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Current issues in co-morbidities and complications

Current issues in co-morbidities and complications. Cristina Mussini. Age distribution of HIV infected individuals in Switzerland from 1988-2007. Swiss. H I V. Cohort. Study. Source : SHCS 12/2007. Medical comorbidities among 66,840 HIV- and 33,420 HIV+ veterans. (Goulet, CID 2007).

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Current issues in co-morbidities and complications

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  1. Current issues in co-morbidities and complications Cristina Mussini

  2. Age distribution of HIV infected individualsin Switzerland from 1988-2007 Swiss H I V Cohort Study Source : SHCS 12/2007

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

  4. Incidence of Multiple Comorbidities Increases With Age in HIV-Infected Pts No comorbidity 100 Patients (%) 1 comorbidity 2 comorbidities 75 3 comorbidities 4 comorbidities 5 comorbidities 50 25 0 ≤ 30 31-40 41-50 51-60 > 60 Age (Years) Cohort of HIV-infected patients attending a metabolic clinic; ≤ 30 years (n = 38), 31-40 years (n = 551), 41-50 years (n = 1216), 51-50 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 2008. Abstract P300. Reproduced with permission.

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

  6. 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, 2011. Abst 809

  7. Increased risk of myocardial infarction in HIV- infected patients in France, relative to the general population men women “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, 24:1228-1230

  8. Results: Of all (ischemic and hemorrhagic) stroke hospitalizations, patients with comorbid HIV infection constituted 0.09% in 1997 vs 0.15% in 2006 (p < 0.0001). 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 < 0.0001), 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.

  9. 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; 1756-61

  10. High Prevalence of Echocardiographic Abnormalities among HIV-infected Persons in the Era of HAART Distribution of cardiac abnormalities Predictors of Echocardiographic Abnormalities among SUN • 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. Mondy et al CID. 2011;52:378-86.

  11. Weighted mean difference (WMD) in carotid intima-media thickness (CIMT) (mm) by HIV positivity Hulten et al Heart 2009; 95:1826-35.

  12. Meta-analysis showing the effect size (Cohen’s D) of the difference in CIMT between patients with rheumatic disease and control subjects. Tyrrell et al ArteriosclerThrombVasc Biol. 2010;30:1014-26.

  13. CV risk factors in an HIV-infected population: the DAD study Prevalence (%) 0 10 20 30 40 50 60 52% Smoking 34% TGs ≥203 mg/dL (2.3 mmol/L) 26% HDL-C ≤35 mg/dL (0.9 mmol/L) 25% Lipodystrophy 25% Age (>45 y male; >55 y female) 22% TC ≥239 mg/dL (6.2 mmol/L) 11% Family history of CHD Un-modifiable 8.5% Hypertension Potentially modifiable 3.5% BMI >30 kg/m2 Lipid & adipose tissue abnormalities potentially modifiable 2.5% Diabetes 1% Previous CHD CHD: coronary heart disease; BMI: body mass index; DAD: Data Collection of Adverse Events Friis-Moller N et al. AIDS 2003;17:1179–1193

  14. How Serious Is the Problem of smoking? • 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+ smoke1 • Swiss HIV Cohort Study of HIV+ smokers • 72% are current/former smokers • 96% among IDUs2 Niaura R, et al. Smoking among HIV-positive persons. Ann Behav Med 1999; 21(Suppl):S116 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;97:425-432

  15. 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: • Complications from HIV medication such as nausea and vomiting AIDS Project Los Angeles, Smoking Tobacco and HIV. On-line: www.thebody.com/content/treat/art57390.html. July 12, 2010.

  16. Smoking and Opportunistic Infections • 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) • 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. Smoking and HIV: Fact Sheet #803. On-Line: www.aidsinfonet.org, Revised August 11, 2010.

  17. Smoking and Cardiovascular Risk “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.” Grinspoon S, Carr A, Cardiovascular risk and body-fat abnormalities in HIV-infected adults. N Engl J Med 2005; 352:48–62

  18. Smoking and Risk of Death • 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. Smoking and HIV: Fact Sheet #803. On-Line: www.aidsinfonet.org, Revised August 11, 2010.

  19. Smoking and Non-AIDS Cancers Of 4797 non-AIDS-defining cancers (1981-2007): • Most frequently observed was lung cancer (847 cases) • Hodgkin’s lymphoma (643 cases) • Anal cancer (254 cases) • 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.

  20. Fracture Rates Higher in HIV-Infected Pts in HOPS Cohort vs General Population • Fracture rate for HOPS participants compared with inpatient and outpatient adults aged 25-54 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 HOPSP = .01 100 Fracture Rate per 10,000 Persons 50 NHAMCS-OPDP = .32 0 2000 2001 2002 2003 2004 2005 2006 2007 2008 Risk Factor Adjusted HR (95% CI) P Value 1.6 ≤ .05 Age ≥ 47 vs < 35 yrs 1.6 Nadir CD4+ cell count < 200 (vs ≥ 350) ≤ .05 1.6 .01 Hepatitis C coinfection 1.6 .05 Diabetes 1.5 Substance abuse .05 0.1 1.0 3.0 Dao C, et al. CROI 2010. Abstract 128. Reproduced with permission.

  21. What about BONE?

  22. 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

  23. Age-adjusted Rates of Osteoporotic Fractures (Entire Cohort) 8 7 6 Vertebral 5 Hip Fracture Rate (per 1,000 patient-years) Wrist 4 Total 3 General population1 2 1Data from Triant V, et al., JCEM 2008;93: 3499–3504 1 0 18-29 30-39 40-49 50-59 60-69 ≥70 Age at Cohort Entry (Years)

  24. Antiretroviral Exposure and Risk of Osteoporotic Fractures: 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.

  25. Exposure to Specific Protease Inhibitors and OF Risk: 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.

  26. 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 Hip, by DEXA Spine, by DEXA 2 1 1 0 0 -1 Change From BL (%) Change From BL (%) -1 -2 Intermittent Intermittent -2 -3 Continuous Continuous -3 -4 0 1 2 3 4 0 1 2 3 4 Years Years n = 109 86 51 9n = 95 75 47 15 n = 112 88 54 10n = 96 77 47 15 Est diff: 1.7 0.8 0.5 2.1P values: .003 .26 .64 .40 Est diff: 1.3 1.7 1.0 2.5P values: .002 .005 .27 .21 Grund B, et al. ICAAC/IDSA 2008. Abstract 2312a. Permission granted to CCO for use of these graphics.

  27. What about KIDNEY?

  28. Cumulative ARV Exposure and Risk of Chronic Kidney Disease in EuroSIDA • 6843 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 (2.51-6.53) • After 12 mos, IRR: 1.12 (0.63-1.99) • Risk of chronic kidney disease after stopping ATV or LPV/RTV similar to patients never exposed Kirk O, et al. CROI 2010. Abstract 107LB.

  29. Aquitaine Cohort: TDF Use, Alone or With Concomitant PI, Associated With CKD • 2693 HIV-infected patients with baseline CrCl > 60 mL/min/1.73 m2 followed from 2004-2008 • 86 cases of incident CKD during follow-up • Among patients with CKD, 96% had baseline CrCl < 90 mL/min/1.73 m2 and 90% had ≥ 3 traditional risk factors* *Other variables associated with increased CKD: female sex, older age, diabetes, hyperlipidemia, preexisting mild renal dysfunction (CrCl 61-89 mL/min/1.73 m2), and low CD4+ cell count. †PIs used: ATV 41%, LPV 35%, FPV 11%, SQV 4%.‡PI vs without PI: P = .02. Morlat P, et al. IAS 2011. Abstract WEPDB0104.

  30. 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: 2.35-4.26) HR for CVA: 2.27 (95% CI: 1.88-2.74) HCV not associated with MI or CVA Bedimo R, et al. IAS 2009. Abstract MOAB202.

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

  32. EACS Guidelines, 2009

  33. Bone disease: diagnosis EACS Guidelines, 2009

  34. Kidneydisease: diagnosis EACS Guidelines, 2009

  35. 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.

  36. 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 3.73 5 3.40 2.62 3.00 2.07 1.73 IRR of MI* 1 Never Smoked Previous Current Baseline Smoking < 1 yr 1-2 yrs 2-3 yrs 3+ yrs Stopped Smoking During Follow-up 0.5 *Adjusted for: age, cohort, calendar yr, antiretroviral treatment, family history of CVD, diabetes, time-updated lipids and blood pressure assessments. Petoumenos K, et al. CROI 2010. Abstract 124. Reproduced with permission.

  37. Smoking Cessation Reduces CVD Risk in HIV • 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. 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.

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

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

  40. Pre-Action Stage Progression Precontemplation Contemplation Preparation Maintenance Action PC C P Moving forward at least 1 stage doubles the chance that the patient will quit in the next 6 months.

  41. Percentage Abstinent Over 18 Months for Smokers in Precontemplation (PC), Contemplation (C), and Preparation (P/A) Stages Before Treatment (n=570) 30 P/A C PC 20 Percentage Abstinent 10 0 Pretest 1 6 12 18 Assessment Periods 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, 583-602.

  42. EACS Guidelines, 2009

  43. Initiating HAART > 350 cells/mLMay Decrease Non-AIDS Defining Complications Cardiovascular Disease HOPS Cohort FIRST SMART Trial Cancer French Hospital Database Chiao • CNS • CHARTER • Renal & Bone • Dao • Ganesan

  44. 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 (447/105 p-y) including 248 MI. HIV– had 3463 CHD events (311/105 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, 2011. Abst 810

  45. Early Initiation of ART in HIV-infected Individuals is Associated with Reduced Arterial Stiffness • Nadir CD4+ count <350/mL 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 Ho et al, CROI 2010

  46. Reasons to switch treatment EACS Guidelines ■ Version 5, 2009

  47. PRINCIPLES EACS Guidelines, 2009

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