[MUSIC] Hi, I'm Henrik Friis, Professor of International Nutrition and Health at the University of Copenhagen. My research group works with researchers in Africa and Asia to improve nutrition and health in children, pregnant women and people with infectious and chronic diseases. My main interest is nutrition and infections and that's what I will talk about now. First I will give a brief introduction, then talk about micronutrients and childhood infections, and finally, about food supplements for people with tuberculosis, TB And HIV. I hope to convince you that it's an exciting research topic and vitally important. As you know, under nutrition and infections are common in low income settings and usually coexist. This coexistence is part, is partly due to poverty being a determinant of both. But it's also reflecting a causal bidirectional relationship, that undernutrition may lead to infections, and infections to undernutrition. So what we may have is a synergistic relationship, a vicious circle, between undernutrition and infections. In other words, undernutrition potentiates the effects of infections. Several million children die each year due to undernutrition. Most of them die from infections. But they die from these otherwise trivial infections because of underlying undernutrition. Now let's look at how these effects are mediated. On the one hand, infections impair nutritional status through reduced appetite and reduced absorption of nutrients, as well as increased utilization and excretion of nutrients. These effects are mainly due to the so-called acute face response accompanying generalized infections, but localized manifestations such as diarrhea and ulcers may also contribute. On the other hand, undernutrition increases the risk and severity of infections by impairing the immune system. This has been called NAIDS, Nutritionally Acquired Immune Deficiency Syndrome, and is the most widespread immunosuppressive disorder globally, more widespread and deadly than HIV. What convinced me about the importance of nutrition for host defense was to see, in a laboratory animal, how you can literally remove a key immune organ, the thymus, by taking the minimum zinc out of the diet. The thymus is in here, behind the chest bone, and it's critically important to development of cellular immunity. This way of removing it is called dietary thymectomy. The thymus has therefore, for several hundred years, been called the barometer of undernutrition. But host undernutrition may also affect the virulence Of the infectious agent. It has been convincingly shown how host deficiencies can make an avirulent virus mutate and become virulent. If deficiency is harmful, then you would expect the permutation to be beneficial right? No not necessarily. Supplementation may actually increase the risk or severity of an infection, as I will get back to later. And that is why we cannot just assume that any nutritional supplement is beneficial, or even harmless. We need research to develop nutritional interventions, and to test their efficacy and even safety before implementation. Before we go on, let me just tell you a bit about the typical diet in a low income setting. It's often monotonous consisting of a stable food such as maize porridge, a bit of vegetables, and little or no animal source foods. There are two problems with such a diet. First, the starch rich maize requires a lot of water to be added to reduce its viscosity. This will dilute the energy and nutrients and the meal becomes very bulky. Second, maize contains so called anti nutrients which will prevent the absorption of important minerals like iron, zinc and phosphorus. So even with access to enough foods, the intake of energy and micronutrients may be inadequate to maintain micronutrient stores and to maintain growth in children, and weight in adults. Consequently, people will be short and deficient in a range of micronutrients. They will probably also be thin, but not necessarily. With the ongoing nutrition transition, energy as refined sugar and fat is increasingly cheap, so people me be overweight but undernourished. Now this was the big picture. Let's now turn to the role of micronutrients in childhood infections. Micronutrients are needed in very small quantities. In contrast to food, it's logistically feasible to put them into tablets and distribute them to individuals at risk. When effective, micronutrient supplementation may be among the most cost-effective health interventions. But micronutrient supplementation is basically unphysiological. It typically provides a single nutrient in a very high dose, and not embedded in a food matrix. Given to individuals who are deficient in a whole range of nutrients and energy, an undernourished body may be overwhelmed and unable to handle the nutrients effectively and safely. Consequently, the nutrient may benefit the pathogen, the virus, bacteria or parasite, rather than the host. And this makes explain why we have seen several examples of unexpected harmful effects of micro nutrient supplementation. But the best example of a cost effective micronutrient intervention is vitamin A supplementation. Since vitamin A can be stored in the liver, it's possible to give a capsule with a high dose which can keep the body going for several month. And vitamin A supplementation has been shown to reduce case fatality among children with measles, and even all-cause mortality among healthy children. However, studies have also shown that vitamin A supplementation of HIV positive women may actually increase mother to child transmission of HIV. Iron is important for pathogens. So the host organism has mechanisms in place to keep iron away from invading pathogens. But these so called iron withholding mechanisms may be impaired during under nutrition and overruled by administration of doses of iron, especially if given by injection. But even when given as a tablet with only the daily requirement of iron. In fact, an iron supplementation trial was stopped because of an increased infectious morbidity and mortality. The World Health Organization has therefore revised their recommendations and now advise caution when giving iron supplements to children in malarious areas. Zinc is a very different nutrient. In contrast to vitamin A and iron, there are no body stores of zinc, so we need it almost daily. Even where zinc deficiency is widespread, and supplementation has been shown to reduce the risk of diarrhea and pneumonia, supplementation is not the way forward to address deficiency. In contrast, children who already have diarrhea may benefit from zinc supplementation for a couple of weeks, as it reduces severity and duration of diarrhea. And this is now recommended by the World Health Organization. Obviously patients with TB or HIV who are often wasted need more than micronutrients, they need food. We have estimated that adult TB patients on average have lost ten kg of weight. And compared to starvation, TB and HIV may lead to a greater loss of lean mass, which is muscles and organ tissues. Nutrition was, for many years, the backbone of TB treatment. But the interest in nutrition declined, at least among the medical profession, with the discovery of effective anti-TB drugs, some 50 years ago. A paper reflecting this paradigm shift and even contributing to it, was based on a famous study conducted in Madras, now Chennai, India in the late 1950s. The patients were randomized to receive TB treatment, either at home, where their diet was poor, or at a sanitorium, where the diet was better. Since the bacteriatical response after 12 months was acceptable in both groups, the authors concluded that chemotherapy can be successful even if the dietary intake is low. Interestingly the authors actually report that clearance of bacteria seem to be delayed in those on the poor diet, and as you can see on this slide, weight regain was considerably lower. Today many programs providing treatment for TB patients, or for HIV patients ,completely neglect the poor nutritional status of their patients. Patients can get drugs on an empty stomach but clinicians see their patients gaining some weight and conclude that the drugs resolve any nutritional problems the patients might have. Is that correct? No. The patient may have lost, say, 10 KG of not only fat, but also lean tissues which have to be rebuilt. So the nutritional requirements are very very high during convalescence. And what happens if requirements are not met? Well, if there's a lack of energy, then the patients will have an inadequate weight gain. If theres a relative lack of micronutrients and protein, then the patients will store the energy as fat rather than rebuilding muscle and tissues. The consequence is that the patients will not recover functionally in terms of physical activity working capacity and immunity. And they may have an increased risk of dying or they may have an increased risk of diabetes, which again, is a risk factor for TB relapse. Where nutritional support offered, it may be a bag of maize and some oil or as shown here corn supplements, which has to be made into a porridge. Or even various lipid based nutrient supplements based on peanut butter developed for small children with acute malnutrition. That's all fine and highly appreciated by the patient, but it's not good enough. There's a need for a research-based approach. We need quality supplements that match the nutritional requirements, support regain of the tissues that have been lost, and optimize functional recovery. Ideally, we need a supplement with effects on a range of infection's specific and general outcomes. With HIV, as an example, we may see effects of nutritional support on the natural history of the infection such as transmission & progression, and risk of opportunistic infections, and we may see effects on adherence and on drug efficacy, safety, and resistance. Furthermore, nutritional supplementation may have equally important general effects related to health and human capital. Unfortunately only few food supplementation trials among TB and HIV patients have been conducted. And they all have serious limitations with respect to design and choice of outcomes. So we don't have any evidence-based interventions to recommend. And the question is not only what to give, but also, when to give it. While I've just argued that there are high requirements after treatment start, it might be beneficial to delay supplementation a bit, or increase it slowly. Why is that? Well, there are two reasons. At the start of treatment TB and HIV patients may still have low appetite as part of the acute phase response, the inflammation. Maybe the low appetite serves a purpose. If we give too early we may favor the pathogen rather than the host, which may not be able to use the nutrients efficiently and instead deposit it as fat. Besides, re-feeding may result in multi-organ failure and death referred to as the re-feeding syndrome. And there are very interesting data from Zambia suggesting that HIV patients When receiving antiretroviral treatment, ART, and starting to eat again, may be at risk of a re-feeding like syndrome. With Ethiopian collaborators, we tested this lipid based nutrient supplement among Ethiopian HIV patients, based on one used for children with acute malnutrition. But modified for [INAUDIBLE] patients and pretested for [INAUDIBLE]. Each patient would take two of these sachets per day providing 4200 Kilojoules for three months. A control group received the same supplement for the same duration but with three months delay. So, we are able to assess the effect of early supplementation compared to no supplementation. And of early compared to delayed supplementation. What we hope to see is a convincing effect not only on weight gain, but especially on gain of lean mass, as well as on immune recovery and functional outcomes. With the result from this trial, we hope it will finally be possible to have evidence based nutritional recommendations for HIV patients starting ART. Thanks for your attention.