Clinical cases discussion Aging

Dr Ignacio Bernardino

Hospital Universitario La Paz. IdiPAZ

Madrid. Spain

Update on Clinical Topics in Antiretroviral Therapy workshop Hospital de Sant Pau Art Nouveau Site, Barcelona, Spain

Thursday 30th and Friday 31st of May 2019

Disclosures

Honoraria for lectures and travel grants from Gilead Sciences, ViiV healthcare, Janssen Pharmaceuticals and Merck Sharp & Dohme

Research grant from Gilead Sciences

Clinical case • 54 y Peruvian male with severe Haemophilia A • HIV diagnosed in 1988 (23 y) • Past medical History:

– Lipoatrophy and Lipohypertrophy – Hepatitis C (SVR in 2006 peg-IFN + RBV) – Haemophilic arthropathy (Multiples joint bleeding episodes) – Cerebral Haemorrhage 2007 (complete recovery) – Depressive syndrome 2012 (escitalopram 10mg) – Total left Knee arthroplasty April 2015

• Smoker (10 cig/day since he was 11 y). • Heavy drinker (1-2 Whiskey per day) • First time in our clinic October 2010 (CD4 900 cells/mm3 HIV-RNA

120 copies/ml) on AZT/3TC + Nevirapine + LOP/r

Clinical case Date Therapy

Feb 1990 AZT monotherapy

Jul 1996 AZT+ddC+ Saquinavir

Apr 1997 AZT+3TC+ Saquinavir

Oct 1997 D4T+3TC+Saquinavir

July 1998

D4T+3TC+Nevirapine

Apr 1999 D4T+3TC+Efavirenz

Dic 1999 AZT+3TC+Indinavir

Jun 2002 AZT+3TC+Nevirapine+Lopinavir/r

Oct 2010 TDF/FTC+Lopinavir/r

Phenotypic resistance test performed in EEUU. Resistance to: AZT, 3TC, D4T, Nevirapine and Efavirenz

Viral load undetectable since 2002

Clinical case

• 48y man, Lipoathrophy, Cured Hep C, depression, Insomnia, tobacco and alcohol use, Haemophilic arthropathy

• Sept 2013 (48 y) – CD4 count 763 cells/mm3 CD8 count 1228 cells/mm3 Viral load < 50

copies/ml. CD4:CD8: 0.62 – Glu: 110 mg/dl, Total Chol: 230 mg/dl, HDL: 30 mg/dl, LDL: 94 mg/dl, TG: 689

mg/dl, Creat: 0.77 mg/dl, CKD-EPI > 90 mL/min/1.73. ApoA1: 105, ApoB, 102, APoE 14,1, HbA1c: 4.9%

– Urine dipstick: normal. Fractional P excretion: normal – Vit D: 23 pg/ml PTH: 58 UI/ml – No complaints apart from Knee pain

• Currently on TDF/FTC + LOP/r. Escitalopram 10mg, Zolpidem, Celecoxib, Factor VII supplements on demand

Clinical case

• Which of the following comorbidities would you be more concern of?

Bone and renal toxicities

Cardiovascular comorbidities

Other (CNS, cancer, etc.)

Allaveda C, et al. PLoS One 2018; 13(9):e0203895. Belén Alejos. Centro Nacional Epidemiología (Personal communication), Smit M et al. Lancet Infect Dis 2015;15:e810-18. Hasse B et al. Clin Infect Dis 2011; 53: 1130-9.

Aging in Europe

Netherland

Swiss

France

Spain

50+

11%

46%

73%

50 +: 8.8% to 21.2% from 2004 to 2014

1996

2006

2030

Prevalence of Age-related conditions higher in PLWH

Wong C et al. Clin Infec Dis 2018; 66(8):1230-1238. Hasse B et al. Clin Infect Dis 2011; 53: 1130-9. Schouten J et al. Clin Infect Dis 2014;59:1787-97. Magodoro et al. BMC Res Notes 2016; 9: 379.

Adapted from Hasse B, et al. Clin Infect Dis 2011;53(11):1130-1139.

Swiss HIV Cohort Study: Incidence of clinical events between January 1, 2008, and June 30, 2010 stratified by age

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Incidence of clinical events increases with age

Aging with HIV. Clinical consequences

BMD: 0.728 g/cm2 T score: -2.0 Z score: -1.7 BMD: 0.944 g/cm2 T score: -1.6 Z score: - 1.1

Clinical case

Silva et al, Journal of Bone and Mineral Research, Vol. 29, No. 3, March 2014

Bone quality– Trabecular Bone Score (TBS)

FRAX score and Frax adjusted for TBS

Clinical case

• Nov 2015 (50 y). Excellent health status. No complaints – Smokes 4 cig per day – No familiar History of early CV disease – CD4 count 962 cells/mm3 Viral load < 50 copies/ml. – Glu: 100 mg/dl, Total Chol: 173 mg/dl, HDL: 30 mg/dl, LDL: 94 mg/dl,

TG: 243 mg/dl, Creat: 0.77 mg/dl, CKD-EPI > 90 mL/min/1.73. Urine: normal

– BP: 120/80 mmHg

• On TDF/FTC + LOP/r. Escitalopram 10mg, Zolpidem, Celecoxib, Factor VII supplements on demand

Clinical case

• Regarding the cardiovascular risk in this

I think this patient has no CV risk. Just Triglycerides and mild

smoker

He’s on a high CV risk. I’d change ARV and add a statin

I would order some more tests to explore subclinical atherosclerosis

IN PLWHIV Risk ratio for CVD was 2.16 (1.68–2.77) The global population–attributable fraction from CVD attributable to HIV increased from 0.36% (0.21%–0.56%) to 0.92% (0.55%–1.41%)

CVD increased 2-fold in PLWH

RR 2.36

RR 1.79

RR 2.56

CV events

Myocardial infarction

Stroke

RR 2.16

Shah AS et al. Circulation 2018; 138:1100–1112.

Bloomfield GS, et al Cardiol Clin 2017; 35:59-70

Which CVD equation is designed for HIV?

ACSV calculator 9.5%

Framingham 17.9%

DAD (R) CV risk calculator 58.42%

Regicor 5%

http://www.eacsociety.org/guidelines/eacs-guidelines/eacs-guidelines.html

Multifactorial Multidisciplinary

HIV as a cardiovacular risk-enhancer factor

Grundy SM, et al. 2018 AHA/ACC/AACVPR/AAPA/ABC/ACPM/ADA/AGS/APhA/ASPC/NLA/PCNA guideline on the management of blood cholesterol: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. J Am Coll Cardiol. 2018

96-weeks European (6 countries), multicenter (32 sites) , prospective, randomized, open-

label, non-inferiority (-10%) trial.

Eligibility criteria

HIV-infected patients with plasma HIV-1 RNA < 50 copies/ml for ≥ 6 months on triple therapy PI/r + 2NRTI’ s

Age >50 years and/or Framingham risk score >10% at 10 years

No documented resistance mutations and no previous episodes of confirmed virological failure whilst receiving ART

unless documented lack of resistance mutations

Randomization 1:1 stratified by country

PI/r + 2NRT´’s (PI/r)

DTG + 2NRTI’s (DTG)

Week 0 48 96

DTG + 2NRTI’s (DTG)

Immediate switching Deferred switching

Primary endpoint

Aortic stiffness Intima media thickness

Carotid plaque

Anckle brachial pressure index ABPI

Coronary calcium score

Carotid PWV (gold standard)

Other complementary indices such as augmentation index (AIx or AIx@75bpm)

PvW: 7.4 m/sg No carotid plaques. IMT normal.

Clinical case

• Feb 2018 (53 y). End of NEAT 022 trial

– His clinician simplified ARV for ABC/3TC/DTG – Quit smoking – CD4 count 962 cells/mm3 Viral load < 50 copies/ml. – Glu: 102 mg/dl, HbA1c: 5.3% Total Chol: 168 mg/dl, HDL: 28

mg/dl, LDL: 100 mg/dl, TG: 140 mg/dl, Creat: 1.00 mg/dl

• No symptoms. On ECG (mandatory in EECC) atrial fibrillation

Clinical case

• What would you do regarding ARV?

In this patient Abacavir is contraindicated. I’d switch to Bic/F/TAF

I’d explore a Nuke sparing regimen such as DTG/RPV

I would not change ARV.

Atrial fibrillation

Echocardiogram: LCEF: 47%, Septum hypokinesia Moderate atrial dilatation Basal aneurismatic segments in posterolateral wall

Discussion with Haematology: No ASA and no anticoagulant

Discussion with Cardiology: An coronary CT angiogram and/or stress echocardiography

Non-obstructive (50%) Mixed plaque in left anterior descending artery.

Agatson Score: 85

Meta-analysis coronary plaques at CCTA in asymptomatic HIV

Non-calcified plaque

Calcified plaque

CAC score > 0 D’Ascenzo, et al Atherosclerosis 2015

Older HIV-infected patients

Complex Adult patients

Polypharmacy Frailty Geriatric syndromes Sarcopenia Hormone dysregulation (low testosterone and S-DHEA levels)

Cardiovascular diseases Bone diseases & fractures Renal diseases COPD Malignancies NCI, dementia, depression

Demographic & genetic factors Tobacco use Alcohol/ Illicit drugs Co-infections (CMV, herpes, HCV, HBV) Physiologic aging

Isolation & discrimination Vulnerability Social disparity Stigma Nutritional deficiencies

Chronic inflammation Immune activation Immune senescence Pro-coagulation

Drug toxicity Insulin resistance Atherogenic lipid profile Mitochondrial toxicity Drug-drug interactions

Comorbidities

Host Traditional risk

factors

ART-related factors

HIV-related factors

Social Factors

Geriatric problems

Montejano R, et al. European Geriatric Medicine 2019 https://doi.org/10.1007/s41999-018-0152-1

Take home messages & questions not resolved

• PLWH are aging. Median age is increasing in all cohorts

• Certain co-morbidities are more frequent in people infected with HIV

• CVD increased 2-fold in PLWH

• HIV as a CV risk factor

• Should we rely on CV risk calculators in HIV?

• Should we screen patients with CV risk for subclinical atherosclerosis?

• Which test should we use (if any)?

• Aggressive management of CV risk factors in primatry and secondary prevention

(lipid, glycemia, lipids, tobacco cessation)

• Optimize ARV if possible.