Gastrointestinal Tract: Nutrient Absorption


Gastrointestinal malabsorption can lead to malnutrition and a
dysfunctional gastrointestinal tract can produce clinical symptoms that contribute to both morbidity and mortality in those
with HIV-1 infection. The etiology of gastrointestinal malabsorption is multifactorial and includes gastrointestinal mucosal abnormalities, which in turn can lead to macro- and
micronutrient malabsorption. These mucosal changes can be

Encyclopedia of Food and Health

due to local HIV infection of the gut or secondary enteric


infections. Villous atrophy and gastrointestinal tract dysfunction are coincident with high levels of HIV-1 viral load in the
gut. There is evidence that certain gastrointestinal epithelial
cells bind and selectively transfer HIV from the cells apical to
basolateral surface, where viral translocation across the epithelium encounters lamina propria macrophages and T cells.
The gastrointestinal tract has substantial CD4 T-cell depletion
in all stages of HIV disease that is discordant with systemic CD4 Tcell repletion with effective ART. This immune derangement may
contribute to altered epithelial permeability thereby permitting
translocation of microbes and generalized immune activation
leading to localized cytokine production and further replication
of HIV. High systemic levels of lipopolysaccharides (LPS) as a
result of bacterial translocation are associated with marked systemic immune activation that increases metabolic rate and sustains HIV infection. ART decreases the levels of LPS and promotes
CD4 T-cell reconstitution and may subsequently decrease the
systemic immune activation, although not completely.
As a result of either local HIV infection with associated
bacterial translocation (which induces proinflammatory
changes in the gastrointestinal mucosa and systemically) or
the injury caused by a secondary infection (this is most typical
when CD4 T cells drop below 200 cells per mm3), mucosal
function can be compromised resulting in gastrointestinal malabsorption, diarrhea, and malnutrition that may eventually
contribute to excess morbidity and mortality, especially in
developing nations.

Body Composition and Energy Expenditure


The interest in body composition of HIV-infected individuals
grew as early as the onset of the HIV epidemic. The importance
stems from the physiological and metabolic changes that have
been attributed to HIV. HIV was initially described as a wasting
disease, and since 1987, the wasting syndrome is considered a
case definition of AIDS. The Centers for Disease Control and
Prevention defines AIDS wasting syndrome as an involuntary
weight loss of greater than 10% baseline body weight during
the previous 12 months or a 5% loss of weight during the
previous 6 months. However, establishing a single definition
of wasting has been difficult for individuals of all ages. Even in
the era of cART, wasting continues to be prevalent. Some have
used the term cachexia as a more relevant description of body
composition changes in HIV. Wasting is associated with weight
loss while cachexia is related to loss of lean body mass. Some
studies found the prevalence of wasting in patients who are
cART-naive to be 48.4%.
The use of cART has become a standard practice in
developed and, now with increasing frequency, developing
nations and is the first line of care for many with HIV infection.

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However, cART has been linked to body composition changes.


Lipodystrophy, the redistribution of body fat characterized by
the combination of lipoatrophy (loss of fat tissue) in the
extremities and lipohypertrophy (excess accumulation of fat,
usually in the trunk, dorsocervical region, and breasts), is
associated with cART and in many situations specifically with
protease inhibitor (PI) use. Fat can also accumulate in the
abdominal viscera (usually the liver and mesentery) and
heart. The prevalence of lipodystrophy is reported to occur in
sometimes over 50% of cohorts with over 5 years of ARV
exposure. However, with the advent of newer classes of antiretrovirals, fat redistribution for many individuals with HIV is
less prevalent.
Mortality, accelerated disease progression, and impairment
of functional status have all been associated with wasting. In one
study, every 1% weight loss resulted in an 11% increase in the
risk of death. Additionally, when weight loss exceeded 10% from
baseline, there was a sixfold increase in relative risk for mortality.
This highlights the importance of preventative measures needed
to obviate the potential effects of wasting in HIV. Recent studies
have assessed the effects of nutritional supplementation, physical activity (specifically resistance training), and the use of
pharmacological methods on wasting and weight loss.
Chronic viral infections can influence energy utilization
and potentially alter nutritional status. These infections can
increase or shunt the effective use of energy substrates from
normal, healthy anabolic patterns to energy pathways associated with inflammatory processes. The chronic viral activity of
HIV is likely no different. Small studies of energy expenditure
have shown few differences in resting energy expenditure
(REE) or total energy expenditure (TEE) between HIV-infected
children with growth failure and those with normal rates of
growth. However, adults with HIV-1 infection show REE
increases with severity of illness, especially with secondary
infection and more advanced HIV disease, yet TEE is similar,
suggesting a compensatory response with reduced physical
activity. As HIV-infected individuals are treated with cART,
previously noted increases in protein catabolism decrease to
more normal rates, suggesting that chronic viral activity leads
to increased protein catabolism and can be brought to more
normal levels with successful viral suppression.

Macronutrients
Although the WHO has played a prominent role in efforts to
fully integrate food and nutrition in all aspects of prevention,
care, and treatment of HIV and AIDS, nutrition-specific recommendations for this patient group are limited. Knowledge
about the nutritional needs of people infected with HIV over
and above those required by uninfected people remains limited. This section discusses existing macronutrients recommendations for people living with HIV.
Patient groups vary in terms of their response to the virus,
stage of the disease, susceptibility and exposure to opportunistic infections, nutritional status, and individual response to the
various treatments received. Although compelling evidence
exists for the direct association between BMI < 18 kg m 2 and
accelerated disease progression, limited data exist regarding the
role of macro- and micronutrients in disease progression.

Existing energy and macronutrient recommendations for


this population based on HIV disease progression are summarized in Table 1. In addition to nutrient-specific recommendations, the nutritional interventions for the amelioration of
growth and weight gain and for the prevention or management
of metabolic complications of HIV disease for all age groups
are discussed in the subsequent sections.
The energy and protein needs of HIV-infected individuals
depend on their age, nutritional status, degree of gastrointestinal dysfunction, and the long-term effects of HIV disease such
as acute/chronic infection or other complications. Some
nutrient-specific recommendations for people living with HIV
have been established for all age groups and pregnant and
lactating women.
Current knowledge with regard to energy supports the existing WHO recommendations (i.e., calories increased by 10%
for asymptomatic children, adolescents, and adults). The additional energy helps children to maintain normal growth, development, activity, and bodily functions. In terms of specific
recommendations for HIV-infected adolescents, overall dietary
goals are consistent with those in uninfected adolescents and
include meeting the needs of normal growth. Most adults
maintain body weight through a reduction in physical activity
and/or an increase in caloric intake, so energy intake above the
110% of that recommended for uninfected population has not
been advised. In those with chronic malnutrition, caloric needs
will be greater, depending on the degree of malnutrition and
other factors such as demands for physical activity.
In resource-rich settings, asymptomatic HIV infection is
unlikely to significantly affect the energy requirements of pregnancy and lactation. Recommendations with regard to energy
intake for pregnant women should be population-based
because of differences in body size. To achieve optimal pregnancy outcomes, energy needs for women with healthy baseline body weight are no higher than the Estimated Energy
Requirement for nonpregnant women until the second trimester; thereafter, the extra energy need per day is 340 and 452 kcal
in the second and third trimesters, respectively. The 10%
increase in REE currently recommended (above those of nonpregnant adult females) is likely reasonable for asymptomatic
HIV-positive pregnant and lactating women. For pregnant and
lactating women in resource-limited settings, some recommendations have been established, and they vary according to
condition (pregnant and breastfeeding), HIV stage (stratified
by CD4 T-cell count), age (1420, >2030, and >3050
years), weight or BMI, food security score, micronutrient status
including hematologic status (presence of anemia), and treatment status (ART or other drugs).
For all age groups, macronutrient (protein, carbohydrate,
and fat) should be consumed at recommended amounts, with
additional adjustments made that are consistent with the
energy needs (i.e., if calories are increased by 10%, the macronutrient content should be increased proportionately).
Although some studies in adults have suggested that protein
requirements may be higher with HIV infection, as yet there is
no consistent evidence that increasing protein intake above the
required amounts for uninfected populations is beneficial.
During periods of acute/chronic infection, during weight
loss, or when metabolic complications become more evident
consequent to prolonged ART exposure, energy and nutrient

HIV Disease and Nutrition

Table 1

Energy and macronutrients needs in HIV infection

Nutrient
Energy

HIV infection factors


Clinical situations
When secondary infections are
absent and growth is
adequate in children and
weight is stable in adults

During illness, decreased


appetite, poor growth,
weight loss

Advanced disease

Overweight or obesity

Protein

During periods of well-being

Fat

Period of catchup growth


During periods of well-being

Fat malabsorption (due to HIV


GI enteropathy or secondary
infections)
Dyslipidemia

Carbohydrate
Fiber

345

During periods of well-being

Nutrition recommendations
Children, adolescents, and adults: target energy intake of 110% of that recommended for uninfected
population (based on actual weight rather than on expected weight for age) (WHO 2009)
Pregnant and lactating women: the 10% increase in REE currently recommended is likely
reasonable for asymptomatic HIV-positive pregnant and lactating women. Energy requirements
may be higher for pregnant adolescents (Raiten et al., 2011)
Standard methods of assessing energy needs calorie levels based on the Estimated Energy
Requirements (EERs) and activity levels from the Institute of Medicine Dietary Reference Intakes
(DRIs) (Macronutrients Report, 2002)
Children: energy requirements can increase by up to 2030% during infections and recovery (WHO,
2009). Equations for estimating catchup growth requirements for both calories and protein can be
used
Adults: increase energy intake by 600960 kcal day 1 in adults with weight loss may increase
body weight (Grobler et al., 2013), which is better achieved by providing a balanced nutritional
supplement
Pregnancy and lactation: the energy needs may be even greater than 10% above those of
nonpregnant adult females for women with inadequate rate of weight gain during pregnancy,
excessive weight loss postpartum, or other ongoing health issues (Raiten et al., 2011)
Up to 50100% additional energy to recover and regain weight (WHO 2003)
For critically ill patients: energy requirements may be calculated by predictive equations or
measured by indirect calorimetry (Singer, 2009), with special attention to the prevention of
complications related to under- or overfeeding (Fraipont and Preiser, 2013)
This is best achieved through enteral or parenteral (if enteral has failed) feeding
Weight management:
Counseling on changing eating habits and patterns
Regular exercise: physical activity counseling or physical activity program participation
As in asymptomatic children, protein should contribute about 1015% of the energy intake and
there is no need for additional protein other than what is present in a balanced diet (WHO, 2009)
Acceptable Macronutrient Distribution Ranges (AMDRs) can be used to ensure sufficient intakes
of essential nutrients (Food and Nutrition Board, 2005)
Use equation for estimating catchup growth requirements
Provide anticipatory guidance regarding the importance of a low-fat, low-saturated-fat, lowcholesterol diet for all otherwise healthy HIV-infected patients older than 2 years and their families
due to increased risk of CVD in HIV-infected populations
AMDR: Food and Nutrition Board (2005)
13 years: 3040% of total calories
418 years: 2535% of total calories
Pregnancy and lactation: essential fatty acid needs are 30% higher than those of nonpregnant
women, and adequate fatty acid intake should be ensured in a manner consistent with
recommendations for uninfected women (Raiten et al., 2011)
In these cases, dietary modification of fat may be required
Supplemental MCT and enteral formulas containing MCT can be used to supplement caloric intake
Dietary intervention with NCEP Therapeutic Lifestyle Changes (NCEP 2002) and exercise have been
shown to reduce triglycerides in both HIV-infected (Stradling et al., 2012) and HIV-uninfected
(Kelley et al., 2011) populations and to reduce LDL cholesterol in the general population (Yu-Poth
et al., 1999)
Counseling on changing eating habits and patterns per AHA/AAP
AMDR: Food and Nutrition Board (2005), 4565% of total calories
Added sugars should comprise no more than 10% of total calories consumed
A reasonable intake is 0.5 g kg 1 day 1 to a maximum of 35 g daily

BMR, basal metabolic rate; EER, Estimated Energy Requirement; FTT, failure to thrive; DRI, dietary reference intake.
Acceptable Macronutrient Distribution Range (AMDR) is the range of intake for a particular energy source that is associated with reduced risk of chronic disease while providing intakes
of essential nutrients.

needs are greater than that recommended for uninfected population. As for uninfected individuals, the estimation of energy
requirements for critically ill patients may be calculated by
predictive equations or measured by indirect calorimetry,
with special attention to the increased risk of overfeeding

during the early phase of acute illness and the increased risk
of underfeeding during the late phase. Once the secondary
infections are successfully treated and energy intake is
increased sufficiently, patients are able to regain weight and
remain weight-stable.

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HIV Disease and Nutrition

Micronutrients
In addition to macronutrient intake, careful attention to
micronutrient status (vitamins and minerals) is a critical
component in the nutritional treatment and care of people
living with HIV infection. The WHO has long taken the
lead in the establishment and dissemination of specific
requirements for micronutrient consumption among people
living with HIV throughout all stages of the life cycle. The
importance of the role specific micronutrients serve in the

Table 2

maintenance of immune system function and in the


reduction of morbidity and mortality from disease- and
treatment-related symptoms has been well established. However, a general consensus of the long-term effects, optimal
composition, and dosing of both single and multiple
micronutrient (MMN) supplements has yet to be reached.
This section provides an overview of current micronutrient
guidelines for people living with HIV. Table 2 provides a
summary of micronutrient guidelines for HIV-infected populations throughout the life cycle.

Micronutrient recommendations in HIV infection

Population

Current micronutrient recommendations

Comments

Children and
adolescents

Maintain current WHO recommendations:


Ensure one Recommended Dietary Allowance (RDA) for all
essential nutrients, preferably through a well-balanced diet
When dietary intakes are insufficient, the use of micronutrient
supplements at RDA levels is supported

Currently, there exists insufficient evidence to support a


general policy encouraging the use of daily oral nutrient
supplements
Careful attention to dietary quality and adequacy of
micronutrients is critical; important factors to consider
include high food insecurity or poor dietary diversity
Additional attention may be justified for specific nutrients
(e.g., vitamin A, vitamin D, calcium, and iron) either in
terms of dietary intake and poor exposure or in the
context of potential treatment interactions
Given the vast diversity of variables and study design
throughout various studies investigating micronutrient
supplementation in this population, it is not possible to
recommend anything other than the current RDA or a
routine multivitamin. However, there still remain safety
concerns for potential harm from higher doses of
selected micronutrients (e.g., vitamin A and multiple
micronutrient (MMN) supplements, which may promote
increased viral replication and increased shedding of
virus in genital secretions, thus potentially increasing risk
of transmission of HIV). Further research into optimal
composition and dosing is warranted
Supplementation at amounts above the RDA is not
advised at this time as some studies have shown that
they may in fact be harmful (e.g., vitamin A, vitamin D
(25), and iron)
Iron supplementation is recommended at the RDA
amount for HIV-positive pregnant women
Iron supplementation is not recommended in lactating
HIV-positive women unless the presence of iron
deficiency is clinically confirmed

Vitamin D intake:
Children on antiretroviral treatment (ART) should be given two
to three times more vitamin D than the RDA for their age group
Adults

Pregnant and
lactating
women

Insufficient evidence to support a change from 2003


recommendations of one RDA for essential micronutrients,
preferably from dietary intake
Adults on ART should be given two to three times more vitamin D
than the RDA for their age group

Supplementation of one RDA amount of micronutrients for all


HIV-positive pregnant and lactating women is recommended due
to the high likelihood of food insecurity, the fact that micronutrient
needs are higher during pregnancy and lactation and that
deficiencies appear to be more common in HIV-infected women
Supplements should contain the 14 core micronutrients provided
in the UNICEF UNIMMAP (UN international multiple micronutrient
preparation) supplement. These micronutrients include vitamins
A, D, and E; thiamine; riboflavin; niacin; folic acid; vitamins B6, B12,
and C; and minerals including zinc, iron, copper, selenium, and
iodine
In areas of endemic vitamin A deficiency, WHO recommends that
a single high dose of vitamin A (200 000 IU) be given to women as
soon as possible after delivery, but no later than 6 weeks after
delivery
Pregnant and lactating women require at least 600 IU day 1 of
vitamin D; at least 15002000 IU day 1 of vitamin D may be
needed to prevent/treat deficiency

Source: Raiten, D. J., Mulligan, K., Papathakis, P. and Wanke, C. (2011). Executive summary nutritional care of HIV-infected adolescents and adults, including pregnant and lactating
women: what do we know, what can we do, and where do we go from here? The American Journal of Clinical Nutrition 94(6): 1667S1676S. http://dx.doi.org/10.3945/
ajcn.111.019711; Holick, M. F., Binkley, N. C., Bischoff-Ferrari, H. A., et al. (2011). Evaluation, treatment, and prevention of vitamin D deficiency: an Endocrine Society clinical
practice guideline. Journal of Clinical Endocrinology and Metabolism 96(7): 19111930. http://dx.doi.org/10.1210/jc.2011-0385; Irlam, J. H., Siegfried, N., Visser, M. E. and Rollins, N.
C. (2013). Micronutrient supplementation for children with HIV infection. Cochrane Database of Systematic Reviews 10: CD010666. http://dx.doi.org/10.1002/14651858.CD010666;
Irlam, J. H., Visser, M. M., Rollins, N. N. and Siegfried, N. (2010). Micronutrient supplementation in children and adults with HIV infection. Cochrane Database of Systematic Reviews (12):
CD003650. http://dx.doi.org/10.1002/14651858.CD003650.pub3; Roberfroid, D., Huybregts, L., Lanou, H., et al. (2012). Impact of prenatal multiple micronutrients on survival and
growth during infancy: a randomized controlled trial. American Journal of Clinical Nutrition 95(4): 916924. http://dx.doi.org/10.3945/ajcn.111.029033.

HIV Disease and Nutrition

Micronutrient deficiencies are often observed in conjunction with a wide range of impaired immune responses and
clinical manifestations including increased susceptibility to
infection, inadequate intake, malabsorption, diarrhea, and
subsequently increased morbidity and mortality among various groups of people living with HIV. Although malnutrition
likely plays a role in disease outcomes, current data regarding
the role of micronutrients in disease progression remain limited. In conjunction with cART, inexpensive micronutrient
supplements could provide several cellular and clinical benefits, ranging from the prevention of mitochondrial toxicity and
oxidative stress to facilitation of immune reconstitution. Per
the established WHO guidelines, HIV-infected children and
adults should consume diets that provide micronutrient
intakes at the Recommended Dietary Allowance (RDA).
These recommendations state that in cases where dietary
intakes are insufficient, the use of micronutrient supplements
at the RDA in HIV-infected individuals of all ages is supported.
Low levels of vitamins, minerals, and other micronutrients
are often observed among HIV-infected children. This may
frequently be the result of inadequate nutritional intake from
their diet or their bodies may demand increased micronutrient
levels for the purpose of fighting the HIV infection itself or
opportunistic infections. Vitamin A supplements, as in children without HIV infection, reduce diarrheal morbidity and
mortality especially in young children. As stated in the 2003
WHO guidelines, HIV-infected 659-month-old children living in resource-limited settings should be given periodic (every
46 months) vitamin A supplements (100 000 IU for infants
612 months and 200 000 IU for children >12 months) in
order to reduce all-cause mortality and diarrhea morbidity.
This level is consistent with WHO recommendations for the
prevention of vitamin A deficiency in children. Furthermore,
studies have shown that vitamin A supplements are beneficial
and safe and can half mortality overall in an analysis of three
trials in different African countries.
Micronutrient supplements in adults are also shown to
reduce the metabolic and cellular complications of cART. A
greater intake of vitamin E and vitamin A in those on cART was
associated with fewer metabolic complications, dyslipidemia,
and insulin resistance. In addition, a daily supplement of
vitamins C and E for 3 months reduced oxidative stress
baseline CD4 counts <100 cell per ml.
Zinc is another important nutritional factor for HIVinfected individuals. Zinc supplements have been shown to
help HIV-infected children recover from diarrheal illnesses,
are safe, and appear to have similar benefits on diarrheal
morbidity in children with HIV as in children without HIV
infection. Long-term (18-month) zinc supplementation potentially reduces the likelihood of opportunistic infection in
adults and children and improves CD4 counts in adults.
There has been considerable growth in clinical interest and
research with respect to vitamin D deficiency and its effects on
the progression of HIV infection. With mounting evidence that
vitamin D deficiency can exacerbate immune dysfunction,
contribute to skeletal fractures, and increase cardiovascular
disease (CVD) and metabolic risk, there has been a great
focus on how this nutrient contributes to disease progression
in HIV. A number of clinical studies among populations in
both developed and developing nations have associated

347

vitamin D deficiency with a variety of poor health outcomes


such as atherosclerotic CVD, increased viral load, and immune
suppression. Up to a third of perinatally HIV-infected children
can be vitamin D-deficient. As a result of the current data, the
National Endocrine Society recognizes that ART increases the
catabolism of 25-hydroxy vitamin D and 1,25-dihydroxy vitamin D levels, therefore recommending that children on ART be
given two to three times more vitamin D for their age group.
As recommended for children and adolescents, HIVinfected adults should also consume well-balanced diets in
order to reach micronutrient intakes of one RDA for essential
micronutrients. In the event that RDA amounts of micronutrient intakes cannot be reached through dietary sources, evidence from current studies on this topic taken collectively
indicates that there is a role for multivitamin supplements at
the level of the RDA in most HIV populations, adults included.
Furthermore, for adults on ART, it is recommended they be
given two to three times more vitamin D than the RDA for their
age group to treat deficiency and potentially mitigate the effects
of ART on calcium balance and bone metabolism.
A well-balanced diet certainly remains the gold standard for
micronutrient intake for all HIV-infected populations. However, the high prevalence of food insecurity, the increased
metabolic and micronutrient demands of pregnancy and lactation, and the observation that deficiencies appear to be more
common in HIV-infected women necessitate micronutrient
supplementation at one RDA for all HIV-positive pregnant
and lactating women. In general, supplements should provide
the 14 core micronutrients that comprise the UNICEF UNIMMAP (UN international multiple micronutrient preparation)
supplement: vitamin A, vitamin D, vitamin E, thiamine, riboflavin, niacin, folic acid, vitamin B6, vitamin B12, vitamin C,
zinc, iron, copper, selenium, and iodine.
Since nutrient deficits are often observed during pregnancy
and lactation and specifically among HIV-infected pregnant
women, current guidelines continue to address specific
instances of common vitamin and mineral deficiency states.
In the case of anemia prevention, the WHO recommends daily
ironfolate supplementation (400 mg of folate and 60 mg of
iron) during 6 months of pregnancy and, in the case of clinically confirmed severe anemia, twice-daily supplements.
Hence, these levels of iron and folate are incorporated into
the UNICEF UNIMMAP supplement. In accordance with the
2003 WHO guidelines, vitamin A intake by HIV-infected
women during pregnancy and lactation should not exceed
the RDA levels as it may be harmful in some cases; in areas of
endemic vitamin A deficiency, a single high dose of vitamin A
should be given to women as soon as possible after delivery,
but no later than 6 weeks after delivery. As for vitamin D, the
National Endocrine Society suggests that pregnant and lactating women require at least 600 IU day 1 of vitamin D; at least
15002000 IU day 1 of vitamin D may be needed to prevent/
treat deficiency. When taken collectively, available evidence
suggests that the approach to caring for HIV-infected women
is the same as that for uninfected women with special attention
to HIV-specific factors such as viral load, CD4 T-cell count, and
ART status.
Although there have been some advances in the study of
MMN and positive clinical outcomes in HIV, the impact of
specific micronutrient supplements as determined through

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HIV Disease and Nutrition

randomized, controlled trials remains few and less clear. Additional research is warranted to determine the long-term clinical
advantages, potential adverse effects, and optimal composition
of micronutrient supplementation among more diverse groups
of HIV-positive research participants.

Cardiometabolic Complications
Obesity and Cardiometabolic Disease
Obesity is an emerging health problem among adolescents and
adults living with HIV/AIDS. With the institution of cART, the
immune and disease status of HIV-infected individuals has
improved and eating patterns (healthy or not) often parallel
those in healthy uninfected individuals. Poverty and food
insecurity are among other factors that can contribute to
childhood obesity that influence both HIV-infected and HIVuninfected populations equally. Immigrant families are particularly vulnerable. As the prevalence of obesity increases among
patients with HIV, the cumulative risk for CVD also increases.

Fat Redistribution
Coincident with the introduction of cART, a clinical syndrome
of body fat redistribution and metabolic changes was first
described initially in adults, but is now commonly reported
among children. HIV-infected patients receiving cART regimens have developed a syndrome of peripheral insulin resistance, hyperlipidemia, and lipodystrophy (truncal obesity,
dorsocervical fat pad, and extremity and facial wasting). Clinical and biochemical abnormalities associated with the fat
redistribution syndrome or commonly termed, lipodystrophy
syndrome, are shown in Table 3. Risk factors associated with
developing the fat redistribution syndrome in adults include
female gender, increasing age, family history of premature
CVD, higher pretherapy body weight, and behavioral patterns
such as tobacco and alcohol use. Complications associated
with the fat redistribution syndrome include higher rates of
diabetes mellitus and premature CVD. Lipodystrophy is almost
exclusive to patients receiving ART and can improve after PI
and NRTI switching. Medical compliance with drug therapy
may be poorer owing to the cosmetic side effects of therapy.
Table 3
Clinical and biochemical abnormalities of the fat
redistribution syndrome
Clinical features

Laboratory features

Increased abdominal (visceral) fat


Increased waist-to-hip ratio (more
reliable in adults)
Buffalo hump
Fat atrophy
Wasting of extremities
Wasting of buttocks

Hyperlipidemia
Increased triglycerides
Increased total cholesterol
Increased LDL-C
Decreased HDL-C
Insulin resistance
Normal to increased serum
glucose
Increased insulin
Increased C-peptide

Loss or thinning of facial fat,


prominence of nasolabial fold
No change to increased weight
Fatigue and weakness

Lipodystrophy is described in children, as well. Early studies showed a beneficial nutritional effect of cART in both adults
and children. Early initiation of cART is associated with more
rapid restoration of growth in children of developing nations.
Growth hormone levels are significantly lower in lipodystrophic HIV-infected adults with visceral adiposity. In addition to the positive improvement in growth and lean body
mass, however, cART is also associated with abnormalities in
fat distribution though some studies report similar lean mass
in HIV-infected and HIV-uninfected individuals. Both peripheral lipoatrophy and central obesity occur in both HIV-infected
adults and children. Fat redistribution can develop fairly rapidly after initiating a cART regimen and changes can progress
over time. Metabolic abnormalities are associated with specific
classes of drugs with many NRTIs and PIs implicated. Newer
agents often have less impact on fat redistribution and are the
preferred therapy if the virus is sensitive to the therapy.

Cardiometabolic Risk
Atherosclerotic CVD is a leading comorbidity and cause of
mortality among HIV-infected adults. Several studies show
that HIV-infected children, compared to healthy peers, have
higher rates of CVD risk factors, including dyslipidemia, insulin resistance, obesity, and central adiposity. HIV infection also
results in prolonged chronic inflammation, thereby increasing
CVD risk. In adults with cART-related fat redistribution, several
studies have suggested an increase in the risk of myocardial
infarction relating to the level of viral control (increased
inflammation) or to ARV exposures (including PIs and certain
NRTIs). Exogenous obesity, common among all individuals
with HIV, can also contribute to CVD risk. Children, compared
to adults with HIV, may be at even greater risk of developing
premature CVD as the lifetime exposures to factors associated
with CVD risk are longer in children.

Dyslipidemia
Prior to the introduction of any ART, elevated triglycerides and
LDL cholesterol and lower HDL cholesterol were reported and
associated with HIV infection. This profile persists in the current era and suggests that chronic immune activation can
influence lipid metabolism. Proinflammatory cytokines (as a
response to the chronic viral infection) may affect lipid pathways. After PI therapy became widespread, several investigators
in the United States and abroad reported a 2050% rise in lipid
levels of HIV-infected individuals. In hepatocyte cell lines, PIs
have been shown to interfere with cholesterol synthesis by the
inhibition of the proteasome, a potent regulator of apolipoprotein B production, among other mechanisms. Other factors
associated with dyslipidemia include successful viral suppression, better CD4 T-cell counts, and demographic factors. The
impact of PIs on lipid levels, independent of HIV, is effectively
described in HIV-seronegative volunteers who developed dyslipidemia following PI treatment.

Insulin resistance and type 2 diabetes mellitus


Abnormal glucose homeostasis was documented in HIVinfected adults with lipodystrophy well before it was reported
in children. The etiology of insulin resistance is multifactorial
and has been linked with PI, NRTI, or nonnucleoside reverse

HIV Disease and Nutrition

transcriptase inhibitor (NNRTI) use both singly and in combination, although exact mechanisms have not been well defined.
HIV-uninfected adults treated with indinavir (a PI) showed a
rapid onset of insulin resistance but not hyperlipidemia or body
shape changes. Leptin, a hormone secreted by adipocytes, is low
in congenital and HIV lipoatrophies. These patients also tend to
have increased intramyocellular lipid in direct correlation to
their degree of insulin resistance. A possible mechanism by
which cART causes insulin resistance is by direct inhibition of
the transport function of glucose transporter type 4 (GLUT4),
which is responsible for insulin-stimulated glucose uptake into
the muscle and fat. Other potential causes of insulin resistance
include NRTI or NNRTI therapy associated with mitochondrial
DNA (mtDNA) mutations or depletions. Although there are
limited data in adults, there are striking similarities between
rare mitochondrial disorders, such as multiple symmetric lipomatosis (MSL), a condition that is phenotypically very similar to
cART-associated lipodystrophy. These mtDNA mutations in
MSL lead to an impaired function of cytochrome c oxidase
and a subsequent decrease in fat turnover. Inflammatory cytokines have been linked to both insulin resistance and diminished adiponectin, which affects insulin signaling and glucose
homeostasis. The adipose tissue is a major determinant of insulin sensitivity and changes associated with lipodystrophy can
alter the secretion of adiponectin. In one study, patients with PIinduced lipodystrophy had increased levels of circulating
inflammatory cytokines.

Vascular inflammation and atherosclerosis


Vascular endothelial dysfunction, a process that is associated
with atherosclerosis, may occur as a result of chronic inflammation and injury in the endothelium. Oxidative stress due to
cART and direct cytopathic effect of the virus are likely causative agents in HIV. In addition, dyslipidemia, insulin resistance, and chronic inflammation due to ongoing immune
activation in HIV-infected individuals also contribute to endothelial damage. The levels of proinflammatory cytokines are
higher in HIV-infected individuals compared to contemporary
controls. These vascular inflammatory biomarkers are positively correlated with clinical markers including higher viral
load, lipids, and waist circumference. Furthermore, Wolf found
that not only were levels of vascular cell adhesion molecule-1
(VCAM-1), intercellular adhesion molecule-1 (ICAM-1), and
von Willebrand factor higher in untreated patients with HIV
infection, but also they decreased significantly after treatment
with a regimen containing either one PI or one NNRTI.
Preatherosclerotic lesions can be defined by imaging studies
of the arterial structures. Common ways of evaluating CVD risk
are through measurements of the carotid intima, brachial
artery reactivity, or pulse wave velocity. Both adults and children with HIV have evidence of increased CVD risk when their
measures are compared with controls.

Nutritional Interventions
People living with HIV are faced with many obstacles that
challenge their ability to sustain proper nutritional status.
Decreased energy intake, increased energy expenditure, and
accelerated protein turnover are common in people with HIV.

349

Promoting and supporting adequate nutrition and food security are critical for this population. Presently, there are a number of different strategies to improve nutritional outcomes for
people living with HIV. Regardless, nutritional interventions in
HIV should be designed under the premise that (1) ARVs are
essential to prolong life and to halt the spread of HIV and (2)
food and sound nutrition are essential to human health.
Table 4 shows the gastrointestinal and nutritional side effects
of current ARVs.
Overall dietary goals for HIV-infected individuals are consistent with those for non-HIV-infected and include meeting the
needs of normal growth of children and adolescents, meeting
the needs of adequate weight gain of pregnant women, consumption of a high-quality, nutrient-dense diet, building good
eating habits, avoiding obesity through limiting intake of
energy-dense but nutritionally poor foods, engaging in physical
activity, and avoiding cigarettes, alcohol, and drugs. The diet
plan should be individualized based on the patients nutritional
status, age, symptoms, and ability to meet nutrient requirements. Regular nutritional assessments are necessary in order
to determine the appropriateness and effectiveness of the interventions. This assessment should include a review of the medical and dietary history, nutrient analysis of usual intake,
anthropometric measurements, body composition, and measurement of biochemical values. In order to guarantee optimal
nutrition care, the team should be multidisciplinary and be
composed of a physician, nurse specialist, social worker, and
dietician.
Consumption of a well-balanced diet remains the optimal
choice for achieving adequate nutritional status for all HIVinfected individuals regardless of age for overall health and
wellness, as well as growth and development in pediatric and
pregnant populations. However, the increased metabolic
demands of HIV infection and symptomatic HIV often present
significant challenges for achieving or maintaining healthy
body weight and immune system function. In circumstances
where malnutrition and food insecurity are present, supplemental food sources and/or enteral nutrition supplements may
be necessary to achieve positive health outcomes and are often
effective when given in the appropriate amounts. Some data
suggest that body weight and lean body mass tend to increase
with nutritional support. Food-based interventions can treat
malnourished HIV-infected patients and are necessary in order
to address both the individual needs of the patients and the
food security of their households. Ready-to-use therapeutic
foods effectively treat malnutrition of HIV-infected individuals
in developing nations.
Incentives provided through food supplements can be a
helpful method to improve clinical adherence. There is limited
evidence regarding the use of balanced nutritional supplements (consisting of 5060% carbohydrate, 1530% protein,
and 2030% fat) for improving energy intake and protein
among HIV-infected adults with weight loss, but no effects on
anthropometric or immunologic parameters. It is likely that
decreased energy intake, not changes in energy expenditure,
plays a major role in the weight loss experienced by those with
HIV and secondary infection. Therefore, with appropriate treatment and nutritional resources, most patients with HIV-related
weight loss will gradually increase ad libitum caloric intake and
gain weight.

350

HIV Disease and Nutrition

Table 4

HIV-related medications and common gastrointestinal and metabolic side effects

Medication

Action

Side effects

Abacavir
Aciclovir
Atazanavir
Atripla (tenofovir, emtricitabine, and
efavirenz)
Azithromycin
Ciprofloxacin

NRTI
Antiviral
PI
Combination

Nausea, vomiting, diarrhea, abdominal pain, pancreatitis, abnormal liver function


Nausea, abdominal pain, diarrhea, abnormal liver function
Nausea, diarrhea, abdominal pain, hyperbilirubinemia
Nausea, vomiting, diarrhea, abdominal pain, hepatitis, bone loss, pancreatitis, lactic acidosis

Antibacterial
Antibacterial

Clarithromycin
Combivir (zidovudinelamivudine)
Complera (rilpivirine, tenofovir,
emtricitabine)
Darunavir
Didanosine (ddI)
Edurant
Efavirenz
Emtricitabine
Epzicom (zidovudine, abacavir)
Erythromycin
Etravirine
Fosamprenavir
Enfuvirtide
Ganciclovir
Indinavir
Ketoconazole
Lamivudine

Antibacterial
Combination
Combination

Nausea, vomiting, melena, jaundice


Ileus, jaundice, bleeding, diarrhea, anorexia, oral ulcers, hepatitis, pancreatitis, vomiting,
abdominal pain
Nausea, diarrhea, abdominal pain, abnormal taste
Nausea, vomiting, abdominal pain, abnormal liver function, pancreatitis, lactic acidosis
Nausea, vomiting, abnormal liver function, lactic acidosis

PI
NRTI
NNRTI
NNRTI
NRTI
Combination
Antibacterial
NNRTI
PI
FI
Antiviral
PI
Antifungal
NRTI

Lopinavir/ritonavir
Maraviroc
Nelfinavir
Nevirapine

PI
EI
PI
NNRTI

Pentamidine
Raltegravir
Rifampin
Rilpivirine
Ritonavir
Saquinavir

Antiparasitic
II
Antibacterial
NNRTI
PI
PI

Stavudine

NRTI

Stribild (elvitegravir, cobicistat,


emtricitabine, tenofovir)
Sulfonamides
Tenofovir
Tipranavir
Tivicay
Trizivir
Combination

Combination

Triumeq (abacavir, dolutegravir,


lamivudine)
Truvada (emtricitabine, tenofovir)
Tybost
Vitekta
Zidovudine (ZDV)

Antibacterial
NRTI
PI
II
Nausea,
vomiting,
abdominal
pain,
Combination
Combination
PE
II
NRTI

Nausea, vomiting, diarrhea, abdominal pain, pancreatitis, hepatitis, constipation


Nausea, vomiting, abdominal pain, pancreatitis, abnormal liver function
Abnormal liver function, lipodystrophy
Nausea, vomiting, abnormal liver function, hyperlipidemia
Lactic acidosis, hepatomegaly, diarrhea, nausea
Nausea, vomiting, abdominal pain, abnormal liver function, lactic acidosis, pancreatitis
Nausea, vomiting, abdominal pain
Nausea, vomiting, diarrhea, abdominal pain, hepatitis
Nausea, diarrhea, vomiting, abdominal pain
Nausea, diarrhea, abdominal pain, hepatitis, pancreatitis, dry mouth, anorexia
Nausea, vomiting, diarrhea, anorexia, abnormal liver function
Nausea, vomiting, abdominal pain, diarrhea, changes in taste, jaundice, abnormal liver function
Hepatotoxicity
Nausea, diarrhea, decreased appetite, vomiting, abdominal pain, pancreatitis, abnormal liver
function
Diarrhea, nausea, vomiting, abdominal pain, lipodystrophy, hyperlipidemia
Nausea, constipation, diarrhea, flatulence, abdominal pain, hepatitis, dysgeusia, stomatitis
Nausea, diarrhea, fatigue, abnormal liver function, exacerbation of chronic liver disease
Stomatitis, nausea, abdominal pain, raised gamma-glutamyl transpeptidase level,
hepatotoxicity
Abdominal pain, bleeding, hepatitis, pancreatitis, nausea, vomiting
Gastritis, hepatitis, nausea, vomiting, abdominal pain, diarrhea, hyperbilirubinemia
Abdominal pain, nausea, vomiting, diarrhea, jaundice
Lipodystrophy
Nausea, vomiting, diarrhea, abdominal pain, anorexia, pancreatitis, abnormal liver function
Mouth ulcers, nausea, abdominal pain, diarrhea, pancreatitis, abnormal liver function,
exacerbation of chronic liver disease
Nausea, vomiting, abdominal pain, diarrhea, pancreatitis, abnormal liver function, hepatic
failure, lipodystrophy, hyperlipidemia, insulin resistance
Lactic acidosis, severe hepatomegaly with steatosis, and posttreatment acute exacerbation of
hepatitis B
Hepatitis, pancreatitis, stomatitis, nausea, vomiting, abdominal pain
Nausea, vomiting, diarrhea, abdominal pain, hepatitis, bone loss, pancreatitis, flatulence
Hyperlipidemia, nausea, vomiting, diarrhea, abdominal pain, pancreatitis, hepatitis
Gastritis, hepatitis, nausea, vomiting, abdominal pain, diarrhea, hyperbilirubinemia
(abacavirlamivudinezidovudine)
pancreatitis, abnormal liver function

Lactic acidosis, abnormal liver function


Lactic acidosis, nausea, vomiting, diarrhea, abdominal pain, hepatitis, bone loss, pancreatitis
Nausea, jaundice
Diarrhea
Nausea, vomiting, abdominal pain, abnormal liver function

HBV, hepatitis B virus; FI, fusion inhibitor; II, integrase inhibitor; EE, entry inhibitor; NRTI, nucleoside reverse transcriptase inhibitor; NNRTI, nonnucleoside reverse transcriptase
inhibitor; PI, protease inhibitor; PE, pharmacokinetic enhancer of PIs.

HIV Disease and Nutrition

Since the advent of cART, much of the wasting seen since


the pre-cART era has been diminished in developed countries.
HIV-infected patients are now faced with metabolic consequences of their ART regimen. Obesity, dyslipidemia, lipodystrophy, insulin resistance, and central adiposity are common
cART-related complications due to increases in fat rather than
lean mass.
HIV infection also results in prolonged chronic inflammation, thereby increasing CVD risk. Even though the mechanisms for these effects are likely multifactorial, care must be
taken to avoid unwarranted weight gain and many nutritionally related components should be targeted. However, there are
no specific guidelines that address lipid abnormalities or insulin resistance specific to HIV-infected patients. A recent metaanalysis has demonstrated a comparable clinical benefit of
dietary intervention or omega-3 supplementation in reducing
triglycerides, but no effects on other lipids in patients without
concurrent lipid-lowering medication. Dietary intervention
with the National Cholesterol Education Program (NCEP)
Therapeutic Lifestyle Changes and exercise have been shown
to reduce triglycerides in both HIV-infected and HIVuninfected populations and to reduce LDL cholesterol in the
general population. Treatment of these complications should,
therefore, follow nutrition and lifestyle interventions guidelines recommended for the general population. Higherintensity dietary interventions may also be required in the
HIV population for LDL cholesterol reduction. Mediterraneanstyle diet plans, which promote the importance of healthy fats
generally found in nuts, seeds, and olive and canola oils, have
recently been shown to be effective in improving the lipid
profiles and CVD risk factors in HIV-infected and HIVuninfected adults. These diet plans are similar to other heart
healthy eating regimens, emphasizing the consumption of
fruits, vegetables, and whole grains.
It is well known that HIV and its treatment impact bone
mineral density, so bone health must be considered when
addressing the nutritional needs of HIV-infected individuals.
Baseline bone assessments are recommended (typically evaluated with dual-energy x-ray absorptiometry), with periodic
follow-up. It is important to ensure adequate intake of vitamin
D and calcium and to emphasize the importance of weightbearing exercise and avoidance of alcohol and tobacco, especially during adolescence, when peak bone mass is achieved.
Addressing food security is essential in the prevention, care,
and treatment of HIV and AIDS. Food insecurity has been
associated with worse ART adherence in low- and middleincome settings as a consequence of negative feedback (e.g.,
ART leads to improved appetite, which, in the absence of food,
leads to poor adherence), worse virological and immunologic
outcomes, worse physical and mental health status, and
increased risk of mortality. Thus, interventions to ensure provision of food with assessment of food security and appropriate referrals to food assistance programs should be well
integrated with HIV care programs. Health providers should
be familiar with locally available resources that can be offered
to this nutritionally vulnerable population.
For HIV-infected individuals who suffer from malnutrition
and food insecurity, nutritional supplements can be effective if
administered in adequate amounts. HIV populations at higher
risk include those with increased metabolic demands such as

351

pregnant and lactating women and children and those with


active infections. Otherwise, with appropriate treatment and
nutritional resources, most patients with HIV-related weight
loss will gradually increase ad libitum caloric intake and gain
weight. Future intervention efforts should quantify HIVspecific requirements across all ages/sexes so that supplements
can be dosed in adequate amounts or administered by meal
replacements. In developing nations, where malnutrition is of
great concern, research should focus on locally based and
sustainable foods. Food supplements that are economically
feasible and efficient have the potential to improve nutritional
intake, curtail weight loss, and alleviate HIV-associated symptoms. Future research efforts should analyze the long-term
effects of nutritional interventions on LDL and HDL cholesterol and triglycerides in children and adults.
In addition to nutritional interventions involving diet, per
se, other strategies to improve the nutritional status of HIVinfected individuals include progressive resistance training and
hormone therapy. Exercise is a valuable option to increase lean
tissue mass. Several studies in children/adolescents and adults
have shown an increase in lean muscle mass as well as strength
and cardiorespiratory fitness. Pharmacological treatments have
also shown some benefit. Growth hormone-releasing hormone can improve central adiposity, while metformin has
been reported to improve glucose homeostasis.

Summary
The multidimensional nature of nutritional problems associated with HIV infection is a microcosm for most nutritional
disorders that span a vast array of both acute and chronic
disease states in humans. With improved therapies and survival of HIV-infected individuals, the state of nutrition will
continue to evolve. Future research and treatments in this
field will focus on using nutrition to augment and optimize
the clinical care of those chronically infected with HIV.

Further Reading
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disease and HIV: strategies to promote exercise and nutrition among HIV-infected
individuals. Current HIV/AIDS Reports 9(4): 351363. http://dx.doi.org/10.1007/
s11904-012-0135-7.
Brenchley JM, Price DA, Schacker TW, et al. (2006) Microbial translocation is a cause
of systemic immune activation in chronic HIV infection. Nature Medicine 12(12):
13651371. http://dx.doi.org/10.1038/nm1511.
Brinkman K, Smeitink JA, Romijn JA, and Reiss P (1999) Mitochondrial toxicity induced
by nucleoside-analogue reverse-transcriptase inhibitors is a key factor in the
pathogenesis of antiretroviral-therapy-related lipodystrophy. Lancet 354(9184):
11121115. http://dx.doi.org/10.1016/S0140-6736(99)06102-4.
Carr A, Samaras K, Chisholm DJ, and Cooper DA (1998) Pathogenesis of HIV-1protease inhibitor-associated peripheral lipodystrophy, hyperlipidaemia, and insulin
resistance. Lancet 351(9119): 18811883. http://dx.doi.org/10.1016/S0140-6736
(98)03391-1.
Chandrasekhar A and Gupta A (2011) Nutrition and disease progression pre-highly
active antiretroviral therapy (HAART) and post-HAART: can good nutrition delay
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Nutrition 94(6): 1703S1715S. http://dx.doi.org/10.3945/ajcn.111.019018.
Drain P, Lupta R, Mugusi F, and Fawzi W (2007) Micronutrients in HIV positive persons
receiving highly active antiretroviral therapy. American Journal of Clinical Nutrition
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HIV Disease and Nutrition

Fields-Gardner C, Campa A, and American Dietetic Association (2010) Position of the


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