Εκπαιδευτικό Σεμινάριο για την HIV λοίμωξη Σεπτεμβρίου 2014 Σούνιο. Θεόδωρος Α.Πέππας Παθολόγος-Λοιµωξιολόγος Γεν.Νοσοκοµείο Νίκαιας-Πειραιά

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1 Εκπαιδευτικό Σεμινάριο για την HIV λοίμωξη Σεπτεμβρίου 2014 Σούνιο. Θεόδωρος Α.Πέππας Παθολόγος-Λοιµωξιολόγος Γεν.Νοσοκοµείο Νίκαιας-Πειραιά 26/9/2014 Θ.Α.Π. 1

2 Σουνιο Aγαπημένος τόπος του Λόρδου Βύρωνα 26/9/2014 Θ.Α.Π. 2

3 Απόσπασμα από τον Don Juan Place me on Sunium's marbled steep, Where nothing, save the waves and I, May hear our mutual murmurs sweep; There, swan- like, let me sing and die: A land of slaves shall ne'er be mine - - Dash down yon cup of Samian wine! 26/9/2014 Θ.Α.Π. 3

4 Βασικά σημεία Χαμηλή οστική πυκνότητα (Low Bone Density, BMD) επιπολάζει σε HIV+ άτομα. Η έναρξη HAART συσχετίζεται με 2-6% ελάττωση της BMD τα δυο πρώτα έτη, ισομεγέθη με την παρατηρούμενη τα 2 πρώτα έτη εμμηνόπαυσης. Τα αίτια πολυπαραγοντικά 26/9/2014 Θ.Α.Π. 4

5 Κατάγματα μετά έναρξη αντιρετροϊκής θεραπείας (AIDS, 2012: ) USA, N=4640 HIV+, μ.ηλικίας 39 ετων, 5ετία 116 κατάγματα σε 106 άτομα, μ.χρόνος έως κάταγμα 2.3 έτη Επίπτωση 0.40 /100 person- years στο σύνολο 0.38 /100 person- years στους ART naive In mul}variate analysis, bisphosphonate use [hazard rate (HR): 11.2;], HCV coinfec}on (HR: 2.2), current smoking (HR: 1.7,), and glucocor}coid use (HR: 3.6) remained associated with higher adjusted hazard of fracture 26/9/2014 Θ.Α.Π. 5

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8 SMART: BMD Loss With Con}nuous vs Intermi ent ART Con}nuous ART associated with significantly larger BMD decline than intermi ent ART; only observed disadvantage of con}nuous treatment in study By year, differences in BMD between arms are sta}s}cally significant only in the first 1-2 years of follow- up; few pa}ents included in analysis in Years 3-4 Change From BL (%) Spine, by DEXA -1 Intermittent -2 Continuous Years n = n = Est diff: P values: Grund B, et al. ICAAC/IDSA Abstract 2312a. Permission granted to CCO for use of these graphics. Change From BL (%) Hip, by DEXA -2 Intermittent -3 Continuous Years n = n = Est diff: P values:

9 Anfretroviral Treatment of Adult HIV Infecfon: 2014 Recommendafons of the Internafonal Anfviral Society- USA Panel Huldrych F. Günthard, MD; Judith A. Aberg, MD; Joseph J. Eron, MD; Jennifer F. Hoy, MBBS, FRACP; Amalio Telen}, MD, PhD; Constance A. Benson, MD; David M. Burger, PharmD, PhD; Pedro Cahn, MD, PhD; Joel E. Gallant, MD, MPH; Marshall J. Glesby, MD, PhD; Peter Reiss, MD, PhD; Michael S. Saag, MD; David L. Thomas, MD, MPH; Donna M. Jacobsen, BS; Paul A. Volberding, MD Θ.Α.Π. 26/9/2014 9

10 When to Start ART: IAS- USA Recommendafons 2014 ART is recommended regardless of CD4 cell count The pa}ent must be willing and ready to ini}ate therapy; pa}ents not ready to start ART should remain in clinical care, with regular monitoring and ongoing discussion about need for ART The strength of recommenda}ons and evidence increase as CD4 cell counts decrease and in the presence of certain condi}ons Slide 10 of 41 26/9/ Θ.Α.Π.

11 Summary of effects of HIV infection and antiretroviral therapy on bone metabolism from in vitro and animal studies. Mayer K H et al. Clin Infect Dis. 2006;42: /9/2014 Θ.Α.Π. 11

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13 RANKL; Receptor acfvator of nuclear factor kappa- B ligand (RANKL), επίσης γνωστό ως tumor necrosis factor ligand superfamily member 11 (TNFSF11), TNF- related acfvafon- induced cytokine (TRANCE), osteoprotegerin ligand (OPGL) osteoclast differenfafon factor (ODF) 26/9/2014 Θ.Α.Π. 13

14 Bone Turnover Coupling: The RANK/RANKL/OPG System RANK, RANKL, and OPG are members of TNF and TNF receptors superfamily. RANK and RANKL involved in forma}on and ac}va}on of osteoclast OPG is decoy receptor compe}ng with RANK- RANKL RANK: receptor ac}vator of NFκB; RANKL: receptor ac}vator of NFκB ligand OPG: osteoprotegerin cf. O, Endo Reviews, 2007

15 Εργαλείο Μέτρησης ΟΠ: DXA Dual- energy X- ray absorpfometry (DXA, πρώην DEXA [ ) 26/9/2014 Θ.Α.Π. 15

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17 Ερμηνεία αποτελεσμάτων Με τη βοήθεια ενός ηλεκτρονικού υπολογιστή τα αποτελέσματα εκφράζονται σε τιμές Τ-score. Η τιμή T-score είναι μία ένδειξη για το πόσο ψηλότερη ή χαμηλότερη είναι η οστική πυκνότητα του εξεταζομένου συγκριτικά με την οστική πυκνότητα ενός υγιούς 30χρονου ενήλικα. Έτσι ασθενείς κατατάσσονται σε τρεις κατηγορίες με βάση την τιμή οστικής πυκνότητας: T-score > -1,0 ΦΥΣΙΟΛΟΓΙΚΗ -1,0 > T-score > -2,5 ΟΣΤΕΟΠΕΝΙΑ

18 Το κόστος; Πριν το ρωτήσετε The cost for DXA scanning varies depending on insurance policies and coverage. In general, a pa}ent without coverage paying cash can expect to pay approximately $200- $250 U.S. for the procedure. 26/9/2014 Θ.Α.Π. 18

19 Πηγή: iatronet.gr Αρχική ΣελίδαΥγείαΙατρικές ΕξετάσειςCheck up Τσεκ απ: Σε ποιο διαγνωστικό κέντρο και πόσο στοιχίζει. Σε ενήλικες άνω των ετών προστίθεται στο ετήσιο check- up και η μέτρηση οστικής μάζας με κόστος τιμή ΦΕΚ 53 ευρώ. Δημοσίευση: 27 Φεβρουαρίου 2014

20 Ποια άτομα χρήζουν να υποβληθούν σε ΜΟΠ (DXA); Γυναίκες μετά την εμμηνόπαυση κάτω των 65 ετών που έχουν επιπλέον παράγοντες κινδύνου για οστεοπόρωση. Γυναίκες μετά την εμμηνόπαυση, που έχουν υποστεί αυτόματο ένα κάταγμα. Οι γυναίκες ηλικίας 65 ετών και άνω. Οι γυναίκες που βρίσκονται σε θεραπεία ορμονικής υποκατάστασης (HRT/ΕΡΤ) για παρατεταμένες χρονικές περιόδους. Οι άνδρες με κλινικές καταστάσεις που σχετίζονται με την οστική απώλεια. Τα άτομα που έχουν διαγνωστεί με σπονδυλικά κατάγματα. Τα άτομα με πολύ χαμηλό σωματικό βάρος / ανορεξία. 26/9/2014 Θ.Α.Π. 20

21 Κατάγματα μετά έναρξη αντιρετροϊκής θεραπείας (AIDS, 2012: ) USA, N=4640 HIV+, μ.ηλικίας 39 ετων, 5ετία 116 κατάγματα σε 106 άτομα, μ.χρόνος έως κάταγμα 2.3 έτη Επίπτωση 0.40 /100 person- years στο σύνολο 0.38 /100 person- years στους ART naïve In mulfvariate analysis, bisphosphonate use [hazard rate (HR): 11.2;], HCV coinfec}on (HR: 2.2), current smoking (HR: 1.7,), and glucocor}coid use (HR: 3.6) remained associated with higher adjusted hazard of fracture 26/9/2014 Θ.Α.Π. 21

22 Validated risk factors for fragility fracture. Mayer K H et al. Clin Infect Dis. 2006;42: by the Infectious Diseases Society of America

23 Age distribu}on of HIV infected individuals in Switzerland from Percent of active patients 100% 90% 80% 70% 60% 50% 40% 30% 20% 10% 0% < Source : SHCS 12/2007 Year Swiss H I V Cohort Study

24 How Serious Is the Problem of smoking? Prevalence of smoking among people with HIV is es}mated to be higher than among the general popula}on New England clinics: More than 70% of HIV+ smoke 1 Swiss HIV Cohort Study of HIV+ smokers 72% are current/former smokers 96% among IDUs 2 1. Niaura R, et al. Smoking among HIV-positive persons. Ann Behav Med 1999; 21(Suppl):S Clifford GM, et al. Cancer risk in the Swiss HIV Cohort Study: Associations with immunodeficiency, smoking and Highly Active Antiretroviral Therapy. J Natl Cancer Inst 2005;97:

25 Conditions Associated With Osteoporosis and Fractures. McComsey G A et al. Clin Infect Dis. 2010;51: by the Infectious Diseases Society of America

26 Bone Mineral Density (BMD) in HIV Low BMD in younger and older HIV+ Osteoporosis 3x higher among HIV+ patients BMD 2% 6% in first 2 years after starting ART, similar to decline in first 2 years of menopause. fracture rates in HIV+ with rates 30% 70% higher than those among HIV- Inflammatory markers (Il- 6 especially) associated with bone loss in aging and estrogen Borderiii M et al Metabolic bone disease in HIV infection AIDS 2009;23 \: Triant VA et al. J Clin Endocrinaol Metab. 2008;93(9):3502 Ding et al. Circulating Levels of Inflammatory Markers Predict Change in Bone Mineral Density and Resorption in Older Adults: A Longitudinal Study. Journal of Clinical Endocrinology & Metabolism. 2008; 93:

27 HIV and HCV Independently Lower BMD through Different Mechanisms

28 Role of HCV in Fracture Risk of HIV Pa}ents HIV and HAART ini}a}on increase fracture risk HCV coinfec}on is a significant risk factor for osteoporo}c fractures in several cohorts of HIV- infected pa}ents: ANRS CO8 APROCO- COPILOTE cohort: HR: 3.6 (95% CI: ) 1 WIHS: HR: 1.86 ( ) 2 ; HOPS: HR: 1.99 ( ) 3 However, the mechanisms of this increased risk (impact of HCV on BMD and bone turnover) is not clearly established. It could be related to HCV- induced liver fibrosis HCV is associated with higher levels of inflammatory markers (TNF- α, IL- 8). 4 These could in turn enhance osteoclastogenesis leading to excessive bone resorpfon and osteoporosis 3 1 Collin et al., AIDS May ; 23(8): Yin et al., AIDS 2010; 24: ; 3 Young et al., Clin Infect Dis 2011; 52: ; 4 Guerra. Dig Liver Dis 2007,39 Suppl 1:S76-82

29 Impact of Severity of Liver Disease on Fracture Risk in HIV Pa}ents Fracture Rate (per 1,000 patient-years) HIV/HCV HIV < APRI US Veterans Cohort: 56,660 HIV pa}ents (98.1% male; 31.2% HCV co- infected; mean age: 45.0 years) 1,2 HCV coinfec}on remained a strong independent predictor of osteoporo}c fractures a er controlling AST- to- platelet ra}o (APRI; HR: 1.32; p= 0.001) or the presence of cirrhosis (HR: 1.30; CI: ; p=0.003). Johns Hopkins Cohort: 179 HIV/HCV pa}ents 3 Severity of liver disease (METAVIR score) did not predict low BMD < > 3.25 FIB-4 1 Bedimo et al., AIDS 2012; 2 Maalouf et al., JBMR 2013; 3 El- Maouche et al. J Hepatol 2011

30 Disease specific factors Goals of the study HCV HIV Q1. What are the mechanisms? The virus (inflammafon) Severity of liver disease? The virus Immune reconsftufon HAART (TDF) Hypogonadism Glucocorfcoids OSTEOPOROSIS and FRACTURE RISK Advancing age, Improved Survival Tobacco, EtOH, Drugs Tradi}onal risk factors Low BMI, Malnutrifon Race/Ethnicity, Genefcs

31 Disease specific factors Goals of the study HCV HIV Q2. How much is HIV? How much HCV? Is there an interaction? The virus (inflammafon) Severity of liver disease? The virus Immune reconsftufon HAART (TDF) Hypogonadism Glucocorfcoids OSTEOPOROSIS and FRACTURE RISK Advancing age, Improved Survival Tobacco, EtOH, Drugs Tradi}onal risk factors Low BMI, Malnutrifon Race/Ethnicity, Genefcs

32 Impact of HIV and HCV on T- Scores BMD T- score Mean (SD) HIV/HCV (N=28) HIV (N=62) HCV (N=45) Controls (N=33) P- value Adj* HIV vs. non- HIV Adj* HCV vs. non- HCV Adj* HIV- HCV inter- acfon Fem Neck (0.8) (1.0) (0.8) (1.0) Total Hip (0.7) (0.9) (0.7) (0.8) 0.05 < L- Spine (1.4) (1.7) (1.5) (1.6) HIV and HCV independently lower T scores (smaller contribu}on for HCV). Effect most pronounced in femoral neck and total hip. No interac}on between the two infec}ons Data shown as mean (standard devia}on) *Controlling for Age, BMI and Race

33 Impact of HIV and HCV on T- Scores Femoral neck Control HCV HIV HIV/HCV Total hip L-spine T-Score

34 Impact of HIV and HCV on Bone Markers HIV/HCV (N=28) HIV (N=62) HCV (N=45) Controls (N=33) P- value Adj* HIV vs. non- HIV Adj* HCV vs. non- HCV Adj* HIV- HCV interaction Osteocalcin ng/ml 18.5 (6.3) 21.7 (8.9) 15.7 (6.5) 15.8 (5.1) <0.01 < Bone Sp Alk Phos U/L 37.1 (12.1) 34.7 (11.4) 33.6 (10.1) 26.1 (8.7) <0.01 <0.01 < C-telopeptide (CTX) ng/ml 0.62 (0.24) 0.58 (0.29) 0.45 (0.23) 0.41 (0.15) 0.01 < Bone Sp Alk Phos U/L C-telopeptide ng/ml Osteocalcin ng/ml Control HCV HIV HIV/HCV HIV groups had higher bone resorp}on and forma}on No increased resorp}on in HCV groups Data shown as mean (standard devia}on) *Controlling for Age, BMI and Race

35 Conclusions HIV and HCV independently lower BMD and T- scores (smaller contribufon for HCV). Effect most pronounced in femoral neck and total hip. No interac}on between the two infec}ons. HIV impact on BMD could be explained by increased turnover (resorp}on and forma}on markers). See Co er et al. 7 th IAS, MOPE077 Turnover doesn t appear to be driven by RANK/RANKL/OPG system HCV is not associated with increased bone resorp}on Increased OPG and trends toward increased RANKL

36 Work-Up for Secondary Causes of Osteopenia and/or Osteoporosis. McComsey G A et al. Clin Infect Dis. 2010;51: by 26/9/2014 the Infectious Diseases Society of America Θ.Α.Π. 36

37 Approach to bone problems in patients with human immunodeficiency virus (HIV) infection. McComsey G A et al. Clin Infect Dis. 2010;51: by the Infectious Diseases Society of America

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39 Fracture Rates Higher in HIV- Infected Pts in HOPS Cohort vs General Fracture rate for HOPS participants compared with inpatient and outpatient adults aged yrs HOPS participants more likely to experience fracture at fragility sites vs controls (P.05 for wrist and vertebra in men and vertebra and femoral neck in women) Fractures at nonfragility sites more common in controls vs HOPS BMD, vitamin D data not available to assess contribution to fracture risk Popula}on Fracture Rate per 10,000 Persons Dao C, et al. CROI Abstract 128. Reproduced with permission Risk Factor Age 47 vs < 35 yrs Nadir CD4+ cell count < 200 (vs 350) Hepatitis C coinfection Diabetes Substance abuse 0.1 Adjusted HR (95% CI) HOPS P =.01 NHAMCS-OPD P = P Value

40 Antiretroviral Exposure and Risk of Osteoporotic Fractures: HAART Era 1,3 1,2 Hazard Ra}o 1,1 1,0 0,9 0,8 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.

41 Exposure to Specific Protease Inhibitors and OF Risk: HAART Era 1,4 Hazard Ra}o 1,2 1,0 0,8 0,6 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.

42 Pharmacotherapy Jun;33(6): Bone health and human immunodeficiency virus infecfon. Schafer JJ 1, Manlangit K, Squires KE. Author informafon. Specific anfretrovirals such as tenofovir may cause a greater loss of bone mineral density compared with other agents. Evaluafng bone mineral density and vitamin D status in persons with HIV may be important steps in idenffying those requiring pharmacotherapy; however, the appropriate fming for bone mineral density and vitamin D screening is uncertain, as is the appropriate method of replacing vitamin D in HIV- posifve pafents who are deficient. Further study is necessary to definifvely determine the approach to evaluafng bone health and managing low bone mineral density and vitamin D deficiency in pafents with HIV infecfon. 26/9/2014 Θ.Α.Π. 42

43 Clin Infect Dis. (2010) 51 (8): Role of tenofovir in osteoporosis. Although TDF exposure has been associated with increased bone loss in HIV- infected pa}ents ini}a}ng ART and those receiving suppressive ART regimens, there have been no properly powered studies to date that have linked TDF use to fracture. Ongoing studies inves}ga}ng the use of TDF for HIV prophylaxis and for the treatment hepa}}s B infec}on will be useful in determining the effect of TDF use, independent of HIV infec}on or the host inflammatory response. At this juncture, there is insufficient evidence to recommend against TDF use in a pa}ent with known low BMD prior to ART ini}a}on. However, alterna}ve ART choice or closer bone monitoring a er TDF ini}a}on may be considered for subjects with fragility fractures or known osteoporosis. Addi}onal inves}ga}on into the mechanisms and clinical impact of TDF use on bone health is required 26/9/2014 Θ.Α.Π. 43

44 General Guidelines for Good Bone Health In prac}ce, it is important to focus on factors important to bone health, including adequate nutrifon, parfcularly calcium and vitamin D intake. Because of the high prevalence of low BMD in HIV infec}on, we recommend that HIV- infected subjects receive mg of calcium and IU of vitamin D daily. The amount of daily sun exposure sufficient for maintaining vitamin D levels without increasing the risk of skin cancer is unknown. Muscle strengthening and balance exercises to prevent falls should also be recommended. Thirty minutes of weight- bearing exercise (including jogging or walking) at least 3 days a week has been recommended Smoking cessafon and limitafon of alcohol intake are strongly recommended. Treatment of secondary causes 26/9/2014 Θ.Α.Π. 44

45 Συμπεράσματα Επιλογή για έλεγχο παρακολούθηση Ιστορικό, εξέταση, αναζήτηση και άλλων Παρέμβαση, αλλά και συμβουλευτική, στον τρόπο ζωής και για τον τομέα αυτό Εξατομίκευση προσέγγισης αποφάσεων 26/9/2014 Θ.Α.Π. 45

46 Mην ξεχνάτε 26/9/2014 Θ.Α.Π. 46

47 Ευχαριστίες 26/9/2014 Θ.Α.Π. 47