Transcript PPT - IAS-USA

Starting and Switching:
Modern Day Antiretroviral Dilemmas;
A Case-Based, Panel Discussion
Joel E. Gallant, MD, MPH
Medical Director of Specialty Services
Southwest CARE Center
Santa Fe, New Mexico
Clinical Professor of Medicine
University of New Mexico School of Medicine
Albuquerque, New Mexico
New York, New York: March 23, 2016
From JE Gallant, MD, MPH, at New York, NY: March 23, 2016, IAS-USA.
ART Strategies
Joel Gallant, MD, MPH
Southwest CARE Center
Santa Fe, New Mexico
Johns Hopkins University School of Medicine
University of New Mexico
From JE Gallant, MD, MPH, at New York, NY: March 23, 2016, IAS-USA.
Learning Objectives
After attending this presentation, participants will
be able to:
 Describe the approach to NRTI selection in patients with
kidney disease and/or cardiac risk factors
 Discuss the use of PrEP in patients with ongoing highrisk behavior
 Discuss the approach to simplification of ART in
treatment-experienced patients with uknown treatment
histories
Slide 3 of 30
From JE Gallant, MD, MPH, at New York, NY: March 23, 2016, IAS-USA.
T.M.
 T.M. is a 48-year-old man with HIV infection.
 His viral load has been suppressed for the last 6 years, CD4 in
700’s, first on TDF/FTC + DRV/r (then DRV/c in 1/15)
 Baseline genotype: no mutations. PI chosen because of his
concern about EFV side effects
 Creatinine rose gradually from 1.02 to 1.52 (eGFR 52)
 He had 1+ proteinuria and 1+ urine glucose (normal plasma
glucose) with a normal serum phos, but FEphos of 25%
 HLA B*5701 was negative, and he was switched from TDF/FTC
to ABC/3TC 1 year ago
Slide 4 of 30
From JE Gallant, MD, MPH, at New York, NY: March 23, 2016, IAS-USA.
T.M.








He takes atorvastatin for hypercholesterolemia
He smokes 1 ppd
He takes losartan/HCTZ for hypertension
His brother and father had MIs in their early 50’s
HbA1C and fasting glucose are consistently normal
Creatinine is now 1.25
He still has 1+ proteinuria, but no longer has glycosuria
FEphos is now 12% (normal serum phos)
Slide 5 of 30
From JE Gallant, MD, MPH, at New York, NY: March 23, 2016, IAS-USA.
T.M. What would you recommend?
2.
3.
4.
5.
6.
Make no changes
Change ABC/3TC to TAF/FTC
Change DRV/c to an integrase inhibitor
Discontinue ABC and leave him
on DRV/c + 3TC
2 and 3
Something else
Slide 6 of 30
26%
25%
21% 21%
3%
4%
Ch Mak
an
e
ge no
Ch AB cha
n
an C/
ge 3TC ges
Di
DR
to
sc
...
on V/
tin c to
ue
a
AB n ..
.
C
an
d.
..
So
2
a
m
et nd
3
hi
ng
el
se
1.
From JE Gallant, MD, MPH, at New York, NY: March 23, 2016, IAS-USA.
TAF vs. TDF: Quantitative Proteinuria
Urine [protein]:Creatinine Ratio
Median % Change from
Baseline (Q1, Q3)
Protein
(UPCR)
Albumin
(UACR)
RBP
76
Beta2microglobulin
133
168
75
51
50
24
20
25
7
9
0
-3
p <0.001
for all
-5
-25
-32
-50
Baseline
E/C/F/TAF
E/C/F/TDF
57
44
mg/g
44
mg/g
5
mg/g
5
mg/g
64
μg/g
67
μg/g
101
μg/g
103
μg/g
Sax P, et al. 22nd CROI; Seattle, WA; February 23-26, 2015. Abst. 143LB.
Slide 7 of 30
From JE Gallant, MD, MPH, at New York, NY: March 23, 2016, IAS-USA.
OLE: Switching Suppressed Pts to LPV/r +
3TC Noninferior to Triple ART at Wk 48
Δ -0.6%
(95% CI: -6.9% to 8.1%)
100 91.5
90.9
Dual ART (n = 118)
Triple ART (n = 121)
Patients (%)
80

New grade 3-4 AEs in 9 pts in
each arm

Numerically greater increases in
lipids, decreases in creatinine in
triple-ART arm

VF in 3 pts in each arm
60
40
20
n=0
Therapeutic
Response*
2.5 2.5
0.8
3.3
5.1 3.3
Virologic
Failure
D/C Due
to AE
D/C for
Other
Reasons
*VL < 50 c/mL at Wk 48 (mITT).
Slide 8 of 30
– 1 pt (dual-ART) tested for
resistance; had K103N and
M184V
Gatell J, et al. AIDS 2014. Abstract LBPE17.
From JE Gallant, MD, MPH, at New York, NY: March 23, 2016, IAS-USA.
P.T.
 P.T. is a 28-year-old, asymptomatic HIV-negative man requesting PrEP
 He has an HIV-positive partner whose viral load is consistently
suppressed on ART
 He sometimes has sex with other partners of unknown HIV status. He
uses condoms “sometimes” for receptive anal sex
 He was treated for secondary syphilis 6 months ago
 A 4th generation HIV test is negative. He has a negative HBsAg and
normal renal function.
 He had unprotected receptive anal sex with a partner of unknown status
1 week ago
Slide 9 of 30
From JE Gallant, MD, MPH, at New York, NY: March 23, 2016, IAS-USA.
What do you do with P.T.?
1%
Or
S
de tar
tP
ra
rE
n
As HIV P n
o
k
St him vira w
ar
l lo
t P to
a
r
E
et ..
Te
P,
u
ll
hi with rn f
or
p
Di m h
sc
e c ote
us
n
s t an s ...
he
ta
rt
vi
rtu ...
es
of
...
1. Start PrEP now
52%
2. Order an HIV viral load, and start
PrEP if it’s negative
3. Ask him to return for
24%
another rapid HIV test after at least
two weeks without any potential exposure 12% 11%
1%
4. Start PEP, with potential for transition to PrEP
5. Tell him he can start PrEP if he agrees
to use condoms consistently
6. Discuss the virtues of abstinence
and monogamy
Slide 10 of 30
From JE Gallant, MD, MPH, at New York, NY: March 23, 2016, IAS-USA.
Slide 11 of 30
From JE Gallant, MD, MPH, at New York, NY: March 23, 2016, IAS-USA.
P.T.
 He had a negative HIV RNA and was started on PrEP.
 He returns for his 3-month follow-up visit and wants to
continue.
 Routine STD screening reveals asymptomatic rectal and
pharyngeal gonorrhea and rectal chlamydia
Slide 12 of 30
From JE Gallant, MD, MPH, at New York, NY: March 23, 2016, IAS-USA.
In addition to treating his STDs, checking for HCV, and discussing
treatment of his partners, what do you do with P.T. now?
1. Tell him you can’t renew PrEP if
he continues to engage in unsafe sex
2. Talk to him about STD prevention,
while quietly whispering under your
breath “Thank God I put him on PrEP!”
96%
Slide 13 of 30
S.
ab
ou
t
oh
im
kt
Ta
l
Te
l
lh
im
yo
uc
an
’t
r
...
.
4%
From JE Gallant, MD, MPH, at New York, NY: March 23, 2016, IAS-USA.
 Of 2499 men, 360 (14.4%) RPR+ at screening; 333
(92.5%) confirmed
 Syphilis incidence during trial: 7.3 cases/100 p-y
• No difference between study arms
 HIV incidence varied by incident syphilis
- 2.8 cases /100 p-y (no syphilis) vs 8.0 (syphilis)
Clinical Infect
2014 ratio 2.6 (95% CI,14
From JE Gallant,
at New York, NY: March 23, 2016, IAS-USA.
• Dis,
Hazard
1.6–4.4;
PMD,
< MPH,
.001)
 2805 men with syphilis (11,714 p-y of follow-up)
 423 (15%) acquired HIV
 Annual incidence 3.6%
 Risk factors (incidence):
– MSM (5.6%)
– Secondary syphilis (4.1%)
– Additional bacterial STD after syphilis (7.9%)
Slide 15 of 30
From JE Gallant, MD, MPH, at New York, NY: March 23, 2016, IAS-USA.
D.T.
 D.T. 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, but there were others he doesn’t remember.
He knows he has “some resistance.”
 He has outlived two of his doctors, and attempts to obtain medical
records from the survivors have been unsuccessful
 His younger friends are all on single-tablet regimens. He wants to
switch to a once-daily regimen, with as few pills as possible (preferably
one)
Slide 16 of 30
From JE Gallant, MD, MPH, at New York, NY: March 23, 2016, IAS-USA.
What do you recommend?
EVG/COBI/FTC/TAF
RPV/FTC/TAF
DTG/ABC/3TC
EFV/TDF/FTC
I would not recommend a
single-tablet regimen, but I
would simplify his regimen in other ways
6. I would order a proviral DNA genotype
7. I would congratulate him on being
alive and tell him to count his
blessings and suck it up
41%
32%
12%
6%
2%
6%
1%
EV
G/
CO
BI
/
RP FTC
V/ /TA
DT FTC F
G / /T
Iw
AB AF
ou
E
F C/
l
I w d n V/T 3TC
ou ot r DF
/
e
I w ld o com FTC
ou rde m
ld r a e.
.
co
ng pro
ra vir
tu ..
la
te
...
1.
2.
3.
4.
5.
Slide 17 of 30
From JE Gallant, MD, MPH, at New York, NY: March 23, 2016, IAS-USA.
You decide to simplify his regimen. What would you do with his RAL
(400 mg bid)?
1. Discontinue it
49%
2. Leave it alone
3. Change to RAL 800 mg once daily
27%
4. Change to DTG 50 mg once daily
8% 7%
5. Change to DTG 50 mg twice daily
9%
1%
Di
sc
on
Ch
Le tin
an
ge av ue i
e
t
Ch
t
an o RA it al
on
g
L
e
Ch e to 80
an
DT 0 m
ge
G
.
50 ..
to
Ch
D
m
an
g
ge TG
50 ...
to
an mg
EV ...
G/
CO
.. .
6. Change to an EVG/COBI-based regimen
Slide 18 of 30
From JE Gallant, MD, MPH, at New York, NY: March 23, 2016, IAS-USA.
What would you do with his ETR (200 mg bid)?
1. Discontinue it
29%28%
24%
18%
2. Leave it alone
3. Change to ETR 400 mg once daily
Di
sc
on
tin
ue
Le
it
av
Ch
e
it
an
al
ge
on
to
e
ET
R
40
0
..
Ch
an
ge
to
RP
V
4. Change to RPV
Slide 19 of 30
From JE Gallant, MD, MPH, at New York, NY: March 23, 2016, IAS-USA.
What would you do with his DRV/r (600/100 mg bid)?
1.
2.
3.
4.
5.
32%
27%
19%
17%
5%
1%
Di
sc
on
Ch
t
an Lea inue
ve
g
i
Ch e to
it t
al
an
D
ge RV one
/r
Ch
t
80
an o D
ge RV ...
Ba
/
se to D c 80
..
R
de
cis V/c .
io
n 80..
on
.
pr
ov
...
6.
Discontinue it
Leave it alone
Change to DRV/r 800/100 mg once daily
Change to DRV/c 800/150 mg once daily
Change to DRV/c 800/150 mg bid
Base decision on proviral DNA genotype
Slide 20 of 30
From JE Gallant, MD, MPH, at New York, NY: March 23, 2016, IAS-USA.
What would you do with his FTC/TDF
44%
34%
Discontinue it
2. Leave it alone
3. Change to FTC/TAF
4. Base decision on proviral DNA genotype
1.
20%
Di
sc
on
tin
ue
Le
it
av
e
it
Ch
al
an
on
g
e
e
Ba
to
se
FT
de
C/
cis
TA
io
F
n
on
pr
ov
...
2%
Slide 21 of 30
From JE Gallant, MD, MPH, at New York, NY: March 23, 2016, IAS-USA.
Recent switch studies in suppressed pts
Trial
From
To
Outcome
GS-123
TDF/FTC + RAL
EVG/COBI/FTC/TDF
✔
GS-264
TDF/FTC/EFV
RPV/FTC/TDF
✔
Strategy-NNRTI
TDF/FTC + NNRTI
EVG/COBI/FTC/TDF
✔
Strategy-PI
TDF/FTC + PI/r
EVG/COBI/FTC/TDF
✔
SPIRIT
2 NRTI + PI/r
RPV/FTC/TDF
✔
SPIRAL
2 NRTI + PI/r (exp’d pts)
2 NRTI + RAL
✔
SALT
ATV/r + 2 NRTI
ATV/r + 3TC
✔
OLE
LPV/r + 2 NRTIs
LPV/r + 3TC
✔
GS-109
TDF-based ART
EVG/COBI/FTC/TAF
✔
STRIIVING
Suppressive ART
DTG/ABC/3TC
✔
ATLAS-M
ATV/r + 2 NRTIs
ATV/r + 3TC
✔
GS-119
“Salvage regimen”
EVG/COBI/FTC/TAF + DRV
✔
LATTE
CAB or EFV + 2 NRTIs
CAB + RPV
✔
GS-1089
TDF/FTC + 3rd agent
TAF/FTC + 3rd agent
✔
SWITCHMRK
2 NRTI + LPV/r (exp’d pts)
2 NRTI + RAL
✗
HARNESS
2 NRTI + 3rd Agent
Slide 22 of 30
Adapted from David Wohl
ATV/r + RAL
✗
From JE Gallant, MD, MPH, at New York, NY: March 23, 2016, IAS-USA.
SWITCHMRK 1 & 2:
From LPV/r + NRTIs to RAL + NRTIs
Wk 12 lipid
analysis
HIV+ pts with viral
suppression on LPV/r-based
ART
for ≥ 3 mos. Not required to
be initial regimen
(N = 702)
(SWITCHMRK 1: 348
SWITCHMRK 2: 354)
Wk 24 efficacy
analysis
Switch to RAL
+ other BL ARVs*
(SWITCHMRK 1: n = 174
SWITCHMRK 2: n = 176)
Continue LPV/r
+ other BL ARVs*
(SWITCHMRK 1: n = 174
SWITCHMRK 2: n = 178)
*All patients continued background regimen including ≥ 2 NRTIs.
Eron JJ, et al. Lancet. 2010;375:396-407.
Slide 23 of 30
From JE Gallant, MD, MPH, at New York, NY: March 23, 2016, IAS-USA.
SWITCHMRK: Prior failure predicts failure
Inferior efficacy of RAL appeared driven by more failure
among pts with previous virologic failure
SWITCHMRK1
Outcome
SWITCHMRK 2
RAL
(n = 174)
LPV/r (n =
174)
RAL
(n = 176)
LPV/r (n =
178)
85.1
85.8
92.5
93.5
Patients without previous virologic failure
 VL < 50 at Wk 24, %
 Treatment difference, % (95% CI)
-0.7 (-9.9 to 8.6)
-1.0 (-8.5 to 6.3)
Patients with previous virologic failure
 VL < 50 at Wk 24, %
 Treatment difference, % (95% CI)
72.3
89.7
-17.3 (-33.0 to -2.5)
79.7
93.8
-14.2 (-26.5 to -2.6)
Eron JJ, et al. Lancet. 2010;375:396-407.
Slide 24 of 30
From JE Gallant, MD, MPH, at New York, NY: March 23, 2016, IAS-USA.
Switching: Caveats
 Know the treatment and resistance history
 Avoid switching from high barrier to lower
barrier agents when you don’t
Slide 25 of 30
From JE Gallant, MD, MPH, at New York, NY: March 23, 2016, IAS-USA.
• Concordance with historical resistance (individual
ARVs): 85%
• NNRTIs: 93%
• PIs: 84%
• NRTIs: 76%
• Identified major wild-type (nonmutant) variants at 97%
• False omission rate 3%.
Toma J, et al. ICAAC 2015, September 17-21, 2015, San Diego.
Slide 26 of 30
From JE Gallant, MD, MPH, at New York, NY: March 23, 2016, IAS-USA.
A.R.
 A.R. is a 35-year-old woman who was diagnosed 5 years
ago. She has had multiple hospitalizations for HIV- and
substance abuse-related problems, but has never kept a
follow-up appointment in the HIV clinic. She has never
taken ART.
 She has a history of depression and bipolar disorder but
has been erratic with psychiatric follow-up and is currently
on no psychiatric medications. She admits to depression.
 CD4 count is 35; viral load is 213,000. Baseline genotype:
wild-type
Slide 27 of 30
From JE Gallant, MD, MPH, at New York, NY: March 23, 2016, IAS-USA.
A.R.
 She now comes to clinic for a new patient appointment, 1 week after
hospitalization for PCP.
 She is taking TMP/SMX and azithromycin prescribed at discharge.
 She continues to use crack cocaine several times a week but denies
active injection drug use.
 She knows several people who have died of AIDS and wants to start
ART, preferably with something “easy.”
 You start her on a previously prescribed mood stabilizer and
antidepressant and refer her to a psychiatrist, an adherence counselor,
and substance abuse treatment.
Slide 28 of 30
From JE Gallant, MD, MPH, at New York, NY: March 23, 2016, IAS-USA.
A.R. What do you do about ART?
Slide 29 of 30
St
ar
t
th
e
...
p.
..
w
he
n
rh
er
AR
T
AR
T
af
te
if
sh
e
AR
T
ar
t
St
St
ar
t
AR
T
on
th
is
vis
it
4.
ar
t
3.
St
2.
Start ART on this visit
Start ART if she returns to the clinic in 2-4 weeks
Start ART after her psychiatrist, adherence
counselor, and substance abuse counselor
feel she is ready
Start ART when the moon and planets line up
0% 0% 0% 0%
re
tu
r..
1.
10
From JE Gallant, MD, MPH, at New York, NY: March 23, 2016, IAS-USA.
When you do start ART, what 3rd agent will you use in
addition to 2 NRTIs?
Slide 30 of 30
0%
0%
0%
0%
DT
G
0%
EF
V
RP
V
0%
V/
c
6.
DR
5.
V/
r
4.
DR
3.
BI
2.
RPV
EFV
EVG/COBI
DRV/r
DRV/c
DTG
EV
G/
CO
1.
10
From JE Gallant, MD, MPH, at New York, NY: March 23, 2016, IAS-USA.