Vieira, Carolina S. MD, PhD*,†; Bahamondes, Maria V. MD, PhD†,‡; de Souza, Roberto M. PhD§; Brito, Milena B. MD, PhD‖; Rocha Prandini, Tatiana R. MD*; Amaral, Eliana MD, PhD‡; Bahamondes, Luis MD, PhD†,‡; Duarte, Geraldo MD, PhD*; Quintana, Silvana M. MD, PhD*; Scaranari, Carolina MD*; Ferriani, Rui A. MD, PhD*,†
The high unplanned pregnancy rates in many developing and developed countries1 are a public health problem because they negatively influence several indicators of women's health, including maternal mortality.2 This problem is more serious for women infected with human immunodeficiency virus (HIV) because the lack of appropriate contraception may increase vertical transmission rates. Consequently, the promotion of effective contraception in HIV-positive women is one of the 4 basic components of the World Health Organization (WHO) strategy for the prevention of mother-to-child transmission.3
Some countries, including Brazil, have initiated highly active antiretroviral therapy (HAART) early in HIV-positive individuals,4,5 however, its use increases fertility rates in HIV-positive women,6 increasing the need for effective contraception. Nevertheless, contraceptive failure has been observed during concomitant use with some HAART regimens and hormonal contraceptives, particularly combined oral contraceptives (COCs), due to reduced bioavailability.7
Long-acting reversible contraceptives (LARCs), such as etonogestrel (ENG)-releasing implant and intrauterine devices, are a cost-effective strategy for reducing the rate of unplanned pregnancies because LARCs have the highest efficacy and continuation rates among all reversible contraceptives.8,9 The WHO classified ENG implant as category 2 for HAART users (the advantages of using the method generally outweigh the theoretical or proven risks)10; however, to the best of our knowledge, no studies have investigated the coadministration of any HAART agents and the ENG implant. Potential interactions of ritonavir-boosted protease inhibitors and nonnucleoside reverse transcriptase inhibitors with hormonal contraceptives are a major concern.7 Case reports of pregnancy in women using ENG implant and HAART with efavirenz (a nonnucleoside reverse transcriptase inhibitor) have been published.11–14 The ENG implant package insert states that concomitant use with the above-mentioned antiretroviral drugs is not recommended because of lack of safety data.15
Therefore, the primary objective of this study was to evaluate the effect of 2 HAART regimens (1 including efavirenz and the other ritonavir-boosted lopinavir) on the pharmacokinetic (PK) parameters of the ENG-releasing implant in HIV-positive women. The secondary objective was to determine the impact of potential PK interactions among the selected HAART regimens and the ENG-releasing implant on luteal activity.
This was a prospective nonrandomized PK study. The sample group included 15 HIV-positive women treated with 1 standard HAART regimen [zidovudine/lamivudine (AZT/3TC) + lopinavir/ritonavir (LPV/r)] for at least 3 months (LPV/r-based HAART group), 15 HIV-positive women treated with another standard HAART regimen [zidovudine/lamivudine (AZT/3TC) + efavirenz (EFV)] for at least 3 months (EFV-based HAART group), and 15 HIV-positive women who were not undergoing HAART (non-HAART group) because no clinical recommendation for HAART was indicated at the time of recruitment. The recommended criterion for HAART initiation in our country at the time of patient enrollment was a CD4 count <350 cells/mm3.5
The study was conducted at the Clinical Research Unit of the Clinical Hospital of Ribeirao Preto Medical School (HCFMRP) and the Department of Obstetrics and Gynecology, School of Medical Sciences, University of Campinas (UNICAMP), Brazil. Participants were recruited at family planning outpatient clinics and HIV/AIDS treatment centers in these cities from September 2010 to April 2012. The study staff performed an active search of patient files and HAART dispensation pharmacy files in all centers that cared for HIV-positive patients in the 2 cities. Consecutive to presentation to care, patients who met the inclusion criteria were invited to participate in the study. The institutional review board of both institutions approved the study, and all participants signed an informed consent form before inclusion.
Women were required to be HIV positive according to criteria from the Brazilian Health Ministry,16 be aged between 18 and 40 years, have selected the ENG implant as a contraceptive method, have regular menstrual cycles (21–35 days), have a body mass index (kg/m2) between 18.0 and 29.9, and have used AZT/3TC + LPV/r or AZT/3TC + EFV for at least 3 months (HAART groups only) to be included in the study. The exclusion criteria were ENG implant use in women with classification in category 3 or 4 according to the WHO medical eligibility criteria,10 childbirth in the previous 42 days, use of other hormonal methods in the previous 60 days, use of depot medroxyprogesterone acetate injection in the previous 6 months, acute infections or other opportunistic illnesses that required treatment in the previous 30 days, drug or alcohol addiction, noncontrolled clinical diseases, use of drugs metabolized by CYP3A4, chronic diarrhea or malabsorption (HAART groups only), and noncompliance with the HAART regimen (HAART groups only).
Participants were requested to attend an appointment within the first 5 days of their menstrual cycle (or any day after pregnancy was excluded in women with postpartum amenorrhea) after an 8-hour fasting period for the insertion of the ENG-releasing subdermal contraceptive implant (Implanon; MSD, Oss, the Netherlands). Before placement, 20 mL of blood was collected to evaluate the serum ENG concentration, viral load (VL), CD4 and CD8 T-cell counts, and progesterone (P) levels. ENG implants were placed on the internal side of the nondominant arm using a standard technique. All participants were instructed to use condoms throughout the study.
The LPV/r-based HAART group took 1 tablet of AZT/3TC (300 mg/150 mg) twice a day and 2 tablets of LPV/r (200 mg/50 mg) twice a day. The EFV-based HAART group took 1 tablet of AZT/3TC (300 mg/150 mg) twice a day and 1 tablet of EFV (600 mg) once a day. Adherence to the HAART regimens was assessed using a questionnaire about the number of pills not taken per month. VL was also used to assess adherence to the HAART regimens. The anthropometric variables assessed were height, body weight, and body mass index (kg/m2). Smoking, education level, and parity were also assessed.
The study included visits at baseline and 2, 4, 6, 8, 10, 12, 16, 20, and 24 weeks after implant placement. The serum ENG concentration (for the PK study) and P levels were measured during all visits (total of 10 measurements/patient), and the VL and CD4 and CD8 T-cell counts were measured at baseline and 24 weeks after implant placement. The VL and CD4 and CD8 T-cell counts were measured in real time, and serum samples obtained for the assessment of ENG and P concentrations were frozen at −70°C until measurement.
VL was measured using the branched (b)-DNA method, and CD4 and CD8 T-cell counts were performed using flow cytometry. The minimum number of copies detected using the VL device was 50 copies per milliliter. The serum P concentration was measured using chemiluminescence with a DPC Immulite 2000 device (DPC, Los Angeles, CA). Luteal activity indicative of ovulation was defined as P levels ≥5 ng/mL (or 16 nmol/L) according to the standards in a previous study on ENG-releasing implants.17 We also added a lower cutoff (≥3 ng/mL) that could indicate luteal activity.18 Technicians who were blinded to sample groups performed all assays in our laboratories.
For each PK study visit, 10 mL of blood was collected. Serum was separated after spontaneous coagulation, and each sample received a unique code. All samples were frozen at −70°C until shipment to Bioanalytics, Merck Research Laboratories (Oss, the Netherlands), where the ENG samples were analyzed. ENG and its international standard (D6-ENG) were isolated from human serum using liquid–liquid extraction (LLE). Ultra-performance liquid chromatography–mass spectrometry was performed to quantify the concentration of ENG in human serum using a Waters UPLC (ultra pressure liquid chromatography) and Applied Biosystems API5000 MS (mass spectrometer) equipment using positive atmospheric pressure chemical ionization in the multireaction mode. The lower limit of quantification was 50 pg/mL, with a linear calibration range of 50–2000 pg/mL. Standard solutions were prepared in ethanol and stored in a refrigerator at approximately 4°C when not in use. The intra- and interassay coefficients were ≤15% for all quality control samples and standards, except for the lowest standard (at a lower limit of quantification level of 50 pg/mL), which was 20%. The technician responsible for the assays in Oss was blinded to the sample groups.
A sample size of 12 women per study arm was estimated as necessary to detect any difference equal to or greater than 25% between logarithmically transformed (log) areas under the curve (AUCs) at 6 months between the HAART groups (LPV/r-based HAART group and EFV-based HAART group) and the non-HAART group19,20 with a power of 80% and a type I error of 5%. The difference was set at 25% because at lower values, the groups could be bioequivalent and the differences would not have clinical significance.
Categorical variables were assessed using the χ2 test and Fisher exact test. Quantitative variables were compared using a mixed-effects linear regression model, with the exception of VL. The comparisons were adjusted for age because the baseline age differed between groups. VL was analyzed using the nonparametric Wilcoxon (intragroup) or Kruskal–Wallis (intergroup) test. Nonparametric tests were performed using R software (R Foundation for Statistical Computing, Vienna, Austria), and the other statistical tests were performed using SAS 9.0 software (SAS Institute Inc, Cary, NC).
We analyzed individual participant concentration–time profiles using standard noncompartmental techniques in R software (R Foundation for Statistical Computing, Vienna, Austria) to estimate the following ENG-releasing implant PK parameters: area under the curve (AUC, 0–24 weeks), maximum concentration (Cmax), minimum concentration (Cmin), and time to maximum concentration (Tmax). AUC (0–24 weeks) was computed using the trapezoidal rule. We calculated the (each HAART group)/(non-HAART group) ratio of the mean of the log-transformed AUC and Cmax, as well as the 90% confidence interval of the ratio, to establish bioequivalence. Bioequivalence was established if the 90% confidence interval of the geometric mean ratio of the PK parameters between the test and reference samples fell within the 80%–125% interval.20
An intention-to-treat analysis was performed relative to all investigated variables. The imputation method used was the last observation carried forward. The significance level was set at 5%.
One woman was excluded in each group: in the non-HAART group, the patient started HAART in week 20; in the LPV/r-based HAART group, the patient developed pulmonary tuberculosis that required a change to her antiretroviral regimen after week 12; and in the EFV-based HAART group, the patient's HAART regimen was changed in week 4 (Fig. 1). These patients continued to use the ENG implant. The remaining 42 participants completed the study. Twelve and 33 patients were followed at the Campinas and Ribeirao Preto centers, respectively.
The age (mean ± SD) of the EFV-based HAART group was higher than that of the other groups (non-HAART group: 28.8 ± 6.2 years old vs. LPV/r-based HAART group: 27.1 ± 3.7 years old vs. EFV-based HAART group: 34.5 ± 6.2 years old, P < 0.01). No difference in the number of years of schooling was observed among the groups (non-HAART group: 10.7 ± 3.7 years vs. LPV/r-based HAART group: 7.7 ± 3.4 years vs. EFV-based HAART group: 8.2 ± 3.6 years; P = 0.07). The percentages of smokers were similar among the groups (non-HAART group and EFV-based HAART group: 33.3% (5/15) vs. LPV/r-based HAART group: 26.7% (4/15); P = 0.76). The percentages of HIV-positive women with 3 or more births were also similar among the groups (non-HAART group and LPV/r-based HAART group: 27% (4/15) vs. EFV-based HAART group: 20% (3/15); P = 0.99). The clinical and immunological baseline variables did not differ among groups, with the exception of VL (P < 0.01), which was higher in the non-HAART group (Table 1).
Intragroup comparisons of immunological and virological data before and after implant placement showed no significant differences (Table 1). Two participants (1 in the non-HAART group and 1 in the LPV/r-based HAART group) showed levels of luteal activity before implant placement, and both women presented postpartum amenorrhea at 45 days. All P levels after implant placement were lower than the cutoff levels (3 and 5 ng/mL) in the group without HAART and the LPV/r-based HAART group, showing no evidence of luteal activity. However, 2.8% of the P samples in the EFV-based HAART group were above the 5 ng/mL cutoff (P = 0.02), and 5% were above the lower cutoff level (3 ng/mL) (P < 0.01) (Fig. 2). Therefore, the rate of luteal activity of the EFV-based HAART group ranged from 2.8% to 5%, depending on the cutoff used, and this rate was significantly higher than that in the other groups.
In the LPV/r-based HAART group, 87% (13/15) of the participants adhered to the HAART regimen. The VL remained at <50 copies per milliliter at week 24 in 12 participants. One patient presented an unsatisfactory VL reduction during the study period (90% over 6 months) despite her report of no lost pills in the questionnaire. All patients in the EFV-based HAART group (except 1 who was excluded after the fourth week because of HAART resistance) adhered to the HAART regimen according to the questionnaire and the finding of a VL of <50 copies per milliliter at week 24. In the non-HAART group, 40% (6/15) of the participants exhibited an increased VL, 13% (2/15) exhibited a decreased VL, and 57% (7/15) exhibited a stable VL over the 6-month follow-up.
No bioequivalence was observed among the groups (Table 2). The mean AUC of ENG in the LPV/r-based HAART group was 52% higher (10,747.7 ± 1569.3 wk·pg/mL; mean ± SD) than that in the non-HAART group (7072.4 ± 1569.3 wk·pg/mL) (P < 0.01). The mean AUC of ENG in the EFV-based HAART group was 63.4% lower (2588.2 ± 1278.4 wk·pg/mL) than that in the non-HAART group (P < 0.01) (Table 2; Fig. 3). The Cmax of ENG in the LPV/r-based HAART group was 60.6% higher than that in the non-HAART group, and the Cmax of ENG in the EFV-based HAART group was 53.7% lower than that in the non-HAART group (Table 2). The maximum levels of ENG were reached at a median of 14 days after ENG implant placement in all groups. The Cmin of ENG in the LPV/r-based HAART group was 33.8% higher than that in the non-HAART group, and the Cmin of ENG in the EFV-based HAART group was 70% lower than that in the non-HAART group (Table 2).
Our study showed that the EFV-based HAART regimen was associated with a major reduction in ENG bioavailability, as shown by the 63.4% decrease in the AUC, 53.7% decrease in the Cmax, and 70% decrease in the Cmin of ENG compared with the non-HAART group. However, the use of the LPV/r-based HAART regimen was associated with a substantial increase in the bioavailability of ENG, as shown by the 52% increase in the AUC, 60.6% increase in the Cmax, and 33.8% increase in the Cmin of ENG compared with the non-HAART group.
No evidence of luteal activity associated with ENG implant use was observed in the LPV/r-based HAART group or in HIV-positive women not using HAART during the 6-month follow-up. However, 2.8% and 5% of P samples in the EFV-based HAART group exhibited luteal activity (for cutoffs of 5 and 3 ng/mL, respectively), which was significantly higher than that in the other 2 groups. Previous studies showed that ENG-releasing implants were associated with an ovulation rate of 0%–3% in non–HIV-positive women based on a 5 ng/mL P cutoff.17,21,22
AZT and 3TC, which are used in both HAART regimens, do not interfere with the bioavailability of COC; therefore, an impact on ENG implant performance was implausible.7 However, LPV/r is one of the antiretroviral combinations that most significantly alters the bioavailability of COCs, apparently because of the presence of ritonavir as a booster.7,23 The latest WHO medical eligibility criteria10 classify this drug as category 3 (confirmed or theoretical risks are greater than the benefits) with respect to all combined contraceptive methods, independent of the route of administration and composition.
The use of LPV/r-based HAART in our study was associated with an increased bioavailability of ENG release from the implant. Ritonavir is a potent inhibitor of CYP3A4 activity, which increases exposure to LPV. LPV originally exhibits low bioavailability due to its extensive metabolism by CYP3A4.24 The LPV/r combination causes a 77% decrease in hepatic CYP3A4 activity.25 CYP3A4 metabolizes ENG,15,26 and the use of a drug that inhibits this enzyme (eg, ritonavir) could increase ENG exposure to a similar degree as LPV associated with ritonavir as a booster. Therefore, our findings suggested that LPV/r coadministration did not affect the contraceptive efficacy of the ENG-releasing implant.
The latest WHO medical eligibility criteria allow the use of hormonal contraceptives in EFV users10; however, subsequent studies have shown that this antiretroviral produces the most pronounced decrease in the bioavailability of COCs and levonorgestrel as an emergency contraceptive.7,27,28 Our study showed that EFV-based HAART decreased the bioavailability of the ENG released from the implant. One possible explanation for this finding could be that EFV is an inducer of CYP3A4 activity, which increases the metabolism and clearance of some drugs, including ENG,26 which are metabolized by these enzymes.29,30
However, the impact of reduced ENG bioavailability on the contraceptive efficacy of the implant is unknown. Some case reports have described unplanned pregnancy in women who concomitantly used an ENG implant and HAART with EFV.11–14 Whether these contraceptive failures fall within the normal method failure rate for the ENG implant or whether EFV reduces the efficacy of the ENG implant is unknown. We observed a 2.8% rate of luteal activity in the EFV-based HAART group based on the same cutoff used in most ENG implant studies.17,21 The apparent ovulation rate in the third year of ENG-releasing implant use is 3%,17,21 and the reduction in ENG concentration due to the coadministration of EFV could impair the efficacy of the implant in the second or third year of use, when a decrease in ENG concentration is well known.19 This decrease does not affect the efficacy of the ENG implant in the general population31; however, in EFV users, the normal decrease in the ENG concentration could be pivotal and alter the efficacy of ENG-releasing implants. In fact, all of the failures reported with the ENG implant and HAART with EFV occurred more than 2 years after ENG implant placement.11–14
One study investigated the use of the ENG-releasing implant in 79 HIV-positive women, 71% of whom used several HAART combinations, for 3 years. No pregnancies occurred, and the discontinuation rate up to 3 years of use was only 6%.32
The role of contraceptives in increasing the risk of HIV transmission and acquisition has been explored in recent years.33–35 Our study showed that the ENG implant did not alter the VL or CD4 T-cell count. However, this study was not designed or powered to assess this question.
Adherence to HAART was satisfactory. Therefore, compliance with treatment did not interfere with the results. Questionnaires are the most widely used method for assessing adherence, despite the potential to elicit incorrect information.36 We also used VL as an indirect marker of adherence to increase the reliability of the questionnaire.
A limitation of our study is that the P level is a surrogate marker of ovulation, which is a predictive marker for pregnancy. Ovulation can be assessed through P levels, ultrasound, endometrial biopsy, and luteinizing hormone measurement.22 However, P measurement is simple and provides a reliable measure of luteal activity, and hence, possible ovulatory function, despite disagreement regarding the ideal cutoffs for the indication of ovulation/luteal activity.22 However, a combination of the P level and ultrasound assessments may be more reliable in the prediction of ovulation. Consequently, we cannot state that ovulation did not occur in the non-HAART group or the LPV/r-based HAART groups. Definitive conclusions regarding the interference of HAART regimens, including LPV/r and EFV, with the efficacy of the ENG-releasing implant would require cohort-based or randomized clinical studies with pregnancy as the primary outcome. The ENG implant failure rate is very low (0.05 pregnancies/100 women/year),37 and a study using pregnancy as the primary outcome will require a large sample of HIV-positive women to be followed for 3 years using the same antiretroviral therapy.
The strengths of our study were the PK evaluation of ENG in HIV-positive women using 2 common HAART regimens, the combination of PK parameters with P levels to translate the impact of PK alterations for clinicians, and the duration of the study. Most PK studies last a few days to less than 3 months, and therefore, the interaction of HAARTs with hormonal contraceptives cannot be fully investigated.
Contraceptive use by HIV-positive women is a cost-effective strategy to avoid unplanned pregnancies, improve women's health, and reduce the vertical transmission rate.38 The use of any LARC-including implants increases the benefit due to high efficacy and compliance37,39,40 because use does not depend on the daily motivation of the users. However, knowledge of the potential interactions of prevalent HAARTs with hormonal contraceptives is important to promote adequate contraceptive counseling.
In conclusion, our study showed that the LPV/r-based HAART regimen increased the bioavailability of ENG released from the implant, suggesting that these antiretroviral drugs did not impair the contraceptive efficacy of the ENG implant. Conversely, the EFV-based HAART regimen decreased the bioavailability of the ENG released from the implant and increased luteal activity, which could impair the efficacy of this contraceptive. These results refer to 6 months of ENG-releasing implant use and do not confirm that EFV reduces the contraceptive efficacy of the ENG implant; however, the results do suggest that the use of these 2 medications together requires caution.
The authors thank the staff at the Clinical Research Unit of the Clinical Hospital of the Schools of Medicine of Ribeirao Preto and Campinas for the care provided to the study volunteers. They also acknowledge the Municipal Health Secretary of Ribeirao Preto of the STD/AIDS Department for supporting the study at the centers for HIV treatment. The authors thank René Megens of the Department of Bioanalytics, Merck Research Laboratories, who coordinated the evaluation of the ENG concentrations of the samples for the PK study. The evaluation was blinded and free of charge.
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