Osteoporosi e switch terapeutico proattivo: quali evidenze

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1 II Sessione: danno renale e osseo tra nuove opzioni e strategie terapeutiche Osteoporosi e switch terapeutico proattivo: quali evidenze Giordano Madeddu Università degli Studi di Sassari

2 Disclosure Dr. Madeddu have received consultancy and/or speakers fees from Abbott, Bristol Myers Squibb, Gilead Sciences, Janssen, Merck Sharp & Dohme and ViiV.

3 Definizione L osteoporosi è una malattia sistemica dell osso caratterizzata da bassa massa ossea e deteriorazione della microarchitettura dell osso con conseguente aumento della fragilità ossea e delle fratture Consensus development conference: Diagnosis, prophylaxis, and treatment of osteoporosis. Am J Med 94(6): ; 1993

4 Diagnosi di osteoporosi Valutazione quantitativa della massa ossea mediante DEXA Criteri WHO 1994 Condizione ossea Caratteristica T-score Z-score Osteopenia BMD <-1-2,5 Non applicabile rischio di frattura Osteoporosi BMD <-2,5, assenza di frattura o <-2 rischio di frattura <-2 e presenza di frattura Non applicabile Osteoporosi grave BMD <-2,5 presenza di frattura rischio di frattura World Health Organ Tech Rep Ser 843:1-129; 1994

5 Fattori di rischio per osteoporosi nel paziente HIV+ Struttura corporea gracile Inadeguato apporto alimentare di calcio e vitamina D Malnutrizione Disturbi del ciclo mestruale: Menopausa Razza caucasica Familiarità Perdita di massa ossea Abitudini di vita: Sedentarietà Fumo Alcool Caffè Terapia antiretrovirale PI NRT(d)I NNRTI Lipodistrofia Invecchiamento Correlati all infezione da HIV: Citochine Ridotta massa muscolare Ridotta massa grassa Deposizione di grasso midollare

6 Picco di Massa Ossea Infanzia Adolescenza Età adulta Menopausa Età senile Femmine Maschi

7 Determinanti del Picco di Massa Ossea Malattie Ormoni Fattori ambientali Esercizio fisico Dieta Fumo Alcool Farmaci Fattori Genetici

8 OSSO TRABECOLARE E CORTICALE: DIFFERENZE DI TURNOVER OSSO TRABECOLARE circa 12 BMU attive per minuto ricambio annuo medio del 25-30% OSSO CORTICALE circa 3 BMU attive per minuto ricambio annuo medio del 2-3%

9 Bone turnover Formation Formation Markers Osteocalcin (OC) Bone-specific alkaline phosphatase (BAP) Amino terminal propeptide of type I collagen (PINP) Carboxyl terminal propeptide of type I collagen (PICP) Resorption Resorption Markers Pyridinoline (Pyr) Deoxypyridinoline (dpyr) Amino terminal telopeptide of type I collagen (NTX) Carboxyl terminal telopeptide of type I collagen (CTX) Tartrate-resistant acid phosphatase (TRAP)14

10 Rischio di osteoporosi: HIV- vs HIV + Brown and Qaqish. AIDS 2006;20:

11 SMART: BMD Loss With Continuous vs Intermittent Antiretroviral Therapy Change From BL (%) Change From BL (%) Continuous ART associated with significantly larger BMD decline than intermittent ART; only observed disadvantage of continuous treatment in study By year, differences in BMD between arms are statistically significant only in the first 1-2 years of follow-up; few patients included in analysis in Years Spine, by DEXA -1 Intermittent -2 Continuous Years 3 4 n = n = Est diff: P values: Hip, by DEXA -2 Intermittent -3 Continuous Years 3 4 n = n = Est diff: P values: Grund B, et al. ICAAC/IDSA Abstract 2312a.

12 Bone mineral density and HIV infection AGE h IV Cohort Study: Prospective comparative study investigating the prevalence of low bone mineral density in 598 HIV+ and 550 HIV- individuals MSM Non-MSM Females Osteoporosis was significantly more prevalent in individuals who were HIV+ with well-suppressed (13.3 vs 6.7%, P<0.001) Lower bone mineral density in treated HIV+ individuals largely explained by both lower body weight and more smoking Kooij KW et al. J Infect Dis 2014 Sep 1. pii: jiu499. [Epub ahead of print] 001/IHQ/14-04//1053ak September 2014

13 Fractures are more common in HIV+ patients Fracture prevalence in women /100 persons Healthcare Registry study 8,525 HIV-infected patients 2,208,792 non HIV-infected patients Fracture rates in women demonstrated 7 HIV+ HIV- 6 5 Overall comparison p= Years Triant VA et al, JCEM 2008;93:

14 Determinanti rischio frattura Funzione neuromuscolare Rischi ambientali Tempo speso a rischio Rischio di caduta Tipo di caduta Risposta protettiva Assorbimento energia BMD Qualità dell osso Microarchitettura Violenza impatto Resistenza dell osso Rischio di frattura

15 Contributors to Bone Strength Factors of Bone Quality Bone Density Bone Turnover Bone Architecture Bone Mineral

16 What happens if bone turnover is outside the normal physiological range? Bone Quality Physiological Too Little Turnover: - Aging bone, un-repaired over-mineralized bone Results in micro-damage,? Bone Turnover Too Much Turnover: - Loss of bone mass and structure, stress risers, under-mineralized bone?

17 Relative Contributions of BMD and Bone Turnover to Reduction of Fracture Risk Other Factors * BMD Other Factors * Bone Turnover (3-6 mo) BMD increases account for 4% 28% of the reduction in risk of vertebral fracture with anti-resorptive drugs Early bone turnover reductions (NTX 3-6 mo) account for 66% of the reduction in risk of vertebral fracture with risedronate * Other factors include bone architecture and bone mineralization.

18 Linee guida Italiane 2014: Ottimizzazione della cart

19 Linee guida Italiane 2014: Ottimizzazione della cart

20 Linee guida Italiane 2014: Gestione dell osteoporosi

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22 Bone fracture risk in randomised HIV clinical trials Data from multiple studies published from Not all regimens have been compared head-to-head in a clinical trial Study N Duration ART type Total fractures n (%) Comments ACTG , weeks FTC/TDF vs 3TC/ABC 80 (4.3%) 10 fractures were atraumatic; no difference between NRTI arms (P=0.73) ACTG weeks FTC/TDF vs 3TC/ABC 15 (5.6%) All fractures were trauma related; no difference between NRTI arms (P=1.00) STEAL weeks TDF vs ABC 4 (1.0%) 2 fractures occurred in each arm Randomised control trials comparing TDF and ABC reported similar, low rates of fracture 1. McComsey G et al. J Infect Dis 2011;203: ; 2. Martin A et al. Clin lnfect Dis 2009;49: /IHQ/14-04//1053ak September 2014

23 TDF: randomised switch trials reporting BMD changes Data from multiple studies published from Not all regimens have been compared head-to-head in a clinical trial Study N Duration ART type Study outcomes RAVE weeks TDF vs ABC No significant difference in median or mean T-score by randomised regimen BICOMBO weeks TDF vs ABC With NNRTI/PI TDF g/cm 2 ; ABC g/cm 2 ; (P=0.217); specific body sites for DXA not reported. STEAL weeks TDF vs ABC Spine T-score: ABC +0.07; TDF -0.04; (P=0.02) Hip T-score: ABC +0.09; TDF -0.07; (P<0.001) Randomised switch trials comparing TDF and ABC Reported similar bone loss (RAVE, BICOMBO) Slightly more bone loss (STEAL) with TDF TDF may cause a reduction in BMD. The effects of TDF-associated changes in BMD on long-term bone health and future fracture risk are currently unknown 5 1. Moyle G et al. CAHR 2006; Quebec City; Abstract PE9.3/2; 2. Curran A et al. IWADRL 2008; London. Abstract P-17; 3. Martin A et al. Clin lnfect Dis 2009;49: ; 4. Cooper D et al. CROI 2009; San Francisco. #576; 5. Gilead. Viread SmPC September /IHQ/14-04//1053ak September 2014

24 Factors associated with bone loss progression in HIV+ patients Retrospective analysis of prevalence and predictive factors for low BMD in Spanish HIV cohort over a long period of follow-up (N=391) 42 yrs median age; 73% male Median time on ART: 8 yrs Median time between first & last DXA: 2.5 yrs Predictive Factors, by Multivariate Analysis Factor OR [95% CI] P value Male 2.23 [1.77,2.8] < Taking PI at the last DXA 1.64 [1.35,2.04] < Time on PIs 1.18 [1.12,1.24] < Low BMI 1.14 [1.11,1.17] < Time on TDF 1.08 [1.03,1.14] <0.001 Age 1.07 [1.05,1.08] < Time spent on PI-containing regimens conferred a higher risk of progression to low BMD than did time spent on TDF Bonjoch A, et al. AIDS 2010;24: /IHQ/14-04//1053ak September

25 Loss of BMD (%) ACTG 5257: Loss of BMD With Firstline Boosted PI vs RAL All arms associated with significant loss of BMD through Wk 96 (P <.001) 0-1 Total Hip Total Spine Total Body Total body BMD loss significantly greater with ATV/RTV than either DRV/RTV or RAL At hip and spine, similar loss of BMD in the PI arms P = P = P = P < P =.004 P =.72 P =.001 Significantly greater loss in the combined PI arms than in the RAL arm ATV/RTV RAL DRV/RTV Combined PI arms Brown T, et al. CROI Abstract 779LB. Reproduced with permission.

26 NEAT: lumbar spine BMD * * *P values from mean differences between arms (unadjusted) 48 weeks 96 weeks N Mean % change (95% CI) N Mean % change (95% CI) DRV/r + RAL n = (-1.98, -0.02) (-1.51, 0.65) DRV/r + TDF/FTC n = (-3.51, -1.47) (-4.0, -1.6) Mean difference (95% CI); p (-2.94, -0.04); p = 0.046* (-4.0, -0.74); p = * Bernardino JI, 54th ICAAC. Washington DC. September 5-9, H-1198

27 NEAT: femoral neck BMD * *P values between arms (unadjusted) * 48 weeks 96 weeks N Mean % change (95% CI) N Mean % change (95% CI) DRV/r + RAL n = (-2.57, -0.25) (-2.96, -0.52) DRV/r + TDF/FTC n = (-4.41, -2.49) (-9.18, -2.80) Mean difference (95% CI); p (-3.53, -0.55); p = * (-7.92, -0.58); p = 0.025* Bernardino JI, 54th ICAAC. Washington DC. September 5-9, H-1198

28 SPIRAL-LIP Substudy: Bone Mineral Density Changes 39 pts switched from PI/RTV to RAL Significant improvements in total femur BMD and T-score in RAL arm No significant changes in BMD or T-scores with continued PI/RTV Significant difference between arms in femoral neck BMD and T- score, favoring RAL No differences seen in lumbar spine Curran AE, et al. CROI Abstract T-Score L1-L T-Score Femoral Neck T-Score Total Femoral bpi baseline bpi 48 wks RAL baseline RAL 48 wks

29 U/L TROP Study: Improvements in Bone Density With TDF to RAL Switch Nmol/mmol creatinine μg/l Multicenter, open-label, nonrandomized study 37 pts (97% male; mean age: 49 yrs) suppressed on TDF/FTC + PI/RTV for 6+ mos with osteopenia/ osteoporosis TDF/FTC + PI/RTV switched to RAL + PI/RTV Bone turnover markers Mean % Change in BMD From Baseline (95% CI) Wk 24 P Wk 48 P Spine 1.5 ( ) ( ) <.0001 Left hip Total hip Femoral neck Right hip Total hip Femoral neck 1.4 ( ) 1.5 ( ) 0.6 (-0.3 to 1.5) 0.4 (-0.9 to 1.7) ( ) 2.1 ( ) 2.7 ( ) 2.3 ( ) < < Bone alkaline phosphatase P< P< N-telopeptide P= P= Osteocalcin P< P< Weeks Weeks Weeks Bloch M, et al. CROI Abstract 878. Bloch M, et al. HIV Med. 2014;15:

30 KITE: BMD results Ofotokun I. et al., AIDS Res Hum Retroviruses Oct;28(10):

31 SECOND-LINE: BMD results Haskelberg H et al, JAIDS 2014, Oct 1;67(2):161-8

32 INSTI Switch: BMD results Study ART Switch N Follow-up (w) Hip (%) Lumbar (%) Trop RAL + PI/r S Kite RAL + LPV/r S = = Second Line RAL + LPV/r S (failure) Spiral lip RAL + BB S =

33 Il futuro?

34 SINGLE: Percent Change in Bone Resorption Biomarkers Adjusted geometric mean change to Week 48, % (95% CI) 100 DTG 50 mg + ABC/3TC QD 80 EFV/TDF/FTC 68% % 20 0 CTx (C-terminal telopeptide of type 1 collagen) Difference between treatment groups was significant (P<0.001) Adapted from Tebas P, et al. ICAAC Abstract H-1461

35 SINGLE: Percent Change in Bone Formation Biomarkers Adjusted geometric mean change to Week 48, % (95% CI) 100 DTG 50 mg + ABC/3TC QD 80 EFV/TDF/FTC 60% 60 48% 66% %* 15%* 30%* 0 OC (osteocalcin) BSAP (bone-specific alkaline phosphatase) P1NP (procollagen type 1 N-terminal propeptide) *Differences between treatment groups are significant (P<0.001) Adapted from Tebas P, et al. ICAAC Abstract H-1461

36 Mean (SD) % Change from Baseline Changes in Spine and Hip BMD Through Week 48 Studies 104 and 111: Week 48 Combined Analysis Spine Hip 2 p < p < Week Week E/C/F/TAF, n 845 E/C/F/TDF, n

37 Conclusioni Elevata prevalenza di osteopenia/osteoporosi associata ad aumentato rischio di frattura in una popolazione di pazienti HIV+ che invecchia Evidenze limitate e spesso indirette riguardo alla gestione della osteoporosi in pazienti già in terapia e virologicamente soppressi Le nuove opzioni terapeutiche sembrano candidate a costituire regimi «bone friendly» ma necessitano di ulteriori studi