Osteoporosis in the HIV-infected Patient: Update on Pathogenesis and Treatment Todd T. Brown, MD, PhD Division of Endocrinology, Diabetes, and Metabolism Johns Hopkins University

Disclosure Dr Brown has served as a consultant for Bristol-Myers Squibb, Abbott Laboratories, EMD-Serono, Theratechnologies, Gilead Sciences, Inc, GlaxoSmithKline, Merck & Co, Inc, and ViiV Healthcare.

The HIV Treatment Revolution Pre-HAART Era HAART Era 1996

The Impact of Highly Active Antiretroviral Therapy (HAART) on HIV Morbidity Palella, NEJM, 1998

Projected For years 2001-2003, data is based on 33 states and U.S. dependent areas with confidential name-based HIV infection reporting, Centers for Disease Control: HIV/AIDS Surveillance Report, 2005. For years 2004-2007, data is based on 34 states and 5 U.S. dependent areas with confidential name-based HIV infection reporting, Centers for Disease Control: HIV/AIDS Surveillance Report, 2007 *Data from 2008, onward projected based on 2001-2007 trends (calculated by author), 2001-2007 data from CDC Surveillance Reports 2007 Slide Courtesy of Amy Justice, MD, PhD

Prevalence of Osteoporosis in HIV-infected Patients vs HIV-uninfected Controls: A Meta-analysis Overall prevalence of osteoporosis in HIV-infected patients 15% Odds ratio (95% CI) Study Amiel (2004) Brown (2004) Bruera (2003) Dolan (2004) Huang (2002) Knobel (2001) Loiseau-Peres (2002) Madeddu (2004) Tebas (2000) Teichman (2003) Yin (2005) Overall (95% CI) 5.03 (1.47,17.27) 4.26 (0.22,82.64) 4.51 (0.26,79.27) 2.11 (0.54,8.28) 3.52 (0.15,81.92) 5.13 (1.80,14.60) 4.28 (0.46,39.81) 29.84 (1.80,494.92) 3.40 (0.19,61.67) 17.41 (0.97,313.73) 2.37 (1.09,5.16) 3.68 (2.31,5.84) .01 1 100 Odds ratio Brown, AIDS, 2006

Fracture Prevalence in HIV-infected and non-HIV-infected Persons in MGH/Partners Healthcare System: 1996-2008 7.0 0.0 1.0 2.0 3.0 4.0 5.0 6.0 7.0 P=0.002 P<0.0001 6.0 (overall comparison) (overall comparison) 5.0 4.0 Fracture Prevalence/100 Persons 3.0 Fracture Prevalence/100 Persons 2.0 1.0 0.0 30-39 40-49 50-59 60-69 70-79 20-29 30-39 40-49 50-59 60-69 HIV Non-HIV HIV Non-HIV Women Men 8,525 HIV-infected 2,208,792 non HIV-infected patients Triant, JCEM, 2008

Multifactorial Etiology of Reduced Bone Mineral Density in HIV Host Disease Medication

Pathophysiology and Risk Factors HIV Disease Factors Inflammation and Viral Proteins ↑bone resorption ↓ bone formation

Pathophysiology and Risk Factors HIV Disease Factors Inflammation and Viral Proteins ↑bone resorption ↓ bone formation Medication Factors ART initiation

Early Reports Suggested that ART was Good for the Bone JCEM, 1999

BMD Loss with ART-initiation: ~2-6% at 48-96 weeks Author, y N Wks ART-type Study outcomes Gallant, 2004 602 144 TDF vs. d4T Spine :TDF-2.2% ; d4T:-1.0% Hip : TDF: -2.8%; d4T:-2.4% Tebas, 2007 157 96 NFV vs EFV 2.5% decrease in total BMC Bonnet, 2007 74 36 PI vs non-PI 0.8% decrease in lumbar BMD Brown, 2009 106 LPV/r vs AZT/3TC/EFV 2.5% loss in total BMD Duvivier, 2009 71 48 PI vs Non-PI Spine: -4.1% , Hip: -2.8% van Vonderen, 2009 50 104 AZT/3TC/LPV/r v NVP/LPVr Fem Neck: -6.3% v -2.3% Spine: -5.1 v -2.6 % Moyle, 2009 385 TDF v ABC Hip: ABC:-1.9%; TDF: -3.6% Spine:ABC: -1.6%; TDF -2.4% McComsey, 2010 258 ATV/r vs EFV Hip: ABC:-2.2%; TDF: -4.0% Spine:ABC: -1.8%; TDF -3.8% Hip: ATV/r:-3.5%; EFV: -3.5% Spine:ATV/r:-3.0%; EFV: -2.0% Huang, 2010 753 TDF v AZT v d4T LPV/r v EFV Total BMD: TDF: -3%; v AZT: -1.75% v d4T: -2%Difference LPV/r vs EFV: -0.5% Qaqish, 2011 160 LPV/r+RAL v LPV/r+TDF/FTC Total BMD: +0.68 v -2.5% Tebas, 2011 349 RPV vs EFV (+NRTI) Total BMD: -1.5% vs -1.5% Moyle, 2011 224 ATV/r v LPV/r (+TDF/FTC) Total BMD: -3% v -4%

Average 2-year Percent Change in BMD in Healthy Women Lumbar Spine Total Body n=336 3.8 1.2 0.5 0.6 -0.6 -0.4 -0.9 -2.1 Warming, Osteo Int, 2002

Estimated Mean 96-week % Total BMD Change (95% Confidence Interval) Lower CD4 cell count prior to ART initiation is associated with greater decreases in BMD Baseline CD4 (cells/ul) Estimated Mean 96-week % Total BMD Change (95% Confidence Interval) p <50 -2.3 (-3.4, -1.3) <0.001 50-199 -0.8(-1.8, 0.2) 200-349 -0.7 (-1.6, 0.3) 350-499 -0.6 (-1.7, 0.4) 500 cell/ul reference; adjusted for age, sex, race, BMI, baseline HIV RNA, protease inhibitor use, tenofovir use n=796 Grant, CID, 2013

High Dose Vitamin D and Calcium Attenuates Bone Loss with Initiation of TDF/FTC/EFV Overton, CROI, 2014

What about specific ART agents?

IAS-USA: Guidelines for Initial ARV Regimens Dual NRTI Key 3rd Drug Recommended TDF/FTC EFV or RPV ATV/r or DRV/r RAL or EVG or DTG ABC/3TC EFV ATV/r DTG + Note the following details from the IAS-USA Guidelines: TDF/FTC: Available as fixed-dose combination alone and with efavirenz Once daily Low genetic barrier to resistance (emtricitabine) Renal dysfunction, decreased bone mineral density associated with tenofovir influence choice EFV: NNRTI class Available in fixed-dose combination with tenofovir/emtricitabine, which has become standard-of-care comparator regimen in most clinical trials Low genetic barrier Major psychiatric illness, first trimester of pregnancy, or intention to become pregnant influences choice Atazanavir/r PI/r class Widely prescribed when PI/r is chosen for initial therapy Leaves options for future regimens Less lipidogenic potential than lopinavir/r Hyperbilirubinemia, need for acid-reducing agents, and risk of nephrolithiasis influence choice Darunavir/r: Once daily in treatment-naive patients Limited experience in treatment-naive patients, presence of other options in most naive patients, and efficacy inpatients with treatment experience and multidrug resistant virus influence choice Raltegravir INSTI class (only 1 FDA approved at present time) Twice daily Low drug interaction potential Rapid decline in HIV-1 RNA slope after initiation Limited experience in naive patients, presence of other options in most naive patients, and efficacy in treatment-experienced patients with multidrug resistant virus influence choice Gunthard, JAMA, 2014

Protease Inhibitors ART initiation Effect on Fracture ↑ lumbar spine BMD loss ATV/r v EFV; similar effect at total hip (ACTG 5224s) ↑ lumbar spine and total hip BMD loss with ATV/r or DRV/r vs RAL (ACTG 5260s) No difference b/t ATV/r and DRV/r (ACTG 5260s) Effect on Fracture

Antiretroviral Exposure and Risk of Osteoporotic Fractures in VA Study: HAART Era Hazard Ratio MV Model 1: Controlling for CKD, age, race, tobacco use, diabetes and BMI; MV Model 2: Controlling for Model 1 variables + concomitant exposure to other ARVs. Bedimo, AIDS, 2012

Protease Inhibitors ART initiation Effect on Fracture ART Switch: Switch from PI to RAL leads to modest increases in BMD (SPIRAL)

TDF ART initiation Effect on Fracture 1-2% additional loss at lumbar spine and hip vs other NRTIs (Gilead 903, A5224s, ASSERT, TAF studies) Effect on Fracture

Antiretroviral Exposure and Risk of Osteoporotic Fractures in VA Study: HAART Era Hazard Ratio MV Model 1: Controlling for CKD, age, race, tobacco use, diabetes and BMI; MV Model 2: Controlling for Model 1 variables + concomitant exposure to other ARVs. Bedimo, AIDS, 2012

TDF ART initiation Effect on Fracture Effect of Switch 1-2% additional loss at lumbar spine and hip vs other NRTIs (Gilead 903, A5224s, ASSERT, TAF studies) Effect on Fracture Effect of Switch

Effect of Switching off TDF in those with Low BMD TDF ABC TDF RAL Percentage Change over 48 Weeks Negredo, CROI, 2013 Bloch, CROI, 2012

To Screen or Not to Screen…. No DXA DXA DXA

2013 US National Osteoporosis Foundation (NOF) Guidelines for DXA Screening Those with a history of fragility fracture Women ≥ 65 yrs, Men ≥ 70 Postmenopausal women and men 50-70 years, if there is concern based on risk factor profile

2013 US NOF Guidelines: Who to Treat* Those with hip or vertebral fractures Those with BMD T-scores ≤ -2.5 at the femoral neck, total hip, or spine by DXA Those with T-score b/t -1 and -2.5 (osteopenia) at above sites AND 10-year hip fracture probability ≥ 3% or 10-year all major osteoporosis-related fracture ≥ 20% based on FRAX model *applies to post-menopausal women and men ≥ 50 years

Secondary Causes of Low BMD Vitamin D deficiency 25 OH Vit D Hyperparathyroidism PTH, Ca++ Subclinical Hyperthyroidism TSH Hypogonadism Males: Free Testosterone Phosphate wasting Fractional Excretion of Phosphate Idiopathic Hypercalciuria 24 hr Urinary Calcium Celiac Sprue Tissue Transglutaminase Multiple Myeloma Serum Protein Electrophoresis Mastocytosis  Serum Tryptase Cushing’s Syndrome  24 hr Urinary Free Cortisol

Secondary Causes of Low BMD Vitamin D deficiency 25 OH Vit D Phosphate wasting Fractional Excretion of Phosphate 29

Osteomalacia Impaired bone mineralization Accompanied by weakness, fracture, pain, anorexia, and weight loss Treated with Vitamin D, Ca++, +/- phosphate, not bisphosphonates Most important differential diagnosis for low BMD

Case 50 y/o Caucasian male dx’d with HIV in 1985, started ART in 1995. CD4 236, VL<50 on TDF/FTC/LPV/r Referred to Endocrine Clinic for HIV Lipodystrophy

“Is there anything else that is bothering you?” Left hip pain for the past 2 weeks. No antecedent trauma

Femoral Neck Fracture

Femoral Neck Fracture Surgical Repair Osteoporosis Risk Factors: Steroid exposure Hypogonadism ? Lactic acidosis/NRTI exposure Smoking Past heavy EtOH use

DXA Results Spine T-score -2.6 Right femoral neck T-score -5.2 Right total hip T-score -4.2

Secondary work-up: 25 OH Vit D 61 ng/mL PTH 15 pg/ml Ca++ 10 mg/dL TSH 1.46 mU/L Testosterone 277 ng/dl Serum Phosphate 0.8 mg/dl Fractional Excretion of Phosphate of 53% 1,25 dihydroxy Vitamin D 150 (nl 6-62)

Case: Treatment Tenofovir  Abacavir Phosphate 500 mg qid Calcium 1 gram tid

DXA Follow Up Spine T-score -2.6 -0.9 R femoral neck T-score -5.2 -2.0 Aug 06 May 07 Change: ↑ 8.9% ↑ 5.5% ↑ 14.6% Spine T-score -2.6 -0.9 R femoral neck T-score -5.2 -2.0 R total hip T-score -4.2 -1.3

Management Options General recommendations Rx options Calcium/vitamin D supplementation Smoking cessation, Alcohol reduction Weight-bearing exercise Assess fall risk (Are you worried about falling?) Strength/Balance Training Rx options Change ART: Switch off TDF or PI Bone Specific Meds: Bisphosphonates Selective estrogen receptor modulator PTH analogue 39

Conclusions Bone loss in HIV is multifactorial ART-initiation is associated with clinically significant bone loss which is more pronounced in those with low pre-treatment CD4 Protease inhibitors and TDF have independent detrimental effects on bone. In persons at increased fracture risk, consider avoiding for ART initiation or switching off for those on ART DXA screening recommended in HIV-infected patients in men > 50 yrs and post-menopausal women Remember secondary causes (Vit D def and phosphate wasting) Treatment guidelines should follow those established for the general population