Etiology Malnutrisi HIV

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Aetiology and management of malnutritionin HIV-positive children

Anna M Rose,1,2 Charles S Hall,2,3 Nuria Martinez-Alier4

1Department of Genetics, UCLInstitute of Ophthalmology,London, UK2UCL Medical School, London,UK3UCL Institute of GlobalHealth, London, UK4Evelina London ChildrensHospital, Guys and St ThomasNHS Foundation Trust, KingsHealth Partners, London, UK

Correspondence toDr Anna M Rose, Departmentof Genetics, UCL Institute ofOphthalmology, 11-43 BathStreet, London EC1V 9EL, UK;

[email protected]

Received 26 April 2013Revised 5 December 2013Accepted 6 December 2013

To cite:Rose AM, Hall CS,Martinez-Alier N.Arch DisChildPublished Online First:[please includeDay Month

Year] doi:10.1136/archdischild-2012-303348

ABSTRACTWorldwide, more than 3 million children are infectedwith HIV and, without treatment, mortality among thesechildren is extremely high. Both acute and chronicmalnutrition are major problems for HIV-positive childrenliving in resource-limited settings. Malnutrition on abackground of HIV represents a separate clinical entity,with unique medical and social aetiological factors.Children with HIV have a higher daily calorierequirement than HIV-negative peers and also a higherrequirement for micronutrients; furthermore, coinfectionand chronic diarrhoea due to HIV enteropathy play amajor role in HIV-associated malnutrition. Contributoryfactors include late presentation to medical services,

unavailability of antiretroviral therapy, other issuessurrounding healthcare provision and food insecurity inHIV-positive households. Treatment protocols formalnutrition have been greatly improved, yet thereremains a discrepancy in mortality between HIV-positiveand HIV-negative children. In this review, the aetiology,prevention and treatment of malnutrition in HIV-positivechildren are examined, with particular focus on resource-limited settings where this problem is most prevalent.

BACKGROUND

Infection with HIV is one of the greatest challengesto global health faced by the medical profession.There are 3.4 million HIV-positive children under15 years of age and 340 000450 000 new infec-tions in the paediatric population each year.1 HIVinfection is particularly aggressive in childrenwithout access to treatment, more than half ofHIV-infected infants die before the age of 2 years,with a median survival of only 23 months.2

Malnutrition affects over one-quarter of under5s in the developing world and is thought to con-tribute to one-third of deaths in this age groupestimated at 12 million deaths per year.3 Themajority of low-income countries (with the highestrates of malnutrition) have insufcient death certi-cation, so this gure might be an underestimate.4

HIV infection and malnutrition often coexist, andthe two conditions overlap and interact. Prevalenceof concurrent HIV infection in children presentingwith severe acute malnutrition (SAM) is variable,with gures of up to 71.8% reported.28

Meta-analysis of 17 large studies in sub-SaharanAfrica suggested that 29.2% of children presentingwith SAM were HIV-positive, although given thehigher prevalence of HIV in this region, this mightnot be globally representative.5 Importantly, mor-tality from SAM is more than three times higher in

HIV-positive children than their HIV-negativepeers.5

SAM is de

ned by the WHO as aweight-for-height z-score of less than 3, or a mid-upper arm circumference of less than 11.5 cm in chil-dren aged 6 months to 5 years.6 SAM can present asnon-oedematous (marasmus) or oedematous disease(kwashiorkor or marasmic-kwashiorkor), with maras-mus being more common in HIV-positive children.6 7

In addition, HIV-positive children with SAM are athigher risk of infectious comorbidities (such as tuber-culosis, respiratory tract infections, gastroenteritisand candidiasis) and other complications (such aspersistent diarrhoea and poor oral intake).

This article sets out to discuss the aetiology ofincreased risk of malnutrition in HIV-positive chil-

dren from both a medical and social viewpoint. Italso aims to discuss management guidelines for thiscomplex condition and preventive measures.

AETIOLOGY OF DISEASE: MEDICALHIV-positive children have greater nutritionalneedsWhen compared with HIV-negative counterparts,HIV-infected children (including asymptomaticchildren) have additional nutritional requirementsto ensure normal growth and development andrequire high-energy, high-protein, nutrient-densediets.8 Calorie intake needs to be increased, with

children requiring up to 150% of the recom-mended daily allowance of calories, and micronu-trient requirement is up to ve times that of anHIV-negative child (table 1).8 It is recommendedthatcompared with HIV-negative childrenasymptomatic HIV-positive children have a 10%increased calorie intake, which is best giventhrough additional household foods, as part of abalanced, varied diet. HIV-positive children withchronic lung disease, chronic TB or chronic diar-rhoea require approximately 2030% increasedcalorie intake, which might be provided throughincreased household foods or through nutritionalsupplementation. Children with severe complica-

tions of HIV infection, such as SAM or stuntedgrowth, require 50100% increased energy intakeeach day, until weight is recovered. These increasednutritional demands reect the increased nutrientcost of immune system support and prevention ofmuscle wasting. In resource-limited settings (RLS)where food availability is limited, it is clear that theincreased nutritional requirements are unlikely tobe met.

Diarrhoea and other infectionsAcute, recurrent and chronic diarrhoea, and subse-quent malabsorption, are common in HIV-positive

children. Common infective organisms include bac-teria (eg, salmonella, shigella, campylobacter),

Rose AM,et al.Arch Dis Child2014;0:16. doi:10.1136/archdischild-2012-303348 1

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viruses (eg, rotavirus, adenovirus, CMV), parasites (eg, ent-

amoeba, giardia, cryptosporidia) and fungi (eg, candida, histo-plasma). Recurrent and chronic diarrhoea are, understandably,risk factors for the development of SAM and growthimpairment.

Furthermore, malnutrition predisposes to gastrointestinal tractinfection through gut mucosal barrier dysfunction, establishinga vicious infection-malnutrition cycle. Other infectionspar-ticularly pneumonia, which is also very common inHIV-positive childrenhave been found to contribute to theincreased risk of malnutrition in children in several lower-income countries.9

Coinfection with HIV andMycobacterium tuberculosis (TB) isan extremely common problem: TB is the largest single cause of

death in HIV-positive individuals and, in areas of high preva-lence, it is the most common coinfection in HIV-positive chil-dren.1012 HIV and TB pathogens interact, resulting in anaccelerated clinical course and premature death. TB infectionresults in secondary wasting: indeed, weight loss is the present-ing feature in almost 50% of cases of TB and persistent anorexiais a feature in approximately one-quarter.13 Weight loss asso-ciated with TB is particularly marked in RLS. For example, inMalawi, TB patients had signicantly lower body fat mass (35%lower) and 19% less lean body mass than matched controls, theextent of wasting being related to severity of TB infection.14

Furthermore, malnutrition is a risk factor for the acquisition ofprimary TB infection, as well as progression to active disease.

HIV enteropathyHIV enteropathy is a unique disease entity caused by directHIV-mediated and indirect cytokine-mediated damage to thegastrointestinal mucosa in the absence of pathogens. It canaffect individuals at all stages of HIV infection and is charac-terised by chronic diarrhoea, gastrointestinal inammation,increased intestinal permeability and malabsorption. HIV enter-opathy causes typical histological changes, including lympho-cytic inltration of the epithelium, villous atrophy/blunting andcrypt hyperplasia.15 Chronic diarrhoea and malabsorptioncaused by HIV enteropathy lead to malnutrition, whichincreases the risk of infective gastroenteritis; the interacting

effects of infection and HIV enteropathy drive a vicious cyclethat propagates malnutrition.16

Late presentation to medical servicesIn RLS, presentation to hospital for SAMand other conditionsis often very late, with consequent poorer outcomes of medicalintervention.17 In HIV-positive children, it has been observed thatmany SAM-related deaths occur within 1 week of admission, indi-cating the advanced stage of disease.18 The reasons underlying latepresentation are complex and involve social, economic and culturalbarriers, but it is likely that late presentation contributes signicantly

to the excess mortality seen in HIV-infected children with SAM.

AETIOLOGY OF DISEASE: SOCIALWasting and malnutrition in HIV-positive children does notsimply reect interactions of biological processes, but includes aseries of failures within the health system, the home andcommunity.8

Food insecurity in HIV-positive householdsFood security is dened as regular physical, social and economicaccess to sufcient quantities of safe and nutritious food, whichmeets the dietary requirements for a healthy life. When theseconditions are not met, food insecurity is said to exist. A com-

bination of reduced earnings due to frailty, reduced savings andassets, the high cost of antiretroviral treatment (ART) and highadult mortality causes food insecurity in HIV households. Foodinsecurity increases the risk of malnutrition in children in thehousehold. However, employment and income amongHIV-positive people increases after prolonged ART treatment,thus improving food security and nutritional status of all house-hold members.19 2 0 A study of 30 000 HIV-positive peopleshowed that treatment with ART resulted in recovery of employ-ment to 90% of baseline compared with 37% before treatmentwas initiated.19

Children born to HIV-positive mothers not receiving ARThave 2.5 times higher risk of dying before their second birthday

than children of HIV-negative women, malnutrition being onecontributing factor.21 In the developing world, women are themain caregivers and food purchasers/preparers in the familyand, therefore, maternal illness from HIV contributes to malnu-trition in children. Timely initiation of ART in HIV mothershas, however, been shown to reduce under ve mortality ratesto levels similar to those of children of HIV-negative women. 22

A large study in rural South Africa demonstrated that the under2s mortality rate fell signicantly following the initiation ofmaternal ARTthis being the most important contributingfactor to the decline in paediatric mortality.23 It is clear, there-fore, through the effects of food security and maternal HIV thatall children in HIV-positive households are at greater risk ofmalnutrition than children in households where neither parent

has HIV/AIDS.

Barriers to accessing healthcareA major contribution to the excess mortality due to malnutri-tion in HIV-positive children is the inaccessibility of timely andappropriate medical services. The barriers to access of medicalcare are plentiful and vary on regional, country and districtlevels.

There is a paucity of hospitals and healthcare facilities inpoorer countries, meaning that distances that individuals musttravel to access healthcare can be great. Distance and transportare reported as the major barriers to accessing maternal andpaediatric health services in many developing countries.24 25 In

addition to the cost of transport, a major nancial barrier totreatment for both HIV and malnutrition is the cost of medical

Table 1 Daily calorie requirements of HIV-positive children

Daily calorie requirement (kcal/day)

Age HIV-negativeHIV-positive(asymptomatic)

HIV-positivewith poorweight gainor othercomplications

HIV-positivewith severecomplications

611months

690 760 830 150220

1223months

900 990 1080 150220

25years

1260 1390 1510 150220

69years

1650 1815 1980 75100

1014years

2020 2220 2420 6090

Data taken from WHO Guidelines.8

2 Rose AM,et al.Arch Dis Child2014;0:16. doi:10.1136/archdischild-2012-303348

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treatment in countries where public healthcare is not available;this can ostracise the poorest in the community.

Although there are relatively few good studies into the effectsof stigma on HIV-positive individuals, it is accepted that stigmais ubiquitous to people living with HIV/AIDS (PLWHA) and thisoffers a constant barrier to treatment. Efforts to reduce preju-dice and discrimination in health workers involved in HIV man-agement, as a mode to reduce stigma, have been met with

unremarkable results.26

Suspicions and fear surrounding Western medicine andhealth interventions have been reported in Zambia and repre-sent another barrier to healthcare provision to HIV-positivechildren.27 Fear of Western science and medicine has also beenobserved in clinical trials from across the developing world andis indicative of a far greater and complex problem that impactson management of malnutrition in HIV-positive children.28 Theroots of this have been mooted from many different anthropo-logical, political and sociological approaches, discussion ofwhich is beyond the scope of this article.

PREVENTION AND TREATMENT OF MALNUTRITION IN

HIV-POSITIVE CHILDRENBest practice in infant feeding

A safe and effective infant feeding regimen that minimises therisk of HIV transmission needs to be implemented in all childrenborn to HIV-positive mothers. Where infection has alreadyoccurred, best practice feeding regimens reduce the risk ofHIV-associated malnutrition. It is estimated that up to 40% ofcases of vertical transmission in sub-Saharan Africa have occurredvia breast feeding.29 The feeding of a child born to anHIV-positive mother must be analysed on an individual and con-textual basis, following published guidelines (table 2). Overall,exclusive breast feeding for the rst 6 months is recommendedfor HIV-positive mothers unless replacement feeding is accept-

able, feasible, affordable, sustainable and safe (AFASS,

gure 1).

30

Treatment with ART minimises the risk of vertical transmission.It is imperative that mixed feeding (ie, part breast; part

formula or semisolid foods) is avoided in the rst 6 months oflife; this is particularly crucial when ART is unavailable orunacceptable to the mother. In children under 6 months, a

mixed feeding regimen of breastmilk and formula milk resultedin an approximately twofold increased risk of vertical transmis-sion of HIV, while mixed feeding with solids increased the riskto 11-fold.3134 Vertical transmission of HIV occurs when viruspresent in the milk infects children through the intestinalmucosa. It has been suggested that the use of formula milk and/or solid foods interferes with the integrity of the infant intes-tinal mucosa, thereby increasing the risk of vertical transmis-

sion.31 35

On the other hand, cessation of breast feeding before6 months has been implicated in increased infant mortality,especially from diarrhoea.36 In high HIV endemic areas, there isemerging evidence that feeding practices differ signicantlyfrom these recommendations. In South Africa, for example, lessthan 8% of infants under 6 months old are exclusively breastfed.37

Education regarding prevention of HIV transmission andoptimal infant feeding regimens are crucial for the preventionof malnutrition. Infant feeding and nutrition has been identiedas a major concern for women living in RLS, which suggeststhat women would be receptive to such education pro-grammes.38 It is particularly helpful if the female educator is apositive role model, whose own children are thriving despitealso living in poor conditions, as this has a signicant andlasting effect on the rates of recovery from malnutrition in bothrural and urban settings in developing countries around theworld, including South Africa, Bangladesh and Haiti.39 40

Treatment of SAMWhen preventative strategies fail, either community-based orhospital-based therapies need to be implemented to preventmortality from SAM. The community-based approach involvesprovision of treatment for those without medical complicationswith ready-to-use therapeutic foods (RUTFs) or other nutrient-dense foods at home. Hospital or special facility-basedapproaches are required for severely malnourished HIV-positivechildren with medical complications, including children withreduced appetite or coexisting infections.

The treatment regimen for SAM of HIV-infected childrenshould follow the WHO guidelines.41 It involves initial stabilisa-tion of the child, followed by a rehabilitation phase. During theinitial stabilisation phase, life-threatening problems are identiedand treated, with the aim of reducing oedema and restoringorgan function.41 42 Key steps include treatment of infections,caloric replacement (such as F75, discussed later) sufcient toprevent loss of further muscle and fat and correction of electro-lyte imbalance. Treatment of acute infection during the

Table 2 Best practice infant feeding regimens for children born toHIV-positive mothers, based on WHO guidelines5253

Age group(months)

Recommended management for feeding children bornto HIV-positive mothers

06 Exclusive breast feeding, unless replacement feeding is

AFASS

If replacement feeding is AFASS, then breast feeding shouldbe avoided

68 If replacement feeding is not AFASS, continue with breastfeeding and introduce complementary alternative foodstuffs

Alternative foods should be fortified with supplements ifanimal food sources are not available

Food should be of a pureed or mashed consistency.

AFASS situation should be constantly assessed

911 As above but with more solid foods, or so-called fingerfoods

1223 In general, children can eat the same meals as familymembers

Daily calorie requirements of children depend on HIV clinical status and can be seen

in table 1.AFASS, acceptable, feasible, affordable, sustainable and safe.

Figure 1 Infants under the age of 6 months born to HIV-positivemothers should be exclusively breast fed unless breast milk substitutes

full the acceptable, feasible, affordable, sustainable and safe criteria,as dened by the Joint United Nations Programme on HIV/AIDS. 36


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stabilisation phase is of particular importance as comorbiditiessuch as gastroenteritis, malaria, pneumonia, bacteraemia (30%)and other invasive bacterial diseases complicate a large propor-tion of early deaths in children admitted for SAM.42

Treatment of TB infection is a crucial step in treatment ofSAM as it in itself can cause signicant wasting. A further infec-tion that warrants particular attention is oesophageal candidia-sis, which affects approximately 10% of HIV-positiveindividuals at some point.43 Oesophageal candidiasis causes dys-phagia and odynophagia, which can lead to poor oral intakeand subsequent wasting, and, as such, treatment of any concur-rent oral or oesophageal candida infection is an important partof treatment of SAM.

The rehabilitation phase involves gradual introduction offoods, use of high-calorie nutritional formulas (such as F75,F100) and micronutrient/vitamin supplementation. The rehabili-tation phase primarily comprises 610 weeks of therapeuticfeeding with 50100% increased calorie intake, as well as holis-tic assessment of the childs health, HIV therapy and familysetting (table 1, gure 2). Alternatively, for children withuncomplicated malnutrition, community or outpatient-basedtreatment with RUTF can be initiated. The major benet ofRUTF is that it addresses the major problem of lack of access toinpatient facilities and allows timely intervention.

There has been some controversy surrounding the efcacy ofmalnutrition treatment regimens in HIV-positive children, with

mortality remaining approximately three times higher inHIV-positive children than HIV-negative children, regardless oftreatment setting.5 The excess mortality observed is likely to bedue to concurrent infections and other medical complications ofHIV infection. Surprisingly, meta-analysis showed that mortalityrates among HIV-positive children in hospital settings comparedwith those receiving community-based treatment were identi-cal.5 These data will need to be re-evaluated once there hasbeen widespread implementation of the guidelines specic toHIV-positive children. It is hoped that these guidelines willreduce the discrepancy in mortality between HIV-positive andHIV-negative children.

Correct timing of initiation of ARTIn recent years, there has been a dramatic increase in the pro-portion of HIV-positive individuals on treatment: for example,in one hyperendemic region in Southern Africa, since the ARTprogramme scale-up, there has been an increase from 0% in2004 to 31% in 2011.44 Use of ART has led to a decrease inmorbidity and mortality in HIV-positive children in RLS.Despite widespread advances in the availability of ART, thereremains a disparity between the number of children who require

ART and the number receiving treatment; furthermore, initi-ation of therapy occurs late in children with already advanced

disease.5

Initiation of ART is associated with a sustainedimprovement in growth responses, especially in younger

Figure 2 Guidelines for treatment of severe malnutrition in HIV-positive children, based on WHO guidelines.8 41 Although early initiation ofantiretroviral treatment is advocated in these guidelines, this remains controversial, and delaying initiation of treatment until after the acute phase

might be prudent.


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children, even in the absence of complete viral suppression.4547

The direct effect of ART on growth, as well as the decreased fre-quency of opportunistic infections in children receiving ART,means that absence (or late initiation) of ART treatment can beconsidered a risk factor for development of malnutrition inHIV-positive children.

This is a controversial area as there have been several reportsshowing that severe malnutrition was precipitated in the months

following ART initiation.48 49

One study reported that approxi-mately 10% of HIV-positive children were hospitalised forsevere malnutrition within 12 weeks of starting ART.48

Furthermore, an unusually large proportion of these childrendeveloped oedematous malnutrition (kwashiorkor), and it hasbeen argued that this is because a degree of immune compe-tence is required to develop oedema.50

It was postulated that the SAM observed might represent aform of immune reconstitution syndrome (IRIS) in childrenwith underlying chronic malnutrition and severe immunosup-pression.48 This is supported by a large study in Peru of childreninitiating ART, where children with IRIS were more likely todevelop one or more indicator(s) of malnutrition comparedwith children without IRIS, this effect being more signicant inchildren under 5 years of age.51 Another plausible explanationis that the development of malnutrition following initiation of

ART represents a variant of re-feeding syndrome or an unusualantiretroviral toxicity reaction.48

Further research is required to establish the pathogenesis ofthis phenomenon and to determine the optimal time of ARTinitiation in children with underlying malnutrition in order toavoid rebound complications. Until there are clear evidence-based guidelines, it would seem prudent to treat SAM and acutemedical problems with initiation of ART once the child isstabilised.

CONCLUSIONS

Malnutrition is a major threat to the health of children living inRLS and is responsible for up to 2 million deaths per year inchildren under 5 years of age. Malnutrition on a background ofHIV infection is a complex medical condition that carries sig-nicant morbidity and mortality for affected children, withgreater mortality from SAM among HIV-positive children thantheir HIV-negative peers. It is crucial that research continuesinto the pathogenesis of SAM on a background of HIV infectionas this will allow the establishment of more effective care path-ways for complicated SAM, thereby decreasing the disparity inmortality between HIV-positive and HIV-negative children.Furthermore, given that there is high HIV prevalence amongchildren with SAM, HIV testing should be considered in all chil-dren from high-risk areas who present with SAM.

Prevention of mother-to-child transmission of HIV remainsone of the most important interventions to improve global childhealth. In particular, an increase in exclusive breastfeeding rateswould lead to decreased vertical transmission. Education andsupport for mothers of HIV-positive children is crucial, espe-cially with regards to infant breastfeeding practices. Supportshould also be given to help meet the increased daily nutritionalneeds of HIV-infected children in order to prevent developmentof SAM. Government-level interventions to improve healthcareinfrastructure and assure food security are other important stepsin the prevention of malnutrition in HIV-positive children.

Coinfection is another major contributor to SAM inHIV-positive children, and efforts to reduce number of infec-

tions, such as gastroenteritis (eg, through water sanitation), areimportant. Given the complex and detrimental interaction

between HIV, TB and malnutrition, the global ght againstmycobacterial infection must continue, and a decrease in TBincidence might improve nutrition among HIV-positive chil-dren. Finally, although it is clearly benecial to startHIV-positive children on ART, the question of when thistherapy should be initiated in children with SAM needs to beaddressed. Further research needs to be conducted into thecorrect timing of therapy in order to maximise the benets of

treatment while minimising the risk of rebound malnutrition.

Contributors AMR and NM-A were responsible for review design and criticalappraisal and editing. AMR and CSH were responsible for writing and production ofgures and tables.

Competing interests None.

Provenance and peer review Commissioned; externally peer reviewed.

Open Access This is an Open Access article distributed in accordance with theCreative Commons Attribution Non Commercial (CC BY-NC 3.0) license, whichpermits others to distribute, remix, adapt, build upon this work non-commercially,and license their derivative works on different terms, provided the original work isproperly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/3.0/

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doi: 10.1136/archdischild-2012-303348published online January 9, 2014Arch Dis Child

Anna M Rose, Charles S Hall and Nuria Martinez-Alierin HIV-positive childrenAetiology and management of malnutrition

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