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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
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Charlotte Charpentier received honoraria and travel grants from ViiV Healthcare, Janssen-Cilag, Gilead Sciences and MSD
CONFLICTS OF INTEREST
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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
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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 %
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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
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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
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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
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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
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• 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
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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
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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)
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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
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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
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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