Antiretroviral Therapy: Challenging Patients and Difficult Problems

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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/FTC1.0

0.8

0.6

0.4

0.2

0.0

0 24 48 72 96 120 144 168 192 216Weeks from Randomization

Prob

abili

ty o

f Rem

aini

ng fr

ee o

f Vi

rolo

gic

Failu

re

1.0

0.8

0.6

0.4

0.2

0.0

0 24 48 72 96 120 144 168 192 216Weeks from Randomization

Prob

abili

ty o

f Rem

aini

ng fr

ee o

f Vi

rolo

gic

Failu

reCD4<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


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


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


NRTI-sparing regimens Study 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

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


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

babi

lity

of n

ot h

avin

g 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

babi

lity

of n

ot h

avin

g a

VF

Log Rank Test p=0.0002

HIV-1 RNA ≤ 100,000 copies/mLHIV-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

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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

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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) 0Any Primary Integrase-R, n 4 -

E92Q 1 -T66I 1 -

Q148R 2 -N155H 2 -

Any Primary PI-R, n - 0Any Primary NRTI-R, n 4 0

M184V/I 4K65R 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/R

18%

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


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

Prim

ary

Endp

oint

* (%

)

OtherMutations

All Patients Q148 + ≥ 1Other Mutation

at Baseline

DTG 50 mg QD (n = 27)DTG 50 mg BID (n = 24)

78

96

33

100 100 92

Slide 10 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)

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


Weighted Scores for ETR Susceptibility

Monogram4: 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

Tibotec3: 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

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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.

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Antiretroviral Therapy Safety During PregnancyClass FDA Category

B C DNRTIs ddI

FTCTDF

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


Antiretroviral Therapy: Challenging Patients and Difficult Problems

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