Выбор начальной схемы АРТ у пациентов старшего...

Choosing and Using First-line Antiretroviral Therapy in Older Patients

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Faculty

José R. Arribas, MDResearch Director (HIV and Infectious Diseases) Hospital La Paz. IdiPAZ. Madrid, Spain

Hans-Jürgen Stellbrink, MDProfessorICH Study Center HamburgHamburg, Germany


Faculty Disclosures

José R. Arribas, MD, has disclosed that he has received consulting fees from AbbVie, Bristol-Myers Squibb, Gilead Sciences, Janssen, Merck, and ViiV.

Hans-Jürgen Stellbrink, MD, has disclosed that he has received consulting fees and fees for non-CME services received directly from a commercial interest or their agents (eg, speaker bureaus) from AbbVie, Bristol-Myers Squibb, Gilead Sciences, Janssen, and Merck and funds for research support from Bristol-Myers Squibb, Gilead Sciences, GlaxoSmithKline, Janssen, and ViiV.

Epidemiology of HIV, Aging, and Associated Comorbidities


ATHENA: Older Pts Becoming More Prevalent in the HIV-Positive Population ATHENA: Observational

cohort of 10,278 HIV-positive 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.

Prop

ortio

n of

HIV

-Pos

itive

Pts

1.0

0.9

0.8

0.7

0.6

0.5

0.4

0.3

0.2

0.1

02010 2015 2020 20302025

> 70 yrs of age60-70 yrs of age50-60 yrs of age

40-50 yrs of age30-40 yrs of age< 30 yrs of age


Aging

Antiviral treatment

HIV infection

Interplay of Age With Morbidity Risk of “comorbidities”

increases as individuals get older

HIV does not cause these illnesses

However, HIV and/or ART may increase the risk


ATHENA: Comorbidities Increase With Age and With HIV InfectionModeling study suggests that in 2030:84% of HIV+ pts will have ≥ 1 NCD

– Increased from 29% in 2010– Pts with comorbidities higher in

every age group in HIV+ pts vs uninfected

28% of HIV+ pts will have ≥ 3 NCDs54% of HIV+ pts will be prescribed meds other than ART

– Increased from 13% in 201020% will take ≥ 3 meds besides ART

– Mostly driven by increase in CVD

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

100

80

60

40

20

0

Indi

vidu

als

With

C

omor

bidi

ties

(%)

HIV Infected HIV Uninfected

Age Group (Yrs)<

4545

-50

50-5

555

-60

60-6

5>

65<

4545

-50

50-5

555

-60

60-6

5>

65

3 or more comorbidities2 comorbidities1 comorbidityNo commodities


< 25 25-49 50-99 100-199 200-349 ≥ 350

Progression to AIDS or Death Within 5 Yrs of ART Initiation Increases With Age Collaborative analysis of 12 HIV cohorts in US and Europe

– Assessed rates of progression to AIDS or death for pts with HIV-1 RNA ≥ 100,000 copies/mL, no previous AIDS-defining illness, and no history of injection-drug use

May M, et al. AIDS. 2007;21:1185-1197.

60

40

20

0

Prog

ress

ion

to A

IDS

or D

eath

(%)

Baseline CD4+ Cell Count (cells/mm3)

16-29 yrs of age30-39 yrs of age40-49 yrs of age50 yrs of age or older


NA-ACCORD: Immunologic but Not Virologic Response Decreased in Older Pts Analysis of pts who received initial ART with a boosted PI or NNRTI-

based regimen in 19 cohort studies (NA-ACCORD; N = 12,196)Cumulative Incidence of CD4+ Cell Count Increase of 100 cells/mm³ in

First 2 Yrs After Starting ART

Cumulative Incidence of HIV-1 RNA ≤ 500 c/mL in

First 2 Yrs After Starting ART

Althoff KN, et al. AIDS. 2010;24:2469-2479.

1.00.90.80.70.60.50.40.30.20.1

0

Cum

ulat

ive

Inci

denc

e of

H

IV-1

RN

A ≤

500

cop

ies/

mL

Mo From ART initiation0 2 4 6 8 10 12 14 16 18 20 22 24

18 to ≤ 30 yrs30 to ≤ 40 yrs 40 to ≤ 50 yrs 50 to ≤ 60 yrs ≥ 60 yrs

1.00.90.80.70.60.50.40.30.20.1

0

Cum

ulat

ive

Inci

denc

e of

C

D4+

≤ 1

00 c

ells

/mm

³

Mo From ART initiation0 2 4 6 8 10 12 14 16 18 20 22 24

18 to ≤ 30 yrs30 to ≤ 40 yrs 40 to ≤ 50 yrs 50 to ≤ 60 yrs ≥ 60 yrs

Guideline Recommendations for ART in Older Adults


DHHS Guidelines: 2015 Recommended Regimens for First-line ART

DHHS Guidelines. April 2015.

Class DHHS-Recommended TherapyRegardless of BL HIV-1 RNA or CD4+ Count

Alternative Regimens

INSTI RAL + TDF/FTC EVG/COBI/TDF/FTC* DTG/ABC/3TC†

DTG + TDF/FTC

Boosted PI DRV/RTV + TDF/FTC ATV/RTV + TDF/FTC ATV/COBI + TDF/FTC* DRV/RTV + ABC/3TC† DRV/COBI + ABC/3TC*†

DRV/COBI + TDF/FTC*

NNRTI EFV/TDF/FTC RPV/TDF/FTC‡

*Only for pts with pre-ART CrCl ≥ 70 mL/min.†Only for pts who are HLA-B*5701 negative. ‡Not recommended in pts with baseline HIV-1 RNA > 100,000 copies/mL and CD4+ cell counts < 200 cells/mm3.


EACS Guidelines: 2014 Recommended Regimens for First-line ART

EACS Guidelines v.7.1. November 2014.

Class Recommended Regimens Alternative CombinationsINSTI RAL + TDF/FTC or ABC/3TC†

EVG/COBI/TDF/FTC* DTG/ABC/3TC†

DTG + TDF/FTC

Boosted PI DRV/RTV + TDF/FTC or ABC/3TC† ATV/RTV + TDF/FTC or ABC/3TC†

LPV/RTV + 2 NRTIs DRV/RTV + RAL LPV/RTV + 3TC

NNRTI EFV/TDF/FTC RPV/TDF/FTC‡

EFV + ABC/3TC RPV‡ + ABC/3TC

NVP + 2 NRTIs

Others MVC + 2 NRTIs ZDV/3TC + third agent

*Only for pts with pre-ART CrCl ≥ 90 mL/min unless this is preferred regimen, then can be given if eGFR is ≥ 70 mL/min.†Only for pts who are HLA-B*5701 negative. Use with caution in pts with high CV risk and in those with HIV-1 RNA > 100,000 copies/mL.‡Not recommended in pts with baseline HIV-1 RNA > 100,000 copies/mL and CD4+ cell counts < 200 cells/mm 3.


DHHS: Key Considerations When Caring for Older HIV-Infected Pts In March 2012, DHHS included older adult pts as a separate special

population with the following recommendations:

– ART is recommended in pts > 50 yrs of age, regardless of CD4+ cell count, because the risk of non-AIDS–related complications may increase and immunologic response to ART may be reduced in older HIV-infected pts

– ART-associated AEs may occur more frequently in older HIV-infected adults than in younger HIV-infected individuals. Therefore, bone, kidney, metabolic, CV, and liver health of older HIV-infected adults should be monitored closely

– The increased risk of drug–drug interactions between ARV drugs and other medications commonly used in older HIV-infected pts should be assessed regularly, especially when starting or switching ART and concomitant medications

– HIV experts and primary care providers should work together to optimize the medical care of older HIV-infected pts with complex comorbidities

– Counseling to prevent secondary transmission of HIV remains an important aspect of the care of the older HIV-infected pt



DHHS Considerations for Initial ART Based on Age-Related ComorbidityScenario ART-Specific Consideration

Do Not Use OptionsCKD (CrCl < 70 mL/min)

EVG/COBI/TDF/FTC (ATV or DRV)/COBI + TDF Consider avoiding TDF

ABC/3TC (if HLA-B*5701 negative; if HIV-1 RNA > 100,000 c/mL, do not use with EFV or ATV/RTV; 3TC dose adjustment if CrCl < 50 mL/min)

DRV/RTV + RAL (if HIV-1 RNA <100,000 c/mL and CD4+ cell count > 200 cells/mm3)

LPV/RTV plus 3TC Modify TDF dose

Osteoporosis Consider avoiding TDF ABC/3TC (if HLA-B*5701 negative; if HIV-1 RNA > 100,000 c/mL, do not use with EFV or ATV/RTV)

CVD Consider avoiding:ABCLPV/RTV

DHHS Guidelines. April 2015. Greene M, et al. JAMA. 2013. 309:1397-1405.


DHHS Considerations for Initial ART Based on Age-Related Comorbidity

ScenarioART-Specific Consideration

Do Not Use Options

Hyperlipidemia

Consider avoiding:PI/RTVABCEFVEVG/COBI

Consider TDF



Practical Challenges With ART Use in Older Pts Comorbidities

Polypharmacy

– DDI, dosing, adherence challenges

Renal or hepatic impairment

– Alterations in pharmacokinetics, potential for drug toxicity

Challenges with single-tablet regimens

– Inability to alter single component dosing (ie, ABC or TDF) as needed

ART for Older Patients With Renal Complications


RAL + TDF/FTC: Efficacy in Older Pts STARTMRK: phase III trial in treatment-naive pts with HIV-1 RNA

> 5000 copies/mL randomized to RAL + TDF/FTC (n = 281) or EFV + TDF/FTC (n = 282)

Through 240 weeks, RAL + TDF/FTC was associated with greater virologic and immunologic efficacy vs EFV + TDF/FTC

Rockstroh JK, et al. J Acquir Immune Defic Syndr. 2013;63:77-85. Rockstroh JK, et al. AIDS 2012. Abstract LBPE19.

Median age: 37 yrs

HIV-1 RNA< 50 copies/mL (%)

CD4+ Count(cells/mm3)

TotalAge, yrs 16-64 ≥ 65 ≤ median > median

-50 -25 0 25 50Difference (95% CI)

Favors EFV

Favors RAL

-250 0 250 500 750Difference (95% CI)

Favors EFV

Favors RAL


EVG/COBI/TDF/FTC: Pooled 96-Wk Efficacy by Age Analysis of 96-wk subgroup efficacy data from 2

randomized, double blind, active-controlled phase III studies

Overall ≥ 40 Yrs

EVG/COBI/TDF/FTC (n = 701)Pooled comparator (n = 707)

85 84

0

20

40

60

80

100Δ: 1.9%

(-2.1 to 5.9)Δ: 1.1%

(-4.7 to 6.9)

83 80

< 40 Yrs

Δ: 2.8% (-2.6 to 7.3)

8482

Cooper D, et al. IAS 2013. Abstract TUPE281.


TAF vs TDF + EVG/COBI/FTC: Efficacy in Older Pts GS-US-292-0104/0111: phase III trials in which treatment-naive pts, HIV-

infected pts with estimated creatinine clearance of ≥ 50 mL/min were randomized to TAF (n = 866) or TDF (n = 867) coformulated with EVG/COBI/FTC

Sax P, et al. Lancet. 2015;385:2606-2615. *HIV-1 RNA < 50 copies/mL as defined by FDA Snapshot algorithm.

EVG/COBI/FTC/TAFEVG/COBI/FTC/TDF

Viro

logi

cal S

ucce

ss (%

)

100

80

60

40

20

0

92 90Overall

800/866

784/867

Age92 90 94 91

< 50 Yrs1.9%

(-1.0 to 4.8)

≥ 50 Yrs3.5%

(-5.2 to 12.2)

716/777

680/753

84/89

104/114n/N =


SPRING-2: phase III trial in which treatment-naive pts with HIV-1 RNA ≥ 1000 copies/mL were randomized to RAL (n = 411) or DTG (n = 411) + 2 NRTIs

DTG inhibits creatinine secretion, increasing creatinine levels, but does not affect eGFR

RAL vs DTG: Changes in Serum Creatinine and CrCl

1. Raffi F, et al. Lancet. 2013;381:735-743. 2. Curtis LD, et al. IAS 2013. Abstract TUPE282.

Change in Serum Creatinine, Mean (± SD)[1]

Mea

n C

hang

e Fr

om B

asel

ine

of C

reat

inin

e (m

g/dL

)

0.28

0.22

0.17

0.11

0.06

0

2 4 8 12 16 24 32 40 48Wk

Baseline (mg/mL): DTG 0.85 vs RAL 0.85

+12.3

+4.7

Change in CrCl, Mean (± SD)[1,2]

Mea

n C

hang

e Fr

om B

asel

ine

(mL/

min

)

10

0

10

-20

-30BL 24 48

WkBaseline (mL/min): DTG 125 vs RAL 128

DTG 50 mg QD (n = 411)

0.06

RAL 400 mg BID (n = 411)


EVG/COBI/TDF/FTC: Creatinine Changes Studies 102/103: randomized, active-controlled phase III studies in treatment-naive

pts with HIV-1 RNA ≥ 5000 copies/mL and eGFR ≥ 70 mL/min

COBI inhibits creatinine secretion, increasing creatinine levels, but does not affect eGFR

1. Sax P, et al. Lancet. 2012;379:2439-2448. 2. DeJesus E, et al. Lancet. 2012;379:2429-2438.

0.35

Cha

nge

From

BL

in S

erum

Cre

atin

ine

(mg/

dL; I

QR

)

0.30

0.25

0

-0.05

-0.10

0.15

0.10

0.05

0.20

2 4 8 12 16 24 32 40 48Wks

EVG/COBI/TDF/FTC

EFV/TDF/FTC

0.28

0.24

0.04

0

-0.04

0.16

0.12

0.08

0.20

Wks2 4 8 12 16 24 32 40 48

EVG/COBI/TDF/FTC

ATV/RTV + TDF/FTC

BLBL

Study 102[1] Study 103[2]


SINGLE: randomized phase III trial in which ART-naive pts with HIV-1 RNA ≥ 1000 c/mL who were HLA-B*5701 negative and had CrCl > 50 mL/min were randomized to DTG + ABC/3TC (n = 414) or EFV/TDF/FTC (n = 419)

EFV/TDF/FTC associated with smaller changes in serum creatinine vs DTG/ABC/3TC

DTG/ABC/3TC vs EFV/TDF/FTC: Change in Creatinine Level

Walmsley S, et al. N Engl J Med. 2013;369:1807-1818.

25201510

50

-5-10M

ean

Cha

nge

From

B

asel

ine

(µm

ol/li

ter)

Wk2 4 8 12 16 24 32 40 48

DTG + ABC/3TC EFV/TDF/FTC


EVG/COBI/FTC/TAF: Impact on Renal Function (GS-US-292-0104/0111)

TAF treatment was also associated with a significantly lower median change in eGFR vs TDF treatment (-6.4 vs -11.2 mL/min; P < .001)

The TAF and TDF groups had 0 and 4 discontinuations due to renal AEs, respectively

Sax P, et al. Lancet. 2015;385:2606-2615.

Med

ian

% C

hang

e Fr

om

Bas

elin

e (Q

1-Q

3)

75

50

25

0

-25

-50

-3

20

76

-5

7 9

51

133 168

24

-32

Baseline (mg/g)

57

Urine (protein): creatinine ratio

Protein (UPCR) Albumin (UACR)

Retinol binding protein

β2-microglobulin

44 44 5 5 64 67 101 103

P < .0001 P < .0001 P < .0001 P < .0001

EVG/COBI/FTC/TAF

EVG/COBI/FTC/TDF


D:A:D: ART Exposure and Risk of CKD Retrospective analysis of pts with

baseline eGFR > 90/mL/min (N = 23,560)

Multivariate analysis: exposure to TDF, ATV/RTV, and LPV/RTV significantly associated with CKD development

Association with TDF or LPV/RTV and CKD remains when excluding those who stopped drugs during or before study entry

When TDF exposure censored, CKD risk per yr of ATV/RTV or LPV/RTV exposure increased substantially

CKD risk with time after stopping TDFCKD Risk by Yrs of ARV Exposure, IRR (95% CI)

Drug 1 Yr 2 Yrs 5 Yrs

TDF 1.12 (1.06-1.18)

1.25 (1.12-1.39)

1.74 (1.33-2.27)

ATV/RTV 1.27 (1.18-1.36)

1.61 (1.40-1.84)

3.27(2.32-4.61)

LPV/RTV 1.16 (1.10-1.22)

1.35 (1.21-1.50)

2.11(1.62-2.75)

Mocroft A, et al. CROI 2015. Abstract 142.

Relationship Between Increasing Exposure to ART and CKD

1.801.601.401.201.000.00

ATV/RTV LPV/RTV TDFUnivariateMultivariate

On treatmentTDF censored


Ryom L, et al. CROI 2015. Abstract 742.

D:A:D: Renal Disease and CVD

Kaplan-Meier Progression to CVD by Confirmed Baseline eGFR

25

20

15

10

5

0

Perc

enta

ge W

ith C

VD

Mos After Baseline

720 12 24 36 48 60

Baseline (confirmed) eGFR≤ 30> 30 to ≤ 60> 60 -to≤ 90> 90


Dose Adjustments for Initial Therapy for Pts With Impaired Renal FunctionARV eGFR (mL/min)

≥ 50 30-49 10-29 < 10 HemodialysisABC[1] 300 mg q12h No adj No adj

FTC[1] 200 mg q24h 200 mg q48h 200 mg q72h 200 mg q96h 200 mg q96h

3TC[1] 300 mg q24h 150 mg q24h 100 mg q24h 50-25 mg q24h

50-25 mg q24h after dialysis

TDF[1] 300 mg q24h 300 mg q48h Not recommended

Not recommended

300 mg q7d after dialysis

DRV/RTV[1] 800/100 mg q24h600/100 mg q12h

No adj No adj No adj No adj

RAL[1] 400 mg q12h No adj No adj No adj No adj/dose after dialysis

EVG/COBI/TDF/FTC[1]

Do not use if < 70 D/C if < 50

DTG[2] 50 mg q24h No adj No adj No adj No adj1. EACS Guidelines. November 2014. 2. Dolutegravir [package insert].


Dose Adjustments for Initial Therapy for Pts With Impaired Renal FunctionARV eGFR (mL/min)

≥ 50 30-49 10-29 < 10 HemodialysisEFV[1] 600 mg q24h No adj No adj No adj No adj

ATV/RTV[1] 300/100 mg q24h No adj No adj No adj No adj

COBI[2] No adj No adj No adj No adj No adj

RPV[3] No adj No adj Use with caution

1. EACS Guidelines. November 2014. 2. Cobicistat [package insert]. 3. Rilpivirine [package insert].


EACS: On-Treatment Monitoring of Pts With Renal Complications

EACS Guidelines. November 2014.

Assessment At HIV Diagnosis

Prior to Starting

ARTFollow-up Frequency Comment

Risk assessment + + Annual More frequent monitoring if CKD

risk factors present and/or prior to starting and on treatment with

nephrotoxic drugseGFR(aMDRD) + + 3-12 mos

Urine dipstick analysis + + Annual

Every 6 mos if eGFR < 60 mL/min; if proteinuria ≥ 1+ and/or eGFR < 60 mL/min, perform UP/C or

UA/C

Start ART immediately where HIV-associated nephropathy or HIV immune complex disease strongly suspected. Immunosuppressive therapy may have a role in immune complex diseases. Renal biopsy to confirm histological diagnosis recommended


ART Considerations for Pts With Renal Complications DHHS considerations

– If CrCl < 70 mL/min: do not use EVG/COBI/TDF/FTC, (ATV or DRV)/COBI + TDF/FTC

– TDF may be associated with progression of CKD

– Modify TDF dose in pts with CrCl < 50 mL/min

– Consider:

– ABC/3TC (3TC needs to be adjusted if CrCl < 50 mL/min)

– DRV/RTV + RAL (only if HIV-1 RNA < 100,000 copies/mL and CD4+ cell count > 200 cells/mm3)

– LPV/RTV + 3TC

ART for Older Patients With Bone Complications


Fracture Prevalence Is Increased in Older HIV-Positive Pts 8525 HIV-infected pts compared with 2,208,792 uninfected

pts in Partners HealthCare System

Women Men

Triant V, et al. J Clin Endocrinol Metab. 2008;93:3499-3504.

Age (Yrs)

7.06.05.04.03.02.01.0

0Frac

ture

Pre

vale

nce/

10

0 Pe

rson

s

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

P = .002(overall comparison)

HIVNon-HIV

HIVNon-HIV

Age (Yrs)

7.06.05.04.03.02.01.0

0Frac

ture

Pre

vale

nce/

10

0 Pe

rson

s

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

P < .0001(overall comparison)


RAL vs Boosted PIs: Loss of BMD (ACTG 5257) ACTG 5257: phase III trial in which

treatment-naive pts with HIV-1 RNA ≥ 1000 copies/mL were randomized to RAL + TDF/FTC (n = 603), ATV/RTV + TDF/FTC (n = 605), or DRV/RTV + TDF/FTC (n = 601)

All arms associated with significant loss of BMD through Wk 96 (P < .001)

At hip and spine, similar loss of BMD in the PI arms

– Significantly greater loss in the combined PI arms than in the RAL arm

ATV/RTV + TDF/FTC RAL + TDF/FTC DRV/RTV + TDF/FTC Combined PI arms

-5

-4

0

-3

-2

-1

-3.9-3.4

-3.7

-2.4

-1.8

-4.0-3.8

-3.6

P = .36

Total Hip Total Spine

P = .005P = .42

P < .001

Brown TT, et al. J Infect Dis. 2015;[Epub ahead of print].


DTG + ABC/3TC associated with less bone turnover than EFV/TDF/FTC

DTG + ABC/3TC vs EFV/TDF/FTC: Bone Parameters (SINGLE)

Tebas P, et al. ICAAC 2013. Abstract H-1461.

Percent Change From Baseline at Wk 48 in Bone Resorption BiomarkersDTG + ABC/3TC EFV/TDF/FTC

*Differences between treatment groups are significant (P < .001).

CTx

33%*

68%

100

80

60

40

20

0

Adj

uste

d G

eom

etric

M

ean

and

95%

CI

OC

22%*

66%

100

80

60

40

20

0A

djus

ted

Geo

met

ric

Mea

n an

d 95

% C

IBSAP P1NP

60%48%

15%30%*


TAF vs TDF + EVG/COBI/FTC: Changes in BMD (GS-US-292-0104/0111)

TAF treatment was associated with smaller BMD loss than TDF treatment

Sax P, et al. Lancet. 2015;385:2606-2615.

Spine

Wk0 24 48

4

2

0

-2

-4

-6

-8

Mea

n %

Cha

nge

From

B

asel

ine

(SD

)

-1.30

-2.86

P < .0001

Pts at Risk, nE/C/F/TAFE/C/F/TDF

845850

797816

784773

Hip

Wk0 24 48

-0.66

-2.95

P < .0001

836848

789815

780767

EVG/COBI/FTC/TAFEVG/COBI/FTC/TDF


EACS Guidelines v. 7.1 November 2014.

EACS: On-Treatment Monitoring of Pts With Bone ComplicationsAssessment At HIV

DiagnosisPrior to

Starting ARTFollow-up Frequency Comment

Bone profile: calcium, PO4, ALP + + 6-12 mos

Risk assessment (FRAX in persons > 40 yrs of age)

+ + 2 yrs Consider DXA in specific persons

25(OH) vitamin D + As indicated Screen at risk persons

Consider DXA in any person with ≥ 1 of:1.Postmenopausal women 4. High risk for falls2.Men ≥ 50 yrs of age 5. Clinical hypogonadism (symptomatic)3.History of low impact fracture 6. Oral glucocorticoid use Preferably perform DXA in those with above risk factors prior to ART initiation. Assess effect of risk factors on fracture risk by including DXA results in the FRAX scoreOnly use if > 40 yrs of ageMay underestimate risk in HIV-positive personsConsider using HIV as a cause of secondary osteoporosis


ART Considerations for Pts With Bone Complications DHHS considerations:

– Consider avoiding TDF: associated with greater decrease in BMD along with renal tubulopathy, urine phosphate wasting, and osteomalacia

– Consider ABC/3TC

Significantly greater BMD loss with PI-based regimens vs RAL-based regimens

DTG + ABC/3TC associated with less bone turnover than EFV/TDF/FTC

ART for Older Patients With Metabolic Complications


MACS: Rates of DM Increased in HIV-Positive Pts on ART Rate of incident DM was 4.7 cases/100 PYs in HIV-

positive men vs 1.4 cases/100 PYs in seronegative men

Brown TT, et al. Arch Intern Med. 2005;165:1179-1184.

HIV seronegativeHIV infected using ART

100

80

60

40

20Pts

Free

of D

M (%

)

0 1 2 3Study Time (Yr)

Pts at Risk, nHIV seronegative

HIV infected using ART361229

265204

177145

8962


RAL vs EFV + TDF/FTC: Lipid Changes (STARTMRK)

EFV + TDF/FTC associated with greater increases in lipid parameters vs RAL + TDF/FTC

Lennox J, et al. Lancet. 2009;374:796-806.

Mea

n C

hang

e fr

omB

asel

ine

at W

k 48

(mm

ol/L

)

RAL + TDF/FTCEFV + TDF/FTC

2.0

1.5

1.0

0.5

0

-0.5TC HDL LDL TG

0.6

1.8

0.2

0.60.3

0.9

-0.2

2.1P < .00012.5

P < .0001

P = .0002

P < .0001


RAL vs Boosted PIs: Fasting Lipid Changes (ACTG 5257)

30

20

10

00 24 48 96 144

15

10

5

0

-50 24 48 96 144

0 24 48 96 144

0 24 48 96 144

10.0

7.55.0

2.5

0

40

20

0

-20

Study Wk

Cha

nge*

(mg/

dL)

Fasting TC

Study Wk

Fasting LDL

Study Wk

Fasting TG

Study Wk

Fasting HDL

ATV/RTV RAL DRV/RTV

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

Cha

nge*

(mg/

dL)

Cha

nge*

(mg/

dL)

Cha

nge*

(mg/

dL)

*From baseline.


COBI-Containing Regimens: Lipid Changes (Studies 103/114) ATV/RTV + TDF/FTC associated with greater increases in TG vs ATV/COBI +

TDF/FTC or EVG/COBI/TDF/FTC

1. De Jesus E, et al. Lancet. 2012;379:2429-2438. 2. Gallant JE, et al. J Infect Dis. 2013;208:32-39. 3. Gallant JE, et al. AIDS 2012. Abstract TUAB0103.

10 8 111156 8

23

P = .006

ATV/RTV + TDF/FTCEVG/COBI/TDF/FTC

Study 103[1]

TC LDL HDL TG

Med

ian

Cha

nge

From

B

asel

ine

to W

k 48

(m

g/dL

)

0

10

20

30

40

50

60

70

59 1111 5

6

19

32

P = .063

ATV/RTV + TDF/FTCATV/COBI + TDF/FTC

Study 114[2,3]

TC LDL HDL TG 0

10

20

30

40

50

60

70

P = .081


DTG/ABC/3TC vs EFV/TDF/FTC: Lipid Changes (SINGLE)

DTG/ABC/3TC and EFV/TDF/FTC similarly alter lipid parameters

Quercia R, et al. Clin Drug Investig. 2015;35:211-219.

1724

139 8518 19

TC LDL HDL TG 0

10203040506070 DTG/ABC/3TC

EFV + TDF/FTC

Med

ian

Cha

nge

From

B

asel

ine

to W

k 48

(m

g/dL

)


TAF vs TDF + EVG/COBI/FTC: Lipid Changes (GS-US-292-0104/0111)

TAF treatment is associated with significantly greater increases in lipid parameters vs TDF when combined with EVG/COBI/FTC

Sax P, et al. Lancet. 2015;385:2606-2615.

Pts initiating lipid-modifying medications: 3.6% EVG/COBI/FTC/TAF vs 2.9% EVG/COBI/FTC/TDF (P = .42)

200

150

100

50

0Med

ian

Valu

es (m

g/dL

)

TCP < .001

LDL P < .001

HDLP < .001

TGP = .027

TC:HDL RatioP = .84

Wk 48Baseline

Wk 48Baseline

5

4

3

2

1

0

3.73.7

189177

115 109

51 48

114 1083.63.6

160 163

101 104

44 44

95 100

EVG/COBI/FTC/TAF EVG/COBI/FTC/TDF


ART and Effects on Lipids

TDF ABCRALDTG

ATV/RTV or ATV/COBIDRV/RTV or DRV/COBIEVG/COBI

EFVRPV


EACS: On-Treatment Monitoring of Pts With Metabolic Complications


Prior to Starting

ART

Follow-up Frequency Comment

Lipids TC, HDL, LDL, TG + + Annual

Repeat in fasting state if used for medical

intervention (ie, ≥ 8 hrs without caloric intake)

Glucose Serum glucose + + 6-12 mos

Consider oral glucose tolerance test/HbA1c

if fasting glucose levels of 5.7-6.9 mmol/L (100-125 mg/dL)



Drug–Drug Interactions With ART and Diabetes and Lipid-Lowering TherapyAntiretroviral Contraindicated Titrate Dose No Dose AdjustmentRPV[1] Atorvastatin

Pitavastatin

EVG/COBI/FTC/TDF[1]

LovastatinSimvastatin

AtorvastatinRosuvastatin

DTG[1,2] Metformin

ATV/RTV[1] LovastatinSimvastatin

AtorvastatinRosuvastatin

Pitavastatin

DRV/RTV[1] LovastatinSimvastatin

AtorvastatinPravastatin

Rosuvastatin

Pitavastatin

EFV[1] AtorvastatinSimvastatinPravastatin

Rosuvastatin

Pitavastatin

RAL[1]

ATV/COBI or DRV/COBI

LovastatinSimvastatin

1. DHHS Guidelines. April 2015. 2. Dolutegravir [package insert].


ART Considerations for Pts With Metabolic Complications DHHS considerations:

– PI/RTV, ABC, EFV, EVG/COBI associated with negative effects on lipids

– TDF has been associated with beneficial lipid effects

RAL + TDF/FTC associated with smaller increases in lipids than boosted PI regimens

DTG/ABC/3TC and EFV/TDF/FTC similarly alter lipid parameters

Several lipid-lowering agents are contraindicated for use with ART components

ART for Older Patients With Cardiovascular Complications


The Link Between HIV and CVD and Age Rate of acute MI higher in HIV-positive pts[1]

HIV infection is a risk factor for ischemic stroke[2]

HIV-infected men have a greater prevalence of coronary artery plaques[1,3]

1. Triant VA, et al. J Clin Endocrinol Metab. 2007;92:2506-2512. 2. Chow FC, et al. J Acquir Immune Defic Syndr. 2012;60:351-358. 3. Post WS, et al. Ann Intern Med. 2014;160:458-467.

Acu

te M

Is/1

000

PYs

18-34 35-44 45-54 55-64 65-740

2040

80100

60

HIV-positive pts

HIV-negative pts

Age (Yrs)


D:A:D: Incidence of MI With Exposure to Combination ART Observational analysis of data from 11 cohorts (N = 23,468 HIV+ pts)

D:A:D Study. N Engl J Med. 2003;349:1993-2003.

7

65

43

21

0

Inci

denc

e of

MI/1

000

PYs

Exposure (Yr)

8

None > 4< 1 1-2 2-3 3-4

Events, nPerson-yrs, n

35714

94140

144801

225847

317220

478477


D:A:D: CVD Deaths Decreased in Era of Modern ART

Smith C, et al Lancet. 2014:384:241-248.

Most Common Causes of Death, 1999-2011

100908070605040302010

0

All

Dea

ths

(%)

Total(N = 3909)

1999-2000(n = 256)

2001-02(n = 788)

2003-04(n = 862)

2005-06(n = 718)

2007-08(n = 658)

2009-11(n = 627)

AIDS relatedLiver related

CVD relatedNon-AIDS cancer

OtherUnknown


Study Association? Description

D:A:D[1] Cohort collaboration (prospective)

Danish HIV Cohort[2] Cohort (linked with registries)

Montreal study[3] Nested case-control study

SMART[4] Post hoc subgroup analysis of RCT (use of ABC not randomised)

STEAL[5] Preplanned secondary analysis of RCT (use of ABC randomised)

Desai et al[6] Cohort (retrospective)

Swiss HIV Cohort[7] Cohort (retrospective)

FHDH ANRS CO4[8] ? Nested case-control study

NA-ACCORD[9] ? Cohort (retrospective)

VA Clinical Case Registry[10] Cohort (retrospective)

Brothers et al. analysis[11] Post hoc meta-analysis of RCTs

ACTG A5001/ALLRT[12] Post hoc meta-analysis of RCTs

FDA meta-analysis[13] Post hoc meta-analysis of RCTs

1. Friis-Møller N, et al. N Engl J Med. 2003;349:1993-2003. 2. Obel N, et al. HIV Med. 2010;11:130-136. 3. Durand M, et al. J Acquir Immune Defic Syndr. 2011;57:245-253. 4. Phillips AN, et al. Antiv Ther. 2008;13:177-187. 5. Martin A, et al. AIDS. 2010;24:2657-2663. 6. Desai M, et al. Clin Infect Dis. 2015;[Epub ahead of print]. 7. Young J, et al. J Acquir Immune Defic Syndr. 2015;[Epub ahead of print]. 8. Lang S, et al. AIDS. 2010;24:1228-1230. 9. Palella F, et al. CROI 2015. Abstract 749LB. 10. Bedimo RJ, et al. Clin Infect Dis. 2011;53:84-91. 11. Brothers CH, et al. J Acquir Immune Defic Syndr. 2009;51:20-28. 12. Ribaudo HJ, et al. Clin Infect Dis. 2011;52:929-940. 13. Ding X, et al. J Acquir Immune Defic Syndr. 2012;61:441-447.

Studies Addressing Abacavir and MI


EACS: On-Treatment Monitoring of Pts With Cardiovascular Complications


Prior to Starting

ART

Follow-up Frequenc

yComment

Cardiovascular disease

Risk assessment (Framingham score)

+ +

Should be performed in all men > 40 yrs of age and women > 50 yrs of

age without CVD

ECG + +/- Annual

Consider baseline ECG prior to starting ARVs

associated with potential conduction problems

Hypertension Blood pressure + + Annual



Drug–Drug Interactions With ART and CVD and Antihypertensive TherapyAntiretroviral Contraindicated Titrate DoseARV/RTV or DRV/RTV Lercanidipine

Dabigatran*Amlodipine, diltiazem, felodipine, lacidipine, nicardipine, nifedipine,

nisoldipine, verapamilo, indapamide, doxazosin, amlodipine,

diltiazem, verapamil, warfarin

EFV Lercanidipine, amlodipine, diltiazem, felodipine, lacidipine,

nicardipine, nifedipine, nisoldipine, verapamilo, indapamide, doxazosin

EVG/COBI LercanidipineDabigatran*

Amlodipine, diltiazem, felodipine, lacidipine, nicardipine, nifedipine,

nisoldipine, verapamilo, indapamide, doxazosin, amlodipine,

diltiazem, verapamil, warfarin

DHHS Guidelines. April 2015. EACS Guidelines v. 7.1 November 2014. Dolutegravir [package insert].

DTG, RAL, ABC, FTC, 3TC, and TDF have no significant interactions.*If CrCl < 50 mL/min.


ART Considerations for Pts With Cardiovascular Complications DHHS considerations

– Consider avoiding ABC, LPV/RTV

Drug–drug interactions occur between calcium channel blockers and ART components

Older Patients and Polypharmacy


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

Predicts that 20% of pts will be taking ≥ 3 meds other than ART in 2030

115 (5.2%) of 2233 participants 50-64 yrs of age and 64 (14.2%) of 450 participants ≥ 65 yrs of age received ≥ 4 meds other than ART

< 50 Yrs 50-64 Yrs ≥ 65 Yrs

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

Prospective Observational study

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

ATHENA Modeling Study[1]

100

80

60

40

20

0Part

icip

ants

(%)

n = 5761 n = 2233 n = 450

No comedication1 comedication2 comedication3 comedications4 or more comedications

16,00014,00012,00010,000

8000600040002000

0

Peop

le (n

)

3 or more comedications2 comedications1 comedicationNo comedication

2010 2015 2020 2025 2030


Additional Drug–Drug Interactions With ART

EACS Guidelines. V7.1. November 2014.

ATV/RTV

DRV/RTV EFV RPV DTG EVG/

COBI RAL ABC FTC 3TC TDF

AntacidsPPIsAlfuzosinBudesonideFluticasoneSlidenafilSt John’s wortEscitalopramAspirinIbuprofenCodeine

MethadoneMorphineOxycodoneTramadolDiazepamMidazolam PimozidePhenytoinRifampicinNo clinically significant interaction expectedThese drugs should not be coadministeredPotential interaction that may require a dosage adjustmentPotential interaction predicted to be of weak intensity


Drug–Drug Interactions Between Boosted PIs and Steroid Preparations Steroid preparations should be given with caution with

boosted PIs, regardless of administration route

Coadministration of budesonide, fluticasone, mometasone, or prednisone either inhaled or intranasal with any RTV- or COBI-boosted PI can result in adrenal insufficiency and Cushing’s syndrome

Do not coadminister unless potential benefits of inhaled or intranasal corticosteroid outweigh the risks of systemic corticosteroid adverse events

Consider alternative corticosteroid (eg, beclomethasone).



ART Considerations for Pts With Polypharmacy Complications Older pts often have multiple comorbidities requiring

comedication

This requires careful consideration of DDIs, dosing, and potential adherence challenges

Use of Internet-based tools that are currently updated is highly recommended (eg, HIV iCHART)

Of the current available third drugs, RAL and DTG have the better interaction profile

Older Patients and NRTI-Sparing Regimens


NRTI-Sparing or NRTI-Limiting RegimensRegimen Results

DRV/RTV + RAL (ACTG 5262)[1] Poor performance at high VLDRV/RTV + RAL (NEAT)[2] Less effective at high VL, low CD4DRV/RTV + 3TC (switch study)[3] Small study; encouraging efficacy

DRV/RTV + MVC (MODERN)[4] Less effective than standard ARTATV/RTV + RAL (HARNESS – switch)[5] Less effective than standard ARTLPV/RTV + RAL (PROGRESS)[6] Small study; few pts with high VL

LPV/RTV + EFV (ACTG 5142)[7] Poorly tolerated but effectiveLPV/RTV + 3TC (GARDEL)[8] As effective as standard ARTLPV/RTV + 3TC or FTC (OLE – switch)[9] As effective as standard ARTATV/RTV + 3TC (SALT – switch)[10] As effective as standard ART

1. Taiwo B, et al. AIDS. 2011;25:2113-2122. 2. Raffi, et al. CROI 2014. Abstract 84LB. 3. Casado JL, et al. J Antimicrob Chemother. 2015;70:630-632 4. Stellbrink HJ, et al. IAS 2014. Abstract MOAB0101. 5. Van Lunzen J, et al. IAC 2014. Abstract A-641-0126-11307. 6. Reynes J, et al. AIDS Res Hum Retroviruses. 2013;29:256-265. 7. Daar ES, et al. Ann Intern Med. 2011;154:445-456. 8. Cahn P, et al. Lancet Infect Dis. 2014;14:572-580. 9. Gatell J, et al. AIDS 2014. Abstract LBPE17. 10. Perez-Molina JA, et al. IAC 2014. Abstract LBPE18.


When to Consider NRTI-Sparing Regimens and What to Choose DRV/RTV + RAL (for pts with HIV-1 RNA < 100,000 copies/mL and

CD4+ cell count > 200 cells/mm3) and LPV/RTV + 3TC

NRTI-sparing regimens may help to avoid renal or bone toxicity

NRTI-free regimens are associated with lower virologic response rates, especially in pts with higher HIV-1 RNA and lower CD4+ cell counts

Guidelines advocate for a careful and selective use of these options

DHHS

– Regimens should be considered when TDF or ABC cannot be used

EACS

– Alternative to recommended regimens

DHHS Guidelines. April 2015. EACS Guidelines. April 2015.


Summary Older pts are becoming more prevalent in the HIV-positive

population

– Comorbidities increase with age

Various issues associated with increased age affect the use of initial ART

– Renal, bone, metabolic, cardiovascular complications

– Polypharmacy concerns

Please take a 2-question survey by following the link below:

clinicaloptions.com/survey

http://www.clinicaloptions.com/HIV/Treatment%20Updates/ART%20in%20Older%20Patients/Interactive%20Virtual%20Presentation/Survey/Pages/Page%201.aspx

Go Online for More Educational Content on ART for Older Patients

Interactive Virtual Presentation featuring streaming narration of these slides and case studies illustrating essential considerations for providing first-line antiretroviral therapy to older HIV patients by José R. Arribas, MD, and Hans-Jürgen Stellbrink, MD

ClinicalThought™ with expert facultycommentaries on first-line treatment for older patients

clinicaloptions.com/OlderPatients

http://www.clinicaloptions.com/HIV/Treatment%20Updates/ART%20in%20Older%20Patients.aspx

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