How to manage comorbidities in relation to antiretroviral ...regist2.virology-education.com/2016/2Taiwan/04_Martinez.pdf · Study (Third Agent) TDF Subjects, n D/C due to Renal AE,

How to manage comorbidities in

relation to antiretroviral therapy in

(aging) HIV-infected individuals

TAIWAN SYMPOSIUM ON HIV COMORBIDITIES 2016Kaohsiung, 1 October 2016

Esteban Martinez

[email protected]

Comorbidities in HIV+ patients

• General overview

• Kidney

• Bone

• Cardiovascular



• Kidney

• Bone

• Cardiovascular

http://www.eacsociety.org/files/2015_eacsguidelines_8_0-english_rev-20160124.pdf

In addition to data collection regarding: medical history, HIVdisease and co-infections

EACS guidelines:

Screening for comorbidities


Kidney Bone CV Cancer CNS

Screening

Blood and

urine

chemistries

DEXA

+/- FRAX

score

Framingham

(or similar)

score

No

(cytology

cervical

cancer)

No

(psychometric

tests?)

Prediction

of clinical

problem

Highly

accurate

Less

accurate

More

innaccurate

More

innacurate

or lacking

Lacking

Not all comorbidities are equally assessed

Avoid antiretrovirals with potential toxicities

impacting on specific comorbidities


High Moderate Low/No

ATV/rit NVP NRTIs (all)

DRV/rit EFV RPV

ATV/cobi ETV MVC

DRV/cobi RAL

EVG/cobi DTG


Avoid antiretrovirals with risk for drug-drug

interactions with comorbidities therapies

Avoid tobacco

http://www.cdc.gov/tobacco/data_statistics/fact_sheets/health_effects/effects_cig_smoking/



• Kidney

• Bone

• Cardiovascular

How to assess kidney function in patients with HIV infection?

To measure the capacity

of renal clearance(Nº of functioning nephons)

To assess the degree of

structural damage

(Kidney disease progression)

Glomerular filtration rate Proteinuria

Creatinine is not enough as a measure of

renal clearance

Johnson R, et al. Comprehensive Clinical Nephrology. 2000. Mosby. St. Louis. 4.15.1–4.15.15.

Inulin Clearance (mL/min/1.73 m2)

Se

rum

Cre

ati

nin

e(m

g/d

L)

9.0

8.0

7.0

6.0

5.0

4.0

3.0

2.0

1.0

0.0

0 20 40 60 80 100 120 140 160 180

Creatinine is a poor

reflector of GFR

GFR versus Serum Creatinine

• Cockcroft-Gault (CG) Equation: CLcr (ml/min) =

[140 –Age (yrs] x Wt (kg) x (0.85 if female)

72 x Serum creatinine (mg/dL)

Overestimates GFR at decreased function

Has been used to develop drug dosing algorithms

• Modification of Diet in Renal Disease (MDRD) Equation

GFR (mL/min/1.73m2) = 186 x (Scr)-1.154 x (Age) -0.203 (x0.742 if female)

(x1.21 if black)

In normal ranges, tends to underestimate GFR

Has not been used to develop drug dosing algorithms

• Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) Equation

GFR (mL/min/1.73m2) = 141 x min(Scr /κ,1)α x max(Scr/κ, 1)-1.209 x

0.993Age x 1.018 [if female] x 1.159 [if black]

More specific methods to estimate renal

clearance

National Kidney Foundation. K/DOQI Clinical Practice Guidelines for Chronic Kidney Disease. Am J Kidney Dis 2002

Wetzels JF et al. Kidney Int. 2007;72:632–637., Glassock R. Nephrology Times 2009

0

20

40

60

80

100

120

140

160

180

200

0 20 40 60 80 100

Estim

ate

d G

FR

(m

L/m

in/1

.73m

2)

Age (years)

Inulin (Davies and Shock, 1950)

NHANES III Estimated GFR (median, 95th percentiles)

eGFR decreases with age

Normal eGFR decrease: 0.5-1 mL/min/1.73m2 per year

The slope of eGFR decline increases with age

Abnormal eGFR decrease: > 3-5 mL/min/1.73m2 per year

Lindeman RD et al. J Am Geriatr Soc 1985

For similar creatinine and age, women have

worse eGFR than men

http://mdrd.com/

Ginsberg JM et. al. N Engl J Med 1983

Random urine:

Protein mg/dl

Creatinine mg/dl

24-hour urine - Gold Standard

Simple assessment of proteinuria using

protein/creatinine ratio

Number of

patients

eGFR with TDF vs. Other

(95% CI)

P value

Meta-analysis 1 517 -3.9 mL/min (-2.3 to -5.7) <0.05

10-year cohort 2

Year 1 483 -3.1 mL/min (-5.6 to -0.5) 0.02

Year 2 358 -4.1 mL/min (-6.0 to -2.1) <0.001

Year 3 241 -2.4 mL/min (-4.6 to -0.3) 0.02

Year 4 149 -3.1 mL/min (-7.0 to +0.8) NS

1. Cooper RD et al. Clin Infect Dis 2010

2. Laprise C et al. Clin Infect Dis 2013

TDF significatively lowers eGFR but short-

term effect is limited

Study (Third Agent)TDF

Subjects, nD/C due to Renal

AE, %Follow-up,

weeks

TDF alone GS-102, 103 (TDF for HBV) 426 <1.5 240

Unboosted

Regimens

STARTMRK (RAL or EFV) 563 NR 48

QDMRK (RAL) 770 NR 48

GS-903 (EFV) 299 0 144

GS-934 (EFV) 257 0 144

ECHO/THRIVE (RPV or EFV) 1096 0 96

GS-236 102, 104 (EFV) 396 0 48

ASSERT (EFV) 193 0 48

Boosted

Regimens

ABT-730 (LPV/r) 664 0 96

ARTEMIS (DRV + RTV or LPV/r) 689 0 96

GEMINI (SQV + RTV or LPV/r) 337 0 48

GS-263 103 (ATV+RTV) 355 0.3% 48

GS-263 102, 103, 104 (STRIBILD) 749 0.8% 48

CASTLE (ATV+RTV or LPV/r) 878 <1% 96

HEAT (LPV/r) 345 <1% 96

ARTEN (ATV+RTV or NVP) 569 <1% 48

ABT-418 (LPV/r) 190 <1% 96

ACTG 5202 (ATV+RTV or EFV) 925 1% 96

BATON (ATV+RTV) 100 1% 48

GS-216 105, 114 (ATV+RTV or ATV+COBI) 771 1.6% 48

ALERT (FPV+RTV or ATV+RTV) 106 2.8% 48

Total 10,657 0 - 2.8% 48-144

NR: not reported

Discontinuation due to renal impairment in

TDF-treated pts

Log-rank test

<59kg vs >67kg p=0.002

59-67kg vs >67kg p=0.073

n=160

n=168

n=167

Nishijima T et al. AIDS 2014

Time to 25% eGFR reduction according to baseline weight categories

Low weight is a risk factor for TDF-related

kidney toxicity

Kearney B et al. J Acquir Immune Defic Syndr 2006

0 6 12 18 2410

100

1000

TDF alone

TDF + LPV/r

mean± 95%CI Time (hr)

Tenofo

vir

Concen

tration (

ng/m

L)

TDF AUC

34%

-60

-40

-20

0

20

40

60

80

100

Cmax

AUC

Cmin

ATV 400 mg TDF 300 mg

-25%-20%

-40%

24%

14%22%

% c

han

ge f

rom

wh

en

do

sed

alo

ne

Kaul S et al. ICAAC 2003

Similar plasma TDF increases with DRV/r and EVG/c

Hill A et al. J Int AIDS Soc 2014

Plasma TDF may increase with PI’s and EVG/c

MRP4

OAT3

Blood

(Basolateral)Urine

(Apical)

OAT1N

NN

N

NH2

OPO

O--O

Tenofovir

Active Tubular Secretion

Cation Transport Pathway

Blood

(Basolateral)Urine

(Apical)

OCT2H+MATE1

N

N

NH2O

Creatinine

Active Tubular Secretion

Anion Transport Pathway

NH

HN

ONH

N

O O

O

N

SS N

N

O

Cobicistat

MRP2

Ritonavir

Stray KM et al. Antimicrob Agents Chemother 2013

Intra-tubular TDF may increase with RTV (but

not with COBI)

Pathogenesis of tenofovir-related kidney

dysfunction

Yombi JC et al. AIDS 2014

Baxi SM et al. AIDS 2014

TENOFOVIR

CREATININE

Ritonavir Ritonavir

Rilpivirine

Dolutegravir

Ritonavir

Cobicistat

Creatinine

Tenofovir Tenofovir

Kidney injury: tubular markers in urine

↓eGFR (progressive)

eGFR (estable)

OAT1

OAT3

OCT2

MRP2

MRP4

MATE1

Blood

Tubular Cell

Urine

age

↓BMI

Ritonavir

Cobicistat

CKD Risk by Yrs of ARV Exposure, IRR (95% CI)

Drug 1 Yr 2 Yrs 5 Yrs

TDF1.12

(1.06-1.18)1.25

(1.12-1.39)1.74

(1.33-2.27)

ATV/RTV1.27

(1.18-1.36)1.61

(1.40-1.84)3.27

(2.32-4.61)

LPV/RTV1.16

(1.10-1.22)1.35

(1.21-1.50)2.11

(1.62-2.75)

Relationship Between Increasing Exposure to ARVS and CKD

1.80

1.60

1.40

1.20

1.00

0.00ATV/RTV LPV/RTV TDF

IRR

(9

5%

CI)

Univariate

Multivariate

On treatment

TDF censored

Mocroft A et al. CROI 2015: abstract 142

ARVs and risk of kidney disease:

Is PI-effect a pure one or is it post-TDF-related?

EuroSIDA

TDF and TAF bioavailability

Lee WA et al. Antimicrob Agents Chemother 2005

n (%)E/C/F/TAF

n=866

E/C/F/TDF

n=867

Events

Renal adverse events leading to discontinuation 0 4 (0.5)

Tubulopathy/Fanconi syndrome 0 0

-6.6p <0.001

-11.2

E/C/F/TAF

E/C/F/TDF

TAF vs. TDF: Renal safety

Sax P et al. 22nd CROI 2015: abstract 143LB

Virologically suppressed adults with stable eGFRCG (30–69 mL/min) switched

from TDF- or non-TDF–containing regimens to open-label E/C/F/TAF

(n=80)

(n=162)

Safety of TAF in renal impairment

Pozniak A et al. 22nd CROI 2015: abstract 795



• Kidney

• Bone

• Cardiovascular

0 10 20 30 40 50 60

Bone m

ass

Age (years)

Men

Women

Menopause

Fracture threshold

Average annual decrease: 1% BMD per year

BMD decreases with age

Compston. Clin Endocrinol 1990

Dual-X absorptiometry (DXA) measures BMD

-6

-5

-4

-3

-2

-1

0

0 24 48 96 144

Adapted from several references: Rivas et al. HIV Medicine 2008; Hansen et al, IAS 2009; Daar et al. CROI 2010

Semanas

Ch

ang

e in

BM

D fro

m b

ase

line

(%

)

Change in BMD from baseline (%)(irrespective of the antiretroviral drugs used)

Initiation of ART causes BMD decrease

Van Vonderen MG et al. CROI 2011

BMD decrease with ART initiation is due to a

high bone turnover

Overton ET et al. CROI 2014; Ofotokun I et al. CROI 2016

Vitamin D Zolendronate

BMD decrease with ART initiation can be

reduced or avoided

McComsey GA et al. J Infect Dis 2011

ACTG 5202

Greater BMD with TDF (vs. ABC) and with

ATV/r (vs. EFV)

Brown T et al. CROI 2014: abstract 779LB

Greater BMD with ATV/r or DRV/r (vs. RAL)

Low vitamin D is a common cause of low

BMD measurement (DXA)

Dao CN et al. Clin Infect Dis 2011

0

0,5

1

1,5

2

2,5

3

3,5

4

4,5

5

40-45 45-50 50-55 55-60 60-65 65-70 70-75 75-80

HIV infected

HIV uninfected

Ag

e-s

pecif

ic f

rac

ture

in

cid

en

ce

-ra

tes

(/1

000 p

ers

on

-yea

rs)

in H

IV i

nfe

cte

d V

S u

nin

fecte

d p

ati

en

ts

Low absolute risk of fractures: Excess risk in

HIV+ >65 years

Guerri-Fernandez R et al. J Bone Mineral Res 2013

1994 WHO classification according to BMD

measurement (DXA)

Assessment of fracture risk and its application to screening for postmenopausal osteoporosis.

Report of a WHO Study Group. Geneva, World Health Organization, 1994

FRAX score (SPAIN)

https://www.shef.ac.uk/FRAX/tool.aspx?country=4

Treatment

decision making:

Major osteporotic >10%

Hip fracture >3%

FRAX score (TAIWAN)

https://www.shef.ac.uk/FRAX/tool.aspx?country=26

Treatment

decision making:

Major osteporotic >10%

Hip fracture >3%

• Normal:

– No intervention

– DXA in ≥5 years

• Osteopenia:

– Exercise, quitting smoking, calcium intake (diet preferred)

– Measure serum vit D: if low, prescribe supplements

– DXA in 2-5 years (inversely proportional to osteopenia intensity)

• Osteoporosis:

– Exercise, quitting smoking, calcium intake (diet preferred)

– Withdraw TDF

– Measure serum vit D: if low, prescribe supplements

– Estimate FRAX:

• If major osteoporotic ≥10% or hip ≥3% fracture risk, send patient to

Rheumatology Unit to consider biphosphonate therapy

• If major osteoporotic <10% and hip <3% fracture risk, DXA in 1-2 years

Clinical care DXA protocol for HIV+ patients in Hospital Clínic Barcelona

Patient 50y or younger with menopause or

hypogonadism should have bone DXA done

From TDF

To TDF

Bloch M. et al. HIV Med 2014.

Negredo E. et al. J Antimicrob Chemother 2014

Rasmussen TA et al. PLoS One 2012

Cotter AG et al. J Clin Endocrinol Metab 2013

SWAP Study -1.8% (-2.6, -1.1)% BMD loss at hip

PREPARE Study -1.73 (2.76)% BMD loss at hip

TROP Study +2.5 (1.6, 3.3)% BMD gain at hip

OsteoTDF Study +2.1 (-0.6, 4.7)% BMD gain at hip

+

-

BM

DIn treated HIV patients, discontinuation of TDF

has a positive effect on BMD

Pozniak A et al. 22nd CROI 2015: abstract 795

Switch from TDF to TAF in treated HIV pts led

to BMD

HIV adults,

TDF>6mo,

HIV RNA

<50c/mL>3mo,

eGFR>60mL/m,

T-score -1

Zoledronic acid

5 mg iv yearly

Switch TDF

BMD

BMD

Randomization

Hypothesis

Zoledronic acid therapy will increase BMD more effectively over 2 years than

switching from TDF to another antiretroviral drug in the HIV treatment regimen

Bisphosphonate Therapy with Zoledronic acid or Tenofovir Switching

to Improve Low Bone Mineral Density in HIV-Infected Adults

24 months

ZEsT : An Strategic Randomized Clinical Trial



• Kidney

• Bone

• Cardiovascular

Law MG, et al. 11th CROI. 2004. Abstract 737.

Duration of HAART (years)

MI

pe

r 1

000

PY

FU

0

1

2

3

4

5

6

7

8

< 1 1-2 2-3 3-4 4+0

Observed

Predicted

Risk of myocardial infarction in HIV+ patients

can be estimated with Framingham score

D:A:D Study

Law MG et al. HIV Med 2006

Framingham score: gender, smoking, age, systolic BP, total and HDL cholesterol

If non-smoking you need to be almost

15y older to have the same CV risk

Man, 50y, smoker = risk >10% Woman, any age, even smoker = risk <10%

http://cvdrisk.nhlbi.nih.gov/

Some practical hints regarding Framingham

risk estimation

However, Framingham does not

include HIV-specific factors

Immune status

Increased inflammatory markers

Insulin resistance

Time on HAART

26510

49091309

302 (1%)

174 (3%)

104 (7%)

0

5000

10000

15000

20000

25000

30000

<10 10-to-20 >20

MI

No MI

If a patient has a low risk, the likelihood of not having a MI is high

D:A:D Study 2009

Framingham score has a low sensitivity, but a

high negative predictive value

Framingham risk score

Num

be

r of patients

Framingham >20

S=18%

E=96%

VPP=7%

VPN=99%

Framingham 10

S=48%

E=81%

VPP=4%

VPN=99%

2013 ACC/AHA score may estimate CV events

better than Framingham score

Triant V et al. 22nd CROI 2015: abstract 751

FRS

0

5

10

15

20

25

5 Y

ear

Eve

nt R

ate

(%

)

<2.5%

2.5-4.9%

5.0-7.4%

7.5-9.9%

5 Year Predicted Risk

Predicted Observed

ACC/AHA

0

5

10

15

20

25

5 Y

ear

Eve

nt R

ate

(%

)

<2.5%

2.5-4.9%

5.0-7.4%

7.5-9.9%

5 Year Predicted Risk

Predicted Observed

Partners HealthCare System HIV longitudinal cohort (n=2270), comprised of patients

seen at Brigham & Women’s Hospital or Massachusetts General Hospital in Boston, MA

Nr of patients 108

Age, years (IQR) 46 (40-52)

Current smoking (%) 50

Total cholesterol (mg/dL) 175

LDL cholesterol (mg/dL) 98

HDL cholesterol (mg/dL) 49

10-year Framingham score, % (IQR) 3 (1-5)

10-year ASCVD score, % (IQR) 3.3 (1.6-6.6)

CD4 cells/mm3 528

Viral load (copies/mL) <50

Patients with any coronary plaque (%) 45

Patients with high-risk plaques (%) 36

Statins recommeded 2004 ATP III (%) 8

Statins recommended 2013 ACC/AHA (%) 21

Zanni MV et al. AIDS 2014

Risk of subclinical CV disease is higher than

predicted

http:// www.europeanaidsclinicalsociety.org/images/stories/EACS-Pdf/EACSGuidelines-v6.1-English-Nov2012.pdf

Prior to 2015


2015

Major steps to intervention on smoking

cessation

U.S. Public Health Service. Agency for Healthcare Research and Quality.

http://www.ahrq.gov/clinic/tobacco/5steps.htm

Smoking cessation studies in HIV patients

Calvo-Sanchez M, Martinez E. HIV Med 2015

• Analysis of MI risk with ABC pre and post 3/08 in D:A:D cohort

• There were trends to less ABC use in high risk individuals post 3/08

• RR with ABC 1.98 (1.72-2.29), Pre 3/08 1.97, Post 3/08 1.97

Overall Pre-March 2008

Post-March 20085

4

3

2

1

0.7

Rela

tive R

isk

ABC and MI risk persists in D:A:D despite

change in ABC use

Sabin C et al. 21st CROI 2014: abstract 747LB

0

0.00 1.00 2.00 3.00 8.00

Full study population

Restricted study population

4.00 5.00 6.00 7.00

Adjusted hazard ratio for MI

Age <40 (vs 50-59) years

Age 40-49 (vs 50-59) years

Age ≥60 (vs 50-59) years

Smoking

Hypertension

Diabetes

eGFR 30-59 (vs ≥60) mL/min/1.73 m2

eGFR <30 (vs ≥60) mL/min/1.73 m2

High (≥240 vs <240 mg/dL) total chol

High (≥300 vs <300 mg/dL) triglycerides

Statin use

Recent ABC use

Adjusted Hazard Ratios of CVD Risk Factors Significantly Associated With MI

Palella F et al. 21st CROI 2015: abstract 747LB

Recent ABC and MI risk:

Controversy in NA-ACCORDMany significant differences in clinically relevant characteristics between

ABC and non-ABC users

Desai M et al. Clin Infect Dis 2015

Current ARV drugs and MI risk:

New data from US Veterans

Marginal Structural Models

(to minimise confounding)

ABC and MI risk: New data from Swiss Cohort

Young J et al. J Acquir Immune Defic Syndr 2015

de Pablo C et al. AIDS 2010; de Pablo C et al. Antivir Ther 2012; de Pablo C et al. J Infect Dis 2013

Satchell CS et al. J Infect Dis 2011; Baum PD et al. AIDS 2011; Chini M et al. Int J Immunopathol Pharmacol 2012;

Falcinelli E et al. Thromb Haemost 2013

• induces Mac-1 on leukocytes, which interacts with ICAM-1 on endothelial cells

• increases platelet activity through inhibition of soluble guanylyl cyclase

• facilitates collagen-induced platelet aggregation

ABC (in vitro or non-controlled in vivo studies):

ICAM-1Platelets

Endothelial cells

LeukocytesMac-1

Abacavir and myocardial infarction:

Pathogenesis

Approximately 1/3 of the PI-related excess risk

for MI in D:A:D is due to DM, HT, or lipids

Adjusted Model 1 Adjusted Model 2

Relative Rate

(95% CI)P Value

Relative Rate

(95% CI)P Value

Exposure to PIs (per year) 1.16 (1.10-1.23) <0.001 1.10 (1.04-1.18) 0.002

Age (per 5 yr) 1.39 (1.31-1.46) <0.001 1.32 (1.23-1.41) <0.001

Male sex 1.91 (1.28-2.86) 0.002 2.13 (1.29-3.52) 0.003

BMI >30 kg/m2 1.70 (1.08-2.69) 0.02 1.34 (0.77-2.34) 0.31

Family history of CHD 1.56 (1.10-2.23) 0.01 1.40 (0.96-2.05) 0.08

Smoking status

Current 2.83 (2.04-3.93) <0.001 2.92 (2.04-4.18) <0.001

Former 1.65 (1.12-2.42) 0.01 1.63 (1.07-2.48) 0.02

Previous cardiovascular event 4.30 (3.06-6.03) <0.001 4.64 (3.22-6.69) <0.001

Diabetes mellitus - - 1.86 (1.31-2.65) <0.001

Hypertension - - 1.30 (0.99-1.72) 0.06

Total cholesterol (per mmol/L increase) - - 1.26 (1.19-1.35) <0.001

HDL cholesterol (per mmol/L increase) - - 0.72 (0.52-0.99) 0.05

D:A:D Study Group. Clin Infect Dis 2008

Martinez E et al. AIDS 2010

RAL arm in SPIRAL led to total-to-HDL cholesterol

ratio

Fisher M et al. 11th International Congress on Drug Therapy in HIV Infection, Glasgow, 2012

RPV arm in SPIRIT also led to total-to-HDL

cholesterol ratio

Median difference of percent change RAL minus PI/r (95% CI)

Martinez E et al. AIDS 2012

• Generally modest or no significant correlation between changes in biomarkers

and changes in lipids

SPIRAL Biomarkers Sub-study

Switching from PI/r to RAL also decreased CV

biomarkers

Lee F et al. HIV Med 2016

Larger decrease in cholesterol fractions with

statin than with PI/r switch

Lo J et al. Lancet HIV 2015

1- year change in non-calcified plaque volume

in HIV+ randomized to atorvastatin vs placebo

Declining relative risk for myocardial

infarction among HIV+ vs. HIV- persons

Klein DB et al. Clin Infect Dis 2015

Documents

How to manage comorbidities in relation to antiretroviral ...regist2.virology-education.com/2016/2Taiwan/04_Martinez.pdf · Study (Third Agent) TDF Subjects, n D/C due to Renal AE,