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Access to antiretroviral therapy (ART) for HIV infection has expanded rapidly throughout sub-Saharan Africa, but malnutrition and food insecurity have emerged as major barriers to program success. Protein-calorie malnutrition (a common form in the region) hastens HIV disease progression, and food insecurity is a barrier to medication adherence. Analyses of patient outcomes have identified a low body mass index (BMI) at ART initiation as an independent predictor of early mortality, but the causes of low BMI are multi-factorial may represent normal anthropometric variation, chronic inadequate food intake, or wasting associated with HIV and other infections. While there is much experience population-level humanitarian food assistance, few data exist to measure the effectiveness of macronutrient supplementation or to identify individuals most likely to benefit. In this report, we review the current evidence supporting macronutrient supplementation for HIV-infected adults; clinical trials in resource-adequate and resource-constrained settings; and highlight priority areas for future research.
Since 2003, access to antiretroviral therapy (ART) for HIV infection has expanded rapidly throughout sub-Saharan Africa, and more than 2.1 million of the estimated 7 million people in need of treatment now have access. Favorable clinical outcomes have been reported from a variety of settings [2–7], but the follow-up period in most analyses is short and further long-term data are needed. The geographic overlap of high HIV prevalence, malnutrition, and chronic food insecurity in much of sub-Saharan Africa has highlighted need for more comprehensive approaches to health care. There is increasing evidence that a low body mass index (BMI) is a powerful and independent predictor of early mortality following ART initiation [2, 8, 9]. The role of malnutrition in HIV disease progression and poor clinical outcomes is significant and likely under-reported .
In contrast to the substantial research on micronutrient supplements [11–16], few studies have examined the impact of macronutrient supplementation on limiting HIV disease progression or improving survival in adults in resource-constrained settings. A 2007 review, for example, found inconsistent and minimal improvements in weight or CD4+ lymphocyte response among HIV-infected individuals provided such an intervention . Direct clinical impact has not been demonstrated, but food insecurity is a barrier to ART adherence and may increase HIV transmission [18–23]. Early evidence suggests that food supplementation programs can help to improve patient retention and ART adherence [24, 25], but the implication of these findings for survival, virologic response, and ART regimen durability is unknown. Nutritional supplementation has been successfully integrated into large ART programs in sub-Saharan Africa, and some funding agencies permit supplementation as a component of care [24, 26–28].
Integrating nutritional supplementation into large ART programs is expensive, but if the health care of clients is substantially improved, then the commitment of resources may be justified. Although there is strong theoretical grounding for its effectiveness, the benefits of macronutrient supplementation should be demonstrated at a population level to support implementation. To this end, we provide a review of the current evidence around this issue, with a focus on resource-constrained settings. We assess the effects of malnutrition on HIV disease progression, discuss potential etiologies for increased mortality among malnourished persons on ART, and evaluate macronutrient supplements readily available in the developing world. We highlight trials of food supplementation conducted in both the developed and developing world and conclude with recommendations for supplement selection and outcome measures for future clinical trials.
The prevalence of adult malnutrition in sub-Saharan Africa is difficult to estimate and varies with natural and man-made disasters, but an analysis of multiple demographic and nutrition surveys estimated that 10–20% of African women age 20–49 are malnourished (BMI <18.5 kg/m2; similar data for men not available) . Protein-calorie malnutrition (PCM), the result of the insufficient intake of both protein and energy, is a common form of malnutrition in areas characterized by food scarcity. Similar to AIDS, PCM is associated with suppression of the antigen-specific arms of the immune system and several generalized host defense mechanisms . PCM is associated with reactivation of viral infections, reversal of the T-helper/suppressor ratio [31, 32], decreased T-cell primary antibody response and memory response , and atrophy of the lymph tissues [34, 35]. Peripheral lymphocyte and eosinophil counts may be reduced and natural killer cells show reduced activity . As with HIV infection, PCM may also induce a generalized pro-inflammatory response, especially in the mucosal barriers, leading to increased susceptibility to environmental pathogens [37, 38]. Persons with PCM are more susceptible to opportunistic infections and suffer greater morbidity [39, 40].
The primary cause of weight loss in HIV-infected patients is thought to be anorexia caused by elevated interleukin-1, interleukin-6, and tumor necrosis factor α [41, 42]. Oral and gastrointestinal infections, and constitutional manifestations of advanced HIV disease (e.g. fatigue, fever, dyspnea), contribute to progressive disability and interfere with an individual’s ability to ingest or obtain food . After initiating ART, side effects to certain antiretroviral drugs (e.g. nausea, insomnia) may be exacerbated if taken without food [21, 44]. and poor nutrition may potentiate drug toxicity [45–47].
While work capacity, muscle strength, and physical activity may be reduced in advanced HIV disease, the total daily energy expenditure may rise due to an increase in the resting metabolic rate (RMR). Most studies found an increase in RMR in HIV-infected persons of 10–30%, which was generally higher in the presence of secondary infections and correlated with increasing plasma viral load, though some reported no change [41, 48–54]. The increased RMR is caused in part by the metabolic expense of maintaining a pro-inflammatory state and an elevated rate of protein turnover [55, 56]. Additionally, elevated pro-inflammatory cytokines in untreated HIV infection prevent weight gain despite sufficient intake of protein .
Other conditions further contribute to malnutrition in advanced HIV disease. Infection by intestinal parasites and mycobacterium, decreased small bowel transit time, decreased carbohydrate absorption, bowel wall edema due to serum hypoalbuminemia, and abnormally high fecal fat excretion can lead to severe malabsorption . The loss of gut-associated lymphoid tissue during the initial phase of HIV infection can cause lasting impairment in the integrity of the gastrointestinal epithelial mucosal barrier , and predispose towards bacterial translocation across the gut wall .
The optimum daily energy and protein intake to prevent HIV-associated weight loss is uncertain. A 2005 World Health Organization (WHO) review on macronutrients and HIV/AIDS recommended that daily energy intake should be increased by 10% in asymptomatic HIV infection or 20–50% during the convalescent period following opportunistic infections . The report found no evidence to support increasing the proportion of protein in the diet beyond the recommended 12–15%.
A 10% or greater decrease from usual body weight, with concomitant chronic diarrhea or chronic weakness and fever, was an early AIDS-defining condition . Weight loss has also been recognized as a significant prognostic factor since the beginning of the epidemic [63–66]. In resource-constrained settings, patients may present for evaluation after significant unmeasured weight loss and, the use of BMI in many ART program outcome analyses may ignore important factors in prognosis and potential response to treatment. A low BMI might be indicative of normal anthropometric variation, chronic inadequate food intake, or wasting associated with HIV and other infections. BMI is an imperfect marker of nutritional status, but studies in developed countries have shown that a low BMI is an independent predictor of mortality and morbidity in HIV-infected patients, even after the introduction of combination ART [67–70]. WHO uses BMI to grade nutritional status in the following manner: mild malnutrition (BMI = 17.00–18.49 kg/m2), moderate malnutrition (BMI = 16.00–16.99 kg/m2), and severe malnutrition (BMI <16.00 kg/m2).
Low BMI at ART initation is an independent predictor of early mortality in several analyses from sub-Saharan Africa. In Zambia, we found that patients starting ART with a BMI of <16.0 kg/m2 had higher mortality in the first 90 days on therapy (adjusted hazard ratio [HR]: 2.4, 95%CI: 1.8–3.2) when compared to those above this BMI threshold . In a cohort of over 1500 persons in rural Malawi, those initiating ART with a BMI ≤15.9 kg/m2 had a 6-fold increased risk of death at three months compared to those with a BMI ≥18.5 kg/m2 (adjusted HR: 6.0, 95%CI: 4.6–12.7), and those with a BMI between 16.0 and 16.9 kg/m2 had more than a 2-fold increased risk (adjusted HR: 2.4, 95%CI: 1.7–6.3) . Similar data were reported from Tanzania, where patients with a BMI <16.0 kg/m2 at ART initiation had a mortality rate double that of patients with a BMI ≥18.5 (adjusted HR: 2.1, 95%CI: 1.1–4.2) .
The causes of early mortality in patients with low BMI initiating ART are poorly understood. A higher burden of opportunistic infections may cause more rapid weight loss and increase the incidence of immune reconstitution inflammatory syndrome. Metabolic derangements related to rapid depletion of muscle mass may also be important. HIV-associated wasting, in comparison to starvation, preferentially depletes muscle over adipose tissue and reduces the muscle phosphate stores necessary to replenish serum phosphate. In patients with wasting and anorexia, a low serum phosphate may be adequate for the relatively low turn-over rate of metabolic intermediates (e.g. ATP and 2,3-DPG), but with increased food intake following ART initiation a precipitous decline can occur [20, 21, 72–75]. This phenomenon – termed “refeeding syndrome” – may be exaggerated in areas when staple foods contain a high carbohydrate to protein and fat ratio [76–78]. As a result of serum phosphate depletion, potassium, magnesium, and sodium homeostasis is disrupted, which may cause cardiac arrhythmias, seizures, coma, pulmonary edema, paralysis and respiratory arrest [79–81]. Further study to define pathophysiologic processes contributing to early mortality in these patients is needed.
There are few studies of macronutrient supplementation on HIV disease progression or survival in adults, and most had relatively short follow-up periods (e.g. 3–6 months). Table 1 summarizes the nine randomized controlled trials (RCTs) of macronutrient supplementation conducted in resource-adequate settings [82–90]. Three trials address the use of amino acid mixtures versus isocaloric or isonitrogenous nutritional placebos in HIV-infected persons. The amino acid mixtures were effective in increasing patient weight; however, there was no evidence of improved immunologic recovery or survival. Six RCTs compared the addition of a balanced oral supplement to a normal diet, with the goal of increasing total energy intake by 560–960 kcal/day. These studies did not include HIV-negative controls or account for baseline dietary adequacy, and all-cause or HIV-related mortality were not included as primary outcome measures.
These trials demonstrated an improvement in energy and protein intake when compared to placebo or no supplementation, but no uniform improvements in body weight, fat mass, or fat-free mass. Only one study reports a significant improvement in CD4+ lymphocyte count with supplementation . All of the studies were conducted in resource-adequate settings where malnutrition is commonly the result of HIV-associated wasting or poor choice of foods. This is in stark contrast to resource-contained environments characterized by food scarcity or limited sources of protein. In addition, mean BMI across the studies were 19.6 kg/m2 or higher, whereas data from sub-Saharan Africa suggests that severe malnutrition (i.e. BMI <16.0 kg/m2) is associated with the greatest risk of early mortality on ART. In these studies, supplementation may have failed to show a benefit because the deleterious conditions associated with a low BMI were not present or were less pronounced; for example, immunosuppression related to PCM was less advanced, there was a lower burden of opportunistic infections, or metabolic abnormalities related to HIV-associated wasting were less severe.
The World Food Programme (WFP) and the Food and Agricultural Organization (FAO) of the United Nations have tailored interventions to address malnutrition and HIV in many of the most heavily affected countries in sub-Saharan Africa. Most of these programs deliver staple foods to areas of scarcity or agricultural training and assistance to promote local production, in a community-level effort to prevent the development or arrest the progression of malnutrition. This “food first” approach is predicated on the observation that the prevalence and severity of a range of diseases are increased in poorly nourished populations. A distinction is necessary, however, between supplementary feeding, which is the provision of food rations (either local staples or specialized foods) to vulnerable or malnourished persons to supplement the local diet and provide balanced and/or adequate daily energy intake, versus therapeutic feeding, which aims for the nutritional rehabilitation of severely malnourished adults with specialized foods that are often energy and nutrient dense. Whether an intervention represents supplementary and therapeutic feeding may depend on the target population or the program intent, but some products may be more suitable to the latter.
The optimal composition of macronutrient supplementation for malnourished adults is still a matter of debate. As a replacement or an addition to local staple foods, three candidate supplements are commonly referenced: high-energy Ready-to-Use Therapeutic Foods (RUTF) , corn-soya blends , and fortified blended foods (FBF) . RUTF is a type of highly nutrient-dense spread (HNDS), a food product high in energy and micronutrients in which all powdered ingredients are suspended in fat and do not require any preparation or the addition of water before ingestion. RUTF, like other HNDS, can be stored for long periods, do not require refrigeration, and can be individually packaged and used effectively in areas where hygiene conditions are not optimal. RUTF has been used successfully for community therapeutic care and nutritional rehabilitation in the pediatric population [94–96] and recommended by WHO for the management of severely malnourished children . Corn-soya blends, also referred to as High-Energy Protein Supplements, are blended flours which have been used effectively in the past in both emergency and protracted food relief operations . Corn-soya blends provide a higher calorie and protein content than many local carbohydrate-rich staple foods they are programmed to replace, but concerns have been raised regarding their suitability for the treatment of severe malnutrition given the low essential fatty acid and overall lipid content . FBF are also blended flours designed to provide more comprehensive nutrition supplementation, and contain mixtures of cereals (typically corn or wheat), pulses, fats, vitamins and minerals. The WFP distributed almost 300,000 metric tons of FBF in 2006 . Table 2 compares the nutritional content of these supplements and local staples.
RUTF has the advantage of higher calorie-to-weight and calorie-to-volume ratios than blended flours, which makes transporting a monthly ration easier [91, 93]. The standard packaging of blended flours in bulk adds uncertainty to the size of the daily ration consumed by the patient. Since patients with advanced HIV often rely on others for food preparation, there is greater likelihood that the ration will be shared . The higher viscosity of RUTF allows for higher levels of vitamin and mineral supplementation without sedimentation during storage, and the physical structure of a spread (i.e. powder mixed into fat) limits exposure to air and prevents vitamin oxidation. The low water content (2% compared to 8–12% for flours) prevents soluble minerals from interacting with vitamins, and decreases bacterial and insect contamination . E. coli introduced into supplementary spreads do not grow, while they grow exponentially in a liquid form . RUTF, however, is not without its drawbacks. It is approximately three times more expensive to produce and requires more sophisticated processing facilities . A recent qualitative study by Medicins Sans Frontiers found that some patients were unable to carry home more than a 2-week ration of RUTF (approximately 5.1 kg). Half of the patients were unable to consume the entire daily ration due to poor taste, dietary boredom, or HIV-related complications such as thrush .
Our review of the medical literature identified two randomized trials of nutritional supplementation for HIV-infected adults in sub-Saharan Africa (Table 3) [24, 105]. A study by Cantrell et al compared ART adherence among persons receiving WFP rations and persons enrolled in clinics not yet receiving food aid. Criteria for assistance were based on household food insecurity, not anthropometrics, and the mean patient BMI in the intervention and control group was 21.0 and 20.8 (women) and 19.6 and 19.7 (men), respectively. Patients in the intervention group were more likely to achieve 95% monthly ARV adherence than patients in the control group (RR 1.5; 95% CI 1.2 to 1.8), but there was no significant difference in weight gain, CD4+ cell response, or mortality. However, the study lacked sufficient power to detect small but potentially relevant weight change differences between groups (e.g. 1–2 kg).
A recent trial in urban Malawi randomized 491 adults initiating ART with a BMI <18.5 kg/m2 to receive 1,360 kcal/day of CSB or Ready-to-Use Fortified Spread (RUFS), similar to RUTF, for 3.5 months. There was not a study arm without nutritional supplementation. After 3.5 months, patients receiving RUFS has a significantly greater increase in BMI (2.2 ±1.9 vs. 1.7 ± 1.6 kg/m2) than those receiving RUFS, buts there were no significant differences in survival, HIV viral load, CD4 count change, or quality of life.
The design of future macronutrient supplementation trials must consider a range of variables, including the proportion of daily calories to supply, the choice of supplement, duration of supplementation, program exit criteria, logistics, and the uncertainties of human behavior. A caloric target could be the WFP recommended minimum daily intake of 2100 kcal for adults, increased by an additional 30% (the upper limit of the estimated increase in RMR in advanced HIV infection) to 2,730 kcal/day [49, 106]. The proportion of calories supplied could be stratified by anthropometric criteria (e.g the grade of malnutrition). The selected product should match the available distribution network and processing capacity; account for potential intrafamilal sharing, climate effects and environmental conditions (e.g. lack of clean water); and should be culturally appropriate. Future trials of macronutrient supplementation should assess a broad range of short and long-term outcome measures to uncover potentially under-recognized prognostic indicators, as suggested in Table 4.
Further study of the treatment of malnutrition at ART initiation is critical to global policy and the treatment of HIV-infected persons in many areas of the developing world. Decisions of this magnitude must be informed by solid evidence, not speculation, but these critically important data do not yet exist. There is a need for a well designed and adequately powered trial of supplementation at ART initiation among HIV-infected adults with evidence of moderate to severe malnutrition. In addition, further studies of the pathophysiologic processes responsible for the observed rise in mortality and improved metrics to identify persons most in need of support are needed. The intersection of malnutrition and HIV infection affects millions of HIV-infected adults in sub-Saharan Africa and represents a critical uncertainty and a major challenge to the success of ART programs.
The authors would like thank Mark Giganti, Mark Manary, and Tony Castleman for their significant contributions to this review. Investigator salary or trainee support is provided by the Fogarty International Center (R24-TW007988, K01-TW06670) and a Clinical Scientist Development Award from the Doris Duke Charitable Foundation (2007061).
No conflicts of interest were reported by any author.