HIV-1-infected Males and Females under Less-Drug Regimens Achieve Antiretroviral Levels above the Inhibitory Concentration in the Genital Tract. Sandrine LEFEUVRE, Julie BOIS-MAUBLANC, Camélia GUBAVU, Barbara DE DIEULEVEULT, Jennifer BURET, Thomas FRANCIA, Christine ROUZIOUX, Laurence GOT, Thierry PRAZUCK, Véronique AVETTAND-FENOEL, Laurent HOCQUELOUX.
BACKGROUND For patient with a long term control of HIV, there is a growing interest to reduce the dosage and the number for antiretrovirals (ARV) (less-drug regimens (LDR)) in order to decrease: side effects toxicity drug-drug interactions But lack of data on the impact of LDR on concentrations in the genital compartment and the risk of sexual transmission We realized a study on the virologic and pharmacological impact of LDR. (L. Hocqueloux et al. IAS 2017 (Paris)) PK LDR versus triple therapy
STUDY DESIGN Recruitment of patients in 3 studies: - 2 randomized controlled trials - 1 cohort with uatv DTG vs DTG/ABC/3TC TDF/FTC vs TDF/FTC/3td agent** uatv + DTG LDR: 4 strategies uatv + 2 NRTI* Study: TDF, FTC, uatv, DTG, ABC, 3TC * TDF/FTC or ABC/3TC ; ** IP/r or NNRTI or INSTI
STUDY DESIGN Monocentric and prospective study Inclusion criteria - Bellow 50 cop/ml for 12 months Classic triple therapy - Abacavir (ABC) + lamivudine (3TC) + DTG - TDF + FTC + (NNRTI / boosted IP / integrase inhibitor) At least 6 months Classic tritherapy for Long term (median 4 years) LDR 4 strategies - dolutegravir (DTG) - tenofovir (TDF) + emtricitabine (FTC) - unboosted atazanavir (uatv) + DTG - unboosted atazanavir (uatv) + (TDF + FTC) Concomitant genital and blood samples were collected: to assess HIV-RNA and HIV-DNA levels to measure ARVs concentrations (C 24h )
METHODS of WITHDRAW and ANALYSIS just before the next drug intake = residual situation Blood and semen samples Blood samples and vaginal lavage (injection of 6mL of saline solution into the posterior fornix and withdrawal after 1 minute). HIV-RNA and HIV-DNA levels were assessed using an ultrasensitive assays adapted from Roche and Biocentric kits ARV concentrations were measured using LC- MS/MS (5500 QTRAP) Because of the dilution of the vaginal lavage, vaginal concentrations were corrected by the method of urea.
RESULTS : PATIENTS 84 patients (M/F=1) LDR n=58 Control n=26 vs DTG = 20 DTG/ABC/3TC = 14 vs TDF/FTC = 13 TDF/FTC/3td = 12 uatv + DTG = 14 uatv 300 mg OAD time of sample withdrawal after drug intake = 23h (IQR: 20-24) uatv + 2NRTI = 11 Comparable for age, sex, CDC stage, CD4 nadir, HIV-DNA in PBMC, viral load, duration with undetectable viral load
RESULTS : PLASMA CONCENTRATION in all patients LDR (ng/ml) LDR IQR Triple therapy Triple Therapy IQR TDF 80 50-110 65 54-90 FTC 93 63-237 89 55-183 uatv 119 65-270 - 55-172 DTG 1630 1070-3830 1220 875-2015 ABC 8 0-27 2 0-48 3TC 110 48-210 100 53-145 No difference between Males and Females (data not shown) * * No difference between LDR and control group EXCEPT for DTG with higher concentrations when uatv is coadministered Low ABC concentration
RESULTS : GENITAL CONCENTRATIONS FOR WOMEN LDR (ng/ml) LDR IQR Triple therapy Triple Therapy IQR TDF 14 9-66 11 2-35 FTC 54 24-164 58 31-127 uatv 13 4-20 - DTG 20 3-168 2 1-6 ABC 1 1-62 4 1-14 3TC 22 11-51 52 23-115 - No difference between LDR and control group except for DTG with higher concentration in LDR group (DDI: DTG is associated with uatv)
RESULTS : GENITAL CONCENTRATIONS FOR MEN LDR (ng/ml) LDR IQR Triple therapy Triple Therap y IQR TDF 46 7-315 259 17-380 FTC 25 12-337 109 54-392 uatv 14 6-20 - 7-30 DTG 43 13-119 78 27-116 ABC - - 19 15-23 3TC 11-455 160-760 - Lower median concentrations in LDR group for all drugs compared to triple therapies
RESULTS : GENITAL CONCENTRATIONS: MEN vs WOMEN LDR group Tritherapy IC50 Women Men Women Men * TDF 11 14 46 11 259 FTC 2 54 25 58 109 uatv 1,41 13 14 - - DTG 0,3 20 43 2 78 ABC 74 1-4 19 3TC 0,45 22 11 52 455 - In triple therapy group, genital concentrations were lower in women compared to men - In LDR group, the differences are less marked - However, genital concentrations exceeded the IC50 for men and women with an exception for ABC
RESULTS : GENITAL CONCENTRATION and IC50 Genital concentrations exceeded the IC50 for both men and women IC50= 1,41 ng/ml* IC50= 2,0 ng/ml** IC50= 11,0 ng/ml** ATV LDR to 10 fold LDR to 20 fold LDR to 5 fold *Product monograph, Reyataz **Product monograph, Truvada
*Product monograph, Triumeq RESULTS : GENITAL CONCENTRATION and IC50 Genital concentrations exceeded the IC50 for both men and women with an exception for ABC IC50= 0,30 ng/ml* IC50= 0,45 ng/ml* IC50= 74 ng/ml* LDR to 100 fold LDR to 40 fold ABC
RESULTS : GENITAL CONCENTRATION and ARN or ADN GENITAL 4 The VIROLOGIC study is not finished but the first results: 2/3 undetectable (HIV-RNA and HIV- DNA) 1/3 residual viremia Similar residual viremia between LDR and Control group. First results not show a correlation between the genital concentration and the HIV RNA or HIV DNA levels. ARV above IC50 3 2 1 0 RNA and/or DNA pos RNA and/or DNA neg HIV detection in the genital tract
CONCLUSION Plasma = No difference between LDR and control group LDR leads to plasma concentration in a therapeutic range Genital in women = No difference between LDR and control group. Genital in men = Lower median concentration in LDR group for all drugs compared to triple herapies. Most patients (regardless of sex and strategy) have concentrations sufficient to exceed the IC50 except for ABC. First virologic results: No evidence that LDR increases the risk of sexual transmission
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