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Slide 1 of 47
From JE Gallant, MD, at Chicago, IL: May 20, 2013, IAS-USA. IAS–USA
Joel E. Gallant, MD, MPHProfessor of Medicine and Epidemiology
The Johns Hopkins UniversitySchool of MedicineBaltimore, Maryland
Antiretroviral Therapy: Challenging Patients and Difficult
Problems
From JE Gallant, MD, at Chicago, IL: May 20, 2013, IAS-USA.
ACTG 5202: Time to Virologic Failure by Baseline Viral Load and CD4 Count
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)
ABC/3TC TDF/FTC
1.0
0.8
0.6
0.4
0.2
0.0
0 24 48 72 96 120 144 168 192 216
Weeks from Randomization
Pro
bab
ilit
y o
f R
emai
nin
g f
ree
of
Vir
olo
gic
Fai
lure
1.0
0.8
0.6
0.4
0.2
0.0
0 24 48 72 96 120 144 168 192 216
Weeks from Randomization
Pro
bab
ilit
y o
f R
emai
nin
g f
ree
of
Vir
olo
gic
Fai
lure
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)
Grant P, et al. CROI 2011. Abstract 535.
Slide 2 of 47
From JE Gallant, MD, at Chicago, IL: May 20, 2013, IAS-USA.
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.
Slide 3 of 47
From JE Gallant, MD, at Chicago, IL: May 20, 2013, IAS-USA.
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]
Slide 4 of 47
From JE Gallant, MD, at Chicago, IL: May 20, 2013, IAS-USA.
NRTI-sparing regimens
Study RegimenEfficacy/
ResistanceLipids 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 + RALMore
ResistanceNeutral - - Elevated
MVC Manufacturer7 ATV/r + MVC Neutral - - - Elevated
MONET8 DRV/r Not Non-Inferior Elevated - - -
A52629 DRV/r + RAL Inferior TBD TBD TBD TBD
1. Riddler S, et al. New Engl J Med 2008;358:2179-2. 2. Huang J, et al. WAIDS 2010. Vienna. WEAB03043. Goicoechea M, J et al. WAIDS 2010. Vienna. WEAB0304 4. Reynes J, et al. WAIDS 2010; Vienna. MOAB01015. Goicoechea M, J et al. WAIDS 2010. Vienna. THPE0068 6. Kozal MJ, et al. WAIDS 2010; Vienna. THLBB2047. Portsmouth S, et al. WAIDS 2010; Vienna. THLBB203 8. Rieger A, et al. WAIDS 2010; Vienna. THLBB2099. Taiwo B, et al. CROI 2011; Boston. Poster 551
Slide 5 of 47
From JE Gallant, MD, at Chicago, IL: May 20, 2013, IAS-USA.
ACTG 5262: DRV/r + RAL
1.0
0.8
0.6
0.4
0.2
0.0
Taiwo B, et al. AIDS 2011, ePub.
Time to Virologic Failure (VF)
1 4 12 24 36 48
Time (weeks)
Pro
bab
ility
of
not
havi
ng a
VF
1.0
0.8
0.6
0.4
0.2
0.0
Time to VF by Baseline HIV-1 RNA
1 4 12 24 36 48
Time (weeks)
Pro
bab
ility
of
not
havi
ng a
VF
Log Rank Test p=0.0002
HIV-1 RNA ≤ 100,000 copies/mL
HIV-1 RNA > 100,000 copies/mL
n with VF: 0 0 3 14 5 6n at risk: 112 111 110 105 89 81
VL ≤ 100,000n with VF: 0 0 1 4 1 1n at risk: 63 63 62 59 54 50VL > 100,000n with VF: 0 0 2 10 4 5n at risk: 40 45 45 45 39 31
43% failure by week 48
Slide 6 of 47
Slide 7 of 47
From JE Gallant, MD, at Chicago, IL: May 20, 2013, IAS-USA.
ARVs and HCV PIs
Telaprevir Boceprevir
ARVs That Can Be Used
ARV[1,2] ARV[3,4]
ATV/rEFV*TDF/FTC†
RAL[5]
RALMVCNRTIs
ARVs That Are Contraindicated/Not Recommended
DRV/rFPV/rLPV/r
EFVRTV-boosted PIs[6]
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.
*↑TVR dose to 1125 mg q8h †Monitor for TDF toxicity
Slide 7 of 47
Slide 8 of 47
From JE Gallant, MD, at Chicago, IL: May 20, 2013, IAS-USA.
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
Any Primary Integrase-R, n 4 -
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
Evolution of Integrase Resistance With Increased Time After VF
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.
†2° mutations with N155H/R: L74M, E92Q, T97A, V151I, G163R
*2° mutations with Q148H/K/R: G140S(A) , E138K
40
0
100
20
80
60
N155H/R†45%
N155H/R18%
Clo
nes
(%) Q148H/K/R*
19%
Q148H/K/R53%
Early after failure
Later time points
Y143R/H/C 6%
Evolution of Viral Clones After Failure of RAL RegimensBENCHMRK[1]
OtherOther
Slide 9 of 47
From JE Gallant, MD, at Chicago, IL: May 20, 2013, IAS-USA.
VIKING: Dolutegravir “Functional Monotherapy” in Pts With RAL Resistance
DTG BID more effective than QD through Day 11 in pts with Q148
Eron J, et al. CROI 2011. Abstract 151LB. *VL < 400 or ≥ 0.7 log10 reduction from baseline at Day 11.
100
80
60
40
20
0
Pri
mar
y E
nd
po
int*
(%
)
OtherMutations
All Patients Q148 + ≥ 1Other Mutation
at Baseline
DTG 50 mg QD (n = 27)
DTG 50 mg BID (n = 24)
78
96
33
100 10092
Slide 10 of 47
From JE Gallant, MD, at Chicago, IL: May 20, 2013, IAS-USA.
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)
Ocfemia MCB, et al. CROI 2012. Abstract 730.
All cases with sequencesCases classified as recent infectionsCases classified as long-standing infections
0
4
Transmitted Drug Resistance Mutations (TDRMs)
1 or more
20
8
12
16
1-class 2-class 3-class NNRTI NRTI PI
15.6
7.86.8
4.1
Slide 11 of 47
From JE Gallant, MD, at Chicago, IL: May 20, 2013, IAS-USA.
Weighted Scores for ETR Susceptibility
Monogram
4: 100I, 101P, 181C/I
3: 138A/G, 179E, 190Q, 230L, 238N
2: 101E, 106A, 138K, 179L, 188L
1: 90I, 101H, 106M, 138Q, 179D/F/M, 181F, 190E/T, 221Y, 225H, 238T
Tibotec
3: 181I/V
2.5: 101P, 100I, 181C, 230L
1.5: 138A, 106I, 190S, 179F
1: 90I, 179D, 101E, 101H, 98G, 179T, 190A
0-2: 74% response2.5-3.5: 52% response> 4: 38% response
> 4 = reduced susceptibility
Slide 12 of 47
From JE Gallant, MD, at Chicago, IL: May 20, 2013, IAS-USA.
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.
Slide 13 of 47
From JE Gallant, MD, at Chicago, IL: May 20, 2013, IAS-USA.
Antiretroviral Therapy Safety During PregnancyClass FDA Category
B C D
NRTIs ddIFTCTDF
ABC3TC d4TZDV
NNRTIs ETRNVPRPV
EFV
PIs ATVNFVRTVSQV
DRVFPVIDV
LPV/rTPV
Entry inhibitors ENFMVC
Integrase inhibitor RAL
DHHS Perinatal Guidelines, September 2011.
Slide 14 of 47
From JE Gallant, MD, at Chicago, IL: May 20, 2013, IAS-USA.