HIV Disease and NutritionTL Miller, P Graham, J Nebhrajani, G Somarriba, SC Tapia, and D Neri, Miller School of Medicine at the Universityof Miami, Miami, FL, USA

ã 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. How-

ever, 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 frommother 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 main-

stay 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 conse-

quences. 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 poten-

tially 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 thera-

pies 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 improve-

ment. 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 symp-

toms that contribute to both morbidity and mortality in those

with HIV-1 infection. The etiology of gastrointestinal malab-

sorption is multifactorial and includes gastrointestinal muco-

sal abnormalities, which in turn can lead to macro- and

micronutrient malabsorption. These mucosal changes can be

Encyclopedia of Food and Health http://dx.doi.org/10.1016/B978-0-12-384947-2.00

due to local HIV infection of the gut or secondary enteric

infections. Villous atrophy and gastrointestinal tract dysfunc-

tion 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 epithe-

lium encounters lamina propria macrophages and T cells.

The gastrointestinal tract has substantial CD4 T-cell depletion

in all stages ofHIV disease that is discordantwith systemicCD4T-

cell 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 sys-

temic immune activation that increases metabolic rate and sus-

tains 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 mal-

absorption, 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.

378-0 343

344 HIV Disease and Nutrition

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 anti-

retrovirals, fat redistribution for many individuals with HIV is

less prevalent.

Mortality, accelerated disease progression, and impairment

of functional status have all been associatedwith wasting. In one

study, every 1% weight loss resulted in an 11% increase in the

risk of death. Additionally, whenweight loss exceeded 10% from

baseline, there was a sixfold increase in relative risk formortality.

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, physi-

cal 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 associ-

ated 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 recom-

mendations 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 lim-

ited. This section discusses existing macronutrients recommen-

dations for people living with HIV.

Patient groups vary in terms of their response to the virus,

stage of the disease, susceptibility and exposure to opportunis-

tic 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 summa-

rized in Table 1. In addition to nutrient-specific recommenda-

tions, 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 gastrointesti-

nal 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 exist-

ing WHO recommendations (i.e., calories increased by 10%

for asymptomatic children, adolescents, and adults). The addi-

tional energy helps children to maintain normal growth, devel-

opment, 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 preg-

nancy and lactation. Recommendations with regard to energy

intake for pregnant women should be population-based

because of differences in body size. To achieve optimal preg-

nancy outcomes, energy needs for women with healthy base-

line body weight are no higher than the Estimated Energy

Requirement for nonpregnant women until the second trimes-

ter; 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 non-

pregnant adult females) is likely reasonable for asymptomatic

HIV-positive pregnant and lactating women. For pregnant and

lactating women in resource-limited settings, some recommen-

dations have been established, and they vary according to

condition (pregnant and breastfeeding), HIV stage (stratified

by CD4 T-cell count), age (14–20, >20–30, and >30–50

years), weight or BMI, food security score, micronutrient status

including hematologic status (presence of anemia), and treat-

ment 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 macro-

nutrient 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

Table 1 Energy and macronutrients needs in HIV infection

NutrientHIV infection factorsClinical situations Nutrition recommendations

Energy When secondary infections areabsent and growth isadequate in children andweight is stable in adults

Children, adolescents, and adults: target energy intake of 110% of that recommended for uninfectedpopulation (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 likelyreasonable for asymptomatic HIV-positive pregnant and lactating women. Energy requirementsmay be higher for pregnant adolescents (Raiten et al., 2011)Standard methods of assessing energy needs – calorie levels based on the Estimated EnergyRequirements (EERs) and activity levels from the Institute of Medicine Dietary Reference Intakes(DRIs) (Macronutrients Report, 2002)

During illness, decreasedappetite, poor growth,weight loss

Children: energy requirements can increase by up to 20–30% during infections and recovery (WHO,2009). Equations for estimating catchup growth requirements for both calories and protein can beusedAdults : increase energy intake by 600–960 kcal day�1 in adults with weight loss may increasebody weight (Grobler et al., 2013), which is better achieved by providing a balanced nutritionalsupplementPregnancy and lactation : the energy needs may be even greater than 10% above those ofnonpregnant 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)

Advanced disease Up to 50–100% additional energy to recover and regain weight (WHO 2003)For critically ill patients: energy requirements may be calculated by predictive equations ormeasured by indirect calorimetry (Singer, 2009), with special attention to the prevention ofcomplications related to under- or overfeeding (Fraipont and Preiser, 2013)This is best achieved through enteral or parenteral (if enteral has failed) feeding

Overweight or obesity Weight management :Counseling on changing eating habits and patternsRegular exercise: physical activity counseling or physical activity program participation

Protein During periods of well-being As in asymptomatic children, protein should contribute about 10–15% of the energy intake andthere 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 intakesof essential nutrients (Food and Nutrition Board, 2005)

Period of catchup growth Use equation for estimating catchup growth requirementsFat During periods of well-being Provide anticipatory guidance regarding the importance of a low-fat, low-saturated-fat, low-

cholesterol diet for all otherwise healthy HIV-infected patients older than 2 years and their familiesdue to increased risk of CVD in HIV-infected populationsAMDR: Food and Nutrition Board (2005)1–3 years: 30–40% of total calories4–18 years: 25–35% of total caloriesPregnancy and lactation : essential fatty acid needs are 30% higher than those of nonpregnantwomen, and adequate fatty acid intake should be ensured in a manner consistent withrecommendations for uninfected women (Raiten et al., 2011)

Fat malabsorption (due to HIVGI enteropathy or secondaryinfections)

In these cases, dietary modification of fat may be requiredSupplemental MCT and enteral formulas containing MCT can be used to supplement caloric intake

Dyslipidemia Dietary intervention with NCEP Therapeutic Lifestyle Changes (NCEP 2002) and exercise have beenshown 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-Pothet al., 1999)Counseling on changing eating habits and patterns per AHA/AAP

Carbohydrate During periods of well-being AMDR: Food and Nutrition Board (2005), 45–65% of total caloriesAdded sugars should comprise no more than 10% of total calories consumed

Fiber 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.

HIV Disease and Nutrition 345

needs are greater than that recommended for uninfected pop-

ulation. 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.

346 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 Micronutrient recommendations in HIV infection

Population Current micronutrient recommendations

Children andadolescents

Maintain current WHO recommendations :

• Ensure one Recommended Dietary Allowance (RDA) fessential nutrients, preferably through a well-balanced

• When dietary intakes are insufficient, the use of microsupplements at RDA levels is supported

Vitamin D intake :

• Children on antiretroviral treatment (ART) should be gto three times more vitamin D than the RDA for their a

Adults • Insufficient evidence to support a change from 2003recommendations of one RDA for essential micronutriepreferably from dietary intake

• Adults on ART should be given two to three times morethan the RDA for their age group

Pregnant andlactatingwomen

• Supplementation of one RDA amount of micronutrientsHIV-positive pregnant and lactating women is recommeto the high likelihood of food insecurity, the fact that micneeds are higher during pregnancy and lactation and thdeficiencies appear to be more common in HIV-infected

• Supplements should contain the 14 core micronutrientsin the UNICEF UNIMMAP (UN international multiple micpreparation) supplement. These micronutrients includeA, D, and E; thiamine; riboflavin; niacin; folic acid; vitaminand C; and minerals including zinc, iron, copper, seleniuiodine

• In areas of endemic vitamin A deficiency, WHO recomma single high dose of vitamin A (200 000 IU) be given to wsoon as possible after delivery, but no later than 6 weekdelivery

• Pregnant and lactating women require at least 600 IU dvitamin D; at least 1500–2000 IU day�1 of vitamin D mneeded to prevent/treat deficiency

Source: Raiten, D. J., Mulligan, K., Papathakis, P. and Wanke, C. (2011). Executive summary –

women: what do we know, what can we do, and where do we go from here? The American J

ajcn.111.019711; Holick, M. F., Binkley, N. C., Bischoff-Ferrari, H. A., et al. (2011). Evaluat

practice guideline. Journal of Clinical Endocrinology and Metabolism 96(7): 1911–1930. http:/C. (2013). Micronutrient supplementation for children with HIV infection. Cochrane Database o

Irlam, J. H., Visser, M. M., Rollins, N. N. and Siegfried, N. (2010). Micronutrient supplementatio

CD003650. http://dx.doi.org/10.1002/14651858.CD003650.pub3; Roberfroid, D., Huybregts, L

growth during infancy: a randomized controlled trial. American Journal of Clinical Nutrition 95

maintenance of immune system function and in the

reduction of morbidity and mortality from disease- and

treatment-related symptoms has been well established. How-

ever, 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 popu-

lations throughout the life cycle.

Comments

or alldietnutrient

iven twoge group

– Currently, there exists insufficient evidence to support ageneral policy encouraging the use of daily oral nutrientsupplements

– Careful attention to dietary quality and adequacy ofmicronutrients is critical; important factors to considerinclude 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 interms of dietary intake and poor exposure or in thecontext of potential treatment interactions

nts,

vitamin D

– Given the vast diversity of variables and study designthroughout various studies investigating micronutrientsupplementation in this population, it is not possible torecommend anything other than the current RDA or aroutine multivitamin. However, there still remain safetyconcerns for potential harm from higher doses ofselected micronutrients (e.g., vitamin A and multiplemicronutrient (MMN) supplements, which may promoteincreased viral replication and increased shedding ofvirus in genital secretions, thus potentially increasing riskof transmission of HIV). Further research into optimalcomposition and dosing is warranted

for allnded dueronutrientatwomenprovidedronutrientvitaminss B6, B12,m, and

ends thatomen ass after

ay�1 ofay be

– Supplementation at amounts above the RDA is notadvised at this time as some studies have shown thatthey may in fact be harmful (e.g., vitamin A, vitamin D(25), and iron)

– Iron supplementation is recommended at the RDAamount for HIV-positive pregnant women

– Iron supplementation is not recommended in lactatingHIV-positive women unless the presence of irondeficiency is clinically confirmed

nutritional care of HIV-infected adolescents and adults, including pregnant and lactating

ournal of Clinical Nutrition 94(6): 1667S–1676S. http://dx.doi.org/10.3945/ion, treatment, and prevention of vitamin D deficiency: an Endocrine Society clinical

/dx.doi.org/10.1210/jc.2011-0385; Irlam, J. H., Siegfried, N., Visser, M. E. and Rollins, N.

f Systematic Reviews 10: CD010666. http://dx.doi.org/10.1002/14651858.CD010666;n in children and adults with HIV infection. Cochrane Database of Systematic Reviews (12):

., Lanou, H., et al. (2012). Impact of prenatal multiple micronutrients on survival and

(4): 916–924. http://dx.doi.org/10.3945/ajcn.111.029033.

HIV Disease and Nutrition 347

Micronutrient deficiencies are often observed in conjunc-

tion 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 vari-

ous 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 lim-

ited. In conjunction with cART, inexpensive micronutrient

supplements could provide several cellular and clinical bene-

fits, 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 chil-

dren without HIV infection, reduce diarrheal morbidity and

mortality especially in young children. As stated in the 2003

WHO guidelines, HIV-infected 6–59-month-old children liv-

ing in resource-limited settings should be given periodic (every

4–6 months) vitamin A supplements (100 000 IU for infants

6–12 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 HIV-

infected 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 poten-

tially 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

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 vita-

min 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, HIV-

infected 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 micronutri-

ent intakes cannot be reached through dietary sources, evi-

dence 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. How-

ever, the high prevalence of food insecurity, the increased

metabolic and micronutrient demands of pregnancy and lac-

tation, 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 UNIM-

MAP (UN international multiple micronutrient preparation)

supplement: vitamin A, vitamin D, vitamin E, thiamine, ribo-

flavin, 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

iron–folate supplementation (400 mg of folate and 60 mg of

iron) during 6 months of pregnancy and, in the case of clini-

cally 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 lactat-

ing women require at least 600 IU day�1 of vitamin D; at least

1500–2000 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

348 HIV Disease and Nutrition

randomized, controlled trials remains few and less clear. Addi-

tional 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 HIV-

uninfected populations equally. Immigrant families are partic-

ularly 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 regi-

mens have developed a syndrome of peripheral insulin resis-

tance, hyperlipidemia, and lipodystrophy (truncal obesity,

dorsocervical fat pad, and extremity and facial wasting). Clin-

ical 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 fatredistribution syndrome

Clinical features Laboratory features

Increased abdominal (visceral) fat HyperlipidemiaIncreased waist-to-hip ratio (morereliable in adults)

Increased triglyceridesIncreased total cholesterol

Buffalo hump Increased LDL-CFat atrophy Decreased HDL-CWasting of extremities Insulin resistanceWasting of buttocks Normal to increased serum

glucoseLoss or thinning of facial fat,prominence of nasolabial fold

Increased insulinIncreased C-peptide

No change to increased weightFatigue and weakness

Lipodystrophy is described in children, as well. Early stud-

ies 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 lipody-

strophic HIV-infected adults with visceral adiposity. In addi-

tion 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 periph-

eral lipoatrophy and central obesity occur in both HIV-infected

adults and children. Fat redistribution can develop fairly rap-

idly 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, insu-

lin 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.

DyslipidemiaPrior 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 cur-

rent era and suggests that chronic immune activation can

influence lipid metabolism. Proinflammatory cytokines (as a

response to the chronic viral infection) may affect lipid path-

ways. After PI therapy became widespread, several investigators

in the United States and abroad reported a 20–50% 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 apolipo-

protein B production, among other mechanisms. Other factors

associated with dyslipidemia include successful viral suppres-

sion, 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 dys-

lipidemia following PI treatment.

Insulin resistance and type 2 diabetes mellitusAbnormal glucose homeostasis was documented in HIV-

infected 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 349

transcriptase inhibitor (NNRTI) use both singly and in combi-

nation, 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 lipo-

matosis (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 cyto-

kines have been linked to both insulin resistance and dimin-

ished adiponectin, which affects insulin signaling and glucose

homeostasis. The adipose tissue is a major determinant of insu-

lin sensitivity and changes associated with lipodystrophy can

alter the secretion of adiponectin. In one study, patients with PI-

induced lipodystrophy had increased levels of circulating

inflammatory cytokines.

Vascular inflammation and atherosclerosisVascular endothelial dysfunction, a process that is associated

with atherosclerosis, may occur as a result of chronic inflam-

mation and injury in the endothelium. Oxidative stress due to

cART and direct cytopathic effect of the virus are likely causa-

tive agents in HIV. In addition, dyslipidemia, insulin resis-

tance, and chronic inflammation due to ongoing immune

activation in HIV-infected individuals also contribute to endo-

thelial damage. The levels of proinflammatory cytokines are

higher in HIV-infected individuals compared to contemporary

controls. These vascular inflammatory biomarkers are posi-

tively 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 child-

ren 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.

Promoting and supporting adequate nutrition and food secu-

rity are critical for this population. Presently, there are a num-

ber 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 consis-

tent 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, con-

sumption 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 patient’s nutritional

status, age, symptoms, and ability to meet nutrient require-

ments. Regular nutritional assessments are necessary in order

to determine the appropriateness and effectiveness of the inter-

ventions. This assessment should include a review of the med-

ical and dietary history, nutrient analysis of usual intake,

anthropometric measurements, body composition, and mea-

surement 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 HIV-

infected 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, supple-

mental 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 supple-

ments (consisting of 50–60% carbohydrate, 15–30% protein,

and 20–30% 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 treat-

ment and nutritional resources, most patients with HIV-related

weight loss will gradually increase ad libitum caloric intake and

gain weight.

Table 4 HIV-related medications and common gastrointestinal and metabolic side effects

Medication Action Side effects

Abacavir NRTI Nausea, vomiting, diarrhea, abdominal pain, pancreatitis, abnormal liver functionAciclovir Antiviral Nausea, abdominal pain, diarrhea, abnormal liver functionAtazanavir PI Nausea, diarrhea, abdominal pain, hyperbilirubinemiaAtripla (tenofovir, emtricitabine, andefavirenz)

Combination Nausea, vomiting, diarrhea, abdominal pain, hepatitis, bone loss, pancreatitis, lactic acidosis

Azithromycin Antibacterial Nausea, vomiting, melena, jaundiceCiprofloxacin Antibacterial Ileus, jaundice, bleeding, diarrhea, anorexia, oral ulcers, hepatitis, pancreatitis, vomiting,

abdominal painClarithromycin Antibacterial Nausea, diarrhea, abdominal pain, abnormal tasteCombivir (zidovudine–lamivudine) Combination Nausea, vomiting, abdominal pain, abnormal liver function, pancreatitis, lactic acidosisComplera (rilpivirine, tenofovir,emtricitabine)

Combination Nausea, vomiting, abnormal liver function, lactic acidosis

Darunavir PI Nausea, vomiting, diarrhea, abdominal pain, pancreatitis, hepatitis, constipationDidanosine (ddI) NRTI Nausea, vomiting, abdominal pain, pancreatitis, abnormal liver functionEdurant NNRTI Abnormal liver function, lipodystrophyEfavirenz NNRTI Nausea, vomiting, abnormal liver function, hyperlipidemiaEmtricitabine NRTI Lactic acidosis, hepatomegaly, diarrhea, nauseaEpzicom (zidovudine, abacavir) Combination Nausea, vomiting, abdominal pain, abnormal liver function, lactic acidosis, pancreatitisErythromycin Antibacterial Nausea, vomiting, abdominal painEtravirine NNRTI Nausea, vomiting, diarrhea, abdominal pain, hepatitisFosamprenavir PI Nausea, diarrhea, vomiting, abdominal painEnfuvirtide FI Nausea, diarrhea, abdominal pain, hepatitis, pancreatitis, dry mouth, anorexiaGanciclovir Antiviral Nausea, vomiting, diarrhea, anorexia, abnormal liver functionIndinavir PI Nausea, vomiting, abdominal pain, diarrhea, changes in taste, jaundice, abnormal liver functionKetoconazole Antifungal HepatotoxicityLamivudine NRTI Nausea, diarrhea, decreased appetite, vomiting, abdominal pain, pancreatitis, abnormal liver

functionLopinavir/ritonavir PI Diarrhea, nausea, vomiting, abdominal pain, lipodystrophy, hyperlipidemiaMaraviroc EI Nausea, constipation, diarrhea, flatulence, abdominal pain, hepatitis, dysgeusia, stomatitisNelfinavir PI Nausea, diarrhea, fatigue, abnormal liver function, exacerbation of chronic liver diseaseNevirapine NNRTI Stomatitis, nausea, abdominal pain, raised gamma-glutamyl transpeptidase level,

hepatotoxicityPentamidine Antiparasitic Abdominal pain, bleeding, hepatitis, pancreatitis, nausea, vomitingRaltegravir II Gastritis, hepatitis, nausea, vomiting, abdominal pain, diarrhea, hyperbilirubinemiaRifampin Antibacterial Abdominal pain, nausea, vomiting, diarrhea, jaundiceRilpivirine NNRTI LipodystrophyRitonavir PI Nausea, vomiting, diarrhea, abdominal pain, anorexia, pancreatitis, abnormal liver functionSaquinavir PI Mouth ulcers, nausea, abdominal pain, diarrhea, pancreatitis, abnormal liver function,

exacerbation of chronic liver diseaseStavudine NRTI Nausea, vomiting, abdominal pain, diarrhea, pancreatitis, abnormal liver function, hepatic

failure, lipodystrophy, hyperlipidemia, insulin resistanceStribild (elvitegravir, cobicistat,emtricitabine, tenofovir)

Combination Lactic acidosis, severe hepatomegaly with steatosis, and posttreatment acute exacerbation ofhepatitis B

Sulfonamides Antibacterial Hepatitis, pancreatitis, stomatitis, nausea, vomiting, abdominal painTenofovir NRTI Nausea, vomiting, diarrhea, abdominal pain, hepatitis, bone loss, pancreatitis, flatulenceTipranavir PI Hyperlipidemia, nausea, vomiting, diarrhea, abdominal pain, pancreatitis, hepatitisTivicay II Gastritis, hepatitis, nausea, vomiting, abdominal pain, diarrhea, hyperbilirubinemiaTrizivir (abacavir–lamivudine–zidovudine)Combination Nausea,

vomiting,abdominalpain,

pancreatitis, abnormal liver function

Triumeq (abacavir, dolutegravir,lamivudine)

Combination Lactic acidosis, abnormal liver function

Truvada (emtricitabine, tenofovir) Combination Lactic acidosis, nausea, vomiting, diarrhea, abdominal pain, hepatitis, bone loss, pancreatitisTybostVitektaZidovudine (ZDV)

PEIINRTI

Nausea, jaundiceDiarrheaNausea, 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.

350 HIV Disease and Nutrition

HIV Disease and Nutrition 351

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 conse-

quences of their ART regimen. Obesity, dyslipidemia, lipody-

strophy, 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 inflamma-

tion, thereby increasing CVD risk. Even though the mecha-

nisms for these effects are likely multifactorial, care must be

taken to avoid unwarranted weight gain and many nutrition-

ally related components should be targeted. However, there are

no specific guidelines that address lipid abnormalities or insu-

lin resistance specific to HIV-infected patients. A recent meta-

analysis 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 HIV-

uninfected populations and to reduce LDL cholesterol in the

general population. Treatment of these complications should,

therefore, follow nutrition and lifestyle interventions guide-

lines recommended for the general population. Higher-

intensity dietary interventions may also be required in the

HIV population for LDL cholesterol reduction. Mediterranean-

style 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 HIV-

uninfected 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 evalu-

ated 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 weight-

bearing exercise and avoidance of alcohol and tobacco, espe-

cially 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 middle-

income 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 pro-

vision of food with assessment of food security and appropri-

ate 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

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 HIV-

specific 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 symp-

toms. Future research efforts should analyze the long-term

effects of nutritional interventions on LDL and HDL choles-

terol and triglycerides in children and adults.

In addition to nutritional interventions involving diet, per

se, other strategies to improve the nutritional status of HIV-

infected 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 hor-

mone can improve central adiposity, while metformin has

been reported to improve glucose homeostasis.

Summary

The multidimensional nature of nutritional problems associ-

ated 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 sur-

vival 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

Botros D, Somarriba G, Neri D, and Miller TL (2012) Interventions to address chronicdisease and HIV: strategies to promote exercise and nutrition among HIV-infectedindividuals. Current HIV/AIDS Reports 9(4): 351–363. http://dx.doi.org/10.1007/s11904-012-0135-7.

Brenchley JM, Price DA, Schacker TW, et al. (2006) Microbial translocation is a causeof systemic immune activation in chronic HIV infection. Nature Medicine 12(12):1365–1371. http://dx.doi.org/10.1038/nm1511.

Brinkman K, Smeitink JA, Romijn JA, and Reiss P (1999) Mitochondrial toxicity inducedby nucleoside-analogue reverse-transcriptase inhibitors is a key factor in thepathogenesis of antiretroviral-therapy-related lipodystrophy. Lancet 354(9184):1112–1115. http://dx.doi.org/10.1016/S0140-6736(99)06102-4.

Carr A, Samaras K, Chisholm DJ, and Cooper DA (1998) Pathogenesis of HIV-1-protease inhibitor-associated peripheral lipodystrophy, hyperlipidaemia, and insulinresistance. Lancet 351(9119): 1881–1883. http://dx.doi.org/10.1016/S0140-6736(98)03391-1.

Chandrasekhar A and Gupta A (2011) Nutrition and disease progression pre-highlyactive antiretroviral therapy (HAART) and post-HAART: can good nutrition delaytime to HAART and affect response to HAART? American Journal of ClinicalNutrition 94(6): 1703S–1715S. http://dx.doi.org/10.3945/ajcn.111.019018.

Drain P, Lupta R, Mugusi F, and Fawzi W (2007) Micronutrients in HIV positive personsreceiving highly active antiretroviral therapy. American Journal of Clinical Nutrition85(2): 333–345.

352 HIV Disease and Nutrition

Fields-Gardner C, Campa A, and American Dietetic Association (2010) Position of theAmerican Dietetic Association: nutrition intervention and human immunodeficiencyvirus infection. Journal of the American Dietetic Association 110(7): 1105–1119.

Fraipont V and Preiser JC (2013) Energy estimation and measurement in critically illpatients. Journal of Parenteral and Enteral Nutrition 37(6): 705–713. http://dx.doi.org/10.1177/0148607113505868.

Food and Nutrition Board, Institute of Medicine (2005) Dietary reference intakes forenergy, carbohydrate, fiber, fat, fatty acids, cholesterol, protein, and amino acids(Macronutrients). Washington, DC: National Academy Press.

Friis-Møller N, Sabin CA, Weber R, et al. (2003) Combination antiretroviral therapy andthe risk of myocardial infarction. New England Journal of Medicine 349(21):1993–2003. PubMed PMID:14627784.

Gidding SS, Lichtenstein AH, Faith MS, et al. (2009) Implementing American HeartAssociation pediatric and adult nutrition guidelines: a scientific statement from theAmerican Heart Association Nutrition Committee of the Council on Nutrition,Physical Activity and Metabolism, Council on Cardiovascular Disease in the Young,Council on Arteriosclerosis, Thrombosis and Vascular Biology, Council onCardiovascular Nursing, Council on Epidemiology and Prevention, and Council forHigh Blood Pressure Research. Circulation 119: 1161–1175.

Grobler L, Siegfried N, Visser ME, Mahlungulu SS, and Volmink J (2013) Nutritionalinterventions for reducing morbidity and mortality in people with HIV. CochraneDatabase of Systematic Reviews 2: CD004536. http://dx.doi.org/10.1002/14651858.CD004536.pub3.

Holick MF, Binkley NC, Bischoff-Ferrari HA, et al. (2011) Evaluation, treatment, andprevention of vitamin D deficiency: an Endocrine Society clinical practice guideline.Journal of Clinical Endocrinology and Metabolism 96(7): 1911–1930. http://dx.doi.org/10.1210/jc.2011-0385.

Irlam JH, Visser MM, Rollins NN, and Siegfried N (2010) Micronutrientsupplementation in children and adults with HIV infection. Cochrane Database ofSystematic Reviews (12): CD003650. http://dx.doi.org/10.1002/14651858.CD003650.pub3.

Irlam JH, Siegfried N, Visser ME, and Rollins NC (2013) Micronutrient supplementationfor children with HIV infection. Cochrane Database of Systematic Reviews10: CD010666. http://dx.doi.org/10.1002/14651858.CD010666.

Kelley GA, Kelley KS, Roberts S, and Haskell W (2011) Efficacy of aerobic exercise and aprudent diet for improving selected lipids and lipoproteins in adults: a meta-analysis of randomized controlled trials. BMC Medicine 9: 74. http://dx.doi.org/10.1186/1741-7015-9-74.

Miller TL, Somarriba G, Orav EJ, et al. (2010) Biomarkers of vascular dysfunction inchildren infected with human immunodeficiency virus-1. Journal of AcquiredImmune Deficiency Syndromes 55(2): 182–188. http://dx.doi.org/10.1097/QAI.0b013e3181e222c9.

National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation,and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III)(2002) Third report of the National Cholesterol Education Program (NCEP) ExpertPanel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults(Adult Treatment Panel III) Final Report. Circulation 106(25): 3143–3421.

Raiten DJ, 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): 1667S–1676S. http://dx.doi.org/10.3945/ajcn.111.019711.

Roberfroid D, Huybregts L, Lanou H, et al. (2012) Impact of prenatal multiplemicronutrients on survival and growth during infancy: a randomized controlled trial.American Journal of Clinical Nutrition 95(4): 916–924. http://dx.doi.org/10.3945/ajcn.111.029033.

Singer P, Berger MM, Van den Berghe G, Biolo G, Calder P, Forbes A, and ESPEN(2009) ESPEN Guidelines on Parenteral Nutrition: intensive care. Clinical Nutrition28(4): 387–400. http://dx.doi.org/10.1016/j.clnu.2009.04.024.

Stradling C, Chen YF, Russell T, Connock M, Thomas GN, and Taheri S (2012) Theeffects of dietary intervention on HIV dyslipidaemia: a systematic review andmeta-analysis. PLoS One 7(6): e38121. http://dx.doi.org/10.1371/journal.pone.0038121.

Wanke C, Kotler D, and HIV Wasting Collaborative Consensus Committee (2004)Collaborative recommendations: the approach to diagnosis and treatment of HIVwasting. Journal of Acquired Immune Deficiency Syndromes 37(Suppl. 5):S284–S288. PubMed PMID:15722872.

Yu-Poth S, Zhao G, Etherton T, Naglak M, Jonnalagadda S, and Kris-Etherton PM(1999) Effects of the National Cholesterol Education Program’s Step Iand Step II dietary intervention programs on cardiovascular diseaserisk factors: a meta-analysis. American Journal of Clinical Nutrition 69(4):632–646.

Relevant Websites

www.unaids.org – Global Report: UNAIDS report on the global AIDS epidemic, 2010.http://www.who.int – Nutrient Requirements for People Living with HIV/AIDS: Report of

a technical consultation, 2003.http://www.who.int – Macronutrients in HIV/AIDS: a review of current research, 2005.http://www.who.int – WHO: Guidelines for an integrated approach to the nutritional care

of HIV-infected children (6 months–14 years), 2009.http://www.who.int/nutrition/publications/hivaids/9789241597524/en/index.html –

WHO. Nutrient Requirements for People Living with HIV/AIDS: Report of a technicalconsultation. 2003. Guidelines for an integrated approach to the nutritional care ofHIV-infected children (6 months–14 years), 2009.

http://www.who.int/nutrition/publications/hivaids/9789241597524/en/index.html –Guidelines for an integrated approach to the nutritional care of HIV-infected children(6 months–14 years), 2009.

http://www.who.int/nutrition/publications/hivaids/9241591196/en/ – HIV/AIDSevidence-based nutrition practice guideline. American Dietetic Association. HIV/AIDS evidence-based nutrition practice guideline. Chicago (IL): American DieteticAssociation, December 2010.

http://www.who.int/gho/hiv/epidemic_status/deaths/en/ – Number of deaths due toHIV/AIDS, 2015.