Long Term Survival of PLHIV

DR Chow TS Infectious Disease Unit Hospital Pulau Pinang

Natural Progression of HIV

Combination ART

cART

• Combination of antiretroviral drugs of at least 3 or more as a regime

• By using

• 2 NRTI plus – 1 NNRTI

– boosted PI.

– INSTI

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

Therapeutic Goal of HAART R

elat

ive

Lev

els

Months Years After HIV Infection

CD4+ T-cells

Plasma HIV Viremia

Acute HIV infection Symptom

Viral Load: Limit of detection

? Long term durability

FIRST LINE FOREVER

MALAYSIA CONSENSUS GUIDELINES ARVT IN ADULT 2016

Current ARV Medications 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)

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

HOW LONG CAN PLHIV SURVIVED WITH ART ?

Expected age of death of 35 year old men with CD4

95% CI (compare to General pop in UK 78 )

<200 71 (68-73)

200-349 78 (74-82)

> 350 77 (72-81)

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)

Adverse effects of ART

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 under-assessed 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

Choosing a lifelong ART – Considering comorbidities

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

Slide credit: clinicaloptions.com DHHS Guidelines. July 2016.

ATHENA and Swiss HIV Cohort Studies: Polypharmacy Among HIV-Infected Pts on ART

• 5.2% of pts 50-64 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 2030

Slide credit: clinicaloptions.com 1. Smit M, et al. Lancet Infect Dis. 2015;15:810-818. 2. Hasse B, et al. Clin Infect Dis. 2011:53;1130-1139.

ATHENA Modeling Study[1]

16,000

14,000

12,000

10,000

8000

6000

4000

2000

0

Pe

op

le (

n)

3+ comedications 2 comedications 1 comedication No comedication

2010 2015 2020 2025 2030

Swiss HIV Cohort Study (N = 8444)[2]

Prospective Observational Study

< 50 Yrs 50-64 Yrs ≥ 65 Yrs

100

80

60

40

20

0

Pa

rtic

ipa

nts

(%

)

n = 5761 n = 2233 n = 450

No comedication

1 comedication

2 comedication

3 comedications

4+ comedications

Elderly : ART and comorbidities Scenario Consider Avoiding

CKD (eGFR

< 60 mL/min)

TDF, especially in RTV-

containing regimens

Osteoporosis TDF

CVD risk ABC

Hyperlipidemia

PI/RTV

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

Slide credit: clinicaloptions.com References in slidenotes.

Key Interactions: INSTI-Containing ART Regimens

• Consider www.hiv-druginteractions.org to assist with identifying potential interactions for all regimens

Regimen Key Drug–Drug Interaction Considerations

All INSTIs[1-5]

Use caution with/avoid simultaneous

polyvalent cation-containing antacids

Eg MMT. Alluminium . Ca

DTG

Dose adjust metformin (diabetes

medication) – need to reduce dose of

metformin

RAL No notable comedications to avoid for RAL

aside from aluminum/magnesium antacids

Slide credit: clinicaloptions.com References in slidenotes.

An Aging Population of PLHIV

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

1996-2014

2006-2014

2000-2005

1996-1999

HIV-Positive Pts

1.00

0.75

0.50

0.25

0

Pro

bab

ility

of

Surv

ival

50 60 70 80 Age (Yrs)

Legarth RA, et al. J Acquir Immune Defic Syndr. 2016;71:213-218. Slide credit: clinicaloptions.com

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 2030

Smit M, et al. Lancet Infect Dis. 2015;15:810-818.

Pro

po

rtio

n o

f H

IV-P

os

itiv

e P

ts

1.0

0.9

0.8

0.7

0.6

0.5

0.4

0.3

0.2

0.1

0 2010 2015 2020 2030 2025

> 70 yrs of age

60-70 yrs of age

50-60 yrs of age

40-50 yrs of age

30-40 yrs of age

< 30 yrs of age

Slide credit: clinicaloptions.com

Comorbidities n 0.68 0.80 1.03 1.15 1.47 0.89 1.35 1.52 1.65 2.04

HIV-negative (n=452)

HIV-positive (n=489)

100

%

80

60

40

20

0

3+ 2 1 0

Significantly more cardiovascular disease, liver disease, renal failure and cancer in HIV+

Comorbidities more common in HIV

Schouten et al. Clin Infect Dis 2014

AGEhIV: Older HIV-Infected Pts at Increased Risk for Multiple Comorbidities

• Cross-sectional analysis of comorbidity prevalence in prospective cohort study of HIV-infected pts (n = 540) vs controls (n = 524) ≥ 45 yrs of age

Schouten J. Clin Infect Dis. 2014;59:1787-1797.

Slide credit: clinicaloptions.com

Pts

(%

)

50

30

20

10

0

40

P < .001

P = .018 P = .008 P = .044

HIV-uninfected pts HIV-infected pts

Factors Related to Non-AIDS Comorbidities in HIV-Infected Pts

Warriner AH, et al. Infect Dis Clin North Am. 2014;28:457-476. Slide credit: clinicaloptions.com

• AGING

• Chronic HIV

infection

• ART toxicity

• HCV and other

coinfections

• Genetics

• Obesity, exercise,

diet, smoking

• Stress

• Depression

Inflammation and

fibrosis

Dyslipidemia

Insulin resistance

Decreased physical

functioning

Cardiovascular

Renal

Metabolic

Functional

Neuropsychiatric

Factors Conditions End Organ

Disease

Is HIV immune activation ? OR immune destruction?

HIV and Inflammation • HIV infection induces a persistent inflammatory

response, resulting in pathogenic responses and end-organ 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]

Slide credit: clinicaloptions.com

1. Tenorio AR, et al. J Infect Dis. 2014;210:1248-1259. 2. So-Armah KA, et al. J Acquir Immune

Defic Syndr. 2016;72:206-213. 3. Nixon DE, et al. Curr Opin HIV AIDS. 2010;5:498-503.

4. Neuhaus J, et al. J Infect Dis. 2010;201:1788-1795.

Inflammation Associated With Disease in Treated HIV Infection

• Mortality[1-4]

• 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

Case discussion 2008

– 54-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 80 ---- 150 umol/ml (creatinine clearance = 62 declined to 45ml/min )

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

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

HIV and CVD , HTN

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 2001-2012 (N = 145,845)

– 71% male; median age: 49 yrs

• From 2001-2012, 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

Slide credit: clinicaloptions.com Hanna DB, et al. Clin Infect Dis. 2016;63:1122-1129.

HIV Infection

ARV

*Metabolic syndrome ARV: antiretroviral therapy; hs-CRP: high-sensitivity C-reactive protein Adapted from Carr A. Clinical Care Options HIV. Available at: www.clinicaloptions.com/hiv

CVD Risk Factors in the

HIV Population

Gender

CVD Risk

- -

Diabetes

Lipids*

Family History

Abdominal Obesity*

Hyper- tension*

Cigarette Smoking

Hyper-glycemia* Insulin

Resistance

Inactivity, Diet

Age

Orange = Modifiable Green = Non-modifiable Purple = HIV-associated

hs-CRP?

Hypertension is more prevalent HIV-Infected Pts

• Analysis of HTN in HIV-infected pts in UNC CFAR HIV Clinical Cohort, 1996-2013 (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/mm3

• 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: 1.25-2.19

Slide credit: clinicaloptions.com 1. Okeke NL, et al. Clin Infect Dis. 2016;63:242-248.

2. van Zoest RA, et al. Clin Infect Dis. 2016;63:205-213.

LIPID: To Treat or Not To Treat ASCVD Risk Estimator

Slide credit: clinicaloptions.com tools.acc.org/ASCVD-Risk-Estimator/.

Consider High Intensity Statin and Aspirin

Hyperlipidemia

Approach to HIV+ on ART with high ASCVD risk

Slide credit: clinicaloptions.com

Observation Recommendations

HIV-infected pts have

increased CVD risk

Virologic suppression can reduce CVD risk

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

ART can increase

dyslipidemia

Manage lipids with statin therapy; consider potential DDIs with

boosted PI- or COBI-containing regimens

Numerous challenges exist

in treating HIV infection in

aging pts

Assess comorbidities and potential interplay with ART

regimens

Bone, lipid, or cardiovascular abnormalities can be

exacerbated by specific therapeutics

Consider polypharmacy and potential DDIs

Approach to Lipid-Lowering (Statin) Therapy

Slide credit: clinicaloptions.com

• 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]

Treatment

Statin therapy is first-line therapy for elevated LDL-C and non-HDL-C[1]

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 Dubé MP. Lipid management. 2015. p. 241-255.

PI- or COBI-Containing Regimens

High-Intensity Statin Moderate-Intensity Statin Low-Intensity Statin

Atorvastatin 20 mg Atorvastatin 10 mg Pravastatin 10-20 mg

Rosuvastatin 10-20 mg Rosuvastatin 5 mg Fluvastatin 20-40 mg

Pravastatin 40-80 mg*

Simvastatin and lovastatin are contraindicated for pts receiving a PI, COBI, and/or RTV

*With darunavir, reduce pravastatin to 20-40 mg

NNRTI-, RAL-, or DTG-Containing Regimens

High-Intensity Statin Moderate-Intensity Statin Low-Intensity Statin

Atorvastatin 40-80 mg Atorvastatin 10-20 mg Pravastatin 10-20 mg

Rosuvastatin 20 mg Rosuvastatin 10 mg Fluvastatin 20-40 mg

Pravastatin 40-80 mg

Lovastatin 40 mg Lovastatin 20 mg

Simvastatin 20-40 mg Simvastatin 10 mg

Suggested Statins with ART

HIV and CKD

#

#

Management of HIV with CKD

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 http://www.chip.dk/Tools.

Monitoring RP

4 weeks 3months 3 months 3 months 3 months 6 months 6 months

HAART

BP, RP, BP, RP, U FEME, UPCR

If creatinine clearance <50 ml/min Urine RBC ++

US KUB Refer Nephrologist

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

http://kdigo.org/ home/guidelines/ckd-evaluation-management)

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

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

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

Dosage of ARV adjustment for CKD

No dose adjustment

NRTI Abacavir, zidovudine

All NNRTI

All PI/r

All INSTI

• Dose adjustment needed NRTI

ARV > 50 30-49 10-29 <10

3TC 300 mg OD

150 mg OD

100 mg OD

50 mg OD

FTC No single agent

TDF 300 mg OD

300 mg every 48 H

#300 mg every 72 H

#300 mg weekly

Tenvir EM One tab OD

One tab every 48 H

Use single agent

# not recommended but if no alternative

HIV on ARV with Frailty and Bone health

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]

• Other tools: FRAIL Scale, Study of Osteoporotic Fractures (SOF) index, Clinical Frailty Scale[3-5]

Slide credit: clinicaloptions.com References in slidenotes.

Fried Frailty Phenotype[2]

Frailty Characteristic Clinical Criteria*

Shrinking Unintentional weight loss (> 10 lbs) in prior year, sarcopenia

Muscle weakness Poor grip strength (lowest quintile by sex, BMI)

Poor endurance/exhaustion Self-reported exhaustion

Slowness Walking time per 15 ft (slowest quintile by sex, height)

Low activity Low kcal/week expenditure (lowest quintile by sex)

*Frailty defined as presence of ≥ 3 criteria; prefrailty as presence of 1-2 criteria.

Frailty Risk Factors in Aging HIV-Positive

Slide credit: clinicaloptions.com Erlandson KM, et al. IAS 2011. Abstract TUPE124.

Incid

en

ce (

%)

Diabetes

Frail (n = 33)

Prefrail (n = 185)

Nonfrail (n = 141)

Risk Factors (OR: Frail vs Nonfrail)

Neurologic

Disease

Psychiatric

Disease

CVD Unhealthy

Weight

Arthritis Osteoporosis Viral

Hepatitis

HR: 5.1

P = .007

HR: 3.9

P < .001

HR: 3.9

P = .002

HR: 3.8

P = .067

HR: 3.7

P = .004

HR: 3.6

P = .001

HR: 3.5

P = .022

HR: 3.3

P = .004

0

20

40

60

80

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 2016. 2. Brown TT, et al. J Infect Dis. 2015;212:1241-1249.

3. Tebas P, et al. AIDS. 2015;29:2459-2464. Slide credit: clinicaloptions.com

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, 1996-2008[2])

Slide credit: clinicaloptions.com

Women Men

Age (Yrs)

7.0

6.0

5.0

4.0

3.0

2.0

1.0

0

Fra

ctu

re P

reva

len

ce

/

10

0 P

ers

on

s

30-39 40-49 50-59 60-69 70-79

P = .002

(overall comparison)

HIV

Non-

HIV

HIV

Non-

HIV

Age (Yrs)

7.0

6.0

5.0

4.0

3.0

2.0

1.0

0 F

ractu

re P

reva

len

ce

/

10

0 P

ers

on

s

20-29 30-39 40-49 50-59 60-69

P < .0001

(overall comparison)

1. Brown TT, et al. AIDS. 2006;20:2165-2174. 2. Triant V, et al. J Clin Endocrinol Metab. 2008;93:3499-3504.

http://www.shef.ac.uk/FRAX; McComsey et al, Clin Infect Dis 2010; http://www.eacsociety.org/Portals/0/Guidelines_Online_131014.pdf

Fracture risk assessment

1 2

Bone disease screening and diagnosis in HIV

Esp TDF

Classic risk factors: older age, female gender, hypogonadism, family history of hip fracture, low BMI (≤

19 kg/m2), vitamin D deficiency, 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 re-screening with DXA in risk groups 3 and 4 unless risk factors change and only

rescreen group 6 if steroid

use ongoing.

Ch

an

ge

(%)

Low BMD therapy: prevention / drug therapy

http://www.nof.org/files/nof/public/content/resource/913/files/580.pdf; Huang et al, AIDS 2009

General

Reduce risk of falls

Exercise

– weight-bearing

– muscle strength

– balance training

Vitamin D and calcium

replacement /

supplementation

Avoid TDF /PI

Bisphosphonate therapy

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.

Recommendations for Evaluation of Bone Disease in HIV

Brown TT, et al. Clin Infect Dis. 2015;60:1242-1251. Slide credit: clinicaloptions.com

HIV-Infected Population Assessment Monitoring

Men 40-49 yrs of age

Premenopausal

women

≥ 40 yrs of age

Assess risk of fragility

fracture using FRAX

For pts with FRAX score ≤ 10%,

monitor FRAX in 2-3 yrs

For pts with FRAX score > 10%,

perform DXA

Men ≥ 50 yrs of age

Postmenopausal

women

Pts with fragility

fracture history,

receiving chronic

glucocorticoids, or at

high risk of falls

Assess BMD using

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

ART and frailty Observation Recommendations

Frailty is more prevalent

among HIV-infected vs HIV-

uninfected individuals

Assess pts for frailty;

consider Fried Frailty Phenotype or other available

tests

Fracture prevalence and low

BMD common among pts

with HIV

Some ART regimens have

larger impact on BMD loss

than others

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

HIV on ARV and Liver dysfunction

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):265-75.

1. DILI-Liver toxicity of antiretroviral drugs Drug Class Drug Severe ALT Elevation (%)*

NRTI Lamivudine15

3.7-3.8

Tenofovir16

4

Zidovudine17

4.1

Emtricitabine18

2-5

Abacavir19

6

Didanosine20

6

Stavudine21

6-13

NNRTI Rilpivirine22

<1-2

Etravirine23

2.6

Delavirdine24

4.1-5.1

Efavirenz25

2-8

Nevirapine26

5.3-14

PI Nelfinavir††27

1-2

Indinavir28

2.6-4.9

Darunavir/ritonavir†29

5.6-6.9

Fosamprenavir/ritonavir30

4-8

Ritonavir31

5.3-8.5

Atazanavir/ritonavir32

3-9

Tipranavir/ritonavir33

9.7

Lopinavir/ritonavir34

3-11

CCR5 blocker Maraviroc35

2.4

Integrase inhibitor Raltegravir36

4

Fusion inhibitor Enfuvirtide37

5.4-6.2

Jones M, Núñez M. Semin Liver Dis 2012 May;32(2):167-76.

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.

DILI-Liver Toxicity of Antiretroviral drugs

Jones M, Núñez M. Semin Liver Dis 2012 May;32(2):167-76. Jones M, Nunez M. Semin Liver Dis 2012 May;32(2):167-76.

GRADING of LIVER Dysfucntion

Cancer and HIV

Cancer screen in HIV

Others NCD – HAND

Back to the Case 2008

– 54-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 80 ---- 150 umol/ml (creatinine clearance = 62 declined to 45ml/min )

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

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 ?

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

1. Ofotokun I, et al. Clin Infect Dis. 2015;60:1842-1851.

2. Gatell JM et al. IAS 2017. Abstract TUAB0102. 3. ClinicalTrials.gov. NCT02098837. Slide credit: clinicaloptions.com

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†

Wk 48 Wk 96

*> 50 yrs of age and/or Framingham risk score > 10% at 10 yrs. †NRTIs to remain the same

throughout study.

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 48

• Switching to DTG associated with improved lipid profile vs continuing boosted PI through Wk 48

Gatell JM et al. IAS 2017. Abstract TUAB0102. Slide credit: clinicaloptions.com

No emergent resistance in pts with VF

No significant differences in grade 3/4 AEs, serious AEs, AE-related d/c

Virologic Success

Virologic Nonresponse

No Virologic

Data

ITT

Po

pu

lati

on

(%)

Treatment difference: -2.1% (95% CI: -6.6% to 2.4%)

4.9 4.4

100

80

60

40

20

0

93.1 95.2

2.0 0.5

DTG PI/RTV 10

5

0

-5

-10

-15

-20

-25

DTG PI/RTV

0.7

-8.7

-11.3

0.5

4.2 2.0 1.1

2.5 0.4

-18.4

-7.7 -7.0

TC Non-HDL-C TG LDL-C HDL-C TC/HDL

Ratio

P < .001 P < .001

P < .001

P < .001 P < .001

P = .286

Mea

n C

han

ge

Fro

m B

L to

Wk

48

(%

)

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

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