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Antiretroviral
Therapy Strategies
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Joel E. Gallant, MD, MPH
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Medical Director of Specialty Services
Southwest CARE Center
Santa Fe, New Mexico
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FORMATTED: 04-30-2015
Chicago, IL: May 18, 2015
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Learning Objectives
After attending this presentation, participants will
be able to:
 List the recommended regimens for initial therapy in the 2015 DHHS and 2014
IAS-USA guidelines
 Describe the rationale for switching therapy in a virologically suppressed patient,
and the factors that should be considered when resistance data or treatment
history are unavailable
 Describe the approach to a patient who has absolute or relative contraindications
to both tenofovir and abacavir.
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Slide 3 of 39
Slide 6 of 39
JP
 JP is a 28-yr-old, otherwise healthy graduate student,
recently diagnosed with HIV infection
 Baseline labs:
– CD4 count 653
– VL is 36,000
– Gentoype: wild-type virus
– Normal renal function, transaminases, lipids
– HBsAg, HCV negative
 His partner is HIV negative. They occasionally have sex
with other partners. STD screening is negative
 He is willing to start ART if you recommend it, and believes
he will be adherent
Chicago, IL: May 18, 2015
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1
DHHS Guidelines, April 2015:
What to Start
Slide 8 of 39
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Recommended regimens
Boosted PI based
 DRV/r + TDF/FTC
INSTI based
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 RAL + TDF/FTC
 EVG/COBI/TDF/FTC
 DTG + TDF/FTC
 DTG/ABC/3TC
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Alternative regimens
NNRTI based
 EFV/TDF/FTC
 RPV/TDF/FTC (VL <100,000; CD4 >200)
PI based
 ATV/c + TDF/FTC (CrCl >70)
 ATV/r + TDF/FTC
 (DRV/c or DRV/r) + ABC/3TC
 DRV/c + TDF/FTC (CrCl >70)
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DHHS Guidelines for Antiretroviral Therapy in Adults and Adolescents, April 2015.
Slide 9 of 39
IAS–USA Guidelines, July 2014
What to Start
Class
NNRTI
Boosted PI
INSTI
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Günthard HF, et al. JAMA. 2014;312:410-425.
Slide 10 of 39
TR
 TR is a 32-year-old man with HIV infection, diagnosed
2 years ago with a baseline CD4 count of 435 and a
viral load of 83,250. Pre-ART genotype showed wildtype virus
 He started TDF/FTC/EFV 18 months ago. He
reported excellent adherence and had undetectable
viral loads, but forgot to bring his medications on a 2week vacation 3 months ago.
 Genotype: K103N and M184V
Chicago, IL: May 18, 2015
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Recommended Regimens
EFV/TDF/FTC
EFV + ABC/3TC
RPV/TDF/FTC
ATV/r + TDF/FTC
ATV/r + ABC/3TC
DRV/r + TDF/FTC
DTG/ABC/3TC
DTG + TDF/FTC
EVG/COBI/TDF/FTC
RAL + TDF/FTC
 His current viral load is 5,450
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Slide 12 of 39
IAS–USA 2014 Guidelines:
Failure of an Initial ART Regimen
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• The second regimen should generally include a boosted
PI because of the high barrier to resistance, especially
when there is evidence of a compromised NRTI
backbone.
• A boosted PI should be used with at least one fully active
agent (NRTI, INSTI, or NNRTI).
• New evidence emerged for the use of an active NRTI
backbone plus a boosted PI or an INSTI plus a boosted
PI after initial failure of an NNRTI-based regimen.
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Günthard et al, JAMA, 2014.
Slide 14 of 39
SECOND-LINE:
LPV/r + RAL vs LPV/r + NRTIs
82.6
VL < 200 c/mL (%)
100
80.8
P = .59
80
60
40
LPV/r + RAL
LPV/r + 2-3 NRTIs
20
0
0
12
24
36
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48
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Wk
Humphries A, et al. CROI 2013. Abstract 180LB
EARNEST: 2nd-Line LPV/r-Based ART
After Initial NNRTI Failure
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 Similar high levels of virologic
suppression with each strategy in
primary mITT analysis[1]
• Randomized, open-label,
international trial
• LPV/r + RAL vs. LPV/r +
2-3 NRTIs in pts failing
initial regimen of NNRTI +
2 NRTIs (N=541)
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Slide 15 of 39
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 Randomized, controlled, open-label, phase III trial
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 Baseline demographics (medians): VL 69,782; CD4 71;
time on ART 4 yrs
Wk 12
Wk 144
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HIV+ adults and
adolescents, received firstline NNRTI-based ART > 12
mos, > 90% adherence in
previous mo,
Treatment failure by WHO
(2010) criteria*
(N = 1277)
LPV/r + 2-3 NRTIs†
(n = 426)
LPV/r + RAL
(n = 433)
LPV/r + RAL
(n = 418)
LPV/r monotherapy
(n = 418)
*Including clinical, CD4 count (VL confirmed), or virologic criteria.
†Selected by physician according to local standard of care.
Paton N, et al. IAS 2013. Abstract WELBB02.
Chicago, IL: May 18, 2015
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3
Slide 16 of 39
EARNEST: 96-week outcomes
LPV/r monotherapy arm discontinued due to inferior
virologic suppression, higher frequency of LPV resistance
100
80
86 86
60 64
60
40
74 73
61
56
44
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LPV/r + NRTI
LPV/r + RAL
LPV/r Mono
20
0
Good Disease
Control*
VL< 400
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VL < 50
* Good
disease control = pt alive, no new WHO 4 events from Wks 0-96, and
CD4 count > 250, and VL < 10,000 or > 10,000 without PI resistance mutations
Paton N, et al. IAS 2013. Abstract WELBB02.
Slide 17 of 39
DT
 DT is a 65-year-old man with HIV infection who has been
doing well for several years on TDF/FTC + DRV/r (600/100
mg bid) + RAL + ETR, with an HIV RNA <20 and CD4 763
 He started ART in the late 80’s, and remembers taking AZT,
d4T + 3TC, NVP, IDV and NFV. He knows he has “some
resistance.” He has outlived two of his doctors, and attempts
to obtain medical records from his surviving doctors have
been unsuccessful
 He asks about switching to a once-daily regimen, with as few
pills as possible (preferably one)
Slide 23 of 39
IAS–USA 2014 Guidelines:
Switching Regimens
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 Reasons to switch:
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– To reduce or prevent toxicity
– To improve convenience, maintain adherence, and
reduce cost to patient
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 Knowledge of archived resistance is crucial
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 Monitor for new toxicities after switch
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 Pre-treatment VL less important than in
treatment-naive patients
Günthard et al, JAMA, 2014
Chicago, IL: May 18, 2015
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4
Slide 24 of 39
Recent Switch Studies: Suppressed
Trial
GS-123
GS-264
Strategy-NNRTI
Strategy-PI
SPIRIT
SPIRAL
SALT
OLE
SWITCHMRK
HARNESS
From
TDF/FTC + RAL
TDF/FTC/EFV
TDF/FTC + NNRTI
TDF/FTC + PI/r
2 NRTI + PI/r
2 NRTI + PI/r
ATV/r + 2 NRTIs
LPV/r + 2 NRTIs
2 NRTIs + LPV/r
2 NRTIs + 3rd Agent
To
TDF/FTC/EVG/cobi
TDF/FTC/RPV
TDF/FTC/EVG/cobi
TDF/FTC/EVG/cobi
TDF/FTC/RPV
2 NRTIs + RAL
ATV/r + 3TC
LPV/r + 3TC
2 NRTIs + RAL
ATV/r + RAL
Outcome
✔
✔
✔
✔
✔
✔
✔
✔
✗
✗
Slide adapted from David Wohl
Slide 25 of 39
SWITCHMRK 1 & 2:
From LPV/r + NRTIs to RAL + NRTIs
Wk 12 lipid
analysis
Switch to RAL
+ other BL ARVs*
(SWITCHMRK 1: n = 174
SWITCHMRK 2: n = 176)
(N = 702)
(SWITCHMRK 1: 348
SWITCHMRK 2: 354)
Continue LPV/r
+ other BL ARVs*
(SWITCHMRK 1: n = 174
SWITCHMRK 2: n = 178)
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Eron JJ, et al. Lancet. 2010;375:396-407.
Slide 26 of 39
SWITCHMRK: Prior failure predicts failure
Inferior efficacy of RAL appeared driven by more
failure among pts with previous virologic failure
SWITCHMRK1
RAL
(n = 174)
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*All patients continued background regimen including ≥ 2 NRTIs.
Outcome
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Wk 24 efficacy
analysis
HIV+ pts with viral
suppression on LPV/r-based
ART
for ≥ 3 mos. Not required to
be initial regimen
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SWITCHMRK 2
LPV/r
RAL
LPV/r
(n = 174) (n = 176) (n = 178)
Patients without previous virologic
failure
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VL < 50 at Wk 24, %
Treatment difference, % (95% CI)
Patients with previous virologic
failure
85.1
85.8
-0.7 (-9.9 to 8.6)
92.5
93.5
-1.0 (-8.5 to 6.3)
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VL < 50 at Wk 24, %
72.3
79.7
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Treatment difference, % (95% CI)
Eron JJ, et al. Lancet. 2010;375:396-407.
Chicago, IL: May 18, 2015
89.7
93.8
-17.3 (-33.0 to -2.5) -14.2 (-26.5 to -2.6)
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5
Switching: Caveats
Slide 27 of 39
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 Know the treatment and resistance history
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 Avoid switching from high barrier to lower
barrier agents when you don’t
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Switching and simplifying therapy:
Slide 28 of 39
“No brainers” and switches that require a brain
“Vertical Switches”: switch to
“Horizontal Switches”: switch to
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drug with equal or higher resistance
barrier
drug with lower resistance
barrier
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 RTV → COBI (boosters)
 Most drug
discontinuations
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 Boosted PI → NNRTI
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 Switches within INSTI class
 EFV or NVP → RPV or ETR
 Boosted PI → INSTI
 LPV/r or ATV/r → DRV/r
 Boosted PI → any STR
 ABC or AZT → TDF
 DRV/r twice daily → once
daily
 Anything → boosted PI
Slide 29 of 39
Options for RW: The good, the bad, and the iffy
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Switch
OK?
Comments
RAL → DTG
Yes
• Reduces pill burden
• DTG superior in ART-exp’d pts (SAILING)
ETR 200 bid → 400 QD
Yes
• Not approved dose but supported by PK
Discontinue TDF/FTC
Maybe
• NRTIs unnecessary if >2 fully active agents (OPTIONS)
• His complex salvage regimen suggests that he
probably has TDF and FTC resistance already
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DRV/r BID → QD
Risky
• DRV mutations? (V11I, V32I, L33F, I47V, I50V, I54L,
I54M, T74P, L76V, I84V, L89V)
• APV and FPV most likely to cause DRV crossresistance
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Change to ABC/3TC/DTG
Risky
• DTG resistance barrier may be as high as a boosted PI
• NRTI resistance unknown
Change to any other STR
No way!
• Remember SWITCHMRK!
Chicago, IL: May 18, 2015
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Slide 30 of 39
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“Provides drug resistance data when standard resistance
testing cannot be performed due to inadequate plasma viral
load. Interrogates the viral archive [amplifies cell-associated
proviral DNA] using next-generation sequencing methods to
provide a list of the archived mutations.”
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Slide 31 of 39
RW
 RW is a 49-yr-old executive Dx’d with HIV 5 years ago
 He’s been reluctant to take ART, but now has CD4 310,
VL 156,000 c/mL, and agrees to start
 Had wild-type virus at time of Dx
 Medical problems:
– Diabetes (HbA1C 9.0% on metformin; refuses insulin)
– Non-nephrotic range proteinuria, creatinine 1.5, eGFR 55
– Hyperlipidemia (LDL 125 on atorvastatin, TG 350 on fibrate)
– Smokes 1/2 pack per day
 Liver enzymes normal, HLA B*5701 negative
 Reports adherence with meds, but wants to keep it simple
Studies addressing association between abacavir and MI
Slide 34 of 39
Study
Association?
Description
D:A:D

Cohort collaboration (prospective)
Danish HIV Cohort

Cohort (linked with registries)
Montreal study

Nested case-control study
SMART

Post-hoc subgroup analysis of RCT (use of
ABC not randomised)
STEAL

Pre-planned secondary analysis of RCT
(use of ABC randomised)
Brighton study

Nested case-control study
VA Clinical Case Registry

Cohort (retrospective)
FHDH ANRS CO4
?
Nested case-control study
Boston Cohort

Cohort (retrospective)
GSK studies

Post-hoc meta-analysis of RCTs
ACTG A5001/ALLRT

Post-hoc meta-analysis of RCTs
FDA meta-analysis

Post-hoc meta-analysis of RCTs
Sabin C, et al. CROI 2013
Chicago, IL: May 18, 2015
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Slide 35 of 39
D:A:D 2014
Use of ABC in cohort over time
% of those with given CVD risk
receiving ABC
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D:A:D presentation
March 2008
35
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Low CVD risk
30
Mod CVD risk
25
20
High CVD risk
15
CVD risk U/K
10
Total cohort
5
RR. 1.97 (1.68, 2.33)
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RR 1.97 (1.43, 2.72)
0
Sabin C, et al. CROI 2013
Slide 35 of 39
NA-ACCORD: Recent Abacavir Use and Risk of MI
• Retrospective analysis of pts in 7
clinical cohorts with recent ABC use
(prescribed in previous 6 mos) from
1/1/1995 to 12/31/2010
• ABC initiators (n = 1948) vs noninitiators (n = 14,785):
– “Full” study population: all ART
users excluding those on ABC at
entry
– “Restricted” population: ART-naive
pts who started ART in the cohort
• Endpoint of incident MIs: presence of
clinical diagnosis or elevation of
cardiac enzymes
Palella F, et al. CROI 2015. Abstract 749LB.
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Adjusted HRs for MI in Those With Recent ABC Use
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D:A:D
Replication
Full Study
1.33
0.00
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1.95
Restricted
Study
1.00
2.00
3.00
4.00
• Recent ABC use significant in restricted
population and D:A:D replication
• Significant predictors:
– Both: Age 60+, HTN, eGFR < 30,
AIDS
– Full: Smoking, DM
Slide 37 of 39
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Chicago, IL: May 18, 2015
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Slide 38 of 39
NRTI-sparing regimens
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DRV/r + RAL (ACTG 52621)
Poor performance at high VL
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DRV/r + RAL (NEAT2)
DRV/r + MVC (MODERN3)
Less effective at high VL, low CD4
Less effective than standard ART
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ATV/r + RAL (HARNESS4 – switch)
Less effective than standard ART
LPV/r + RAL (PROGRESS5)
Small study; few pts with high VL
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LPV/r + EFV (ACTG 51426)
LPV/r + 3TC (GARDEL7)
LPV/r + 3TC or FTC (OLE8 – switch)
Poorly tolerated but effective
As effective as standard ART
As effective as standard ART
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ATV/r + 3TC (SALT9 – switch)
As effective as standard ART
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Regimen
1.
Results
Taiwo B, et al. AIDS. 2011;25:2113-22
2. Raffi, et al. CROI 2014, Abstract 84LB
3. Stellbrink H-J, et al. IAD 2014. Abstract MOAB0101
4. Van Lunzen J, et al. IAC 2014. Abstract A-641-0126-11307
5. Reynes J, et al. AIDS Res Hum Retroviruses. 2013;29:256-65
6. Daar ES, et al. Ann Intern Med 2011
7. Cahn P, et al. Lancet Infect Dis 2014;14:572-80
8. Gatell J, et al. AIDS 2014. Abstract LBPE17.
9. Perez-Molina J.A., et al. IAC 2014. AbstractL BPE18.
Slide 39 of 39
Next year in Chicago, will anyone still
talk about NRTI-sparing regimens?
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Chicago, IL: May 18, 2015
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