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Current issues in co-morbidities and complications Cristina Mussini.

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1 Current issues in co-morbidities and complications Cristina Mussini

2 Source : SHCS 12/2007 Swiss Cohort Study H I V Age distribution of HIV infected individuals in Switzerland from

3 Medical comorbidities among 66,840 HIV- and 33,420 HIV+ veterans (Goulet, CID 2007)

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6 Incidence of Multiple Comorbidities Increases With Age in HIV-Infected Pts Cohort of HIV-infected patients attending a metabolic clinic; 30 years (n = 38), years (n = 551), years (n = 1216), years (n = 253), and > 60 years (n = 69) Comorbid conditions: diabetes, obesity, cardiovascular disease, hypertension, hepatic disease, kidney disease, osteoporosis, and hypothyroidism Guaraldi G, et al. Glasgow Abstract P300. Reproduced with permission. No comorbidity 1 comorbidity 2 comorbidities 3 comorbidities 4 comorbidities 5 comorbidities > 60 Age (Years) Patients (%)

7 Comorbidities to Consider in patients with HIV infection Cardiovascular disease Bone health Renal impairment

8 HIV Is Associated with Clinically Confirmed Myocardial Infarction after Adjustment for Smoking and Other Risk Factors 81,229 veterans (33% HIV+) from the Veterans Aging Cohort Study Virtual Cohort (VACS) During a median 4.6 years, there were 497 MI events (44% HIV+). Rates of MI were higher for HIV+ (21.7, 95%CI 19.0 to 24.7) per 10,000 p-y) than uninfected veterans (13.1, 95%CI 11.7 to 14.8 per 10,000 person- years), resulting in an increased relative risk of MI (HR 1.86, 95%CI 1.54 to 2.26) after adjusting for established risk factors including age (HR 1.04, 95%CI 1.03 to 1.05), Hispanic ethnicity (HR 1.35, 95%CI 1.01 to 1.80); hypertension (HR 1.40, 95%CI 1.15 to 1.70); hyperlipidemia (HR 1.29, 95%CI 1.07 to 1.56); diabetes (HR 2.06, 95%CI 1.69 to 2.50); and smoking (HR 1.48, 95%CI 1.14 to 1.93). Among HIV-infected participants, baseline CD4 counts, HIV-1 RNA levels, and class of ART were not associated with MI after adjustment for established risk factors (p >0.2). Freiberg et al. 18th CROI; Boston, Abst 809

9 Increased risk of myocardial infarction in HIV- infected patients in France, relative to the general population The higher relative risks of MI found in younger men and women raises the possibility of a premature aging effect of HIV infection on the cardiovascular system Lang et al. AIDS 2010, 24: women men

10 clinicaloptions.com/hiv Answering the Questions: Initiating Antiretroviral Therapy Results: Of all (ischemic and hemorrhagic) stroke hospitalizations, patients with comorbid HIV infection constituted 0.09% in 1997 vs 0.15% in 2006 (p < ). Actual numbers of overall US stroke hospitalizations lessened 7% (998,739 to 926,997), while actual numbers of stroke hospitalizations with coexisting HIV infection rose 60% (888 to 1,425). Patients with comorbid HIV infection comprised 0.08% of ischemic strokes in 1997 vs 0.18% in 2006 (p < ), but their proportion of hemorrhagic strokes did not significantly change. Factors independently associated with higher odds of comorbid HIV diagnosis were Medicaid insurance, urban hospital type, dementia, liver disease, renal disease, and cancer.

11 An increase of vascular age was detected in 162 pts (40.5%) with a mean increase of 15 years (range 1-43) compared to real age. Guaraldi et al : CID 2009:49;

12 High Prevalence of Echocardiographic Abnormalities among HIV-infected Persons in the Era of HAART The prevalence of subclinical functional and structural cardiac abnormalities was greater than expected for age. Abnormalities were mostly associated with expected and often modifiable risks. Lifestyle modification should become a greater priority in the management of chronic HIV disease. Distribution of cardiac abnormalities Predictors of Echocardiographic Abnormalities among SUN Mondy et al CID. 2011;52:

13 Weighted mean difference (WMD) in carotid intima- media thickness (CIMT) (mm) by HIV positivity Hulten et al Heart 2009; 95:

14 Meta-analysis showing the effect size (Cohens D) of the difference in CIMT between patients with rheumatic disease and control subjects. Tyrrell et al Arterioscler Thromb Vasc Biol. 2010;30:

15 CV risk factors in an HIV-infected population: the DAD study Friis-Moller N et al. AIDS 2003;17:1179– % 34% 26% 25% 22% 11% 8.5% 3.5% 2.5% 1% Smoking TGs 203 mg/dL (2.3 mmol/L) HDL-C 35 mg/dL (0.9 mmol/L) Lipodystrophy Age (>45 y male; >55 y female) TC 239 mg/dL (6.2 mmol/L) Family history of CHD Hypertension BMI >30 kg/m 2 Diabetes Previous CHD Prevalence (%) Un-modifiable Potentially modifiable Lipid & adipose tissue abnormalities potentially modifiable CHD: coronary heart disease; BMI: body mass index; DAD: Data Collection of Adverse Events

16 clinicaloptions.com/hiv HIV/AIDS Highlights From Rome How Serious Is the Problem of smoking? Prevalence of smoking among people with HIV is estimated to be higher than among the general population Prevalence of smoking among people with HIV is estimated to be higher than among the general population New England clinics: More than 70% of HIV+ smoke 1 New England clinics: More than 70% of HIV+ smoke 1 Swiss HIV Cohort Study of HIV+ smokers 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):S116 2.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:

17 clinicaloptions.com/hiv HIV/AIDS Highlights From Rome Health Effects of Smoking for PLWHA In PLWHA: –HIV meds can exacerbate risks by raising cholesterol and triglycerides –Smoking aggravates oral diseases, increasing risk of oral cancers –Increased risk of pulmonary disorders/diseases, including lung cancer, emphysema, chronic obstructive pulmonary disease (COPD), pneumonia and other lung infections over HIV- smokers –Increased risk for some long-term side effects of HIV disease and treatment, such as: –Osteoporosis (weak bones that can lead to fractures) –Osteonecrosis (bone death) –Weakened immune system can undermine effects of HIV meds People with HIV who smoke are more likely to suffer: People with HIV who smoke are more likely to suffer: –Complications from HIV medication such as nausea and vomiting AIDS Project Los Angeles, Smoking Tobacco and HIV. On-line: July 12, 2010.

18 clinicaloptions.com/hiv HIV/AIDS Highlights From Rome Smoking and Opportunistic Infections PLWHA who smoke are more likely to develop: PLWHA who smoke are more likely to develop: –Thrush –Oral hairy leukoplakia (whitish mouth sores) –Bacterial pneumonia –Pneumocystis pneumonia For women, smoking can increase the risk and severity of infection with human papillomavirus (HPV) For women, smoking can increase the risk and severity of infection with human papillomavirus (HPV) –Increased risk for cervical cancer –Increased risk for anal cancer (also in MSM) Mycobacterium avium (the bacteria that causes MAC) has been linked to smoking. It has been found in tobacco, cigarette paper, and filters even after they had been burned. Mycobacterium avium (the bacteria that causes MAC) has been linked to smoking. It has been found in tobacco, cigarette paper, and filters even after they had been burned. Smoking and HIV: Fact Sheet #803. On-Line: Revised August 11,

19 clinicaloptions.com/hiv HIV/AIDS Highlights From Rome Smoking and Cardiovascular Risk Cigarette smoking is the most important modifiable cardiovascular risk factor among HIV-infected patients.Cigarette smoking is the most important modifiable cardiovascular risk factor among HIV-infected patients. Cessation of smoking is more likely to reduce cardiovascular risk than either the choice of antiretroviral therapy or the use of any lipid-lowering therapy.Cessation of smoking is more likely to reduce cardiovascular risk than either the choice of antiretroviral therapy or the use of any lipid-lowering therapy. Grinspoon S, Carr A, Cardiovascular risk and body-fat abnormalities in HIV-infected adults. N Engl J Med 2005; 352:48–62

20 clinicaloptions.com/hiv HIV/AIDS Highlights From Rome Smoking and Risk of Death Smoking among PLWHA has been linked to a higher rate of death, both for current and ex-smokers. Smoking among PLWHA has been linked to a higher rate of death, both for current and ex-smokers. Greatest increase in the risk of death 60% was for cardiovascular (heart) disease and some cancers. Greatest increase in the risk of death 60% was for cardiovascular (heart) disease and some cancers. Smoking and HIV: Fact Sheet #803. On-Line: Revised August 11,

21 clinicaloptions.com/hiv HIV/AIDS Highlights From Rome Smoking and Non-AIDS Cancers Of 4797 non-AIDS-defining cancers ( ): –Most frequently observed was lung cancer (847 cases) –Hodgkins lymphoma (643 cases) –Anal cancer (254 cases) Incidence of other cancers associated with cigarette smoking was also elevated amongst people with HIV, including: Incidence of other cancers associated with cigarette smoking was also elevated amongst people with HIV, including: –Kidney and laryngeal cancer Shiels MS, et al. A meta-analysis of the incidence of non-AIDS cancers in HIV-infected individuals. J Acquire Immune Deficiency Syndrome (online edition), 2009.

22 clinicaloptions.com/hiv HIV Highlights From San Francisco Fracture Rates Higher in HIV-Infected Pts in HOPS Cohort vs General Population Dao C, et al. CROI Abstract 128. Reproduced with permission. 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 Risk FactorAdjusted HR (95% CI) Hepatitis C coinfection Age 47 vs < 35 yrs Nadir CD4+ cell count < 200 (vs 350) P Value Diabetes Substance abuse Fracture Rate per 10,000 Persons HOPS P =.01 NHAMCS-OPD P =.32

23 What about BONE?

24 Risk of Osteoporotic Fractures Associated with Cumulative Exposure to Tenofovir and Other Antiretroviral Agents Roger Bedimo, MD; Song Zhang, PhD; Henning Drechsler, MD; Pablo Tebas, MD; Naim Maalouf, MD

25 clinicaloptions.com/hiv HIV/AIDS Highlights From Rome Age-adjusted Rates of Osteoporotic Fractures (Entire Cohort) Age at Cohort Entry (Years) Fracture Rate (per 1,000 patient-years) Vertebral Hip Wrist Total General population 1 1 Data from Triant V, et al., JCEM 2008;93: 3499–3504

26 clinicaloptions.com/hiv HIV/AIDS Highlights From Rome Antiretroviral Exposure and Risk of Osteoporotic Fractures: HAART Era 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. Hazard Ratio

27 clinicaloptions.com/hiv HIV/AIDS Highlights From Rome Exposure to Specific Protease Inhibitors and OF Risk: HAART Era 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. Hazard Ratio

28 SMART: BMD Loss With Continuous vs Intermittent ART 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 3-4 Grund B, et al. ICAAC/IDSA Abstract 2312a Years Change From BL (%) 2 n = n = Est diff: P values: Years Change From BL (%) 2 Intermittent Continuous Intermittent Continuous n = n = Est diff: P values: Spine, by DEXA Hip, by DEXA Permission granted to CCO for use of these graphics.

29 What about KIDNEY?

30 clinicaloptions.com/hiv HIV Highlights From San Francisco Cumulative ARV Exposure and Risk of Chronic Kidney Disease in EuroSIDA Kirk O, et al. CROI Abstract 107LB HIV-infected patients with 3 serum creatinine measures and corresponding body weight measures from EuroSIDA study –21,482 patient-yrs of follow-up Cumulative exposure to TDF, ATV, LPV/RTV, or IDV each associated with increased risk of chronic kidney disease Risk of chronic kidney disease after stopping TDF remained elevated for 1 yr –Within 12 mos, IRR: 4.05 ( ) –After 12 mos, IRR: 1.12 ( ) Risk of chronic kidney disease after stopping ATV or LPV/RTV similar to patients never exposed

31 clinicaloptions.com/hiv HIV/AIDS Highlights From Rome Aquitaine Cohort: TDF Use, Alone or With Concomitant PI, Associated With CKD 2693 HIV-infected patients with baseline CrCl > 60 mL/min/1.73 m 2 followed from cases of incident CKD during follow-up –Among patients with CKD, 96% had baseline CrCl < 90 mL/min/1.73 m 2 and 90% had 3 traditional risk factors* Morlat P, et al. IAS Abstract WEPDB0104. Association With CKD (Multivariate Analysis)Risk Ratio (95% CI) TDF use (adjusted for other risk factors)2.5 ( ) Without 6 months of concomitant PI 1.8 ( ) With 6 months of concomitant PI 3.5 ( ) *Other variables associated with increased CKD: female sex, older age, diabetes, hyperlipidemia, preexisting mild renal dysfunction (CrCl mL/min/1.73 m 2 ), and low CD4+ cell count. PIs used: ATV 41%, LPV 35%, FPV 11%, SQV 4%. PI vs without PI: P =.02.

32 clinicaloptions.com/hiv HIV/AIDS Highlights From IAS 2009 Chronic Kidney Disease Associated With Increased Risk of MI Pts with CKD significantly more likely to receive ABC vs TDF –12.3% vs 7.2%; P <.0001 CKD (eGFR < 60 mL/min/1.73 m²) associated with higher risk of MI and CVA after adjustment for last ART regimen –HR for MI: 3.16 (95% CI: ) –HR for CVA: 2.27 (95% CI: ) HCV not associated with MI or CVA Estimated GFR, mL/min/1.73 m 2 MICVA Rate per 1000 Pt-Yrs Unadjusted HR P ValueRate per 1000 Pt-Yrs Unadjusted HR P Value < < < Ref--9.74Ref-- Bedimo R, et al. IAS Abstract MOAB202.

33 What we should do as clinicians? For CVD: do we have to perform a CT scan of the heart in all patients?

34 clinicaloptions.com/hiv HIV/AIDS Highlights From Rome

35 clinicaloptions.com/hiv HIV/AIDS Highlights From Rome EACS Guidelines, 2009

36 Bone disease: diagnosis EACS Guidelines, 2009

37 Kidney disease: diagnosis EACS Guidelines, 2009

38 clinicaloptions.com/hiv HIV/AIDS Highlights From Rome Smoking Cessation Reduces CVD Risk in HIV Risk of cardiac events drops sharply when HIV-positive smokers quit. Previous smokers, compared to the control group, had: –73% increase in MI (myocardial infarction) risk –60% increase in CHD (coronary heart disease) risk –38% increase in CVD (cardiovascular disease) risk Current smokers, compared to the control group, had: –340% elevated risk for MI –250% elevated risk for CHD –220% elevated risk for CVD Petoumenos K, et al. Rates of cardiovascular disease following smoking cessation in patients with HIV infection: results from the DAD Study. CROI 2010; Abstract 124.

39 clinicaloptions.com/hiv HIV/AIDS Highlights From Rome D:A:D Study: Smoking Cessation Reduces Risk of CVD in HIV-Infected Patients Cessation of tobacco smoking reduced risk of MI, coronary heart disease, and CVD in HIV-infected patients –No association of time since smoking cessation and mortality risk Petoumenos K, et al. CROI Abstract 124. Reproduced with permission. *Adjusted for: age, cohort, calendar yr, antiretroviral treatment, family history of CVD, diabetes, time-updated lipids and blood pressure assessments. Never SmokedPrevious Current Baseline Smoking < 1 yr 1-2 yrs 2-3 yrs 3+ yrs Stopped Smoking During Follow-up 5 IRR of MI*

40 clinicaloptions.com/hiv HIV/AIDS Highlights From Rome Smoking Cessation Reduces CVD Risk in HIV Current but not previous smokers had an increased risk for all-cause mortality. Current but not previous smokers had an increased risk for all-cause mortality. Quitting smoking during the study reduced the risk of an adverse cardiac outcome. Quitting smoking during the study reduced the risk of an adverse cardiac outcome. Petoumenos K, et al. Rates of cardiovascular disease following smoking cessation in patients with HIV infection: results from the DAD Study. CROI 2010; Abstract 124.

41 The 5 As for Patients Willing to Quit ASK about tobacco use at every visit ASK about tobacco use at every visit ADVISE to quit with a clear, strong, personalized message ADVISE to quit with a clear, strong, personalized message ASSESS willingness to make a quit attempt within the next 30 days ASSESS willingness to make a quit attempt within the next 30 days ASSIST in quit attempt with a brief (3-5 min) counseling intervention ASSIST in quit attempt with a brief (3-5 min) counseling intervention ARRANGE for follow-up (ANTICIPATE relapse) ARRANGE for follow-up (ANTICIPATE relapse)

42 Smoking Cessation Interventions Complementary and alternative approaches Complementary and alternative approaches – Acupuncture, meditation, herbs, hypnosis Behavioral change approaches Behavioral change approaches – Cold turkey – Individual or group therapeutics – Cognitive Behavioral Therapy (CBT) – Motivational approaches and health behavior theories. DRUGS

43 Pre-Action Stage Progression Contemplation Precontemplation Action PreparationMaintenance PCCP Moving forward at least 1 stage doubles the chance that the patient will quit in the next 6 months.

44 Assessment Periods Percentage Abstinent Percentage Abstinent Over 18 Months for Smokers in Precontemplation (PC), Contemplation (C), and Preparation (P/A) Stages Before Treatment (n=570) Pretest PC C P/A Prochaska, JO, Velicer, WF, Fava, Jl, et al. (2001). Evaluating a population-based recruitment approach and a stage-based expert system intervention for smoking cessation. Addictive Behavior, 26,

45 EACS Guidelines, 2009

46 Initiating HAART > 350 cells/mL May Decrease Non-AIDS Defining Complications Cardiovascular Disease – HOPS Cohort – FIRST – SMART Trial Cancer – French Hospital Database – Chiao CNS –CHARTER Renal & Bone –Dao –Ganesan

47 Adjusted rate ratios for CHD among HIV+ individuals by recent and lowest CD4 20,775 HIV+ and 215,158 HIV–, contributing for 90,961 and 1,133,444 p-y, respectively HIV+ had 399 CHD events (447/10 5 p-y) including 248 MI. HIV– had 3463 CHD events (311/10 5 p-y), including 1825 MI, for an adjusted CHD RR of 1.2 (95%CI 1.1 to 1.4; p <0.001), and an adjusted MI RR of 1.4 (95%CI 1.3 to 1.7; p <0.001). Increased risk for cardiovascular complications is not seen for patients with relatively preserved CD4, possibly supporting earlier initiation of ART. Klein et al 18th CROI; Boston, Abst 810 Recent CD4Lowest KP CD4 RR95%CIp valueRR95%CIp value ART+, CD ( ) ( )0.396 ART+, CD ( )< ( )0.818 ART+, CD4 < ( )< ( )<0.001 ART-, CD ( ) ( )0.514 ART-, CD ( ) ( )0.142 ART-, CD4 < ( ) ( )0.932

48 Early Initiation of ART in HIV-infected Individuals is Associated with Reduced Arterial Stiffness Ho et al, CROI 2010 Nadir CD4+ count <350/ L is an independent predictor of arterial stiffness in HAART-treated individuals. Prospective studies evaluating the CV risk associated with early vs late initiation of HAART are warranted Nadir CD4 < 350 N=65 median (IQR) Nadir CD4 350 N=15 median (IQR) p-value (10-22)4 (-8- 12)< PWV (m/s)5.5 ( )5.0 ( )0.009

49 - Documented toxicity- Side-effects- Planned pregnancy- Wish to simplify regimen- Actual regimen no longer recommended- Prevention of long-term toxicity (preemptive switch) - Aging and/or co-morbidity with a possible negative impact of drug(s) in current regimen eg on CVS risk, metabolic parameters. - Management of potential drug interactions- Management of TB, HBV or HCV infection Reasons to switch treatment EACS Guidelines Version 5, 2009

50 1. Intra-class switch if drug-specific related adverse event 2. Bid to qd NRTI switch for simplification, prevention of long-term toxicity 3. PI/r to NNRTI switch for simplification, prevention or improvement of metabolic abnormalities, adherence facilitation. NVP has the advantage of its metabolic profile. EFV has the advantage of possible FDC of 3 drugs (Atripla®). 4. Switching from PI/r to NNRTI or raltegravir only possible if 1) no history of prior virological failure; and 2) NRTI backbone fully active. 5. PI/r or enfuvirtide to raltegravir switch for simplification, prevention or improvement of metabolic abnormalities, adherence facilitation. 6. Simplification of a complex multi-drug regimen in antiretroviral-experienced patients with 1) substitution of drugs difficult to administer (enfuvirtide) and/or with poor activity (NRTI in case of multiple NRTI resistance) and/or poor tolerability and 2) addition of new well- tolerable, simpler and active agent(s). PRINCIPLES EACS Guidelines, 2009

51 PI/r monotherapy with bid LPV/r,or qd DRV/r, might represent an option in patients with intolerance to NRTI or for treatment simplification. Such strategy only applies to patients without history of failure on prior PI-based therapy and who have had viral load < 50 c/ml in at least the past 6 months. ANOTHER STRATEGY EACS Guidelines, 2009

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55 Health professionals need to cooperate, communicate, and integrate care in teams to ensure that care is continuous and reliable Institute of Medicine (2003). Health Professions Education: A Bridge to Quality

56 Healthcare Ecosystem Evolution Past Context Younger population Fewer complex comorbidities Less sophisticated technology More healthcare resources Future Context Aging population More complex comorbidities More sophisticated technology Fewer healthcare resources Past Healthcare System Solo, individualistic care model Disease-centered care Emphasis on acute care Evolving Healthcare System Team-based collaborative care model Patient-centered care Emphasis on full range of healthcare continuum TIME PASTFUTURE Evolution

57 Multidisciplinary Practice vs Interprofessional Team Multidisciplinary Practice – a bunch of doctors -Little or no interdisciplinary interaction toward patient care -No identified leader Interprofessional Team – HCPs working as a team -Interdisciplinary interaction to achieve patient health outcomes -Clearly identified roles and responsibilities -Respect and understanding for respective skills an competencies -Approach to address and resolve conflict -Identified leader with leadership competencies Source: Murray, S. Silver, I., Patel, D, Dupuis, M., Hayes, S. & Davies, D. (2008). Community group practices in Canada: Are they ready to reform their practice? Journal of Continuing Education in the Health Profession. 28(2),

58 How Interprofessional Collaboration Makes a Difference Higher patient satisfactionHigher patient satisfaction Enhanced professional fulfillmentEnhanced professional fulfillment Consistency of communicationsConsistency of communications Enhanced patient adherenceEnhanced patient adherence Team efficiency (QI)Team efficiency (QI) Patient Safety (QI)Patient Safety (QI)

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