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POTENTIAL CONCERN FOR TIMING OF DMPA INJECTION AMONG WOMEN TREATED FOR HIV AND TB
Rosie Mngqibisa1, Susan E. Cohn2, Michelle A. Kendall3, Xingye Wu3, Kelly E. Dooley4, Helen Mcilleron5, Jennifer A. Robinson4, Cindy Firnhaber6, Jhoanna C. Roa7, Sharlaa Badal-Faesen8, Francis Angira9, Mpho S. Raesi10, James G. Hakim11, Catherine Godfrey12
1Enhancing Care Foundation, Durban, South Africa,2Northwestern University, Chicago, IL, USA,3Harvard University, Boston, MA, USA,4Johns Hopkins University School of Medicine, Baltimore, MD,5University of Cape Town, Cape Town, South Africa,6University of Colorado, Aurora, CO, USA,7Social & Scientific Systems, Silver Spring, MD, USA,8University of the Witwatersrand, Johannesburg, South Africa,9KEMRI-UCSF, Kisumu, Kenya,10Botswana Harvard AIDS Institute Partnership, Gabarone, Botswana,11University of Zimbabwe, Harare, Zimbabwe,12National Institute of Allergy and Infectious Diseases, Bethesda, MD, USA
Effective contraception is of upmost importance for young women with HIV-associated TB, as unintended pregnancy among such women is associated with increased maternal and infant morbidity and mortality. Rifampicin (RIF) and Efavirenz (EFV) are both inducers of metabolizing enzymes and can reduce concentrations of contraceptive medications. Effects of these drugs on the pharmacokinetics (PK) of depot medroxyprogesterone acetate (DMPA), the most commonly used contraceptive in sub-Saharan Africa (SSA) and globally, are unknown. Safety of concurrent use of these 3 drugs is also unknown. We hypothesized that clearance of MPA would be increased when given with RIF and EFV, potentially resulting in levels of MPA <0.1 ng/mL (levels associated with escape ovulation) prior to 12 weeks post-DMPA dose.
ACTG A5338 was a multicentre, single arm, PK study among women in SSA stable on EFV-based antiretroviral therapy (ART) and RIF-based TB treatment. We determined plasma MPA concentrations pre-dose and 2, 4, 6, 8, 10 and 12 weeks after DMPA 150 mg injection and measured plasma progesterone levels from week 2 onwards. The primary outcome measure was the proportion of women with sub-therapeutic MPA levels (<0.1 ng/mL) at week 12. MPA PK parameters were calculated using non-compartmental methods and compared with historical ART-naïve controls without TB who received DMPA.
Baseline characteristics of the 42 evaluable participants are shown in Table 1. Five women [11.9% (95% CI 4.0-25.6%)] had MPA <0.1 ng/mL at week 12 with one of the five having MPA <0.1 ng/ml at week 10 compared to one of 16 (6,3%) at week 12 among the historical controls. No participant had progesterone levels >5 ng/mL (suggesting ovulation) throughout the study including at week 12. Compared to historical controls, median area under the concentration-time curve over 12 weeks (AUC0-12) was lower (7.63 vs. 12.38 ng*wk/mL, p=0.004) and apparent clearance was higher (19,681 vs. 12,117 L/wk, p=0.004). There were no grade 3 or higher adverse effects attributed to DMPA.
DMPA, when given with EFV-based ART and RIF-based TB therapy, was safe and well tolerated. MPA clearance was higher than in controls, leading to sub-therapeutic concentrations of MPA in some women at 10 and 12 weeks post-dose, though progesterone levels typically associated with ovulation were not observed. It may be prudent to dose DMPA more frequently than every 12 weeks in women on EFV with HIV-associated TB taking RIF.