SEMINAL HIV-1 RNA AND DRUG CONCENTRATIONS IN

DTG + 3TC DUAL THERAPY (ANRS 167 LAMIDOL)

Virology Lab Bichat-Claude Bernard Hospital, UFR Médecine Paris Diderot, INSERM UMR 1137- IAME, Paris, France

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

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 sida et 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 2DTG

+ 2 NRTIs DTG + 3TC

D0 W48W-8

ANRS 167 LAMIDOL VIROLOGICAL PLASMA SUB-STUDY

HIV DNAUltra-sensitive HIV RNA

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

USpVL D0 (n = 101)

W24 (n = 101)

W48 (n = 99)

< LOD 38 % 41 % 49 %

LOD < USpVL < LOQ 30 % 30 % 21 %

<LOQ 29 % 29 % 30 %

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

OBJECTIVEThe 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/mL2 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• 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 à 5.9 % (95 % CI: 0.1 – 28.6)

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

Patient IDSeminal plasma HIV RNA (c/mL)

Ultra-sensitive plasma viral load (c/mL)

Blood HIV DNA(log10 c/106 PBMC)

D0 W24 D0 W24 D0 W48# 1 475 <100 < LOD < LOQ 2.95 2.89# 2 < 100 440 < LOQ < LOD 3.12 2.98# 3 < 100 365 < LOD < LOD 2.42 2.52

• 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

Total drug concentrations (ng/mL) in the three participants with HIV RNA detection in seminal plasma

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 W24 D0 (FTC) W24 (3TC)

D0 (FTC) W24 (3TC)

# 1 475 <100 2 334 1 295 168 243 101 54 1 640 2 928# 2 < 100 440 2 095 1 813 50 283 137 91 1 252 2 267# 3 < 100 365 2 695 2 533 129 191 527 112 447 541

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)

DTG Cmin (ng/mL)

Total D0 Total W24 Total D0 Total W24 Free D0 Free W24

10

100

1000

PBIC 95

5000

BLOOD SEMINAL PLASMA BLOOD

PA-IC90

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

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

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

• Median 3TC seminal plasma Cminwas 967 ng/mL (IQR = 595 – 1 935; n = 18)

good penetration in sem

inal plasma

FTC D0 3TC W24 FTC D0 3TC W2410

100

1000

5000

BLOOD SEMINAL PLASMA

(X)TC concentrations (ng/mL)DTG Cmin(ng/mL)

DTG, 3TC AND FTC SEMINAL PENETRATION

0.10

8.8

19.8

Seminal/PlasmaCmin Ratio

Moderate seminal DTG penetration

Good seminal 3TC/FTC penetration

0.1 1 10 100

C

C

Total 3T

Total FT

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

MOPEB 268

3TC/FTC CONCENTRATIONS

AcknowledgementsWe thank all the participants in the ANRS 167 trial, the patients’ association organizations and the TRT5 group for advice and support, the staff fromthe centres participating in the Lamidol trial and the members of the Data Safety Monitoring Board (Firouze Bani Sadr, Dominique Costagliola, SabineYerly and Jean Claude Alvarez).Members of the ANRS 167 Study GroupHôpital Avicenne, Bobigny: BOUCHAUD, Olivier; Hôpital Bicêtre, Le Kremlin Bicêtre: GOUJARD, Cécile; Hôpital Bichat, Paris: JOLY, Véronique, PHUNG,Bao; Hôpital Hotel Dieu, Paris: VIARD, Jean Paul; Hôpital Européen Georges Pompidou, Paris: WEISS, Laurence; Hôpital Necker, Paris: DUVIVIER,Claudine; Hôpital Pitié-Salpêtrière, Paris: KATLAMA, Christine; Hôpital Saint Antoine, Paris: GIRARD, Pierre Marie; Hôpital Saint Louis, Paris: MOLINA,Jean Michel; Hôpital Saint André, Bordeaux: MORLAT, Philippe; Hôpital Gabriel Montpied, Clermont Ferrand: JACOMET, Christine; Hôpital du Bocage,Dijon: PIROTH, Lionel; Hôpital Pierre Zobda-Quitman, Fort de France: CABIÉ, André; Hôpital Saint Marguerite, Marseille: POIZOT-MARTIN, Isabelle;Hôpital Gui de Chauliac, Montpellier: REYNES, Jacques; Hôpital Hotel Dieu, Nantes: ALLAVENA, Clotilde, BILLAUD, Eric, BOUTOUILLE, David, RAFFI,François, RELIQUET, Véronique; Hôpital de l’Archet, Nice: ROENTHAL, Eric; Hôpital de l’Archet, Nice: NAQVI, Alissa; Centre Hospitalier, Perpignan:AUMAITRE, Hughes; Hôpital Pontchaillou, Rennes: SOUALA, Faouzi; Hôpital Bretonneau, Tours: BERNARD, Louis; Hôpital Purpan, Toulouse: BIEZUNSKI,Noemie; Hôpital Gustave Dron, Tourcoing: AJANA, Faiza; Hôpital de la Croix Rousse, Lyon: MIAILHES, Patrick; Institut Médecine EpidémiologieAppliquée, Paris: AMAT, Karine, BENALICHERIF, Aida, SYLLA, Babacar.

Drugs for this study was provided by ViiV Healthcare »