HIV-related endocrinopathies recent 2.pptx

Hiv and its effect of various endocrine glands

1. Endocrinopathy in HIV Dr. Vivek Jha SR Endocrinology

2. Contents Introduction and Prevalence of HIV. HIV and Adrenal dysfunction. HIV and Gonadal Dysfunction. HIV and Thyroid disorders. HIV and Bone disorders HIV and anterior pituitary dysfunction AIDS related lipodystrophy and Wasting syndrome HIV and effect on Glucose haemostasis

3. Introduction HIV can involve any endocrine gland of the body. Isolated glandular involvement rare. Predictors of involvement: Lower baseline CD4 count IRIS Syndrome ART.

4. Causes of Endocrine Dysfunction P eak of the epidemic in 1996 : O pportunistic infections N eoplasms, including HIV-related malignancies Concomitant systemic illness Newer Concept Chronic metabolic complications of HIV therapy(ART) like I nsulin resistance and diabetes mellitus (DM) Dyslipidaemias A lterations in body fat distribution H ypogonadism Bone disease

5. Prevalence of HIV (NACO fact sheet) Adult (15-49 years) Prevalence (In %) 0.21 Number of people living with HIV (In Lakh) 24.01 HIV incidence per 1000 uninfected population 0.05

6. Adrenal Function

7. Adrenal Insufficiency Membreno L. et al, The Journal of Clinical Endocrinology & Metabolism. 1987; Most common endocrine disease in HIV. Diagnosis may be missed as the common presenting features are attributed to HIV/AIDS itself. Clinical Symptoms: 4% MC Aetiology: Opportunistic Infection

8. Aetiology of Adrenal Insufficiency

9. Predictors of Adrenal Insufficiency Female Longer disease duration IRIS Hyperkalemia Lower fasting glucose Low DHEAS Low Vitamin D

10. Infections

11. Drugs

12. Evaluation

13. Male Gonadal Function

14. Prevalence Secondary Hypogonadism>>Primary Hypogonadism B iochemical hypogonadism in AIDS - 50% Hypogonadism in HIV - 9% to 16%

15. Predisposing factors Age Obesity Insulin resistance CLD

16. Drugs

17. High SHBG levels - 30% to 55% Use bioavailable or free testosterone to diagnose hypogonadism. HIV and Male Hypogonadism

18. Proportion of hypogonadal men with normal T, low FT

19. Management Acute/chronic illness as suspected cause – retest by measuring an early morning free testosterone level on resolution of the illness. In patients who remain hypogonadal: Administration of physiologic testosterone replacement after appropriate diagnostic workup for the cause. No role of anabolic steroids alone or in combination with testosterone for the treatment of hypogonadism .

20. RATIONALE FOR TESTOSTERONE THERAPY Increases lean body mass Increases body weight Improves muscle strength

21. Female Gonadal Dysfunction

22. Presentation of Hypogonadism Clark RA et al. Frequency of anovulation and early menopause among women enrolled in selected adult AIDS clinical trials group studies. J Infect Dis. 2001

23. Causes of Androgen deficiency

24. Thyroid Function

25. Facts AND EVIDENCE Prevalence of overt hypothyroidism 2.5% Subclinical hypothyroidism 4% Overt hyperthyroidism 1%. Nonthyroidal illness 17% HIV therapy and specific antiretroviral medications were not associated with thyroid dysfunction Madge S et al., HIV Med. 2007 Regular screening is not warranted

26. Patterns of thyroid dysfunction in hiv Raised thyroid-binding globulin (TBG) levels. Decreased T3 levels With increasing illness :- Decreased rT3 levels How is it different from non-thyroidal illness?   Reverse T3 (rT3) levels do not rise in association with decreasing T3 levels. Asymptomatic HIV infected patients with stable body weight generally maintain normal thyroid function.

27. immune reconstitution syndrome (IRIS) and thyroid dysfunction Graves’ disease is most often reported in this context. E stimated P revalence 3% for women 0.2% for men Mechanism: Production of new immune cells targeting thyroid antigens.

28. infections

29. Drugs

30. Fluid Balance and Electrolytes

31. Sodium Prevalence of Hyponatremia with AIDS: 40% to 60% of hospitalized patients 20% of outpatients. SIADH 23% to 47% of hyponatremic patients Etiology: caused by infections/tumors Causes Hyponatremia among ill HIV-infected patients . : Adrenal insufficiency. HIV nephropathy : impaired water clearance Drugs : Vidarabine, miconazole, and pentamidine – (hyponatremia of unknown cause) Volume depletion (diarrhea, vomiting) with excessive free water Hypernatremia - by foscarnet -induced nephrogenic diabetes insipidus.

32. Potassium

33. Calcium Homeostasis and Bone Changes

34. hypocalcemia Prevalence of hypocalcemia – 6.5 % Calcium levels decrease progressively with stage of disease. Among patients with hypocalcemia, 48% were vitamin D deficient , and the expected increase in parathyroid hormone (PTH) levels was lacking in the majority. (mechanism unknown) Vitamin D deficiency may be caused by malabsorption from AIDS enteropathy or by specific effects of antiretroviral drugs.

35. Drugs

36. hypercalcemia

37. Bone disorders Risk factors: A ctivation of T-cells L ow CD4 cell count C oinfection with hepatitis B and C  HIV itself H ypogonadism Relative GH deficiency Vitamin D deficiency  Lipodystrophy ART(TDF) Patterns of bone Dysfunction Osteopenia Osteoporosis Osteomalacia Fractures

38. Bone Loss Osteopenia - 47.5% Secondary osteoporosis - 23% Factors associated with progression of bone loss: Age Male sex Lower body mass index (BMI) PI use TDF use Progression rates for osteopenia and osteoporosis Over 2.5 years follow up: 12.5% and 15.6% respectively. Over 5 years :18% and 29%

39. Screening for osteoporosis D ual-energy X-ray absorptiometry S creening is recommended earlier. P ostmenopausal Women and Men > 50 years of age.

40. Effects of “ART” on Bone Health I nitiation of ART is associated D ecrease in bone mineral density (BMD) of 2% to 6% Over a time period of 96 weeks . Mechanism Fanconi Syndrom (TDF>>TAF) Osteomalacia  Impairment of 1- α- hydroxylase(PPIs, Efavirenz) IRIS

41. Rasmussen TA, et al Comparison of bone and renal effects in HIV-infected adults switching to abacavir or tenofovir based therapy in a randomized trial. PLoS One. 2012

42. Age-specific fracture incidence rates (per 100 person-years) in human immunodeficiency virus–infected versus uninfected patients. Guerri-Fernandez R et al. J Bone Miner Res. 2013 Not significant

43. strategies to mitigate bone loss Avoid TDF /Protease inhibitors If already on TDF : Switch to abacavir, raltegravir , or tenofovir alafenamide(TAF). Smoking cessation and weight-bearing exercise Correction of hypogonadism. Calcium and Vitamin D supplementation

44. High-dose vitamin D3 (4000 IU/day) and calcium (1000 mg/day) At the time of ART initiation With TDF/emtricitabine/efavirenz Shown to attenuate ART-initiation– associated bone loss by 50%

45. Single dose of zoledronic acid (5 mg) prior to ART initiation prevented bone loss over 96 weeks (for patients at risk for fracture because of older age, lower BMD, or the presence of other fracture risk factors).

46. Osteoporosis treatment Mondy K et al. J Acquir Immune Defic Syndr . 2005 Bolland MJ, et al. J Clin Endocrinol Metab.2012 Fairfield WP et al. J Clin Endocrinol Metab . 2001

47. denosumab

48. Yin MT, Lund E, Shah J, et al. Lower peak bone mass and abnormal trabecular and cortical microarchitecture in young men infected with HIV early in life. AIDS . 2014 Subjects: HIV infected adults ages 20 to 25 years Tanner stage 5 I nfected either perinatally or during adolescence B oth volumetric bone density and cortical and trabecular thickness on high-resolution peripheral qCT was reduced S uggesting lower peak bone mass among HIV-infected patients

49. Vitamin D supplementation

50. The GH/IGF1 Axis

51. WHY basal and mean overnight GH concentrations ARE LOWER?

52. Based on GHRH and arginine stimulation test, up to one third of HIV-infected patients show evidence of biochemical growth hormone deficiency (GHD), albeit to a lesser degree compared with patients with structural pituitary disease. Reduced GH levels are inversely correlated with visceral obesity in HIV lipodystrophy. Biochemical GHD is more common in HIV-infected men than women (due to differences in adipose tissue distribution pattern). Diagnosis of GHD by stimulatory testing does not necessarily indicates clinical GHD. Management of GHD in HIV is controversial.

53. A summary of the effect of HIV on anterior pituitary Growth hormone Reduction in hormone levels Prolactin Increase in hormone levels ACTH Increase in hormone levels Thyroid hormones Increase and decrease of TSH depending on secondary factors FSH and LH decrease in FSH and LH

54. The AIDS Wasting Syndrome Definition Weight < 90% ideal body weight or weight loss greater than 10% over 3 months. Characterized by disproportionate loss of lean body mass, with relative sparing of body fat. Increased resting energy expenditure of 8% to 9%. Mechanisms: Cytokine Storm. Chronic weight loss associated with malabsorption. Hypogonadism(30% to 50%) may contribute to loss of lean body mass.

55. Treatment of AIDS Wasting - men Testosterone : B eneficial effect on lean body mass (2.0 kg over 6 months) improved quality of life. Anabolic steroids : Short-term use of anabolic steroids Nandrolone (100 mg intramuscularly every other week) I ncreasing weight and lean body mass with weight loss Prerequisite: E ugonadal patients with severe wasting. Role of DHEA I mprove mood and depression with subsyndromal depression and dysthymia.

56. Treatment of AIDS Wasting - women Testosterone Route: Transdermal patch (150 to 300 μg/day). Improvement of functional capacity and strength. Increase in lean body mass over 6 months. No Hirsutism and virilization. Dolan Looby SE, Collins M, Lee H, Grinspoon S. Effects of long-term testosterone administration in HIV-infected women: a randomized, placebo-controlled trial. AIDS. 2009 300 μg /day Testosterone : Increase in lean body mass. Increased BMD at the hip. Improved depression indices without aggravation of lipid or glucose parameters.

57. other treatment Options If Severe wasting refractory to conventional Treatment: High-dose, supraphysiologic GH (0.1 mg/kg per day). No role of Megestrol acetate.

58. Obesity and HIV Proportion of study sample by body mass index category at antiretroviral therapy initiation versus 2 years on therapy among treatment-naive human immunodeficiency virus–infected patients at the University of Alabama at Birmingham 1917 HIV/AIDS Clinic, 2000-2008. Purple bars = therapy initiation; teal bars = 24 months. HIV disease may be associated with overweight and obesity. Prevalence of underweight < 10% Prevalence of overweight and obesity - 44% (despite high viral load at ART initiation) With ART, 20% of patients increased from normal to overweight or overweight to obese . Subjects with more severe immune dysfunction and using boosted PIs tended to gain the most weight with ART.

59. Lipodystrophy Lipo-hypertrophy Visceral fat accumulation(VAT) +Subcutaneous fat normal/Decreased. F at accumulation in the dorsocervical area, trunk, and upper chest. Prevalence:70% May coexist with lipoatrophy. Lipoatrophy Loss of subcutaneous fat in the face, arms, legs, abdomen, and/or buttocks.  Not associated with loss of lean body mass(Unlike AIDS Wating). A/w Dysglycaemia and dyslipidaemia Risk Factors: Iatrogenic(NRTIs ,stavudine >>Zidovudine) Disease Severity Baseline body type

60. Natural History

61. Treatment

62. Percentage change from baseline in VAT and SAT at 26 (A) and 52 (B) weeks

63. Other Treatment Options for Lipo-hypertrophy Bhasin S et al. J Clin Endocrinol Metab . 2007 ; Kotler DP et al. J Acquir Immune Defic Syndr . 2004 ;

64. Increases in visceral fat and reductions in limb fat are independently associated with increased mortality rate in hiv -infected patients.

65. Lipid Abnormalities Prevalence: 54% More common in Lipodystrophy syndrome Before starting ART Hypertriglyceridemia(57%) Low HDL(46%) Low LDL High Atherogenic small LDL(Some studies) After starting ART LDL and Total cholesterol Returns to baseline Persistent Low HDL

66. Effect of art on lipid profile A ssociated with dyslipidemia in 28% to 80 % of patients. Lipid Unfavourable : Lopinavir/ritonavir, Tipranavir and fosamprenavir . Lipid favourable : D arunavir Atazanavir Mechanism I nhibition of adipocyte differentiation and lipogenesis, D ecreased clearance of chylomicrons and VLDL I ncreased synthesis of triglycerides by the liver Protease inhibitors

67. Effect of art on lipid profile N on-Nucleoside R everse T ranscriptase I nhibitors (NNRTIs) Lipid Unfavourable : Efavirenz Lipid favourable : Rilpivirine E travirine N evirapine  NRTIs Lipid Unfavourable : Stavudine, D idanosine , Zidovudine. Lipid favourable : A bacavir T enofovir Integrase standard transfer inhibitors (INSTIs)  Lipid Neutral

68. Hyperglycemia AND HIV P revalence of DM is between 2% to 14% . Recent study: DM prevalence of 11.8% Mechanism: Insulin resistance Predictive factors for DM in HIV:- BMI Lipodystrophy Low CD4 counts Exposure to stavudine and indinavir Significantly higher than 8.0% DM prevalence in general population

69. Mechanism of INSULIN RESISTANCE

70. Hyperglycemia and HIV Hemoglobin A1c (HbA1c) underestimates glycemia in HIV-infected patients by 0.2% to 0.5%. Why HbA1c underestimated? L ow-grade hemolysis H igher mean corpuscular volume NRTI use (specifically abacavir) R educed CD4 count Diagnosis of DM in HIV: HbA1c threshold cutoff is 5.8%.

71. Drugs

72. Management A ccording to current guidelines for the general population. Combination of Saxagliptin and PIs should be avoided. D olutegravir + Metformin combination :- Total daily dose of metformin should be limited to 1,000 mg. NRTIs should be cautiously used with pioglitazone:Because of downregulation of PPARγ .

73. NACO guidelines for dM in HIV All PLHIV should undergo screening, through random blood glucose test at Registration into HIV care or ART Initiation. 1–2 months after ART initiation and then at every 6 months. At change of regimen (substitution or switch). NNRTIs and PIs - increase/decrease in level of sulfonylureas, which may require dose adjustment of the sulfonylurea.

74. Leptin Treatment Prerequisites : Low Leptin levels +Lipodystrophy. HIV+ Lipoatrophy : I mprovements in insulin sensitivity. HDL and T riglyceride R educed truncal and visceral fat. Mulligan K et al. The effects of recombinant human leptin on visceral fat, dyslipidemia , and insulin resistance in patients with human immunodeficiency virus-associated lipoatrophy and hypoleptinemia . J Clin Endocrinol Metab . 2009 HIV + Mixed lipoatrophy and lipohypertrophy : Improvement in total cholesterol and non-HDL cholesterol Glucose parameters But not HDL or triglyceride or lipid kinetics.

75. Take home message Clinicians need to have a high index of suspicion for endocrine abnormalities in people with HIV as they can be potentially life threatening if untreated. Endocrine evaluation should be pursued as in the general population, with focus on prevention, early detection and treatment to improve quality of life and longevity. Compared to older ARTs, current ART regimens have significantly less adverse effects on lipid and glucose metabolism.  A wareness of possible drug interactions with concurrent HIV treatment is essential.

76. Next Seminar Newer Insulin Analogs and Once weekly Insulin. By Dr. Ashish.