HIV-1 Infection, Tuberculosis
Conditions
Brief summary
This study was done to evaluate the effect of HIV and TB treatment on a commonly used birth control method. It enrolled women who were infected with HIV and TB and were taking efavirenz (EFV; Sustiva®; an anti-HIV medication), rifampicin (RIF; an anti-TB medication), and isoniazid (INH; an anti-TB medication). The purpose of this study was to find out the best frequency to give depot medroxyprogesterone acetate (DMPA; a hormonal birth control method that is given as a shot every 3 months) in these women. This study also tried to find out if a 150 mg injection of DMPA was effective in preventing ovulation, the process by which the ovaries (the ovaries are part of the female reproductive system) release an egg for fertilization, for 12 weeks in women who are taking EFV and RIF. Another purpose of this study was to find out if it is safe to take RIF, EFV and DMPA at the same time.
Detailed description
Globally, women comprise 52% of all people living with human immunodeficiency virus (HIV). Decisions about contraception in a population of women infected with both tuberculosis (TB) and HIV are of paramount importance. In the setting of the treatment of active TB, preventing pregnancy becomes even more important because it allows women to attain a level of health that will support healthy future pregnancies. Treatment options for TB may be limited in pregnancy because of concerns about teratogenicity. Millions of women around the world use depot medroxyprogesterone acetate (DMPA, trade name Depo-Provera) for prevention of pregnancy. DMPA is an intermediate-acting progesterone-only injectable contraceptive with a high efficacy rate. Unfortunately, DMPA's safety and effectiveness among women co-infected with TB and HIV is unknown since the interactions of TB treatment, combination ART (cART), and DMPA have not been well studied. The results of this study are likely to be applicable to women receiving RIF-containing TB treatment who are not being treated concurrently with EFV as well, given that addition of EFV to RIF is unlikely to increase induction of metabolizing enzymes significantly beyond the induction achieved with RIF alone. The study population included premenopausal women, 18 to 46 years of age, who were co-infected with HIV and TB. To be eligible to enroll in the study, participants must have been on EFV 600 mg once daily plus two or more nucleoside reverse transcriptase inhibitors (NRTIs) for at least 28 days prior to study entry with no plans to change therapy for the 12 weeks of the study. Women must have been on the continuation phase of active TB treatment (with a minimum of 12 weeks remaining) taking RIF 8-12 mg/kg orally and INH 4-6 mg/kg orally on a 5-day or more per week schedule (or as directed by national guidelines for TB treatment). At study entry/week 0, DMPA 150 mg was administered intramuscularly as a single dose. Study duration was 12 weeks. Visits occurred at weeks 0, 2, 4, 6, 8, 10, and 12. The key evaluations included physical examination, clinical assessments, hematology, chemistry, HIV RNA, pregnancy testing, plasma progesterone levels, and plasma DMPA concentration levels. The sample size was 46 participants, of which 42 had to be evaluable. Participants who missed two successive visits prior to week 8 and those who did not complete the week 10 and week 12 clinic visits with available DMPA concentrations and progesterone levels were not evaluable and replaced in the sample size. The final number of participants enrolled was 62 participants, with only 42 evaluable.
Interventions
Depot medroxyprogesterone acetate intramuscular injection
Sponsors
National Institute of Allergy and Infectious Diseases (NIAID)
Advancing Clinical Therapeutics Globally for HIV/AIDS and Other Infections
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
FEMALE
Age
18 Years to 46 Years
Healthy volunteers
No
Inclusion criteria
* HIV-1 infection. * Current tuberculosis infection, confirmed or probable diagnosis. * Currently stable on EFV-based cART for at least 28 days with no intention to change the regimen during the 12-week study period. * Currently receiving RIF and Isoniazid (INH)-based TB therapy on at least 5 days per week schedule after completion of the intensive phase of TB treatment (minimum of 8 weeks of TB treatment) and expected to be on TB treatment for a minimum of 12 weeks after enrollment. \[Does not exclude the use of ethambutol on study.\] * Premenopausal female with presumed normal ovarian function based on normal menstrual history and absence of previous ovarian dysfunction diagnosis. * Last menstrual period (LMP) ≤35 days prior to study entry. * Negative serum or urine-HCG pregnancy test within 30 days prior to study entry and negative pregnancy test at entry at any network-approved laboratory that operates in accordance with Good Clinical Practices and participates in appropriate external quality assurance programs. * All participants must agree not to participate in a conception process (e.g., active attempt to become pregnant or in vitro fertilization) for the duration of the study. Women of reproductive potential, who are participating in sexual activity that could lead to pregnancy, must agree to use an additional reliable method of contraception while in the study. Acceptable forms of contraceptives include: * Condoms (male or female) with or without a spermicidal agent * Diaphragm or cervical cap with spermicide * Non-hormonal IUD * Bilateral tubal ligation * Male partner vasectomy * Laboratory values within 30 days prior to study entry: * Absolute neutrophil count ≥500 cells/mm\^3 * Platelet count ≥50,000 platelets/mm\^3 * Hemoglobin ≥8.0 g/dL * Aspartate transaminase (AST) and alanine aminotransferase (ALT) \<5 x upper limit of normal (ULN) * Creatinine ≤1.5 x ULN * Total bilirubin ≤2.0 x ULN * Ability and willingness to provide written informed consent.
Exclusion criteria
* Receipt of DMPA or any other injectable contraceptive within 180 days prior to study entry. * Receipt of other hormonal contraceptives within 30 days prior to study entry. * Use of any drugs other than RIF and EFV known to: 1) induce CYP3A4 system within 30 days and to 2) inhibit the CYP3A4 system with one week prior to study entry. \[Because ethambutol does not induce or inhibit the CYP3A4 system, its use is consistent with the language in the protocol.\] * ≤40 kg in weight. * Bilateral oophorectomy. * Less than 30 days postpartum at study entry. * Hypersensitivity to DMPA, medroxyprogesterone acetate (MPA), or any of the other ingredients in DMPA. * Any previous breast cancer diagnosis. * Serious illness requiring systemic treatment and/or hospitalization within 21 days prior to study entry. * Karnofsky performance score \<70 within 14 days prior to study entry. * Use of any immunosuppressant medication including systemic corticosteroids within 30 days prior to study entry. * Active drug or alcohol use or dependence that, in the opinion of the site investigator, would interfere with adherence to study requirements. * History of deep venous thrombosis or pulmonary emboli.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percent of Participants With DMPA Concentrations Below 0.1 ng/mL at Week 12 | Week 12 | The percent of participants with plasma DMPA concentrations below 0.1 ng/mL was calculated with an exact Clopper-Pearson 95% confidence interval. Suppression of ovulation generally occurs as long as the DMPA level is =\> 0.1 ng/mL. |
| Percent of Participants With Progesterone Levels Above 1 ng/mL at Week 12 | Week 12 | The percent of participants with plasma progesterone levels above 1 ng/mL was calculated with an exact Clopper-Pearson 95% confidence interval. Ovulation generally occurs when the progesterone level is \> 5 ng/mL. If there were participants with plasma progesterone levels \> 1 ng/mL, then the percent of participants with plasma progesterone levels \> 5 ng/mL would have been calculated by study week. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| DMPA AUC | Weeks 0, 2, 4, 6, 8, 10, and 12 | Describe the DMPA plasma area under the curve (AUC) between 0 and 12 weeks, where AUC(0-12wks) was calculated using non-compartmental methods.The Week 0 time point was drawn prior to DMPA injection. |
| DMPA Cmin | Weeks 0, 2, 4, 6, 8, 10, and 12 | Describe the DMPA minimum observed concentration (Cmin) between 0 and 12 weeks. The Week 0 time point was drawn prior to DMPA injection. |
| DMPA Cmax | Weeks 0, 2, 4, 6, 8, 10, and 12 | Describe the DMPA maximum observed concentration (Cmax) between 0 and 12 weeks. The Week 0 time point was drawn prior to DMPA injection. |
| Percent of Participants With DMPA Concentrations Below 0.1 ng/mL at Weeks 2, 4, 6, 8, and 10 | Weeks 2, 4, 6, 8, and 10 | The percents of participants with plasma DMPA concentrations below 0.1 ng/mL at weeks 2, 4, 6, 8, and 10 were calculated with exact Clopper-Pearson 95% confidence intervals. Suppression of ovulation generally occurs as long as the DMPA level is =\> 0.1 ng/mL. |
| Percent of Participants Who Experienced a Grade 3 or Higher Sign/Symptom or Laboratory Abnormality | Weeks 2, 4, 6, 8, 10, and 12 | The percent of participants who experienced a grade 3 (severe) or higher sign/symptom or laboratory abnormality were calculated with an exact Clopper-Pearson 95% confidence interval. Events were graded (1=mild, 2=moderate, 3=severe, 4=life-threatening, 5=death) according to the DAIDS AE Grading Table (V1.0). |
| DMPA Half-life | Weeks 0, 2, 4, 6, 8, 10, and 12 | Describe the terminal elimination half-life of DMPA (t½) between 0 and 12 weeks, where t½ was calculated using nonlinear mixed-effects (NLME) modelling. The Week 0 time point was drawn prior to DMPA injection. |
| Time at Which Participant-specific Estimated Elimination Slopes for DMPA Level Cross the Threshold of 0.1 ng/mL | Weeks 0, 2, 4, 6, 8, 10, and 12 | Describe the time at which DMPA levels drop below the threshold of 0.1 ng/mL, based on participant-specific estimated elimination slopes from nonlinear mixed-effects (NLME) models. The Week 0 time point was drawn prior to DMPA injection. |
| DMPA CL/F | Weeks 0, 2, 4, 6, 8, 10, and 12 | Describe the apparent DMPA clearance (CL/F) between 0 and 12 weeks. The Week 0 time point was drawn prior to DMPA injection. |
| Cumulative Percentage of Participants With DMPA < 0.1 ng/mL | Weeks 0, 2, 4, 6, 8, 10, and 12 | The cumulative percentage of participants having a DMPA concentration less than 0.1 ng/mL at week 12 was calculated using a Kaplan-Meier estimator with an associated standard error. The confidence interval was calculated using a log-log transformation. Suppression of ovulation generally occurs as long as the DMPA level is =\> 0.1 ng/mL. |
Countries
Botswana, Kenya, South Africa, Zimbabwe
Participant flow
Recruitment details
Study participants were recruited at five ACTG Clinical Research Sites in four countries (two sites from South Africa and one site from each of Botswana, Kenya, and Zimbabwe) between November 2015 and March 2017.
Pre-assignment details
Of the 85 women screened, 62 were deemed eligible and enrolled into this single-arm study.
Participants by arm
| Arm | Count |
|---|---|
| Arm A: Depot Medroxyprogesterone Acetate At study entry/week 0, participants received depot medroxyprogesterone acetate (DMPA) 150 mg administered intramuscularly as a single dose and co-administered with rifampicin (RIF) and efavirenz (EFV). | 62 |
| Total | 62 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Death | 1 |
| Overall Study | Lost to Follow-up | 6 |
| Overall Study | Not Willing to Adhere to Requirements | 1 |
| Overall Study | Protocol-mandated Discontinuation | 7 |
| Overall Study | Unable to get to clinic | 3 |
Baseline characteristics
| Characteristic | Arm A: Depot Medroxyprogesterone Acetate |
|---|---|
| Age, Continuous | 32 years |
| Age, Customized 20-29 years | 24 Participants |
| Age, Customized 30-39 years | 25 Participants |
| Age, Customized 40-49 years | 13 Participants |
| Body Mass Index (BMI) | 20.8 kg/m^2 |
| CD4+ Cell Count | 407 cells/mm^3 |
| HIV Antiretroviral Therapy EFV + more than two NRTIs | 0 Participants |
| HIV Antiretroviral Therapy EFV + two NRTIs | 62 Participants |
| HIV RNA < 400 copies/mL | 52 Participants |
| HIV RNA => 400 copies/mL | 9 Participants |
| Race/Ethnicity, Customized Black African | 62 Participants |
| Region of Enrollment Botswana | 7 Participants |
| Region of Enrollment Kenya | 12 Participants |
| Region of Enrollment South Africa | 35 Participants |
| Region of Enrollment Zimbabwe | 8 Participants |
| Sex: Female, Male Female | 62 Participants |
| Sex: Female, Male Male | 0 Participants |
| TB Treatment RIF and INH | 52 Participants |
| TB Treatment RIF, INH, and ethambutol | 10 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 1 / 62 |
| other Total, other adverse events | 6 / 62 |
| serious Total, serious adverse events | 1 / 62 |
Outcome results
Primary
Percent of Participants With DMPA Concentrations Below 0.1 ng/mL at Week 12
The percent of participants with plasma DMPA concentrations below 0.1 ng/mL was calculated with an exact Clopper-Pearson 95% confidence interval. Suppression of ovulation generally occurs as long as the DMPA level is =\> 0.1 ng/mL.
Time frame: Week 12
Population: Participants who did not have DMPA concentrations at weeks 10 and 12 were excluded from the analysis
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Arm A: Depot Medroxyprogesterone Acetate | Percent of Participants With DMPA Concentrations Below 0.1 ng/mL at Week 12 | 11.9 percentage of participants |
Primary
Percent of Participants With Progesterone Levels Above 1 ng/mL at Week 12
The percent of participants with plasma progesterone levels above 1 ng/mL was calculated with an exact Clopper-Pearson 95% confidence interval. Ovulation generally occurs when the progesterone level is \> 5 ng/mL. If there were participants with plasma progesterone levels \> 1 ng/mL, then the percent of participants with plasma progesterone levels \> 5 ng/mL would have been calculated by study week.
Time frame: Week 12
Population: Participants who did not have progesterone concentrations at weeks 10 and 12 were excluded from the analysis.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Arm A: Depot Medroxyprogesterone Acetate | Percent of Participants With Progesterone Levels Above 1 ng/mL at Week 12 | 0.0 percentage of participants |
Secondary
Cumulative Percentage of Participants With DMPA < 0.1 ng/mL
The cumulative percentage of participants having a DMPA concentration less than 0.1 ng/mL at week 12 was calculated using a Kaplan-Meier estimator with an associated standard error. The confidence interval was calculated using a log-log transformation. Suppression of ovulation generally occurs as long as the DMPA level is =\> 0.1 ng/mL.
Time frame: Weeks 0, 2, 4, 6, 8, 10, and 12
Population: Participants who did not have DMPA concentrations at weeks 10 and 12 were excluded from the analysis.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Arm A: Depot Medroxyprogesterone Acetate | Cumulative Percentage of Participants With DMPA < 0.1 ng/mL | 11.9 cumulative percentage of participants |
Secondary
DMPA AUC
Describe the DMPA plasma area under the curve (AUC) between 0 and 12 weeks, where AUC(0-12wks) was calculated using non-compartmental methods.The Week 0 time point was drawn prior to DMPA injection.
Time frame: Weeks 0, 2, 4, 6, 8, 10, and 12
Population: Participants who did not have DMPA concentrations at weeks 10 and 12 were excluded from the analysis.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Arm A: Depot Medroxyprogesterone Acetate | DMPA AUC | 7.63 ng*week/mL |
Secondary
DMPA CL/F
Describe the apparent DMPA clearance (CL/F) between 0 and 12 weeks. The Week 0 time point was drawn prior to DMPA injection.
Time frame: Weeks 0, 2, 4, 6, 8, 10, and 12
Population: Participants who did not have DMPA concentrations at weeks 10 and 12 were excluded from the analysis.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Arm A: Depot Medroxyprogesterone Acetate | DMPA CL/F | 19681 L/week |
Secondary
DMPA Cmax
Describe the DMPA maximum observed concentration (Cmax) between 0 and 12 weeks. The Week 0 time point was drawn prior to DMPA injection.
Time frame: Weeks 0, 2, 4, 6, 8, 10, and 12
Population: Participants who did not have DMPA concentrations at weeks 10 and 12 were excluded from the analysis.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Arm A: Depot Medroxyprogesterone Acetate | DMPA Cmax | 1.04 ng/mL |
Secondary
DMPA Cmin
Describe the DMPA minimum observed concentration (Cmin) between 0 and 12 weeks. The Week 0 time point was drawn prior to DMPA injection.
Time frame: Weeks 0, 2, 4, 6, 8, 10, and 12
Population: Participants who did not have DMPA concentrations at weeks 10 and 12 were excluded from the analysis.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Arm A: Depot Medroxyprogesterone Acetate | DMPA Cmin | 0.33 ng/mL |
Secondary
DMPA Half-life
Describe the terminal elimination half-life of DMPA (t½) between 0 and 12 weeks, where t½ was calculated using nonlinear mixed-effects (NLME) modelling. The Week 0 time point was drawn prior to DMPA injection.
Time frame: Weeks 0, 2, 4, 6, 8, 10, and 12
Population: Participants who did not have DMPA concentrations at weeks 10 and 12 were excluded from the analysis.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Arm A: Depot Medroxyprogesterone Acetate | DMPA Half-life | 55 hours |
Secondary
Percent of Participants Who Experienced a Grade 3 or Higher Sign/Symptom or Laboratory Abnormality
The percent of participants who experienced a grade 3 (severe) or higher sign/symptom or laboratory abnormality were calculated with an exact Clopper-Pearson 95% confidence interval. Events were graded (1=mild, 2=moderate, 3=severe, 4=life-threatening, 5=death) according to the DAIDS AE Grading Table (V1.0).
Time frame: Weeks 2, 4, 6, 8, 10, and 12
Population: All enrolled participants were included in the analysis.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Arm A: Depot Medroxyprogesterone Acetate | Percent of Participants Who Experienced a Grade 3 or Higher Sign/Symptom or Laboratory Abnormality | 12.9 percentage of participants |
Secondary
Percent of Participants With DMPA Concentrations Below 0.1 ng/mL at Weeks 2, 4, 6, 8, and 10
The percents of participants with plasma DMPA concentrations below 0.1 ng/mL at weeks 2, 4, 6, 8, and 10 were calculated with exact Clopper-Pearson 95% confidence intervals. Suppression of ovulation generally occurs as long as the DMPA level is =\> 0.1 ng/mL.
Time frame: Weeks 2, 4, 6, 8, and 10
Population: Participants who did not have a DMPA concentration at the analysis week of interest were excluded from each analysis as appropriate. For example, participants missing a DMPA concentration at week 4 were excluded from the week 4 analysis.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Arm A: Depot Medroxyprogesterone Acetate | Percent of Participants With DMPA Concentrations Below 0.1 ng/mL at Weeks 2, 4, 6, 8, and 10 | Week 10 DMPA < 0.1 ng/mL | 2.4 percentage of participants |
| Arm A: Depot Medroxyprogesterone Acetate | Percent of Participants With DMPA Concentrations Below 0.1 ng/mL at Weeks 2, 4, 6, 8, and 10 | Week 2 DMPA < 0.1 ng/mL | 0.0 percentage of participants |
| Arm A: Depot Medroxyprogesterone Acetate | Percent of Participants With DMPA Concentrations Below 0.1 ng/mL at Weeks 2, 4, 6, 8, and 10 | Week 4 DMPA < 0.1 ng/mL | 0.0 percentage of participants |
| Arm A: Depot Medroxyprogesterone Acetate | Percent of Participants With DMPA Concentrations Below 0.1 ng/mL at Weeks 2, 4, 6, 8, and 10 | Week 6 DMPA < 0.1 ng/mL | 0.0 percentage of participants |
| Arm A: Depot Medroxyprogesterone Acetate | Percent of Participants With DMPA Concentrations Below 0.1 ng/mL at Weeks 2, 4, 6, 8, and 10 | Week 8 DMPA < 0.1 ng/mL | 0.0 percentage of participants |
Secondary
Time at Which Participant-specific Estimated Elimination Slopes for DMPA Level Cross the Threshold of 0.1 ng/mL
Describe the time at which DMPA levels drop below the threshold of 0.1 ng/mL, based on participant-specific estimated elimination slopes from nonlinear mixed-effects (NLME) models. The Week 0 time point was drawn prior to DMPA injection.
Time frame: Weeks 0, 2, 4, 6, 8, 10, and 12
Population: Participants who did not have DMPA concentrations at weeks 10 and 12 were excluded from the analysis.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Arm A: Depot Medroxyprogesterone Acetate | Time at Which Participant-specific Estimated Elimination Slopes for DMPA Level Cross the Threshold of 0.1 ng/mL | 74.2 days |