Pakistan J. Med. Res.
Vol. 43 No.2, 2004 REVIEW ARTICLE
The Relationship between Vitamin A and HIV Infection
Oguntibeju OO, Van Schalkywk FE & Van Den Heever WMJ
School of Health Technology, Technikon Free State, P/Bag X20539, Bloemfontein 9300, South Africa
Vitamin A deficiency has been shown to alter immune and haematological status in HIV infected subjects. Malnutrition remain an endemic problem in many African countries which has been recently complicated by the impact of HIV/AIDS. Malnutrition is known to affect micronutrient status and more so in HIV-infected persons. Research studies observed that several vitamins especially vitamin A are critical in fighting HIV infection. This is because these vitamins (vitamin A inclusive) are utilized by the immune system and important organs to attack infectious pathogens hence, the need to examine relationship between vitamin A and HIV infection in this paper.
Key words: Vitamin A, HIV infection, deficiency, AIDS.
Vitamins appear to have considerable clinical importance in HIV infection. Research and observational studies have shown that certain vitamins are frequently deficient in HIV-infected patients1,2. Vitamin deficiency appears to be related to altered immune and haematological status in the infected patients1. A number of vitamins including vitamin A may enhance (and their deficiency impair) the immune response in HIV-infected patients2. Of the micronutrients, the role of vitamin A in HIV infection has received prominent attention. This is because of its well-known role in affecting child morbidity and mortality, as well as early observations that vitamin A status was associated with increased risk of mother-to-child-transmission (MTCT) of HIV3, progression to AIDS4, 5, 6, adult survival1, 3, 4, infant morbidity7 and mortality8.
Vitamin A has been recognized as a likely potential co-factor (micronutrient) in HIV progression and disease expression9. HIV positive persons may be at particular risk for vitamin A deficiency for some reasons. These include chronic and recurrent infections, chronic inflammatory conditions, poor intake, diarrhoea with or without malabsorption9, 10. Vitamin A has remarkable positive effects including established roles in haematopoiesis, the maintenance of epithelial integrity and optimal function of the immune system.
We aim to examine the role of vitamin A, vitamin A in HIV infection, its deficiency in relation to HIV infection, consequences of its deficiency and the benefits of vitamin A supplementation in HIV persons.
Role of Vitamin A
Vitamin A is a fat-soluble substance and can be ingested either preformed (retinal) or synthesized within the body from ingested plant carotenoids11. The best known function of vitamin A is in the visual process where, as 11-cis-retinal, it serves as the photosensitive chromophoric group of the visual pigments of rod and cone cells of the retina 8, 9, 10, 11. Vitamin A has a clear vital role in the differentiation of epithelial cells. It is documented that vitamin A deficient individuals experienced replacement of normal mucus-secreting cells by cells that produce keratin, particularly in the conjunctiva and cornea of the eye, the trachea, the skin and of ectodermal tissues8, 9, 10, 11.
Vitamin A is also necessary for reproduction. For example, rats maintained with retinoic acid grow well and appear healthy, but lose reproductive ability (male show impaired spermatogenesis and females abort and resorb their feotuses). Studies show that injection of retinal into the testis restores spermatogenesis, indicating that vitamin A has a direct role in that organ13. Vitamin A is important in supporting immune competence. Vitamin A-deficient animals and humans are typically more susceptible to infection than are individuals of adequate vitamin A nutrition. Epidemiological studies have found that low vitamin A status is frequently associated with increased disease incidence and mortality rates8, 9, 10, 11.
Vitamin A status in HIV Infection
The impact of HIV infection on vitamin A status has been examined in a number of studies. Mean serum retinal levels for HIV positive adults fall within the normal range. However, a significant number of persons (although in the minority) have retinal levels below 1.05 µmol/L, the cut-off for biochemical deficiency2, 12. In a micronutrient survey of 112 asymptomatic homosexuals, Baum et al 2 found biochemical vitamin A deficiency in 16%. Although the authors stated that the proportion of individuals with multiple vitamin deficiencies increased over-time, no data were provided to follow-up vitamin A status changes with HIV disease progression. Their observations could not be explained by decreased vitamin A intake since none of the study subjects consumed less than the recommended daily allowance (RDA) for vitamin A. Similar report have also been documented by the same group in a study where they examined 100 homosexuals and 42 heterosexual individuals with HIV infection 9.
Bogden et al 12 studied a smaller number of subjects (N=30) at various stages of HIV infection. The result showed that the mean serum retinal level was normal and 12% were biochemically deficient in vitamin A. Although the total number of subjects in this study is relatively small, the data suggest an association between HIV infection and vitamin A and is consistent with deterioration of vitamin A status with advancing HIV infection.
Vitamin A deficiency in HIV Infection
Some populations are at increased risk for vitamin A deficiency. These groups include intravenous drug users, alcoholics, the homeless and persons with chronic diseases. HIV-infected persons are disproportionately represented in these risk groups10. Besides, several characteristics of HIV infection are likely to increase the demand for and decrease the supply of this vitamin. These include chronic and repeated acute bacterial or viral infections, decrease oral intake (due to oral thrush, mental status changes), active liver disease (impaired storage) and decreased intestinal absorption10, 13.
Vitamin A deficiency has been said to be rare in developed countries. However, the prevalence of hyporetinaemia in HIV-1 infected individuals in industrialized countries has risen to 29%. In developing countries, up to 60% of HIV-infected women are hyporetinaemic. In such women, the relative risk of peri-natal transmission may be increased more than fourfold14. According to Watson 15 vitamin A deficiency is associated with decreased CD4 T-cell production, depressed cellular immunity and reduced humoral response to protein antigens. In a study by Karter (1995) on “Vitamin A deficiency in non-supplemented patients with AIDS”; sixty eligible patients with AIDS provided serum samples that were analyzed for retinal content. Exclusion criteria included current use of vitamin supplements. Past dietary intake was determined using a standardized food intake frequency questionnaire. The prevalence of hyporetinaemia was 22%. There was a positive association between serum retinal status and dietary intake but 27% of those with adequate intake had serum retinal levels below the normal range. These findings suggest that regardless of intake, patients with AIDS may represent a population at considerable risk of vitamin A deficiency. Vitamin A deficiency is strongly associated with iron deficiency anaemia15. Hemosiderosis of the liver has been found at autopsy in children who die with vitamin A deficiency suggesting the inability to mobilize hepatic iron stores underlies the associated anaemia15. The disruption of iron metabolism has also been reported in HIV positive persons and anaemia is an early and consistent finding in HIV infection10. Severe anaemia requiring transfusion has been reported in advanced HIV infection. Hemosiderosis has also been reported in few cases in HIV infection. Factors contributing to this include direct infection of erythrocyte precursors in the bone marrow, chronic infections and decreased production of erythropoietin16, 17, 18. In animals deprived of vitamin A, there is disruption of mucosal surfaces with loss of cilia and disintegrated microvilli in the respiratory, gastrointestinal tracts, vagina and salivary glands. The effects of vitamin A on the vagina mocusa raise the possibility that changes in vitamin A status may influence heterosexual and peri-natal transmission of HIV15, 16, 19. The evidence that vitamin A deficiency impairs normal immune function comes from several sources. These include animal studies with experimental depletion and repletion, in vitro studies of human immune cell function with supplemental retinoids and field studies of deficiency 20, 21, 22, 23.
Although the immunological impact of changes in vitamin A status has been less studied in man, retinoids have been found to influence a wide range of human immune cell functions in vitro. These include proliferation of thymocytes, B-cells, T-cells and the production of a number of cytokines24, 25, 26. Vitamin A-deficient children respond poorly to tetanus toxoid, are found to have low CD4+/CD8+ ratios and suffer increased infection-related mortality. Vitamin A repletion is associated with increased CD4+ counts and CD4+/CD8+ ratios as well as improved antibody production 3, 26.
Consequences of Vitamin A deficiency in HIV Infection
The consequences of vitamin A deficiency resulting from HIV infection are potentially severe. Watson19 examined a population group of 53 HIV-sero-negative and 126 HIV-sero-positive subjects in a cross-sectional study of vitamin A status. Two of the 53 HIV-1 sero-negative (3.7% and 19 of the 126 sero positive subjects (15.1%) had serum vitamin A levels <1.05 µmol/L. There was a strong association between low serum retinal levels and absolute CD4 counts for both sero-positive and sero-negative subjects. The mean follow-up was 22.8 months during which time 15 subjects died from AIDS-related causes.
Kaplan-Meier product limit estimates for subgroups stratified by vitamin A status (above or below 1.05 µmol/L) revealed that individuals with vitamin A deficiency had significantly decreased mean survival time by the log-rank test (P<0.0001). The adjusted odds ratio for serum retinal as an independent predictor of mortality was 4.3 compared to 10.0 for CD4+ cell counts <200 mm3. Increased infant mortality has also been observed in children born to HIV positive mothers with vitamin A deficiency 8. These findings suggest strongly that vitamin A status is an important co-factor in HIV progression.
Vitamin A supplementation in HIV infection
The potential role for vitamin A as an adjuvant therapy in HIV-infected populations is very relevant especially in the developing world. In these settings, the risk of vitamin deficiency is great and the range of available treatments for HIV infection is limited. The cost of a bimonthly 200,000 IU capsule of vitamin A compares well with other form of interventions in HIV infection. While this may not be a panacea, the demonstration of a beneficial effect of vitamin A supplementation in HIV infection may offer hope of treatment where there is currently none15, 19.
In a study of 288 HIV-positive homosexual men in Baltimore, dietary and supplemental intake of vitamin A (9000-20000 IU/day was associated with slower progression to AIDS during a seven-year follow-up15, 19. Kennedy 29 examined the effects of vitamin A supplementation during pregnancy and early lactation on maternal weight among HIV-1 sero-positive South African women. The author observed a benefit on maintenance of post-natal weight in vitamin A deficient women. It was concluded that in a population for whom anti-retroviral therapy is not readily available or accessible, the finding that vitamin A improve post-partum weight lends some hope to a relatively inexpensive treatment. Vitamin A could thus be used for helping to ameliorate some weight loss that is common during HIV infection.
According to Nimmagadda14, vitamin A supplementation may be especially useful in adjunctive therapy for HIV-infected pregnant women who live in the developing world. Vitamin A supplementation of women during pregnancy improved vitamin A status of mothers and of their infants30. It has also been demonstrated from recent studies that vitamin A supplementation during pregnancy enhanced the concentration of retinal levels in breast milk30. Coutsoudis et al (1995) carried out a double-blind randomized controlled trial of vitamin A supplementation on children of HIV-positive mothers in Durban, South Africa. It was demonstrated from the study that 28% of the supplemented group had reduction in the incidence of prolonged diarrhoea and 77% had reductions in hospital admissions for diarrhoea. Benefits from vitamin A supplementation include not only improved health and welfare for individuals and family, but also improved chances of prolonged survival for HIV infected persons29-31. In Tanzania, vitamin A supplementation of HIV-infected children reduced all-cause mortality by 63% among HIV-infected children aged six months to five years and was associated with a 68% reduction in AIDS-related deaths and a 92% reduction in diarrhoea-related deaths31, 27. To date, despite demonstrated associations between vitamin A deficiency and HIV infection, there is no clear evidence yet that vitamin A supplementation can positively alter HIV vertical transmission or disease progression in adults. It is known that good nutrition and a healthy diet may help prolong the period of time between HIV infection and onset of secondary infections commonly attributed to progression to AIDS. This is because of the relationship between nutritional status and immune system function and integrity.
Further research is urgently needed on the nutritional management of HIV/AIDS especially that on vitamin A supplementation especially in the African countries, where HIV is spreading rapidly, where malnutrition is endemic and resources for the management of both HIV and malnutrition are extremely constrained. Studies are needed to determine the efficacy and safety of micronutrient supplements for improving nutritional status, preventing disease progression and delaying AIDS-related mortality in populations that are endemically deficient and may also experience chronic food insecurity.
1. Coodley GO, Nelson HD, Loveless MO and Folk C. Beta-carotene in HIV infection. J AIDS 1993; 6: 272.
2. Baum MK, Shor-Posner G, Bonveni P, Cassetti I, Mantero-Atienza E et al.. Influence of HIV on vitamin status and requirements. Ann N Y Acad Sci 1992; 669: 165.
3. Semba RD, Caiaffa WT, Graham NHM. Vitamin A deficiency and wasting as predictors of mortality in HIV-infected drug users. J Inect Dis 1994; 171: 1196-1202.
4. Nduati RW, John GC, Richardson BA. Human immuno-deficiency virus type 1-infected cells in breast milk: Association with immuno suppression and vitamin A deficiency. J Infect Dis 1995; 172: 1461-1468.
5. John GC, Nduati RW, Mbori ND. Genital shedding of human immuno-deficiency virus type 1 DNA during pregnancy: Association with immuno suppression, abnormal cervical or vaginal discharge and severe vitamin A deficiency. J Infect Dis 1997; 175: 57-62.
6. Tang AM, Graham NM, Kirby AJ. Dietary micronutrient intake and risk of progression to acquired immunedeficiency syndrome (AIDS) in human immunodeficiency type 1 (HIV-1)-infected homosexual men. Am J Epidemiol 1993; 138: 937-951.
7. Coutsoudis A, Bobat RA, Coovadia HM. The effects of vitamin A supplementation on the morbidity of children born to HIV-infected women. Am J Public Health 1995; 85: 1076-1081.
8. Dushimimana A, Graham NHM, Humphrey JH. Maternal vitamin A levels and HIV-related birth outcomes in Rwanda. Abstr. POC 4221 1992. Paper presented at the V111 International AIDS conference/STD World Congress, Amsterdam, The Netherlands.
9. Beach RS, Mantero-Atienza E, Van Riel F and Fordyce-Baum. Potential implications of nutritional deficiencies in early HIV-1 infected patients. Arch AIDS Res 1989; 3: 225.
10. Chaisson DE and Volberding PA. Clinical manifestations of HIV infection. In principles and practice of Infectious Diseases. Mandell GL et al. (eds): Churchill Livingston, New York 1990:1059.
11. Barker BM. Vitamin A. In vitamins in Medicine. Vol 2, Fourth edition. London: Heinemann 1983: 211.
12. Bogden JD, Baker H, Frank O, Perez G Kemp E, Bruening K. Micronutrient status and human immunodeficiency virus (HIV) infection. Ann N Y J Acad Sci 1990; 587: 189.
13. Beach RS, Mantero-Atienza E, Shor-Posner G, Javier JJ, et al. Specific nutrient abnormalities in asymptomatic HIV-1 infection. AIDS 1992; 6: 701.
14. Nimmagadda AP, O’Brien WA, Goetz MB. The significance of vitamin A and carotenoid status in persons infected by the human immunodeficiency virus. Clin Infect Dis 1998; 26: 711-718.
15. Mejia LA, and Arroyave G, Viteri F, and Torun B. Vitamin A deficiency and anaemia in Central American children. Am J Clin Nutr 1977; 30: 1175.
16. Gherardi RK, Mhiri C, Baudrimont M, Roullet E, Berry JP. Iron pigment deposits, small vessel vasculitis and erythrophagocutosis in the muscle of human immunodeficiency-infected patients. Hum Pathol 1991; 22: 1187.
17. Folks TM, Kessler SW, Orenstein JM, Justement JS, Jaffee ES and Fauci AS. Infection and replication of HIV-1 in purified progenitor cells of normal human bone marrow. Science 1988; 242: 919.
18. Miles SA. Erythropoietin in the treatment of anaemia in AIDS patients: Results of a multicenter, double-blind, placebo-controlled study, Symposium Proceedings. V Int Conf AIDS 1989; 5: 19.
19. Watson RR. Nutrition and AIDS CRC Press Boca Raton, London Tokyo 1994: 1-14.
20. Ongaskul M, Sirisinha S, and Lamb AJ. Impaired blood clearance of bacteria and phagocytic activity in vitamin A deficient rats. Proc Soc Exp Biol Med 1985; 178: 204.
21. Bowman TA, Goonewardene IM, Pasatiempo AMG, Ross and Taylor CE. Vitamin A deficiency decreases natural killer cell activity and interferon production in rats. J Nutr 1990; 120: 1264.
22. Seifer E, Rettura G, and Leventson SM. Decreased resistance of C3H/HeHa mice to C3HBA tumour transplant: increased resistance due to supplemental vitamin A. J Natl Cancer Inst 1981; 67: 467.
23. Smith SM, and Hayes CE. Impaired immunity in vitamin A deficient mice. J Nutr 1986; 117: 857.
24. Goldfarb RH, and Herberman RB. Natural killer cell reactivity: regulatory interactions among phorbol ester, interferon, cholera toxin and retinoic acid. J Immunol 1982; 126: 2129.
25. Soppi E, Tertti R, Soppi A-M, Toivanen A and Jansen. Differential in vitro effects of etretinate and retinoic acid on the PHA and CON A induced lymphocyte transformation, suppressor cell induction and leucocyte migration inhibitory factor (LMIF) production. J Immunopharmacol 1982; 4: 437.
26. Matikainen S, Serkkola E, and Hurme M. Retinoic acid enhances IL-I beta expression in myeloid leukaemia cells and in human monocytes. J Immunol 1990; 147: 162.
27. Semba RD, Muhilal, Ward BJ, Griffin DE, Scott AL et al. Altered T cell subsets in vitamin A deficiency. Lancet 1993; 341: 5.
28. Alexander M, Newmark H, and Miller G. Oral beta-carotene can increase the number of OKT4 positive cells in human blood. Immunology 1985; 9: 221.
29. Kennedy-Oji C, Coutsoudis A, Kuhn L. Effects of vitamin A supplementation during pregnancy and early lactation on body weight on South African HIV-infected women. J Health Popl and Nutr 2001; 19 (3): 167-176.
30. Muslimatun S, Schmidt MK, Schultink W. Weekly supplementation with iron and vitamin A during pregnancy increases haemoglobin concentration in Indonesian pregnancy women. J Nutr 2001; 13 (1): 85-90.
31. Piwoz EG and Preble EA. HIV/AIDS and nutrition infection: A review of the literature and recommendations for nutritional care and support in sub-Saharan Africa, 2000; 1-35.