Pharmacokinetic Study of Antiretroviral Drugs and Related Drugs During and After Pregnancy

Study Overview
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Brief Summary
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IMPAACT P1026s is a Phase IV prospective clinical study to evaluate the pharmacokinetics (PKs) of antiretroviral (ARV) and tuberculosis (TB) medications in pregnant women and their infants. (Pharmacokinetics are the various interactions between a drug and the body.) This study also evaluated the PKs of certain ARVs in postpartum women before and after starting hormonal contraceptives. The PKs of these drugs were evaluated by measuring the amount of medicine present in blood and/or vaginal secretions.

Detailed Description
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Pregnant women experience unique physiological changes that may result in clinically significant alterations in drug PKs. Unfortunately, there have been few clinical trials to study the PKs of ARV, TB, and hormonal contraceptive drugs in pregnant women. The development of appropriate dosing regimens for the HIV-infected pregnant woman is critical to the health of both mother and fetus. Overdosing may lead to maternal adverse events and increased risk of fetal toxicity, while underdosing may lead to inadequate virologic control, increased risk of developing drug resistance mutations, and a higher rate of perinatal HIV transmission. This study evaluated the PKs of ARVs used during pregnancy; the PKs of TB drugs used during pregnancy, both in women who are HIV-positive and also taking ARVs and in women who are HIV-negative and not taking ARVs; and the PKs of hormonal contraceptive medications taken along with ARVs. P1026s is a Phase IV clinical study. Participants were not assigned to the drugs under study, but were already receiving the drugs for clinical care by prescription of their clinical care providers. They were enrolled into study arms according to the drugs they were receiving through clinical care, and if on multiple drugs of interest, were able to enroll into multiple arms simultaneously. No drugs were provided as part of this study. This observational study was added to an existing investigational new drug (IND) number because several of the drugs were studied at a higher does than the approved dose after the PK results for the approved dose were found to be inadequate. P1026s went through 10 protocol versions, with the first and last versions of the protocol finalized in 2002 and 2016, respectively. New study arms were added and analyzed separately with each update of the protocol version. In general, there were five main groups of study arms: HIV-infected pregnant women taking ARVs without TB treatment, HIV-infected pregnant women taking ARVs with first-line TB treatment, HIV-uninfected pregnant women taking no ARVs with first-line TB treatment, HIV-infected and HIV-uninfected pregnant women with or without ARVs with second-line TB treatment for drug-resistant TB, and HIV-infected postpartum women taking ARVs and hormonal contraceptives. The primary analysis of each arm was designed and conducted as a separate single arm evaluation of the drug (or combination of drugs) of interest. Women who were 20 0/7 weeks to 37 6/7 weeks pregnant were enrolled in this study and remained in the study for up to 12 weeks after delivery. Postpartum women were enrolled at 2 to 12 weeks after delivery and followed until 6 to 7 weeks after starting contraceptives. Infants were enrolled in-utero and followed for 16 to 24 weeks of life. At all study visits, participants underwent a medical history, a physical exam, and blood collection. At some visits, women in some arms underwent a vaginal swab. Blood collection from the mother and the detached umbilical cord occurred during delivery. Intensive PK sampling was performed at study visits during the second and third trimester of pregnancy and/or postpartum, depending on the study arm. Additional study visits may have occurred depending on the ARV drug regimen prescribed. Infant washout PK samples were collected at 2-10, 18-28, 36-72 hours after birth, and 5-9 days of life. There are a total of 49 study arms across all versions of P1026s protocols. Out of the 49 study arms, 2 did not have PK data* [didanosine delayed release (DDI) and lopinavir/ritonavir (LPV/RTV) African sites only]; 2 never enrolled any participants [amprenavir (APV) and nevirapine/rifampicin (NVP/RIF) with at least one first line TB drug]; 9 are in the line to be tested/analyzed due to batched analysis which has to be done after the end of the study, the lengthy process of development, validation and approval (regulatory burdens), and laboratory delays related to the COVID-19 pandemic [all TB arms and all but 3 contraceptive arms (atazanavir/ritonavir/tenofovir (ATV/RTV/TFV) with etonogestrel (ENG), efavirenz (EFV) with ENG, and LPV/RTV with ENG)]; and 8 had completion dates earlier than December 26, 2007 [nevirapine (NVP), abacavir (ABC), LPV/RTV 400/100 mg twice daily (b.i.d.), LPV/RTV 400/100mg then 533/133mg b.i.d, nelfinavir (NFV), emtricitabine (FTC), indinavir/ritonavir (IDV/RTV), and tipranavir/ritonavir]. In this submission, the Results Section presents participant flow, baseline characteristics and adverse events for all study arms (except the 2 arms that never enrolled), and outcome measure results for the 28 remaining study arms that have been completed and have final results available. For study arms completed prior to December 26, 2007, refer to the study publications in the References section for outcome measures. For arms with very low enrollment (N<3), some results throughout the record (e.g. baseline characteristics and outcome measures) were not reported in order to avoid making individual participant data identifiable. In the Outcome Measures section, there could be multiple outcome measures for same PK parameters (e.g. AUC12) depending on different units or summary statistics used in the analyses (such as median with range vs. median with interquartile range (IQR)).

Official Title
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Pharmacokinetic Properties of Antiretroviral and Related Drugs During Pregnancy and Postpartum

Conditions
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HIV Infections

Intervention / Treatment
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* Drug: atazanavir/cobicistat
* Drug: darunavir/ritonavir dosage #1
* Drug: darunavir/ritonavir dosage #2
* Drug: darunavir/ritonavir dosage #3
* Drug: elvitegravir/cobicistat
* Drug: dolutegravir
* Drug: tenofovir alafenamide fumarate (TAF)
* Drug: TAF w/cobicistat
* Drug: TAF w/cobicistat or ritonavir
* Drug: efavirenz
* Drug: darunavir/cobicistat
* Drug: lopinavir/ritonavir dosage #1
* Drug: atazanavir/ritonavir/tenofovir dosage #1
* Drug: rifampicin
* Drug: ethambutol
* Drug: isoniazid
* Drug: pyrazinamide
* Drug: kanamycin
* Drug: amikacin
* Drug: capreomycin
* Drug: moxifloxacin
* Drug: levoflaxacin
* Drug: ofloxacin
* Drug: ethionamide/prothionamide
* Drug: terizidone/cycloserine
* Drug: para-aminosalicylic acid (PAS)
* Drug: high dose INH
* Drug: bedaquiline
* Drug: clofazamine
* Drug: delamanid
* Drug: linezolid
* Drug: pretomanid
* Drug: ethinyl estradiol
* Drug: etonogestrel implant
* Drug: nevirapine
* Drug: amprenavir
* Drug: abacavir
* Drug: lopinavir/ritonavir dosage #2
* Drug: indinavir/ritonavir dosage #1
* Drug: fosamprenavir/ritonavir
* Drug: lopinavir/ritonavir dosage #3
* Drug: atazanavir/ritonavir dosage #1
* Drug: didanosine delayed release (Videx® EC)
* Drug: emtricitabine
* Drug: tenofovir
* Drug: nelfinavir dosage #1
* Drug: tipranavir/ritonavir
* Drug: lopinavir/ritonavir dosage #4
* Drug: raltegravir
* Drug: etravirine
* Drug: maraviroc
* Drug: atazanavir/ritonavir dosage #2
* Drug: tenofovir/atazanavir/ritonavir dosage #2
* Drug: nelfinavir dosage #2
* Drug: indinavir/ritonavir dosage #2
* Drug: rilpivirine
* Drug: darunavir/ritonavir dosage #4


Participation Criteria
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Eligibility Criteria
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Maternal Inclusion Criteria: Participant must belong to one of the following 5 groups: HIV-infected pregnant women greater than or equal to 20 weeks gestation NOT on TB treatment receiving one or more of the ARV drugs/drug combinations specified in the protocol HIV-infected pregnant women greater than or equal to 20 weeks gestation receiving one of the ARV drugs/drug combinations specified in the protocol and TB treatment with at least one of the TB drugs, specified in the protocol, at study entry HIV-uninfected pregnant women greater than or equal to 20 weeks gestation receiving at least two of the first-line TB drugs, specified in the protocol, at study entry HIV-infected and HIV-uninfected pregnant women greater than or equal to 20 weeks gestation receiving at least two of the second-line TB drugs, specified in the protocol, at study entry HIV-infected women 2 to 12 weeks (14 to 84 days) post-delivery receiving one of the ARV drug combinations listed in the protocol AND starting postpartum contraceptives as listed in the protocol The woman must be stable on the ARV drug/drug combination and/or TB drug combination for at least 2 weeks prior to PK sampling If a woman is receiving a specific generic ARV formulation, the protocol team has approved this formulation HIV-infected pregnant women must be planning to continue on current ARV regimen until postpartum PK sampling is completed. HIV-infected postpartum women on hormonal contraceptives must be planning to continue on ARV and contraceptive regimens until final PK sampling is completed For HIV-infected women: confirmed HIV infection, documented by positive results from two samples collected at different time points prior to study entry. More information on this criterion can be found in the protocol. HIV-uninfected pregnant women must have documented negative HIV antibody test during current pregnancy. Note: adequate source documentation, including the date of specimen collection, date of testing, test performed, and test result, must be available. Participants enrolling in the 3rd trimester must enroll by 37 6/7 weeks gestation Participant can provide legal informed consent per local regulations If a woman has completed this study and becomes pregnant again, she may re-enroll in the study only if she is enrolled in a different arm than that studied during her initial enrollment Maternal Exclusion Criteria: Women on medicines known to interfere with absorption, metabolism, or clearance of the drug being evaluated (see protocol for more information). Rifampicin is permitted for women being evaluated for TB and ARV drug interactions If pregnant, carrying multiple fetuses Clinical or laboratory toxicity that, in the opinion of the site investigator, would be likely to require a change in the medicine regimen during the period of study Infant Enrollment Criteria: - All infants of mothers enrolled during pregnancy (meeting criteria specified above) are enrolled, in utero, immediately after maternal enrollment. Infant Requirements for Washout Pharmacokinetic Sampling: Born to HIV-infected mother enrolled during pregnancy in an ARV arm (does not include infants born to HIV-uninfected mothers receiving TB drugs) Birth weight greater than 1000 grams Is NOT receiving disallowed medications described in Section 7 of the protocol Does not have any severe congenital malformation or other medical condition not compatible with life or that would interfere with study participation or interpretation, as judged by the site investigator Born after singleton delivery (not after multiple birth)
Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| DRV/RTV 600 or 800 or 900/100mg b.i.d. then 800 or 900/100mg b.i.d. then 600/100mg b.i.d.<br>HIV-infected pregnant women ≥ 20 weeks gestation NOT on tuberculosis treatment who received: darunavir/ritonavir (DRV/RTV) 600/100 mg twice daily (b.i.d.) or 800/100 mg b.i.d. until 30 weeks gestation; then 800/100 mg b.i.d. until postpartum hospital discharge; then 600/100 mg b.i.d. after postpartum hospital discharge until 2 week postpartum PK samples are drawn. OR darunavir/ritonavir twice daily 600/100 mg b.i.d. or 900/100 mg b.i.d. until 30 weeks gestation; then 900/100 mg b.i.d. until postpartum hospital discharge; then 600/100 mg b.i.d. after postpartum hospital discharge until 2 week postpartum PK samples are drawn. | Drug: darunavir/ritonavir dosage #1<br>* darunavir/ritonavir twice daily 600/100 mg b.i.d.<br>Drug: darunavir/ritonavir dosage #2<br>* darunavir/ritonavir twice daily 800/100 mg b.i.d.<br>Drug: darunavir/ritonavir dosage #3<br>* darunavir/ritonavir twice daily 900/100 mg b.i.d.<br>|
| DTG 50mg q.d.<br>HIV-infected pregnant women ≥ 20 weeks gestation NOT on tuberculosis treatment who received dolutegravir (DTG) 50 mg once a day (q.d.). | Drug: dolutegravir<br>* dolutegravir 50 mg q.d.<br>|
| TAF 25mg q.d.<br>HIV-infected pregnant women ≥ 20 weeks gestation NOT on tuberculosis treatment who received tenofovir alafenamide fumarate (TAF) 25 mg q.d. without cobicistat or ritonavir boosting. | Drug: tenofovir alafenamide fumarate (TAF)<br>* TAF 25 mg q.d. without cobicistat or ritonavir boosting<br>|
| TAF 10mg q.d. w/COBI<br>HIV-infected pregnant women ≥ 20 weeks gestation NOT on tuberculosis treatment who received tenofovir alafenamide fumarate (TAF) 10 mg q.d. with cobicistat (COBI). | Drug: TAF w/cobicistat<br>* TAF 10 mg q.d. with cobicistat<br>|
| TAF 25mg q.d. w/COBI or RTV boosting<br>HIV-infected pregnant women ≥ 20 weeks gestation NOT on tuberculosis treatment who received tenofovir alafenamide fumarate (TAF) 25 mg q.d. with cobicistat (COBI) or ritonavir (RTV) boosting. | Drug: TAF w/cobicistat or ritonavir<br>* TAF 25 mg q.d. with cobicistat or ritonavir boosting<br>|
| EVG/COBI 150/150mg q.d.<br>HIV-infected pregnant women ≥ 20 weeks gestation NOT on tuberculosis treatment who received elvitegravir/cobicistat (EVG/COBI) 150/150 mg q.d | Drug: elvitegravir/cobicistat<br>* elvitegravir/cobicistat 150/150 mg q.d.<br>|
| DRV/COBI 800/150 mg q.d.<br>HIV-infected pregnant women ≥ 20 weeks gestation NOT on tuberculosis treatment who received darunavir/cobicistat (DRV/COBI) 800/150 mg q.d. | Drug: darunavir/cobicistat<br>* darunavir/cobicistat 800/150 mg q.d.<br>|
| ATV/COBI 300/150 mg q.d.<br>HIV-infected pregnant women ≥ 20 weeks gestation NOT on tuberculosis treatment who received atazanavir/cobicistat (ATV/COBI) 300/150 mg q.d. | Drug: atazanavir/cobicistat<br>* atazanavir/cobicistat 300/150 mg q.d.<br>|
| EFV 600 mg q.d. (outside THA)<br>HIV-infected pregnant women ≥ 20 weeks gestation NOT on tuberculosis treatment who received efavirenz (EFV) 600 mg q.d. (Participants outside of Thailand only) | Drug: efavirenz<br>* efavirenz 600 mg q.d.<br>|
| EFV 600mg q.d. and at least one 1st line TB drug<br>HIV-infected pregnant women ≥ 20 weeks gestation who received efavirenz (EFV) 600mg q.d.and TB treatment with at least one of the following TB drugs at study entry: rifampicin 8-12 mg/kg (max 600 mg) q.d.; 8-12 mg/kg (max 900 mg) t.i.w. ethambutol 15-20 mg/kg q.d., 25-35 mg/kg t.i.w. isoniazid 4-6 mg/kg (max 300 mg) q.d.; 8-12 mg/kg (max 900 mg) t.i.w. pyrazinamide 20-30mg/kg q.d.; 30-40mg/kg t.i.w. | Drug: efavirenz<br>* efavirenz 600 mg q.d.<br>Drug: rifampicin<br>* rifampicin 8-12 mg/kg (max 600 mg) q.d.; 8-12 mg/kg (max 900 mg) t.i.w.<br>Drug: ethambutol<br>* ethambutol 15-20 mg/kg q.d., 25-35 mg/kg t.i.w.<br>Drug: isoniazid<br>* isoniazid 4-6 mg/kg (max 300 mg) q.d.; 8-12 mg/kg (max 900 mg) t.i.w.<br>Drug: pyrazinamide<br>* pyrazinamide 20-30mg/kg q.d.; 30-40mg/kg t.i.w.<br>|
| LPV/RTV 800/200mg b.i.d. and at least one 1st line TB drug<br>HIV-infected pregnant women ≥ 20 weeks gestation who received lopinavir/ritonavir (LPV/RTV) 800/200mg b.i.d. and TB treatment with at least one of the following TB drugs at study entry: rifampicin 8-12 mg/kg (max 600 mg) q.d.; 8-12 mg/kg (max 900 mg) t.i.w. ethambutol 15-20 mg/kg q.d., 25-35 mg/kg t.i.w. isoniazid 4-6 mg/kg (max 300 mg) q.d.; 8-12 mg/kg (max 900 mg) t.i.w. pyrazinamide 20-30mg/kg q.d.; 30-40mg/kg t.i.w. | Drug: lopinavir/ritonavir dosage #1<br>* lopinavir/ritonavir 800/200mg b.i.d.<br>Drug: rifampicin<br>* rifampicin 8-12 mg/kg (max 600 mg) q.d.; 8-12 mg/kg (max 900 mg) t.i.w.<br>Drug: ethambutol<br>* ethambutol 15-20 mg/kg q.d., 25-35 mg/kg t.i.w.<br>Drug: isoniazid<br>* isoniazid 4-6 mg/kg (max 300 mg) q.d.; 8-12 mg/kg (max 900 mg) t.i.w.<br>Drug: pyrazinamide<br>* pyrazinamide 20-30mg/kg q.d.; 30-40mg/kg t.i.w.<br>|
| No ARVs and at least two 1st line TB drugs<br>HIV-uninfected pregnant women ≥ 20 weeks gestation who received at least two of the following first line TB drugs at study entry: rifampicin 8-12 mg/kg (max 600 mg) q.d.; 8-12 mg/kg (max 900 mg) t.i.w. ethambutol 15-20 mg/kg q.d., 25-35 mg/kg t.i.w. isoniazid 4-6 mg/kg (max 300 mg) q.d.; 8-12 mg/kg (max 900 mg) t.i.w. pyrazinamide 20-30mg/kg q.d.; 30-40mg/kg t.i.w. | Drug: rifampicin<br>* rifampicin 8-12 mg/kg (max 600 mg) q.d.; 8-12 mg/kg (max 900 mg) t.i.w.<br>Drug: ethambutol<br>* ethambutol 15-20 mg/kg q.d., 25-35 mg/kg t.i.w.<br>Drug: isoniazid<br>* isoniazid 4-6 mg/kg (max 300 mg) q.d.; 8-12 mg/kg (max 900 mg) t.i.w.<br>Drug: pyrazinamide<br>* pyrazinamide 20-30mg/kg q.d.; 30-40mg/kg t.i.w.<br>|
| At least two 2nd line TB drugs w/ or w/out ARVs<br>HIV-infected and HIV-uninfected pregnant women ≥ 20 weeks gestation who received at least two of the following second line TB drugs at study entry: Injectable agents: kanamycin amikacin capreomycin Fluoroquinolones: moxifloxacin levofloxacin ofloxacin Oral bacteriostatic second-line agents: ethionamide/prothionamide terizidone/cycloserine para-aminosalicylic acid (PAS) Other agents: high dose INH bedaquiline clofazamine delamanid linezolid pretomanid | Drug: kanamycin<br>* kanamycin (2nd line TB drug)<br>Drug: amikacin<br>* amikacin (2nd line TB drug)<br>Drug: capreomycin<br>* capreomycin (2nd line TB drug)<br>Drug: moxifloxacin<br>* moxifloxacin (2nd line TB drug)<br>Drug: levoflaxacin<br>* levofloxacin (2nd line TB drug)<br>Drug: ofloxacin<br>* ofloxacin (2nd line TB drug)<br>Drug: ethionamide/prothionamide<br>* ethionamide/prothionamide (2nd line TB drug)<br>Drug: terizidone/cycloserine<br>* terizidone/cycloserine (2nd line TB drug)<br>Drug: para-aminosalicylic acid (PAS)<br>* para-aminosalicylic acid (PAS) (2nd line TB drug)<br>Drug: high dose INH<br>* high dose INH (2nd line TB drug)<br>Drug: bedaquiline<br>* bedaquiline (2nd line TB drug)<br>Drug: clofazamine<br>* clofazamine (2nd TB drug)<br>Drug: delamanid<br>* delamanid (2nd line TB drug)<br>Drug: linezolid<br>* linezolid (2nd line TB drug)<br>Drug: pretomanid<br>* pretomanid (2nd line TB drug)<br>|
| DRV/COBI 800/150mg q.d. or ATV/COBI 300/150mg q.d with 30-35ug EE<br>HIV-infected women 2-12 weeks (14-84 days) post-delivery who received darunavir/cobicistat (DRV/COBI) 800/150 mg q.d. or atazanavir/cobicistat (ATV/COBI) 300/150 mg q.d. postpartum and starting combined oral contraceptives formulated with 30-35 μg ethinyl estradiol | Drug: atazanavir/cobicistat<br>* atazanavir/cobicistat 300/150 mg q.d.<br>Drug: darunavir/cobicistat<br>* darunavir/cobicistat 800/150 mg q.d.<br>Drug: ethinyl estradiol<br>* oral contraceptives formulated with 30-35 μg ethinyl estradiol<br>|
| DRV/COBI 800/150mg q.d. or ATV/COBI 300/150mg q.d with ENG<br>HIV-infected women 2-12 weeks (14-84 days) post-delivery who received darunavir/cobicistat (DRV/COBI) 800/150 mg q.d. or atazanavir/cobicistat (ATV/COBI) 300/150 mg q.d. postpartum and starting etonogestrel (ENG) implant | Drug: atazanavir/cobicistat<br>* atazanavir/cobicistat 300/150 mg q.d.<br>Drug: darunavir/cobicistat<br>* darunavir/cobicistat 800/150 mg q.d.<br>Drug: etonogestrel implant<br>* etonogestrel implant contraceptive<br>|
| EFV 600mg q.d. with 30-35ug EE<br>HIV-infected women 2-12 weeks (14-84 days) post-delivery who received efavirenz (EFV) 600mg q.d. postpartum and starting combined oral contraceptives formulated with 30-35 μg ethinyl estradiol (EE) | Drug: efavirenz<br>* efavirenz 600 mg q.d.<br>Drug: ethinyl estradiol<br>* oral contraceptives formulated with 30-35 μg ethinyl estradiol<br>|
| ATV/RTV/TFV 300/100/300mg q.d. with 30-35ug EE<br>HIV-infected women 2-12 weeks (14-84 days) post-delivery who received atazanavir/ritonavir/tenofovir (ATV/RTV/TFV) 300/100/300 mg q.d. postpartum and starting combined oral contraceptives formulated with 30-35 μg ethinyl estradiol (EE) | Drug: atazanavir/ritonavir/tenofovir dosage #1<br>* atazanavir/ritonavir/tenofovir 300/100/300mg q.d.<br>Drug: ethinyl estradiol<br>* oral contraceptives formulated with 30-35 μg ethinyl estradiol<br>|
| NVP 200mg b.i.d<br>HIV-infected pregnant women ≥ 26 weeks gestation who received nevirapine (NVP) 200 mg twice a day | Drug: nevirapine<br>* nevirapine 200 mg twice a day<br>|
| APV 1200mg b.i.d<br>HIV-infected pregnant women ≥ 26 weeks gestation who received amprenavir (APV) 1200mg twice a day | Drug: amprenavir<br>* amprenavir 1200mg twice a day<br>|
| ABC 300mg b.i.d<br>HIV-infected pregnant women ≥ 20 weeks gestation who received abacavir (ABC) 300mg twice a day | Drug: abacavir<br>* abacavir 300mg twice a day<br>|
| LPV/RTV Arm 1: 400/100mg b.i.d<br>HIV-infected pregnant women ≥ 26 weeks gestation who received lopinavir/ritonavir (LPV/RTV) 400/100mg twice a day | Drug: lopinavir/ritonavir dosage #2<br>* lopinavir/ritonavir (Kaletra) 400/100mg twice a day<br>|
| IDV/RTV Arm 1: 800/100mg b.i.d<br>HIV-infected pregnant women ≥ 26 weeks gestation who received indinavir/ritonavir (IDV/RTV) 800/100 mg twice a day | Drug: indinavir/ritonavir dosage #1<br>* indinavir/ritonavir 800/100mg twice a day<br>|
| FPV/RTV 700/100mg b.i.d.<br>HIV-infected pregnant women ≥ 20 weeks gestation who received fosamprenavir/ritonavir (FPV/RTV)700/100mg twice a day | Drug: fosamprenavir/ritonavir<br>* fosamprenavir/ritonavir 700/100 mg twice a day<br>|
| LPV/RTV Arm 2: 400/100mg b.i.d. then 533/133mg b.i.d.<br>HIV-infected pregnant women ≥ 20 weeks gestation who received Kaletra (LPV/RTV) 400/100 mg twice a day until 30 weeks gestation, then 533/133 mg twice a day until results of postpartum PK evaluation were available | Drug: lopinavir/ritonavir dosage #2<br>* lopinavir/ritonavir (Kaletra) 400/100mg twice a day<br>Drug: lopinavir/ritonavir dosage #3<br>* lopinavir/ritonavir (Kaletra) 533/133 mg twice a day<br>|
| ATV/RTV Arm 1: 300/100mg q.d.<br>HIV-infected pregnant women ≥ 20 weeks gestation who received atazanavir/ritonavir (ATV/RTV) 300/100 mg once a day | Drug: atazanavir/ritonavir dosage #1<br>* atazanavir/ritonavir 300/100 mg once a day<br>|
| DDI 400mg or 250mg q.d.<br>HIV-infected pregnant women ≥ 20 weeks gestation who received didanosine delayed release (Videx® EC) (DDI) 400 mg once a day if weight > 60 kg; 250 mg once a day if weight < 60 kg | Drug: didanosine delayed release (Videx® EC)<br>* didanosine delayed release (Videx® EC) 400 mg once a day if weight > 60 kg; 250 mg once a day if weight < 60 kg<br>|
| FTC 200mg q.d.<br>HIV-infected pregnant women ≥ 20 weeks gestation who received emtricitabine (FTC) 200 mg once a day | Drug: emtricitabine<br>* emtricitabine 200 mg once a day<br>|
| TFV 300mg q.d.<br>HIV-infected pregnant women ≥ 20 weeks gestation who received tenofovir (TFV) 300 mg once a day | Drug: tenofovir<br>* tenofovir 300 mg once a day<br>|
| TFV/ATV/RTV Arm 1: 300/300/100mg q.d.<br>HIV-infected pregnant women ≥ 20 weeks gestation who received tenofovir/atazanavir/ritonavir (TFV/ATV/RTV) 300/300/100 mg once a day | Drug: atazanavir/ritonavir/tenofovir dosage #1<br>* atazanavir/ritonavir/tenofovir 300/100/300mg q.d.<br>|
| NFV Arm 1: 1250mg b.i.d.<br>HIV-infected pregnant women ≥ 20 weeks gestation who received nelfinavir (NFV) [625 mg tablets] 1250 mg twice a day | Drug: nelfinavir dosage #1<br>* nelfinavir [625 mg tablets] 1250 mg twice a day<br>|
| EFV 600mg q.d.<br>HIV-infected pregnant women ≥ 20 weeks gestation who received efavirenz (EFV) 600 mg once a day | Drug: efavirenz<br>* efavirenz 600 mg q.d.<br>|
| TPV/RTV 500/200mg b.i.d.<br>HIV-infected pregnant women ≥ 20 weeks gestation who received tipranavir/ritonavir (TPV/RTV) 500/200 mg twice a day | Drug: tipranavir/ritonavir<br>* tipranavir/ritonavir 500/200 mg twice a day<br>|
| LPV/RTV Arm 3: 400/100mg b.i.d. then 600/150mg b.i.d. then 400/100mg b.i.d.<br>HIV-infected pregnant women ≥ 20 weeks gestation who received lopinavir/ritonavir (LPV/RTV) tablets 400/100 mg [2 tablets] twice a day until 30 weeks gestation, then 600/150 mg [3 tablets] twice a day until postpartum hospital discharge; and 400/100 mg [2 tablets] twice a day after postpartum hospital discharge, until 2 week postpartum PK sample is drawn | Drug: lopinavir/ritonavir dosage #2<br>* lopinavir/ritonavir (Kaletra) 400/100mg twice a day<br>Drug: lopinavir/ritonavir dosage #4<br>* lopinavir/ritonavir (Kaletra) tablets 600/150 mg [3 tablets] twice a day<br>|
| RAL 400mg b.i.d.<br>HIV-infected pregnant women ≥ 20 weeks gestation who received raltegravir (RAL) 400 mg twice a day | Drug: raltegravir<br>* raltegravir 400 mg twice a day<br>|
| ETR 200mg b.i.d.<br>HIV-infected pregnant women ≥ 20 weeks gestation who received etravirine (ETR) 200mg twice a day | Drug: etravirine<br>* etravirine 200 mg twice a day<br>|
| MVC 150 or 300mg b.i.d.<br>HIV-infected pregnant women ≥ 20 weeks gestation who received maraviroc (MVC)150 mg or 300 mg twice a day | Drug: maraviroc<br>* maraviroc 150 mg or 300 mg twice a day<br>|
| DRV/RTV 800/100mg q.d.<br>HIV-infected pregnant women ≥ 20 weeks gestation who received darunavir/ritonavir (DRV/RTV) 800/100 mg once a day | Drug: darunavir/ritonavir dosage #4<br>* darunavir/ritonavir once daily 800/100 mg q.d.<br>|
| DRV/RTV 600/100mg b.i.d.<br>HIV-infected pregnant women ≥ 20 weeks gestation who received darunavir/ritonavir (DRV/RTV) 600/100 mg twice a day | Drug: darunavir/ritonavir dosage #1<br>* darunavir/ritonavir twice daily 600/100 mg b.i.d.<br>|
| ATV/RTV Arm 2: 300/100mg q.d. then 400/100mg q.d. then 300/100mg q.d.<br>HIV-infected pregnant women ≥ 20 weeks gestation who received atazanavir/ritonavir (ATV/RTV) 300/100 mg once a day until 30 weeks gestation then 400/100 mg once a day until postpartum hospital discharge; then 300/100 mg once a day after postpartum hospital discharge until 2 week postpartum PK samples drawn | Drug: atazanavir/ritonavir dosage #1<br>* atazanavir/ritonavir 300/100 mg once a day<br>Drug: atazanavir/ritonavir dosage #2<br>* atazanavir/ritonavir 400/100mg once a day<br>|
| TFV/ATV/RTV Arm 2: 300/300/100mg q.d. then 300/400/100mg q.d then 300/300/100mg q.d.<br>HIV-infected pregnant women ≥ 20 weeks gestation who received tenofovir/atazanavir/ritonavir (TFV/ATV/RTV) 300/300/100 mg once a day until 30 weeks gestation; then 300/400/100 mg once a day until postpartum hospital discharge; then 300/300/100 mg once a day after postpartum hospital discharge until 2 week postpartum PK samples drawn | Drug: atazanavir/ritonavir/tenofovir dosage #1<br>* atazanavir/ritonavir/tenofovir 300/100/300mg q.d.<br>Drug: tenofovir/atazanavir/ritonavir dosage #2<br>* tenofovir/atazanavir/ritonavir 300/400/100 mg once a day<br>|
| NFV Arm 2: 1250mg b.i.d. then 1875mg b.i.d. then 1250mg b.i.d.<br>HIV-infected pregnant women ≥ 20 weeks gestation who received nelfinavir (NFV) [625 mg tablets] 1250 mg twice a day until 30 weeks gestation; then 1875 mg twice a day until postpartum hospital discharge; then 1250 mg twice a day after postpartum hospital discharge until 2 week postpartum PK samples drawn | Drug: nelfinavir dosage #1<br>* nelfinavir [625 mg tablets] 1250 mg twice a day<br>Drug: nelfinavir dosage #2<br>* nelfinavir [625 mg tablets] 1875 mg twice a day<br>|
| IDV/RTV Arm 2: 400/100mg q.d. (only THA)<br>HIV-infected pregnant women ≥ 20 weeks gestation who received indinavir/ritonavir (IDV/RTV) 400/100 mg twice a day only to participants enrolling in Thailand | Drug: indinavir/ritonavir dosage #2<br>* indinavir/ritonavir 400/100 mg twice a day<br>|
| LPV/RTV Arm 4: 400/100mg b.i.d. then 600/150mg b.i.d. then 400/100mg b.i.d. (only African sites)<br>HIV-infected pregnant women ≥ 20 weeks gestation who received lopinavir/ritonavir (LPV/RTV, Alluvia tablets) 400/100 mg [2 tablets] twice day until 30 weeks gestation; then 600/150 mg [3 tablets] twice a day until postpartum hospital discharge; then 400/100 mg [2 tablets] twice a day after postpartum hospital discharge until 2 week postpartum PK sample drawn only to participants enrolling in Uganda | Drug: lopinavir/ritonavir dosage #2<br>* lopinavir/ritonavir (Kaletra) 400/100mg twice a day<br>Drug: lopinavir/ritonavir dosage #4<br>* lopinavir/ritonavir (Kaletra) tablets 600/150 mg [3 tablets] twice a day<br>|
| RPV 25mg q.d.<br>HIV-infected pregnant women ≥ 20 weeks gestation who received rilpivirine (RPV) (25 mg q.d.) | Drug: rilpivirine<br>* rilpivirine (25 mg q.d.)<br>|
| NVP 200mg b.i.d. and RIF and at least one 1st line TB drug<br>HIV-infected pregnant women > 20 weeks gestation who received nevirapine (NVP) 200 mg b.i.d AND rifampicin 8-12 mg/kg (max 600 mg) q.d.; 8-12 mg/kg (max 900 mg) t.i.w. and at least one of the following drugs at study entry: ethambutol 15-20 mg/kg q.d., 25-35 mg/kg t.i.w. isoniazid 4-6 mg/kg (max 300 mg) q.d.; 8-12 mg/kg (max 900 mg) t.i.w. pyrazinamide 20-30mg/kg q.d.; 30-40mg/kg t.i.w. | Drug: ethambutol<br>* ethambutol 15-20 mg/kg q.d., 25-35 mg/kg t.i.w.<br>Drug: isoniazid<br>* isoniazid 4-6 mg/kg (max 300 mg) q.d.; 8-12 mg/kg (max 900 mg) t.i.w.<br>Drug: pyrazinamide<br>* pyrazinamide 20-30mg/kg q.d.; 30-40mg/kg t.i.w.<br>Drug: nevirapine<br>* nevirapine 200 mg twice a day<br>|
| ATV/RTV/TFV 300/100/300mg q.d. with ENG<br>HIV- infected women 2-12 weeks postpartum who received atazanavir/ritonavir/tenofovir (ATV/RTV/TFV) 300/100/300 mg q.d. postpartum and starting postpartum etonogestrel (ENG) implant | Drug: atazanavir/ritonavir/tenofovir dosage #1<br>* atazanavir/ritonavir/tenofovir 300/100/300mg q.d.<br>Drug: etonogestrel implant<br>* etonogestrel implant contraceptive<br>|
| LPV/RTV 400/100 b.i.d. with 30-35ug EE<br>HIV- infected women 2-12 weeks postpartum who received lopinavir/ritonavir (LPV/RTV) 400/100 b.i.d. postpartum and starting combined oral contraceptives formulated with 30-35 μg ethinyl estradiol (EE) | Drug: ethinyl estradiol<br>* oral contraceptives formulated with 30-35 μg ethinyl estradiol<br>Drug: lopinavir/ritonavir dosage #2<br>* lopinavir/ritonavir (Kaletra) 400/100mg twice a day<br>|
| LPV/RTV 400/100 b.i.d. with ENG<br>HIV- infected women 2-12 weeks postpartum who received lopinavir/ritonavir (LPV/RTV) 400/100 b.i.d. postpartum and starting postpartum etonogestrel (ENG) implant | Drug: etonogestrel implant<br>* etonogestrel implant contraceptive<br>Drug: lopinavir/ritonavir dosage #2<br>* lopinavir/ritonavir (Kaletra) 400/100mg twice a day<br>|
| EFV 600mg q.d. with ENG<br>HIV-infected women 2-12 weeks postpartum who received efavirenz (EFV) 600mg q.d. postpartum and starting postpartum etonogestrel (ENG) implant | Drug: efavirenz<br>* efavirenz 600 mg q.d.<br>Drug: etonogestrel implant<br>* etonogestrel implant contraceptive<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| PK Parameter: Area Under the Curve From 0 to 12 Hours (AUC12) With Median (IQR) for ARVs and TB Drugs | Pharmacokinetic parameters were determined from plasma concentration-time profiles using noncompartmental methods. AUC12 (area under the curve from 0 to 12 hours) were determined using the linear trapezoidal rule. | Measured in 2nd trimester (20-26 wks gestation), 3rd trimester (30-38 wks gestation), and either 2-3 wks, 2-8 wks, or 6-12 wks postpartum depending on study arm. Blood samples were drawn pre-dose and at 1, 2, 4, 6, 8, and 12 hrs post dosing. | 
| PK Parameter: Area Under the Curve From 0 to 12 Hours (AUC12) With Median (Range) for ARVs and TB Drugs | Pharmacokinetic parameters were determined from plasma concentration-time profiles using noncompartmental methods. AUC12 (area under the curve from 0 to 12 hours) were determined using the linear trapezoidal rule. | Measured in 2nd trimester (20-26 wks gestation), 3rd trimester (30-38 wks gestation), and either 2-3 wks, 2-8 wks, or 6-12 wks postpartum depending on study arm. Blood samples were drawn pre-dose and at 1, 2, 4, 6, 8, and 12 hrs post dosing. | 
| PK Parameter: Area Under the Curve From 0 to 12 Hours (AUC12) With Geometric Mean (95% CI) for ARVs and TB Drugs | Measured in 2nd trimester (20-26 wks gestation), 3rd trimester (30-38 wks gestation), and either 2-3 wks, 2-8 wks, or 6-12 wks postpartum depending on study arm. Blood samples were drawn pre-dose and at 1, 2, 4, 6, 8, and 12 hrs post dosing. | Measured in 2nd trimester (20-26 wks gestation), 3rd trimester (30-38 wks gestation), and either 2-3 wks, 2-8 wks, or 6-12 wks postpartum depending on study arm. Blood samples were drawn pre-dose and at 1, 2, 4, 6, 8, and 12 hrs post dosing. | 
| PK Parameter: Area Under the Curve From 0 to 24 Hours (AUC24) With Median (IQR) for ARVs and TB Drugs | Pharmacokinetic parameters were determined from plasma concentration-time profiles using noncompartmental methods. AUC24 (area under the curve from 0 to 24 hours) were determined using the linear trapezoidal rule. | Measured at 2nd trimester (20-26 wks gestation), 3rd trimester (30-38 wks gestation), and either 2-3 wks, 2-8 wks or 6-12 wks postpartum depending on study arm. Blood samples were drawn pre-dose and at 1, 2, 4, 6, 8, 12 and 24 hours post dosing. | 
| PK Parameter: Area Under the Curve From 0 to 24 Hours (AUC24) With Median (Range) for ARVs and TB Drugs | Pharmacokinetic parameters were determined from plasma concentration-time profiles using noncompartmental methods. AUC24h (area-under-the-curve from 0 to 24 hours) were determined using the trapezoidal rule. | Measured at 2nd trimester (20-26 wks gestation), 3rd trimester (30-38 wks gestation), and either 2-3 wks, 2-8 wks or 6-12 wks postpartum depending on study arm. Blood samples were drawn pre-dose and at 1, 2, 4, 6, 8, 12 and 24 hours post dosing. | 
| PK Parameter: Maximum Concentration (Cmax) in mg/L With Median (IQR) for ARVs and TB Drugs | Pharmacokinetic parameters were determined from plasma concentration-time profiles using noncompartmental methods. Cmax was the maximum observed concentration after a dose. | Measured at 2nd trimester (20-26 wks gestation), 3rd trimester (30-38 wks gestation), and either 2-3 wks, 2-8 wks or 6-12 wks postpartum depending on study arm; Blood samples were drawn pre-dose and at 1, 2, 4, 6, 8,12 (and 24) hours post dosing. | 
| PK Parameter: Maximum Concentration (Cmax) in mg/L With Median (Range) for ARVs and TB Drugs | Pharmacokinetic parameters were determined from plasma concentration-time profiles using noncompartmental methods. Cmax was the maximum observed concentration after a dose. | Measured at 2nd trimester (20-26 wks gestation), 3rd trimester (30-38 wks gestation), and either 2-3 wks, 2-8 wks or 6-12 wks postpartum depending on study arm; Blood samples were drawn pre-dose and at 1, 2, 4, 6, 8,12 (and 24) hours post dosing. | 
| PK Parameter: Maximum Concentration (Cmax) in ng/mL With Median (IQR) for ARVs and TB Drugs | Pharmacokinetic parameters were determined from plasma concentration-time profiles using noncompartmental methods. Cmax was the maximum observed concentration after a dose. | Measured at 2nd trimester (20-26 wks gestation), 3rd trimester (30-38 wks gestation), and either 2-3 wks, 2-8 wks or 6-12 wks postpartum depending on study arm; Blood samples were drawn pre-dose and at 1, 2, 4, 6, 8,12 (and 24) hours post dosing. | 
| PK Parameter: Maximum Concentration (Cmax) in ng/mL With Median (95% CI) for ARVs and TB Drugs | Pharmacokinetic parameters were determined from plasma concentration-time profiles using noncompartmental methods. Cmax was the maximum observed concentration after a dose. | Measured at 2nd trimester (20-26 wks gestation), 3rd trimester (30-38 wks gestation), and either 2-3 wks, 2-8 wks or 6-12 wks postpartum depending on study arm; Blood samples were drawn pre-dose and at 1, 2, 4, 6, 8,12 (and 24) hours post dosing. | 
| PK Parameter: Trough Concentration (C12) With Median (IQR) for ARVs and TB Drugs | Pharmacokinetic parameters were determined from plasma concentration-time profiles using noncompartmental methods. Trough concentration was the measured concentration from the 12h post-dose sample after an observed dose. | Measured at 2nd trimester (20-26 wks gestation); 3rd trimester (30-38 gestation); and either 2-3 wks, 2-8 wks, or 6-12 wks postpartum, depending on study arm. Trough concentration was measured 12 hrs after an observed dose. | 
| PK Parameter: Trough Concentration (C12) With Median (Range) for ARVs and TB Drugs | Pharmacokinetic parameters were determined from plasma concentration-time profiles using noncompartmental methods. Trough concentration was the measured concentration from the 12h post-dose sample after an observed dose. | Measured at 2nd trimester (20-26 wks gestation); 3rd trimester (30-38 gestation); and either 2-3 wks, 2-8 wks, or 6-12 wks postpartum, depending on study arm. Trough concentration was measured 12 hrs after an observed dose. | 
| PK Parameter: Trough Concentration (C12) With Geometric Mean (95% CI) for ARVs and TB Drugs | Pharmacokinetic parameters were determined from plasma concentration-time profiles using noncompartmental methods. Trough concentration was the measured concentration from the 12h post-dose sample after an observed dose. | Measured at 2nd trimester (20-26 wks gestation), 3rd trimester (30-38 wks gestation), and either 2-3 wks, 2-8 wks or 6-12 wks postpartum depending on study arm. Trough concentration was measured 12 hrs after an observed dose. | 
| PK Parameter: Trough Concentration (C24) With Median (IQR) for ARVs and TB Drugs | Pharmacokinetic parameters were determined from plasma concentration-time profiles using noncompartmental methods. Trough concentration was the measured concentration from the 24h post-dose sample after an observed dose. For the TAF 25 mg q.d., 10 mg q.d. w/COBI, and 25 mg q.d. w/COBI or RTV boosting arms, samples were all below the limit of quantification and statistical analyses were not conducted. | Measured at 2nd trimester (20-26 wks gestation), 3rd trimester (30-38 wks gestation), and either 2-3 wks, 2-8 wks or 6-12 wks postpartum depending on study arm. Trough concentration was measured 24 hrs after an observed dose. | 
| PK Parameter: Trough Concentration (C24) With Median (Range) for ARVs and TB Drugs | Pharmacokinetic parameters were determined from plasma concentration-time profiles using noncompartmental methods. Trough concentration was the measured concentration from the 24h post-dose sample after an observed dose. | Measured at 2nd trimester (20-26 wks gestation), 3rd trimester (30-38 wks gestation), and either 2-3 wks, 2-8 wks or 6-12 wks postpartum depending on study arm. Trough concentration was measured 24 hrs after an observed dose. | 
| Number of Women Who Met PK Target of Area Under the Curve (AUC) for ARVs | Pharmacokinetic parameters were determined from plasma concentration-time profiles using noncompartmental methods. AUC (area under the curve) were determined using the linear trapezoidal rule. See PK target in the Protocol Appendix V. | Measured at 2nd trimester (20-26 wks gestation), 3rd trimester (30-38 wks gestation), and either 2-3 wks, 2-8 wks or 6-12 wks postpartum depending on study arm. Blood samples were drawn pre-dose and at 1, 2, 4, 6, 8, 12 (and 24) hours post dosing. | 
| Number of Women Who Met PK Target of Maximum Concentration (Cmax) for First Line TB Drugs | Pharmacokinetic parameters were determined from plasma concentration-time profiles using noncompartmental methods. Cmax was the maximum observed concentration after a dose. See PK target in Protocol Appendix V. No results are available for this outcome measure at this time. The TB drugs are being assayed in batches (not real-time) after the study completion. Labs have been experiencing additional delays due to urgent COVID-19 pandemic related work. | Measured at 2nd trimester (20-26 wks gestation), 3rd trimester (30-38 wks gestation), and either 2-3 wks, 2-8 wks or 6-12 wks postpartum depending on study arm. Blood samples were drawn pre-dose and at 1, 2, 4, 6, 8, 12 (and 24) hours post dosing. | 
| Plasma Concentration for Contraceptives | Serum concentrations of the contraceptives. Note that no historical controls were provided by team pharmacologists and thus no comparisons were done for contraceptive concentrations in women using hormonal contraceptives and selected ARV drugs as compared to historical controls not using those ARV drugs. | Measured at 6-7 weeks after contraceptive initiation postpartum | 
| Area Under the Curve From 0 to 12 Hours (AUC12) of ARVs for Contraceptive Arms | Pharmacokinetic parameters were determined from plasma concentration-time profiles using noncompartmental methods. AUC12h (area-under-the-curve from 0 to 12 hours) were determined using the linear trapezoidal rule. | Measured at 2-12 wks postpartum before contraceptive initiation and 6-7 wks after contraceptive initiation. Blood samples were drawn pre-dose and at 0, 1, 2, 6, 8 and 12 hours post dosing. | 
| Area Under the Curve From 0 to 24 Hours (AUC24) of ARVs for Contraceptive Arms | Pharmacokinetic parameters were determined from plasma concentration-time profiles using noncompartmental methods. AUC24h (area-under-the-curve from 0 to 24 hours) were determined using the linear trapezoidal rule. | Measured at 2-12 wks postpartum before contraceptive initiation and 6-7 wks after contraceptive initiation. Blood samples were drawn pre-dose and at 0, 1, 2, 6, 8, 12, and 24 hours post dosing. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| PK Parameter: Cord/Maternal Blood Concentration Ratio With Median (IQR) for ARVs and TB Drugs | Cord blood and maternal plasma concentrations were collected and measured at delivery, and compared as a ratio. | Measured at time of delivery with single cord blood and single maternal plasma sample. | 
| PK Parameter: Cord/Maternal Blood Concentration Ratio With Median (Range) for ARVs and TB Drugs | Cord blood and maternal plasma concentrations were collected and measured at delivery, and compared as a ratio. For arms with zero overall participants analyzed, samples were below the limit of quantification and ratios could not be calculated. | Measured at time of delivery with single cord blood and single maternal plasma sample. | 
| Pharmacokinetic (PK) Parameter: Infant Plasma Washout Half-life (T1/2) of ARVs and TB Drugs | Infant plasma concentrations were collected and measured during the first 9 days of life. Half-life is defined as 0.693/k, where k, the elimination rate constant, is the slope of the decline in concentrations. | Infant plasma samples at 2-10, 18-28, 36-72 hours and 5-9 days after birth. | 
| Pharmacokinetic (PK) Parameter: Infant Plasma Washout Concentration of ARVs and TB Drugs | Infant plasma concentrations were collected and measured during the first 9 days of life. | Blood samples were collected at 2-10, 18-28, 36-72 hours and 5-9 days after birth. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Pregnancy, Pharmacokinetics, Treatment Experienced