Long Term Survival of PLHIV. DR Chow TS Infectious Disease Unit Hospital Pulau Pinang

Transcription

1 Long Term Survival of PLHIV DR Chow TS Infectious Disease Unit Hospital Pulau Pinang

2 Natural Progression of HIV

3 Combination ART

4 Combination of antiretroviral drugs of at least 3 or more as a regime By using 2 NRTI plus 1 NNRTI boosted PI. INSTI cart

5 Goal of Antiretroviral Therapy Improve quality of life Reduce HIV-related morbidity and mortality Restore and/or preserve immunologic function Maximally and durably suppress HIV viral load Prevent HIV transmission

6 Relative Levels Therapeutic Goal of HAART FIRST LINE CD4+ FOREVER T-cells Plasma HIV Viremia? Long term durability Viral Load: Limit of detection Months Years After HIV Infection Acute HIV infection Symptom

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8 MALAYSIA CONSENSUS GUIDELINES ARVT IN ADULT 2016

9 NRTI Abacavir (ABC) Didanosine (ddi) Emtricitabine (FTC) Lamivudine (3TC) Stavudine (d4t) Tenofovir (TDF) Zidovudine (AZT, ZDV) NNRTI Delavirdine (DLV) Efavirenz (EFV) Nevirapine (NVP) Etravirine (ETR) Rilpivirine (RPV) Current ARV Medications PI Atazanavir (ATV) Darunavir (DRV) Fosamprenavir (FPV) Indinavir (IDV) Lopinavir (LPV) Nelfinavir (NFV) Ritonavir (RTV) Saquinavir (SQV) Tipranavir (TPV) Integrase Strand Transfer Inhibitor (INSTI) Raltegravir (RAL) Dolutegravir (DTG) Fusion Inhibitor Enfuvirtide (ENF, T-20) CCR5 Antagonist Maraviroc (MVC) 9

10 HOW LONG CAN PLHIV SURVIVED WITH ART?

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12 Expected age of death of 35 year old men with CD4 < (68-73) (74-82) > (72-81) 95% CI (compare to General pop in UK 78 )

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15 PLHIV on LONG TERM ART More long term morbidity due to ART AE > OI of AIDS Need to deal with more NCD as aging is common among PLHIV Choosing the right ART is important: Potent ART Toxicity (acute and long term) Simplicity (fixed dose combination)

16 Adverse effects of ART

17 Choosing a lifelong ART Considering comorbidities ART accelerates comorbidities e.g. CVD, CKD, fractures Comorbidities increase complexity of care reduce ART adherence reduce ART options increase in polypharmacy for those age 45+ Reported in only ~25% of initial ART trials, and underassessed in routine care, so under-appreciated Gifford et al, JAIDS 2000; DAD study group, AIDS 2010 ; Hasse et al, Clin Infect Dis 2011 Krentz et al. Antiviral Therapy, 2012; Lee et al, ADR Workshop, 2013; Shahmanesh et al, ADR workshop 2013

18 Concern for Older Pts with ART AE from ART and concomitant drugs common Polypharmacy is common in older HIV-infected pts Greater risk of drug drug interactions Bone, kidney, metabolic, cardiovascular, and liver should be monitored closely DHHS Guidelines. July Slide credit: clinicaloptions.com

19 Participants (%) People (n) ATHENA and Swiss HIV Cohort Studies: Polypharmacy Among HIV-Infected Pts on ART Swiss HIV Cohort Study (N = 8444) [2] Prospective Observational Study n = 5761 n = 2233 n = 450 < 50 Yrs Yrs 65 Yrs No comedication 1 comedication 2 comedication 3 comedications 4+ comedications 16,000 14,000 12,000 10, ATHENA Modeling Study [1] 3+ comedications 2 comedications 1 comedication No comedication % of pts yrs of age and 14.2% of pts 65 yrs of age received 4 meds other than ART Predicts that 20% of pts will be receiving 3 meds other than ART in Smit M, et al. Lancet Infect Dis. 2015;15: Hasse B, et al. Clin Infect Dis. 2011:53; Slide credit: clinicaloptions.com

20 Elderly : ART and comorbidities Scenario CKD (egfr < 60 ml/min) Consider Avoiding TDF, especially in RTVcontaining regimens Osteoporosis CVD risk Hyperlipidemia TDF ABC PI/RTV

21 Key Interactions: Boosted PI- or NNRTI-Containing ART Regimens Regimen Key Drug Drug Interactions Boosted PI ATV/RTV LPV/RTV DRV/RTV Avoid lovastatin, simvastatin (lipid-lowering agents), salmeterol (asthma/copd medication) Use caution with other lipid-lowering agents (eg, atorvastatin, rosuvastatin, pravastatin) Use caution with/avoid specific antiarrhythmics (eg, amiodarone) Avoid PPIs (eg, omeprazole) with ATV RPV Avoid PPIs (eg, omeprazole, pantoprazole), dexamethasone EFV No notable comedications to avoid for EFV; consider alternative corticosteroid to dexamethasone References in slidenotes. Slide credit: clinicaloptions.com

22 Key Interactions: INSTI-Containing ART Regimens Consider to assist with identifying potential interactions for all regimens Regimen All INSTIs [1-5] DTG RAL Key Drug Drug Interaction Considerations Use caution with/avoid simultaneous polyvalent cation-containing antacids Eg MMT. Alluminium. Ca Dose adjust metformin (diabetes medication) need to reduce dose of metformin No notable comedications to avoid for RAL aside from aluminum/magnesium antacids References in slidenotes. Slide credit: clinicaloptions.com

23 An Aging Population of PLHIV

24 Probability of Survival Decreased Life Expectancy in Older HIV-Positive Adults in Modern ART Era Population-based cohort study of survival in HIV-infected pts (n = 2440) and uninfected controls matched by age and sex (n = 14,588) in Denmark HIV-Negative Controls HIV-Positive Pts Age (Yrs) Legarth RA, et al. J Acquir Immune Defic Syndr. 2016;71: Slide credit: clinicaloptions.com

25 Proportion of HIV-Positive Pts ATHENA: Older Pts Becoming More Prevalent in the HIV-Infected Population Observational cohort of 10,278 HIV-infected pts in the Netherlands Modeling study projections: Proportion of HIV-positive pts 50 yrs of age to increase from 28% in 2010 to 73% in 2030 Median age of HIV-positive pts on combination ART to increase from 43.9 yrs in 2010 to 56.6 yrs in > 70 yrs of age yrs of age yrs of age yrs of age yrs of age < 30 yrs of age Smit M, et al. Lancet Infect Dis. 2015;15: Slide credit: clinicaloptions.com

26 Comorbidities more common in HIV % HIV-negative (n=452) HIV-positive (n=489) Comorbidities n Significantly more cardiovascular disease, liver disease, renal failure and cancer in HIV+ Schouten et al. Clin Infect Dis 2014

27 Pts (%) AGEhIV: Older HIV-Infected Pts at Increased Risk for Multiple Comorbidities Cross-sectional analysis of comorbidity prevalence in prospective cohort study of HIVinfected pts (n = 540) vs controls (n = 524) 45 yrs of age P <.001 HIV-uninfected pts HIV-infected pts P =.018 P =.008 P =.044 Schouten J. Clin Infect Dis. 2014;59: Slide credit: clinicaloptions.com

28 Factors Related to Non-AIDS Comorbidities in HIV-Infected Pts Factors AGING Chronic HIV infection ART toxicity HCV and other coinfections Genetics Obesity, exercise, diet, smoking Stress Depression Conditions Inflammation and fibrosis Dyslipidemia Insulin resistance Decreased physical functioning End Organ Disease Cardiovascular Renal Metabolic Functional Neuropsychiatric Warriner AH, et al. Infect Dis Clin North Am. 2014;28: Slide credit: clinicaloptions.com

29 Is HIV immune activation? OR immune destruction?

30 HIV and Inflammation HIV infection induces a persistent inflammatory response, resulting in pathogenic responses and endorgan disease Elevated levels of inflammatory markers, including IL- 6, associated with increased risk of non-aids comorbidities and mortality in HIV-infected pts [1-4] ART partially reduces some inflammatory biomarker levels; however, they may still remain elevated vs healthy HIV-uninfected individuals [3,4] 1. Tenorio AR, et al. J Infect Dis. 2014;210: So-Armah KA, et al. J Acquir Immune Defic Syndr. 2016;72: Nixon DE, et al. Curr Opin HIV AIDS. 2010;5: Neuhaus J, et al. J Infect Dis. 2010;201: Slide credit: clinicaloptions.com

31 Inflammation Associated With Disease Mortality [1-4] in Treated HIV Infection Cardiovascular disease [5] Cancer [6] Venous thromboembolism [7] Type 2 diabetes [8] Radiographic emphysema [9] Renal disease [10] Bacterial pneumonia [11] Cognitive dysfunction [11] Depression [13] Functional impairment/frailty [14] References in slidenotes. Slide credit: clinicaloptions.com

32 Case discussion year old man Presented with Pneumocystis pneumonia CD4 20, VL > 2 million cp/ml Underlying HTN, DM (creatinine 80, clearance 62 ml/min) commences ART with TDF/FTC/EFV 2 weeks later 2009 switched to TDF-FTC + LPV/r because of ongoing CNS side effects of EFV (VL <20) CD4 > 350, plasma HIV RNA always <20 copies/ml Dev chronic diarrhoea but not too bad (no LOW) 2017 (now 63 year old man) smoker, BMI 30 TG 14.3, Total Choleterol 6.4, HDL 0.8 FBS 9.8 BP 160/90 Creatinine umol/ml (creatinine clearance = 62 declined to 45ml/min )

33 Current Medication: ART: TDF/FTC/LPV/r HTN : perindropril 4 mg OD, amlodipine 10 mg OD Hyperlipidemia: Atorvastatin 60 mg ON and Lipanthyl penta 145 mg ON DM: Metformin 1 gm BD, Gliclazide 80 mg BD Total medicine = 8 types

34 What is the issue here? 1. Aging 2. CKD 3. Hyperlipidemia (Cholesterol and TG) 4. DM uncontrolled 5. HTN uncontrolled 6. Increased ASCVD risk 7. Bone health

35 HIV and CVD, HTN

36 CVD Mortality Higher in HIV-Infected (Even With Virologic Suppression) Analysis of CVD-related mortality in HIV-infected pts in New York City HIV Surveillance Registry (N = 145,845) 71% male; median age: 49 yrs From , CVD mortality increased in HIV-infected pts (from 6% to 15%) while decreasing in the general population Age-adjusted rate of CVD mortality markedly decreased for HIV-infected pts with virologic suppression HIV-1 RNA 400 copies/ml, 8.02/1000 PY HIV-1 RNA < 400 copies/ml, 3.99/1000 PY General population, 3.22/1000 PY Hanna DB, et al. Clin Infect Dis. 2016;63: Slide credit: clinicaloptions.com

37 CVD Risk Factors in the HIV Population Gender Age Family History HIV Infection Orange = Modifiable Green = Non-modifiable Purple = HIV-associated hs-crp? ARV Lipids* CVD Risk *Metabolic syndrome ARV: antiretroviral therapy; hs-crp: high-sensitivity C-reactive protein Adapted from Carr A. Clinical Care Options HIV. Available at: Insulin Resistance Inactivity, Diet Hyperglycemia* Diabetes Abdominal Obesity* Cigarette Smoking - Hypertension*

38 Hypertension is more prevalent Analysis of HTN in HIV-infected pts in UNC CFAR HIV Clinical Cohort, (N = 3141) [1] Hypertension incidence 1996: 1.68 cases/100 PY 2013: 5.35 cases/100 PY Key risk factors Age Obesity Diabetes Renal insufficiency Nadir CD4+ cell count < 500 cells/mm 3 1. Okeke NL, et al. Clin Infect Dis. 2016;63: van Zoest RA, et al. Clin Infect Dis. 2016;63: HIV-Infected Pts Analysis of HTN in HIV-infected (n = 527) and HIV-uninfected (n = 517) persons in AGEhIV cohort [2] HTN rate higher among HIV-infected vs HIV-uninfected persons 48% vs 36%; aor: 1.65; 95% CI: Slide credit: clinicaloptions.com

39 LIPID: To Treat or Not To Treat ASCVD Risk Estimator Consider High Intensity Statin and Aspirin tools.acc.org/ascvd-risk-estimator/. Slide credit: clinicaloptions.com

40 Hyperlipidemia

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42 Approach to HIV+ on ART with high Observation ASCVD risk Recommendations Virologic suppression can reduce CVD risk HIV-infected pts have increased CVD risk ART can increase dyslipidemia Numerous challenges exist in treating HIV infection in aging pts Controlling other metabolic comorbidities (many of which occur more frequently in HIV-infected pts) can also reduce the risk of CVD HTN, T2DM, CKD, lipid abnormalities Lifestyle modification (exercise, diet, smoking cessation) may also reduce risk Manage lipids with statin therapy; consider potential DDIs with boosted PI- or COBI-containing regimens Assess comorbidities and potential interplay with ART regimens Bone, lipid, or cardiovascular abnormalities can be exacerbated by specific therapeutics Consider polypharmacy and potential DDIs Slide credit: clinicaloptions.com

43 Approach to Lipid-Lowering (Statin) Therapy HIV-infected patients are at increased risk for ASCVD [1,2] ART can cause increases in triglycerides and total, VLDL, LDL, and HDL cholesterol Prescribing statins can be challenging due to DDIs, insulin resistance, adverse events, and increased pill burden [1] Aspect of Statin Therapy Recommendation Goal of therapy CVD risk reduction [1] Screening A fasting lipid panel should be obtained in all newly diagnosed HIV-infected pts [1,3] Lipid screening annually [3] Statin therapy is first-line therapy for elevated LDL-C and non-hdl-c [1] Treatment Moderate- or high-intensity statin therapy should be considered [1] Lifestyle therapy is the recommended first step [4] Other Patient-provider discussion is central to decisions on drug treatment [1] References in slidenotes. Slide credit: clinicaloptions.com

44 Suggested Statins with ART PI- or COBI-Containing Regimens High-Intensity Statin Moderate-Intensity Statin Low-Intensity Statin Atorvastatin 20 mg Atorvastatin 10 mg Pravastatin mg Rosuvastatin mg Rosuvastatin 5 mg Fluvastatin mg Pravastatin mg* Simvastatin and lovastatin are contraindicated for pts receiving a PI, COBI, and/or RTV *With darunavir, reduce pravastatin to mg NNRTI-, RAL-, or DTG-Containing Regimens High-Intensity Statin Moderate-Intensity Statin Low-Intensity Statin Atorvastatin mg Atorvastatin mg Pravastatin mg Rosuvastatin 20 mg Rosuvastatin 10 mg Fluvastatin mg Pravastatin mg Lovastatin 40 mg Simvastatin mg Lovastatin 20 mg Simvastatin 10 mg Dubé MP. Lipid management p Slide credit: clinicaloptions.com

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46 # HIV and CKD

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48 Management of HIV with CKD

49 Monitoring Kidney Disease For egfr: Use CKD-EPI formula based on serum creatinine, gender, age and ethnicity because egfr quantification is validated > 60 ml/ min. The abbreviated modification of diet in renal disease (amdrd) or the Cockcroft-Gault (CG) equation may be used as an alternative; see

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51 Monitoring RP BP, RP, BP, RP, U FEME, UPCR 4 weeks 3months 3 months 3 months 3 months 6 months 6 months HAART If creatinine clearance <50 ml/min Urine RBC ++ US KUB Refer Nephrologist

52 home/guidelines/ckd-evaluationmanagement) Definition of CKD egfr < 60 ml/min for > 3 months. If not known to have CKD, confirm the egfr within 2 weeks. Use of DTG, COBI and RTV boosted PIs is associated with an increase in serum creatinine/reduction of egfr due to inhibition of proximal tubular creatinine transporters without impairing actual glomerular filtration: consider new set point after 1-2 months

53 ARV- TDF associated Nephrotoxicity TDF - Proximal tubulopathy with any combination of: 1. Proteinuria: urine dipstick 1, or confirmed increase in UP/C > 30 mg/mmol 2. Progressive decline in egfr and egfr < 90 ml/min 3. Phosphaturia: confirmed hypophosphataemia secondary to increased urine phosphate leak Assessment: Tests for proximal renal tubulopathy/renal Fanconi syndrome Consider renal bone disease if hypophosphataemia of renal origin: measure 25(OH) vitamin D, PTH, DXA scan Consider stopping TDF if: Progressive decline in egfr and no other cause Confirmed hypophosphataemia of renal origin and no other cause Osteopenia/osteoporosis in the presence of increased urine phosphate leak

54 ARV- PI associated Nephrotoxicity ATV / IDV (DRV) induced nephrolithiasis Crystalluria Hematuria Leucocytes in urine Loin pain AKI Assessment: Urinalysis for crystalluria/stone analysis Exclude other cause for nephrolithiasis Renal tract imaging including CT scan Consider stopping IDV/ATV if: Confirmed renal stones Recurrent loin pain +/- haematuria

55 ARV- PI associated Nephrotoxicity IDV/ATV induced interstitial nephritis Progressive decline in egfr Tubular proteinuria Hematuria Leucocyte casts in urine Assessment: Renal ultrasound Refer to nephrologist Consider stopping IDV/ATV if: Progressive decline in egfr and no other cause

56 Dosage of ARV adjustment for CKD No dose adjustment NRTI Abacavir, zidovudine All NNRTI All PI/r All INSTI Dose adjustment needed NRTI ARV > <10 3TC FTC TDF 300 mg OD No single agent 300 mg OD 150 mg OD 300 mg every 48 H 100 mg OD #300 mg every 72 H 50 mg OD #300 mg weekly # not recommended but if no alternative Tenvir EM One tab OD One tab every 48 H Use single agent

57 HIV on ARV with Frailty and Bone health

58 The Concept of Frailty Multisystem clinical syndrome that reflects biological rather than chronological age; regarded as an end-stage state [1] Associated with loss of functional homeostasis, inability to recover fully after stressors, and morbidity and excess mortality [1] Frailty Characteristic Shrinking Muscle weakness Poor endurance/exhaustion Fried Frailty Phenotype [2] Clinical Criteria* Unintentional weight loss (> 10 lbs) in prior year, sarcopenia Poor grip strength (lowest quintile by sex, BMI) Self-reported exhaustion Slowness Other tools: FRAIL Scale, Study Walking of Osteoporotic time per 15 ft Fractures (slowest quintile (SOF) by index, sex, height) Clinical Frailty Scale [3-5] Low activity Low kcal/week expenditure (lowest quintile by sex) *Frailty defined as presence of 3 criteria; prefrailty as presence of 1-2 criteria. References in slidenotes. Slide credit: clinicaloptions.com

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60 Incidence (%) Frailty Risk Factors in Aging HIV-Positive HR: 3.9 P <.001 Risk Factors (OR: Frail vs Nonfrail) HR: 3.9 P =.002 HR: 3.7 P =.004 HR: 3.6 P =.001 Frail (n = 33) Prefrail (n = 185) Nonfrail (n = 141) HR: 3.3 P = HR: 5.1 P =.007 HR: 3.8 P =.067 HR: 3.5 P = Diabetes Neurologic Disease Psychiatric Disease CVD Unhealthy Weight Arthritis Osteoporosis Viral Hepatitis Erlandson KM, et al. IAS Abstract TUPE124. Slide credit: clinicaloptions.com

61 ART Considerations for Pts With Bone Complications TDF Consider avoiding TDF: associated with greater decrease in BMD along with renal tubulopathy, urine phosphate wasting, and osteomalacia Consider ABC/3TC TDF/FTC + INSTI OR PI/r: Significantly greater BMD loss with PI/r vs RAL-based regimens (when used with FTC/TDF) [2] DTG/ABC/3TC associated with less bone turnover than EFV/TDF/FTC [3] 1. DHHS Guidelines. July Brown TT, et al. J Infect Dis. 2015;212: Tebas P, et al. AIDS. 2015;29: Slide credit: clinicaloptions.com

62 Fracture Prevalence/ 100 Persons Fracture Prevalence/ 100 Persons Fracture Prevalence Increased in Older HIV-Infected Pts Meta-analysis: HIV-positive pts had 6.4-fold increased risk of low BMD and 3.7-fold increased risk of osteoporosis [1] (8525 HIV-infected pts compared with 2,208,792 uninfected pts in Partners HealthCare System, [2]) HIV Non- HIV Women P =.002 (overall comparison) Age (Yrs) Men P <.0001 (overall comparison) Age (Yrs) HIV Non- HIV Brown TT, et al. AIDS. 2006;20: Triant V, et al. J Clin Endocrinol Metab. 2008;93: Slide credit: clinicaloptions.com

63 Fracture risk assessment McComsey et al, Clin Infect Dis 2010;

64 Bone disease screening and diagnosis in HIV Classic risk factors: older age, female gender, hypogonadism, family history of hip fracture, low BMI ( 19 kg/m2), vitamin D deficiency, Esp TDF smoking, physical inactivity, history of low trauma fracture, alcohol excess (> 3 units/day), steroid exposure (minimum prednisone 5 mg/qd or equivalent for > 3 months) If T-score normal, repeat after 3-5 years in risk groups 1, 2 and 5; no need for rescreening with DXA in risk groups 3 and 4 unless risk factors change and only rescreen group 6 if steroid use ongoing.

65 Change (%) Huang et al, AIDS 2009 Low BMD therapy: prevention / drug therapy General Reduce risk of falls Bisphosphonate therapy Exercise weight-bearing muscle strength balance training Vitamin D and calcium replacement / supplementation Avoid TDF /PI Bisphosphonate treatment of: alendronate 70 mg once weekly po; risedronate 35 mg once weekly po; ibandronate 150 mg po or 3 mg iv every 3 months; zoledronic acid 5 mg iv once yearly.

66 Recommendations for Evaluation of Brown TT, et al. Clin Infect Dis. 2015;60: Bone Disease in HIV HIV-Infected Population Assessment Monitoring Men yrs of age Premenopausal women 40 yrs of age Men 50 yrs of age Postmenopausal women Pts with fragility fracture history, receiving chronic glucocorticoids, or at high risk of falls Assess risk of fragility fracture using FRAX Assess BMD using DXA For pts with FRAX score 10%, monitor FRAX in 2-3 yrs For pts with FRAX score > 10%, perform DXA For pts with advanced osteopenia, monitor DXA in 1-2 yrs For pts with mild or moderate osteopenia, monitor DXA in 5 yrs For pts started on bisphosphonates (significantly reduced BMD or fracture history), repeat DXA in 2 yrs Slide credit: clinicaloptions.com

67 ART and frailty Observation Frailty is more prevalent among HIV-infected vs HIVuninfected individuals Fracture prevalence and low BMD common among pts with HIV Some ART regimens have larger impact on BMD loss than others Assess pts for frailty; Recommendations consider Fried Frailty Phenotype or other available tests Assess pts for BMD loss or risk of bone disease depending on risk factors For pts at risk for or with BMD loss or bone disease, consider ART modifications Backbone: consider ABC/3TC > TDF/FTC Greater BMD loss observed with PI-based regimens vs INSTI based regimens

68 HIV on ARV and Liver dysfunction

69 Abnormal LFT in HIV Co infection with HCV and HBV Opportunistic infections Non-viral causes of abnormal LFT: common etiologies Drug-induced liver injury (DILI) include herbs, supplements and ART Alcohol Fatty liver in HIV - multifactorial, potentially reversible etiology for chronic liver disease Autoimmune hepatitis Acharya C, et al. Clin Liver Dis 2015 Feb;19(1):1-22. Molina PE, et al. Curr HIV Res. 2014;12(4):

70 1. DILI-Liver toxicity of antiretroviral drugs Drug Class Drug Severe ALT Elevation (%)* NRTI Lamivudine Tenofovir 16 4 Zidovudine Emtricitabine Abacavir 19 6 Didanosine 20 6 Stavudine NNRTI Rilpivirine 22 <1-2 Etravirine Delavirdine Efavirenz Nevirapine PI Nelfinavir Indinavir Darunavir/ritonavir Fosamprenavir/ritonavir Ritonavir Atazanavir/ritonavir Tipranavir/ritonavir Lopinavir/ritonavir CCR5 blocker Maraviroc Integrase inhibitor Raltegravir 36 4 Fusion inhibitor Enfuvirtide DILI, drug-induced liver injury; NRTI, nucleoside reverse transcriptase inhibitor; NNRTI, nonnucleoside reverse transcriptase inhibitor; PI, protease inhibitor; CCR5, chemokine receptor type 5; ALT, alanine aminotransferase; ULN, upper limit of normal. * Note. No data provided in package insert for Saquinavir. Jones M, Núñez M. Semin Liver Dis 2012 May;32(2):

71 GRADING of LIVER Dysfucntion Jones M, Nu n ez M. Semin Liver Dis 2012 May;32(2):

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74 Cancer and HIV

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76 Cancer screen in HIV

77 Others NCD HAND

78 Back to the Case year old man Presented with Pneumocystis pneumonia CD4 20, VL > 2 million cp/ml Underlying HTN, DM (creatinine 80, clearance 62 ml/min) commences ART with TDF/FTC/EFV 2 weeks later 2009 switched to TDF-FTC + LPV/r because of ongoing CNS side effects of EFV (VL <20) CD4 > 350, plasma HIV RNA always <20 copies/ml Dev chronic diarrhoea but not too bad (no LOW) 2017 (now 63 year old man) smoker, BMI 30 TG 14.3, Total Choleterol 6.4, HDL 0.8 FBS 9.8 BP 160/90 Creatinine umol/ml (creatinine clearance = 62 declined to 45ml/min )

79 What is the issue here? Aging CKD Hyperlipidemia (Cholesterol and TG) DM uncontrolled HTN uncontrolled Increased ASCVD risk Bone health Frailty avoid TDF Avoid TDF (adjust dose) High ASCVD risk > 50 % Avoid ABC Hyperglycemia and hyperlidemia due to Kaletra Optimised anti HTN and antilipid Anti platelet therapy

80 Modify ARVT First line/ Never failed therapy (Intolerant to NNRTI) Cessation of smoking, start aspirin 75 mg OD Atorvastatin 60 mg OD 80 mg OD ( BUT once stopped PI/r, TG and Chol level will reduced and blood sugar as well) Continue fenofibrate Add ezetimibe 10 mg OD? Switched PI/r? NNRTI? Which one?

81 NEAT 022: Switch From Boosted PI to DTG in Suppressed Pts With High CV Risk PI-based regimens associated with increased risk of dyslipidemia [1] NEAT 022: international, randomized, open-label phase IV study [2,3] Primary endpoints at Wk 48: proportion with HIV RNA < 50 c/ml (ITT), change in total plasma cholesterol Wk 48 Wk 96 Pts with stable HIV-1 RNA < 50 c/ml on PI/RTV + 2 NRTIs, high CV risk,* no resistance mutations, no VF (N = 415) Immediate switch to DTG + 2 NRTIs (n = 205) Continue PI/RTV + 2 NRTIs (n = 210) Deferred switch to DTG + 2 NRTIs *> 50 yrs of age and/or Framingham risk score > 10% at 10 yrs. NRTIs to remain the same throughout study. 1. Ofotokun I, et al. Clin Infect Dis. 2015;60: Gatell JM et al. IAS Abstract TUAB ClinicalTrials.gov. NCT Slide credit: clinicaloptions.com

82 ITT Population (%) Mean Change From BL to Wk 48 (%) NEAT 022: Switch From Boosted PI to DTG in Suppressed Pts With High CV Risk Switching to DTG noninferior to continuing boosted PI through Wk Virologic Success Treatment difference: -2.1% (95% CI: -6.6% to 2.4%) Virologic Nonresponse No Virologic Data No emergent resistance in pts with VF No significant differences in grade 3/4 AEs, serious AEs, AE-related d/c DTG PI/RTV 10 Switching to DTG associated with improved lipid profile vs continuing boosted PI through Wk DTG PI/RTV 0.7 P < P < P < P <.001 P =.286 P <.001 TC Non-HDL-C TG LDL-C HDL-C TC/HDL Ratio Gatell JM et al. IAS Abstract TUAB0102. Slide credit: clinicaloptions.com

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84 Case discussion High CVD risk with hyperlipidemia secondary to PI/r Renal function declining (creatinine clearance < 50 ml/min) Issue of Aging, bone health and frailty Avoid ABC, and TDF, avoid PI /r Dolutegravir 50 mg OD + 3TC 150 mg OD

85 Summary With ART, life expectancy of PLHIV has increased Appropriate Mx of co morbidities : CV, Renal, Liver, Bone, CNS and Cancer screening need to be done as part of the Mx for HIV Multidisciplinary approach Monitor not only CD4 and HIV VL Metabolic screen and CVD risk modification Renal function and liver function Cancer screen Bone health and Fried frailty score Neurocognitive assessment IHDS and MOCA ART prolonged survival of PLHIV, maintain quality of health is ultimate aim

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