Zinc Supplements in HIV Infection
February 1, 1998 6 minutes read
Zinc Supplements in HIV Infection
By E.P. Barrette, MD
Use of nutritional and vitamin supplements by HIV-positive patients is common. On the one hand, several studies suggest that use of vitamin E, vitamin C, B group vitamins, and possibly vitamin A may slow progression of HIV. Low serum levels of Vitamin B12 are seen in rapidly progressing disease, while high vitamin E serum levels are associated with a slower course. On the other hand, use of zinc supplements has been uniquely associated with poorer outcomes in HIV-positive patients.Introduction
Zinc is an essential mineral. Zinc deficiency has been seen in patients receiving early formulations of TPN devoid of zinc, in Wilson’s disease patients receiving penicillamine, and in patients with chronic malabsorption (e.g., celiac sprue or cystic fibrosis). Though overt zinc deficiency is felt to be rare, clinical manifestations may include dermatitis, diarrhea, immune dysfunction, and failure to thrive. Zinc supplements have been recommended for acne, diabetes, hypertension, peptic ulcers, benign prostatic hyperplasia, and other conditions in doses up to 45 mg/d. A recent study of zinc gluconate lozenges for the common cold awakened popular interest in zinc last winter.1
The most recent recommended dietary allowances, or RDAs (1989, 10th edition, National Academy Press), of elemental zinc suggest 15 mg/d for adult males, 12 mg/d for adult females, and 15-19 mg/d during pregnancy and lactation. Normal serum values for zinc are 11.5-18.5 mmol/dL (75-120 mg/dL).
RDAs do not attempt to define the optimal daily allowance; complementary practitioners may quote "suggested optimal daily nutrients allowances" (SONAs) of 15-20 mg/d. Complementary practitioners argue that RDAs are inadequate and do not take into account diet, alcohol use, stress, or smoking. The typical American diet may only provide 10 mg of zinc daily.
History
The introduction of antiretroviral therapy for AIDS did not occur until late 1986, and, with limited conventional therapeutic options, many people sought alternatives. In the late 1980s, several brief reports described progressive decline in serum zinc levels with advancing HIV infection.2 Lower zinc levels were also seen in patients with lower CD4+ cell counts. Several years later, 64% of a cohort of HIV-positive gay men were reported to be taking zinc supplements.3 Megadosing, using more than 10 times the RDA, is common among HIV patients: 22% were consuming 2-5 times the RDA, while 15% were consuming six or more times the RDA (> 90 mg/d). Even in 1984, prior to the reports suggesting a link between zinc and HIV progression, 31% of a group of homosexual men recruited for AIDS research were using zinc supplements.4
Mechanisms of Action
Metalloenzymes containing zinc have multiple functions. They are critical in normal spermatogenesis, embryo development, and turnover of skin and gastrointestinal mucosa. Zinc’s role in immune function is often touted. Deficiency results in thymic atrophy, decreased circulating T-lymphocytes, depressed humoral and cell-mediated immunity, impaired delayed-type hypersensitivity, and decreased phagocytic function of neutrophils.
Clinical Studies
In a cohort of asymptomatic HIV-positive homosexual men, 26% were deficient in zinc (< 75 mg/dL) and 24% had marginal zinc values (75-94 mg/dL).5 In a case-control study, serum zinc levels were lower in HIV-positive men who developed AIDS (mean follow-up, 2.5 years) compared to those who did not progress even after adjusting for CD4+ cell count and age.6 Similarly high rates of low zinc levels have been found in other studies.
For HIV-positive individuals, normalization of zinc levels was associated with an increase in CD4+ cell counts (estimated change in CD4+ count was an increase of 61; P = 0.0112). However, this finding was no longer significant when zidovudine was included as a covariate, and dietary intake of zinc did not correlate with measured serum levels.7
Two reports from the Baltimore/Washington, DC, sites of the Multicenter AIDS Cohort Study (MACS) suggest that high zinc intake may be dangerous. The MACS is a natural history study of homosexual men enrolled in 1984. At their first six-month follow-up, the men were asked to complete a food frequency questionnaire for the previous 12 months (88% completion rate). Among the 1153 enrolled, 341 (29.6%) were HIV positive at their baseline visit. Excluding men who developed AIDS within one year, 281 HIV-positive men with nutritional surveys were followed. After a median follow-up of 6.8 years, increased zinc intake was associated with a two-fold risk of developing AIDS (relative risk [RR] = 2.06 for the highest quartile, 95% CI 1.16-3.64).4 After eight years of follow up, an increased risk of death was seen with use of any zinc supplement. (RR = 1.49; P < 0.05). When all zinc intake was analyzed, and controlling for other nutrients, increasing intake correlated with poorer survival suggesting a dose response (thirrd quartile 14-20 mg/d; RR = 1.87; 95% CI 1.17-2.99; fourth quartile > 20 mg/d; RR = 2.28; 95% CI 1.38-3.78).8
Adverse Effects
Low doses of zinc are felt to be nontoxic. However, 150 mg bid in 11 healthy men for six weeks resulted in diminished lymphocyte and polymorphonuclear leukocyte function, decreased HDL, and increased LDL. Chronic ingestion of greater than 100 mg results in anemia and neutropenia due to copper deficiency.
Drug Interactions
Zinc salts decrease the gastrointestinal absorption and serum levels of fluoroquinolones and tetracycline, though doxycycline appears to not be affected.
Formulations
Foods rich in zinc include legumes, peanuts, whole grains, beef, lamb, pork, and, especially, oysters and liver. Various salts chemically provide 1.5-50 mg of elemental zinc (e.g., 200 mg of zinc sulfate provides 45 mg elemental zinc; 50 mg of zinc gluconate provides 7 mg of zinc). Since only 10-40% of an oral dose of zinc is absorbed, 200 mg of zinc sulfate generally provides 4.5-22 mg of bioavailable zinc. Foods high in calcium, bran, and phytates such as dark leafy greens eaten concurrently with zinc-containing foods may further decrease absorption. Zinc picolinate and zinc monomethionine may be better absorbed than other zinc compounds.
Conclusion
Zinc levels appear to decline with advancing HIV infection. Deficient levels are frequently found in HIV-positive patients even when asymptomatic. Lower levels may be a marker for increased risk of progression. However, cohort studies suggest that increasing dietary intake of zinc or use of any zinc supplement increases the risk of disease progression and worsens survival. This increased risk for zinc appears to be unique among the micronutrients studied in HIV-positive cohorts. Conversely, daily multivitamin use has been shown to decrease the risk of developing AIDS (RR = 0.7; 95% CI 0.5-1.0) and to reduce the risk for low CD4+ cell counts (RR = 0.6; 95 % CI 0.4-0.9) in HIV-positive men.9
For HIV-positive patients, daily multivitamins and supplements of B complex, vitamins E and C should be recommended. However, zinc supplements should be discouraged until further studies prove its safety. Short controlled trials measuring the effect of zinc on viral load/HIV RNA levels and other immune markers would be informative.
References
1. Zinc for the common cold. Med Lett 1997;39:9-10.
2. Falutz J, et al. Zinc as a cofactor in human immunodeficiency virus-induced
suppression. JAMA 1988; 259:2850- 2851.
3. Baum M, et al. Inadequate dietary intake and altered nutrition status
in early HIV-1 infection. Nutrition 1994;10:16-20.
4. Tang AM, et al. Dietary micronutrient intake and risk of progression
to acquired immunodeficiency syndrome (AIDS) in human immunodeficiency
virus type 1 (HIV-1)-infected homosexual men. Am J Epidemiol 1993;138:937-
951.
5. Beach RS, et al. Specific nutrient abnormalities in asymptomatic
HIV-1 infection. AIDS 1992;6:701-708.
6. Graham NMH, et al. Relationship of serum copper and zinc levels
to HIV-1 seropositivity and progression to AIDS. J Acquir Immune Defic
Syndr 1991;4:976-980.
7. Baum MK, et al. Micronutrients and HIV-1 disease progression. AIDS
1995;9:1051-1056.
8. Tang AM, et al. Effects of micronutrient intake on survival in human
immunodeficiency virus type 1 infection. Am J Epidemiol 1996;143:1244-1256.
9. Abrams B, et al. A prospective study of dietary intake and acquired
immune deficiency syndrome in HIV-seropositive homosexual men. J Acquir
Immune Defic Syndr 1993;6:949-958.
Dr. Barrette is an Assistant Professor in the Department of Medicine
at the University of Washington Medical Center in Seattle.
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