Introduction

HIV infection remains a major challenge in adults and children worldwide. It is estimated that there were approximately 3.2 million children under the age of 15 years worldwide living with HIV at the end of 2013, over 90% of these children live in sub-Saharan Africa [11. Joint United Nations Programme on HIV/AIDS (UNAIDS) (2014) Progress report on the global plan: towards the elimination of new HIV infections among children by 2015 and keeping their mothers alive. ]. The number of children newly infected with HIV worldwide in the same year (2013) was 240 000, and the overwhelming majority of these children are infected perinatally through mother-to-child transmission [22. World Health Organization (WHO) (2014) Optimizing treatment options and improving access to priority products for children living with HIV. Geneva, Switzerland: World Health Organization 2014. ].

Common clinical features observed in HIV-infected children include compromised nutritional status (including moderate and severe acute malnutrition), diarrhoeal disease and respiratory tract infection [33. Pol RR, Shepur TA, Ratageri VH (2007) Clinico-laboratory profile of pediatric HIV in Karnataka. Indian Journal of Pediatrics 74: 1071-1075.]. Compromised nutritional status may present as moderate acute malnutrition or severe acute malnutrition. The WHO defines severe acute malnutrition (SAM) as weight-for-height Z-score < -3SD, mid-upper arm circumference (MUAC) ≤ 11.5 cm in children aged 6 months to 5 years, visible wasting and nutritional oedema [44. World Health Organization (WHO) (2009) Guidelines for an integrated approach to the nutritional care of HIV-infected children (6 months-14 years). Geneva, Switzerland: World Health Organization 2009. ]. On the hand, moderate acute malnutrition is defined as weight-for-height between -2 and -3 SD or MUAC < 12.5 cm but ≥ 11.5 cm, without nutritional oedema in both instances [55. World Health Organization (WHO) (2010) WHO, UNICEF, WFP and UNHCR Consultation on the programmatic aspects of the management of moderate acute malnutrition in children under five years of age. Geneva Switzerland: World Health Organization 2010.]. Guidelines for the management of SAM have been developed and refined by the WHO and are designed to reduce mortality in these children [66. World Health Organization (WHO) (2013) Guideline: Updates on the management of severe acute malnutrition in infants and children. Geneva, Switzerland: World Health Organization 2013. ]. The management of HIV-infected children with SAM, which includes the WHO 10 steps to management of SAM, is similar to that of children with SAM who are not HIV-infected [66. World Health Organization (WHO) (2013) Guideline: Updates on the management of severe acute malnutrition in infants and children. Geneva, Switzerland: World Health Organization 2013. ].

Children with compromised nutritional status are more prone to acquiring diarrhoeal disease and respiratory tract infections (including pneumonia and tuberculosis) [77. De Pee S, Semba RD (2010) Role of nutrition in HIV infection: Review of evidence for more effective programming in resource-limited settings. Food and Nutrition Bulletin 4: S313-S344.,88. Chisti MJ, Ahmed T, Pietroni MAC, Faruque ASG, Ashraf H, et al. (2013) Pulmonary tuberculosis in severely-malnourished or HIV-infected children with pneumonia: a review. Journal of Health Population and Nutrition 23: 308-313.]. Repeated episodes of diarrhoeal disease and respiratory tract infections in turn worsen the nutritional status, thus creating a vicious cycle [77. De Pee S, Semba RD (2010) Role of nutrition in HIV infection: Review of evidence for more effective programming in resource-limited settings. Food and Nutrition Bulletin 4: S313-S344.].

In the absence of treatment, HIV infection in children progresses rapidly when compared with adults. Without treatment more than 50% of children perinatally infected with HIV die within the first two years of life [99. Prendergast A, Tudor-Williams G, Jeena P, Burchett S, Goulder P (2007) International perspectives, progress, and future challenges of paediatric HIV infection. Lancet 370: 68-80. ]. Antiretroviral drugs are the mainstay of treatment in HIV-infected persons. The development of highly active antiretroviral therapy (HAART) is considered as one of the important successes of modern medicine; HAART has changed HIV from a virtually universally fatal illness to a chronic illness [1010. Delaney M (2006) History of HAART – the true story of how effective multi-drug therapy was developed for treatment of HIV disease. Retrovirology 3: S6. ]. Indeed early diagnosis of HIV and initiation of HAART has been noted to reduce mortality [1111. Koye DN, Ayele TA, Zeleke BM (2012) Predictors of mortality among children on antiretroviral therapy at a referral hospital, Northwest Ethiopia: A retrospective follow up study. BMC Pediatrics 12: 161.]. The provision of antiretroviral therapy for the prevention of mother-to-child transmission of HIV has had markedly reduced the incidence of HIV globally [11. Joint United Nations Programme on HIV/AIDS (UNAIDS) (2014) Progress report on the global plan: towards the elimination of new HIV infections among children by 2015 and keeping their mothers alive. ]. Since 2009, a 43% decline in new HIV infections among children from countries that had the highest number of pregnant women living with HIV, has been observed [11. Joint United Nations Programme on HIV/AIDS (UNAIDS) (2014) Progress report on the global plan: towards the elimination of new HIV infections among children by 2015 and keeping their mothers alive.]. However, while there has been a major improvement in access to HAART, only 23% of the estimated 3.2 million children living with HIV were receiving HAART by December 2013 [22. World Health Organization (WHO) (2014) Optimizing treatment options and improving access to priority products for children living with HIV. Geneva, Switzerland: World Health Organization 2014. ].

Risk factors for mortality in children initiating HAART

The introduction of HAART has markedly reduced the mortality of HIV-infected children. However, there are number of factors associated with early mortality in children initiating HAART. These include low CD4 counts, advanced HIV clinical stage, stunting, underweight, anemia and co-infection with tuberculosis (TB) [88. Chisti MJ, Ahmed T, Pietroni MAC, Faruque ASG, Ashraf H, et al. (2013) Pulmonary tuberculosis in severely-malnourished or HIV-infected children with pneumonia: a review. Journal of Health Population and Nutrition 23: 308-313.,1212. Taye B, Shiferaw S, Enquselassie F (2010) The impact of malnutrition in survival of HIV infected children after initiation of antiretroviral treatment (ART). Ethiopian Medical Journal 48: 1-10.]. Co-infection with TB has been noted to be common in HIV-infected children [88. Chisti MJ, Ahmed T, Pietroni MAC, Faruque ASG, Ashraf H, et al. (2013) Pulmonary tuberculosis in severely-malnourished or HIV-infected children with pneumonia: a review. Journal of Health Population and Nutrition 23: 308-313.]. Compromised nutrition is also common seen in children infected with TB [88. Chisti MJ, Ahmed T, Pietroni MAC, Faruque ASG, Ashraf H, et al. (2013) Pulmonary tuberculosis in severely-malnourished or HIV-infected children with pneumonia: a review. Journal of Health Population and Nutrition 23: 308-313.]. Nutritional supplementation may thus be important for HIV-infected children who are co-infected with TB.

Nutritional status of HIV-infected children

The nutritional status of HIV-infected children as measured by anthropometric indices and micronutrient concentrations has been noted to be compromised. A hospital based study conducted in the Republic of South Africa revealed that the concentrations of micronutrients and weight-for-age and height-for-age Z-scores of antiretroviral therapy naïve HIV-infected children were significantly lower than those of HIV-uninfected children [1515. Mda S, van Raaij JM, MacIntyre UE, de Villiers FP, Kok FJ (2011) Duration of hospitalization and appetite of HIV-infected South African children. Maternal and Child Nutrition 7: 175-87.].

There are a number of reasons why HIV-infected children have a poor nutritional status. These include reduced food intake, malabsorption and diarrhoea, and impaired storage and increased utilization of nutrients [77. De Pee S, Semba RD (2010) Role of nutrition in HIV infection: Review of evidence for more effective programming in resource-limited settings. Food and Nutrition Bulletin 4: S313-S344.]. The reduced food intake often affects both macronutrients and micronutrients and may occur as a result of poor appetite, difficulty and pain on swallowing, and nausea and vomiting [1616. Semba RD, Tang AM (1999) Micronutrients and the pathogenesis of human immunodeficiency virus infection. British Journal of Nutrition 81: 181-189.]. Food insecurity due to reduced family income as a result of parental HIV-related illness also plays an important role in the reduced food intake observed in HIV-infected children [1717. Heikens GT, Bunn J, Amadi B, Manary M, Chhagan M, et al. (2008) Case management of HIV-infected severely malnourished children: challenges in the area of highest prevalence. Lancet 371: 1305-1307. ]. Malabsorption of fats, carbohydrates and micronutrients is common with HIV infection and may be due to opportunistic infections causing diarrhoea or due to the HIV itself [77. De Pee S, Semba RD (2010) Role of nutrition in HIV infection: Review of evidence for more effective programming in resource-limited settings. Food and Nutrition Bulletin 4: S313-S344.]. HIV infection has a major impact on the structure and function of the alimentary tract. The virus produces the transactivating peptide (Tat) which plays a role in the pathogenesis of diarrhoea in HIV-infected patients [1818. Canani RB, Ruotolo S, Buccigrossi V, Passariello A, Porcaro F, Siani MC, et al. (2007) Zinc fights diarrhoea in HIV-1-infected children: in-vitro evidence to link clinical data and pathophysiological mechanism. AIDS 21: 108-110.]. Tat stimulates active fluid secretion into the gut lumen and inhibits fluid absorption at the intestinal level [1919. Canani RB, Cirillo P, Mallardo G, Secondo A, Annunziato L, et al. (2003) Effects of HIV-1 Tat protein on the sodium D-glucose symporter of human ion secretion and on cell proliferation in human intestinal epithelial cells. Gastroenterology 124: 368-376.,2020. Canani RB, De Marco G, Passariello A, Buccigrossi V, Ruotolo S, et al. (2006) Inhibitory effect of HIV-1 Tat protein on the sodium-D-glucose symporter of human intestinal epithelial cells. AIDS 20: 5-10. ]. The inflammation associated with the infections occurring in HIV can lead to catabolism of tissues and muscle and inefficient utilisation of nutrients. Indeed rest energy expenditure has been shown to be increased even in asymptomatic HIV-infected persons [77. De Pee S, Semba RD (2010) Role of nutrition in HIV infection: Review of evidence for more effective programming in resource-limited settings. Food and Nutrition Bulletin 4: S313-S344.].

Treatment with HAART is associated with sustained improvement in growth [2121. Rose AM, Hall CS, Martinez-Allier N (2014) Aetiology and management of malnutrition in HIV-positive children. Archives of Disease in Childhood 99, 546-551.]. HIV-infected children from Malawi and Uganda had significant improvements in weight-for-age and height-for-age Z-scores within one to two years of HAART initiation [2222. Weigel R, Phiri S, Chiputula F, Gumulira J, Brinkhof M, et al. (2010) Growth response to antiretroviral treatment in HIV-infected children: a cohort study from Lilongwe, Malawi. Trop Med Int Health 15: 934-944.,23. Musoke PM, Mudiope P, Barlow-Mosha LN, Ajuna P, Bagenda D, et al. (2010) Growth, immune and viral load responses in HIV-infected African children receiving highly active antiretroviral therapy: a prospective cohort study. BMC Pediatrics 10: 56.]. However, among the Malawian children neither the median weight-for-age Z-score nor the height-for-age Z-score reached normal values after two years on HAART among children who were underweight or stunted at initiation of HAART [2222. Weigel R, Phiri S, Chiputula F, Gumulira J, Brinkhof M, et al. (2010) Growth response to antiretroviral treatment in HIV-infected children: a cohort study from Lilongwe, Malawi. Trop Med Int Health 15: 934-944.]. Likewise a study from Tanzania revealed that HIV-infected children on HAART were more likely to be underweight and/or wasted compared to HIV-uninfected children [2424. Sunguya BF, Poudel KC, Otsuka K, Yasuoka J, Mlunde LB, et al. (2011) Undernutrition among HIV-positive children in Dar es Salaam, Tanzania: antiretroviral therapy alone is not enough. BMC Public Health 11: 869.].

The nutritional status of HIV-infected children may affect the pharmacokinetics of antiretroviral drugs. A Ugandan study revealed that there was a difference between the pharmacokinetics of Lopinavir and Efavirenz in Ugandan children (48% of whom were malnourished) and those in children from resource-rich countries [2525. Bartelink IH, Savic RM, Dorsey G, Ruel T, Gingrich D, et al. (2015) The effect of malnutrition on the pharmacokinetics and virologic outcomes of lopinavir, efavirenz and nevirapine in food insecure HIV-infected children in Tororo, Uganda. Pediatr Infect Dis J 34: e63-70.]. The bioavailability of lopinavir and efavirenz (but not of Nevirapine) was lower in Ugandan children [2525. Bartelink IH, Savic RM, Dorsey G, Ruel T, Gingrich D, et al. (2015) The effect of malnutrition on the pharmacokinetics and virologic outcomes of lopinavir, efavirenz and nevirapine in food insecure HIV-infected children in Tororo, Uganda. Pediatr Infect Dis J 34: e63-70.].

Macronutrient intervention

As previously mentioned, HIV-infected persons are at great risk of malnutrition, and this includes those who are on HAART. Nutritional interventions may thus play an important role as an adjunct to antiretroviral medicines. These nutrients may be macronutrients or micronutrients. Macronutrients may be defined as essential nutrients that are required by the body in relatively large amounts, these are carbohydrates fats and proteins [2626. Grobler L, Siegfried N, Visser ME, Mahlungulu SSN, Volmink J (2013) Nutritional interventions for reducing morbidity and mortality in people with HIV. Cochrane Database Syst Rev 2, CD004536.].

A meta-analysis of 14 trials evaluating the effectiveness of macronutrient supplements compared with no supplements in HIV-infected adults and children indicated that these supplements increased energy and protein intake [2626. Grobler L, Siegfried N, Visser ME, Mahlungulu SSN, Volmink J (2013) Nutritional interventions for reducing morbidity and mortality in people with HIV. Cochrane Database Syst Rev 2, CD004536.]. While the increased energy and protein intake among those who received the supplements did increase body weight in most instances, there was no effect on CD4 cell counts and viral load [2626. Grobler L, Siegfried N, Visser ME, Mahlungulu SSN, Volmink J (2013) Nutritional interventions for reducing morbidity and mortality in people with HIV. Cochrane Database Syst Rev 2, CD004536.]. These authors noted that the supplements increased weight and body mass index in the first 3 months of supplementation [2626. Grobler L, Siegfried N, Visser ME, Mahlungulu SSN, Volmink J (2013) Nutritional interventions for reducing morbidity and mortality in people with HIV. Cochrane Database Syst Rev 2, CD004536.]. After this period there was no significant difference in weight and body mass index gain between those who received the macronutrient supplements and those who did not [2626. Grobler L, Siegfried N, Visser ME, Mahlungulu SSN, Volmink J (2013) Nutritional interventions for reducing morbidity and mortality in people with HIV. Cochrane Database Syst Rev 2, CD004536.]. Nonetheless, it should be remembered that mortality in HIV-infected children initiating HAART seems to be highest in the first 3 to 6 months of initiation.

Macronutrient supplementation may also be of benefit in HIV-infected children who are co-infected with TB. A systematic review revealed that the provision of high-energy nutritional products seems to result in a modest increase in weight gain during treatment for active TB [2727. Sinclair D, Abba K, Grobler L, Sudarsanam TD (2011) Nutritional supplements for people being treated with treated for active tuberculosis. Cochrane Database Syst Rev 2011; 11: CD006086.].

The WHO has developed guidelines for the nutritional care of HIV-infected children [44. World Health Organization (WHO) (2009) Guidelines for an integrated approach to the nutritional care of HIV-infected children (6 months-14 years). Geneva, Switzerland: World Health Organization 2009. ], and the energy requirements of these children are summarized in Table 1.

1. 

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   Table 1:

   Total daily calorie of HIV-infected children in kcal/kg/day.
   
   

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   Table 1: Total daily calorie of HIV-infected children in kcal/kg/day.
   Age	HIV-uninfected	HIV-infected (asymptomatic)	HIV-infected with complications	HIV-infected with severe complications
   6 - 11 months	690	760	830	150 – 220
   12 - 23 months	900	990	1080	150 – 220
   2 - 5 years	1260	1390	1510	150 – 220
   6 - 9 years	1650	1815	1980	75 – 100
   10 - 14 years	2020	2220	2420	60 – 90
   Obtained from WHO guidelines [44. World Health Organization (WHO) (2009) Guidelines for an integrated approach to the nutritional care of HIV-infected children (6 months-14 years). Geneva, Switzerland: World Health Organization 2009. ]

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Provision of Ready to Use Therapeutic Foods (an energy-dense lipid paste made of peanut butter, milk powder, oil, sugar, minerals, vitamin, and protein mix) to HIV-infected children on HAART for at least four months, resulted in a significant improvement in weight-for-age and weight-for-height Z-scores compared with HIV-infected Tanzanian children on HAART who did not receive the foods [2828. Sunguya BF, Poudel KC, Otsuka K, Yasuoka J, Mlunde LB, et al. (2012) Ready to Use Therapeutic Foods (RUTF) improves undernutrition among ART-treated, HIV-positive children in Dar es Salaam, Tanzania. Nutr J 11: 60.].

Supplementation with macronutrients seems to improve energy and protein intake and may also improve weight, but an effect on morbidity and mortality does not seem to have been demonstrated.

Micronutrient Intervention

HIV infection and deficiency of micronutrients are both independently associated with immune deficiency. HIV infection often results in micronutrient deficiency partly through poor dietary intake, malabsorption of micronutrients and increased utilisation of the micronutrients. The resultant micronutrient deficiency will further suppress immunity and will cause faster progression of HIV disease. This progression will intensify susceptibility to infections (including diarrhoea) resulting in even more loss of micronutrient. This vicious cycle is well described in the review by Semba and Tang [1616. Semba RD, Tang AM (1999) Micronutrients and the pathogenesis of human immunodeficiency virus infection. British Journal of Nutrition 81: 181-189.].

Micronutrient deficiencies have been noted to be more common in HIV-infected children compared with HIV-uninfected ones. Serum concentrations of zinc, iron and ferritin were significantly lower in HAART naïve HIV-infected South African children compared with HIV-uninfected children [1515. Mda S, van Raaij JM, MacIntyre UE, de Villiers FP, Kok FJ (2011) Duration of hospitalization and appetite of HIV-infected South African children. Maternal and Child Nutrition 7: 175-87.].

The provision of multiple micronutrient supplements to HAART naïve HIV-infected South African children resulted in improvement in weight-for-height Z-score and fewer episodes of respiratory symptoms compared with a placebo [2929. Mda S, van Raaij JM, de Villiers FP, Kok FJ (2013) Impact of multi-micronutrient supplementation on growth and morbidity of HIV-infected South African children. Nutrients 5: 4070-4092.]. A review of 11 trials indicated that Vitamin A supplementation is safe and is of benefit in children with HIV infection and that zinc is safe and has the same benefits on diarrhoeal morbidity in children with HIV as in children without HIV infection [3030. Irlam JH, Siegfried N, Visser ME, Rollins NC (2013) Micronutrient supplementation for children with HIV infection. Cochrane Database Syst Rev 10: CD010666. ]. The review further concluded that multiple micronutrient supplements have some clinical benefit in poorly nourished HIV-infected children [3030. Irlam JH, Siegfried N, Visser ME, Rollins NC (2013) Micronutrient supplementation for children with HIV infection. Cochrane Database Syst Rev 10: CD010666. ].

Conclusion

Undernutrition is an important risk factor for mortality in HIV-infected children who are initiating HAART. Deficiencies of macronutrients and micronutrients play a major role in the under nutrition observed in them. Children initiating HAART are at the greatest risk of mortality within the first 3 to 6 months of initiating HAART. Early diagnosis of HIV and initiation of HAART, as well as identification of malnutrition in these children is thus important. Macronutrient supplementation to HIV-infected persons initiating HAART seems to be of benefit in improving energy and protein intake and weight gain, but does not seem to have any effect on the immunological deterioration and mortality. The beneficial effects of macronutrients on weight gain in patients initiating HAART have been noted to be mainly in the first three months. As more evidence is obtained, the role of macronutrient supplements in this population is likely to become clearer.

Micronutrient supplementation has been shown to be beneficial in improving in weight and reducing morbidity (particularly diarrhoea and respiratory symptoms) in HIV-infected children. Supplementation with both macronutrients and micronutrients in HIV-infected children initiating HAART should be implemented according to the malnutrition category, i.e. moderate or severe acute malnutrition.