Resistance Characteristics of Integrase Inhibitorsregist2.virology-education.com/2017/2GlobalHCF/02_Charpentier.pdf · Dr Charlotte CHARPENTIER Laboratoire de Virologie Hôpital Bichat-Claude

Dr Charlotte CHARPENTIER

Laboratoire de VirologieHôpital Bichat-Claude Bernard

INSERM UMR 1137- IAMEUniversité Paris Diderot

Resistance Characteristicsof Integrase Inhibitors

Plan

• 1st generation: Raltegravir (RAL) and Elvitegravir (EVG/c)

• 2nd generation: Dolutegravir (DTG)

• Epidemiology of resistance to integrase inhibitors

• Ongoing: Bictegravir (BIC) and Cabotegravir (CAB)

Plan





In vitro selection experiments

EVGRAL

RAL and EVG mean FC of single mutation SDMs

• Phase 3 clinical trials conducted in highly-experienced patients with resistant viruses: RAL + Optimized Background Treatment

• VL <400 c/mL in 78 % of patients at W16 (vs 42 % in placebo group)

• Genotypic resistance to RAL in 60 % of patients in VF with available integrase sequence at VF

• Three major resistance mutations: codons 143, 148 and 155

• Emergence of resistance mainly occurred during the first years of the trial, rarely after the third year

RAL: analysis of resistance in the BENCHMRK trials

Cooper et al., NEJM, 2008; Eron et al., Lancet Infect Dis, 2013

Combined analysis of resistance at W96 in the TDF and TAF/FTC/EVG/c trials in ARV-naïve patients

Callebaut et al., IHDRW 2016, Abs. 32; CROI 2016, Abs. 496

E/c/F/TAF

(n = 866)

E/c/F/TDF

(n = 867)

Patients meeting criteria

for resistance analysis19 (2 %) 16 (2 %)

Resistance mutations 10 (1.2 %) 8 (0.9 %)

RT mutations 10 (1.2 %) 7 (0.8 %)

M184I/V 9 6

K65N/R 2 3

K70R 1 1

Integrase mutations 8 (0.9 %) 5 (0.6 %)

T66A/I/V 2 0

E92Q 4 2

Q148R 1 2

N155H/S 2 2

Rare selection of resistance and in similar proportions in the TAF and TDF arms

Distribution of resistance mutations at time of VF

TDF

EVG

FTCTAF

EVG

FTC

0

1

2

3

4

S48 S96 S48 S96

E/C/F/TAF

E/C/F/TDF

Patients with criteria for resistance analysis

Resistance development (%)

Emergence of resistance

16 19 27 28 7 5 10 8

Switch from 155 to 148 resistance profile

1 000

100

10

1

Maximum

Fold Change

Y1

43

R

Y1

43

C

N1

55

H

Q1

48

R

Q1

48

H

+T

97

A

+T

97

A

+E

92

Q

+G

14

0S

+G

14

0S

100

50

0

Y1

43

R

Y1

43

C

N1

55

H

Q1

48

R

Q1

48

H

+T

97

A

+T

97

A

+E

92

Q

+G

14

0S

+G

14

0S

RAL Fold-Change

Viral replicative capacity (%)

Fransen et al., CROI 2009, Abs. 69Fransen et al., Antimicrob Agents Chemother, 2009

Major mutations and secondary mutations

Major mutations Secondary mutations

Q148H/K/R G140A/S, E138K

N155H E92Q, L74M, V151I, G163R

Y143C/H/R T97A, E92Q, E157Q

Secondary mutations: restoration of viral replicative capacity and of resistance level

• Low genetic barrier to resistance

• High level of cross resistance RAL and EVG

Nucleic Acids Research, 2009

Plan





In vitro selection experiments

DTG

DTG, RAL and EVG mean FC against RAL & EVG-relatedsingle mutation SDMs

Resistance Fold-Change to RAL and DTG according to integrase mutations profiles

Underwood et al., IHDRW 2013, Abs. 85

• 143 and 155: most favorable resistance profiles for DTG activity • 148 (specially 140/148 double mutants): worst resistance profile for DTG activity

VIKING-3 trial: virological response at D8 and W24 according to baseline integrase mutations

Day 8 response Week 24 response

IN mutationDecline in VL (log10 c/mL)

Full responsea

< 50 c/mL

n Median n (%) n n (%)

No Q148 122 -1.65 112 (92 %) 72 57 (79 %)

Q148 + 1b 35 -1.10 25 (71 %) 20 9 (45 %)

Q148 + >2b 20 -0.74 9 (45 %) 9 1 (11 %)

a Full response: decline in HIV-1 RNA > 1 log10 c/mL or 50 c/mL at D8b L74I, E138A/K/T and G140A/C/S

Vavro et al., IHVDRW 2013, Abs. 29

• VIKING-3 is a single-arm, open-label phase III study in which therapy-experienced adults with INI-resistant virus received DTG 50 mg bid while continuing their failing regimen (without raltegravir or elvitegravir) through day 7, after which the regimen was optimized with ≥1 fully active drug and DTG continued

-3.5

0.5 1 2 4 8 16 32

-3.0

-2.5

-2.0

-1.5

-1.0

-0.5

0.0

0.5

Baseline FC IN IC95 relative to wild type virus for DTG

Ch

ange

fro

m b

ase

line

in p

lasm

a H

IV-1

RN

A a

t d

ay 8

(lo

g 10

c/m

L)

Q148 + > 2

Q148 + 1

N155

Y143

> 2 primary mutations

Primary not detected

Baseline INI resistant mutation category

Vavro et al., IHVDRW 2013, Abs. 29

VIKING-3 trial: relationship between baseline integrase mutations and D8 virological response

lemeilleur

…de la CROI 2014

Impact of mutations selected by RAL or EVG on DTG activity

• Assessment of different Q148 mutants on the phenotypic susceptibility to DTG

• Phenotypic assays using clinical isolates and site-directed mutants

10

100

1Mutations 66, 74, 92, 97, 138, 143,

147, 155, and 163 excluded

n = 127

Median fold-change = 4.3

Range = 1.5-22

Susceptibility of clinical isolates

with Q148H + G140S to DTG

(fold-change)

Huang et al., CROI 2014, Abs. 595

Susceptibility of Q148 + E138 mutants

and Q148 + G140 to DTG

(fold-change)

Q148K mutation associated with other integrase

mutations showed a higher of susceptibility to

DTG than Q148H/R viruses

High variability of DTG susceptibility

to G140S + Q148H double mutants

10

100

0.1

0.5 0.4

2.74.0

0.7

2.13.4 3.8

0.7

7.3

58.9

1.81

DTG in ARV-naïve patients

• To date, no INI or NRTI resistance mutations detected at VF in the DTG arms of the phase 3 randomized clinical trials:

- SPRING: 2 NRTI + DTG vs. RAL

- SINGLE: ABC/3TC + DTG vs. EFV

- FLAMINGO: 2 NRTI + DTG vs. DRV/r

• But:

- Very few VF, sequences performed on the first plasma samples at VF, only known INI resistance mutations analyzed

DTG 50 mg qd, n (%) RAL 400 mg bid, n (%)

VF week 24 (VL > 400 c/mL) 14 (4) 34 (9)

BL and VF data 9 (64) 27 (80)

Any emergent IN substitutions 2 (22) 9 (33)

Emergence of IN mutations associated with development of resistance to INI class

L68V, L74M, E92Q, T97A, G140A/S, Y143C/H/R, Q148H/R, V151I, N155H, E157Q, G163K 0 9 (33)

R263K, R263R/K 2 (22) 0


SAILING trial: resistance analysis through W24 (1)• Phase 3 randomized clinical trial, ARV-experienced patients but INI-naïve with VL

>400 c/mL (2x) or >1000 c/mL (1x)

Strain IN substitution / FC IC50 DTG RAL EVG

NL432a R263K 1.5 0.8 1.3

HXB2 RVAb

V260I 1.0 0.7 5.3

R263K 2.1 0.6 10.6

V260I/R263K 2.0 0.5 6.3

DTG, RAL and EVG Fold-Change IC50

a HeLa-CD4 cells, 3-day assay, B-gal readout, b MT4 cells, 5-day assay, cell tier glow readout


SAILING trial: resistance analysis through W24 (2)

lemeilleur

…de l’IAS-EACS 2015

BL W120 W132

VL (c/mL) 733 622 1 054

IN Mutation WTA49G, S230R,

R263K

A49G, S230R,

R263K

DTG fold change 0.73 3.82 5.77

RAL fold change 0.54 2.39 2.62

RC (% WT) 20 % 7 % 12 %

Patient 1VL (log10 c/mL)


• Subtype C

• TDF + DRV/r

• PSS = 2; GSS = 2

BL W72

VL (c/mL) 84 313 27 050

IN Mutation WTI60L, T97A,

N155H

DTG fold change 0.66 2.4

RAL fold change 0.52 113

RC (% WT) ND ND

BL W108

VL (c/mL) 25 105 3 895

IN Mutation WT N155H

DTG fold change 0.97 1.8

RAL fold change 1.18 12

RC (% WT) ND ND

C24h DTG (ng/mL): W4 = 1 780, W48 = 1 230 C24h DTG: W4 = 1 114, W24 <20, W48 = 1 600

SAILING trial: resistance analysis after W48

Underwood et al., EUHHW 2015, Abs. 6

• Subtype A

• ABC + 3TC

• PSS = 2; GSS = 0.5


• Subtype B

• TDF + FTC

• PSS = 2; GSS = 2

C24h DTG (ng/mL): W4 = 360, W24 = 220, W48 = 30

622 c/mL1 054 c/mL

386 c/mL

1

2

3

4

0 12 24 36 48 60 72 84 96 108 120 132 144

27 050 c/mL

132 100 c/mL

9 870 c/mL

1

2

3

4

5

6

0 12 24 36 48 60 72 84 96

3 895 c/mL

407 c/mL

0 12 24 36 48 60 72 84 96 108 1201

2

3

4

5

lemeilleur

…de la CROI 2017

• 45 years old man, HIV diagnosis with inaugural pneumocystosis: CD4 = 78/mm3, VL = 1 970 000 c/mL (6.3 log10 c/mL)

• Baseline resistance genotype RT: WT; protease: E35D-L63P-A71T-V77I; integrase not performed

• ARV initiation: TDF/FTC + DTG in the hospital

Follow-up of VL and CD4 Integrase ultra-deep sequencing(codons 142 to 165)

• Emergence of M184V mutation in RT

• Emergence of I151V and G163E mutations in integrase at the second time-point

• Emergence of Q148K viruses: from 0.002 % to 20.9 % between T2 and T3 (< 10 days)

Time 1 Time 2 Time 3

Wild-type

Q148K

I151V-G163E

Silent mutation

I151V

G163E

I151M

Y143L-N144Q-P145S

S147N

I162M

Add DRV/r

RT: M184V

IN: G163E

12

3

107

106

105

104

103

102

101

0 20 40 60 80 100Days

VL (c/mL)

0

400

200

600

800

1 000CD4 (/mm3)

First case report of integrase mutation selection at VF of a DTG-based first-line regimen

Fulcher et al., CROI 2017, Abs. 500LB

DOMONO trial Pooled observational cohorts

French observational cohort

n 104 122 28

Number of VF 8/77 (10 %) 11/122 (9 %) 3/28 (11 %)

Number of IN mutations in VF patients

3/5 (60 %) 9/11 (82 %) 3/3 (100 %)

IN mutations N155HS230RR263K

N155H (n=1)T97A-N155H (n=1)E92Q-N155H (n=1)

Q148H-N155H (n=1)E138K-Q148K (n=1)

G118R (n=2)G140S-Q148H/R (n=2)

N155HL74I-E92Q

E138K-G140A-Q148R

Wijting et al., CROI 2017, Abs. 451LB Blanco et al., CROI 2017, Abs. 42 Katlama et al., EACS 2015, Abs. PS4/4

DTG monotherapy in switch: explored and avoided

High rate of VF and of resistance selection, strategy definitively not recommended

• A Dutch multicenter randomized clinical trial: DOMONO trial• Pooled analysis of 3 observational cohorts (Barcelona, Montréal, Munich)• A monocentric observational cohort in Paris, France

Plan





lemeilleur

…de la CROI 2014

INI resistance profiles in United States: 2009-2012

• HIV integrase sequences issued from 1 677

patients experiencing a VF when receiving a

RAL-based treatment

• INI resistance in 26 % of samples

• Most prevalent resistance profiles:

Q148H/K/R (36 %), N155H (31 %)

Hurt et al., CROI 2013, Abs. 591

R2

63

K

F1

21

Y

S1

47

G

T6

6A

/I/K

E9

2Q

/V

E1

38

A/K

Y1

43

C/H

/R

N1

55

H

Q1

48

H/K

/R

G1

40

A/C

/S

160

140

120

100

80

60

40

20

0

79 % single

Y143C/H/R

(n = 45)

21 %

with other

mutations

(n = 12)

80 % single

N155H

(n = 108)

20 %

with other

mutations

(n = 27)

64 %

Q148H/K/R +

G140A/C/S

(n = 99)

35 %

with other

mutations

(n = 54)

1 %

single Q148H/K/R

(n = 2)

Q148

(n = 155)

N155

(n = 135)

Y143

(n = 57)

INI resistance mutations (n)

Description of major INI resistance mutations

• 12.3 % of high level of resistance to DTG in case of major INI resistance mutations selected at time of VF when receiving a RAL-based treatment

• National multicenter cross-sectional study

• n = 502 patients experiencing a VF when receiving a RAL-based treatment

• 71 % subtype B

• Median VL = 2.9 log10 c/mL

39 % with INI mutation

• Factors associated with presence of INI resistance mutations at VF:- VL at time of VF- GSS <2

13.9 % of resistance to DTG

lemeilleur

…de VIH 2016

3 25

9

35

31

8

15

3

00

10

20

30

40

50

60

Marcelin et al., HIV Glasgow 2016, Abs. O332

INI mutations prevalence at VF (%)

• INI resistance mutation in 36 % of patients

– 22 %: 1 INI resistance mutation

– 8 %: 2 INI resistance mutations

– 6 %: > 2 INI resistance mutations

ANRS study: INI resistance prevalence in patients experiencing a VF with an INI (1)

• National multicenter cross-sectional study

• n = 439 patients experiencing a VF when

receiving an INI-based treatment since

October 2014

• 56 % subtype B

• Median VL = 3.0 log10 c/mL

23 % of resistance to DTG qd and 3.5 % to DTG bid in patients failing RAL or EVG

lemeilleur

…de VIH 2016

DTG bid DTG qd RAL EVG

Susceptible, n (%) 39 (95) 39 (95) 39 (95) 39 (95)

Possible resistance, n (%) 2* (5) 2* (5) - -

Resistance, n (%) 0 0 2* (5) 2* (5)

* 2 patients with single E157Q

– Subtype B (n = 2)

– Present at baseline in 1 case (ongoing BL sequencing for the second patient)

• Subgroup analysis of patients in VF of a DTG first-line regimen (n = 41)

- Treated in median since 0.4 years (IQR = 0.2 - 0.7)

- Median VL at VF: 2.7 log10 c/ml (IQR = 2.1 - 4.4)

- No major INI resistance mutation at VF

- Mutations detected at VF: L74M (n = 1) and E157Q (n = 2)

INI resistance interpretation (%)

ANRS study: INI resistance prevalence in patients experiencing a VF with an INI (2)

Marcelin et al., HIV Glasgow 2016, Abs. O332

• E157Q and L74M are polymorphisms naturally present in some ARV-naïve patients

• Prevalence of 5 % in chronically-infected ARV-naïve patients

• Differential distribution of the E157Q polymorphism among HIV-1 subtypes: Subtype B: 2.3 %, CRF02_AG: 7.5 %

• Selected in vivo in patients failing RAL-based treatment

• Case report of a non virological response to a DTG-based regimen

Malet et al., Antimicrob Agents Chemother, 2008

E157Q mutation: polymorphic and acquired

J Antimicrob Chemother, 2009

Assoumou et al., IAS 2017, Abs. TUPEC0851

Danion et al., J Antimicrob Chemother, 2015

Saladini et al., EHDRW 2017, Abs. 72

E157Q mutation: in vitro analysis

- 3 fold increase of the strand-transfer activity

- 9 fold factor of resistance compared with WT virus

• Virus from the non response to a DTG-based regimen

Danion et al., J Antimicrob Chemother, 2015 Saladini et al., EHDRW 2017, Abs. 72

• Phenotypic analysis of 7 clinical isolates

- 1 virus at the limit of the RAL biological cut-off (FC=1.5)

- All 7 clinical samples susceptible to DTG

Role of the E157Q polymorphism not clearly elucidated

INI acquired drug resistance

• The rate of selection of resistance mutations at time of VF is not so high, between 26 % and 39 % in the US and French studies

• Do we know everything on INI resistance mechanisms ?- Rare resistance profiles ?- Genotypic determinants of resistance outside integrase ?

• These data show that G118R and F121Y represent new RAL resistance pathways that may also be involved in DTG resistance

Fold Change to RAL and DTG

EC50 values were obtained from cell culture assays and IC50 values were obtained from assays using recombinant IN proteins. Each value represents the mean+SD for three independent experiments.

106

105

104

103

102

105 6 9 12 2 2

2016

0

400

200

600

100

700

500

300

120152014

7 8 10 11 1 3 4 5 6 7 8 9 10 11 12

RALTDF/FTC

DRV

VL (c/mL)CD4 (/mm3)

IN: L74FV75I

IN: L74V-V75I I60M-V72I

IN: WT

RAL EVG DTG CAB

L74F 1.5 2.3 0.4 0.7

V75I 0.7 1.2 0.5 0.7

L74F-V75I 4.5 8,1 0.3 1.0

I60M-L74F-V75I 3.7 12 0.5 0.7

V72I-L74F-V75I 11 17 0.5 1.5

I60M-V72I-L74F-V75I 3.9 15 0.3 1.0

Newly described and rare resistance RAL pathways

J Antimicrob Chemother, 2015 Hachiya et al., CROI 2017, Abs. 496

Mutations L74F and V75I: a case report

• Codons that may indirectly affect the Mg2+ coordination position

• The I60M mutation restores the viral RC

lemeilleur

…de la CROI 2017

A high level of resistance to DTG associated with mutations outside integrase

• Objective: in vitro selection experiments but under very high concentrations of DTG ( 500 nM) in order to force the virus to select DTG resistance

• Results– Detection of resistant virus between M2 and M3 of culture

– Integrase sequencing: no emergent mutation

– Whole genome sequencing: mutations in 3’PPT region (nef gene)

Position 9053 // 9068 9069 9070 9071 9072 9073

Reference

sequenceC // G G G G G G

Mutant virus

sequenceT // G C A G T -

Malet et al., CROI 2017, Abs. 499

5’AAAAGAAAAG(G9069C)(G9070A)G(G9072T)(G9073del)0.010

0.1 1 10 100 1 000

50

100 3’ PPT mutated virusWild-type virus

DTG (nM)

• In vitro analysis– High level of resistance to DTG but also RAL and EVG associated with low viral RC (10 %)

– Able to produce newly infections of MT4 cells

• Conclusion: mutations selected in vitro by DTG and located outside the integrase gene can confer

themselves very high-level of resistance to all known INI

Transmitted drug resistance to INI

IN mutations

Assoumou et al., IAS 2017, Abs. TUPEC0851

• National epidemiological survey (ANRS virology network, n = 33 centers, n = 597 patients)

• Chronically-infected ARV-naïve patients diagnosed between October 2015 and March 2016

• Two patients with transmission of major INI resistance mutations (Q148)

• High prevalence of INI transmitted drug resistance mutations

• Pre-therapeutic integrase resistance testing is recommended in France

TDR prevalence by drug class

• : IAS list** : IAS list + E157Q

%

%

Plan





formerly GSK1265744

lemeilleur

…de VIH 2016

In vitro activity of bictegravir (BIC) against INI-resistant viruses

White et al., EWHDR 2016, Abs. O-01

Susceptible Resistance

FC < 2,5 2,5 < FC < 10 FC > 10

+E138K

+G163K

143+E138K

+E138K

+L74M+E138K

+E138K

+T97A

+L74M

+E138A

+T97A

WT

Q148H/R + G140A/C/S + 1Susceptible Reduced susceptibility Resistance

FC < 2,5 2,5 < FC < 10 FC > 10

143143

Q148H/R + G140A/S

WT

Susceptible Resistance

FC < 2,5 2,5 < FC < 10 FC > 10

143 92E92Q

F121Y

Y143R

143Y143R

143N155H

Y143C

143T97A

92E92Q

WT

Single mutantSusceptible Resistance

FC < 2,5 2,5 < FC < 10 FC > 10

143155H+163R

143

92Q+157Q

97A+74M

143C+68V

143R+68,74

155H+74M

155H+157Q

148R+138A

148R+138K

WT

Double mutant

BIC

DTG

EVG

RAL

Reduced susceptibility



lemeilleur

…de la CROI 2017

Phase 2 trial comparing BIC versus DTG (+ TAF/FTC) in first-line - Week 48 results

VL < 50 c/mL, ITT snapshot

Sax et al., CROI 2017, Abs. 41 ; Lancet HIV 2017

VL < 50 c/mL; difference, % (95 % CI)

-6 18,8

6,4

-8,5 14,2

2,9

-12 % 12 %

W24

W48

0

Favors

DTG + FTC/TAF

Favors

BIC + FTC/TAF

BIC + FTC/TAF (n = 65)

DTG + FTC/TAF (n = 33)

97

30

97

2 2

94

60

91

63

0

20

40

60

80

100

Virological

success

Virological

failure

No data Virological

success

Virological

failure

No data

W24 W48

• No NRTI or INI resistance detected

• Change in CD4/mm3 at W48: + 258 vs + 192 (p = 0.16)

lemeilleur

…de la CROI 2015

Dudas et al., IHDRW 2015, Abs. 13

• LATTE trial: RCT assessing the efficacy of a dual-therapy in maintenance with RPV + CAB (10 mg,

30 mg or 60 mg) IM

Mutation CAB DTG RAL EVG

Y143C 1.1 0.95 3.2 1.5

Y143H 1.1 0.89 1.8 1.5

Y143R 1.4 1.4 16 1.8

Q148H 0.86 0.97 13 7.3

Q148K 5.6 1.1 83 > 1 700

Q148R 5.1 1.2 47 240

N155H 0.99 1.2 11 25

Phenotypic susceptibility to INI of SDM

(Fold-change)

Highest FC to Q148K/R viruses with CAB than with

DTG (factor 4), suggesting that CAB might be more

impacted by the Q148K/R than DTG

Plasma VL (log10 c/mL)

LATTE trial: resistance analysis of a VF in the CAB 10 mg + RPV arm at W48

481

2

3

4

5CAB +

TDF/FTC

CAB +

RPV

Q148R INT

E138Q RT

Weeks0 12 24 36

Sub-optimal plasma concentrations of CAB and RPV

lemeilleur

…de la CROI 2017

• Objective: modeling in the macaque the risk of emergence of resistance associated with the

initiation of CAB LA during a recent undiagnosed HIV infection

• Methods

– 6 Rhésus macaques

– Infection by intravenous of RT-SHIV virus with SIVmac239 integrase

– 3 monthly IM injections of CAB LA at the dose of 50 mg/kg

ELISA+

RNA RT-SHIV+

CAB LA injectionsRT-SHIV

Infection

M1 M2

Radzio et al., CROI 2017, Abs. 84

Resistance analysis in macaques treated with CAB LA during primary infection (1)

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…de la CROI 2017

Macaque # Integrase mutations1st day of resistance

mutations detectionCompartment

10D181 E92Q-Q124R-G140R 81Blood, rectum,

vagina

35451 E92G 143 Blood

CH54 G118R-A122T 57 Blood, rectum

01D520 None - -

33996 A122T 162 Blood

CJ92 I72T-S135A 32 Blood

E92Q: SIV (EVG: FC ≅ 4; CAB: FC = 2-4); HIV-1 (RAL: FC > 5; DTG: FC > 30)

E92G: SIV (not described); HIV-1 (EVG: FC ≅10)

G118R: SIV (DTG: FC = 11; RAL: FC = 3; EVG: FC = 10); HIV-1 (DTG, RAL and EVG: FC = 5-20)

Phenotypic tests ongoing

• Conclusions

– Frequent selection of resistance

– Presence of resistant viruses in compartments (rectum, vagina) risk of resistance transmission

Resistance analysis by INT sequencing

Resistance analysis in macaques treated with CAB LA during primary infection (2)

Radzio et al., CROI 2017, Abs. 84

To summarize:


- Low genetic barrier to resistance

- Cross resistance +++

- Selection of mutations in 40 % of VF


- Higher genetic barrier to resistance than RAL/EVG but not a PI (cfmonotherapy strategy)

- bid dosing is required after a VF under INI first generation

- Q148+G140 double mutants, most prevalent mutants at VF, showed an increased phenotypic FC to DTG

VirologyPr Diane Descamps

Dr Charlotte Charpentier

Dr Florence Damond

Dr Nadhira Houhou-Fidouh

Dr Houria Ichou

Dr Lucile Larrouy

Dr Vincent Mackiewicz

Dr Marine Perrier

Dr Benoit Visseaux

Dr Quentin Le Hingrat

Mélanie Bertine

Gilles Collin

Alice Mariaggi

Sarah Peerbaccus

Alexandre Storto

Infectious DiseasesPr Yazdan Yazdanpanah

Pr Elisabeth Bouvet

Pr Sophie Matheron

Pr Patrick Yéni

Dr Véronique Joly

Dr Roland Landman

Dr Sylvie Lariven

Dr Xavier Lescure

Dr Christophe Rioux

Dr Paul Loubet

Clinical PharmacologyDr Gilles Peytavin

Dr Minh Lê

Clinical trials Dr Bao-Chau Phung

Dr Adriana Pinto Dr Ornella Cabras

Cindy GodardDjamila Rahli

Françoise LouniMalikhone Chansombat

Zelie Julia

Documents

Resistance Characteristics of Integrase Inhibitorsregist2.virology-education.com/2017/2GlobalHCF/02_Charpentier.pdf · Dr Charlotte CHARPENTIER Laboratoire de Virologie Hôpital Bichat-Claude