Novedades en la prevención y control de las comorbilidades asociadas al VIH

Transcription

1 IX Congreso Nacional GeSIDA Vigo, 28 Noviembre-1 Diciembre 2017 Novedades en la prevención y control de las comorbilidades asociadas al VIH Esteban Martinez estebanm@clinic.ub.es

2 Comorbidities in HIV+ patients General overview Kidney Bone Cardiovascular

3 Comorbidities in HIV+ patients General overview Kidney Bone Cardiovascular

4 Comorbidities common with increasing age and more common in HIV+: SCREEN!!! In addition to data collection regarding: medical history, HIVdisease and co-infections

5 Screening not equally easy or useful for all comorbidities Kidney Bone CV Cancer Neurocognitive impairment Screening Blood and urine chemistries DEXA +/- FRAX score Framingham (or similar) score Very few (cervical, anal, breast, colon,?) No (psychometric tests?) Prediction of clinical problem Highly accurate Not so highly accurate Less accurate At most, early diagnosis Lacking Esteban Martinez, personal communication

6 Adverse effects of antiretroviral drugs

7 Avoid antiretrovirals with risk for drug-drug interactions with comorbidities therapies High Moderate Low/No ATV/rit NVP NRTIs (all) DRV/rit EFV RPV ATV/cobi ETV MVC DRV/cobi EVG/cobi RAL DTG

8 «Atypical» antiretroviral regimens more common in patients with comorbidities Atypical: Older More comorbidities Polypharmacy % Triple (2NRTI+3rd): Younger Less comorbidities Less polypharmacy 0 2NRTI+1II 2NRTI+1PI/r/c 2NRTI+1PI 2NRTI+1NNRTI 1 drug 2 drugs 3 drugs other >=4 drugs other Hospital Clínic, data not published

9 Avoid tobacco

10 Comorbidities in HIV+ patients General overview Kidney Bone Cardiovascular

11 Estimated GFR (ml/min/1.73m 2 ) egfr decreases with age Inulin (Davies and Shock, 1950) NHANES III Estimated GFR (median, 95th percentiles) Age (years) National Kidney Foundation. K/DOQI Clinical Practice Guidelines for Chronic Kidney Disease. Am J Kidney Dis 2002 Wetzels JF et al. Kidney Int. 2007;72: , Glassock R. Nephrology Times 2009

12 The slope of egfr decline increases with age Normal egfr decrease: ml/min/1.73m 2 per year Abnormal egfr decrease: > 3-5 ml/min/1.73m 2 per year Lindeman RD et al. J Am Geriatr Soc 1985

13 For similar creatinine and age, women have worse egfr than men

14 TDF significatively lowers egfr but shortterm effect is limited Number of patients egfr with TDF vs. Other (95% CI) P value Meta-analysis ml/min (-2.3 to -5.7) < year cohort 2 Year ml/min (-5.6 to -0.5) 0.02 Year ml/min (-6.0 to -2.1) <0.001 Year ml/min (-4.6 to -0.3) 0.02 Year ml/min (-7.0 to +0.8) NS 1. Cooper RD et al. Clin Infect Dis Laprise C et al. Clin Infect Dis 2013

15 Pathogenesis of tenofovir-related kidney dysfunction Kidney injury: tubular markers in urine egfr (progressive) Ritonavir Ritonavir age BMI Ritonavir Cobicistat Tenofovir TENOFOVIR OAT1 OAT3 Tenofovir MRP2 MRP4 CREATININE Creatinine OCT2 MATE1 Rilpivirine Dolutegravir Tubular Cell Ritonavir Cobicistat Blood egfr (estable) Urine Yombi JC et al. AIDS 2014 Baxi SM et al. AIDS 2014

16 IRR (95% CI) PIs and risk of kidney disease: Is it a pure effect or a post-tdf-related effect? EuroSIDA CKD Risk by Yrs of ARV Exposure, IRR (95% CI) Drug 1 Yr 2 Yrs 5 Yrs TDF ATV/RTV LPV/RTV 1.12 ( ) 1.27 ( ) 1.16 ( ) 1.25 ( ) 1.61 ( ) 1.35 ( ) 1.74 ( ) 3.27 ( ) 2.11 ( ) Relationship Between Increasing Exposure to ARVS and CKD Univariate Multivariate On treatment TDF censored 0.00 TDF ATV/RTV LPV/RTV Mocroft A et al. CROI 2015: abstract 142

17 TDF and TAF bioavailability: implications for tenofovir-related toxicity Lee WA et al. Antimicrob Agents Chemother 2005

18 Comorbidities in HIV+ patients General overview Kidney Bone Cardiovascular

19 Bone mass BMD decreases with age Menopause Men Women Fracture threshold Age (years) Average annual decrease after peak bone mass: 1% BMD per year ( 2% during menopause) Compston. Clin Endocrinol 1990

20 Dual-X absorptiometry (DXA) measures BMD

21 Trabecular bone score (TBS) measures more accurately bone microarchitecture than BMD Silva et al, Journal of Bone and Mineral Research, Vol. 29, No. 3, March 2014 Silva BC et al. J Bone Mineral Res 2014

22 Change in BMD from baseline (%) Initiation of ART causes BMD decrease Change in BMD from baseline (%) (irrespective of the antiretroviral drugs used) Semanas Adapted from several references: Rivas et al. HIV Medicine 2008; Hansen et al, IAS 2009; Daar et al. CROI 2010

23 BMD decrease with ART initiation is due to a high bone turnover Van Vonderen MG et al. CROI 2011

24 BMD decrease with ART initiation can be reduced or avoided Vitamin D Zolendronic acid Overton ET et al. CROI 2014; Ofotokun I et al. CROI 2016

25 Greater BMD with TDF (vs. ABC) and with ATV/r (vs. EFV) ACTG 5202 McComsey GA et al. J Infect Dis 2011

26 Greater BMD with ATV/r or DRV/r (vs. RAL) Brown T et al. CROI 2014: abstract 779LB

27 Low vitamin D is very common in the HIV+ and the general population Dao CN et al. Clin Infect Dis 2011

28 Low vitamin D potentiates TDF bone toxicity (from the kidney, not from the bone!) Tenofovir Vitamin D Deficit Phosphate tubular resorption PTH Bone mineral density (BMD) Yin M. Top Antivir Med 2012

29 Age-specific fracture incidence-rates (/1000 person-years) in HIV infected VS uninfected patients Low absolute risk of fractures: Excess risk in HIV+ >60-65 years 5 4,5 4 3,5 HIV infected HIV uninfected 3 2,5 2 1,5 1 0, Guerri-Fernandez R et al. J Bone Mineral Res 2013

30 Patient 50y or younger with menopause or hypogonadism should have bone DXA done Normal (T-score >-1): No intervention DXA in 5 years Osteopenia (T-score between -1 and -2.5): Exercise, quitting smoking, calcium intake (diet preferred) Measure serum vit D: if low, prescribe supplements DXA in 2-5 years (inversely proportional to osteopenia intensity) Osteoporosis (T-score <-2.5): Exercise, quitting smoking, calcium intake (diet preferred) Withdraw TDF Measure serum vit D: if low, prescribe supplements Estimate FRAX: If major osteoporotic 10% or hip 3% fracture risk, consider biphosphonate therapy If major osteoporotic <10% and hip <3% fracture risk, DXA in 1-2 years Clinical care DXA protocol for HIV+ patients in Hospital Clínic Barcelona

31 FRAX score (SPAIN) Treatment decision making: Major osteporotic >10% Hip fracture >3%

32 FRAX score (JAPAN) Treatment decision making: Major osteporotic >10% Hip fracture >3%

33 Zoledronic acid is superior to TDF switching for low BMD in HIV-infected adults Bisphosphonate Therapy with Zoledronic Acid or Tenofovir Switching to Improve Low Bone Mineral Density in HIV-Infected Adults (ZEsT) HIV adults, TDF>6mo, HIV RNA <50c/mL>3mo, egfr>60ml/m, T-score -1 Zoledronic acid 5 mg iv yearly (n=44) Switch TDF (n=43) 24 months BMD BMD Mean (SD) change spine BMD Mean (SD) change femoral neck BMD ZOL (n=43) +7.4% (4.3) +4.1% (3.8) TDF switch (n=44) +2.9% (4.5) +2.1% (4.6) Mean (95%CI) difference 4.4% ( ) 2.0% ( ) Hoy J et al. 9th IAS Conference on HIV Science, Paris, July 2017 (oral presentation)

34 Comorbidities in HIV+ patients General overview Kidney Bone Cardiovascular

35 MI per 1000 PYFU Risk of myocardial infarction in HIV+ patients can be estimated with Framingham score Observed Predicted D:A:D Study 0 < Duration of HAART (years) Framingham score: gender, smoking, age, systolic BP, total and HDL cholesterol Law MG, et al. 11th CROI Abstract 737. Law MG et al. HIV Med 2006

36 Some practical hints regarding Framingham risk estimation Man, 50y, smoker = risk >10% Woman, any age, even smoker = risk <10% However, Framingham does not include HIV-specific factors Immune status Increased inflammatory markers Insulin resistance Time on HAART If non-smoking you need to be almost 15y older to have the same CV risk

37 Number of patients Framingham score has a low sensitivity, but a high negative predictive value If a patient has a low risk, the likelihood of not having a MI is high (1%) Framingham 10 S=48% E=81% VPP=4% VPN=99% 174 (3%) (7%) 1309 <10 10-to-20 >20 Framingham risk score Framingham >20 S=18% E=96% VPP=7% VPN=99% MI No MI D:A:D Study 2009

38 Measurement of sub-clinical CV disease might be more predictive of CV events than scores Carotid intima media thickness Esteban Martinez, personal communication

39 Larger decrease in cholesterol fractions with statin than with PI/r switch Lee F et al. HIV Med 2016

40 HIV-infected patients with CV risk factors are undertreated compared with non-hiv-infected Ladapo JA et al. J Am Heart Assoc 2017

41 Statins decrease inflammation and immune activation in HIV+ patients on cart Funderburg NT et al. J Acquir Immune Defic 2015

42 Randomized trial to prevent CV events in HIV: REPRIEVE (ACTG 5332) Time Asymptomatic HIV+ patients with no history of CVD R (n=6500) Screening And Consent Randomization Placebo Pitavastatin 4mg/day Intervention 6 year F/u Mechanistic Study Coronary plaque, vascular inflammation, immune activation (n=800) Mechanistic Primary Endpoint CV Death MI Unstable Angina Stroke Arterial Revasc Clinical Primary Endpoint Individual components of primary endpoint All cause death Incidence/Progression of noncalcified plaque; High-risk plaque Inflammatory, immunological, metabolic biomarkers Secondary Endpoints Predictors All Cause of statin Death effects Statin safety and non AIDS comorbidities: DM, Infections, Cancer Figure 4. Schematic overview of REPRIEVE trial design.

43 Comorbidities in HIV+ patients General overview Kidney Bone Cardiovascular

44 Muchas gracias!