Comorbidities: a moving area. Paul De Munter ARC Leuven BREACH

Transcription

1 Comorbidities: a moving area Paul De Munter ARC Leuven BREACH

2 Contents Introduction Comorbidities Cardiovascular disease and lipids Diabetes mellitus Hepatitis C Frailty Conclusion

3 Introduction Comorbidity Metabolic Coinfections Medication side effects Cancer Psychiatric Metabolic comorbidity Dyslipidemia Insulin resistance/diabetes Renal dysfunction Bone loss Cardiovascular events Competing HIVrelated morbidity Mortality

4 Comorbidities and mortality Smith CJ, Lancet 2014

5 Cardiovascular disease and HIV Classic risk factors more prevalent in HIV: Smoking Hypertension Obesity Illicit drug use HIV and cardiovascular risk Antiretroviral treatment and cardiovascular risk

6 Other factors than HIV and ART Infect Dis Clin N Am 28 (2014) 458

7 Smoking, HIV and comorbidity Hasse B, OFID 2015

8 Role HIV/ART in CV events: SMART vs START But mainly young patients with low CV risk Lundgren, EACS 2015

9 Cardiovascular events and ART D:A:D, NEJM 2007

10 Lipids and antiretroviral treatment Palella FJ, AIDS 2014 INTI and rilpivirine seem least harmful Lake JE, Lancet Infect Dis 2013 Martinez E, AIDS 2010

11 UZ Leuven cohort, Changing times ART and virological and immunological result Increase in ART use in suppressed patients in immune function may result in decreased inflammation and decreased CV events? Proportion VL<50 Proportion on ART Proportion CD4 > 500

12 Changing times Proportion on PI Proportion on INTI Without considering the fact that we were already using PI (and NNRTI) with better metabolic profiles UZ Leuven cohort, Decrease in PI use may result in decreased dyslipidemia, insulin resistance and decreased CV events?

13 Cardiovascular risk and HIV Full D:A:D model First calculate the predicted covariate score, normalised to the mean covariate values: Xb = ( *ln(age) *male *diabetes *famgp *currsmk *exsmk *ln(chol) *ln(hdl) *ln(syst) *ln2(cd4) *nonabc *cumpi *cumnuc ) - ( *ln(40.412) * * * * * *ln(5.001) *ln(1.214) *ln( ) *ln2( ) * * *3.313 ) The predicted five-year risk is estimated using the Cox five-year survival at the mean values of predictors, S(5)=0.9853, using Predicted risk = exp(Xb) no online calculator yet?

14 Statin as primary prevention in HIV? Currently no evidence ACTG A5332 REPRIEVE trial: pitavastatin/placebo HIV infected men and women between the ages of 40 and 75 On HIV medications for at least 6 months CD4 cell count greater than 100 No history of cardiovascular disease, such as heart attack, stroke, etc. No history of cancer in the last 3 years Not currently using a statin drug Currently recruiting 6500 patients

15 Cardiovascular risk and abacavir ACTG, CID 2011 D:A:D study group, Lancet 2008

16 Statin use and diabetes Jupiter trial* (rosuvastatin in men >50 and women >60 without diabetes or prior CV events, with LDL<130, with hscrp increased) Risk CV events decreased by near 50% Risk of incident diabetes 3% vs 2.4% Confirmed in several metaanalyses In patients with diabetes** slight initial increase in HgbA1c (0.14%)/antidiabetic treatment intensity after start of atorvastatin, no further increase with exposure until 4y In study period no evidence of decreased CV lowering effect of statins Effect in HIV-patients? Limited studies mixed results. Altered statin drug levels/metabolites due to interactions? Altered glucose tolerance with protease inhibitors? *Ridker, NEJM 2008 **Livingstone SJ, Diabetologia 2015

17 Diabetes mellitus and HIV Leading cause of CV events, blindness, end stage renal disease, amputations DM in up to 14% of HIV-patients (CID 2015); HIV on its own disputed risk factor General risk factors: age, obesity, genetics, Hep C coinfection, medication (antipsychotics, corticosteroids, opiates), low testosterone HIV-associated risk factors: lipoatrophy and lipohypertrophy, inflammation Specific issues in HIV: HgbA1c testing Drug interactions

18 DM and antiretroviral medications (some) PI and (some) NRTI increase insulin resistance and (some) PI decrease insuline secretion Stavudine and indinavir associated with developing diabetes Minimal increases of glucose with current ART (atazanavir less than efavirenz in comparative trial)

19 Diabetes mellitus - diagnosis Hgb A1c may underestimate diabetes in HIV-infected patients Underestimation may be associated with: High MCV NRTI use (especially abacavir) Low CD4 count => In HIV-patients: test every 6 to 12 months with Fasting plasma glucose consider testing 1 to 3 months after starting ART

20 Diabetes mellitus - management Life style changes Medical nutrition therapy Moderate intensity physical activity (150 /week spread over >=3 days) Modify antiretroviral therapy Switch away from lopinavir/ritonavir and from zidovudine/stavudine

21 Lipolysis in adipose tissue Hepatic glucose production Low insulin secretion pancreatic cells Neurotransmitter dysfunction brain Glucagon secretion pancreatic cells Diabetes mellitus - management Low incretin effect small intestine Targets: HgbA1c < 7%*; fasting glucose <130; postprandial glucose <180 * As HgA1c may underestimate diabetes in HIV, consider stricter for HIV Drug class Benefits Risks Concerns in HIV Biguanides (metformin) Sulfonylureas Tiazolidinediones Insulin Incretins: GLP-1 analogues Incretins: DPP-IV inhibitors 1% reduction HgbA1c independent CVD risk reduction no hypoglycemia 1% reduction HgbA1c CVD risk reduction 1% reduction HgbA1c No hypoglycemia Unlimited reductions in HgbA1c 1% reduction HgbA1c No hypoglycemia Weight loss Gastrointestinal side effects Rare lactic acidosis weight gain risk hypoglycemia Weight gain Fluid retention/worsening heart failure Hypoglycemia Weight gain Gastrointestinal side effects (nausea) 0.5% reduction HgbA1c Gastrointestinal side effects Combination with dolutegravir (Lactic acidosis) Combination with PI (CYP2C8) Saptagliptin: combination with CYP3A4 inhibitors Low glucose uptake skeletal muscles Glifozins Weight loss No hypoglycemia Lower blood pressure Glucosuria Initial increased risk of CV events? Combination with ritonavir Glucose reabsorption kidneys Meglitinides Less hypoglycemia

22 The kidney Kidney damage Comorbidity (Diabetes, Hypertension, Hep C) HIV: HIV associated nephropathy Antiretrovirals: PI: kidney stones Tenofovir Tenofovir Alafenamide vs TDF Sax PE, JAIDS 2014

23 Hepatitis C Highly effective treatment Many treatment options High incidence of acute (re)infection (and TASP for HIV does not solve this) Lambers FAE, AIDS 2011 Treatment at a price

24 Changing times: aging UZ Leuven cohort,

25 Frailty a clinical state of vulnerability to stressors thought to reflect dysfunction of multiple physiological systems associated with adverse health outcomes such as falls, disability, and mortality Aging (HIV: >50y) Kooij K, EACS 2015 Chronic inflammation

26 Conclusion Comorbidities in HIV-infected patients Contribute more to morbidity and mortality as HIV-related morbidity decreases Treatment of HIV may decrease the risk of cardiovascular events, especially when using (virologically effective) antiretrovirals with low potential for metabolic harm Dyslipidemia and diabetes are frequent in HIV-infected patients Diabetes should be diagnosed timely and treated with life style changes, metformin and additional drugs if necessary Dyslipidema should be managed with lifestyle changes; drug treatment only indicated if significant CV risk Hepatitis C: very effective treatments, but affordability is an issue Effective prevention of (re)infection urgently needed

27 Suggested reading Monroe AK et al. Diagnosing and managing diabetes in HIV-infected patients: current concepts, CID 2015 Lake JE et al. Metabolic disease in HIV infection, Lancet Infect Dis 2013

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