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Metabolic, Endocrine, and Gastrointestinal Disorders in Drug Abuse and HIV/AIDS

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Meeting Summary

Sponsored by the Center for AIDS and Other Medical Consequences of Drug Abuse, NIDA and the Office of Dietary Supplements, NIH

Jag H. Khalsa, Ph.D., Sander Genser, M.D., M.P.H., and Henry Francis, M.D.
Center for AIDS and Other Medical Consequences of Drug Abuse, NIDA

Abstracts

Nutritional Aspects of Drug Abuse and HIV

Sherwood L. Gorbach, M.D.
Tufts University of Medicine

Learning Objectives

  • Understand the nutritional deficiencies seen in protein-caloric malnutrition and their relation to HIV infection.
  • Learn the role of decreased dietary intake and micronutrient deficiency in progression of HIV.

Abstract

Drug abuse has become the leading risk factor for acquisition of HIV in the USA. The minority communities are especially impacted by the twin treats of drugs and the virus. There is accumulating evidence that nutritional status influences the progression of HIV and also has implications for response to HAART and side effects of treatment. AIDS patients can develop severe weight loss, known as wasting, which is seen even in patients who are receiving HAART. A persistent question in AIDS wasting is the extent to which protein-calorie malnutrition (PCM) plays a role in the immunological and clinical findings, particularly in drug abusers who may have borderline dietary intake. It is known that PCM can produce multiple immunologic defects, most of which are also seen in HIV infection. All of these abnormalities are reversed in PCM by nutritional rehabilitation, the major differentiating point between PCM and HIV. Yet, a recent study among HIV patients in Africa by Fawzi et al. showed that micronutrient supplementation can increase the numbers of CD4 cells. The role of PCM and micronutrient deficiencies in drug abusers with HIV is poorly defined because of a paucity of good nutrition and metabolic studies. More information is needed among drug abusers with HIV, with an emphasis on the minority communities and women, in order to develop appropriate nutritional interventions.

Nutritional Disorders in a Cohort of Persons with HIV/AIDS Including Drug Abusers

Janet E. Forrester, Ph.D., and Sherwood L. Gorbach, M.D.
Tufts University School of Medicine

Lecture Outline

  1. Expected body composition changes in normal males losing weight due to caloric restriction.
  2. Body composition in relation to CD4 counts in HIV disease.
  3. Body composition in relation to drug abuse in persons with HIV.
  4. Micronutrient intake in relation to drug abuse in persons with HIV.

Learning Objectives

  • What nutritional deficiencies are found in drug abusers?
  • What changes in body composition occur in persons who abuse drugs?
  • What changes in body composition occur in persons who have HIV and abuse drugs?
  • How does drug abuse affect the outcome of disease in HIV, and is this related to changes in nutritional status due to drug abuse?

Abstract

The changes in body composition that occur in HIV disease are controversial. HIV wasting has alternately been found to be predominantly a loss of lean body mass (1,2) or a predominance of fat loss (3,4). We examined body composition in relation to CD4 counts in a cross-sectional analysis of the baseline data from the first 516 enrollees in the Nutrition for Life cohort, a 3-year longitudinal study of HIV and nutrition. Weight was stable above 600 CD4 counts and declined linearly thereafter at a rate of 1.9 kg per 100 decline in CD4 cells (p<0.0001). Below 600 CD4 cells, fat mass declined at a rate of 1.5 kg (p<0.0001), and lean body mass at a rate of 0.45 kg (p=0.026) per 100 CD4 cells. However, loss of lean body mass was dependent on percent body fat: In males with less than 15% and females with less than 23% body fat, loss of lean body mass was negatively associated with percent body fat. Loss of lean body mass was not associated with body fat at levels above 15% in males and 23% in females. Our results suggest that in persons with adequate fat stores, loss of weight with disease progression is predominantly fat, while in persons with low fat stores, a higher proportion of the weight lost is lean body mass, and that the amount of lean body mass lost depends on the percent body fat. We also present preliminary data on body composition and nutrient intake in drug abusers.

References

  • Kotler, DP, Wang J Pierson RN Am J Clin Nutr. 1985; 42: 1255-1265. Body composition studies in patients with the acquired immunodeficiency syndrome .
  • Paton NIJ, Macallan DC, Jebb SA et al. Longitudinal changes in body composition measured with a variety of methods in patients with AIDS. J Acquir Immune Defic Syndr. 1997; 14: 119-127.
  • Schwenk A, Hoffer-Belitz E, Jung B et al. Resting energy expenditure, weight loss and altered body composition in HIV infection. Nutrition 1996; 12: 595-601.
  • Mulligan K, Tai VW and Schamblean M. Cross-sectional and longitudinal evaluation of body composition in men with HIV. J Acquir Immune Defic Syndr 1997; 15: 43-48.

Nutritional Assessment in HIV/AIDS Intravenous Drug Users

Ellen Smit, Ph.D., R.D.
Johns Hopkins University, School of Hygiene and Public Health

Lecture Outline

  1. Assessing nutritional status: Review of methods with respect to their use in IDUs/HIV populations.
    • Dietary intake assessment
    • Body composition
    • Biochemical measurements
  2. Methods currently being used: A review of studies reported during the 12th World AIDS Conference.
  3. Current research on methodology: What is being done? Dietary assessment and calibration validation studies Body composition and biochemical methods research
  4. Future research needs in nutrition methodology. Dietary intake assessment, body composition, biochemical measurements

Learning Objectives

  • To increase knowledge of methodological issues related to assessing nutritional status in IDU/ HIV populations.
  • To identify future research needs in nutrition methodology.

Abstract

Assessment of nutritional status may include any combination of biochemical and body composition measurements, dietary intake assessment, and metabolic studies. Each method has its strengths and weaknesses and we may disagree on which tool is best. What we can agree on, however, is that at the moment we do not have a perfect tool. When assessing nutritional status in injection drug users (IDU) and in HIV-infected individuals, the decision in what method(s) to use becomes even more complex. A review of studies reported during the 12th World AIDS Conference reveals that out of 64 abstracts on the topic of nutrition in HIV-infected adults, only 11 assessed diet, with 41 assessing anthropometry and 24 assessing some form of biochemical measurements. The most common methods for dietary intake included 24-hour recalls, food records, and food frequencies. The most common methods for body composition included height, weight, bioimpedance, and DEXA. Biochemical measurements included a variety of blood nutrients, lipids and albumin. Methods varied greatly, and caution should be taken when trying to compare results between studies using different methods. Currently, there are few studies dealing with the development of methods that can be used for research in HIV and IDU populations, especially methods that will allow us to track changes in nutritional status over time. We need to work toward better tools in dietary intake assessment, body composition, and biochemical measurements.

References

  • Conference Record, Bridging the Gap, 12th World Aids Conference, Geneva, 1998.
  • Dwyer JT. Dietary assessment. In: Modern Nutrition in Health and Disease, Shils ME, Olson JA, and Shike M (editors), Lea & Febiger, PA, pp. 842-860, 1994.
  • Forbes GB. Body composition: influence of nutrition, disease, growth and aging. In: Modern Nutrition in Health and Disease, Shils ME, Olson JA, and Shike M (editors), Lea & Febiger, PA, pp. 781-801, 1994.
  • Heymsfield SB, Tighe A, Wang Z. Nutritional assessment by anthropometric and biochemical methods. In: Modern Nutrition in Health and Disease, Shils ME, Olson JA, and Shike M (editors), Lea & Febiger, PA, pp. 812-841, 1994.
  • Margetts BM, Nelson M. Design Concepts in Nutritional Epidemiology. Oxford University Press, New York, NY, 1991.
  • Thompson FE, Byers T. Dietary Assessment Resource Manual. J Nutr 124:supplement, 1994.
  • Willett W. Nutritional Epidemiology. Oxford University Press, New York, NY, 1990.
  • Yanovski SZ, Hubbard VS, Heymsfield SB, Lukaski HC. Bioelectrical Impedance Analysis. Am J Clin Nutr 64:supplement, 1996.

Role of Micronutrients in HIV-Infected Intravenous Drug Users

Marianna K. Baum, Ph.D.
University of Miami School of Medicine

Lecture Outline

  1. OBJECTIVES OF STUDIES
    Determination of nutritional profile and impact on HIV-1 disease.
  2. ASSESSMENTS 
    Immune evaluation, nutritional profile.
  3. DESCRIPTION OF COHORTS
    Miami cohorts: HIV-1 infected men who have sex with men, male and female drug abusers, pediatric cases.
  4. NUTRITIONAL PROFILE 
    Nutritional alterations are widespread even during early stages. Different prevalence of deficiencies in homosexuals, drug users (men vs women).
  5. IMPACT OF NUTRITIONAL ALTERATIONS ON HIV-1 DISEASE
    Alterations affect immune function, disease progression, and survival.
  6. MICRONUTRIENT DEFICIENCIES AND RISK OF HIV-1-RELATED MORTALITY
    Subclinical malnutrition and individual deficiencies of vitamin A, vitamin B12, zinc, and selenium over time are associated with HIV-1-related mortality.
  7. SELENIUM-INDEPENDENT PREDICTOR OF HIV DISEASE PROGRESSION AND SURVIVAL
    Relative risk of 10.8, p<0.002 (Chronic drug users). Selenium deficiency associated with HIV-1-related mortality (OR=6.76, p=0.01) in MSM. Low levels of selenium in pediatric cohort associated with decreased survival.
  8. WASTING IN RELATIONSHIP TO MICRONUTRIENT STATUS 
    Wasting predicts mortality. Selenium status may be a sensitive predictor of wasting.
  9. NUTRITIONAL CONSIDERATIONS
    To supplement or not supplement?

Two Learning Objectives

Upon completion of this lecture, the participants will:

  • Understand that nutritional alterations are prevalent in HIV-1 disease, vary among different cohorts, and affect the course of HIV-1 disease progression and survival.
  • Become familiar with the importance of specific micronutrients as sensitive markers of wasting and mortality.

Abstract

A major focus of our research investigations has been to evaluate the role of nutritional status as a cofactor in HIV-related disease progression and survival. Nutritional deficiencies are widespread in HIV-1-seropositive homosexual men (Beach et al., 1992; Baum et al., 1995) as well as male and female drug abusers (Baum et al., 1997a) and children, although the prevalence of nutritional alterations varies among the groups. Low levels of vitamin A, vitamin B12, zinc, and selenium are common and have been demonstrated to be associated with HIV-1-related mortality, independent of CD4 cell count <200/mm3 at baseline and CD4 cell count over time (Baum, 1997b). As multiple nutrient deficiencies tend to occur simultaneously, the joint effect of deficiencies that singly predicted HIV-related mortality was also investigated. In this multivariate analysis only deficiency of selenium was profoundly associated with decreased survival in HIV-1 disease, with a relative risk of 10.8, p<0.002 (Baum et al., 1997b). In other investigations, selenium deficiency has been demonstrated to be predictive of HIV-1-related prognosis (Constans et al., 1995) and in our cohort of HIV-1-infected pediatric patients has been associated with immune dysfunction (Bologna et al., 1994) and decreased survival. Moreover, our longitudinal studies indicate that selenium deficiency is significantly associated with both body weight and body mass index, independent of CD4 cell count, age, gender and race, suggesting that selenium status may be a sensitive predictor of wasting in HIV-1-infected individuals.

The profound impact of selenium deficiency on HIV-1 disease processes and survival underscores the importance of maintaining optimal nutritional status in HIV-1-infected cohorts. Supplementation with selenium may help to increase the enzymatic defense systems in HIV-1-infected patients (Sappey et al., 1994; Delmas-Beauvieux et al., 1996) and be an effective method of delaying disease progression, through its ability to modulate viral expression via selenoprotein genes (Taylor et al., 1997).

References

  • Baum MK, Shor-Posner G, Lu Y et al., Micronutrients and HIV-1 disease progression. AIDS 1995;9:1051-1056.
  • Baum MK, Shor-Posner G, Zhang G et al., HIV-1 infection in women is associated with severe nutritional deficiencies. J Acquir Immun Defic Syndr 1997a;16:272-278.
  • Baum MK, Shor-Posner G, Lai S et al., High risk of mortality in HIV infection is associated with selenium deficiency. J Acquir Immun Defic Syndr 1997b;15:370-374.
  • Beach RS, Mantero-Atienza E, Shor-Posner G et al., Specific nutrient abnormalities in asymptomatic HIV-1 infection. AIDS 1992;6:701-708.
  • Bologna R, Indocochea F, Shor-Posner G et al., Selenium and immunity in HIV-1 infected pediatric patients. J Nutr Imm 1994;3:41-49.
  • Constans J, Pellegrin JL et al., Serum selenium predicts outcome in HIV infection. J Acquir Immun Defic Syndr 1995;3:392.
  • Delmas-Beauvieux M-C, Peuchant E, Coucouron A et al., The enzymatic antioxidant system in blood and glutathione status in human immunodeficiency virus (HIV)-infected patients: effects of supplementation with selenium or B-carotene. Am J Clin Nutr 1996;64:101-107.
  • Sappey C, Legrand-Poels S, Best-Belpomme M, Favier A, Rentier B, Piette J. Stimulation of glutathione peroxidase activity decreases HIV type 1 activation after oxidative stress. AIDS Res Human Retrovir 1994;10:1451-1461.
  • Taylor EW, Bhat A, Nadimpalli R, Zhang W, Kececioglu J. HIV-1 encodes a sequence overlapping env gp41 with highly significant similarity to selenium-dependent glutathione peroxidases. J Acquir Immun Defic Syndr 1997;15:393-394.

Mechanism of Action of Micronutrients in HIV Infection and Drug Abuse

Ethan Will Taylor, Ph.D.
University of Georgia College of Pharmacy

Outline

The talk will focus on the roles of Se and Zinc, involving the following key points: (i) why injection drug use may place an increased oxidative stress on the body and the immune system; (ii) evidence that oxidative stress activates HIV replication and antioxidants inhibit it; (iii) brief review of clinical studies documenting correlations between Se and zinc status and HIV disease progression and mortality; (iv) evidence for the existence of HIV-encoded selenoproteins, including a glutathione peroxidase gene; (v) the identification of the same gene in Hepatitis C virus (HCV), a very common co-infection in HIV+ injection drug users; and (vi) the potential role of HIV-encoded selenoproteins in the clinical observations cited above.

Abstract

Injection drug users (IDUs) are a population known to be exceptionally prone to malnutrition. Nutritional deficiencies have been linked to compromised immune function even in drug users who are not infected with HIV, which is not surprising in light of the importance of nutrition for maintaining optimal immune function [1].

Of particular significance for HIV+ IDUs is the fact that injection drug use exerts an exceptional oxidant stress on the body and the immune system. In part because of tissue damage and cellular injury, drug abusers show increased lipid peroxidation products in blood, liver and urine [2-3], and low serum thiol levels indicative of increased oxidative stress are predictive of outcome in HIV+ IDUs [4]. This effect of drug abuse would lead to an increased requirement for nutritional antioxidants, which is very unlikely to be met in typical malnourished drug users. A study of heroin users showed significantly low urinary levels of the antioxidant trace mineral selenium (Se) [5], which suggests that Se intake is low and/or that absorption is impaired in IDUs.

Certain micronutrient deficiencies particularly Se and zinc have been associated with more rapid disease progression and increased mortality risk in various HIV+ populations [e.g., 6]. Because Se is known to be essential for cellular immunity [1,7], in addition to being an important antioxidant required to counter the increased lipid peroxidation caused by drug abuse, it could be especially critical for HIV disease progression in drug-abusing populations having malnutrition as a cofactor.

Significantly, a progressive deficit in serum Se has been consistently documented in HIV/AIDS [6,8,9], establishing powerful correlations between Se status and HIV disease progression and mortality in all HIV risk groups. In a recent longitudinal study, Se deficiency was associated with a 20-fold increase in AIDS-related mortality in HIV+ IDUs [6]. This proves the critical role of Se in HIV disease progression in IDUs, who have the dual risk factors of malnutrition and increased oxidative stress due to drug use.

It is now apparent that some viruses, including HIV-1 [9], a pox virus [10], and hepatitis C virus (HCV), encode homologues of glutathione peroxidase (GPx), the prototypical mammalian selenoprotein, in which selenocysteine is inserted at a UGA codon, which more commonly serves as a stop codon in the genetic code. Theoretical and in vitro data also support the possibility of selenoprotein coding potential associated with the nef gene region of HIV-1, due to the existence of highly conserved potential frameshift sequences in nef, and conserved UGA codons associated with the overlapping -1 reading frame and the 3'-terminal of nef [8]. We have demonstrated (Blumberg and Taylor, submitted for publication) that several of the predicted nef features are functional in vitro, including: (1) an active-1 frameshift site in nef, (2) Se-dependent readthrough of the 3'-terminal UGA of nef, and (3) incorporation of 75Se in a nef isoform during in vitro translation. These results are particularly significant because the nef gene has been widely implicated in HIV-1 pathogenesis.

A theoretical model will be presented whereby virally encoded selenoproteins serve to regulate HIV replication, e.g., relative to cellular redox status. By depleting Se in an infected cell, overexpression of HIV-encoded selenoproteins (e.g., nef isoforms) could actively contribute to an antioxidant defect and exacerbate the effects of Se deficiency or drug-induced oxidative stress, thus explaining the critical role of Se for survival in HlV-infected IDUs.

In principle, the situation is similar for the role of zinc in HIV infection, because HIV has several proteins that incorporate tightly bound zinc ions. Zinc is also essential for immune function, and zinc deficiency has also been correlated with increased mortality in HIV+ IDUs [6]. Thus, it is possible that HlV-related zinc incorporation could exacerbate the effects of zinc deficiency.

References

  • R.K. Chandra (1997) Nutation and the immune system: an introduction. Am. J. Clin. Nutr. 66: 460S463S.
  • A.M. Seledtsov (1995) Lipid peroxidation and status of the antioxidant system in opiate addiction, chronic alcoholism, or substance abuse caused by inhaling solvent vapors. Vopr. Med. Khim. 41: 50-53.
  • J.A. Knight, R.K. Pieper, S.E. Smith, H.H. Crockett(1988) Increased urinary lipoperoxides in drug abusers. Ann. Clin. Lab. Sci. 18: 374-377.
  • M. Marmor, P. Alcabes, S. Titus, K. Frenkel, K. Krasinski, A. Penn, R.W. Pero (1997) Low serum thiol levels predict shorter times-to-death among HlV-infected injecting drug users. AIDS 11: 1389-1393.
  • E.M. Rodriguez Rodriguez, M. Sanz Alaejos, C. Diaz Romero (1994) Urinary selenium concentrations in heroin abusers. Clin. Chim. Acta 231: 3946.
  • M.K. Baum, G. Shor-Posner, S. Lai, et al. (1997) High risk of mortality in HIV infection is associated with selenium deficiency. J. AIDS Human Retrovirol. 15: 370-374.
  • L. Kiremidjian-Schumacher, M. Roy, H.I. Wishe, M.W. Cohen, and G. Stotzky (1992): Regulation of cellular immune response by selenium. Biol. Trace Elem. Res. 33: 23-35.
  • E.W. Taylor, R.G. Nadimpalli and C.S. Ramanathan (1997): Genomic structures of viral agents in relation to the biosynthesis of selenoproteins. Biol. Trace Elem. Res., 56: 63-91.
  • E.W. Taylor, A. Bhat, R.G. Nadimpalli, W. Zhang, and J. Kececioglu (1997): HIV-1 encodes a sequence overlapping env gp41 with highly significant similarity to selenium-dependent glutathioneperoxidases. J. AIDS Human Retrovirol. 15: 393-394.
  • J.L. Shisler, T.G. Senkevich, M.J. Berry, B. Moss, Ultraviolet-induced cell death blocked by a selenoprotein from a human dermatotropic poxvirus. Science, 279: 102-105.

Dysregulation of Growth in Pediatric HIV Infection

Stephen M. Arpadi, M.D.
St. Luke's-Roosevelt Hospital Center
Columbia University College of Physicians and Surgeons

Outline

  1. Growth in HIV-infected children
    • Failure to thrive was reported in the earliest case reports of pediatric HIV/AIDS.
    • Various patterns of disturbed growth are reported, including compromised ponderal and linear growth and weight loss.
    • Multiple definitions for abnormal growth is problematic for data evaluation (e.g., attained wt and ht vs wt loss vs growth rate).
  2. Growth in HIV-exposed infants
    • Effect of maternal HIV on pregnancy outcomes and intrauterine growth are inconsistent.
    • Studies from Africa and Haiti indicate HIV-exposed infants have lower birth wt (St. Louis 1993, Ryder 1989).
    • European and U.S. studies have not found differences after maternal drug use and alcohol is considered (Selwyn 1989, Minkoff 1990).
  3. Growth in HIV-infected infants
    • Numerous studies have demonstrated that HIV-infected neonates are smaller than HIV- exposed but uninfected after adjusting for other factors.
    • At birth HIV+ infants are .28 kg lighter lighter and 1.64 cm shorter than HIV-E.
    • The effect on head circumference is .7cm (Moye 1996).
  4. Postnatal growth in HIV-infected infants
    • HIV+ infants have progressively increasing decrements of ponderal and linear growth during the first 1-2 yrs of life.
    • By 18 mos HIV+ are .71 kg lighter and 2.25cm shorter than HIV-E.
    • Prenatal drug exposure has significant effect on 18 mos wt (-.445 z-score).
    • Prenatal alcohol has significant effect on 18 mos linear growth (-.212 z-score).
  5. Growth in older HIV+ children
    • Although data are limited, at present progressive stunting appears to be the most prevalent abnormality.
    • 18/43(42%) prepubertal HIV+ children >5yrs have growth velocity <5th %-tile, (mean growth rate 3.1+ 1.5 cm/yr).
    • A pattern of stunting without wasting was observed ( HAP 26 vs 60, p<.0001,wt/ht 54 vs 60%, p=.08).
    • Growth abnormalities and survival
    • Poor growth has been associated with poor survival in U.S., European, African, and HIV+ hemophilia populations.
    • In U.S. children on antivirals, poor wt gain is an independent risk factor for death (RR=2) (95%CI:1.3-3.2) (McKinney 1994).
    • In Uganda, infants with low wt had a 5-fold increase in risk of death by age 25 mos (Berhane 1997).
  6. Body composition in HIV-infected children
    • II. Body composition characterized by a disproportionate decrease in BCM with preservation of BF (Arpadi 1998).
    • This pattern is distinct from observations in children with nutritionally based stunting.
    • It is similar to other wasting disorders including adult HIV infection and other conditions where anabolism is altered (e.g., GH/IGF-1, thyroid deficiency, etc.).
  7. Micronutrients in children with HIV
    • A number of micronutrient and trace element deficiencies impair immune function in children (e.g., vit A, E, Zn, Se).
    • Nutrient deficiencies appear to occur early in adult HIV infection and may be associated with disease progression.
    • Pediatric data are derived from small samples, confounded by maternal status and drug exposure, and results are conflicting.
  8. Vitamin A
    • Vitamin A important for normal immune function.
    • Occurrence and frequency of childhood illnesses increased in vitamin A deficiency.
    • Increased mortality with deficiency
    • Depletion may occur during infection.
    • Linear and ponderal growth in early childhood influenced by vitamin A status.
  9. Vitamin A and mother-to-infant HIV transmission
    • In a population with high prevalence of vitamin A deficiency, reduced maternal vit A an independent risk factor for MTC T of HIV (Semba 1994).
    • Mean vit A lower among non-transmitting compared to transmitting mothers (0.86 vs 1.07 umol/dl, p<.0001). IV. TR increased with decrease in maternal vit A.
  10. Vitamin A and MTCT
    • Effect of maternal vit A independent of maternal CD4 #, CD4 %, CD4:CD8 ratio.
    • No relationship has been observed in populations with low prevalence of vitamin A deficiency.
  11. Vitamin A-effect on infant growth
    • Maternal vit A deficiency was related to ponderal and linear growth independent of infant HIV (Semba 1997).
    • By 12 mos infants of vit A-deficient mothers weighed 8% less and were 2% shorter.
  12. Vitamin A
    • Vitamin A deficiency in 70% of HIV-exposed infants in U.S. (Cunningham-Rundles 1995).
    • Vitamin A was reduced esp in AIDS, but not deficient (Periquet 1995).
    • GF+ children in the U.S. had increased vitamin A (Henderson 1997).
    • Supplementation reduced diarrheal illnesses in HIV-E African infants (Coutsoudis 1995).
  13. Trace elements etc.
    • No differences in serum and RBC Zn or Se observed in French children. Cu elevated in non-AIDS (Periquet 1995).
    • No differences in Zn or Se in U.S. children, including those with GF (Henderson 1997). vRBC glutathione reduced in HIV especially with GF (Arpadi 1992).
  14. Neuroendocrine function in children with HIV
    • A number of endocrine abnormalities with the potential to affect growth have been identified
    • Isolated endocrine deficiencies are encountered (e.g., hypothyroidism).
    • No single endocrine abnormality has consistently been associated with growth ds.
  15. Thyroid function in HIV-infected children
    • While study results are inconsistent, thyroid abnormalities, clinical and subclinical, appear to be highly prevalent.
    • Primary hypothyroidism, low free T4, elevated TSH seen in 18% (Hirshfeld 1996).
    • Thyroid disease has not in general been established as an important factor in GF, but is a reversible cause for some children.
  16. Adrenal function in children with HIV
    • Basal cortisol levels normal (Geffner 1993).
    • Oberfield found elevated mean basal and stimulated cortisol levels in association with hypocampal atrophy (Oberfield 1994).
    • Adrenal suppression does occur with megestrol acetate (Daaboul 1998).
  17. GH and IGF-1
    • Laue, Geffner found IGF-1 to be normal.
    • Lepage and Schwartz found IGF-1 to be reduced.
    • In vitro resistance to IGF-1 and GH erythroid progenitor cells.
    • No association low IGF-1 and poor growth (Matarazzo 1994).
    • IGF-1 reduced in children with GF with decreased IGFBP-3/ternary complex (Frost 1996).
  18. Gastrointestinal disease in children with HIV infection
    • The role of GI infections and malabsorption in malnutrition, poor growth, and immune dysfunction has not be established.
    • Some enteric pathogens common in adults are rare in children (e.g., Isospora, E. histolytica Microsporidium, etc.) (Winter 1995).
    • Cryptosporidium parvum, C. difficile, Salmonella spp, Camplobacter spp, CMV, HSV, rotavirus are common.
  19. Gastrointestinal disease in children with HIV
    • Malabsorption of carbohydrates, fat, and protein are highly prevalent.
    • CHO:30-50%, Fat: 30%, PRO: 32% (Miller 1991, Yolken 1991, Italian HIV study 1993).
    • No association with malabsorption and growth.
    • Association of malabsorption with diarrhea is inconsistent in studies.
    • Studies is limited due to x-sectional design.
  20. Energy balance, viral replication, body composition, and growth in prepubertal HIV- infected children
    • Arpadi S, Cuff P, Kotler D, Wang J, Matthews D.
      St. Luke's-Roosevelt Hospital Center
      Department of Pediatrics and Body Composition Unit
      Columbia University, New York, NY and Clinical Research Center, University of Vermont
  21. Objective
    • To evaluate if abnormalities in energy balance contribute to growth failure in HIV- infected children.
    • Examine the relationships among HIV replication, energy balance, body composition, and growth.
  22. Methods
    • 43 prepubertal HIV-infected children, including 18 with growth failure (GF) defined as 12-mos growth velocity<5th%tile.
    • Energy intake (EI) measured by 24-hr recall performed 3 times over 10 days.
    • Viral replication measured by HIV RNA PCR (Amplicor).
    • Resting energy expenditure (REE) measured fasting using open-circuit indirect calorimetry.
    • Total energy expenditure (TEE) measured by differential excretion rates over 10 days of orally administered 18O and h3.
    • Energy balance determined by subtracting EI from TEE (EI-TEE).
    • Energy of physical activity determined by TEE-REE.
    • Fat-free mass (FFM) was measured by dual x-ray absorptiometry (Lunar) using pediatric software.
    • REE measures were compared with age norms based on FAO/WHO equations.
    • t-tests were used to compare GF+ vs GF-.
    • ANCOVA was used to adjust for the effect of age on EI, REE, TEE, FFM.
    • Univariate and multiple regression models were also used.
  23. Conclusions
    • HIV-infected children with GF have a negative energy balance despite relative reductions in REE and TEE.
    • Dietary intake is an important determinant of GF.
    • Viral replication appears to adversely affect FFM and growth.
    • In contrast to findings in adults, no association was observed between HIV replication and REE.
    • HIV replication was significantly correlated with the quantity of FFM.
    • Future studies evaluating the effect of viral replication, antiviral therapies, and host immune response on energy intake, anabolism, and growth are warranted.

Abstract

Disturbances in growth and body composition occur commonly in children with HIV. 1 2 3 Poor growth affects survival, increasing the risk of death as much as 5-fold.4 The etiology of growth failure is likely multifactorial. While primary hypothyridiism appears to affect growth in some children, 5 and other abnormalities have been reported, 6 7 no single endocrine disturbance has been established as causally related to poor growth. Gastrointestinal dysfunction, including infection and malabsorption, has also been reported, but no clear relationship to growth failure has been documented.8 Although the prevalence and effects of micronutrients have not been fully evaluated, maternal vitamin A deficiency adversely affects the transmission of HIV as well as postnatal growth, irrespective of infant HIV status.9 10 Energy balance studies have not been performed in children with HIV. We measured energy intake and expenditures in 43 HIV-infected prepubescent children, including 18 with growth failure (GF+), defined as 12-month growth velocity <5th %-tile. Resting energy expenditure (REE), total energy expenditure (TEE), energy intake (EI), viral load (VL), and body composition were evaluated. The mean plasma HIV RNA content among the children with GF was significantly higher than in children with normal growth. HIV+/GF+ children had significantly less total calorie intake per day compared to the HIV+/GF- group. The mean age-adjusted REE and TEE were lower in GF+ children compared to GF- children; however, these differences did not reach statistical significance. Children with GF were estimated to have a daily energy deficit compared to GF- children who had an energy surplus. These data indicate an important role for viral replication and decreased dietary intake in HIV-associated growth failure. Despite relative decreases in total energy expenditure, a significant energy deficit was observed in children with HIV-associated GF.

References

  • Moye J, Rich KC, Kalish LA, Sheon AR, Diaz C, Cooper ER. Natural history of somatic growth in infants born to women infected by human immunodeficiency virus. J Pediatr 1996;128:58-69.
  • McKinney R, Robertson WR, et. al. Effect of human immunodeficiency virus infection on the growth of young children. J Pediatr 1993;123:579-82.
  • Arpadi S, Horlick M, Wang J, Cuff P, Bamji M, Kotler D. Body composition in prepubertal children with human immunodeficiency virus type-1. Arch Ped Adol Med. 1998152:688-93.
  • Berhane R, Bagenda D, Maurm L, Aceng E, Ndugwa C, Bosch RJ, Olness K. Growth failure as a prognostic indicator in pediatric HIV infection. Pediatr 1997;100e7.
  • Hirschfeld S, Laue L, Cutler G, Pizzo P. Thyroid abnormalities in children infected with human immunodeficiency virus. J Pediatr 1996;128:70-4.
  • Frost RA, Nachman SA, Lang CH, Gelato M. Protesolysis of insulin-like growth factor- binding protein-3 in human immunodeficiency virus-positive children who fail to thrive. J Clin Endocr Metabol 1996:81:2957-62.
  • Oberfield SE, Cowan L, Levine LS, George A, Raphael D, Litt A, Rojas V, Kairam R.Altered cortisol response and hippocampal atrophy in pediatric HIV disease. J Acq Immun Def Syn 1994;7:57-62.
  • Italian Pediatric Intestinal/HIV Study Group. Intestinal malabsorption of HIV-infected children: relationship to diarrhoea, failure to thrive, enteric micro-organisms and immune impairment. AIDS 1993;7:1435-40.
  • Semba RD, Miotti PG, Chiphangwi JD, Saah AJ, Canner JK, Dallabetta GA, Hoover DR. Maternal vitamin A deficiency and mother-to-child transmission of HIV-1 Lancet 1994;343:1593-7.
  • Semba RD, Miotti P, Chiphangwi JD, Henderson R, Dallabetta G, Li-Ping Y, Hoover D. Maternal vitamin A deficiency and child growth failure during human immunodeficiency virus infection. J Acq Imm Def Syn Hum Retrovir 199714:219-222.

Oxidative Stress in HIV-1-Infected Injection Drug Users

Alice M. Tang, Ph.D.
Johns Hopkins University, School of Hygiene and Public Health

Lecture Outline

  1. Rationale for research on the role of oxidative stress in HIV-1 infected injection drug users (IDUs).
  2. Review of oxidative stress.
  3. Review of studies linking oxidative stress and low-serum antioxidant levels in HIV infection.
  4. How do injection drug use and antiretroviral therapy complicate the issue?
  5. Areas for future research on the interactions between oxidative stress and antioxidants in the era of protease inhibitors.

Learning Objectives

Participants should be able to:

  • Understand the current knowledge on the role of oxidative stress and antioxidants in HIV infection.
  • Identify future research needs in the area of oxidative stress and antioxidants in injection drug users in the era of protease inhibitors.

Abstract

It has been hypothesized that the low-serum antioxidant levels observed in many HIV-infected populations is largely due to an increase in oxidative stress. Oxidative stress is defined as a disturbance in the equilibrium status of pro-oxidant/antioxidant systems of intact cells (1). In HIV infection, oxidative stress may be caused by both overproduction of reactive oxygen intermediates (ROIs) and a simultaneous deficiency of antioxidant defenses (2). Furthermore, injection drug use has been associated with increased levels of oxidative stress in animal models (3,4). Currently, there is widespread use of self-prescribed antioxidant supplementation among the HIV-infected population and a prevailing belief that high-dose supplementation is beneficial, or at the very least, not harmful. Data from our studies show that HIV-positive injection drug users (IDUs) who are on antiretroviral combination therapies including a protease inhibitor have significantly higher mean serum levels of several antioxidants, independent of dietary and supplemental intake, compared with both HIV-negatives and HIV-positives not taking protease inhibitors. This suggests that oxidative stress may be reduced in patients taking protease inhibitors. Based on our preliminary data, and preliminary data from other studies (5,6), it appears likely that the future of antioxidant supplementation therapy, if any, will be one in which different doses of supplements are recommended for HIV-infected patients on the various antiretroviral treatment regimens. More research is needed to determine the interactions among injection drug use, oxidative stress, antiretroviral therapy, and the use of antioxidant supplements in HIV infection. Until more known, caution should be exercised when using or recommending high-dose antioxidant supplementation in HIV-infected individuals, particularly in those on protease inhibitors, since moderate levels of oxidative stress are involved in a number of useful physiologic processes.

References

  • Thomas JA. Oxidative stress, oxidant defense, and dietary constituents. In: Shils ME, Olson JA, Shike M, eds. Modern nutrition in health and disease. Eighth ed. Philadelphia: Lea & Febiger, 1994, p. 501-512.
  • Greenspan HC and Aruoma OI. Oxidative stress and apoptosis in HIV infection: a role for plant-derived metabolites with synergistic antioxidant activity. Immunology Today 1994;15:209-213.
  • Devi BG and Chan AWK. Impairment of mitochondrial respiration and electron transport chain enzymes during cocaine-induced hepatic injury. Life Sci 1997;60:849-855.
  • Devi BG and Chan AWK. Cocaine-induced peroxidative stress in rat liver: antioxidant enzymes and mitochondria. J Pharm Exp Therap 1996;279:359-366.
  • Baruchel S and Wainberg MA. The role of oxidative stress in disease progression in individuals infected by the human immunodeficiency virus. J Leuk Biol 1992;52:111-114.
  • Repetto M, Reides C, Gomez Carretro ML, et al. Oxidative stress in blood of HIV infected patients. Clin Chim Acta 1996;255:107-117.

Endocrine Disorders in Drug Abuse and HIV/AIDS

Adrian Sandra Dobs, M.D., M.H.S.
Johns Hopkins School of Medicine

Lecture Outline

  1. Introduction to the endocrine system
    • Hypothalamic-pituitary-gonadal axis
    • Hypothalamic-pituitary-adrenal axis
  2. Associations of the endocrine system with drug use
    • Opiates
    • IVDA
    • Marijuana
    • HIV infection with or without IVDA
  3. End-organ effects of endocrine abnormalities
    • Sexual function
    • Body composition
    • Cardiovascular
  4. Unanswered questions about endocrine function in IVDA
    • Verification of abnormalities
    • Mechanism of abnormalities
    • Benefits of treating the endocrine imbalance

Lecture Objective

  • To understand the associations among endocrine abnormalities and chronic illness, HIV infection, and drug abuse.
  • To appreciate the effects of these endocrine abnormalities on the prognosis of the underlying illness.

Abstract

Endocrine abnormalities can be primary to organ pathology or secondary to other disease states. Hormonal imbalances secondary to acute or chronic illness is becoming better recognized and appreciated as both a result of illness and a cause of further decline. Very little is known of the hormonal milieu in individuals with IVDA. Older studies suggest declines in serum sex hormones in both men and women. More recent studies have noted increases in ACTH and cortisol, which could result in immunosuppression. The hypogonadism observed in the presence of HIV infection is due to the general effects of chronic illness and the specific actions of drugs and infections unique to the condition. The relationship of low-serum testosterone levels to decreased lean body mass and wasting has presented new opportunities for treatment. The possible benefits of hormonal replacement therapy on body composition is intriguing, but completely untested at this point. A better understanding of the interrelationships of IVDA and hormones is still needed.

Synergism Among Nutrient Deficiencies and Immune Dysfunction in Murine AIDS: Roles of Cocaine, Alcohol, and DHEA Supplementation

Ronald Ross Watson, Ph.D.
University of Arizona School of Medicine

Lecture Outline

  1. Definition of the murine AIDS model.
  2. Overview of methods to slow immune dysfunction and thus nutritional deficiencies during murine AIDS: T-cell receptor peptide, anti-IL-4, interferon-gamma replacement, DHEA vitamin E supplementation.
  3. Description of the effects of cocaine on retroviral immune dysfunction.
  4. Discussion of recent model study where DHEA therapy reduced immune dysfunction while ethanol consumption accentuated it. DHEA also reduced the toxic effects of alcohol on immune and nutritional parameters.
  5. Conclusions: Use of murine AIDS model rapidly defines studies and hypotheses for testing in HIV-infected humans. It shows the potential actions of drugs of abuse on immune and nutritional damage due to retroviral infection.

Abstract

Infection of female C57BL/6 mice with LP-BM5 murine retrovirus mixture is an economic model (1) that has most of the immune and nutritional changes seen in HIV-infected people. After 4.5 months of infection, severe loss of cytokine dysregulation, suppressed resistance to opportunistic pathogens, reduced antioxidant vitamin levels (2), and B-cell leukemia occur (1). Simultaneous cocaine injection at 40 mg/kg/day (3,4) or consumption of water containing 40% or food containing 30% (5) ethanol during murine AIDS accentuates these changes.

The murine AIDS model has rapidly defined several methods to maintain much of immune function and normal nutritional state using T-cell receptor peptide injection (6), vitamin E or A supplementation (7), melatonin or DHEA (dehydroepiandrosterone) consumption (8,9), replacement of suppressed production of interferon-gamma, and anti-IL-4 antibody suppression of excessive T helper 2 cell cytokine production (10). Our recent data show that DHEA supplementation helped overcome some of the immune and nutritional damage due to retrovirus infection (9) including their accentuation by ethanol consumption. Production of Th1 cytokines was suppressed by murine AIDS, with ethanol consumption accentuating this process. DHEA retarded this suppression while overcoming some of the excessive cytokine secretion by Th3 cells and their related suppression of B and T cell mitogenesis. Simultaneously, increased oxidation and loss of tissue vitamin E due to murine AIDS and accelerated by ethanol use were reduced. Similar synergistic effects would be expected from cocaine and murine retrovirus infection. Reduction of cytokine dysregulation by DHEA (9) as well as other agents (5-7) also reduces nutritional deficiencies.

Thus the murine AIDS model offers a rapid, economic, and immunologically relevant way to assert the effects of hormones and nutrient supplements on retroviral and drug-induced immune damage. Supported by NIH grant 59794.

References

  • Liang, B.; Wang, J.Y.; and Watson, R.R. Murine AIDS, a key to understanding retrovirus- induced immunodeficiency. Viral Immunol 98:225-239, 1998.
  • Zhang, Z.; Inserra, P.; Liang, B.; and Watson, R.R. Antioxidants and AIDS. In: Nutrients and Foods in AIDS. CRC Press, 1998. pp. 179-192.
  • Lopez, M.D.; Chen, G.J.; Huang, D.S.; and Watson, R.R. Modification of spleen cell subsets by chronic cocaine administration and murine retrovirus infection in normal and protein-malnourished mice. Int J Immunopharmacol 14:1153-1163, 1992.
  • Darban, H.; Watson, R.R.; Alak, J.; and Thomas, N. Cocaine facilitation of cryptosporidiosis by murine AIDS in male and female C57/BL6 mice. In: Drugs of Abuse, Immune and AIDS, 1993. pp. 143-151.
  • Wang, J.Y.; Liang, B.; and Watson, R.R. Alcohol consumption alters cytokine release during murine AIDS. Alcohol 14:155-159, 1997.
  • Liang, B.; Ardestani, S.; Chow, H.H.; Eskelson, C.; and Watson, R.R. Vitamin E deficiency and immune dysfunction are prevented in retrovirus-infected C57BL6 mice by T cell receptor peptide treatment. J Nutr 126:1389-1397, 1996.
  • Wang, Y.; Huang, D.S.; Liang, B.; and Watson, R.R. Nutritional status and immune responses in mice with murine AIDS are normalized by vitamin E supplementation. J Nutr 124:2024-2032, 1994.
  • Watson, R.R.; Chung, S.; Huls, A.; and Araghiniknam, M. Dehydroepiandrosterone (DHEA) and diseases of aging. Drugs Aging 9:274-291, 1996.
  • Arighiniknam, M.; Liang, B.; Zhang, Z.; Ardestani, S.; and Watson, R.R. Modulation of immune dysfunction during murine leukemia retrovirus infection of old mice by dehydroepiandrosterone sulfate (DHEAS). Immunology 90:344-349, 1997.
  • Wang, Y.; Ardestani, S.K.; Liang, B.; Beckham, C.; and Watson, R.R. Anti-interleukin-4 monoclonal antibody and interferon-gamma administration retards development of immune dysfunction and cytokine dysregulation during murine AIDS. Immunology 83:384-389, 1994.

Changes in Weight and Body Composition Among HIV+ Substance-Using African-American and Latino Men and Women

Sai Subhasree Raghavan, Ph.D.
Harlem Hospital Center and Columbia University College of Physicians and Surgeons

Lecture Outline

  1. Prevalence and predictors of wasting among HIV+ substance users.
  2. Comparison of body composition among substance-using and non-substance-using HIV+ and HIV- individuals.
  3. Gender differences in body composition between HIV+ substance- and non-substance- using individuals.
  4. Comparison of longitudinal changes in weight and body composition among HIV+ substance-using and non-substance-using individuals, pre-HAART and post-HAART era.
  5. Impact of substance use on weight gain during pregnancy and its effect on infant outcome in HIV+ and HIV- women.
  6. Incidence of HAART-related metabolic complications among substance-using and non- substance-using individuals.
  7. Special issues and ethical dilemmas in treatment of nutritional problems among substance users.

Learning Objectives

  • To learn the impact of substance use on weight and body composition among HIV+ individuals.
  • To learn to differentiate substance-use-associated wasting from that of HIV-associated wasting.

Abstracts

Substance use plays a central role in HIV infection, accounting for one-third of the HIV-infected cases and accounting directly or indirectly for 80% of AIDS cases in women in the United States. Nutrient deficiencies are common in substance-using individuals due to increased nutrient needs, compromised liver and kidney activation of vitamins and coenzymes, poor or haphazard nutrient intake, increased catabolism and hyperexcretion, reduced liver storage, malabsorption and malutilization, and drug inactivation of vitamins. It is well documented that use of drugs such as heroin, cocaine, and marijuana affects food and liquid intake behavior, which in turn will result in development of malignant and infectious complications. Malnutrition due to inadequate food intake can impair immunity and, thus, influence susceptibility to infectious agents, including HIV. Despite two decades of research on AIDS- associated wasting, limited information is available on the prevalence, pathophysiology, and treatment of nutritional deficiencies among drug users.

We conducted several studies to answer a few of these crucial questions. One such study will examine the changes in weight and body composition among drug-using and non-drug-using HIV+ men and women to differentiate the impact of substance use from that of HIV. Additional studies that will be discussed include the impact of substance use on weight gain during pregnancy in HIV+ women and the incidence of metabolic complications among substance-using and non-substance-using HIV+ individuals on HAART therapy.

References

  • Alcabes P and Friedland G, Injection drug use and Human Immunodeficiency Virus Infection, Clinical Infectious Diseases, 1995;20:1467-79.
  • Mohs ME, Watson RR, Leonard-Green T, Nutritional effects of Marijuana, heroin, cocaine and nicotine, J. Am. Diet Assoc 1990; 90: 1216-7.
  • Altes J, Dolz C, Obrador A, Forteza-Rei J. Prevalence of protein-energy malnutrition in heroin addicts hospitalized for detoxification. J Clin Nutr Gastroenterology 1988; 68:519-31.
  • Mosenson M, Zeleniuch-Jacquotte A, Belsito DV, Shore RE, Marmor M, Pasternack B. The potential role of nutritional factors in the induction of immunological abnormalities in HIV-positive homosexual men. J Acquir Immune Defic Syndrome 1989; 2:235-47.

Medical Consequences in Malnourished HIV-Infected Drug Abusers

Michael S. Hickey, M.D.
University of California at San Francisco

Outline

  1. Introduction
    1. Level I Trauma Center
    2. County facility
    3. High-volume HIV/malnourished patients
  2. San Francisco General Hospital Nutrition Support Service
    1. Daily census: 15-20
    2. 20-25% patients are HIV positive
    3. Average admission albumin less than 2.5 gm
    4. Average weight loss of HIV-positive patients treated by the Trauma Surgical Service is greater than 14 kg
  3. SFGH Trauma Surgical admissions
    1. Soft tissue infections (STI) admitted to SFGH Trauma Surgical Service in:
      1996 = 1,131
      1997 = 1,299
    2. Total admissions to SFGH Trauma Surgical Service in:
      1996 = 19,992
      1997 = 20,622
    3. % STI vs. total admissions in:
      1996 = 5.6
      1997 = 6.3
  4. Clinical examples of soft tissue infections/necrotizing infections secondary to intravenous drug abuse
  5. Operative analysis
    1. STI requiring operative procedures:
      1996 = 841
      1997 = 858
    2. Total trauma surgical operatives procedures:
      1996 = 3,094
      1997 = 3,008
    3. % STI vs. total operative procedures:
      1996 = 27.18
      1997 = 28.50
  6. Cost per 4 day STI operative admission
    1. Hospital and miscellaneous fees: $8,000.00
    2. Professional fees: 500.00
    3. Medication costs: 100.00
      Total: $8,600.00
  7. Cost analysis
    1. Average length of stay (days) of STI patients requiring operative procedures:
      1996 = 4.3
      1997 = 3.9
    2. Average cost per STI operative admission:
      1996 = $8,600
      1997 = $9,000
    3. Total cost for STI operative admissions:
      1996 = $7,232,600.00
      1997 = $7,722,000.00
  8. Potential risk factors for recurrent STI
    1. Malnutrition:
      Depleted body cell mass
      Depleted fat mass
      Malabsorption
    2. HIV status:
      Malabsorption
      Change in body composition
    3. Social factors:
      Access to clean needles
      Access to food
  9. Factors to evaluate in the STI study
    1. HIV status
    2. Nutritional status
    3. Degree of malabsorption
    4. Impact of social/nutritional support
  10. Intervention strategies
    1. Nutrition:
      Acute
      Chronic
    2. Social support
    3. Oral antibiotics for patients with gut dysfunction (malabsorption)
  11. Questions

Abstract

Soft tissue infections (STI) in malnourished, HIV-positive intravenous drug abusers are a challenging problem. San Francisco General Hospital (SFGH) is a county facility designated as a Level I Trauma Center. Twenty to twenty-five percent of the patients treated by the SFGH Trauma Surgical Service are HIV positive. The average albumin of these patients is 2.5 gm; the average weight loss is greater than 14 kg.

The Trauma Surgical Service admitted 1,131 patients with STI in 1996; 1,299 in 1997. These admissions represented 5.6 and 6.3 percent of all hospital admissions respectively. Soft tissue infections requiring operative procedures numbered 841 in 1996; 858 in 1997 or 27.18 and 28.50 percent of all operations performed in the respective years.

The management of these infections is both time consuming and costly. The length of hospitalization ranges from overnight to frequently several months duration. The average length of stay, however, was 4.3 days in 1996; 3.9 days in 1997. Hospital and miscellaneous fees average $2,000.00 per day in 1996. Professional and medication fees per admission averaged $500.00 and $100.00 respectively in 1996. The average cost per STI admission was $8,600.00 in 1996, but increased to $9,000.00 in 1997. The total cost for STI admissions was $7,232,600.00 in 1996; $7,722,000.00 in 1997.

Recurrent STI is a major problem. Ten to twenty percent of the STI treated by the Trauma Surgical Service fall into this category. Many of the patients treated at SFGH are admitted 5-10 times per year for incision and drainage of abscesses and expensive antibiotic therapy. The potential risks for recurrent STI include malnutrition (depleted body cell and fat mass, malabsorption), HIV status (malabsorption, change in body composition), and social factors (access to clean needles and food).

Potential factors to evaluate in an STI study would include HIV and nutritional status, degree of malabsorption and the impact of both social and nutritional support. Intervention strategies to consider would include aggressive nutritional therapy, both acute and chronic, social programs, and specific oral antibiotics modified for patients with gut dysfunction.

Suggested References

  • Santolaria-Fernandez, F.J. Nutritional assessment of drug addicts. Drug Alcohol Depend 38:11-18, 1995.
  • McCombie, L. Letters to the editor. Addiction 90:1117-1121, 1995.
  • Kotler, D.P.; Wang, J.; and Pierson, R.N. Body composition studies in patients with AIDS. Am J Clin Nutr 42:1255-1265, 1985.
  • Altes, J. Prevalence of protein-energy malnutrition in heroin addicts hospitalized for detoxication. J Clin Nutr Gastroenterol 3:55-58, 1988.
  • Aylett, P. Some aspects of nutritional state in "hard" drug addicts. Br J Addict 73:77-81, 1978.

Cognitive Function in HIV-1-Infected Intravenous Drug Users

Gail Shor-Posner, Ph.D.
University of Miami School of Medicine

Lecture Outline

  1. HIV and the Brain
    • Blood Brain Barrier
    • CNS Effects
  2. Cognitive Impairment
    • Evaluation
    • Prevalence of Deficits
    • Confounding Factors
    • Onset of Alterations
  3. Treatment/Prevention of Cognitive Dysfunction
    • Nutrition Cofactors
    • Antiretrovirals
  4. Future Research
    • Need for Further Studies
    • Areas of Concern/Limited Information

Learning Objectives

  • Understand the controversy regarding the prevalence and onset of cognitive alterations in HIV-1-infected drug users.
  • Become familiar with possible strategies for prevention/treatment of HIV-1-associated cognitive dysfunction.

Abstracts

Loss of cognitive ability, the most common neuropsychological complication in HIV-1 disease, may affect compliance, functional capacity, and be a significant predictor of early mortality (1). Detectable deficits in cognitive/motor function among HIV-1+ drug users have been described (2-4) and are similar to those observed in predominantly homosexual groups. In other studies, the use of toxic substances appears to be more important than the effect of the virus (5,6) and age and education more powerful predictors of cognitive function (7). Determination of cognitive impairment presents substantial difficulties, as confounding factors including substance abuse can affect performance and contribute to impairment. Additional research is necessary to clarify the effect of specific drugs and HIV-1 aspects of neuropsychological performance.

There is also controversy regarding the onset of cognitive impairment. Similar to research in other HIV-1-seropositive cohorts, some studies report that neuropsychological alterations in HIV-1-infected drug users precede clinical evidence of AIDS, as opposed to investigations revealing no evidence of dysfunction in the asymptomatic stage (5,6,8), emphasizing the need for further research.

Some of the cognitive dysfunction, observed in HIV-1-infected non-drug-using cohorts, may be due to inadequate nutritional status. Whereas low levels of cobalamin (vitamin B12) appear to contribute to cognitive changes (9), an increase in cobalamin has been linked to improved performance (10), underscoring the importance of determining nutritional status in cognitive assessment. Further research will be required to determine whether cobalamin administration and/or supplementation with micronutrients, which prevent oxidative damage, can be of therapeutic value in preventing cognitive decline in HIV-1-infected drug users.

References

  • Wilkie FL, Goodkin K, Eisdorfer C et al., Mild cognitive impairment and risk of mortality in HIV-1 infection. J Neuropsychiatry and Clinical Neurosciences 1998;10:125-132.
  • Del Pesce M, Franciolini B, Censori B et al., Cognitive behavior in asymptomatic (CDC stage II and III) HIV-seropositive intravenous drug users (IVDUs). Ital J Neurol Sci. 1993;17:619-625.
  • Handelsman L, Aronson M, Roick H, Mauss S, Arendt G. HIV-specific changes in the motor performance of HIV-positive intravenous drug abusers. J Neurol 1994;242:20-25.
  • Silberstein CH, O'Dowd MA, Chartock et al., A prospective four-year follow-up of neuropsychological function in HIV seropositive and seronegative methadone-maintained patients. Gen Hosp Psychiatry 1993;15:351-359.
  • Egan VG, Crawford JR, Brettle RP, Goodwin GM. The Edinburgh cohort of HIV-positive drug users: current intellectual function is impaired, but not due to early AIDS dementia complex. AIDS 1990;4:651-656.
  • Grassi MP, Clerici F, Perin C et al., HIV infection and drug use: influence on cognitive function. AIDS 1995;9:165-170.
  • Concha M, Graham NMH, Munoz A et al., Effect of chronic substance abuse on the neuropsychological performance of intravenous drug users with a high prevalence of HIV-1 seropositivity. Am J Epidemiol 1992;136:1338-48.
  • Selnes, OA, Galai N, McArthur JC et al., HIV infection and cognition in intravenous drug users: Long-term follow-up. Neurology 1997;48:223-230.
  • Beach RS, Morgan R, Wilkie F et al., Plasma vitamin B12 level as a potential cofactor in studies of human immunodeficiency virus type 1-related cognitive changes. Arch Neurol 1992;49:501-506.
  • Shor-Posner G, Morgan R, Wilkie F, Eisdorfer C, Baum MK. Plasma cobalamin levels affect information processing speed in a longitudinal study of HIV-1 disease. Arch Neurol 1995;52:195-198.

Potential Interventions for HIV/AIDS Wasting: Overview

Donald I. Abrams, M.D.
Community Consortium

Abstract

Prior to the current era of highly active antiretroviral therapies (HAART), the wasting syndrome was a frequent late-stage manifestation of advanced HIV infection. The etiology of wasting was felt to be multifactorial. Attempts to reverse the syndrome with nutritional or single pharmacologic interventions were generally unsatisfactory. Just as potential progress in the treatment of weight loss from the use of combined modalities of therapy was about to become realized, the AIDS wasting syndrome all but disappeared with the advent of HAART. Now, after 3 years of widespread use of protease-inhibitor-containing regimens, another constellation of alterations in body composition is presenting patients and providers with a new set of therapeutic challenges. Again, a multipronged approach to therapy will likely be required.

Numerous approaches to HIV-associated weight loss have been attempted. Prevention is always a desirable goal. A recent CPCRA trial demonstrated no effect of dietary supplements in forestalling weight loss in at-risk patients. Appetite stimulants (megestrol acetate and dronabinol) have been approved for treatment of HIV-associated anorexia and weight loss, but both are associated with some untoward side effects. Smoked marijuana has become a popular alternative in some regions. Anabolic agents such as testosterone, anabolic steroids, and recombinant human growth hormone may improve weight loss alone or in combination with appetite stimulants or resistance exercise. Inhibitors of tumor necrosis factor alpha, such as thalidomide, are also being investigated and show some promise as therapy, with combination regimens currently under evaluation.

References

  • Berger JR, Pall L, Hall CD, Simpson DM, Berry PS, Dudley R. Oxandrolone in AIDS-wasting myopathy. AIDS 10:1657-62, 1996.
  • Bhasin S, Storer TW, Berman N, Callegari C, Clevenger B, Phillips J, Bunnell TJ, Tricker R, Shirazi A, Casaburi R. The effects of supraphysiologic doses of testosterone on muscle size and strength in normal men. N Engl J Med 335(1):1-7, 1996.
  • Bucher G, Berger DS, Fields-Gardner C, Jones R, Reiter WM. A prospective study on the safety and effect of nandrolone decanoate in HIV-positive patients. Int Conf AIDS 11(1)26. Abstract no. Mo.B.423, 1996.
  • Gold J, High H, Li Y, Michelmore H, Bodsworth NJ, Finlayson R, Furner VL, Allen BJ, Oliver CJ. Safety and efficacy of nandrolone decanoate for treatment of wasting in patients with HIV infection. AIDS 10:745-52, 1996.
  • Gorter R, Seefried M. Volberding P: Dronabinol effects on weight in patients with HIV infection. AIDS 6:127-128, 1992.
  • Oster MH, Enders SR, Samuels SJ, et al. Megestrol acetate in patients with AIDS and eachexia. Ann Intern Med 121:400-408, 1994.
  • Schambelan M, Mulligan K, Grunfeld C, et al. Recombinant human growth hormone in patients with HIV-associated wasting: A randomized, placebo-controlled trial. AIDS 125:873-882, 1996.
  • Stack JA, Bell SJ, Burke PA, Forse RA. High-energy, high-protein, oral, liquid, nutrition supplementation in patients with HIV infection: Effect on weight status in relation to incidence of secondary infection. J Am Diet Assoc. 96:337-41, 1996.
  • Von Roenn JH, Armstrong D, Kotler DP, Cohn DL, Klimas NG, Tchekmedyian NS, Cone L, Brennan PJ, Weitzman SA. Megestrol acetate in patients with AIDS-related cachexia. Ann Intern Med 121:393-99, 1994.
  • Von Roenn JH, Knopf, K. Anorexia/cachexia in patients with HIV: Lessons for the oncologist. Oncology 10(7):1049-56, 1996.

Pathogenesis of and Intervention for Malnutrition in HIV Infection

Donald P. Kotler, M.D.
St. Luke's-Roosevelt Hospital Center
Columbia University College of Physicians and Surgeons

Learning Objectives

  • To review the major pathogenic features underlying malnutrition in HIV infection.
  • To review the studies of nutritional support in HIV infection.

Abstract

Malnutrition is common in HIV-infection and plays an independent and significant role in its morbidity and mortality. Early studies showed weight loss and evidence of protein depletion, while body composition documented depletion of body cell mass in HIV-infected men, with more prominent losses of fat in women. Malnutrition in HIV infection promotes adverse clinical outcomes, including shortened survival and diminished quality of life. The development of malnutrition is multifactorial, varies as a function of disease stage and disease complications, and includes alterations in intake, absorption, or metabolism. Metabolic abnormalities in HIV-infected individuals include elevations in resting energy expenditure (REE), increased protein turnover in clinically ill patients, alterations in fat metabolism, and hypogonadism. HIV infection itself may promote malnutrition, as body cell mass depletion and elevated REE occur in early-stage subjects, weight loss and REE correlate with plasma viral load, and weight gain may occur during antiretroviral therapy. The relative contributions of the various pathogenic mechanisms is uncertain, though two studies have shown that decreased food intake is the major predictor of weight loss and that total energy expenditure is not elevated in systemic infections associated with weight loss.

Several studies have documented weight gain during nutritional support. Increasing caloric intake by nutritional counseling, nutritional formulae, appetite stimulants, and enteral and parenteral tube feedings all may increase caloric intake and body weight. However, these techniques may fail to lead to body cell mass repletion. For this reason, adjunctive therapies for wasting have been applied, including anabolic agents, cytokine inhibitors, and resistance exercise training. The optimal nutritional support for an HIV-infected individual remains to be determined.

References

  • Coodley, G.O.; Loveless, M.O.; Nelson, H.D.; and Coodley, M.K. Endocrine function in the HIV wasting syndrome. J Acq Immunodefic Syndr 7:46-51, 1994.
  • Grinspoon, S.; Corcoran, C.; Miller, K.; Biller, B.M.K.; Askari, H.; Eang, E.; Hubbard, J.; Anderson, E.J.; Basgoz, N.; Heller, H.M.; and Klibanski, A. Body composition and endocrine function in women with the acquired immunodeficiency syndrome. J Clin Endocrinol Metab 82:1332-1337, 1997.
  • Grunfeld, C.; Pang, M.; Shimizu, L.; Shigenaga, J.K.; Jensen, P.; and Feingold, K.R. Resting energy expenditure, caloric intake, and short-term weight change in human immunodeficiency virus infection and AIDS. Am J Clin Nutr 55:455-460, 1992.
  • Grunfeld, C., and Feingold, K.R. Metabolic disturbances and wasting in the acquired immunodeficiency syndrome. N Engl J Med 327:329-337, 1992.
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