Sally L. Hodder M.D. Professor of Medicine New Jersey Medical School UMDNJ Newark, New Jersey

Transcription

1 Sally L. Hodder M.D. Professor of Medicine New Jersey Medical School UMDNJ Newark, New Jersey

2 At the conclusion of this presentation, participants should be able to: Select appropriate antiretroviral therapy for older HIVinfected persons in your practice to minimize toxicity and co-morbidity Screen for selected age-related comorbidities in HIVinfected persons

3 This presentation will include discussion of the following investigational uses of products Statins to decrease immune activation

4 Percentage of Reported HIV Cases Occurring in Persons >50 Years Year CDC. HIV/AIDS Surveillance Report, 2005; Smith G. US Senate Special Committee on Aging. Serial no ; May 12, 2005.

5 Assessed deaths in 13 HIV-1 cohorts comprising 39,727 persons Of 1876 deaths, definitive cause in 85% 9 Non-AIDS related deaths in 50.5% % 0 3 Of those: Renal 3.1 Respiratory 14 Liver Related 14.1% Other 9% Malignancy 23.5% 23.5 Violence Sub Abuse 15.4% CVD 15.7% Infection Non-AIDS 16.3% 16.3 Clin Inf Dis 2010;50:

6 Age-Adjusted Mortality Rates per 10,000 PLWA CVD Substance Abuse Lung Cancer Black Hispanic White/Other PLWA CVD includes chronic ischemic heart disease, acute MI, hypertension related deaths Sackoff J et al. Ann Intern Med. 2006;145:

7 HIV infection and immune activation Relevance to aging Possible importance of CMV Responses to antiretroviral therapy Immunologic Virologic Implications Age-related co-morbidities Cardiovascular Disease Osteoporosis Malignancy

8 HIV infection and immune activation Relevance to aging Possible importance of CMV Responses to antiretroviral therapy Immunologic Virologic Implications Age-related co-morbidities Cardiovascular Disease Osteoporosis Malignancy

9 HIV infection is associated with immune activation In established infection, 50% of peripheral CD8+ T cells appear to be activated, compared with <10% in HIV-uninfected persons Similar trends in the CD4+ T-cell population as well as plasmacytoid dentritic cells Frequency of activated T cells predicts disease progression, independent of HIV-1 RNA Antiretroviral therapy reduces HIV-associated T-cell activation, though often incompletely

10 Model of HIV-1 Mediated Immunosenesence & Aging HIV-1 Infection CD4 Depletion Immune Response to HIV-1 Bacterial Translocation Viral Reactivation (e.g., CMV) HIV Proteins Gp120, nef Immune Activation T Apoptosis Increased Cell turnover Cytokine Secretion (e.g. IL-6, TNFL) Immune Exhaustion Malignancy Inflam-Ageing (e.g. atherosclerosis Osteoporosis) (Adapted from Appay et al. J Pathel 214: , 2008)

11 Prospective trial of valganciclovir (VAL) in CMV seropositive HIV-1 infected persons on HAART 100% with suppressed CMV DNA at 8 and 12 weeks VAL arm (n=14) with significant (p=0.01) decrease in CD8+ cell activation Decreased 4.1% (constituted 20% reduction) hscrp decreased significantly in VAL arm (p=0.014), however, no significant difference between arms CMV and possibly other viruses appear to be determinant of CD8+ activation Hunt et al. CROI 2010, San Francisco. Abrstract 380

12 Model of HIV-1 Mediated Immunosenesence & Aging HIV-1 Infection CD4 Depletion Immune Response to HIV-1 Bacterial Translocation Viral Reactivation (e.g., CMV) HIV Proteins Gp120, nef Immune Activation T Apoptosis Increased Cell turnover Immune Exhaustion Malignancy (Adapted from Appay et al. J Pathel 214: , 2008) Cytokine Secretion (e.g. IL-6, TNFL) Inflam-Ageing (e.g. atherosclerosis Osteoporosis)

13 HIV infection and immune activation Relevance to aging Possible importance of CMV Responses to antiretroviral therapy Immunologic Virologic Implications Age-related co-morbidities Cardiovascular Disease Osteoporosis Malignancy

14 Patients 50 years have higher risk of clinical progression but improved virologic response compared with younger patients Prospective cohort study of 3015 treatment-naive patients initiating ART Aged 50 years: n=401 Aged < 50 years: n=2614 Median follow-up: 31.5 months At BL, older patients more likely to have AIDS-defining event (P =.0001) Lower CD4 T-cell count (P =.0002) Higher HIV-1 RNA level (P =.0001) Outcome Adjusted HR P value Progression to ADE or death Progression to new ADE HIV-1 RNA <500 copies/ml 1.23 <.05 Grabar S. AIDS. 2004;18(15): ADE, AIDS-defining event; BL, baseline; HR, hazard ratio; yoa, years of age.

15 Kaiser Permanente of Northern California chart review study of all members who initiated ART from (N=5090) 18 years of age Starting 3 antiretrovirals in combination Laboratory test results available for year before and year after ART initiation Excluded patients with laboratory test result abnormality in year before ART Analysis of patients who developed grade 2-4 abnormality while on ART Median follow-up: 3.8 years Parameter % With Abnormality All patients years years 50 years P value TC or LDL Glucose <.001 Creatinine NR Silverberg MJ. Arch Intern Med. 2007;167(7): TC, total cholesterol; LDL, low-density lipoprotein

16 HR (95% CI) Age 50 years Age years 0.6 Model: Age Age + adherence Age + Charlson comorbidity All predictors Kaiser Permanente study compared patients years and 50 years to patients years of age Patients >50 years more likely to achieve HIV-1 RNA <500 copies/ml compared to patients years, even when adjusting for comorbidities Adherence major advantage for older patients Silverberg MJ. Arch Intern Med. 2007;167(7): CI, confidence interval; HR, hazard ratio; yoa, years of age

17 Monthly CD4 T-cell count increases significantly lower in patients 50 years of age Mean CD4 T-Cell Count Increase/Month, cells/mm 3 Within First 6 Months of ART a Age <50 years Age 50 years After 6 Months of ART a Age <50 years Age 50 years BL HIV-1 RNA <5 log 10 copies/ml BL HIV-1 RNA 5 log 10 copies/ml a P<.0001 for <50 yoa vs 50 yoa in all subgroups. Grabar S. AIDS. 2004;18(15): yoa, years of age

18 HIV infection and immune activation Relevance to aging Possible importance of CMV Responses to antiretroviral therapy Immunologic Virologic Implications Age-related co-morbidities Cardiovascular Disease Osteoporosis Malignancy

19 CVD is presently the #1 cause of death in the US and worldwide An estimated 80.7 million (1 in 3) Americans have 1 or more types of CVD Approximately 38 million of those patients are 60 years of age CVD accounted for 36.3% of all deaths in the US as of 2004 Rosamond W, et al. Circulation. 2008;117(4):e25-e146.

20 Deaths in Thousands CVD Disease Mortality Trends for Males and Females United States: Years Males Females

21 Percent of Population CVD Prevalence in adults > 20 Years by Age and Sex (NHANES: ) Men Women These data include coronary heart disease, heart failure, stroke and hypertension Source: NCHS and NHLBI

22 Per 100,000 Population Age-adjusted Death Rates Selected Diagnoses in Women Coronary Heart Disease Stroke Lung Cancer Breast Cancer White Females Black Females Source: NCHS and NHLBI.

23 Percentage of Cohort With Risk Factor at Baseline Large cohort of HIV-infected patients on HAART followed longitudinally (N = 23,468) 18,962 (80.8%) with previous ART exposure; 4506 (19.2%) antiretroviral naive Family History of CHD 1.5 Previous History of CHD Current Smoking BMI HTN Diabetes > 30 mg/m 2 Mellitus 21.1 Total Cholesterol 32.3 TG Friis-Møller N, et al. AIDS. 2003;17:

24 Predicting MI Risk Using Framingham Equation Risk Score Results Age Sex M F M M M M M M M Total cholesterol, mg/dl HDL cholesterol, mg/dl Smoker No No No No No No No Yes Yes SBP, mm Hg On antihypertensive meds No No No No No No No No No Risk score 9% 3% 1% 6% 5% 11 % 11 % 22 % 27% National Cholesterol Education Program. Available at: Accessed November 16, 2007.

25 High Risk (> 25% over 10 years or DM) HIV+ men: 17% HIV+ women: 12% Persons with income <$10,000 were more than twice as likely to have moderate/high CHD risk In CPCRA First Study, Blacks had greater risk for cardiovascular disease Unadjusted HR = 3.83 ( ) HR (after adjustment) = 2.64 ( ) Kaplan RC. Clin Inf Dis 2007; 45: Tedaldi EM. JAIDS 2008;47:

26 Incidence per 1000 PY 126 patients had an MI during 36,199 PY Incidence of MI According to the Duration of Exposure to ART Exposure to ART Age (per 5 years) History of smoking Previous history of CVD RR 95% CI P value < < <.001 Male sex No. of events No. of PY DAD Study Group. New Engl J Med. 2003;349(21): None < > Exposure (yr)

27 Adjusted Relative Rate 8.0 PI NNRTI < > 6 Exposure (Years) DAD Study Group. New Engl J Med. 2007;356(17):

28 Cumulative Exposure to Each Drug 1.2 PIs NNRTIs RR per year 95% CI IDV NFV LPV/r SQV NVP EFV #PYFU: 68,469 56,529 37,136 44,657 61,855 58,946 #MI: Lundgren J, et al. 16 th CROI; 2009; Montreal. Abstract 44LB.

29 Overall 580 MIs in 33,308 patients (178,835 PY of observation) 1.9 Recent Exposure* Cumulative Exposure 1.5 RR 95% CI * * ZDV ddi ddc d4t 3TC ABC TDF #PYFU: 138,109 74,407 29,676 95, ,009 53,300 39,157 #MI: Recent use=current or within last 6 months. **Not shown (low number of patient currently on ddc) Lundgren J, et al. 16 th CROI; 2009; Montreal. Abstract 44LB.

30 No further adjustment b Adjusted also for: Latest CD4 count Latest VL Latest lipids Latest blood pressure Diabetes Fat loss/gain Latest glucose Relative Rate of MI Associated With Recent a ABC Use Adjusted Relative Rate (95% CI) Rates of MI for Recent a Use of ABC by Predicted 10-year CHD Risk No recent ABC Recent ABC Overall Low Moderate High Not known Predicted 10-year CHD risk a. Still using or stopped within last 6 months. b. All data depicted also adjusted for demographic factors, calendar year, cohort, CV risk factors unlikely to be modified strongly by ART use, and cumulative exposure to other ARVs. D:A:D Study Group. Lancet. 2008;371:

31 Relative Risk of MI < >2.11 C-Reactive Protein Concentration (mg/liter) Ridker et al. N Engl J Med 1997;336:

32 Adjusted for other biomarkers Marker RR(95% CI) hscrp 1.4( ) SAA 1.1( ) sicam-1 1.1( ) IL-6 0.9( ) Chol:HDL 1.4( ) Adjusted for other biomarkers AND traditional CVD Risk Factors Marker RR(95% CI) hscrp 1.5( ) SAA 1.1( ) sicam-1 1.1( ) IL-6 0.8( ) Chol:HDL 1.4( ) Ridker et al. N Engl J Med 2000;342:

33 Biomarker HIV+ Group N=32 Median (IQR) HIV- Group N=29 Median (IQR) P Value hscrp μg/ml 1.94 ( ) 1.46 ( ) 0.49 IL-6 pg/ml 1.79 ( ) 1.26( ) 0.01 sicam-1 ng/ml 312( ) 225( ) <0.01 D-dimer μg/ml 0.39( ) 0.19( ) 0.02 Baker et al. J Inf Dis 2010;201:

34 HIV-1-infected patients with CD4+ cell count > 350 cells/mm 3 Virologic Suppression (VS) Continuous ART throughout follow-up Drug Conservation (DC) ART stopped/deferred until CD4+ < 250 cells/mm 3 then episodic ART to increase CD4+to > 350 cells/mm 3

35 SMART: HIV Progression With Continuous HAART vs Interruption CD4-guided drug conservation strategy associated with significantly greater disease progression or death compared with continuous viral suppression: RR: 2.5 (95% CI: ; P <.001) Parameter No. of Patients With Events RR (95% CI) Severe complications CVD, liver, or renal deaths Nonfatal CVD events Nonfatal hepatic events Nonfatal renal events Risk of Complications El-Sadr W, et al. N Engl J Med. 2006;355: Favors TI 1.0 Favors CT 10.0

36 Biomarker OR(4 th /1 st quartile) Unadjusted P-value Adjusted* OR(4 th /1 st quartile) P- value Hs-CRP IL < < Amyloid A D-dimer 12.4 < < * Adjusted for age, race, ART, HIV RNA level, CD4+ cell count, smoking, BMI, prior CVD, diabetes, antihypertensive and/or lipid lowering agent use, total/hdl cholesterol, Hepatitis B or C coinfection Kuller L et al. PLoS 2008;10:

37 Circulating markers of inflammation and endothelial activation were significantly elevated in treatment-naïve HIV+ patients compared with healthy HIV- controls Initiation of ART in HIV+ patients reduced or normalized the levels of the majority of these markers after 3 months, an effect that remained at 12 months HIV- Controls HIV+ Patients Baseline Baseline 3 months of ART sicam-1* 144 ±12 ng/ml 296 ±24 ng/ml 248 ±12ng/mL hscrp* 6665 ±2063 ng/ml 28,060 ±5530 ng/ml 14,708 ±2358 ng/ml svcam ±39 ng/ml 957 ±40 ng/ml 766 ±33 ng/ml E-selectin 15.8 ±1.2 ng/ml 17.9 ±1.1 ng/ml 15.1 ±0.8 ng/ml *P<0.001, HIV+ patients vs HIV- controls; P<0.001, HIV+ patients baseline vs 3 months ART; P>0.05, HIV+ patients baseline vs 3 months ART. Kristoffersen et al. 15th CROI. 2008; abstract #953.

38 hscrp concentration (μg/ml) P= for trend Henry K et al. AIDS 2004;18:

39 μg/ml Suggests HIV viremia effect on endothelium, leading to increased tissue factors and initiation of coagulation cascade Change in D-Dimer* (BL to 1 mo) P= for trend , ,000 50, >50,000 Month 1 HIV RNA (c/ml) *DC pts on ART at BL with HIV RNA 400 c/ml Kuller L, et al. PLoS 2008;10:

40 IL-6 (pg/ml) HDL (μmol/l) IL-6 HDL P= for trend P< for trend ,000 10,000-50,000 >50,000 Month 1 HIV RNA Level (copies/ml) * DC patients on ART at baseline with HIV RNA 400 copies/ml SMART/INSIGHT: Duprez et al, CROI, 2009

41 Circulating inflammatory markers were significantly elevated in treatmentnaïve HIV+ patients compared with healthy HIV- controls Initiation of antiretroviral therapy in HIV+ patients reduced levels of the majority of these markers after 3 months; effect remained at 12 months HIV- Controls HIV+ Patients Baseline Baseline 3 months of ART sicam-1* ng/ml ng/ml ng/mL hscrp* ng/ml 28, ng/ml 14, ng/ml svcam ng/ml ng/ml ng/ml E-selectin ng/ml ng/ml ng/ml *P<0.001, HIV+ patients vs HIV- controls; P<0.001, HIV+ patients baseline vs 3 months ART; P>0.05, HIV+ patients baseline vs 3 months ART. Kristoffersen et al. 15th CROI. 2008; abstract #953.

42 Abnormal endothelial function is strong risk factor for cardiovascular disease (CVD) Endothelial function impaired in virologically suppressed HIV-1 infected persons (3.5%) compared with HIV-uninfected controls (5.3%) Higher hscrp levels associated with impaired flow mediated dilation in HIV-infected persons on ART with suppressed HIV RNA viral loads (p=0.03) Age more predictive of abnormal flow mediated dilation in HIV-uninfected controls (p=0.004) Hsue P. CROI 2010, San Francisco. Abstract #708 Hsue et a.lcroi 2010; San Fracisco. Abstract 708.

43 Median Change in FMD From Baseline, % HIV infection itself affected endothelial function Baseline FMD: 3.7% FMD improved during HAART No consistent correlations between changes in FMD and changes in any lipids or glycemic parameter Improvement in FMD significantly associated with decrease in VL at Week 24 No relationship with baseline VL Overall Week 4 Week 24 * * LPV/NRTI EFV/NRTI EFV/LPV *P <.01 compared with baseline. P <.01 compared with baseline and within group. * Torriani F, et al. Lipodystrophy Workshop Abstract O-18. Torriani F, et al. IAS Abstract WEAB302.

44 Blocking HMG-CoA reductase reduces mevalonate, a precursor to geranylpyrophosphate and farnesylpyrophosphate, necessary to turn on IL-6 gene IL-6 stimulates CRP in human hepatocytes Animal models have shown that statins decrease LPS induced IL-6, CRP, and TNF-α Mayer C. J Clin Pharmacol 2007; 45: Mumford R. N Engl Jour Med. 2001; 344: Marz W. Am Jour Cardiol. 2003; 92: Diomede L et al. Aterioscler Thromb Vasc Biol. 2001;21: Kleemann R et al. Circulation 2003;108:

45 Meticulous management of modifiable risk factors Smoking Hypertension Lipids Weight Control of HIV infection Customized antiretroviral selection? Future treatment of inflammatory markers?

46 HIV infection and immune activation Relevance to aging Possible importance of CMV Responses to antiretroviral therapy Immunologic Virologic Implications Age-related co-morbidities Cardiovascular Disease Osteoporosis Malignancy

47 Multiple studies have found increased prevalence of osteoporosis and osteopenia in HIV-infected persons compared with uninfected persons Meta-analytical review of studies 67% HIV infected persons had reduced BMD (OR 6.4) 15% HIV+ had osteoporosis (OR 3.7) Brown et al AIDS 2006;20:

48 Fracture Prevalence/100 Persons Fracture Prevalence/100 Persons Population: 8,525 HIV+ and 2, HIV- Patients with fracture: 245 HIV+ and 39,073 HIV- Overall fracture prevalence (per 100 persons): 2.87 HIV+ and 1.77 HIV P=0.002 Women HIV Non-HIV P< Men HIV Non-HIV P= P= P=0.01 P= P< P= Any Vertebral Hip Wrist 0 Any Vertebral Hip Wrist Triant VA et al. J Clin Endocrinaol Metab. 2008;93(9):3502.

49 Age 5.9 fold higher in women years compared with years 14.3 fold higher in women years Race Caucasians at higher risk Low Body Weight Hormone status Previous fragility fracture Family History Alcohol Use Concomitant medications Corticosteroids

50 HIV-1 p55 gag and gp120 Significantly decrease calcium deposition in vitro 1 Reduce RUNX-2 activity in vitro 1 gp120 increases PPARγ activity 1 gp120 (100 ng/ml) induces RANKL 2 RUNX-2 (Runt-related transcription factor-s) promotes osteoblast differentiation. PPARγ (Peroxisome proliferator-activated receptor gamma) promotes adipogenesis. RANKL (Receptor Activator for Nuclear Factor κ B Ligand), activates osteoclasts. 1. Cotter EJ et al. AIDS Res Hum Retroviruses. 2007;23(12): Fakruddin JM et al. J Biol Chem. 2003;278:

51 Change From Baseline (%) Change From Baseline (%) Gilead 903 Study d4t + 3TC + EFV TDF + 3TC + EFV n= n= P=0.06 Baseline Weeks Intermittent (Fracture 0.03/100 PY) Continuous (Fracture 0.13/100 PY) 1 n = n = Est. diff.: P values: Gallant et al. JAMA 2004, 292:191. Grund B et al. ICAAC/IDSA Abstract 2312a SMART Study Years

52 Antiretroviral Therapy Overall Protease Inhibitor Therapy Study Odds ratio (95%CI) Study Odds ratio (95%CI) Amiel (2004) Bruera (2003) Garcia (2001) Knobel (2001) Knishi (2005) Mededdu (2004) Vescini (2003) Overall (95%CI) 0.01 Odds ratio (0.77, 7.58) 4.81 (0.60, 38.74) 1.60 (0.13, 19.84) 2.68 (0.70, 10.33) 0.84 (0.03, 22.43) (0.65, ) 0.54 (0.05, 5.68) 2.38 (1.20, 4.75) Amiel (2004) Brown (2004) Bruera (2003) Dolan (2004) Huang (2002) Knobel (2001) Mededdu (2004) Mondy (2003) Nolan (2001) Tebas (2000) Vescini (2003) Yiu (2005) 0.61 (0.21, 1.72) (0.57, ) 1.18 (0.37, 3.78) 0.71 (0.11, 4.51) 1.57 (0.05, 43.79) 1.97 (0.47, 8.27) 2.63 (1.13, 7.03) 1.89 (0.23, 15.81) 3.25 (2.08, 9.83) 1.83 (0.35, 9.62) 1.24 (0.34, 4.52) 0.77 (0.15, 2.34) Caveat: Few studies adjusted for age or duration of infection Brown TT et al. AIDS. 2006, 22:2168. Overall (95%CI) 1.57 (1.05, 2.34)

53 47% Boston outpatient HIV clinic (n=57) 1 Low Vitamin D intake in 31% < 50 years and 76% years Low calcium intake in in 37% < 50 years and 71% years 81% Italian HIV treatment-experienced patients (n=48) 2 86% in Spanish cohort of men (n=30) 3 Mean 25,OH Vitamin D level 14.3 ng/ml in healthy controls vs.11.4 ng/ml (p=0.044) 1. Rodriguez M et al. AIDS Res Hum Retroviruses. 2009;25(1): Seminari E et al. HIV Med. 2005;6: Garcia Aparicio AM et al. Clin Rheumatol. 2006;25(4):

54 Incidence Rate (per 1000 Person-Years) of Fracture by Quartiles of Inflammatory Inflammatory marker Q1 Q2 Q3 Q4 CRP IL TNF IL-2sR IL-6sR TNF sri TNF srii P<.05 from trend test. P<.01 from trend test. P<.001 from trend test. Cauley JA et al. J Bone Miner Res. 2007;22:1091.

55 % With Non-spine Fracture *CRP, IL-6, TNFα Years 2+ 0 or 1 P = (log rank test) Cauley JA et al. J Bone Miner Res. 2007;22:1092.

56 HIV-Uninfected Women >65 years Younger if other risks Men > 70 years Younger if other risks HIV-Infected Women > 65 yrs Younger of other risks Consider > 50 years if 1 or more risk factors other than female/postmenopausal Qaseem A. Ann Int Med 2008; 148: US Prevent Serv Task Force at Aberg J. Clin Inf Dis. 2009;49:

57 Likely multiple additional risks for osteoporosis in HIVinfected persons Meticulous attention to identification of risk for osteoporosis

58 HIV infection and immune activation Relevance to aging Possible importance of CMV Responses to antiretroviral therapy Immunologic Virologic Implications Age-related co-morbidities Cardiovascular Disease Osteoporosis Malignancy

59 Event Rate 1,000 PYFU ADM, n=112 nadm, n=193 PYFU, person-years of follow-up < Monforte A. AIDS. 2008;22(16): Age Group ADM, AIDS-defining malignancies (n=112) nadm, non-aids-defining malignancies (n=193)

60 Meta-analysis: 444,172 people with HIV, 31,977 transplant patients For 20 / 28 cancers examined there was significantly increased incidence in both groups strongly suggesting a link with immunodeficiency Standardized Incidence Ratio HIV/AIDS Transplant Lung Leukaemia Kidney Oesophagus Stomach Grulich et al, Lancet 2007.

61 Risk of AIDS-related cancers decreased due to benefit of ART Except HPV-induced genital cancers HIV-infected population is aging Risk of fatal non-aids-defining cancers increases 47% per 5 year older age (i.e. >2-fold increase over a 10 year period Secondary cancers - may further increase the 47% estimate) 1 Immunodeficiency Chronic pro-oncogenic viral infections e.g. HPV, EBV, viral hepatitis Other cancers (and associated therapy hereof) e.g. bladder cancer after prostate cancer 2 ; leukemia after NHL 3 ART? 1 D:A:D study group, AIDS Shirodkar et al, Curr Opin Urol Mudie et al, J Clin Oncol 2006

62 Smoking cessation Hepatitis prevention and treatment Screening Current guidelines in HIV-infected persons Colonoscopy age 50 years then every 10 years Earlier if strong family history Mammography Annually after age 50 Age 40 depending on individual risk/benefit assessment Cervical Pap Annually after 2 normal tests in first year after HIV diagnosis More frequent if abnormal Pap Aberg J. Clin Inf Dis. 2009;49:

63 HIV-infected persons are living longer Morbidity associated with normal aging may be enhanced by HIV-infection and possibly antiretroviral treatment Key to optimal management of the HIV-infected patient: Meticulous identification of co-morbidities Individualized antiretroviral selection to maximize HIVsuppression while minimizing co-morbidity Aggressive screening to identify co-morbid conditions at an early stage and effectively manage these conditions to prevent morbidity and early mortality

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