1. Nutrition: A Co-factor in HIV Infection/AIDS Progression Phara Jourdan Rosabelle Campos March 28, 2005

2. Outline Trends & Prevalence Overview of HIV Infection/AIDS Application of HAART AIDS Wasting Syndrome HIV-Associated Lipodystrophy Nutritional Interventions Case Study Summary Discussion

3. HIV/AIDS Worldwide 38 million people live with HIV/AIDS worldwide. Sub-Saharan Africa is home to 70% of the people living with HIV. 2.1 million children are infected with HIV/AIDS in the world

4. Top HIV/AIDS-Infected Countries 1. South Africa 2. Nigeria 3. Zimbabwe 4. Tanzania 5. The Congo 6. Ethiopia 7. Kenya 8. Mozambique Source: Steinbrook R. The AIDS epidemic in 2004. NEJM. 2004;351:115-117. 9.United States 10.Russian Federation 11.China 12.Brazil 13.Thailand Sub- Saharan Africa

5. AIDS Rates reported in 2002, US

6. Proportion of AIDS Cases, by Race/Ethnicity

7. AIDS = Acquired Immune Deficiency Syndrome Acquired - because it's a condition one must acquire or get infected with, not something transmitted through the genes Immune - because it affects the body's immune system, the part of the body which usually works to fight off germs such as bacteria and viruses Deficiency - because it makes the immune system deficient Syndrome - because someone with AIDS may experience a wide range of different diseases and opportunistic infections

8. Modes of Transmission Unprotected intercourse Injection drug use Other unsafe injections Blood transfusions Direct blood contact Mother to child Sources: 2004 Report on the global AIDS epidemic. Geneva: Joint United Nations Program on HIV/AIDS, July 2004. Steinbrook R. The AIDS epidemic in 2004. NEJM. 2004;351:115-117.

9. The Human Immune Deficiency Virus

10. Pathophysiology of HIV/AIDS A retrovirus unknown until early 1980s: 1. Cannot replicate outside of living host cells 2. Contains only RNA; no DNA 3. Destroys the body’s ability to fight infections and certain cancers 4. Infects CD4 cells – the primary target of HIV infection Patients infected with HIV are at risk for illness and death from: 1. Opportunistic infections 2. Neoplastic complications

11. CD4 Count in HIV infection The CD4 cell, also known as "T4" or "helper T cell“ is responsible for signaling other parts of the immune system to respond to an infection. Normal counts range from 500 to 1500 cells per cubic millimeter of blood Initially in HIV infection there is a sharp drop in the CD4 count and then the count levels off to around 500-600 cells/mm 3. CD4 count is a marker of likely disease progression. CD4 percentage tends to decline as HIV disease progresses. CD4 counts can also be used to predict the risks for particular conditions such as Pneumocystis carinii pneumonia, CMV disease or MAI disease. Treatment decisions are often based on Viral Load and CD4 count.

12. Natural History of Untreated HIV Infection

13. Opportunistic Infections

14. Manifestations of HIV Infection Primary InfectionClinical LatencyAdvanced Disease often asymptomatic or overlooked symptoms 1-6 weeks after infection viral like syndrome: sore throat, fever, lymphadenopathy, rash differential includes EBV, CMV, hepatitis, toxoplasmosis antibody (ELISA, Western Blot) may not be detected usually asymptomatic lymph nodes site of ongoing viral latency massive viral production destruction of CD4 cells a decrease in lean body mass without apparent total body weight change vitamin B12 deficiency increased susceptibility to food and water-borne pathogens. Symptomatic Plasma viremia begins to rise CD4 cell count falls further A decline in nutrient status or body composition Opportunistic infections develop: fever, weight loss, lymphadenopathy, thrush, diarrhea, malignancies, wasting syndrome, neurologic syndrome including dementia

15. AIDS Defined HIV positive with a CD4 cell count that is or has been less than 200 cells/mm 3 HIV positive with a CD4 percent below 14%. HIV positive and with an AIDS defining illness such as PCP, toxoplasmosis, MAC, Kaposi’s Sarcoma, etc. regardless of CD4 cell count

16. Antiviral Drug Therapy Nucleoside/ Nucleotide Analogues Nonnucleoside Reverse Transcriptase Inhibitors Protease Inhibitors Fusion Inhibitors Abacavir Didanosine Emtricitabine Lamivudine Stavudine Tenofovir Zalcitabine Zidovudine Delavirdine Efavirenz Nevirapine Amprenavir Atazanavir Fosamprenavir Indinavir Lopinavir/Ritonavir Nelfinavir Ritonavir Saquinavir Enfuvirtide

17. How HIV Drugs Work

18. Adverse Drug Effects Mitochondrial dysfunction Metabolic abnormalities Hematologic complications Allergic reactions Lactic acidosis Hepatic toxicity Pancreatitis Peripheral neuropathy Lipodystrophy Fat accumulation Lipoatrophy Hyperlipidemia/ ? Premature CAD Hyperglycemia Insulin resistance/DM Bone disorders: oesteoporosis and osteopenia Bone marrow suppression Hypersensitivity reactions Skin rashes

19. Medication Side Effects Anorexia Sore/dry/painful mouth Swallowing difficulties Constipation/Diarrhea Nausea/Vomiting/Altered Taste Depression/Tiredness/Lethargy

20. Pathogenesis of Malnutrition in HIV Infection

21. Malnutrition can... √ Contribute to impaired immune response √ Result in more rapid disease progression & shortened survival √ Contribute to increased frequency and severity of infections √ Result in fatigue, loss of appetite, sense of taste and smell, and decreased quality of life √ Decrease tolerance to therapy and lessen medication efficacy

22. Weight Loss: Independent Predictor of Mortality Weight loss and wasting have been predominant features of HIV disease progression since the beginning of the HIV/AIDS epidemic and have long been established as strong predictors of morbidity and mortality in patients infected with HIV. Several studies in the pre-HAART era showed that HIV-related wasting was strongly associated with more rapid disease progression and increased mortality in HIV-infected patients. With the advent of HAART and prophylaxis for opportunistic infections, many AIDS-defining illnesses that were previously frequent are now rarely seen in successfully treated patients. So the prevalence of HIV-related wasting syndrome has greatly diminished ; however, several studies have concluded that patients treated with HAART were still at risk for wasting. Wanke et al. found that ~1/3 of HIV-infected patients in the NFHL study who were treated with HAART were still at risk for wasting. Thus weight loss, regardless of treatment status, remains a strong predictor of death.

23. ‘The Wasting Syndrome’ The wasting syndrome is defined as weight loss >10% of baseline body weight with chronic fever, weakness, or diarrhea in the absence of other related illnesses contributing to the weight loss. ‘unexplained weight loss’ believed to be due to the HIV virus The wasting syndrome is so common in HIV infection that it is classified according to the Center for Disease Control (CDC 1987) as a diagnostic indicator of AIDS.

24. Pathophysiology AIDS Wasting Oxidative StressMicronutrient Deficiency Malabsorption/ Dysphagia Dietary Intake Negative Energy Balance Intestinal Parasites Protein Loss Fat Loss HIV Opportunistic Infection Immune Function Pro-inflammatory Cytokines (TNF alpha) Anorexia Metabolic Rate Endocrine Disorder Skeletal Protein Breakdown J AIDS 1988

25. Potential Mechanisms of AIDS Wasting 1) Increased energy expenditure 2) Decreased energy intake 3) Altered metabolism 4) Hormonal Alterations

26. Energy Expenditure A review of the literature shows: Increased REE depending on the stage of immunodeficiency (denoted by the CD4 count) and the presence of active infections—measured by indirect calorimetry. Elevated REE in asymptomatic subjects A direct relationship between REE and plasma HIV viral burden Compared with healthy controls, pts with AIDS and active infections had a 34% increase in BMR; stable pts with AIDS were found to have 21% increase. Melchior JC, et al, Mulligan et al

27. Calculating Energy Needs BWH standard is BMR x AF x SF + weight gain (if applicable) Injury/Stress Factors: HIV = 8-15% AIDS = 20-30% AIDS with secondary infection = 30% Protein: 1.2 – 1.8g/kg (depending on clinical status)

28. Nutritional Problems Decreased appetite may result from fever, pain, fatigue, emotional stress, and altered sensations of taste and smell due to medication side effects. Lactose intolerance is an early effect of HIV on the intestinal tract due to the loss of lactase. The HIV infection changes the structure of the gut wall, resulting in a decreased lactase level. Intolerance results in fermentation causing abdominal cramping and a bloated feeling. Oral Lesions, caused by Candida albicans, herpes, or Kaposi’s sarcoma can make chewing and swallowing difficult and painful.

29. Nutrional Problems (cont) Diarrhea and malabsorption can result from direct HIV infection in the intestine but are more often caused by other pathogens such as bacteria, Crytosporidium, or herpes simplex that take advantage of the depressed immune system. Medications can interfere with eating by causing GI discomfort, nausea, vomiting, diarrhea, and altered taste Depression often leads to isolation, apathy, neglect of self-care, and diminished appetite – all which can affect immunocompetence Socioeconomic factors play an important role in whether the patient can afford adequate and nutritious food.

30. Altered Metabolism Early studies documented weight loss and protein depletion in untreated patients The application of HAART has led to a decreased incidence of malnutrition Syndrome of altered body fat distribution has emerged (lipodystrophy) associated with PIs Hypertriglyceridemia, hypercholesterolemia, and insulin resistance are commonly seen in patients treated with HAART therapy.

31. HIV-Associated Lipodystrophy FatatrophyFataccumulation Hyperlipidemia Insulin resistance

32. What Causes Lipodystrophy? Syndrome most likely has a multi-factorial etiology Most patients who have lipodystrophy started noticing symptoms while they were on triple-drug therapy. Lipodystrophy was first reported among patients taking combinations of drugs that included a protease inhibitor (PI). There are also some patients who have experienced one or more symptoms of lipodystrophy without taking any anti-HIV drugs at all. It's still not clear what role these anti-HIV drugs play in the development of lipodystrophy.

33. What does Lipodystrophy look like?

34. Hormonal Factors Testosterone deficiency: Testostereone levels have been found to be markedly reduced in some HIV-infected patients and a reduction in free serum testosterone levels correlates closely with loss of BCM. Growth hormone resistance or deficiency: Many HIV-infected patients with hypogonadism or malnutrition display functional GH resistance. Anabolic/Anti-catabolic agent Important in maintaining protein balance and muscle mass

35. Nutritional Supplements in HIV Infection to counteract AIDS Wasting MVI Glutamine Carnitine Appetite Stimulant Hormone Therapy Resistance Training

36. Role of Micronutrients in the Pathogenesis of HIV infection Micronutrients play important roles in maintaining immune function and neutralizing the reactive oxygen intermediates produced by activated macrophages and neutrophils in their response to microorganism Micronutrient deficiencies are common among HIV infected persons. Micronutrient deficiency has been associated with further immunopression, oxidative stress, subsequent acceleration of HIV replication and CD4+ T-cell depletion. (semba)

37. Fawzi et al. Study: Randomized controlled trial of multivitamin supplementation among HIV-infected pregnant women in Tanzania. Subjects: n=1078, 2 yr study Method: Compared supplementation consisting of multivitamins alone, vitamin A alone, or both with placebo Results: Women who were randomly assigned to receive multivitamin supplementation were less likely to have progression to advance stages of HIV disease, had better preservation of CD4+ T-cell counts and lower viral loads had lower HIV-related morbidity and mortality rates Vitamin A appeared to reduce the effect of multivitamins and, when given alone, had some negative effects Conclusion: Multivitamin supplementation could reduce the risk of or delay HIV-associated disease and mortality. New England Journal Medicine, 2004

38. Glutamine Application in HIV/AIDS Glutamine is the most abundant amino acid in the body and is considered a conditionally essential amino acid during periods of catabolism. During periods of increased metabolic stress, glutamine is released freely from the skeletal muscle, and intracellular glutamine concentrations fall by more than 50% Increased de novo synthesis of glutamine in the skeletal muscle often results in muscle-wasting syndrome Glutamine synthesis cannot keep up with the higher requirements during stress. Individuals deficient in glutamine manifest changes in gut morphology including increased membrane permeabilitiy resulting in bacterial translocation, malabsorption, and diarrhea Lack of support to immunocytes and fibroblasts cause immunosuppression and impaired wound healing

39. Glutamine Application in HIV/AIDS (cont…) Data suggest that glutamine supplementation offers the potential to limit skeletal muscle wasting, reduce diarrhea and malabsorption, enhance immune host defense, and reduce the incidence of opportunistic infections associated with HIV infection and AIDS Shabert J et al. Med Hypotheses. 1996;46:252-256

40. Glutamine: ↑body BCM in AIDS patients with Weight Loss Double-blind, placebo-controlled trial N=26 patients with >5% weight loss since disease onset Subjects received GLN-antioxidants (40g/d) in divided doses or glycine (40g/d) as the placebo for 12 wks. Result: Over 3 mos, the GLN-antioxidant group gained 2.2kg in body weight (3.2%), whereas the control group gained 0.3kg (0.4%) P=0.04 for difference between groups. The GLN-antioxidant group gained 1.8kg in body cell mass, whereas the control group gained 0.4kg (P=0.007.) Intracellular water increased in the GLN-antioxidant group but not in the control group. In conclusion, GLN-antioxidant supplementation can increase body weight, body cell mass, and intracellular water when compared with placebo supplementation. Shabert J, Winslow C. et al. Nutrition 1999;15:860-864

41. L-Carnitine in HIV Infection Carnitine is a conditionally essential amino acid found predominantly in red meat. It is also found in milk (human and cow’s), pork, lamb, tempeh, and supplements. It is conditionally essential because the body can make it from lysine and methionine with assistance from Vitamin C and other compounds produced in the body. Carnitine is synthesized in the Kidney and stored in the muscles. Carnitine’s function is to shuttle long-chain fatty acids into the mitochondria to be utilized as fuel. HIV/AIDS is a risk factor for carnitine deficiency

42. Carnitine cont’d (Morretti, et al.) Small study (n=11), Italy Pt’s refusing ART, normal Carnitine levels, stable weight, declining CD4 counts, asymptomatic 6 g intravenous Carnitine Qday times 150 days By second week, all subjects report increased feeling of well-being CD4 cell counts significantly increased by day 90 and 150, but there was an evident (non-significant) positive trend at day 15 and 30 compared to baseline. Overall upward trend in CD8 cell counts as well Only moderate changes in plasma viral load No toxicity was reported at this level Authors conclude that carnitine targets immune system rather than virus Authors propose possibility that carnitine’s antiapoptotic effect could be due to antioxidant activity Morretti, et al. Effect of L-Carnitine on Human Immunodeficiency Virus-1 Infection-Associated Apoptosis: A Pilot Study, Blood, Vol 91, No. 10, May 15, 1998: pp 3817-3824

43. Appetite Stimulant: Dronabinol Derived from delta-9-tetrahydrocannabinol (major active component of Marijuana) Useful in decreasing nausea and increasing appetite Insignificant gains or even loss of total BW May induce central nervous system events such as anxiety, confusion, emotional lability and hallucinations, possibly addictive. Treatment Guidelines for HIV Associated Wasting, Mayo Clinic Proceedings, April 2000

44. Appetite Stimulant: Megestrol Acetate (Megace) A synthetic derivative of the natural steroid hormone, progesterone. Improved appetite in a number of studies Takes two weeks for effect. Considerable increases in BW, although mostly in body fat May be due to testosterone lowering effect, not reversed by supplementation w/testosterone May induce or exacerbate DM, cause adrenal insufficiency when abruptly discontinued after long-term use Treatment Guidelines for HIV Associated Wasting, Mayo Clinic Proceedings, April 2000

45. Testosterone & Testosterone Analogues About half of men with advanced HIV have androgen deficiency. May contribute to muscle wasting. May be due to effects of undernutrition, chronic illness, or medications such as Megesterol acetate’s effect on gonadotropin secretion. 25% have primary hypogondadism most often idiopathic but may be due to OI, malignant infiltration of testes, or testicular effects of HIV infection or medication. Most studies have shown IM testosterone supplementation to result in wt gain, increased LBM, overall feeling of well-being. Studies of testosterone analogues show varied efficacy in improving nutritional status but may carry risks for hepatic toxic effects: Nandrolone decanoate 100mg/mL IM q 2wks = increased BW, LBM and quality of life. Oxymethalone 150 mg/day found to have similar results Testosterone cypionate 200mg IM q 2wks for 3 mos, no result except for increased quality of life. Treatment Guidelines for HIV Associated Wasting, Mayo Clinic Proceedings, April 2000

46. Growth Hormone AIDS pts may be growth hormone resistant. In studies of GH in AIDS pts, doses used are significantly higher than those required for replacement. GH has been shown to increase LBM and protein synthesis and reduce urinary nitrogen excretion. GH costs ~$18,000/yr but Medicaid has approved reimbursement, making this therapy more accessible. Short-term use of growth hormone (12 wks) has effects on wt gain that persist after therapy is discontinued. Using GH for short periods when required, rather than as continuous therapy will minimize costs while maximizing patient nutritional status. Indicated for use when all other methods have failed and pt has normal testosterone levels or on replacement testosterone for at least 4-6 wks. Contraindicated if pt has malignancy Treatment Guidelines for HIV Associated Wasting, Mayo Clinic Proceedings, April 2000

47. Resistance Training Supervised exercise training is a promising anabolic strategy for pts with AIDS. Studies of exercise training have shown increased muscle function, wt gain, strength, LBM. Effects of resistance training alone in AIDS wasting pts remains unknown. However, use of resistance training with testosterone and oxandralone has been shown to be effective in AIDS pts with AIDS wasting. Journal of the American Medical Association, April 14 199, Volume 281(14), pp 1282-1290. The New England Journal of Medicine, June 3 1999

48. Resistance Training (cont) Strawford, et al studied 24 eugonadal men with HIV associated wt loss. All subjects received supervised progressive resistance exercise with physiologic IM testosterone replacement 100 mg/wk to suppress endogenous testosterone for 8 weeks. Randomization was between anabolic steroid, oxandralone, 20 mg/day and placebo. Measured: LBM, nitrogen balance (10d met ward measure), body wt, muscle strength, and androgen status Result: 22 completed the study (11per group). Both showed sig increase in N retention, LBM, wt, and strength. The mean gains were sig greater in oxandrolone group than in placebo, greater strength gains for upper/lower body muscle groups by max wt lifted, and dynomometry. Mean HDL cholesterol dropped sig in oxandrolone group. Protease inhibitors made no difference in outcome. Conclusion: moderate androgen regimen (with oxandrolone) substantially increased lean tissue, strength gains from PRE, compared to testosterone replacement alone. Journal of the American Medical Association, April 14 1999

49. Summary HIV/AIDS remains an epidemic worldwide Malnutrition is a complication in HIV related morbidity and mortality Weight loss is an independent predictor of mortality Despite HAART, patients remain at risk for AIDS wasting syndrome Contributors of AIDS wasting syndrome include increased energy expenditure, decreased energy intake, altered metabolism, and hormonal factors Multivitamin supplementation could reduce the risk of or delay HIV-associated disease and mortality. Data suggest glutamine supplementation may help limit skeletal muscle wasting and increase BCM in patients with weight loss

50. Summary (cont) Pts have been found to be deficient in Carnitine, may benefit from supplementation since it may have antiapoptic effect through antioxidant activity. Appetite Stimulants may result in wt gain, but mostly in fat and may also have some negative side effects. Testosterone deficiency may lead to wasting, supplementation may be beneficial leading to improved sense of well being, strength, etc, however Testosterone analogues may be hepatotoxic. Correction of Growth Hormone resistance may help reverse wasting, but it is a costly intervention if pt does not have Medicaid. Short term use has been shown to be beneficial. Resistance training has been shown to increase wt and LBM, but one study found that training plus oxandralone was most beneficial.

51. Discussion Questions?

52. References Semba RD, Tang AM. Micronutrients and the pathogenesis of human immunodeficiency virus infection. Br J Nutrition 1999;81:181-9. Fawzi WW, Msamanga GI, Spiegelman D, et al. A randomized trial of multivitamin supplements and HIV disease progression and mortality. N Engl J Medicine 2004;351:23-32. Melchior JC, Niyongabo T, Henzel D, et al. Malnutrition and wasting, immunodepression, and chronic inflammation as independent predictors of survival in HIV-infected patients. Nutrition 1999; 15:865-9 Suttmann U, Ockenga J, Selberg O, et al. Incidence and prognostic value of malnutrition and wasting in human immunodeficiency virus-infected outpatients. J Acquir Immune Defic Syndrome Hum Retrovirol 1995;8:239-46. Silva M. Skolnik PR, Gorbach Sl, et al. The effect of protease inhibitors on weight and body composition n HIV-infected patients. AIDS 1998; 12:1645-51. Wanke CA, Silva M, Knox TA, et al. Weight loss and wasting remain common complications in individuals infected with human immunodeficiency virus in the era of highly active antiretroviral therapy. Clin Infect Dis 2000; 31:803-5 Tang, Alice M. et al. Weight loss and survival in HIV-Positive Patients in the Era of Highly Active Antiretroviral Therapy. JAIDS 2002;31:230-236 Mittendorfer B, Gore D, Herndon D, et al. Accelerated glutamine synthesis in critically ill patients cannot maintain normal intramuscular free glutamine concentration. J Parenter Enteral Nutri. 1999;23:243-252.

53. References Kotler, Donald P. Nutritional Alterations Associated with HIV infection. JAIDS 2000;25:81-87 Ott M, Lambke B, Fischer H, et al. Early changes of body composition in human immunodeficiency virus-infected patients: tetrapolar body impedance analysis indicates significant malnutrition. Am J Clin Nutr 1993;57:15-19 Melchior JC, Salmon D, Rigaud D, et al. Resting energy expenditure is increased in stable, malnourished HIV-infected patients. AM J Clin Nutr 1991;53:437-41 Rivera S, Briggs W, Qian D, et al. HIV RNA levels correlate with prior weight loss. Mulligan k, Tai VW, Schambelan M. Energy expenditure in human immunodeficiency virus infection. N engl J Med 1997; 336:70-1. HIV Prevalence in the United States, 2000. 9th Conference on Retroviruses and Opportunistic Infections, Seattle, Wash., Feb. 24-28, 2002. Abstract 11. Centers for Disease Control and Prevention (CDC). HIV and AIDS - United States, 1981-2001. MMWR 2001;50:430-434.4 Centers for Disease Control and Prevention (CDC). HIV Prevention Strategic Plan Through 2005. January 2001.5. Centers for Disease Control and Prevention (CDC). HIV/AIDS Surveillance Report 2002;14:1-40. Gerrior, Jul. Nutritional Challenges in HIV Infection. Tufts University School of Medicine Nutrition Infection Unit

54. References Morretti, et al. Effect of L-Carnitine on Human Immunodeficiency Virus-1 Infection-Associated Apoptosis: A Pilot Study, Blood, Vol 91, No. 10, May 15, 1998: pp 3817-3824 Treatment Guidelines for HIV Associated Wasting, Mayo Clinic Proceedings, April 2000, Volume 75(4), pp 386-394. Drug Therapy: Treatments for Wasting in Patients with the Acquired Immunodefeciency Syndrome, The New England Journal of Medicine, June 3 1999, Volume 340(22), pp 1740-50. Strawford, et al. Resistance Exercise and Supraphisilogic Androgen Thearpy in Eugonadal Men with HIV-Related Weight Loss: A Randomized Controlled Trial, Journal of the American Medical Association, April 14 1999, Volume 281(14), pp 1282-1290. Shabert J, Winslow C, Lacey JM. Wilmore DW. Glutamine-antioxidant supplementation increases body cell mass in AIDS patients with weight loss: a randomized, double-blind controlled trial. Nutrition 1999;15:860-864. Shabert JK, Wilmore DW. Glutamine deficiency as a cause of human immunodeficiency virus wasting. Med Hypotheses 1996;46:252-256.