Virology LabBichat-Claude Bernard Hospital

UFR Médecine Paris DiderotINSERM UMR 1137- IAME

Paris, France

SEMINAL HIV-1 RNA AND DRUG CONCENTRATIONS IN

DTG + 3TC DUAL THERAPY (ANRS 167 LAMIDOL)

Abstract #5

Charlotte Charpentier, Gilles Peytavin, Charles Burdet, Roland Landman, Minh Lê, Christine Katlama, Gilles Collin, Aida Benalycherif, André Cabié, France

Mentré, Yazdan Yazdanpanah, Diane Descamps, Véronique Joly

Charlotte Charpentier received honoraria and travel grants from ViiV Healthcare, Janssen-Cilag, Gilead Sciences and MSD

CONFLICTS OF INTEREST

INTRODUCTION

• The dual-class therapy containing the integrase strand-transfer inhibitor (INSTI) dolutegravir (DTG) and the nucleoside reverse transcriptase inhibitor (NRTI) lamivudine (3TC) has been evaluated in the Agence Nationale de Recherche sur le sidaet les hépatites virales (ANRS) 167 LAMIDOL trial

• ANRS 167 LAMIDOL was a single-arm, prospective multicentre trial in HIV-1-infected patients who were virologically suppressed on a first-line cART based on two NRTIs and a third agent consisting of a boosted PI, an NNRTI or an INSTI with no previous virological failure

• ANRS 167 LAMIDOL showed an overall success rate at week 48 of 97 % (95 % CI: 94-100)

Phase 1 Phase 2

DTG + 2 NRTIs DTG + 3TC

D0 W48W-8

ANRS 167 LAMIDOL VIROLOGICAL SUB-STUDY

Charpentier C. et al., CROI 2019, Abst. 491

HIV DNAUltra-sensitive HIV RNA

• No significant change in HIV DNA or in plasma residual viremia during the first year of DTG + 3TC

LOQ: 3 c/mLLOD: no PCR signal

USpVLD0

(n = 101)W24

(n = 101) W48

(n = 99)

< LOD 38 % 41 % 49 %

LOD < USpVL < LOQ 30 % 30 % 21 %

OBJECTIVE

The aim of this pharmaco-virological sub-study on seminal plasma of the ANRS 167 LAMIDOL trial was to assess at D0 and W24 of the dual-therapy:

• Total DTG seminal plasma concentrations• Total 3TC seminal plasma concentrations• HIV RNA in seminal plasma

• Total and unbound DTG blood plasma concentrations• Total 3TC blood plasma concentrations• Total HIV DNA• Ultra-sensitive HIV RNA (USpVL)

Seminalplasma

Blood plasma

METHODS

• Quantification of HIV RNA in seminal plasma: COBAS® TaqMan® HIV-1 Test, v2.0 (Roche®) (LOQ = 100 c/mL)

• Quantification of HIV total DNA: PCR kit GENERIC HIV DNA Cell® (Biocentric®) (LOQ = 10 c/PCR)

• Quantification of USpVL:– maximum volume of available plasma was centrifuged,

the pellet was resuspended, and USpVL was determined using COBAS® HIV-1, v2.0– the LOQ depended on the amount of plasma volume available (3 c/mL in 90 %)– the LOD was defined as an undetected PCR signal

• Measurement of plasma or seminal drug concentrations (24 h the last drug intake, Cmin) – UPLC-MS/MS (LOQ < 10 ng/mL for DTG and 3TC/FTC) 1

– DTG blood plasma protein binding was obtained using ultrafiltration assay (Millipore Centrifree®)

– interpretation was made according to in vitro protein-adjusted IC95(PA-IC90) for WT HIV:PBIC90 DTG = 64 ng/mL

2 and adequate plasma 3TC Cmin = 100 - 200 ng/mL3

and FTC = 90 +/- 70 ng/mL3

1. Jung et al., Biomed Chromatogr BMC, 2007; 2. Min et al., AIDS, 2011; 3. 3TC/FTC Summary Product Information

PATIENTS CHARACTERISTICS (n = 104)

Characteristic Value

Male, n (%) 89 (86)

Age, years, median (min – max) 45 (24 – 71)

Mode of transmission, n (%)MSMHeterosexualPeople Who Inject Drugs

73 (70)29 (28)

2 (2)

Time since HIV diagnosis, years, median (min – max) 6.2 (2.3 – 24.5)

Nadir CD4 cell count, /mm3, median (min – max) 339 (203 – 1 155)

CDC stage, A/B/C 88% / 9% / 4%

cART duration, years, median (min – max) 4.5 (2.0 – 11.0)

Time on current cART, years, median (min – max) 4.0 (0.5 – 11.3)

NRTI backbone (FTC-TDF / ABC-3TC) 76% / 24%

Duration of VL < 50 c/mL, years, median (min – max) 4.2 (2.0 – 9.1)

CD4 cell count at enrollment, /mm3, median (min – max) 743 (373 – 1 571)

Third agent in cART at screening, n (%)NNRTIPIINSTI

RAL/EVG/DTG

58 (56)24 (23)22 (21)8/7/7

RESULTS – HIV RNA DETECTION IN SEMINAL PLASMA (1)

• Among the 104 enrolled patients, seminal plasma samples were collected from 18 participants, including 16 paired samples at D0 and W24 of DTG + 3TC

• HIV RNA was detected in seminal plasma of 3 patients (patients received a DTG-based triple-therapy regimen during 8 weeks before switching to DTG + 3TC):

• Concomitant USpVL was below the LOD in all 3 cases

• These 3 patients did not experienced virological failure or plasma viral blip along the study and had no concomitant sexually transmitted infection

1 patient at D0 of DTG + 3TC → 5.9 % (95 % CI: 0.1 – 28.6)

2 patients at W24 of DTG + 3TC→ 11.8 % (95 % CI: 1.5 – 36.4)

Patient ID

Seminal plasma HIV RNA (c/mL)

Ultra-sensitive plasma viral load (c/mL)

Blood HIV DNA(log10 c/10

6 PBMC)

D0 W24 D0 W24 D0 W48

# 1 475

• All 3 participants, except one, presented a DTG Cmin in seminal plasma above the in vitro protein-binding adjusted PA-IC90 DTG (i.e. 64 ng/mL)

• As expected, 3TC/FTC demonstrated a good penetration in seminal compartment

Patient ID

Seminal plasma HIV RNA (c/mL)

DTG Blood Plasma Cmin

DTG Seminal Plasma Cmin

XTC Blood Plasma Cmin

XTC Seminal Plasma Cmin

D0 W24 D0 W24 D0 W24D0

(FTC)W24 (3TC)

D0 (FTC)

W24 (3TC)

# 1 475

RESULTS – DTG CONCENTRATIONS

• Median total DTG blood plasma Cmin was 1 838 ng/mL (IQR = 1 207 – 2 336; n = 34)

• Median total DTG seminal plasma Cmin was 198 ng/mL (IQR = 94 – 239; n = 34)

• The unbound blood plasma/total DTG blood plasma Cmin ratio was 0.21 % (IQR = 0.17 – 0.25 %; n = 29)

PA-IC90

RESULTS – 3TC/FTC CONCENTRATIONS

FTC D0 3TC W24 FTC D0 3TC W2410

100

1000

5000

BLOOD SEMINAL PLASMA

• Median FTC blood plasma Cmin was 172 ng/mL (IQR = 113 – 282; n = 18)

• Median 3TC blood plasma Cmin was 69 ng/mL (IQR = 40 – 112; n = 18)

• Median FTC seminal plasma Cmin was 1 480 ng/mL (IQR = 447 – 1 857; n = 18)

• Median 3TC seminal plasma Cmin was 967 ng/mL (IQR = 5957 – 1 857; n = 18)

good penetration in seminal plasma

(X)TC concentrations (ng/mL)

DTG, 3TC AND FTC SEMINAL PENETRATION

0.10

8.8

19.8

Seminal/Plasma Cmin Ratio

Moderate seminal DTG penetration

Good seminal 3TC/FTC penetration

0.1 1 10 100

Total 3TC

Total FTC

Total DTG

CONCLUSIONS

- No significant difference in the proportion of patients with HIV RNA detection in semen between sampling when receiving triple class-therapy and sampling at W24 of DTG + 3TC dual-therapy

- Results in accordance with the study of Gianella et al. (J AIDS, 2018) conducted in ASPIRE and ACTG 5353 trials (DTG + 3TC)

- Lower DTG Cmin in seminal than in blood plasma (10-fold); however, DTG seminal exposure was higher than the free drug concentration in blood plasma, suggesting that drug uptake transporters in addition to passive diffusion of unbound drug may be implicated in DTG penetration in the male genital tract

- Results in accordance with the study of Imaz et al. in patients initiating a DTG-based first-line triple-therapy (J Infect Dis., 2016)

- Good penetration of 3TC/FTC in seminal plasma

• Virology

• The data of this PK/virological sub-study are reassuring regarding DTG + 3TC dual-class therapy in terms of male genital tract reservoir

• Pharmacology

VirologyPr Diane Descamps

Dr Charlotte Charpentier Dr Benoit Visseaux

Dr Florence DamondDr Nadhira Houhou-Fidouh

Dr Houria IchouDr Lucile Larrouy

Dr Vincent MackiewiczDr Quentin Le Hingrat

Dr Valentine FerréMélanie Bertine

Gilles CollinAlexandre Storto

Infectious DiseasesPr Yazdan Yazdanpanah

Pr Sophie MatheronPr Xavier Lescure Dr Véronique Joly

Dr Jade GhosnDr Roland Landman

Dr Sylvie LarivenDr Christophe Rioux

ClinicalPharmacologyDr Gilles Peytavin

Dr Minh Lê

Clinical trials Dr Bao-Chau Phung

Dr Antoine BachelardDr Valentina Isernia

Sylvie Le GacCindy Godard

Françoise LouniMalikhone Chansombat

Zelie Julia

ANRS 167 LAMIDOLinvestigatorsand patients