In this downloadable slideset, José R. Arribas, MD, and Hans-Jürgen Stellbrink, MD, review essential considerations for providing first-line antiretroviral therapy to older HIV patients. Format: Microsoft PowerPoint (.ppt) File size: 3.38 MB Date posted: 9/4/2015

1. Choosing and Using First-line
Antiretroviral Therapy in Older
Patients
This activity is supported by an independent educational grant from
Janssen Therapeutics.

2. clinicaloptions.com/hiv
Choosing and Using First-line ART in Older Patients
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3. clinicaloptions.com/hiv
Choosing and Using First-line ART in Older Patients
Faculty
José R. Arribas, MD
Research Director (HIV and
Infectious Diseases)
Hospital La Paz. IdiPAZ.
Madrid, Spain
Hans-Jürgen Stellbrink, MD
Professor
ICH Study Center Hamburg
Hamburg, Germany

4. clinicaloptions.com/hiv
Choosing and Using First-line ART in Older Patients
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.

5. Epidemiology of HIV, Aging, and
Associated Comorbidities

6. clinicaloptions.com/hiv
Choosing and Using First-line ART in Older Patients
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.
ProportionofHIV-PositivePts
1.0
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0
2010 2015 2020 20302025
> 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

7. clinicaloptions.com/hiv
Choosing and Using First-line ART in Older Patients
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

8. clinicaloptions.com/hiv
Choosing and Using First-line ART in Older Patients
ATHENA: Comorbidities Increase With
Age and With HIV Infection
Modeling 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 NCDs
54% of HIV+ pts will be prescribed
meds other than ART
– Increased from 13% in 2010
20% 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
IndividualsWith
Comorbidities(%)
HIV Infected HIV Uninfected
Age Group (Yrs)
<
4545-5050-5555-6060-65
>
65
<
4545-5050-5555-6060-65
>
65
3 or more comorbidities
2 comorbidities
1 comorbidity
No commodities

9. clinicaloptions.com/hiv
Choosing and Using First-line ART in Older Patients
< 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
ProgressiontoAIDS
orDeath(%)
Baseline CD4+ Cell Count (cells/mm3
)
16-29 yrs of age
30-39 yrs of age
40-49 yrs of age
50 yrs of age or older

10. clinicaloptions.com/hiv
Choosing and Using First-line ART in Older Patients
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.
1.0
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0
CumulativeIncidenceof
HIV-1RNA≤500copies/mL
Mo From ART initiation
0 2 4 6 8 10 12 14 16 18 20 22 24
18 to ≤ 30 yrs
30 to ≤ 40 yrs
40 to ≤ 50 yrs
50 to ≤ 60 yrs
≥ 60 yrs
1.0
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0
CumulativeIncidenceof
CD4+≤100cells/mm³
Mo From ART initiation
0 2 4 6 8 10 12 14 16 18 20 22 24
18 to ≤ 30 yrs
30 to ≤ 40 yrs
40 to ≤ 50 yrs
50 to ≤ 60 yrs
≥ 60 yrs

11. Guideline Recommendations
for ART in Older Adults

12. clinicaloptions.com/hiv
Choosing and Using First-line ART in Older Patients
DHHS Guidelines: 2015 Recommended
Regimens for First-line ART
DHHS Guidelines. April 2015.
Class DHHS-Recommended Therapy
Regardless 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
.

13. clinicaloptions.com/hiv
Choosing and Using First-line ART in Older Patients
EACS Guidelines: 2014 Recommended
Regimens for First-line ART
EACS Guidelines v.7.1. November 2014.
Class Recommended Regimens Alternative Combinations
INSTI  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/mm3
.

14. clinicaloptions.com/hiv
Choosing and Using First-line ART in Older Patients
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 Guidelines. April 2015.

15. clinicaloptions.com/hiv
Choosing and Using First-line ART in Older Patients
DHHS Considerations for Initial ART
Based on Age-Related Comorbidity
Scenario ART-Specific Consideration
Do Not Use Options
CKD (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:
ABC
LPV/RTV
DHHS Guidelines. April 2015. Greene M, et al. JAMA. 2013. 309:1397-1405.

16. clinicaloptions.com/hiv
Choosing and Using First-line ART in Older Patients
DHHS Considerations for Initial ART
Based on Age-Related Comorbidity
Scenario
ART-Specific Consideration
Do Not Use Options
Hyperlipidemia
Consider avoiding:
PI/RTV
ABC
EFV
EVG/COBI
 Consider TDF
DHHS Guidelines. April 2015.

17. clinicaloptions.com/hiv
Choosing and Using First-line ART in Older Patients
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

18. ART for Older Patients With
Renal Complications

19. clinicaloptions.com/hiv
Choosing and Using First-line ART in Older Patients
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
)
Total
Age, yrs
16-64
≥ 65
≤ median
> median
-50 -25 0 25 50
Difference (95% CI)
Favors
EFV
Favors
RAL
-250 0 250 500 750
Difference (95% CI)
Favors
EFV
Favors
RAL

20. clinicaloptions.com/hiv
Choosing and Using First-line ART in Older Patients
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
100
Δ: 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)
84
82
Cooper D, et al. IAS 2013. Abstract TUPE281.

21. clinicaloptions.com/hiv
Choosing and Using First-line ART in Older Patients
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/TAF
EVG/COBI/FTC/TDF
VirologicalSuccess(%)
100
80
60
40
20
0
92 90
Overall
800/
866
784/
867
Age
92 90 94 91
< 50 Yrs
1.9%
(-1.0 to 4.8)
≥ 50 Yrs
3.5%
(-5.2 to 12.2)
716/
777
680/
753
84/
89
104/
114n/N =

22. clinicaloptions.com/hiv
Choosing and Using First-line ART in Older Patients
 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]
MeanChangeFromBaseline
ofCreatinine(mg/dL)
0.28
0.22
0.17
0.11
0.06
0
2 4 8 12 16 24 32 40 48
Wk
Baseline (mg/mL): DTG 0.85 vs RAL 0.85
+12.3
+4.7
Change in CrCl, Mean (± SD)[1,2]
MeanChangeFromBaseline
(mL/min)
10
0
10
-20
-30
BL 24 48
Wk
Baseline (mL/min): DTG 125 vs RAL 128
DTG 50 mg QD (n = 411)
0.06
RAL 400 mg BID (n = 411)

23. clinicaloptions.com/hiv
Choosing and Using First-line ART in Older Patients
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 eGFR1. Sax P, et al. Lancet. 2012;379:2439-2448. 2. DeJesus E, et al. Lancet. 2012;379:2429-2438.
0.35
ChangeFromBLinSerumCreatinine
(mg/dL;IQR)
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 48
Wks
EVG/COBI/TDF/FTC
EFV/TDF/FTC
0.28
0.24
0.04
0
-0.04
0.16
0.12
0.08
0.20
Wks
2 4 8 12 16 24 32 40 48
EVG/COBI/TDF/FTC
ATV/RTV + TDF/FTC
BLBL
Study 102[1]
Study 103[2]

24. clinicaloptions.com/hiv
Choosing and Using First-line ART in Older Patients
 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.
25
20
15
10
5
0
-5
-10
MeanChangeFrom
Baseline(µmol/liter)
Wk
2 4 8 12 16 24 32 40 48
DTG + ABC/3TC EFV/TDF/FTC

25. clinicaloptions.com/hiv
Choosing and Using First-line ART in Older Patients
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.
Median%ChangeFrom
Baseline(Q1-Q3)
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

26. clinicaloptions.com/hiv
Choosing and Using First-line ART in Older Patients
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 TDF
CKD 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
1.80
1.60
1.40
1.20
1.00
0.00
ATV/RTV LPV/RTVTDF
Univariate
Multivariate
On treatment
TDF censored

27. clinicaloptions.com/hiv
Choosing and Using First-line ART in Older Patients
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
PercentageWithCVD
Mos After Baseline
720 12 24 36 48 60
Baseline (confirmed) eGFR
≤ 30
> 30 to ≤ 60
> 60 -to≤ 90
> 90

28. clinicaloptions.com/hiv
Choosing and Using First-line ART in Older Patients
Dose Adjustments for Initial Therapy for
Pts With Impaired Renal Function
ARV eGFR (mL/min)
≥ 50 30-49 10-29 < 10 Hemodialysis
ABC[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 q24h
600/100 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 adj
1. EACS Guidelines. November 2014. 2. Dolutegravir [package insert].

29. clinicaloptions.com/hiv
Choosing and Using First-line ART in Older Patients
Dose Adjustments for Initial Therapy for
Pts With Impaired Renal Function
ARV eGFR (mL/min)
≥ 50 30-49 10-29 < 10 Hemodialysis
EFV[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].

30. clinicaloptions.com/hiv
Choosing and Using First-line ART in Older Patients
EACS: On-Treatment Monitoring of Pts
With Renal Complications
EACS Guidelines. November 2014.
Assessment
At HIV
Diagnosis
Prior to
Starting
ART
Follow-up
Frequency
Comment
Risk
assessment
+ + Annual More frequent monitoring if CKD
risk factors present and/or prior to
starting and on treatment with
nephrotoxic drugs
eGFR
(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

31. clinicaloptions.com/hiv
Choosing and Using First-line ART in Older Patients
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

32. ART for Older Patients
With Bone Complications

33. clinicaloptions.com/hiv
Choosing and Using First-line ART in Older Patients
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)
7.0
6.0
5.0
4.0
3.0
2.0
1.0
0
FracturePrevalence/
100Persons
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
FracturePrevalence/
100Persons
20-29 30-39 40-49 50-59 60-69
P < .0001
(overall comparison)

34. clinicaloptions.com/hiv
Choosing and Using First-line ART in Older Patients
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 = .005
P = .42
P < .001
Brown TT, et al. J Infect Dis. 2015;[Epub ahead of print].

35. clinicaloptions.com/hiv
Choosing and Using First-line ART in Older Patients
 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 Biomarkers
DTG + ABC/3TC
EFV/TDF/FTC
*Differences between treatment groups are significant (P < .001).
CTx
33%*
68%
100
80
60
40
20
0
AdjustedGeometric
Meanand95%CI
OC
22%*
66%
100
80
60
40
20
0
AdjustedGeometric
Meanand95%CI BSAP P1NP
60%
48%
15%
30%*

36. clinicaloptions.com/hiv
Choosing and Using First-line ART in Older Patients
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
Wk
0 24 48
4
2
0
-2
-4
-6
-8
Mean%ChangeFrom
Baseline(SD)
-1.30
-2.86
P < .0001
Pts at Risk, n
E/C/F/TAF
E/C/F/TDF
845
850
797
816
784
773
Hip
Wk
0 24 48
-0.66
-2.95
P < .0001
836
848
789
815
780
767
EVG/COBI/FTC/TAF
EVG/COBI/FTC/TDF

37. clinicaloptions.com/hiv
Choosing and Using First-line ART in Older Patients
EACS Guidelines v. 7.1 November 2014.
EACS: On-Treatment Monitoring of Pts
With Bone Complications
Assessment
At HIV
Diagnosis
Prior to
Starting ART
Follow-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 falls
2.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 score
Only use if > 40 yrs of age
May underestimate risk in HIV-positive persons
Consider using HIV as a cause of secondary osteoporosis

38. clinicaloptions.com/hiv
Choosing and Using First-line ART in Older Patients
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

39. ART for Older Patients With
Metabolic Complications

40. clinicaloptions.com/hiv
Choosing and Using First-line ART in Older Patients
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 seronegative
HIV infected using ART
100
80
60
40
20
PtsFreeofDM(%)
0 1 2 3
Study Time (Yr)
Pts at Risk, n
HIV seronegative
HIV infected using ART
361
229
265
204
177
145
89
62

41. clinicaloptions.com/hiv
Choosing and Using First-line ART in Older Patients
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.
MeanChangefrom
BaselineatWk48(mmol/L)
RAL + TDF/FTC
EFV + TDF/FTC
2.0
1.5
1.0
0.5
0
-0.5
TC HDL LDL TG
0.6
1.8
0.2
0.6
0.3
0.9
-0.2
2.1
P < .0001
2.5
P < .0001
P = .0002
P < .0001

42. clinicaloptions.com/hiv
Choosing and Using First-line ART in Older Patients
RAL vs Boosted PIs: Fasting Lipid
Changes (ACTG 5257)
30
20
10
0
0 24 48 96 144
15
10
5
0
-5
0 24 48 96 144
0 24 48 96 144
0 24 48 96 144
10.0
7.5
5.0
2.5
0
40
20
0
-20
Study Wk
Change*(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.
Change*(mg/dL)
Change*(mg/dL)
Change*(mg/dL)
*From baseline.

43. clinicaloptions.com/hiv
Choosing and Using First-line ART in Older Patients
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
1111
56
8
23
P = .
006
ATV/RTV + TDF/FTC
EVG/COBI/TDF/FTC
Study 103[1]
TC LDL HDL TG
MedianChangeFrom
BaselinetoWk48
0
10
20
30
40
50
60
70
5
9 11
11
5
6
19
32
P = .
063
ATV/RTV + TDF/FTC
ATV/COBI + TDF/FTC
Study 114[2,3]
TC LDL HDL TG
0
10
20
30
40
50
60
70
P = .
081

44. clinicaloptions.com/hiv
Choosing and Using First-line ART in Older Patients
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.
17
24
13
9 85
18 19
TC LDL HDL TG
0
10
20
30
40
50
60
70 DTG/ABC/3TC
EFV + TDF/FTC
MedianChangeFrom
BaselinetoWk48(m

45. clinicaloptions.com/hiv
Choosing and Using First-line ART in Older Patients
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
0
MedianValues(mg/dL)
TC
P < .001
LDL
P < .001
HDL
P < .001
TG
P = .027
TC:HDL Ratio
P = .84
Wk 48
Baseline
Wk 48
Baseline
5
4
3
2
1
0
3.73.7
189
177
115 109
51 48
114 108
3.63.6
160 163
101 104
44 44
95 100
EVG/COBI/FTC/TAF EVG/COBI/FTC/TDF

46. clinicaloptions.com/hiv
Choosing and Using First-line ART in Older Patients
ART and Effects on Lipids
TDF ABCRAL
DTG
ATV/RTV or ATV/COBI
DRV/RTV or DRV/COBI
EVG/COBI
EFVRPV

47. clinicaloptions.com/hiv
Choosing and Using First-line ART in Older Patients
EACS: On-Treatment Monitoring of Pts
With Metabolic Complications
Assessment
At HIV
Diagnosis
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)
EACS Guidelines v. 7.1 November 2014.

48. clinicaloptions.com/hiv
Choosing and Using First-line ART in Older Patients
Drug–Drug Interactions With ART and
Diabetes and Lipid-Lowering Therapy
Antiretroviral Contraindicated Titrate Dose No Dose Adjustment
RPV[1]
Atorvastatin
Pitavastatin
EVG/COBI/FTC/
TDF[1]
Lovastatin
Simvastatin
Atorvastatin
Rosuvastatin
DTG[1,2]
Metformin
ATV/RTV[1]
Lovastatin
Simvastatin
Atorvastatin
Rosuvastatin
Pitavastatin
DRV/RTV[1]
Lovastatin
Simvastatin
Atorvastatin
Pravastatin
Rosuvastatin
Pitavastatin
EFV[1]
Atorvastatin
Simvastatin
Pravastatin
Rosuvastatin
Pitavastatin
RAL[1]
ATV/COBI or
DRV/COBI
Lovastatin
Simvastatin
1. DHHS Guidelines. April 2015. 2. Dolutegravir [package insert].

49. clinicaloptions.com/hiv
Choosing and Using First-line ART in Older Patients
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

50. ART for Older Patients With
Cardiovascular Complications

51. clinicaloptions.com/hiv
Choosing and Using First-line ART in Older Patients
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.
AcuteMIs/1000PYs
18-34 35-44 45-54 55-64 65-74
0
20
40
80
100
60
HIV-positive pts
HIV-negative pts
Age (Yrs)

52. clinicaloptions.com/hiv
Choosing and Using First-line ART in Older Patients
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
6
5
4
3
2
1
0
IncidenceofMI/1000PYs
Exposure (Yr)
8
None > 4< 1 1-2 2-3 3-4
Events, n
Person-yrs, n
3
5714
9
4140
14
4801
22
5847
31
7220
47
8477

53. clinicaloptions.com/hiv
Choosing and Using First-line ART in Older Patients
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
100
90
80
70
60
50
40
30
20
10
0
AllDeaths(%)
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 related
Liver related
CVD related
Non-AIDS cancer
Other
Unknown

54. clinicaloptions.com/hiv
Choosing and Using First-line ART in Older Patients
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

55. clinicaloptions.com/hiv
Choosing and Using First-line ART in Older Patients
EACS: On-Treatment Monitoring of Pts
With Cardiovascular Complications
Assessment
At HIV
Diagnosis
Prior to
Starting
ART
Follow-up
Frequenc
y
Comment
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
EACS Guidelines v. 7.1 November 2014.

56. clinicaloptions.com/hiv
Choosing and Using First-line ART in Older Patients
Drug–Drug Interactions With ART and
CVD and Antihypertensive Therapy
Antiretroviral Contraindicated Titrate Dose
ARV/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 Lercanidipine
Dabigatran*
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.

57. clinicaloptions.com/hiv
Choosing and Using First-line ART in Older Patients
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

58. Older Patients and Polypharmacy

59. clinicaloptions.com/hiv
Choosing and Using First-line ART in Older Patients
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
0
Participants(%)
n = 5761 n = 2233 n = 450
No comedication
1 comedication
2 comedication
3 comedications
4 or more
comedications
16,000
14,000
12,000
10,000
8000
6000
4000
2000
0
People(n)
3 or more comedications
2 comedications
1 comedication
No comedication
2010 2015 2020 2025 2030

60. clinicaloptions.com/hiv
Choosing and Using First-line ART in Older Patients
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
Antacids
PPIs
Alfuzosin
Budesonide
Fluticasone
Slidenafil
St John’s wort
Escitalopram
Aspirin
Ibuprofen
Codeine
Methadone
Morphine
Oxycodone
Tramadol
Diazepam
Midazolam
Pimozide
Phenytoin
Rifampicin
No clinically significant interaction expected
These drugs should not be coadministered
Potential interaction that may require a dosage adjustment
Potential interaction predicted to be of weak intensity

61. clinicaloptions.com/hiv
Choosing and Using First-line ART in Older Patients
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).
DHHS Guidelines. April 2015.

62. clinicaloptions.com/hiv
Choosing and Using First-line ART in Older Patients
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

63. Older Patients and
NRTI-Sparing Regimens

64. clinicaloptions.com/hiv
Choosing and Using First-line ART in Older Patients
NRTI-Sparing or NRTI-Limiting Regimens
Regimen Results
DRV/RTV + RAL (ACTG 5262)[1]
Poor performance at high VL
DRV/RTV + RAL (NEAT)[2]
Less effective at high VL, low CD4
DRV/RTV + 3TC (switch study)[3]
Small study; encouraging efficacy
DRV/RTV + MVC (MODERN)[4]
Less effective than standard ART
ATV/RTV + RAL (HARNESS – switch)[5]
Less effective than standard ART
LPV/RTV + RAL (PROGRESS)[6]
Small study; few pts with high VL
LPV/RTV + EFV (ACTG 5142)[7]
Poorly tolerated but effective
LPV/RTV + 3TC (GARDEL)[8]
As effective as standard ART
LPV/RTV + 3TC or FTC (OLE – switch)[9]
As effective as standard ART
ATV/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.

65. clinicaloptions.com/hiv
Choosing and Using First-line ART in Older Patients
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.

66. clinicaloptions.com/hiv
Choosing and Using First-line ART in Older Patients
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

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68. Go Online for More Educational
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first-line antiretroviral therapy to older HIV patients by José R. Arribas,
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commentaries on first-line treatment for
older patients
clinicaloptions.com/OlderPatients