HIV and Nutrition

The first case of human immunodeficiency virus (HIV) was reported in 1985. The global burden of the disease is approximately 38 million, with 67% of those affected living in impoverished sub-Saharan Africa, where malnutrition is rampant because the daily household income is less than 1 US dollar per day. The progression of the disease and death from AIDS reached an incredible 72% in 2008. New cases of HIV globally peaked at 3.16 million in 1999 and have gradually decreased to 1.94 million in 2017. ^[1]  According to UNAIDS, at the end of December 2020, 27.5 million people were accessing antiretroviral therapy, up from 7.8 million in 2010, but the global population continues to get infected. HIV is contracted during early adulthood in a lot of developing countries; this also results in difficulty in procuring food because many of those affected are the sole bread winners for their family and themselves.

Note the chart below. ^[1]

HIV causes significant immunosuppression in the infected individual. Weight loss of more than 5% with concomitant HIV infection is associated with accelerated disease progression, impaired functional status, and increased mortality. ^[1]  Malnutrition in individuals with HIV is not only a problem in low income countries but also in developed countries. Several analyses have shown accelerated mortality (< 6 months) with initiation of Antiretroviral therapy (ART) if the patient's body mass index (BMI) was less than 18. ^{[2, 3]} A BMI of less than 16 is associated with a 2-fold increase in death if the HIV patient is also on ART.

The relationship between nutrition and HIV infection is very complex and is modified by factors such as nutritional status, including wasting or obesity, and micronutrient deficiencies along with HIV disease stage. Starting assessment, counseling, and education regarding nutrition shortly after HIV diagnosis is imperative. Good nutrition has been proven to increase resistance to infection and disease and improves energy. Severe malnutrition in HIV-infected persons is recognized as the “wasting syndrome,” defined by the Centers for Disease Control and Prevention (CDC) as a body weight loss equal to or greater than 10% with associated fatigue, fever, and diarrhea unexplained by another cause. ^[4]

Mehta et al (2008), in his study on pregnant HIV-infected women in Africa, noted that having a BMI of less than 21.8, a hemoglobin concentration of less than 8.5 g/dL, and weight loss or excessive weight gain during pregnancy was associated with adverse outcomes. ^[5]

Weight loss incurred in adults with HIV is multifactorial. Protein energy malnutrition is the most common form of malnutrition seen in patients with HIV disease worldwide. It is marasmus predominant and results in T-lymphocyte function and number depression numbers, ^[6] along with impaired complement activation resulting in further health embarrassment.

Tumor necrosis factor alpha (TNF), IL-6, and IL-1 beta elevated levels have been implicated in HIV-mediated cachexia. ^[7] Both in combination cause appetite suppression by affecting the hypothalamus via serotonergic pathways and accelerated proteolysis, causing skeletal muscle break down by activating the ubiquitin proteosome pathway. ^[8] Since anaerobic glycolysis is preferred in infection, lactic acid accumulation occurs, which can lead to appetite suppression. TNF also works by inhibiting lipoprotein lipase, which results in depletion of fat stores and further wasting.

Micronutrient deficiencies affect replication of the HIV virus, elevate hepatic protein synthesis, increased urinary nitrogen loss, insulin resistance with resultant hyperglycemia, and increased gluconeogenesis. This persistent hyperglycemia contributes to anorexia and weight loss. ^[9]

Malnourished patients also exhibit delayed cutaneous sensitivity, reduced bactericidal properties, ^[10] and impaired serological response after immunizations. During infections, reactive oxygen molecules and prooxidant cytokines are released from activated phagocytes, ^[11] leading to increased consumption of vitamins like vitamin E and C, and β -carotene, which serve as antioxidants and minerals like zinc, copper, manganese, and selenium, which serve as components of antioxidant enzymes. ^[12] Deficiencies of antioxidants cause increased oxidative stress, which leads to apoptosis of T cells and indirectly compromise cell-mediated immunity and may stimulate HIV replication.

Deficiencies of water-soluble vitamins appear to occur less frequently than those of fat-soluble vitamins, and only cobalamin (B12) deficiency is associated with HIV disease progression. ^[13] Zinc levels decline as HIV disease progresses, and zinc supplementation in HIV infection has been shown to improve immune responses, although clinical benefits have not been documented. Selenium supplementation trials in HIV-infected individuals failed to demonstrate improvements in CD4+ T-cell counts, rates of opportunistic infections, or mortality despite improvements in markers of oxidative stress. ^[14] Glutathione, an intracellular antioxidant, was noted to be reduced in children with HIV infection, especially those showing growth failure. ^[15]

In a recent study published by Koethe et al, an optimal BMI in the range of 25-30 was associated with the greatest increase in CD4⁺ T-lymphocyte count reiterating the need for appropriate nutrition in HIV patients prior to initiating ART. ^[16] Overnourishment, a disease of developed countries, resulting in obesity (BMI>30) has the same effects on the immune system as malnourishment. Immune dysregulation in obesity has been attributed to elevated leptin levels and leptin resistance, increased interferon gamma levels leading to depressed T-cell function. ^[17]

Vitamin A deficiency has been associated with the progression of HIV disease, development of secondary infections, increased HIV-associated mortality, and increased maternal-fetal transmission. ^[18] Fawzi and colleagues in a subsequent trial on pregnant women in Tanzania could not demonstrate reduced transmission of HIV virus to children born to mothers with HIV receiving Vitamin A supplementation in conjunction with multivitamins. ^[19] However, they did conclude that patients, in the multivitamin treatment arm, did have delay in progression of HIV. ^[20]

A complete workup includes a thorough dietary history, physical examination, and laboratory testing (see WHO guidelines for nutrition al assesment in HIV infected adults below). Other problems pertaining to food intake, for example nausea, dysphagia, gastroesophageal reflux, food security, and drug and food interactions, should also be considered. The stage of HIV should also be determined in accordance with the WHO criteria based on the history and physical examination. ^[21]

Baseline laboratory parameters required are a complete blood count, CD 4 count, plasma HIV RNA levels, lipid panel, serum albumin (results should be interpreted with keeping liver disease and sever illnesses in mind), transferrin, transthyretin, and prealbumin. Prealbumin is only useful for revealing short-term changes in nutritional status. Reductions in plasma HIV RNA levels from a patient's baseline have been associated with increased muscle mass.

WHO guidelines for nutritional assesment in adults with HIV

With regard to nutrition assessment:

• Measure weight, weight change, height, BMI, and mid upper-arm circumference (MUAC).

• Assess appetite, difficulty swallowing, nausea, diarrhea, and drug-food interaction effects.

• Assess household food security.

With regard to malnutrition:

• Mild to moderately malnourished adults (BMI < 18.5 kg/m2), regardless of HIV status, should receive supplementary feeding. Usually, fortified blended foods, such as corn-soya blend (CSB), are provided, but compressed bars or biscuits and lipid-based nutrient supplements (pastes) may also be used.

• Severely malnourished adults (BMI < 16 kg/m2) should receive a therapeutic food, nutritionally equivalent to F100.

• For initial treatment of severely malnourished adults aged 19 to 75 years, energy intake should be 40 kcal/kg/day; for initial treatment of those aged 15-18 years, energy intake should be 50 kcal/kg/day.

With regard to dietary intake:

• Energy intake in asymptomatic HIV infection should be increased by 10%.

• During infection, the aim should be to reach the maximum achievable intake of 20-30% above normal intake; during the recovery phase, intake should be increased to the maximum extent possible.

• Multivitamin supplements should be started.

Prevention of weight loss in patients with HIV can be done in the following 2 ways, in addition to ART initiation:

1. Dietary treatment coupled with exercise

2. Use of pharmacologic therapy

Dietary Treatment

Oral supplements in the management of patients with malnutrition and HIV prevented weight loss by increasing fat–free mass. ^{[22, 23]} The effect of combined oral nutritional supplements and nutritional counseling on whole-body protein metabolism was assessed and compared to control group; whole body protein catabolism measured by leucine oxidation rates were shown to be lesser, and a favorable change in body composition with increased lean body mass and decreased fat mass occurred in the intervention group compared to controls at 12 weeks. ^[24]

In patients with HIV infection and in the early stages of AIDS without a secondary infection, weight gain and/or maintenance has been shown to be achievable with a high-energy, high-protein diet (1.5 g/kg ideal body weight), including at least one oral liquid nutrition supplement in conjunction with nutrition counseling. ^[25] Patients who developed secondary infections in this study lost weight despite the use of supplements and counseling. ^[26]

Total parenteral nutrition and enteral feeding through percutaneous endoscopic gastrostostomy tube are options in advanced AIDS wasting not responding to medical nutrition therapy but have associated risks, and limited data exists in literature regarding its use in patients with HIV and AIDS.

Activity

A Cochrane database review of randomized controlled trials showed that aerobic exercise plays an important role in the care of adults living with HIV. Meta-analyses suggest that performing constant or interval aerobic exercise, or a combination of constant aerobic and progressive resistance exercises for at least 20 minutes 3 times per week for at least 5 weeks appears to be safe and may lead to improvements in selected outcomes of cardiopulmonary fitness (VO2max), body composition (leg muscle area, percent body fat), and psychological status (depression-dejection symptoms). ^[27]

Pharmacological Therapy

Anabolic steroids

Physiologic testosterone replacement has been shown to increase lean body mass and improve quality of life among androgen-deficient men with the AIDS wasting syndrome. In a randomized double-blinded placebo-controlled study of HIV-positive men with wasting and testosterone deficiency, patients receiving intramuscular testosterone enanthate therapy gained fat-free mass, lean body mass, and muscle mass compared to placebo.

The changes in weight, fat mass, total-body water content, and exercise functional capacity did not significantly differ between the groups. ^[28] In a meta-analysis including 6 randomized, placebo-controlled trials that compared the effects of testosterone therapy with placebo in HIV patients with wasting, testosterone therapy increased lean body mass more than placebo. The increase was greater if the therapy is given intramuscularly. ^[29]

A Cochrane database review included 13 Randomized controlled trials that compared the use of an anabolic steroid to placebo to treat weight loss in adults with HIV for change from baseline in lean body mass or in body weight as outcome measures. Although the results of the trials were heterogeneous, on average, the administration of anabolic steroids appeared to result in a small increase in both lean body mass (1.3 kg), and body weight (1.1 kg; 95% CI, 0.3 -  2.0) as compared with placebo, but, due to limitation in studies, no treatment recommendations could be made. ^[30] Studies for anabolic steroids in the HIV wasting syndrome are small and include bias, necessitating larger studies that define the patient subset for which anabolic steroids will be useful and whether it translates into improvement in physical function and survival. In the presence of hypogonadism, testosterone replacement should be given consideration.

Appetite stimulants

Megestrol is a synthetic oral progestin that has been widely used in advanced breast cancer and has been shown to stimulate appetite and cause non – fluid weight gain in advanced hormone nonresponsive cancers. In 1993, megestrol acetate was approved by the Federal Drug Administration for the treatment of anorexia, cachexia, or unexplained weight loss in patients with AIDS.

A review of randomized controlled trials, which are few, showed improved appetite and weight gain with use of megestrol, but, due to the small number of patients, methodological shortcomings, and poor reporting, recommendations regarding its use could not be made. ^[31]

Two randomized controlled trials of megestrol acetate therapy in patients with AIDS and weight loss resulted in improvement in appetite, weight gain, and patient perception of well-being at doses of 800 mg/day. Although lean body mass was reported to have improved, much of the weight gain was due to increase in fat mass. ^{[32, 33]} Long-term follow-up data regarding maintenance of weight, impact on morbidity, and survival is lacking.

Megestrol has been shown to bind to the glucocorticoid receptor and exhibit glucocorticoid activity with manifestations of hyperglycemia, suppression of hypothalamic-pituitary axis and adrenal insufficiency, and addisonian crisis after abrupt withdrawal reported in the literature. It has a greater potential for suppression of the hypothalamic-pituitary axis than manifestations of peripheral glucocorticoid activity. ^{[34, 35]} When discontinuing megestrol therapy, slow taper rather than abrupt stopping is suggested. The possibility of adrenal insufficiency should be considered in patients on long-term and high-dose megestrol therapy. These patients may require stress-dose glucocorticoid therapy at times of surgery and critical illness.

Growth hormone

Growth hormone (GH) is secreted by the anterior pituitary and acts via somatomedins and insulinlike growth factor-1 (IGF-1) to increase muscle growth. In patients with HIV, direct disruption of the GH/IGF-1 axis occurs by the HIV virus (gp-120), which suppresses GH release. This results in a catabolic state. ^[8] Moyle et al used recombinant growth hormone in HIV patients at doses of 6mg/day for 12 weeks with lean body mass increases of approx 5 kg in the treatment arm. Exogenous GH comes with an unfavorable side effect profile, which includes hyperglycemia, arthralgias, myalgias, and peripheral edema; the decision to use GH should be done on an individual basis.

Importance of regular follow-up to address medical, social, and emotional aspects of care of patients with HIV and wasting cannot be stressed enough. The frequency of follow-up and interventions will have to be decided on a case-to-case basis, and involving family and patient’s support system is greatly helpful.