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Raltegravir Concentrations in the Cervicovaginal Compartment Exceed the Median Inhibitory Concentration in HIV-1-infected Women Treated with a Raltegravir-containing Regimen: DIVA 01 Study
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Reported by Jules Levin
CROI 2010 Feb 16-20 SF
"The penetration of RAL into the genital tract was good in HIV-infected women, confirming a previous report in 7 HIV-negative females. The median RAL CVF concentration was approximately 16-fold higher than the IC95 on wild type HIV-1 in this study, likely contributing to virological control in the compartment."
Cyril Clavel1, L Mandelbrot2, A-G Marcelin1, C Crenn-Hebert2, I Heard1, F Bissuel3, H Ichou2, C Ferreira2, R Tubiana1, and G Peytavin4
1INSERM U943, Hosp Pitie-Salpetriere, Paris, France; 2Hosp Louis Mourier, Colombes, France; 3Hosp André-Bouron, Saint-Laurent-du-Maroni, Guyane, France; and 4Hosp Bichat Claude Bernard, Paris, France
ABSTRACT
Background: There is concern about the penetration of new drugs including integrase inhibitors into the female genital tract, which may impact sexual and vertical transmission as well as antiretroviral drug resistance. The objective of this study was to evaluate the penetration of raltegravir (RAL) into the cervicovaginal fluids and the concurrent intragenital HIV1-RNA concentration in HIV-1 infected women.
Methods: HIV-1 infected women over 18 years old receiving a stable RAL (400 mg bid)-containing antiretroviral therapy with good adherence and a plasma HIV-RNA <40 copies/mL for at least 3 months were enrolled with informed consent. Paired samples of blood plasma and cervicovaginal fluids were collected. Intervals between last drug intake and sampling were recorded. Cervicovaginal fluid sampling using blotting papers was performed in the absence of menstruation, sexual intercourse or intra-vaginal treatment within the last 2 days. Screening for genital tract infections was performed at time of sampling. HIV-RNA was determined (Roche Taqman) in blood plasma and cervicovaginal fluid with limits of detection of 40 and 200 copies/mL, respectively. RAL blood plasma and cervicovaginal fluid concentrations were measured at steady-state using UPLC-MS/MS method (Acquity UPLCÒ - Acquity TQDÒ) after sample pretreatment (LOQ ∼ 1 ng/mL). Results are presented as median (IQR 25% to 75%).
Results: Fourteen women were enrolled. None of the participants was pregnant; the median age of participants was 43 (33 to 64) years, and median CD4 lymphocyte count was 463/mL (122 to 1325). The duration of RAL treatment was 292 (49 to 490) days. RAL was associated with a median of 3 other antiretroviral drugs (1 to 6), including darunavir/r in 7, etravirine in 5, maraviroc in 4 cases, and 10/14 regimens contained NRTI. At the time of sampling, all patients had undetectable cervicovaginal fluid HIV-RNA despite evidence of genital infection for 3 of them and a low HIV replication detected in blood plasma in 2 others (88 copies/mL and 169 copies/mL). RAL concentrations, determined 13.6 (13.0 to 14.5) hours after the last drug intake, were 93 (48 to 167) ng/mL in blood plasma and 235 (135 to 775) ng/mL in cervicovaginal fluid. Within patient variability of RAL concentrations were 127% in blood plasma and 176% in cervicovaginal fluid.
RAL concentrations in cervicovaginal fluid were about 2.3 fold those in blood plasma.
Conclusions: The penetration of RAL into the genital tract was good in HIV-infected women, confirming a previous report in 7 HIV-negative females. The median RAL CVF concentration was approximately 16-fold higher than the IC95 on wild type HIV-1 in this study, likely contributing to virological control in the compartment.
REFERENCES
1 Jones AE,et al. First-Dose and Steady-State Pharmacokinetics of Raltegravir in the Genital Tract of HIV Negative Women10th International Workshop on Clinical Pharmacology of HIV Therapy. Amsterdam, Netherlands. April 15-17, 2009. Abstract 0-06.
2 Iwamoto, M., et al. Safety, tolerability, and pharmacokinetics of raltegravir after single and multiple doses in healthy subjects. Clin. Pharmacol. Ther. 83:293–299.
3Dumond JB, et al. AIDS 2007; 21: 1899–907
4Merck & Company FDA Approves Isentress (raltegravir) Tablets, First-in-Class Oral HIV-1 Integrase Inhibitor [Press Release], October 12, 2007. Available at: http://www.isentress.com/raltegravir/isentress/hcp/news/product_news1.jsp. Accessed 02/06/09. 5Cianfriglia, M., M. L. Dupuis, A. Molinari, A. Verdoliva, R. Costi, C. M.Galluzzo, M. Andreotti, A. Cara, R. Di Santo, and L. Palmisano. 2007.HIV-1 integrase inhibitors are substrates for the multidrug transporter MDR1-P-glycoprotein. Retrovirology 4:17.6Ménard A, et al. Etravirine–raltegravir, a marked interaction in HIV-1-infected patients: about four cases AIDS.2009 Apr 27;23(7):869-71
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