the majority of women with human immunodeficiency virus 1 ( hiv ) are of reproductive age and may use an efavirenz- ( efv- ) containing antiretroviral ( arv ) regimen [ 1 , 2 ] . efv is a nonnucleoside reverse transcriptase inhibitor ( nnrti ) indicated in combination with other antiretroviral agents for the treatment of hiv . efv is an fda pregnancy category d drug based on animal studies and human case reports of fetal neural tube defects [ 36 ] . pregnancy rates for hiv - infected women range from 6.0 to 8.2 pregnancies per 100 person - years , and in 2001 , 49% of all pregnancies in the united states were unintended [ 79 ] . women with hiv not desiring pregnancy are advised to use dual methods of contraception to prevent pregnancy and hiv transmission to their partners . some women use emergency hormonal contraception to prevent pregnancy after unprotected sex or contraceptive failure ( condom breakage ) . plan b is a levonorgestrel- ( lng- ) containing emergency contraceptive pill indicated for pregnancy prevention following unprotected intercourse or a known or suspected contraceptive failure . it is taken as soon as possible within 72 hours after unprotected intercourse either as a single dose ( lng 1.5  mg ) or as two doses ( 0.75  mg ) taken twelve hours apart . lng use for emergency hormonal contraception has been shown to reduce pregnancy rates by 85% . few data are available on the pharmacokinetics ( pk ) of progesterone - based contraceptives with nnrtis . a study of depomedroxyprogesterone acetate ( dmpa ) depot injections in hiv - infected women on antiretroviral therapy revealed no significant change in plasma levels of mpa or efv , nevirapine , or nelfinavir . however , in a study of efv and the combination oral contraceptive pill orthotricyclen - lo and orthocyclen ( 25  mcg ethinyl estradiol plus 0.180.25  mg norgestimate ) , lng area under the concentration time curve from 0 to 12 hours ( auc12 ) , maximum concentration ( cmax ) , and minimum concentration ( cmin ) were decreased by 80% , 83% , and 86% , respectively . a case of contraceptive failure with ectopic pregnancy in an hiv - infected woman occurred with the etonogestrel contraceptive implant and efv . subjects were hiv - seronegative women ages 1845 years with normal body mass index and no recent use of hormonal contraceptive agents ( oral or vaginal hormonal contraception use within 60 days or injectable hormonal contraception use within 180 days of study entry ; subjects with mirena iud were excluded ) or other medications / therapies known to interact with efv . subjects who had not undergone surgical sterilization used 2 nonhormonal types of contraception throughout the study period and for 2 weeks following study completion . the protocol was approved by the institutional review board at participating sites , and informed consent was obtained from each woman before participation . this was a prospective , open - label , single - arm , two - period , pk equivalence study . the primary objective was to compare plan b lng auc12 prior to and during steady - state efv . secondary objectives included ( 1 ) characterization of other lng plasma pk parameters , ( 2 ) assessment of the safety and tolerability of coadministration of plan b and efv , and ( 3 ) evaluation of potential effects of lng on efv auc24 with comparison to previous data in hiv+ women . study participants received lng 0.75  mg at time 0 and 12 hours at baseline ( visit 1-day 0 ) and after steady state efv dosing ( visit 2-day 17 ) . subjects were begun on efv 600  mg at bedtime on empty stomach 72 hours after visit 1 for a total duration of 14 days . participants fasted at least 12 hours prior to the pk study visits and ate a standardized breakfast with lng dosing ( 600  kcal ; 15% protein , 30% fat , and 55% carbohydrates ) . serial blood ( plasma ) sampling for lng pk analysis was performed after lng dosing at 0 ( predose ) , 2 , 3 , 4 , 6 , 8 , 10 , and 12 hours at visit 1 and 2 . blood ( plasma ) sampling for efv pk analysis was performed prior to lng dose , 6 and 12 hours after lng dose at visit 2 only ( corresponding to approximately 10 , 16 , and 22 hours from efv dosing ) . relevant clinical adverse events were assessed at study and 4 telephone visits ( study days 4 , 11 , 16 , and 2028 ) . safety and laboratory profiles and pregnancy testing were performed at screening and visits 1 , 2 ( lft 's only ) , and 3 . efv adherence was assessed by subject self - report at telephone visits approximately 7 and 17 days after efv was initiated . lng plasma concentrations were determined with a liquid chromographic assay with ms / ms detection linear in the range of 5025000  pg / ml . efv plasma concentrations were determined using a validated hplv / uc method linear in the range of 2020,000  ng / ml . accuracy and precision were within 15% with 0.2  ml plasma . samples were frozen and shipped to ppd , inc . for lng analysis and university of colorado pharmacology lab for efv analysis . sample size calculations assumed that expected lng auc12 was 123.1  nghr / ml with a standard deviation of 50.1 . assuming equal variances and a modest correlation of 0.5 , the standard deviation of the difference is also 50.1 . 18 subjects were required to detect a difference of 49.2 ( a 40% change ) in lng auc12 using a two - sided , paired t - test with a significance level of 0.05 and 97.5% power . to account for drop - outs lng pk was determined by noncompartmental methods ( winnonlin v5.2.1 , pharsight corporation , mountain view , ca ) . lng auc12 was calculated with the linear - log trapezoidal rule and lng cmin , cmax , and time to cmax ( tmax ) determined visually . lng half - lives ( t1/2 ) were calculated as 0.693 divided by z , where z was the terminal elimination rate constant . lng total apparent oral clearance ( cl / f ) was determined as dose divided by auc12 . apparent volume of distribution ( v / f ) was determined by cl / f divided by z . a post hoc bayesian approach ( nonmem vvi ) was used to estimate each subject 's efv auc24 based on the three measured efv levels . the estimated auc24 was compared to data from a previous pk study of hiv+ women using a 2-sample t - test . for the primary hypothesis , equivalence was defined as a decrease of less than 40% lng auc12 after addition of efv based on previous studies utilizing a 40% difference in contraceptive steroid hormone auc as that which is clinically relevant . the null hypothesis of equivalence was rejected if the corresponding 95% confidence interval included values 40% . point estimates and 90% confidence intervals for geometric means of lng auc12 , cmax , cmin , v / f and cl / f , and t1/2 were determined for lng dosed alone and with efv . geometric mean ratios ( gmr ) for lng auc12 , cmax , and cmin with versus without efv were calculated . evaluable pk data was generated for 21 women who had a mean age of 31 years ( range 2145 ) and bmi of 27 ( range 2135 ) . the majority of subjects were white ( 62% ) , and 24% were latina and 10% black . contraception use included condoms , spermicide , diaphragm , abstinence , and intrauterine device . the estimated percent decrease in lng auc12 with efv was 56% ( table 1 ) , and the corresponding 95% confidence interval ( 49% , 62% ) excluded a change of 40% ( p < 0.0001 ) , such that the equivalence hypothesis was rejected . a decrease in lng auc12 of > 40% was observed in 90.5% ( 95% ci : 0.70% , 0.99% ) of women . the geometric mean efv auc24 in combination with lng was 69597  nghr / ml . this value was compared to a previous study of efv pk in hiv - infected females which demonstrated an efv geometric mean auc24 of 61361  nghr / ml ( 90% ci 19076 , 197379  nghr / ml ) ( p  value = 0.35 ) . study participants had a > 95% adherence with efv dosing , and all had detectable efv levels . headache , abdominal pain , diarrhea , and menstrual cycle changes were the most common adverse events occurring in > 10% of subjects after plan b dosing alone . the incidence of abdominal pain , diarrhea , and menstrual cycle changes was decreased , while incidence of fatigue was increased with efv . the occurrence of rash , pruritus , abnormal dreams , and insomnia was similar to previous studies of efv . adverse events were mild ( grade 1 ) to moderate ( grade 2 ) in majority and were resolved at follow - up visits . one subject had a grade 2 rash likely related to study treatment ( efv ) and resolved at follow - up visits . one subject had grade 3 syncope not related to study treatment and attributed to a vasovagal reaction with phlebotomy . data are limited regarding the use of hormonal contraception in hiv - infected women on antiretroviral therapy . interactions have been described between steroid hormones and both protease inhibitors and nnrti which could lead to decreased protection from pregnancy or increased contraceptive side effects . previous studies have focused predominantly on combined oral contraceptive pills , injectable dmpa , and one small study evaluated pk with the transdermal contraceptive patch [ 12 , 13 , 18 ] . women taking efv are specifically advised to avoid pregnancy due to this agents ' potential role in fetal neural tube defects [ 3 , 19 ] . thus , emergency hormonal contraception , like plan b , may be even more important for these women . we sought to evaluate the effect of efv on plasma concentration of lng in plan b in healthy hiv - negative women . we found that pretreatment with efv for 14 days was associated with a 56% , 41% , and 67% decrease in lng auc12 , cmax , and cmin , respectively . efv is an inducer of cyp3a and uridine - diphosphate glucuronosyl transferases ( ugts ) in vivo . lng exposures are reduced approximately 40% with the anticonvulsants phenytoin and carbamazepine ( inducers of cyp3a ) and 19% with lamotrigine ( an inducer of glucuronidation enzymes ) [ 20 , 21 ] . a study of rifampin and oral contraception demonstrated considerable reduction in contraceptive hormone levels ; however , ovulation suppression persisted . these findings may have important ramifications with regard to the efficacy of plan b when taken with this arv . however , the clinical relevance of this finding is unclear as the minimal effective lng plasma concentration is unknown . it is possible the alternate plan b single dosing of lng 1.5  mg would mitigate this effect ; however , this is unlikely given the magnitude of our observed difference . further clinical studies of plan b and efv are thus needed to inform providers of potential need for plan b dosing adjustments for these women . hiv providers ' role in providing family planning services including contraception and preconception counseling is significant given the inherent complexities with hiv and antiretroviral therapy .