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OBSOLETE: Nutrition and HIV
Nutrition and HIV H Friis, University of Copenhagen, Frederiksberg, Denmark MF Olsen, Nordic Cochrane Centre, Copenhagen, Denmark S Filteau, London School of Hygiene and Tropical Medicine,. London, UK ã 2014 Elsevier Inc. All rights reserved.
Introduction Nutrition and Infections Immune Functions and Resistance to Infections Nutrition, Food Security and HIV Infection Nutrition Affects HIV Progression and Transmission HIV Infection Impairs Nutritional Status Nutrition and Antiretroviral Treatment Infant Feeding and HIV Infection Conclusion References
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Introduction When first described in Africa, the advanced stage of HIV infection – acquired immune deficiency syndrome, or AIDS – was called ‘slim disease,’ due to the pronounced wasting that is a cardinal manifestation, especially in individuals with poor dietary intake before and after being infected. Sub-Saharan Africa continues to have the highest HIV burden in the world with well over two-thirds of the 35.2 million individuals living with HIV infection in 2012. Of a global 1.6 million AIDS deaths and 2.3 million new HIV infections in 2012, sub-Saharan Africa accounted for 1.2 million and 1.6 million, respectively (UNAIDS, 2013). In low-income populations nutrition and HIV infection are closely linked at the level of the individual, the household, and the community. The HIV epidemic is not driven by poverty per se, but rather thrives in a context of socioeconomic inequality. However, poor individuals are much more vulnerable to the consequences of HIV infection and its associated stigma, which may increase the risk of food insecurity. The consequences of inadequate dietary intake in turn increase the susceptibility to infection and the progression of disease, and reduce the effects of medical treatment. Thus, food insecurity and undernutrition may be determinants as well as consequences of HIV infection (Figure 1). Even in high-income populations some patients may not have a diet meeting the nutritional requirements. This could be because the health system fails to provide nutritional advice to the patient, and the patient lacks knowledge or resources to obtain an adequate diet. Many organizations and internet sites provide information on the importance of diet, and people living with HIV often take nutritional supplements, herbs, or other complementary food-based therapies, although the evidence for efficacy and safety is lacking.
Nutrition and Infections Adequate intake of energy and nutrients is necessary to maintain health. The macronutrients (i.e. carbohydrates, protein, and fat) provide energy and the micronutrients (i.e. vitamins and minerals) are essential for general and specific metabolic functions. A diet that is inadequate in energy and nutrients fails to sustain optimal growth of children and maintain weight and body composition of adults, and impairs specific body functions. In low-income populations, the typical diet is often based on a starch-rich staple, such as cereals or tubers, with legumes, few vegetables and fruits, and little, if any, animal foods. Such a diet has a low energy and nutrient density. The bulkiness of the diet renders it difficult to meet the energy and nutrient requirements, particularly for children, even if the access to food is adequate. In addition, the quality of the diet is often low. Vitamin A, for example, is rarely available as preformed vitamin A, found in animal foods, but mainly as provitamin carotenoids found in plant-based foods. The conversion of provitamin A carotenoids to vitamin A in the body is less efficient than previously believed, and further impaired by deficiency of other nutrients. Iron is mainly available as the poorly absorbable non-heme iron from plant sources, and rarely as heme iron from animal foods. Furthermore, the staple foods contain high levels of phytic acid and other antinutrients, which bind essential minerals like zinc and iron and prevent their absorption. In addition to the low intake and bioavailability of micronutrients, a high burden of infectious diseases increases the requirements and considerably contributes to the high prevalence of deficiencies. Women and children are particularly vulnerable to nutritional deficiencies. Since women often have inadequate dietary intake before and during pregnancy, fetal growth will be retarded and the child born with low weight and inadequate nutrient stores.
Reference Module in Biomedical Research
http://dx.doi.org/10.1016/B978-0-12-801238-3.03064-6
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Figure 1 The vicious circle due to a synergistic relationship between HIV infection and food insecurity and undernutrition, at individual, household, and community levels. HIV leads to nutritional defeciences in the individual, and to food insecurity in the household and community. Food insecurity increases risk of HIV infection, and undernutrition increases progression of HIV infection.
Although exclusive breast-feeding up to 6 months of age is recommended by the World Health Organization (WHO), many children receive water, tea, cows’ milk, porridge, and so on, from the first few weeks of life. The combination of early nutritional deficiencies and contaminated liquids and solid foods increases the risk of diarrhea and pneumonia, which further impair the nutritional status of the child. Deficiencies of vitamin A, iron, and zinc, as well as other micronutrients, are widespread in low-income populations. Lack of micronutrients may impair specific body functions, such as cognitive functions, vision, production of red blood cells, and immune functions. Some micronutrients have antioxidant (e.g. vitamins C and E, and selenium) or prooxidant (e.g. iron) properties, which means that they are able to either counteract or generate, respectively, harmful oxidative stress. Cheap and feasible public health interventions exist, whereby the intake of micronutrients, in contrast to macronutrients, can be increased in populations. These include dietary diversification, food fortification, food modification, and nutritional supplementation. In addition, interventions to prevent and treat common infections serve to prevent further increases in requirements.
Immune Functions and Resistance to Infections Immune suppression caused by lack of nutrients has been called nutritionally acquired immunodeficiency syndrome, or NAIDS. Lack of zinc, of which only about 1 mg is needed every day to replace losses, leads to virtual disappearance of the thymus, a key immunological organ. Thus micronutrient deficiencies often increase risk and severity of infectious diseases. Since infections also impair nutritional status, they form a synergistic two-way relationship or a vicious circle (Figure 1). Nevertheless, even if a specific nutritional deficiency impairs immunity, administration of that nutrient may favor the pathogen more than the host – especially if unphysiological doses or routes are used – and hence increase the risk and severity of infectious diseases. For example, parenteral and even oral administration of iron may stimulate growth of bacteria or parasites and lead to increased morbidity. Vitamin A is essential for a range of immune functions, and large randomized trials have found that periodic administration of vitamin A capsules to children under 5 years reduces mortality by 23–30%. Vitamin A supplementation, given in large doses two or three times per year, is therefore recommended by the WHO. Given the considerable effect of vitamin A on mortality, the adequacy of dosing only a couple of times per year, often in combination with national immunization days, and the low price per capsule, makes vitamin A supplementation one of the most cost-effective health interventions. Zinc supplementation may prevent diarrhea and pneumonia in populations with an inadequate zinc intake, and has also been shown to reduce the duration and severity of diarrhea when given therapeutically. In contrast to vitamin A, zinc has to be taken frequently, if not daily, since there are no body stores. Thus, zinc supplementation may be feasible in the treatment of children hospitalized or attending health facilities due to diarrhea but is not a feasible intervention in the prevention of diarrhea and pneumonia as it would have to be given daily.
Nutrition, Food Security and HIV Infection The synergistic relationship between nutrition and infections is a central component of the HIV epidemic. The risks and consequences of HIV infection are closely linked through both biological and social pathways, which are elaborated below.
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Figure 2 Conceptual framework of the role of micronutrient (MN) defeciences and iron loading in HIV infection. Even early HIV infection (HIV+) leads to MN deficiences, which cause oxidative stress and NAIDS. Oxidative stress and NAIDS may increase progression of HIV infection (HIV+++). Modified from Friis H (2006) Micronutrient interventions and HIV infection: A review of current evidence. Tropical Medicine and International Health. 11: 1849–1857, Blackwell Publishers.
Nutrition Affects HIV Progression and Transmission In HIV-infected individuals, micronutrient deficiencies and iron accumulation may accelerate progression of HIV infection, as shown in the conceptual framework in Figure 2. Deficiencies of antioxidant vitamins and minerals and accumulation of the prooxidant iron could lead to oxidative stress, which is known to activate a transcription factor that increases replication of HIV, which results in increased HIV progression. The iron accumulation may also result in flare-up of latent tuberculosis (TB) and possibly other infections, which stimulate HIV replication. Deficiencies of micronutrients essential to immune functions lead to NAIDS, which could contribute to the risk of co-infections and to the decline in the number of CD4 cells, that is, the cells infected and destroyed by HIV. Data from laboratory and clinical studies support this conceptual framework. Accordingly, it is likely that iron supplementation is harmful, as it may increase HIV progression. Yet, iron supplementation is given routinely to pregnant women seeking antenatal care, and occasionally to TB patients presenting with anemia, even in settings where HIV infection is prevalent. In contrast, data from randomized, placebo-controlled trials document a beneficial effect of supplementation with other micronutrients during HIV infection. For example, among HIV-infected pregnant women in Tanzania not receiving ART, a daily supplement containing high doses of vitamins B, C, and E was shown to increase CD4 count and to reduce HIV load. After 2 years, those receiving the multivitamins had 29% lower risk of progression to or dying from AIDS (Fawzi et al., 2004). Similarly, a trial among adult Thai men and women with HIV infection found that a daily supplement containing approximately one RDA of a range of micronutrients reduced mortality (Jiamton et al., 2003). Treatment of a HIV or TB does not eliminate the need for nutritional support, as it is often assumed. In fact, if the infection has resulted in a growth or weight deficit, then treatment, by allowing a growth spurt or weight gain, considerably increases nutritional requirements. If these requirements are not met, then it is likely that the weight gain will result in fat rather than lean body mass. It is also likely that it may exacerbate NAIDS, and potentially worsen the outcome of the TB infection or HIV. Thus, nutritional support providing multiples of the RDA may be needed to meet the requirements during the initial phase of medical treatment. Currently, nutritional assessment, advice, and support are rarely integrated in the management of HIV infection and TB in low-income countries. To the extent nutritional deficiency contributes to progression of HIV and increase in HIV viral load, then it is also likely to be a determinant of infectiousness, and hence, of mother-to-child or sexual transmission. As such, the supplement containing vitamins B, C, and E, mentioned previously, was also found to reduce mother-to-child HIV transmission, although only among women with signs of poor health. Vitamin A is essential to a range of immune functions and initial observational data suggested that vitamin A supplementation might reduce mother-to-child HIV transmission. However, later data from randomized, controlled trials found no effect of vitamin A supplementation in two trials, and increased transmission in a third. The vitamin A supplement contained both preformed vitamin A and provitamin A carotenoids, and it is not clear which of these compounds caused the increase in transmission, and why it was not the case in one of the other trials using a similar intervention (Friis, 2006). Due to the importance of various nutrients to epithelial integrity and mucosal immunity, it is likely that deficiencies may also affect susceptibility to infection, when exposed to HIV. However, there are currently no data to confirm this. On the other hand, individuals living with food insecurity may be more prone to engage in risk behaviours which increase their exposure to HIV.
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HIV Infection Impairs Nutritional Status HIV has direct effects on nutritional status, in addition to the indirect effects through its impact on food security. HIV infection increases nutritional requirements by reducing absorption and increasing utilization and loss of nutrients, and by increasing resting energy expenditure. Yet, the intake of nutrients and energy may be reduced, due to loss of appetite and compromised food security. It has been shown that HIV leads to a decline in muscle function and thereby reduced work capacity. In sub-Saharan Africa, many HIV patients are relying on labour-demanding jobs in the informal sector with no job security or compensation for lost income if too ill to work. Maintaining physical capacity and an adequate activity level is thus of crucial importance for their livelihoods. In addition to the physiological impact of HIV, the infection is often accompanied by social stigma, which may further compromise the food security of patients, by reducing their chances of finding and retaining work. HIV affects the whole household when they, in addition to losing a breadwinner, may have to stay home to look after a sick family member and face expenses for medical treatment and transportation. Stigma may also lead to social exclusion, where HIV-affected households are cut off from their usual coping strategies, such as borrowing money or food from others in times of shortfall. The entire community may become affected by HIV, if many of its productive members are lost, which may in turn lead to a decreased agricultural yield or otherwise stagnated development. While individual supplementation may be needed at critical points, such as initiation of ART, it is essential to keep in mind that long term strategies are also necessary to protect the livelihoods and food security of people living with HIV. Depending on a patient’s dietary intake of nutrients and energy, micronutrient status may be impaired, with fat and particularly lean body mass lost even at early stages of the infection. With more advanced HIV infection, when opportunistic and other infections occur, resting energy expenditure is further increased, whereas food intake may be further reduced, due to painful sores and infections in the mouth and esophagus. If the additional energy requirements are not met, then weight will be lost, unless physical activity is substantially reduced. If the additional nutrient requirements are not met, then specific deficiencies will eventually occur, or existing deficiencies will become exacerbated, which will impair important body functions, including maintenance of lean body mass and immune functions. An exception is iron. Although absorption of iron may be impaired, even early HIV infection results in anemia of infection, which is due to suppression of the production of red blood cells in the bone marrow. But red blood cells will continue to age, and eventually be engulfed by white blood cells and taken to the stores, where iron will accumulate as it is now longer incorporated into new red blood cells. Energy requirements are estimated to be 10% higher during asymptomatic HIV infection to maintain body weight and physical activity, and they are estimated to be 30% higher during symptomatic HIV infection (WHO, 2004). In contrast, protein requirements do not seem to be increased. The requirements for most vitamins and minerals are increased, and it is recommended that patients with HIV eat a healthy diet. In practice, many patients are advised to take a daily supplement containing one recommended dietary allowance (RDA) of the essential vitamins and minerals, except iron. But the extent to which the requirements are increased by HIV infection is still not clear, as it will be different for different micronutrients and depend on the stage of HIV infection. Nevertheless, recommendations should not only be based on which intakes are necessary to avoid deficiency, but on which intakes give optimal health, and prevent progression of HIV infection.
Nutrition and Antiretroviral Treatment The development of ART and prophylaxis for opportunistic infections in the mid-1990s was expected to mark the end of HIV-related weight loss. However, it has been observed that treatment doesn’t necessarily lead to weight recovery, even in patients with good viral control, and weight loss continues to be a common complication of HIV after the global scale-up of ART. According to current treatment guidelines, an HIV-infected individual is only eligible for ART when CD4-counts are below 500 cells per ml, but many come when the CD4 count is much lower. Since poor nutritional status is widespread, even in uninfected individuals, and deteriorates with progression of HIV infection, it is obvious that many HIV-infected individuals are in a poor nutritional status at the start of treatment. Data from large ART programmes in sub-Saharan Africa indicate that one in three patients entering ART care have a body mass index (BMI, kg m2) below 18.5, indicating some grade of malnutrition, and one in ten have a BMI below 16, indicating severe malnutrition. It is likely that nutritional deficiencies will affect absorption and metabolization of one or more of the different drugs given, and hence affect either efficacy or toxicity of the drugs. Furthermore, unsustainable access to adequate food is known to be a barrier for adherence to medical treatment. Indeed, low BMI has consistently been identified as an independent predictor of morbidity and mortality during the early phase of ART (Gupta et al., 2011; May et al., 2010). In a cohort of 40 000 HIV patients initiating ART in Lusaka, Zambia, mild malnutrition was associated with a two-fold risk of death within the first 90 days of treatment, while moderate and severe malnutrition was associated with four- and six-fold risks, respectively (Koethe et al. 2010)(Figure 3). After 90 days of treatment mortality rates became similar between BMI groups. Other countries have reported similar increases in mortality risk and show that these persist after controlling for immune status. Furthermore, it is known from high-income countries that some of the ARV drugs affect lipid metabolism, and cause maldistribution of fat (i.e., lipodystrophia) and metabolic syndrome with a high risk of coronary heart disease and diabetes. It is unknown to what extent prior undernutrition and inadequate diet during treatment affect the risk of lipodystrophia and metabolic syndrome.
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Infant Feeding and HIV Infection For virtually all infants globally, breastfeeding is the safest and healthiest feeding practice (Figure 4). The WHO recommends that infants are exclusively breastfed, that is, given breast milk and nothing else, for the first 6 months of life. Infants should then continue breastfeeding, while also receiving complementary foods, into the second year of life. These recommendations are based primarily on the greater survival of infants in low-income countries who are fed this way but there is also evidence from highincome countries of improved health and development of breastfed, compared with non-breastfed, infants. The HIV epidemic has called into question the universal applicability of the WHO recommendations since there is strong evidence that HIV can be transmitted through breast milk. A randomised controlled trial conducted in Nairobi, Kenya, showed an excess 16% mother-to-child HIV transmission (MTCT) to children allocated to breastfeeding compared to those allocated to free formula. However, infants who were not breastfed in this and other African studies were at greater risk of infections, particularly diarrhea, and death from other causes than HIV. HIV-infected mothers thus have the difficult problem of trying to balance the risk of transmitting HIV through breast milk with the risk of their non-breastfed infants dying from other infections. In order to help these HIV-infected women, WHO and other international agencies have kept actively in touch with researchers and policy-makers as ongoing research clarifies our understanding of risks and benefits of different feeding modes for HIV-exposed infants. This has resulted in rapid, every few years, changes in international recommendations. While this was done for the best of
Figure 3 Time to death stratified by BMI among patients at ART initiation (n ¼ 40 778). Koethe JR, Lukusa A, Giganti MJ, et al. (2010) Association between weight gain and clinical outcomes among malnourished adults initiating antiretroviral therapy in Lusaka, Zambia. J. Acquir. Immune Defic. Syndr. 53, 507–513.
Figure 4 While ongoing research aims at clarifying risks and benefits of different feeding modes for HIV-exposed infants, there has been rapid changes in international recommendations for HIV-infected mothers. Photo: Henrik Friis
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reasons – to get scientific evidence quickly into practice in order to save infant lives – it has often been difficult for health staff to keep abreast of current recommendations and it has resulted in confusion for both staff and HIV-infected mothers. Several areas of research have had particular impact on the changing WHO recommendations. One relates to the observation, originally in a study in Durban, South Africa, that early exclusive breastfeeding was associated with a lower risk of MTCT than was mixed feeding with breast milk plus other foods. The mechanism for this effect has not been determined and, since feeding mode was not randomly assigned in this or similar observational studies, it is possible that the relationship is not causal and that both a high risk of transmission and an inability to breastfeed exclusively are secondary to some other factor, for example, poor maternal health. The Zambian Exclusive Breastfeeding Study tested whether removing the usual period of mixed feeding breast milk and complementary foods would decrease MTCT. The team randomly allocated women who were successfully exclusively breastfeeding early either to maintain the usual practice of gradual weaning off the breast with addition of complementary foods or to wean abruptly at about 5 months. The group which weaned abruptly had marginally less MTCT but more illness and there was no difference in HIV-free survival at age 2 years. Messages which had already circulated to health staff that exclusive breastfeeding with abrupt weaning around 6 months was recommended thus had to be changed (Kuhn et al., 2008). Other research trials have focused on provision of different ART regimens to mothers and infants, often including concomitant randomisation to different infant feeding modes. The success of ART at reducing MTCT and the increasing availability of ART in Africa have now largely made obsolete other attempts to make breast milk safer, for example heat treatment of expressed breast milk. Early exclusive breastfeeding, with ART provision, is recommended for infants of HIV-infected women, not as a way to prevent MTCT but because exclusive breastfeeding is considered the best feeding mode for all infants. Although there have been concerns that breastfeeding may have adverse effects on the health of the mother, possibly as a result of the nutritional stress of lactation, in general research has not borne this out. As for all lactating women, HIV-infected women should receive appropriate nutritional, medical, and psychosocial support to enable successful breastfeeding. Another factor, in addition to changing scientific knowledge, which has led to changing international recommendations for HIV and infant feeding is observation how the recommendations were perceived and used on the ground. For example, for several years there were efforts to determine whether women had access to AFASS – acceptable, feasible, affordable, sustainable, and safe – replacement foods for their infants in order to determine who could safely avoid breastfeeding; however, this terminology proved hard to understand and has been dropped from international recommendations. Replacement feeding is not common in Africa and, in addition to potential stigma for women not breastfeeding in some areas, there is the problem of communicating how to prepare safe and nutritionally adequate replacement feeds. Exclusive breastfeeding is also rarely the norm but there are many studies showing that women can be taught and supported to exclusively breastfeed. Finally, in order to promote autonomy and choice, HIV-infected women are supposed to be individually counselled on risks and benefits of different infant feeding modes. However, communicating the messages is challenging and time consuming, especially in a busy African maternal and child health clinic, and there is evidence that many mothers and health workers do not understand the issues well enough to choose and would prefer a more top-down approach to their medical care. The more recent WHO recommendations for ART during normal lactation have the advantage of moving the choice, specifically which ART regimen, to the level of governments and their scientific consultants.
Conclusion Undernutrition and food insecurity play a pivotal role in the global HIV/AIDS epidemic, affecting both risks of HIV transmission and the subsequent AIDS-related impacts. The response to the HIV/AIDS epidemic thus needs to be comprehensive in focusing on broad-based approaches to prevention, treatment and care, and mitigation, as well as interventions to improve nutritional status and food security globally.
References Fawzi WW, Msamanga GI, Spiegelman D, et al. (2004) A randomized trial of multivitamin supplements and HIV disease progression and mortality. New England Journal of Medicine 351: 23–32. Friis H (2006) Micronutrient interventions and HIV infection: A review of current evidence. Tropical Medicine and International Health 11: 1849–57. Gupta A, Nadkarni G, Yang W-T, et al. (2011) Early mortality in adults initiating antiretroviral therapy (ART) in low- and middle-income countries (LMIC): a systematic review and metaanalysis. PLoS One 6: e28691. Jiamton S, Pepin J, Suttent R, et al. (2003) A randomized trial of the impact of multiple micronutrient supplementation on mortality among HIV-infected individuals living in Bangkok. AIDS 17: 2461–2469. Koethe JR, Lukusa A, Giganti MJ, et al. (2010) Association between weight gain and clinical outcomes among malnourished adults initiating antiretroviral therapy in Lusaka, Zambia. Journal of Acquired Immune Deficiency Syndromes 53: 507–513. Kuhn L, Aldrovandi GM, Sinkala M, et al. (2008) Effects of early, abrupt weaning on HIV-free survival of children in Zambia. New England Journal of Medicine 359: 130–141. May M, Boulle A, Phiri S, et al. (2010) Prognosis of patients with HIV-1 infection starting antiretroviral therapy in sub-Saharan Africa: a collaborative analysis of scale-up programmes. The Lancet 376: 449–457. UNAIDS (2013) UNAIDS report on the global AIDS epidemic. Global Report. Geneva, Switzerland: UNAIDS http://www.unaids.org/en/resources/documents/2013/name,85053, en.asp (accessed January 2014). World Health Organization (2004) Nutrient requirements for people living with HIV/AIDS. Report of a technical consultation. Geneva, Switzerland: WHO. http://www.who.int/nutrition/ publications/hivaids/9241591196/en/ (accessed March 2014).
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Further Reading Coutsoudis A, Pillay K, Kuhn L, et al. (2001) Method of feeding and transmission of HIV-1 from mothers to children by 15 months of age: Prospective cohort study from Durban, South Africa. AIDS 15: 379–387. Interagency Task Team, UNICEF, WHO (2013) Expanding and simplifying treatment for pregnant women living with HIV: Managing the transition to Option B/B+. http://www.who.int/ hiv/pub/mtct/iatt_optionBplus_toolkit/en/. Mofensen LM (2008) Antiretroviral Prophylaxis to Reduce Breast Milk Transmission of HIV Type 1: New Data but Still Questions. Journal of Acquired Immune Deficiency Syndromes 48: 237–240. Nduati R, John G, Mbori-Ngacha D, et al. (2000) Effect of breastfeeding and formula feeding on transmission of HIV-1: a randomized clinical trial. Journal of the American Medical Association 283: 1167–1174. WHO Collaborative Study Team on the Role of Breastfeeding on the Prevention of Infant Mortality (2000) Effect of breastfeeding on infant and child mortality due to infectious diseases in less developed countries: A pooled analysis. The Lancet 355: 451–455. World Health Organization (2010) Guidelines on HIV and infant feeding 2010: Principles and recommendations for infant feeding in the context of HIV and a summary of evidence. http://www.who.int/nutrition/publications/hivaids/9789241599535/en/index.html.
Introduction Nutrition and Infections Immune Functions and Resistance to Infections Nutrition, Food Security and HIV Infection Nutrition Affects HIV Progression and Transmission HIV Infection Impairs Nutritional Status Nutrition and Antiretroviral Treatment Infant Feeding and HIV Infection Conclusion References
1 1 2 2 3 4 4 5 6 6
Introduction When first described in Africa, the advanced stage of HIV infection – acquired immune deficiency syndrome, or AIDS – was called ‘slim disease,’ due to the pronounced wasting that is a cardinal manifestation, especially in individuals with poor dietary intake before and after being infected. Sub-Saharan Africa continues to have the highest HIV burden in the world with well over two-thirds of the 35.2 million individuals living with HIV infection in 2012. Of a global 1.6 million AIDS deaths and 2.3 million new HIV infections in 2012, sub-Saharan Africa accounted for 1.2 million and 1.6 million, respectively (UNAIDS, 2013). In low-income populations nutrition and HIV infection are closely linked at the level of the individual, the household, and the community. The HIV epidemic is not driven by poverty per se, but rather thrives in a context of socioeconomic inequality. However, poor individuals are much more vulnerable to the consequences of HIV infection and its associated stigma, which may increase the risk of food insecurity. The consequences of inadequate dietary intake in turn increase the susceptibility to infection and the progression of disease, and reduce the effects of medical treatment. Thus, food insecurity and undernutrition may be determinants as well as consequences of HIV infection (Figure 1). Even in high-income populations some patients may not have a diet meeting the nutritional requirements. This could be because the health system fails to provide nutritional advice to the patient, and the patient lacks knowledge or resources to obtain an adequate diet. Many organizations and internet sites provide information on the importance of diet, and people living with HIV often take nutritional supplements, herbs, or other complementary food-based therapies, although the evidence for efficacy and safety is lacking.
Nutrition and Infections Adequate intake of energy and nutrients is necessary to maintain health. The macronutrients (i.e. carbohydrates, protein, and fat) provide energy and the micronutrients (i.e. vitamins and minerals) are essential for general and specific metabolic functions. A diet that is inadequate in energy and nutrients fails to sustain optimal growth of children and maintain weight and body composition of adults, and impairs specific body functions. In low-income populations, the typical diet is often based on a starch-rich staple, such as cereals or tubers, with legumes, few vegetables and fruits, and little, if any, animal foods. Such a diet has a low energy and nutrient density. The bulkiness of the diet renders it difficult to meet the energy and nutrient requirements, particularly for children, even if the access to food is adequate. In addition, the quality of the diet is often low. Vitamin A, for example, is rarely available as preformed vitamin A, found in animal foods, but mainly as provitamin carotenoids found in plant-based foods. The conversion of provitamin A carotenoids to vitamin A in the body is less efficient than previously believed, and further impaired by deficiency of other nutrients. Iron is mainly available as the poorly absorbable non-heme iron from plant sources, and rarely as heme iron from animal foods. Furthermore, the staple foods contain high levels of phytic acid and other antinutrients, which bind essential minerals like zinc and iron and prevent their absorption. In addition to the low intake and bioavailability of micronutrients, a high burden of infectious diseases increases the requirements and considerably contributes to the high prevalence of deficiencies. Women and children are particularly vulnerable to nutritional deficiencies. Since women often have inadequate dietary intake before and during pregnancy, fetal growth will be retarded and the child born with low weight and inadequate nutrient stores.
Reference Module in Biomedical Research
http://dx.doi.org/10.1016/B978-0-12-801238-3.03064-6
1
2
Nutrition and HIV
Figure 1 The vicious circle due to a synergistic relationship between HIV infection and food insecurity and undernutrition, at individual, household, and community levels. HIV leads to nutritional defeciences in the individual, and to food insecurity in the household and community. Food insecurity increases risk of HIV infection, and undernutrition increases progression of HIV infection.
Although exclusive breast-feeding up to 6 months of age is recommended by the World Health Organization (WHO), many children receive water, tea, cows’ milk, porridge, and so on, from the first few weeks of life. The combination of early nutritional deficiencies and contaminated liquids and solid foods increases the risk of diarrhea and pneumonia, which further impair the nutritional status of the child. Deficiencies of vitamin A, iron, and zinc, as well as other micronutrients, are widespread in low-income populations. Lack of micronutrients may impair specific body functions, such as cognitive functions, vision, production of red blood cells, and immune functions. Some micronutrients have antioxidant (e.g. vitamins C and E, and selenium) or prooxidant (e.g. iron) properties, which means that they are able to either counteract or generate, respectively, harmful oxidative stress. Cheap and feasible public health interventions exist, whereby the intake of micronutrients, in contrast to macronutrients, can be increased in populations. These include dietary diversification, food fortification, food modification, and nutritional supplementation. In addition, interventions to prevent and treat common infections serve to prevent further increases in requirements.
Immune Functions and Resistance to Infections Immune suppression caused by lack of nutrients has been called nutritionally acquired immunodeficiency syndrome, or NAIDS. Lack of zinc, of which only about 1 mg is needed every day to replace losses, leads to virtual disappearance of the thymus, a key immunological organ. Thus micronutrient deficiencies often increase risk and severity of infectious diseases. Since infections also impair nutritional status, they form a synergistic two-way relationship or a vicious circle (Figure 1). Nevertheless, even if a specific nutritional deficiency impairs immunity, administration of that nutrient may favor the pathogen more than the host – especially if unphysiological doses or routes are used – and hence increase the risk and severity of infectious diseases. For example, parenteral and even oral administration of iron may stimulate growth of bacteria or parasites and lead to increased morbidity. Vitamin A is essential for a range of immune functions, and large randomized trials have found that periodic administration of vitamin A capsules to children under 5 years reduces mortality by 23–30%. Vitamin A supplementation, given in large doses two or three times per year, is therefore recommended by the WHO. Given the considerable effect of vitamin A on mortality, the adequacy of dosing only a couple of times per year, often in combination with national immunization days, and the low price per capsule, makes vitamin A supplementation one of the most cost-effective health interventions. Zinc supplementation may prevent diarrhea and pneumonia in populations with an inadequate zinc intake, and has also been shown to reduce the duration and severity of diarrhea when given therapeutically. In contrast to vitamin A, zinc has to be taken frequently, if not daily, since there are no body stores. Thus, zinc supplementation may be feasible in the treatment of children hospitalized or attending health facilities due to diarrhea but is not a feasible intervention in the prevention of diarrhea and pneumonia as it would have to be given daily.
Nutrition, Food Security and HIV Infection The synergistic relationship between nutrition and infections is a central component of the HIV epidemic. The risks and consequences of HIV infection are closely linked through both biological and social pathways, which are elaborated below.
Nutrition and HIV
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Figure 2 Conceptual framework of the role of micronutrient (MN) defeciences and iron loading in HIV infection. Even early HIV infection (HIV+) leads to MN deficiences, which cause oxidative stress and NAIDS. Oxidative stress and NAIDS may increase progression of HIV infection (HIV+++). Modified from Friis H (2006) Micronutrient interventions and HIV infection: A review of current evidence. Tropical Medicine and International Health. 11: 1849–1857, Blackwell Publishers.
Nutrition Affects HIV Progression and Transmission In HIV-infected individuals, micronutrient deficiencies and iron accumulation may accelerate progression of HIV infection, as shown in the conceptual framework in Figure 2. Deficiencies of antioxidant vitamins and minerals and accumulation of the prooxidant iron could lead to oxidative stress, which is known to activate a transcription factor that increases replication of HIV, which results in increased HIV progression. The iron accumulation may also result in flare-up of latent tuberculosis (TB) and possibly other infections, which stimulate HIV replication. Deficiencies of micronutrients essential to immune functions lead to NAIDS, which could contribute to the risk of co-infections and to the decline in the number of CD4 cells, that is, the cells infected and destroyed by HIV. Data from laboratory and clinical studies support this conceptual framework. Accordingly, it is likely that iron supplementation is harmful, as it may increase HIV progression. Yet, iron supplementation is given routinely to pregnant women seeking antenatal care, and occasionally to TB patients presenting with anemia, even in settings where HIV infection is prevalent. In contrast, data from randomized, placebo-controlled trials document a beneficial effect of supplementation with other micronutrients during HIV infection. For example, among HIV-infected pregnant women in Tanzania not receiving ART, a daily supplement containing high doses of vitamins B, C, and E was shown to increase CD4 count and to reduce HIV load. After 2 years, those receiving the multivitamins had 29% lower risk of progression to or dying from AIDS (Fawzi et al., 2004). Similarly, a trial among adult Thai men and women with HIV infection found that a daily supplement containing approximately one RDA of a range of micronutrients reduced mortality (Jiamton et al., 2003). Treatment of a HIV or TB does not eliminate the need for nutritional support, as it is often assumed. In fact, if the infection has resulted in a growth or weight deficit, then treatment, by allowing a growth spurt or weight gain, considerably increases nutritional requirements. If these requirements are not met, then it is likely that the weight gain will result in fat rather than lean body mass. It is also likely that it may exacerbate NAIDS, and potentially worsen the outcome of the TB infection or HIV. Thus, nutritional support providing multiples of the RDA may be needed to meet the requirements during the initial phase of medical treatment. Currently, nutritional assessment, advice, and support are rarely integrated in the management of HIV infection and TB in low-income countries. To the extent nutritional deficiency contributes to progression of HIV and increase in HIV viral load, then it is also likely to be a determinant of infectiousness, and hence, of mother-to-child or sexual transmission. As such, the supplement containing vitamins B, C, and E, mentioned previously, was also found to reduce mother-to-child HIV transmission, although only among women with signs of poor health. Vitamin A is essential to a range of immune functions and initial observational data suggested that vitamin A supplementation might reduce mother-to-child HIV transmission. However, later data from randomized, controlled trials found no effect of vitamin A supplementation in two trials, and increased transmission in a third. The vitamin A supplement contained both preformed vitamin A and provitamin A carotenoids, and it is not clear which of these compounds caused the increase in transmission, and why it was not the case in one of the other trials using a similar intervention (Friis, 2006). Due to the importance of various nutrients to epithelial integrity and mucosal immunity, it is likely that deficiencies may also affect susceptibility to infection, when exposed to HIV. However, there are currently no data to confirm this. On the other hand, individuals living with food insecurity may be more prone to engage in risk behaviours which increase their exposure to HIV.
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HIV Infection Impairs Nutritional Status HIV has direct effects on nutritional status, in addition to the indirect effects through its impact on food security. HIV infection increases nutritional requirements by reducing absorption and increasing utilization and loss of nutrients, and by increasing resting energy expenditure. Yet, the intake of nutrients and energy may be reduced, due to loss of appetite and compromised food security. It has been shown that HIV leads to a decline in muscle function and thereby reduced work capacity. In sub-Saharan Africa, many HIV patients are relying on labour-demanding jobs in the informal sector with no job security or compensation for lost income if too ill to work. Maintaining physical capacity and an adequate activity level is thus of crucial importance for their livelihoods. In addition to the physiological impact of HIV, the infection is often accompanied by social stigma, which may further compromise the food security of patients, by reducing their chances of finding and retaining work. HIV affects the whole household when they, in addition to losing a breadwinner, may have to stay home to look after a sick family member and face expenses for medical treatment and transportation. Stigma may also lead to social exclusion, where HIV-affected households are cut off from their usual coping strategies, such as borrowing money or food from others in times of shortfall. The entire community may become affected by HIV, if many of its productive members are lost, which may in turn lead to a decreased agricultural yield or otherwise stagnated development. While individual supplementation may be needed at critical points, such as initiation of ART, it is essential to keep in mind that long term strategies are also necessary to protect the livelihoods and food security of people living with HIV. Depending on a patient’s dietary intake of nutrients and energy, micronutrient status may be impaired, with fat and particularly lean body mass lost even at early stages of the infection. With more advanced HIV infection, when opportunistic and other infections occur, resting energy expenditure is further increased, whereas food intake may be further reduced, due to painful sores and infections in the mouth and esophagus. If the additional energy requirements are not met, then weight will be lost, unless physical activity is substantially reduced. If the additional nutrient requirements are not met, then specific deficiencies will eventually occur, or existing deficiencies will become exacerbated, which will impair important body functions, including maintenance of lean body mass and immune functions. An exception is iron. Although absorption of iron may be impaired, even early HIV infection results in anemia of infection, which is due to suppression of the production of red blood cells in the bone marrow. But red blood cells will continue to age, and eventually be engulfed by white blood cells and taken to the stores, where iron will accumulate as it is now longer incorporated into new red blood cells. Energy requirements are estimated to be 10% higher during asymptomatic HIV infection to maintain body weight and physical activity, and they are estimated to be 30% higher during symptomatic HIV infection (WHO, 2004). In contrast, protein requirements do not seem to be increased. The requirements for most vitamins and minerals are increased, and it is recommended that patients with HIV eat a healthy diet. In practice, many patients are advised to take a daily supplement containing one recommended dietary allowance (RDA) of the essential vitamins and minerals, except iron. But the extent to which the requirements are increased by HIV infection is still not clear, as it will be different for different micronutrients and depend on the stage of HIV infection. Nevertheless, recommendations should not only be based on which intakes are necessary to avoid deficiency, but on which intakes give optimal health, and prevent progression of HIV infection.
Nutrition and Antiretroviral Treatment The development of ART and prophylaxis for opportunistic infections in the mid-1990s was expected to mark the end of HIV-related weight loss. However, it has been observed that treatment doesn’t necessarily lead to weight recovery, even in patients with good viral control, and weight loss continues to be a common complication of HIV after the global scale-up of ART. According to current treatment guidelines, an HIV-infected individual is only eligible for ART when CD4-counts are below 500 cells per ml, but many come when the CD4 count is much lower. Since poor nutritional status is widespread, even in uninfected individuals, and deteriorates with progression of HIV infection, it is obvious that many HIV-infected individuals are in a poor nutritional status at the start of treatment. Data from large ART programmes in sub-Saharan Africa indicate that one in three patients entering ART care have a body mass index (BMI, kg m2) below 18.5, indicating some grade of malnutrition, and one in ten have a BMI below 16, indicating severe malnutrition. It is likely that nutritional deficiencies will affect absorption and metabolization of one or more of the different drugs given, and hence affect either efficacy or toxicity of the drugs. Furthermore, unsustainable access to adequate food is known to be a barrier for adherence to medical treatment. Indeed, low BMI has consistently been identified as an independent predictor of morbidity and mortality during the early phase of ART (Gupta et al., 2011; May et al., 2010). In a cohort of 40 000 HIV patients initiating ART in Lusaka, Zambia, mild malnutrition was associated with a two-fold risk of death within the first 90 days of treatment, while moderate and severe malnutrition was associated with four- and six-fold risks, respectively (Koethe et al. 2010)(Figure 3). After 90 days of treatment mortality rates became similar between BMI groups. Other countries have reported similar increases in mortality risk and show that these persist after controlling for immune status. Furthermore, it is known from high-income countries that some of the ARV drugs affect lipid metabolism, and cause maldistribution of fat (i.e., lipodystrophia) and metabolic syndrome with a high risk of coronary heart disease and diabetes. It is unknown to what extent prior undernutrition and inadequate diet during treatment affect the risk of lipodystrophia and metabolic syndrome.
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Infant Feeding and HIV Infection For virtually all infants globally, breastfeeding is the safest and healthiest feeding practice (Figure 4). The WHO recommends that infants are exclusively breastfed, that is, given breast milk and nothing else, for the first 6 months of life. Infants should then continue breastfeeding, while also receiving complementary foods, into the second year of life. These recommendations are based primarily on the greater survival of infants in low-income countries who are fed this way but there is also evidence from highincome countries of improved health and development of breastfed, compared with non-breastfed, infants. The HIV epidemic has called into question the universal applicability of the WHO recommendations since there is strong evidence that HIV can be transmitted through breast milk. A randomised controlled trial conducted in Nairobi, Kenya, showed an excess 16% mother-to-child HIV transmission (MTCT) to children allocated to breastfeeding compared to those allocated to free formula. However, infants who were not breastfed in this and other African studies were at greater risk of infections, particularly diarrhea, and death from other causes than HIV. HIV-infected mothers thus have the difficult problem of trying to balance the risk of transmitting HIV through breast milk with the risk of their non-breastfed infants dying from other infections. In order to help these HIV-infected women, WHO and other international agencies have kept actively in touch with researchers and policy-makers as ongoing research clarifies our understanding of risks and benefits of different feeding modes for HIV-exposed infants. This has resulted in rapid, every few years, changes in international recommendations. While this was done for the best of
Figure 3 Time to death stratified by BMI among patients at ART initiation (n ¼ 40 778). Koethe JR, Lukusa A, Giganti MJ, et al. (2010) Association between weight gain and clinical outcomes among malnourished adults initiating antiretroviral therapy in Lusaka, Zambia. J. Acquir. Immune Defic. Syndr. 53, 507–513.
Figure 4 While ongoing research aims at clarifying risks and benefits of different feeding modes for HIV-exposed infants, there has been rapid changes in international recommendations for HIV-infected mothers. Photo: Henrik Friis
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reasons – to get scientific evidence quickly into practice in order to save infant lives – it has often been difficult for health staff to keep abreast of current recommendations and it has resulted in confusion for both staff and HIV-infected mothers. Several areas of research have had particular impact on the changing WHO recommendations. One relates to the observation, originally in a study in Durban, South Africa, that early exclusive breastfeeding was associated with a lower risk of MTCT than was mixed feeding with breast milk plus other foods. The mechanism for this effect has not been determined and, since feeding mode was not randomly assigned in this or similar observational studies, it is possible that the relationship is not causal and that both a high risk of transmission and an inability to breastfeed exclusively are secondary to some other factor, for example, poor maternal health. The Zambian Exclusive Breastfeeding Study tested whether removing the usual period of mixed feeding breast milk and complementary foods would decrease MTCT. The team randomly allocated women who were successfully exclusively breastfeeding early either to maintain the usual practice of gradual weaning off the breast with addition of complementary foods or to wean abruptly at about 5 months. The group which weaned abruptly had marginally less MTCT but more illness and there was no difference in HIV-free survival at age 2 years. Messages which had already circulated to health staff that exclusive breastfeeding with abrupt weaning around 6 months was recommended thus had to be changed (Kuhn et al., 2008). Other research trials have focused on provision of different ART regimens to mothers and infants, often including concomitant randomisation to different infant feeding modes. The success of ART at reducing MTCT and the increasing availability of ART in Africa have now largely made obsolete other attempts to make breast milk safer, for example heat treatment of expressed breast milk. Early exclusive breastfeeding, with ART provision, is recommended for infants of HIV-infected women, not as a way to prevent MTCT but because exclusive breastfeeding is considered the best feeding mode for all infants. Although there have been concerns that breastfeeding may have adverse effects on the health of the mother, possibly as a result of the nutritional stress of lactation, in general research has not borne this out. As for all lactating women, HIV-infected women should receive appropriate nutritional, medical, and psychosocial support to enable successful breastfeeding. Another factor, in addition to changing scientific knowledge, which has led to changing international recommendations for HIV and infant feeding is observation how the recommendations were perceived and used on the ground. For example, for several years there were efforts to determine whether women had access to AFASS – acceptable, feasible, affordable, sustainable, and safe – replacement foods for their infants in order to determine who could safely avoid breastfeeding; however, this terminology proved hard to understand and has been dropped from international recommendations. Replacement feeding is not common in Africa and, in addition to potential stigma for women not breastfeeding in some areas, there is the problem of communicating how to prepare safe and nutritionally adequate replacement feeds. Exclusive breastfeeding is also rarely the norm but there are many studies showing that women can be taught and supported to exclusively breastfeed. Finally, in order to promote autonomy and choice, HIV-infected women are supposed to be individually counselled on risks and benefits of different infant feeding modes. However, communicating the messages is challenging and time consuming, especially in a busy African maternal and child health clinic, and there is evidence that many mothers and health workers do not understand the issues well enough to choose and would prefer a more top-down approach to their medical care. The more recent WHO recommendations for ART during normal lactation have the advantage of moving the choice, specifically which ART regimen, to the level of governments and their scientific consultants.
Conclusion Undernutrition and food insecurity play a pivotal role in the global HIV/AIDS epidemic, affecting both risks of HIV transmission and the subsequent AIDS-related impacts. The response to the HIV/AIDS epidemic thus needs to be comprehensive in focusing on broad-based approaches to prevention, treatment and care, and mitigation, as well as interventions to improve nutritional status and food security globally.
References Fawzi WW, Msamanga GI, Spiegelman D, et al. (2004) A randomized trial of multivitamin supplements and HIV disease progression and mortality. New England Journal of Medicine 351: 23–32. Friis H (2006) Micronutrient interventions and HIV infection: A review of current evidence. Tropical Medicine and International Health 11: 1849–57. Gupta A, Nadkarni G, Yang W-T, et al. (2011) Early mortality in adults initiating antiretroviral therapy (ART) in low- and middle-income countries (LMIC): a systematic review and metaanalysis. PLoS One 6: e28691. Jiamton S, Pepin J, Suttent R, et al. (2003) A randomized trial of the impact of multiple micronutrient supplementation on mortality among HIV-infected individuals living in Bangkok. AIDS 17: 2461–2469. Koethe JR, Lukusa A, Giganti MJ, et al. (2010) Association between weight gain and clinical outcomes among malnourished adults initiating antiretroviral therapy in Lusaka, Zambia. Journal of Acquired Immune Deficiency Syndromes 53: 507–513. Kuhn L, Aldrovandi GM, Sinkala M, et al. (2008) Effects of early, abrupt weaning on HIV-free survival of children in Zambia. New England Journal of Medicine 359: 130–141. May M, Boulle A, Phiri S, et al. (2010) Prognosis of patients with HIV-1 infection starting antiretroviral therapy in sub-Saharan Africa: a collaborative analysis of scale-up programmes. The Lancet 376: 449–457. UNAIDS (2013) UNAIDS report on the global AIDS epidemic. Global Report. Geneva, Switzerland: UNAIDS http://www.unaids.org/en/resources/documents/2013/name,85053, en.asp (accessed January 2014). World Health Organization (2004) Nutrient requirements for people living with HIV/AIDS. Report of a technical consultation. Geneva, Switzerland: WHO. http://www.who.int/nutrition/ publications/hivaids/9241591196/en/ (accessed March 2014).
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Further Reading Coutsoudis A, Pillay K, Kuhn L, et al. (2001) Method of feeding and transmission of HIV-1 from mothers to children by 15 months of age: Prospective cohort study from Durban, South Africa. AIDS 15: 379–387. Interagency Task Team, UNICEF, WHO (2013) Expanding and simplifying treatment for pregnant women living with HIV: Managing the transition to Option B/B+. http://www.who.int/ hiv/pub/mtct/iatt_optionBplus_toolkit/en/. Mofensen LM (2008) Antiretroviral Prophylaxis to Reduce Breast Milk Transmission of HIV Type 1: New Data but Still Questions. Journal of Acquired Immune Deficiency Syndromes 48: 237–240. Nduati R, John G, Mbori-Ngacha D, et al. (2000) Effect of breastfeeding and formula feeding on transmission of HIV-1: a randomized clinical trial. Journal of the American Medical Association 283: 1167–1174. WHO Collaborative Study Team on the Role of Breastfeeding on the Prevention of Infant Mortality (2000) Effect of breastfeeding on infant and child mortality due to infectious diseases in less developed countries: A pooled analysis. The Lancet 355: 451–455. World Health Organization (2010) Guidelines on HIV and infant feeding 2010: Principles and recommendations for infant feeding in the context of HIV and a summary of evidence. http://www.who.int/nutrition/publications/hivaids/9789241599535/en/index.html.