Essential trace elements and progression and management of HIV-1 infection

Essential trace elements and progression and management of HIV-1 infection

Journal Pre-proof Essential trace elements and progression and management of HIV-1 infection Keneil K Shah, Rebeka Verma, James M Oleske, Anthony Sco...

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Journal Pre-proof Essential trace elements and progression and management of HIV-1 infection

Keneil K Shah, Rebeka Verma, James M Oleske, Anthony Scolpino, John D Bogden PII:

S0271-5317(18)31297-1

DOI:

https://doi.org/10.1016/j.nutres.2019.08.001

Reference:

NTR 8037

To appear in:

Nutrition Research

Received date:

13 November 2018

Revised date:

25 July 2019

Accepted date:

1 August 2019

Please cite this article as: K.K. Shah, R. Verma, J.M. Oleske, et al., Essential trace elements and progression and management of HIV-1 infection, Nutrition Research(2019), https://doi.org/10.1016/j.nutres.2019.08.001

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© 2019 Published by Elsevier.

Journal Pre-proof Essential trace elements and progression and management of HIV-1 Infection

Keneil K Shah a, Rebeka Verma a, James M Oleske b, Anthony Scolpinob, and John D Bogdenc, * Rutgers New Jersey Medical School students a, Department of Pediatrics, Rutgers New Jersey Medical School b, and Department of Microbiology, Biochemistry, & Molecular Genetics, Rutgers New Jersey Medical School, Newark, NJ c

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To whom correspondence should be addressed at: [email protected]

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*

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Abbreviations AIDS: Acquired Immune Deficiency Syndrome: CD4; cluster of differentiation 4 HAART; Highly Active Anti-Retroviral Therapy

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HIV; Human Immunodeficiency Virus

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Journal Pre-proof Abstract This review was written to update the Review that we published in Nutrition Research in 2007 by examining studies published in the last eleven years, which describe the effects of trace mineral deficiencies and micronutrient supplementation on Human Immunodeficiency Virus (HIV) infection and its progression. In addition, we included studies that explore the interactions between Highly Active Anti-Retroviral Therapy (HAART) and micronutrient nutrition, focusing on the essential trace minerals. This review summarizes the results described in relevant articles that were identified by literature searches conducted using the OVID Medline database. Four of

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the nine essential trace minerals, specifically chromium, iron, selenium, and zinc, can influence

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HIV progression and/or its treatment. Notably, copper-containing filters may prevent transmission of the HIV virus via breastfeeding. However, there a lack of good evidence to date

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that fluoride, iodine, manganese, or molybdenum influence HIV infection. Recent studies reveal that HAART can alter serum trace mineral and vitamin concentrations, but the effects vary based

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on the medications used. Although they have contributed useful new data, the sample sizes for

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most of these studies was too small to draw definitive conclusions to introduce changes in the management of HIV infection. Larger studies are needed to better define the roles of trace

infected patients.

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mineral and vitamin deficiency and supplementation in the management and treatment of HIV-

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Keywords: Review, HIV, AIDS, Malnutrition, Micronutrients, Trace minerals, HIV progression,

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Highly Active Anti-Retroviral Therapy (HAART)

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1. Introduction: 1.1 HIV and Malnutrition Globally, about 37 million individuals were living with Human Immunodeficiency Virus (HIV) infection in 2017 [1]. Many of the HIV-infected individuals, as well as a substantial fraction of new infections, occur in adults living in Eastern and Southern Africa. Globally, the incidence of HIV infections has decreased annually and was approximately 1.8 million in 2016, a decrease from approximately 3.0 million in 2000. The number of individuals with access to Highly Active Antiretroviral Therapy (HAART) has increased – 21.7 million in 2017 -, which is an impressive

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increase from 685,000 in 2000 [1]. Despite substantial efforts and successes in prevention and

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management of HIV, as many as 1 million people die from AIDS-related complications annually [1]. A large proportion of the population in Eastern and Southern Africa is also further impacted

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by undernutrition, and more than one third of children under the age of 5 living in this region

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have stunted growth [2]. There is a significant geographic overlap between the incidence of HIV infection and undernutrition, as seen in Figures 1 and 2 [2,3]. Both HIV infection rates and

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undernutrition can be attributed to the socioeconomic and political status of the geographical region, as there is substantial evidence that nutritional deficiencies adversely affect a patient’s

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disease course. Many people in Africa are caught in a perpetual cycle in which low birth weight and micronutrient deficiencies in infancy lead to stunted growth and reduced mental capacity and

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productivity as an adolescent. In turn, this leads to frequent, chronic infections and poor socioeconomic status as an adult, resulting in increased perinatal complications in offspring, and

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thus repeating the cycle [4]. Increasing food intake to meet the increased energy requirement of AIDS patients is complicated by the symptoms of HIV infection, such as lost appetite, oral sores, dysphagia, and the symptoms/side effects of HAART, such as nausea.

1.2 Objectives of this Review When we published our prior review [5] in 2007, recommendations using supplementation to correct micronutrient deficiencies were limited, as sufficient literature to inform such recommendations was not available. The objective of this narrative review is to update our 2007 review. This review summarizes key studies of the effects of essential trace minerals on HIV progression and management that were published in the last eleven years since the publication of our prior 4

Journal Pre-proof review on this subject. In addition, recent studies on the effects of HAART on serum micronutrient and vitamin levels, including the different effects of various anti-retroviral drugs, were reviewed.

1.3 Interdependence of Nutrition, HIV Infection, and Stage of Disease In response to undernutrition, the immune system undergoes a dramatic change. Moderate to severe protein-energy malnutrition (PEM) has been shown to diminish the host immune response against infection. Lymphoid cells around the spleen and within the thymus decrease in number,

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secondary to reduced lymphocyte proliferation and DNA synthesis. Most complement

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components, including C3, C5, and factor B, also exhibit decreased activity, thus resulting in

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impaired phagocytosis of bacteria [6].

The primary mechanism of micronutrient loss in HIV infection varies based on the stage of the

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patient’s disease. Primary HIV infection occurs 2-4 weeks after the patient has been exposed to

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the virus, and it is characterized by a flu-like illness with accompanying fever, vomiting, diarrhea, and anorexia [7]. The decreased food intake and increased nutrient loss leads to an

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acute loss of body stores of micro- and macronutrients. Further catabolic loss of macronutrients occurs as the patient is forced to meet higher energy requirements due to the increased metabolic rate that accompanies the infection. When the patient’s own carbohydrate and lipid stores are

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insufficient to meet those demands, gluconeogenesis occurs. Alanine and glutamine, among

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other amino acids, are mobilized from skeletal muscle under the influence of cytokines such as interleukin-1, which are released during active infection. These amino acids are then utilized as energy, leading to a net catabolic loss of protein. These acute losses are not significant in individuals who are in otherwise good health. The population at greatest risk of increased morbidity and mortality during primary HIV infection includes those who already have micronutrient deficiencies or lack access to an adequate diet [8]. This particular population is likely to suffer from worse outcomes, as the acute phase of infection is characterized by rapid viral replication and spread to multiple organs. Thus, a micronutrient deficiency at the onset of infection can dramatically reduce host defenses and facilitate HIV progression [9].

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Journal Pre-proof In the subclinical HIV-infected individual, micronutrient losses begin to occur as the virus slowly replicates, causing asymptomatic but significant changes throughout the host, including in the GI tract [10]. Asymptomatic HIV-associated enteropathy is characterized by villous atrophy and crypt hyperplasia of the mucosal lining of the small and large bowel, as well as increased T cell-mediated inflammation and impaired tight-junction function. This leads to increased permeability of the bowel lining and reduced absorption. A double-blind, randomized control trial of 38 Zambian adults examined the effects of supplementation with multiple micronutrients on small bowel architecture (crypt depth, villous height, and width; and villous perimeter and

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cross-sectional area per 100 µm of muscularis mucosa) in HIV-negative patients with

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environmental enteropathy (an asymptomatic disorder of chronic intestinal inflammation seen most frequently in malnourished individuals) and in patients with environmental enteropathy

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with superimposed HIV-infection. Of the 38 subjects, 18 received a supplement that included vitamins A, B, C, D, E, and K and all nine essential trace minerals, while the other 20 received

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placebos. Six of the 18 who received the micronutrient supplements were HIV-positive. In the

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HIV-negative patients, “large and significant increases in villous height, villous perimeter, and villous area” were observed; previous studies have suggested that villous height is inversely

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related to intestinal permeability. In the 6 HIV-positive patients, no such changes were seen, thus suggesting a pathophysiological process specific and unique to HIV infection [10].

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The final stage of infection, characterized as AIDS, occurs when the patient’s CD4 count falls

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below 200 cells/mm3. These patients are increasingly susceptible to opportunistic infections that lead to acute phase responses and enteric lesions, further reducing nutrient absorption.

A World Health Organization report recommended in 2003 that asymptomatic HIV-infected adults increase their energy intakes by about 10% in order to maintain body weight, whereas symptomatic HIV-infected adults would require a 20% increase to maintain body weight [11]. The recommendations on supplementing to correct micronutrient deficiencies were more limited, as sufficient literature had yet to exist in 2003.

Optimal management of HIV-1 infection requires careful attention to the nutritional status of a patient, including micronutrient nutrition. Because of the constant cellular turnover and very 6

Journal Pre-proof large number of immune cells, the immune system requires a substantial quantity of micronutrients. Immunity and micronutrients have an interdependent relationship in which a deficiency of a micronutrient can prevent a proper response to an infection, while conversely, an infection can negatively impact micronutrient nutritional status [12].

All of these factors emphasize the need for clinicians to consider nutritional health and nutrient supplementation when indicated by disease state in order to improve the care of patients with HIV infection and delay the progression of symptoms and physiological impact, thus improving

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the overall quality of life. The primary therapeutic intervention to address these deficiencies is

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supplementation of deficient nutrients. Successful therapy not only requires continued access to the supplements but also adequate education of individual patients for whom supplements are

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prescribed.

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2. Approach

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The nine essential trace minerals are chromium, copper, fluoride, iodine, iron, manganese, molybdenum, selenium, and zinc. Of these, chromium, copper, iron, selenium, and zinc are

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shown to be necessary for maintaining good immune function.

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A literature search was conducted using the Ovid MEDLINE database. The following search queries were used to retrieve the studies analyzed in this paper: (HIV OR HIV-1 OR HIV

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infections) AND (micronutrients OR chromium OR selenium OR copper OR iron OR zinc OR fluoride OR iodine OR manganese OR molybdenum), and (Antiretroviral Therapy, Highly Active) AND (micronutrients). Searches were limited to articles published between 2007 – 2018.

3. The Essential Trace Minerals and HIV Infection 3.1 Chromium Chromium plays an important role in improving insulin resistance. Insulin mediates glucose uptake from skeletal muscles through a cascade of reactions. Insulin binds to the extracellular alpha subunit of the Insulin Receptor, leading to phosphorylation of the intracellular beta subunit, and thus activating the tyrosine-kinase domain of the receptor. The activated receptor 7

Journal Pre-proof then initiates a series of events that end with the translocation of vesicles containing glucosetransporter-4 from the cytoplasm to the cell surface, leading to glucose uptake. Laboratory studies involving rats injected with potassium chromate have demonstrated a significant and dose-proportional increase in insulin-dependent tyrosine kinase activity, consequently indicating its importance in glucose uptake [13].

Chromium deficiency was first described in diabetic patients receiving chronic total parenteral nutrition. In these patients, low serum chromium concentrations were associated with increased

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insulin resistance [14]. There have been several conflicting studies about whether chromium

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supplementation improves glycemic control in this patient population [15,16]. Given the adverse metabolic effects of certain anti-retroviral medications, such as protease inhibitors, chromium

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supplementation for HIV-infected individuals has also been explored.

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In a randomized double-blind clinical trial, 52 HIV-positive subjects with evidence of insulin

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resistance based on a homeostasis model of assessment (HOMA) calculation were randomized to receive either 400 µg/day of chromium-nicotinate or placebo for 16 weeks. The group given

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chromium supplementation demonstrated a significant decrease in HOMA score, insulin requirement, triglycerides, total body fat mass, and trunk fat mass compared to the placebo group. Although the trial had a small sample size, it nevertheless demonstrates that it may be

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advantageous to provide supplemental chromium to HIV-infected patients in order to reduce the

3.2 Selenium

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metabolic effects of antiretroviral medications [17].

Selenocysteine, is an amino acid at the active site for glutathione peroxidase [18]. Studies performed with rats demonstrate that the effectiveness of glutathione peroxidase in preventing ascorbate and H2O2-induced hemoglobin oxidations is dependent on the presence of selenium in the hemolyzate [19].

Dietary selenium is known to have an important role in maintaining host immune competence, as it is essential to the formation of the antioxidant glutathione peroxidase [20]. Selenium deficiency has been linked to reduced immune function and increased susceptibility to viral 8

Journal Pre-proof illness. The causes of selenium deficiency are multifactorial, but among them is low dietary consumption because of low selenium levels in soil, particularly in sub-Saharan Africa [21]. In our previous review article, we discussed several studies that suggested better outcomes with selenium supplementation in patients with advanced HIV infection. Until recently though, studies had not been performed on recently-infected, HAART-naïve subjects.

In one recent double blinded, placebo controlled, randomized clinical trial of 300 HAARTnaïve, HIV-infected individuals in Rwanda, the effects of selenium on the rate of CD4 decline,

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viral suppression, and morbidity were monitored. Subjects were divided into two groups and

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given either a daily tablet containing 200 µg of selenium or a placebo over a 24-month period. The recommended dietary allowance (RDA) of selenium is 20-70 µg, depending on patient age.

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During the 24-month period, the rate of CD4 decline was reduced by 43.8% [7.1-79.8%] in those who were given selenium, decreasing from an average of 3.97 cells/µL per month to 2.23

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cells/µL per month. Although this was a small study with limited statistical power, it provided

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evidence that selenium supplementation can slow the progression of HIV infection [22].

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Another study published in JAMA [23] also sought to determine whether micronutrient supplementation, specifically with selenium and vitamins B1, B2, B3, B6, B9, B12, C, and E, can slow HIV disease progression in the early stages of infection in HAART-naïve patients. This

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randomized, double-blind clinical trial involved 878 HIV-infected, HAART-naïve adult subjects

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in Botswana with a CD4 count greater than 350 cells/µL. These subjects were divided into 4 groups and administered either a daily supplement of 200 µg selenium + vitamins, 200 µg selenium alone, vitamins alone, or a placebo. The trial demonstrated that the group that received the selenium + multivitamins, as compared to the placebo group, had a significantly reduced risk of developing a CD4 count of < 250 cells/µL. In addition, subjects in the selenium + multivitamin group, when compared to those in the placebo group, had a reduced risk of suffering from the clinical manifestations of AIDS-related conditions and AIDS-related death. There was no statistically significant difference in any outcome for subjects in the selenium only group and the multivitamin only group, when compared to those in the placebo group. These results indicate that selenium plays an important role in maintaining the immune system, much like the previous study. However, in this study, selenium was effective in preventing a decline in 9

Journal Pre-proof CD4 cell counts only when administered along with a multivitamin. Although the outcomes of the above two studies differed, they reveal the potential benefits of selenium, either with or without supplementation with other micronutrients, in individuals at early HIV stages of infection [23].

3.3 Copper Copper is a micronutrient essential to processes involving energy production, such as the functioning of cytochrome c oxidase, which facilitates ATP production in the mitochondrial

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electron transport chain. It also plays a role in cellular defense against reactive oxygen species,

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as do selenium and iron. Superoxide dismutase, an antioxidant responsible for converting the superoxide radical O2- into H2O or H2O2, requires copper to be effective. Furthermore, copper

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deficiency impairs neutrophilic response to infection and decreases the total number of neutrophils present [24]. Impaired macrophage function (respiratory burst, candidacidal activity)

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in copper-deficient rats has also been observed [25].

Our previous review article summarized several investigations that revealed elevated serum

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copper concentrations in patients with HIV-1 infection. This is an expected finding, as copper is an acute phase reactant that is found incidentally to be elevated in a variety of inflammatory conditions and infectious diseases. Thus, measuring serum copper cannot provide a definitive

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assessment of copper status. Two recent studies have, however, investigated the use of copper

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filters to prevent transmission of HIV via blood or breast milk. Copper is known to have viricidal activity and has been shown to effectively inactivate HIV virus [26]. In one study, Borkow et al. examined the capacity of filters containing copper oxide powder or copper oxide-impregnated filters in inactivating HIV-1 in medium. They found that HIV in medium was inactivated in a dose-dependent manner [27]. Four years after that initial study, Borkow et al [28] published another proof of concept study testing HIV transmission from breast milk through a copper oxide filter. Twenty breastmilk samples were taken from HIV-seropositive, HAART-negative women between birth and 8 weeks postpartum. The breast milk was passed through the copper oxide filter and HIV growth was cultured. Of the 20 samples, growth was obtained from only 4; andin those 4 samples, a >99% reduction in infectious viral titers was observed. The results of this

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Journal Pre-proof small study suggest that filters imbued with copper may be used to prevent transmission of HIV via breastfeeding.

3.4 Iron Iron is an essential micronutrient that is required for the development of antioxidants designed to combat reactive oxygen species. Catalase is an iron-dependent enzyme found within the peroxisome of a cell that catalyzes the reaction of H2O2 into water and oxygen. Iron is also required for the production of the microbiocidal hypochlorous acid. An iron deficiency has been

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shown to decrease overall serum T lymphocyte concentrations and phagocytosis by

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polymorphonuclear cells [29].

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In our previous review, we explored the relationship between anemia and the progression of HIV infection. HIV-infected patients were found to have some combination of both iron deficiency

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anemia (likely secondary to malabsorption) and anemia of chronic disease (due to the HIV

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infection), as indicated by elevated serum ferritin concentrations [30].

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Since that review, several studies have examined the relationship between hepcidin levels and progression of HIV infection. Hepcidin plays a major role in iron regulation and functions by breaking down the iron export protein ferroportin, thus facilitating the sequestration of iron

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within the cell. Wisaksana examined hepcidin levels in an Indonesian cohort and determined that

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serum hepcidin levels were significantly elevated in those with advanced HIV infection, likely secondary to HIV-associated inflammation. In contrast, HIV-infected individuals without any major comorbidities like tuberculosis and those with serum CD4 counts > 200 cells / µL had serum hepcidin levels similar to that of healthy patients. The authors suggest that elevated hepcidin can result in iron trapping within macrophages, thus leading to increased susceptibility to intracellular infections [31]. Malvoisin analyzed serum hepcidin levels in 182 HIV-infected women on HAART therapy and found a significant association between higher serum hepcidin levels and CD4 counts < 500 cells / µL. Hepcidin levels were considerably elevated in HIVinfected patients with high viremia. In HIV-infected patients with an undetectable viral load, however, serum hepcidin levels were found to be lower than those of healthy controls. The authors inferred that patients with the low viral loads may have been suffering from primary iron 11

Journal Pre-proof deficiency anemia, thus downregulating hepcidin. Those patients with severely elevated viral load, had abnormally elevated serum hepcidin due to the chronic inflammation and preferential intracellular sequestration of iron [32]. In our 2007 review, we noted that previous studies had shown that iron chelation therapy can decrease HIV transcription [5]. Another study analyzed the effects of ferroportin and hepcidin on HIV-1 transcription. This “in vitro” study showed that expression of ferroportin on 293T cells led to reduced HIV transcription, and subsequent addition of hepcidin reversed this effect. Further, exposure of human macrophages to hepcidin

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and iron led to increased viral production [33].

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The effects of additional iron supplementation were investigated in cohorts of HIV-infected children in Malawi and India. In the Malawian cohort, children receiving iron supplementation

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were found to have greater increases in hemoglobin concentration and reduced risk of anemia for up to 6 months of follow-up. Further, there was an improved CD4 response at 3 months. There

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was, however, an increased incidence of malaria in the iron supplementation group after 6

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months. The authors concluded that iron supplementation for HIV-infected children should be considered, with the stipulation that those who live in malaria-endemic regions should receive

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adequate protection from malaria [34].

Perinatally infected Indian children, between the ages of 2 and 12, were enrolled in a study

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conducted by Shet [35]. When compared to the control group, children in the treatment group

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who received iron supplementation were found to have a modest increase in median hemoglobin levels from 10.4 to 10.9 over a 3-month span, with a peak of 11.3 mg/dl after 6 months. There was no significant association of iron supplementation with improvement in growth, markers of inflammation, and CD4 counts, after adjusting for the effects of HAART. There were no major adverse effects associated with iron supplementation, and thus, the authors concluded that iron therapy should be considered in iron deficient children, for a duration of no more than 6 months and with sufficient monitoring of effectiveness.

3.5 Zinc Zinc plays a prominent role in cellular immunity. TNF-alpha and IL-1ß are inflammatory cytokines produced by activated macrophages and monocytes that generate reactive oxygen 12

Journal Pre-proof species [36]. An effect of zinc supplementation in healthy adults is a decrease in the production of the oxidative-stress related byproducts malondialdehyde, 4-hydroxyalkenals, and 8hydroxydeoxyguanine, as well as tumor necrosis factor (TNF) alpha and IL-1β [37]. Zinc deficiency, which can occur due to insufficient dietary intake, malabsorption, or chronic illness, can cause a variety of adverse effects, including depressed immunity, impaired host defense, diarrhea, and alopecia [38]. Previously, we identified studies that suggested that zinc deficiency is associated with decreased HIV survival, but with little to no positive effect of zinc supplementation on HIV progression. A recent study conducted by Martinez [39] examined the

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effects of low serum zinc on HIV-infected patients afflicted with comorbid liver disease. Nearly

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25% of HIV patients are co-infected with hepatitis C, which results in an accelerated progression to liver cirrhosis and hepatocellular carcinoma [40,41]. In this study, 487 HIV-mono-infected

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and HIV-HCV co-infected individuals were given blood draws periodically to measure plasma zinc and mitochondrial DNA 8-hydroxyguanosine levels to determine their relationship to

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oxidative damage and to calculate fibrosis-4 (FIB-4) scores to determine progression of liver

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disease. The authors concluded that lower plasma zinc levels were associated with increased mitochondrial oxidative stress and accelerated progression of liver fibrosis [40]. Poudel

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examined serum zinc and C-reactive protein (CRP) levels to study the role of zinc in inflammation of HIV-infected patients on HAART therapy. They found that higher concentrations of serum zinc were significantly associated with lower levels of inflammation, as

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indicated by a low serum CRP, but the results were not statistically significant [42]. A limitation

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of using serum zinc to assess zinc status is that various infectious and inflammatory diseases reduce serum zinc to levels below the normal range, however this effect is not a reliable indicator of the presence of zinc deficiency.

The effects of zinc supplementation of HIV-infected patients appear to be inconsistent, a result unchanged from our previously reported conclusion in 2007. A double-blind, case-controlled trial was performed in India in which HIV-infected children greater than 6 months of age and on HAART were assigned to receive 20 mg zinc or a placebo daily for 6 months. The authors found no significant difference in CD4%, viral load or overall morbidity [43]. However, another study of HIV-infected adults on HAART with immunological discordance (patients on HAART with CD4 count < 200 cells/µl despite viral load < 40 copies/mL) conducted in Thailand demonstrated 13

Journal Pre-proof a statistically significant increase in CD4 count with zinc supplementation in those with zinc deficiency, compared to controls [44]. The conflicting results of studies on zinc supplementation suggest a need for additional carefully-designed clinical trials to clarify the effects of zinc administration on HIV-infection.

3.6 The Other Essential Trace Elements: There is little to no evidence to date that fluoride, iodine, manganese, or molybdenum influence

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3.7 Highly Active Anti-Retroviral Therapy (HAART)

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the progression of HIV infection.

When our initial review was written in 2006-2007, there were few studies examining the effects

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of micronutrient supplementation on HIV-infected patients undergoing HAART therapy. At that time, it was thought that the substantial effects of HAART initiation would overshadow the more

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subtle, but nevertheless important, benefits of improved micronutrient nutrition. Since then,

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several studies have been published examining the interactions between nutritional support and the effects of HAART. Flax et al. [45] examined the association of micronutrient-fortified lipid-

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based nutrient supplements (LNS) and protease inhibitor-centric HAART therapy on micronutrient concentrations of HIV-infected pregnant Malawi women. The LNS included copper, iodine, iron, selenium, and zinc, as well as several vitamins including B12 and folate [45].

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They found that HAART compromised the expected increases in serum levels of folate or

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vitamin B12. However, patients exhibited elevated retinol-binding proteins, indicating improved vitamin A status after HAART. LNS alone had no significant effect on ferritin, transferrin receptor, or hemoglobin in this study, whereas an increased concentration of transferrin receptor was reported in the group receiving HAART alone, indicating some worsening of iron deficiency due to HAART, as compared to baseline. No other significant changes to micronutrient concentrations were identified as a result of HAART initiation [46]. This study focused on only protease inhibitor-centric HAART, and, depending on which therapy is used, different effects may be observed with other treatment protocols. Abdissa explored the effects of LNS on an Ethiopian cohort at initiation of HAART with either efavirenz or nevirapine [47]. They found that LNS supplementation led to significantly decreased serum levels of nevirapine compared to no LNS supplementation. No such effect was seen in patients taking efavirenz. This suggests that 14

Journal Pre-proof nutrient supplementation of patients given some HAART drugs may compromise the effectiveness of their treatment.

4. Knowledge Gaps and Future Research There is a substantial and urgent need for further research on micronutrient nutrition in HIVinfected patients. Studies upon the effects of micronutrient supplementation during HAART therapy have only recently beagn. Currently, only the one publication by Abdissa [47] describes

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the effects of micronutrient supplementation on serum drug levels of efavirenz and nevirapine. Given that we already know that the other types of HIV medications possess class-specific side

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effects, further studies should be performed on the interactions between micronutrient

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supplementation and HAART therapy with other drugs, in addition to efavirenz and nevirapine. If it were determined that certain combinations of drugs have different effects on some

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micronutrients, this research could prove to be very important in selecting a medication regimen

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for an individual patient. For instance, if a specific HAART drug were found to significantly lower serum zinc, a patient with a zinc deficiency could be treated with another medication.

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Nearly all the data we currently have with regard to the effects of micronutrient supplementation on HIV infection was obtained from randomized-controlled trials performed in Africa. Though

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they have contributed useful data, the sample sizes for most of these studies have been too small

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to support the definitive conclusions required to make changes in the management of HIV infection. Larger studies of HIV-infected individuals are needed to more accurately define the role of trace nutrient supplementation. Finally, future studies should stratify HIV-infected subjects by CD4+ count to determine whether differences exist in the effects of micronutrient supplementation based on severity and stage of disease.

5. Conclusion This review summarizes key studies on the effects of the essential trace minerals on HIV progression and management that were published in the last eleven years, since the publication of our prior review of this topic. The effect of trace element deficiency and poor nutrition status on HIV is illustrated in Figure 3. Chromium, iron, selenium, and zinc can influence HIV 15

Journal Pre-proof progression and facilitate its treatment. Copper-containing filters may prevent transmission of the HIV virus via breastfeeding. However, there is no good evidence to date that fluoride, iodine, manganese, or molybdenum affect HIV infection.

In addition, recent studies have shown that HAART does affect some serum trace mineral and vitamin levels and that differences exist based on which medications are used, thus indicating the need for further studies on this topic. There is a complex interaction that occurs between patient nutritional status and HAART when HIV-infected patients are first started on the latter.

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Therefore, anti-retroviral therapy should always be accompanied by careful monitoring of a

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patient’s nutritional status at the onset of therapy and throughout treatment, in order to enable the best patient outcome. This should include a careful analysis of the impact of nutritional

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supplementations of all types when used in HIV-infected populations for possible interaction with the anticipated progressive use of established, as well as newly developed HIV, treatment

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regimens. While appropriate attention to nutrition in HIV disease is critical, nutritional

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supplementation needs to be studied, for both the benefits as well as possible inadvertent adverse

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consequences, during the complex treatment of HIV infection.

In general, good nutritional status improves the health of children and adults with HIV infection. Furthermore, proper nutrition is also vital for children’s growth and development. Multiple

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nutrients, both macronutrients and micronutrients, are required by the immune system. HIV

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infection may worsen nutritional status and poor nutrition may accelerate the progression of HIV

This narrative review/update differs in approach and scope from a 149-page “systematic review”, entitled “Micronutrient Supplementation in Adults with HIV Infection”, that was published in 2017 in the Cochrane Database of Systematic Reviews. This current review focuses on the nine essential trace minerals, while the micronutrients discussed in the Cochrane review focused on 11 of the 14 essential vitamins. Although the Cochrane review includes discussion of the essential trace minerals, this includes content on only three of them: iron, selenium, and zinc, with limited or no coverage of the other six trace minerals. Despite the differing approaches and scope, the major conclusions of the two reviews are very similar; specifically two points. First, 16

Journal Pre-proof supplementation of HIV- infected patients with single or multiple micronutrients can cforrect micronutrient deficiencies, especially in the many patients with access to insufficient food or poor diets, but it does not consistently improve treatment outcomes. Second, the number of subjects enrolled in studies on the effects of micronutrient supplementation, including studies of patients receiving anti-retroviral drug therapy, have not included enough patients to evaluate

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their impact on the major long-term outcomes of morbidity and mortality.

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Acknowledgment

Funding for review this review was provided in part by various grants awarded to one of the

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authors, JM Oleske. Shruti Niravane, a graduate student, conducted one of the literature searches.

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The authors declare no conflict of interest.

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Journal Pre-proof References:

1. Joint United Nations Programme on HIV/AIDS. Global HIV & AIDS statistics – 2018 fact sheet. http://www.unaids.org/en/resources/fact-sheet. Accessed May 17, 2019.

2. United Nations Children’s Fund. Malnutrition. https://data.unicef.org/topic/nutrition/malnutrition. Accessed May 20, 2018.

3. World Health Organization. Global Health Observatory Data: HIV/AIDS. http://www.who.int/gho/hiv/en. Accessed June 20, 2018.

4. Bailey R, West Jr. K, Black, R. The epidemiology of global micronutrient

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deficiencies. Annals of Nutrition and Metabolism 2015; 66: 22-33.

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in adults with HIV infection. Cochrane Database of Systematic Reviews 2017; Issue 5: 1-147, Art. No. CD003650

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FIGURE 1: Percentage of children under 5 with stunted growth in 2017 [2]. The percentages range from < 5% in the United States and Australia to > 40% in some African and Asian

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countries. For many countries, including Argentina, Canada, Russia, and several countries in

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Africa, Asia, and Europe, there is no data available for 2017.

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FIGURE 2: Prevalence of adults infected with HIV by WHO region in 2017 [3]. Data are provided as percentages and range from 0.1% in the Eastern Mediterranean and Western Pacific

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to 4.2% in most of Africa. The estimated global prevalence is 0.8%.

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FIGURE 3: The cycle of macronutrient and micronutrient deficiency in HIV infection as

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presented herein. Other nutrients that influence nutritional status and infection include vitamins and some phytochemicals. Nutrient deficiency will compromise the immune system and

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increase risk of infection.

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Journal Pre-proof Highlights Chromium, iron, selenium, and zinc, influence HIV progression and/or its treatment.

Copper-containing filters can prevent transmission of the HIV virus via breastfeeding.

Larger studies are needed to better define the role of trace mineral and vitamin supplementation

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in the management and treatment of HIV-infected patients.

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