HIV that Is Resistant to HIV that Is Resistant to Dolutegravir May not be Dolutegravir May not be

TransmissibleTransmissible

Mark A WainbergMark A Wainberg McGill University AIDS CentreMcGill University AIDS Centre

Jewish General HospitalJewish General Hospital

Disclosures

I have received honoraria from

AbbVie, Bristol Myers Squib, Gilead, Janssen,Merck, ViiV

14th European AIDS Conference; October 16-19, 2013; Brussels, Belgium

FLAMINGO (ING114915) Study Design

Clotet et al. EACS 2013; Brussels, Belgium. Abstract LBPS4/6.

Primary endpoint: proportion with HIV-1 RNA <50 c/mL at Week 48, FDA Snapshot analysis, -12% non-inferiority (NI) marginSecondary endpoints: antiviral activity, safety, tolerability, health outcomes and viral resistance

HIV+ ART-naiveVL ≥1,000 c/mL

Stratified by screening plasma HIV-1 RNA

(≤ vs >100,000 c/mL) and background dual NRTI

(ABC/3TC or TDF/FTC*)

Week 96 analysis

Randomization Week 48 analysis

DRV/r 800 mg/100 mg QD + 2 NRTIs

DTG + ART

Open-label randomized phase

DTG 50 mg QD + 2 NRTIs

Extension phase

*Investigator selected backbone of choice

14th European AIDS Conference; October 16-19, 2013; Brussels, Belgium

Results were confirmed in per protocol analysis: 91% DTG versus 84% DRV/r, ∆ (CI): 7.4 (1.4 - 13.3)

Proportion (95% CI) of Individuals With HIV-1 RNA <50 c/mL Over Time – Snapshot

Clotet et al. EACS 2013; Brussels, Belgium. Abstract LBPS4/6.

DTG: 90%

DRV/r: 83%

WeekBL 4 8 12 16 3624 48

Prop

ortio

n (%

) 95% CI for differencea

FavoursDRV/r

FavoursDTG

-20% 0 20%

7.10.9 13.2

-12%

Test for superiority: P=0.025

Resistance to INSTIs in clinical trials in treatment-naïve patients

TreatmentMajor resistance mutations detected by genotyping in treatment-naïve patients failing therapy

Minor resistance mutations

RaltegravirY143

N155HQ148

Multiple

Elvitegravir

T66IE92Q

N155HQ148

Multiple

Dolutegravir NONE NONE

RALTEGRAVIRCooper et al., NEJM, 2008Sichtig et al, JAC, 2009Canducci et al, AIDS, 2009Hatano et al, JAIDS, 2010

ELVITEGRAVIRSax et al, Lancet, 2012DeJesus et al, Lancet, 2012

DOLUTEGRAVIRvanLunzen et al., Lancet Infect. Dis., 2012

Major resistance pathways against INSTIs(clinical and tissue culture data)

Resistance pathwaysFold resistance

RAL EVG DTGY143 pathway

Y143C <10 <2 <2Y143R <50 <2 <2

T97A/Y143C >100 <2 <2T97A/Y143R >100 <2 <2

L74M/T97A/Y143G <50 ND <2L74M/T97A/E138A/Y143C <20 ND <2

N155 pathway N155H <50 <50 <2

E92Q/N155H <100 >100 <10L74M/N155H <50 <50 <2

Q148 pathway Q148H <20 <10 <2Q148K <100 <100 <2Q148R <50 <100 <2

E138K/Q148H <10 <20 <2E138K/Q148K >100 >100 <20E138K/Q148R >100 >100 <10G140S/Q148H >100 >100 <20G140S/Q148K <10 <100 <2G140S/Q148R >100 >100 <10

E138A/G140S/Y143H/Q148H >100 ND <50

Quashie et al., Curr. Opin. Infect. Diseases, in press

Secondary INSTI-resistance mutations often restore HIV replication capacity

Mbisa et al., Infect. and drug resistance, 2011--Canducci et al., JAC, 2010--Reigadas et al., Plos One, 2010--Delelis et al., AAC, 2009

Secondary Mutations (pathway)

Effect on viral fitness in the presence of primary resistance mutations

Y143 pathway - (often) L74M, T97A +

N155H pathway - Q95K, T97Q,

G163R/K +

Q148 pathway - G140A/S/C, E138K/A +

Dolutegravir activity on RAL-resistant clinical isolates (n=39)

(median IC50 for wild-type=1.07 nM)

Genotype Median fold change

N155H 1.37

Y143R/T97A 1.05

Q148H/G140S 3.75

Q148R/G140S 13.3

Underwood et al., JAIDS, 2012

Subtype-specific mutations selected in vitro with dolutegravir

HIV-1 subtype Most common mutations selected with dolutegravir

B R263K, H51Y

C G118R, H51Y

Quashie, Mesplède et al., Journal of Virology, 2012

The R263K mutation confers low-level resistance to dolutegravir

in cell culture

Genotype IC50 fold change*

R263K 2.5 to 6

*Methodological differences(EC50 for wild-type ≈1-6nM) Quashie, Mesplède et al., Journal of Virology, 2012

SAILING

• CROI 2013. A study in which Dolutegravir was shown to be superior to Raltegravir in treatment-experienced integrase inhibitor-naïve subjects.

• The R263K mutation was present in two individuals who either rebounded or did not achieve virologic suppression to <50 c/ml.

The R263K mutation decreases integrase activity in cell-free assaysB

0 5 10 15 20 250

5000

10000

15000

20000ININR263K

[Target DNA] (nM)

RFU

INR263K

0

5000

10000

15000

20000

RFU

C Quashie, Mesplède et al., Journal of Virology, 2012

The R263K mutation decreases dolutegravir residency time

in an integrase-vDNA complex

The addition of H51Y to R263K further decreases IN strand transfer activity

A B

The combination of H51Y and R263K negatively impacts viral fitness

Dolutegravir resistance associates with

a decrease in viral replication capacity

Genotype Resistance Effect on viral fitness

R263K + -

H51Y None None

H51Y/R263K ++ - -

G118R + -

H51Y/G118R ++ - -

Virus Weeks 8-15  

WT M184VH51Y M184IR263K M184IH51Y/R263K NoneG118R NoneH51Y/G118R None

Selection of DTG-Resistant Viruses with 3TC

The R263K Mutation Confers a Higher Level of Drug Resistance against DTG than INSTI Mutations

Associated with RAL and EVG

Mutations at positions

Fold resistance to

RAL EVG DTG

E92Q 2-3.5 15-20 <2

Y143 3-16 1.5-2 <1.5

Q148 10-50 10-100 <1.2

N155H 5-15 25-50 <1.2

R263K <1 2-4 4-5

This explains why R263K is selected preferentially by DTG and why the R263K virus is then unable to proceed along any of the alternative INSTI resistance pathways that are associated with high level resistance against all members of the INSTI family of drugs

Replication Capacity of HIV Containing Various Combinations of INSTI Resistance Mutations

Mutation(s) % fitnessE92Q ≈ 75%Y143 ≈ 72%Q148 ≈ 75%N155 ≈ 75%R263K ≈ 70%G140/Q148 ≈ 95%R263K/H51Y ≈ 25%R263K/E138K ≈ 25%R263K/Q148R 0R263K/Y143C 0R263K/E92Q 0

Conclusions• Resistance mutations selected in vitro with dolutegravir are:

R263K or G118R plus H51Y

• R263K and G118R confer low-level resistance against dolutegravir, e.g. 2.5-6 fold

• The addition of H51Y to either R263K or G118R increases resistance against DTG but also further decreases viral fitness

• These findings help to explain why resistance against dolutegravir in INSTI-naïve patients has not been observed

No compensatory mutations in regard to DTG resistance and viral fitness have developed over more than two years in culture.

• Bluma Brenner• Hongtao Xu• Dimitri Coutsinos• Jerry Zaharatos• Maureen Oliveira• Thibault Mesplède• Peter Quashie

Acknowledgements

MERCI

Long-Term Safety and Efficacy of Raltegravir-Based Versus Efavirenz-Based Combination Therapy in Treatment-Naïve HIV-1 Infected Patients:

Final 5-Year Double-Blind Results From STARTMRK

AIDS 2012 AIDS 2012 Poster #LBPE19

Proportion (%) of Patients Achieving HIV RNA <50 copies/mL (95% CI) Over Time

Non-Completer = Failure Approach

86

82

81

79

75

69

76

67

281278279 280 281 281 277 280 281 281 277 279

282282282 281 282 282 281 281 282 282 282 279

Raltegravir 400 mg bid.

Efavirenz 600 mg qHS.

0 12 24 48 72 96 120 144 168 192 216 240

Weeks

0

20

40

60

80

100

Pe

rce

nt

of

Pa

tien

ts w

ithH

IV R

NA

Le

vels

<5

0 C

op

ies/

mL

Number of Contributing Patients

71%

61%

Change From Baseline in CD4-Cell Count (95% CI) Over Time

361

301

331

295

240

225

189

163

281272266 258 255 250 240 235 231 235 227 222

281268266 251 252 243 234 228 224 220 218 212

Raltegravir 400 mg bid.

Efavirenz 600 mg qHS.

0 12 24 48 72 96 120 144 168 192 216 240

Weeks

0

50

100

150

200

250

300

350

400

C

ha

ng

e f

rom

Ba

selin

e

CD

4 C

ell

Co

un

t (c

ells

/mm

3 )

Number of Contributing Patients

374

312

Thanks to CIHR and CANFAR