to 238.4) and less diarrhoea (RR=0.83; 95% CI: 0.71 to 0.98 at 24 months)64, as well as improved growth during the first two years of life (weight-for-age: mean difference = 0.42; 95% CI 0.07 to 0.77)65 compared with placebo. Mortality was reduced among the children of supplemented women with low lymphocyte counts (<1340/ mm3) (RR=0.30;
95% CI: 0.1 to 0.92 at 24 months)46.
A randomised, placebo-controlled trial among Zimbabwean women found that multimicronutrient supplementation was associated with higher birth weight overall (49 g; 95% CI: −6 to 104). The effect was greater for the third of the population that was HIV-infected than among the HIV-negative women, although the interaction was not significant66.
and prophylaxis, dietary intake of other nutrients, and other infections has been suggested36 as an explanation for the increased risk of MTCT associated with vitamin A supplementation in the Tanzanian trial.
There is also a concern that zinc may potentiate HIV replication, since the HIV-Tat protein and the HIV nucleocapsid NCp7 proteins are strongly zinc-dependent70. Evidence from one observational study suggested that high-dose zinc supplementation was associated with increased HIV/AIDS disease progression and mortality in HIV-infected adults18. Two studies in children demonstrated no adverse effects in terms of increase in viral load or reduction in CD4+ counts, however54 (unpublished data, Heloise Buys, 2006).
Conclusions and recommendations
Relevant to policy:
Micronutrient deficiencies are common in people with HIV/AIDS and are more I.
pronounced in individuals with advanced disease and in those with inadequate diets.
Such deficiencies may hasten disease progression, increase mortality, and facilitate MTCT of HIV.
Observational studies have shown a direct correlation between micronutrient intake II.
(especially vitamins A and B, multivitamins, zinc and selenium) and favourable clinical outcomes in patients with HIV infection. However, observational studies lack valid markers of micronutrient status, and the effects of micronutrient deficiencies are prone to confounding by other factors, including micronutrient interaction.
Based on limited evidence from randomised trials, supplementation with vitamin III.
A/beta-carotene does not seem to have any significant beneficial or adverse clinical effects in HIV-infected non-pregnant adults. In HIV-infected children receiving vitamin supplements, reductions in morbidity and mortality have been reported, but these conclusions are based either on small trials or subgroup analyses. Vitamin A possibly increases the risk of vertical transmission in HIV-infected pregnant and lactating women, and the risk of mortality in infants of supplemented mother-infant pairs.
The concerns about the safety of universal maternal and neonatal supplementation in IV.
HIV-endemic areas may have important policy implications for South Africa.
There is sound evidence that multivitamin supplementation (excluding vitamin A) in V.
HIV-infected pregnant women reduces the risk of disease progression, AIDS-related mortality and adverse pregnancy outcomes.
Results derived from a few small trials indicate that zinc supplements given VI.
to HIV-infected children are safe and effective in reducing morbidity, but zinc
supplementation in HIV-infected pregnant women seems to have no benefit and may be harmful to the women.
Finally, the evidence-base on the effects of micronutrient supplementation in people VII.
with HIV is remarkably limited. It seems reasonable at this stage to support the recommendations of the WHO that everything possible should be done to promote and support adequate dietary intake of micronutrients at Individual Nutrient Intake Level (INL98) levels71, while recognising that this may not be sufficient to correct nutritional deficiencies in all HIV-infected individuals. In situations where micronutrient deficiencies are endemic, these nutrients should be provided through food fortification or micronutrient supplements where available that contain at least 1−2 INL98s.
Relevant to research:
There is a critical need for adequately powered studies to answer questions related to I.
the efficacy and safety of micronutrient supplements in people with HIV infection in both the medium and long term. Apart from vitamins, attention should be given to other promising interventions, such as zinc and selenium.
Research should focus on both asymptomatic HIV-infected individuals and those II.
with more advanced disease (with and without ART therapy) and should take into account the special needs of children and adults, including pregnant women. It is important to determine how the effects of micronutrients in immunocompromised individuals differ from those in people with normal immune function
Future research should determine whether HAART initiation restores micronutrient III.
concentrations, independent of inflammatory markers, and whether micronutrient supplements affect HIV-related outcomes in HIV-infected persons receiving HAART72
The optimal composition and dosage of various supplements requires investigation, as IV.
preparations can vary considerably and may not have equivalent effects.
All nutritional interventions to improve the health and well-being of persons V.
living with HIV/AIDS need to be optimised and research into identifying optimal interventions and operational strategies is therefore required. Such research should not be to the detriment of antiretroviral treatment, as this remains the one intervention to date that has consistently been shown to reduce morbidity and mortality associated with HIV/AIDS.
The influence of nutrition on the risk and outcomes of tuberculosis
This chapter critically reviews the scientific data supporting the contention that malnutrition is an important risk factor for TB, and that nutritional intervention in conjunction with appropriate chemotherapy may contribute to improved clinical outcomes in malnourished patients. It focuses principally on published observations in humans, with occasional reference to appropriate studies conducted in highly relevant animal models.
Introduction
Mycobacterium tuberculosis is a highly evolved human pathogen. Over millennia, this pathogen and its human host have adapted to each other to an astonishing degree, resulting in an impasse in which the organism can reside for decades within the tissues of most infected individuals1. While the cellular and molecular determinants of this stand-off have not been elucidated, it is clear that a successful immune response is able to keep the microbe in check in most individuals, albeit without eliminating it completely2. Any immunosuppressive condition, such as HIV infection, malnutrition, aging, etc., may tip the balance in favor of the pathogen, resulting in reactivation tuberculosis (TB)3. Nutritional deficiencies, in particular, are known to affect adversely precisely those immunological mechanisms that are crucial for successful control of mycobacteria, namely the functions of T-lymphocytes and a variety of phagocytic cells4. This chapter therefore focuses on the relationship between malnutrition and TB.
A priori, one could hypothesise several ways in which nutritional deficiencies could affect the prevention and management of TB. Malnutrition has cognitive and behavioural consequences that could increase the risk of primary infection, i.e. consequences that would respond to nutritional rehabilitation – apathy, intellectual impairment, inactivity, etc. Therefore, while we tend to concentrate on the molecular and cellular mechanisms by which malnutrition can affect the risk of TB, we must also keep in mind that malnutrition may affect TB risk in other ways.
Theoretically, malnourished individuals might exhibit increased susceptibility to primary, pulmonary infection with M. tuberculosis. It is clear that not all individuals exposed to an infectious case of TB (e.g. household contacts) become infected as indicated by a conversion of their tuberculin (purified protein derivative, PPD) skin test to positive, raising the possibility that innate mechanisms of resistance may be impaired by nutritional insufficiency5. Innate resistance may involve the enhanced anti-mycobacterial functions of alveolar macrophages or lung dendritic cells which are activated via Toll- like or other pathogen receptors6 and which could, at least theoretically, be impacted by nutrient deficiencies. However, there is little evidence that the intrinsic susceptibility to infection is altered by nutritional status. Evidence to support the contention that malnutrition may not affect the establishment of primary infection comes from studies of chronically protein-deficient guinea pigs that demonstrated no alteration in the number of tubercles resulting from low-dose aerosol exposure to virulent M. tuberculosis: the same number of inhaled, retained bacilli resulted in pulmonary granulomas in both well-nourished and malnourished guinea pigs7. This conclusion must be tempered by the fact that malnourished individuals are more likely to be anergic. PPD skin test reactivity is likely to underestimate their prevalence of infection.
In populations residing in countries with endemic bovine tuberculosis, malnutrition may affect the risk of gastrointestinal tuberculosis following the consumption of unpasteurised dairy products. Deficiencies of protein and calories have a profound impact on the gastrointestinal mucosa, e.g. flattening of microvilli, atrophy of Peyer’s patches, which could facilitate mycobacterial invasion of the mucosal barrier and increased risk of peritoneal TB, scrofula, mycobacteraemia and disseminated TB. This is another condition that would respond to nutritional rehabilitation.
Another way in which malnutrition could alter the pathogenesis of TB would be to increase the risk of progression from infection to primary disease in the short term, or to increase the risk of reactivation disease in the long term. This aspect of pathogenesis appears to be most profoundly affected by nutritional deficiencies. The progression from infection to disease is prevented in most healthy individuals by a successful adaptive immune response involving cooperation between populations of T lymphocytes and phagocytes8. Malnutrition is known to impair precisely these immune responses4, hence allowing sub-clinical infection to develop into full-blown clinical illness. Several epidemiological studies relating specific nutrient deficiencies to clinical tuberculosis are reviewed below.
Nutritional status also may affect progression from TB infection to disease by altering the availability of essential nutrients to meet the metabolic requirements of the pathogen as well as the person. For example, increased severity of TB (and HIV) has been observed in persons with hemochromatosis due to drinking traditional beer fermented in iron
vessels9. M. tuberculosis requires iron and obtains it within the host by means of various iron scavenging mechanisms that must compete with highly avid host iron-binding proteins (e.g. lactoferrin, transferrin) to be effective10, 11. Depending upon the relative availability of iron to the pathogen and host, the effect of iron deficiency or excess may be beneficial for the microbe or the patient. Iron chelation therapy has even been suggested for TB patients and HIV-infected individuals with iron overload12. Although not as well studied, the consequences of the availability to the pathogen of other essential nutrients in a malnourished individual could provide a non-immunological mechanism by which nutritional deficiencies alter progression from infection to disease in TB.
Still another way in which nutritional deficiencies could impact on TB is by interfering with appropriate chemotherapy in diseased individuals. Current anti-mycobacterial drug regimens are highly effective if given properly to individuals infected with drug-sensitive strains of M.tuberculosis13. However, concurrent malnutrition could blunt the effects of these antibiotics, which must be administered for several months to cure the patient.
Since malnutrition-induced loss of some immune functions is reversed rapidly upon correction of the nutritional deficiency14, nutritional intervention in conjunction with appropriate chemotherapy could improve the outcome in malnourished TB patients.
Several intervention trials have been conducted and are summarised below.
Finally, malnutrition could interfere with the protective efficacy of BCG vaccine, thus increasing the disease burden in vaccinated populations suffering from nutritional deficiencies. BCG vaccine is thought to work by inducing the same array of protective T lymphocyte responses which are responsible for preventing the progression from infection to disease in non-vaccinated individuals15, 16. Nutrient deficiencies could therefore also impact on vaccine-induced immunity. Unfortunately, no clinical studies of the effect of nutrient deprivation on BCG vaccine efficacy have been conducted. Most of the information related to the loss of BCG-induced protection in malnutrition comes from experimental animal studies17, reviewed below.