Slide 1 of 47
Antiretroviral Therapy: Challenging
Patients and Difficult Problems
Joel E. Gallant, MD, MPH
Professor of Medicine and Epidemiology
The Johns Hopkins University
School of Medicine
Baltimore, Maryland
From JE Gallant, MD, at Chicago, IL: May 20, 2013, IAS-USA.
IAS–USA
Slide 2 of 47
ACTG 5202: Time to Virologic Failure by
Baseline Viral Load and CD4 Count
ABC/3TC
TDF/FTC
1.0
0.8
0.6
0.4
CD4<50, RNA≥100K (n=98, 35 VF)
CD4<50, RNA<100K (n=78, 23 VF)
CD4 50 to <200, RNA≥100K (n=80, 19 VF)
CD4 50 to <200, RNA<100K (n=153, 10 VF)
CD4 200 to <350, RNA≥100K (n=39, 6 VF)
CD4 200 to <350, RNA<100K (n=273, 28 VF)
CD4≥350, RNA≥100K (n=23, 5 VF)
CD4≥350, RNA<100K (n=184, 29 VF)
0.2
Probability of Remaining free of
Virologic Failure
Probability of Remaining free of
Virologic Failure
1.0
0.0
0.8
0.6
0.4
CD4<50, RNA≥100K (n=80, 6 VF)
CD4<50, RNA<100K (n=83, 17 VF)
CD4 50 to <200, RNA≥100K (n=70, 9 VF)
CD4 50 to <200, RNA<100K (n=158, 19 VF)
CD4 200 to <350, RNA≥100K (n=55, 8 VF)
CD4 200 to <350, RNA<100K (n=289, 29 VF)
CD4≥350, RNA≥100K (n=20, 2 VF)
CD4≥350, RNA<100K (n=173, 24 VF)
0.2
0.0
0
24
48
72
96 120 144 168 192 216
Weeks from Randomization
From JE Gallant, MD, at Chicago, IL: May 20, 2013, IAS-USA.
0
24
48
72
96 120 144 168 192 216
Weeks from Randomization
Grant P, et al. CROI 2011. Abstract 535.
Slide 3 of 47
Abacavir and MI Risk
• Conflicting data from observational and
prospective studies
• Proposed pathogenic models:
– Inflammation (higher hsCRP1)
– Increased platelet reactivity/adhesion2
– Impaired endothelial function3
• Guidelines: use “with caution” in patients
with high CV risk
1. McComsey G, et al. 19th CROI; Seattle, WA; March 5-8, 2012. Abst. 835.
2. 2. Baum PD, et al. AIDS 2011, 25:2243–2248.
3. Hsue PY, et al. AIDS 2009;23:2021-7.
From JE Gallant, MD, at Chicago, IL: May 20, 2013, IAS-USA.
Slide 4 of 47
VA Study: TDF and risk of kidney
disease
• 10,841 HIV+ pts at VA
• Time to first occurrence of 1) proteinuria 2) rapid decline
in kidney function and 3) CKD (eGFR rate < 60 )
• Each year of exposure to TDF associated with:
– 34% increased risk of proteinuria (p < 0.0001)
– 11% increased risk of rapid decline (p = 0.0033)
– 33% increased risk of CKD (p < 0.0001).
• Pre-existing renal risk factors did not appear to worsen
the effects of tenofovir.
Scherzer R, et al. AIDS 2012 [Epub ahead of print]
From JE Gallant, MD, at Chicago, IL: May 20, 2013, IAS-USA.
Slide 5 of 47
NRTI-sparing regimens
Regimen
Efficacy/
Resistance
Lipids
Renal
Bone
Bilirubin
A51421-3
LPV/r + EFV
Neutral
Elevated
Neutral
Neutral
-
PROGRESS4
LPV/r + RAL
Neutral
Elevated
Neutral
-
-
CCTG5895
LPV/r + RAL
Neutral
-
-
-
-
SPARTAN6
ATV + RAL
More
Resistance
Neutral
-
-
Elevated
ATV/r + MVC
Neutral
-
-
-
Elevated
DRV/r
Not Non-Inferior
Elevated
-
-
-
DRV/r + RAL
Inferior
TBD
TBD
TBD
TBD
Study
MVC
Manufacturer7
MONET8
A52629
1. Riddler S, et al. New Engl J Med 2008;358:2179-2.
3. Goicoechea M, J et al. WAIDS 2010. Vienna. WEAB0304
5. Goicoechea M, J et al. WAIDS 2010. Vienna. THPE0068
7. Portsmouth S, et al. WAIDS 2010; Vienna. THLBB203
9. Taiwo B, et al. CROI 2011; Boston. Poster 551
2. Huang J, et al. WAIDS 2010. Vienna. WEAB0304
4. Reynes J, et al. WAIDS 2010; Vienna. MOAB0101
6. Kozal MJ, et al. WAIDS 2010; Vienna. THLBB204
8. Rieger A, et al. WAIDS 2010; Vienna. THLBB209
From JE Gallant, MD, at Chicago, IL: May 20, 2013, IAS-USA.
Slide 6 of 47
ACTG 5262: DRV/r + RAL
Time to VF by Baseline HIV-1 RNA
1.0
1.0
0.8
0.8
Probability of not having a VF
Probability of not having a VF
Time to Virologic Failure (VF)
0.6
0.4
0.2
0.0
1 4
n with VF:
n at risk:
12
Time (weeks)
0 0
3
112 111 110
Taiwo B, et al. AIDS 2011, ePub.
24
36
48
14
105
5
89
6
81
43% failure by
week 48
0.6
0.4
HIV-1 RNA ≤ 100,000 copies/mL
0.2
HIV-1 RNA > 100,000 copies/mL
Log Rank Test p=0.0002
0.0
1 4
12
24
36
48
Time (weeks)
VL ≤ 100,000
n with VF:
n at risk:
VL > 100,000
n with VF:
n at risk:
0 0
63 63
1
62
4
59
1
54
1
50
0 0
40 45
2
45
10
45
4
39
5
31
Slide 7 of 47
ARVs and HCV PIs
Telaprevir
Boceprevir
ARVs That Can Be Used
ARV[1,2]




ARV[3,4]
 RAL
 MVC
 NRTIs
ATV/r
EFV*
TDF/FTC†
RAL[5]
ARVs That Are Contraindicated/Not Recommended
 DRV/r
 FPV/r
 LPV/r
 EFV
 RTV-boosted PIs[6]
*↑TVR dose to 1125 mg q8h
†Monitor for TDF toxicity
1. Telaprevir [package insert]. 2011. 2. Sulkowski M, et al. CROI 2011. Abstract 146LB. 3 Boceprevir [package insert]. 2011.4.
Sulkowski M, et al. IDSA 2011. Abstract LB-37. 5. Van Heeswijk R, et al. ICAAC 2011. Abstract A-1738a. 6. Dear HCP letter 3 Feb 2012.
From JE Gallant, MD, at Chicago, IL: May 20, 2013, IAS-USA.
Slide 8 of 47
GS 103: Drug resistance through week 48
Quad
(n=353)
ATV/r + FTC/TDF
(n=355)
Subjects Analyzed for Resistancea, n (%)
12 (3)
8 (2)
Subjects with Resistance to ARV Regimen, n (%)
5 (1)
0
4
-
Any Primary Integrase-R, n
E92Q
1
-
T66I
1
-
Q148R
2
-
N155H
2
-
Any Primary PI-R, n
-
0
Any Primary NRTI-R, n
4
0
M184V/I
4
K65R
1
DeJesus E, et al. Lancet 2012;379:2429-38
From JE Gallant, MD, at Chicago, IL: May 20, 2013, IAS-USA.
Slide 9 of 47
Evolution of Integrase Resistance With
Increased Time After VF
Evolution of Viral Clones After Failure of RAL Regimens
BENCHMRK[1]
100
Other
Clones (%)
80
60
Q148H/K/R*
19%
Y143R/H/C 6%
40
20
0
Other
N155H/R†
45%
Early after
failure
Q148H/K/R
53%
N155H/R
18%
Later time
points
*2° mutations with Q148H/K/R: G140S(A) , E138K
†2° mutations with N155H/R: L74M, E92Q,
T97A, V151I, G163R
 SCOPE cohort: genotypic and
phenotypic resistance increased
over time on INSTI therapy[2]
– More pts with multiple
resistance mutations at later
time points
 Q148H/K/R or Y143R/H/C
associated with high-level
phenotypic resistance
– Change in IC50 > 100-fold
 N155H associated with low-level
phenotypic resistance
– Change in IC50 < 50-fold
1. Fransen S, et al. J Virol. 2009;83:11440–11446.
2. Hatano H, et al J Acquir Immune Defic Syndr. 2010;54:389-393.
From JE Gallant, MD, at Chicago, IL: May 20, 2013, IAS-USA.
Slide 10 of 47
VIKING: Dolutegravir “Functional
Monotherapy” in Pts With RAL Resistance
Primary Endpoint* (%)
 DTG BID more effective than QD through Day 11 in pts with Q148
80
100
96
100
100
92
78
60
40
33
20
0
All Patients
Q148 + ≥ 1
Other
Other Mutation Mutations
at Baseline
*VL < 400 or ≥ 0.7 log10 reduction from baseline at Day 11.
Eron J, et al. CROI 2011. Abstract 151LB.
From JE Gallant, MD, at Chicago, IL: May 20, 2013, IAS-USA.
DTG 50 mg QD
(n = 27)
DTG 50 mg BID
(n = 24)
Slide 11 of 47
Prevalence of Transmitted HIV Drug
Resistance in US, 2006-2009
 Genotypic analysis of samples from newly diagnosed patients in
CDC National HIV Surveillance System (N = 12,668)
20
All cases with sequences
Cases classified as recent infections
Cases classified as long-standing infections
16 15.6
12
7.8
8
6.8
4.1
4
0
1 or more
1-class
2-class
3-class
NNRTI
NRTI
Transmitted Drug Resistance Mutations (TDRMs)
Ocfemia MCB, et al. CROI 2012. Abstract 730.
From JE Gallant, MD, at Chicago, IL: May 20, 2013, IAS-USA.
PI
Slide 12 of 47
Weighted Scores for ETR
Susceptibility
Monogram
Tibotec
4: 100I, 101P, 181C/I
3: 181I/V
3: 138A/G, 179E, 190Q, 230L,
238N
2.5: 101P, 100I, 181C, 230L
2: 101E, 106A, 138K, 179L, 188L
1: 90I, 101H, 106M, 138Q,
179D/F/M, 181F, 190E/T, 221Y,
225H, 238T
1.5: 138A, 106I, 190S, 179F
1: 90I, 179D, 101E, 101H,
98G, 179T, 190A
0-2: 74% response
> 4 = reduced susceptibility
2.5-3.5: 52% response
From JE Gallant, MD, at Chicago, IL: May 20, 2013, IAS-USA.> 4: 38% response
Slide 13 of 47
DHHS Perinatal Guidelines, 2011
 HIV-infected pregnant women who meet criteria for ART
per adult guidelines should receive ART as recommended
for nonpregnant adults, taking into account what is known
about specific drugs in pregnancy and risk of
teratogenicity (AI)
– For women who require immediate initiation of ART for their
own health, treatment should be started as soon as possible,
including in first trimester (AII)
DHHS Perinatal Guidelines, September 2011.
From JE Gallant, MD, at Chicago, IL: May 20, 2013, IAS-USA.
Slide 14 of 47
Antiretroviral Therapy Safety During
Pregnancy
Class
FDA Category
B
C
NRTIs
ddI
FTC
TDF
ABC
3TC
d4T
ZDV
NNRTIs
ETR
NVP
RPV
PIs
ATV
NFV
RTV
SQV
Entry inhibitors
ENF
MVC
Integrase inhibitor
DHHS Perinatal Guidelines, September 2011.
From JE Gallant, MD, at Chicago, IL: May 20, 2013, IAS-USA.
D
EFV
DRV
FPV
IDV
LPV/r
TPV
RAL