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HIV Infections | Pharmacokinetic Study of Antiretroviral Drugs and Related Drugs During and After Pregnancy

HIV Infections research study

What is the primary objective of this study?

The purpose of this study is 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 will also evaluate the PKs of certain ARVs in postpartum women before and after starting hormonal contraceptives. The PKs of these drugs will be evaluated by measuring the amount of medicine present in blood and/or vaginal secretions.

Who is eligible to participate?

Maternal Inclusion Criteria: - Participant must belong to one of the following 5 groups: 1. 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 2. 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 3. 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 4. 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 5. 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)

Which medical condition, disease, disorder, syndrome, illness, or injury is researched?

HIV Infections

Study Interventions

Interventions can include giving participants drugs, medical devices, procedures, vaccines, and other products that are either investigational or already available or noninvasive approaches such as surveys, education, and interviews.

Drug:atazanavir/cobicistatWomen will receive atazanavir/cobicistat as prescribed by their clinicians. (Dosage will vary for each participant.)

Drug:darunavir/ritonavirWomen will receive darunavir/ritonavir as prescribed by their clinicians. (Dosage will vary for each participant.)

Drug:darunavir/cobicistatWomen will receive darunavir/cobicistat as prescribed by their clinicians. (Dosage will vary for each participant.)

Drug:etravirineWomen will receive etravirine as prescribed by their clinicians. (Dosage will vary for each participant.)

Drug:elvitegravir/cobicistatWomen will receive elvitegravir/cobicistat as prescribed by their clinicians. (Dosage will vary for each participant.)

Drug:dolutegravirWomen will receive dolutegravir as prescribed by their clinicians. (Dosage will vary for each participant.)

Drug:tenofovir alafenamide fumarate (TAF)Women will receive TAF as prescribed by their clinicians. (Dosage will vary for each participant.)

Drug:TAF/cobicistatWomen will receive TAF/cobicistat as prescribed by their clinicians. (Dosage will vary for each participant.)

Drug:TAF/ritonavirWomen will receive TAF/ritonavir as prescribed by their clinicians. (Dosage will vary for each participant.)

Drug:efavirenzWomen will receive efavirenz as prescribed by their clinicians. (Dosage will vary for each participant.)

Drug:lopinavir/ritonavirWomen will receive lopinavir/ritonavir as prescribed by their clinicians. (Dosage will vary for each participant.)

Drug:nevirapineWomen will receive nevirapine as prescribed by their clinicians. (Dosage will vary for each participant.)

Drug:rifampicinWomen will receive rifampicin as prescribed by their clinicians. (Dosage will vary for each participant.)

Drug:ethambutolWomen will receive ethambutol as prescribed by their clinicians. (Dosage will vary for each participant.)

Drug:isoniazidWomen will receive isoniazid as prescribed by their clinicians. (Dosage will vary for each participant.)

Drug:pyrazinamideWomen will receive pyrazinamide as prescribed by their clinicians. (Dosage will vary for each participant.)

Drug:rifampicinWomen will receive rifampicin as prescribed by their clinicians. (Dosage will vary for each participant.)

Drug:kanamycinWomen will receive kanamycin as prescribed by their clinicians. (Dosage will vary for each participant.)

Drug:amikacinWomen will receive amikacin as prescribed by their clinicians. (Dosage will vary for each participant.)

Drug:capreomycinWomen will receive capreomycin as prescribed by their clinicians. (Dosage will vary for each participant.)

Drug:moxifloxacinWomen will receive moxifloxacin as prescribed by their clinicians. (Dosage will vary for each participant.)

Drug:levofloxacinWomen will receive levofloxacin as prescribed by their clinicians. (Dosage will vary for each participant.)

Drug:ofloxacinWomen will receive ofloxacin as prescribed by their clinicians. (Dosage will vary for each participant.)

Drug:ethionamide/prothionamideWomen will receive ethionamide/prothionamide as prescribed by their clinicians. (Dosage will vary for each participant.)

Drug:terizidone/cycloserineWomen will receive terizidone/cycloserine as prescribed by their clinicians. (Dosage will vary for each participant.)

Drug:para-aminosalicylic acid (PAS)Women will receive PAS as prescribed by their clinicians. (Dosage will vary for each participant.)

Drug:high dose isoniazid (INH)Women will receive high dose INH as prescribed by their clinicians. (Dosage will vary for each participant.)

Drug:bedaquilineWomen will receive bedaquiline as prescribed by their clinicians. (Dosage will vary for each participant.)

Drug:clofazamineWomen will receive clofazamine as prescribed by their clinicians. (Dosage will vary for each participant.)

Drug:delamanidWomen will receive delamanid as prescribed by their clinicians. (Dosage will vary for each participant.)

Drug:linezolidWomen will receive linezolid as prescribed by their clinicians. (Dosage will vary for each participant.)

Drug:pretomanidWomen will receive pretomanid as prescribed by their clinicians. (Dosage will vary for each participant.)

Drug:atazanavir/ritonavir/tenofovirWomen will receive atazanavir/ritonavir/tenofovir as prescribed by their clinicians. (Dosage will vary for each participant.)

Drug:ethinyl estradiol oral contraceptiveWomen will receive ethinyl estradiol oral contraceptive as prescribed by their clinicians. (Dosage will vary for each participant.)

Drug:etonogestrel implantWomen will receive etonogestrel implant as prescribed by their clinicians. (Dosage will vary for each participant.)

Study Arms

Research studies and clinical trials typically have two or more research arms. An arm is a group of people who receive the same treatment in the study.

Women taking ARVs without TB treatmentHIV-infected pregnant women will be assigned to this arm if receiving one or more of the following ARV drugs/drug combinations but not receiving TB treatment: atazanavir/cobicistat, darunavir/ritonavir, darunavir/cobicistat, etravirine, elvitegravir/cobicistat, dolutegravir, tenofovir alafenamide fumarate (TAF), TAF/cobicistat, TAF/ritonavir, efavirenz, or lopinavir/ritonavir. Note: As of February 2016, the study will no longer enroll women receiving etravirine or increased dose lopinavir/ritonavir.

Women taking ARVs with TB treatmentHIV-infected pregnant women will be assigned to this arm if receiving efavirenz, lopinavir/ritonavir, or nevirapine and TB treatment with at least one of the following TB drugs at study entry: rifampicin, ethambutol, isoniazid, or pyrazinamide. Note: As of February 2016, the study will no longer enroll women receiving nevirapine.

Women taking no ARVs with TB treatmentHIV-uninfected pregnant women will be assigned to this arm if receiving at least two of the following first-line TB drugs at study entry: ethambutol, isoniazid, pyrazinamide, or rifampicin.

Women with/without ARVs w/TB treatment for drug-resistant TBHIV-infected and HIV-uninfected pregnant women with or without ARVs will be assigned to this arm if receiving at least two of the following second-line TB drugs at study entry: kanamycin, amikacin, capreomycin, moxifloxacin, levofloxacin, ofloxacin, ethionamide/prothionamide, terizidone/cycloserine, para-aminosalicylic acid (PAS), high dose isoniazid (INH), bedaquiline, clofazamine, delamanid, linezolid, or pretomanid.

Women taking ARVs with postpartum hormonal contraceptivesHIV-infected women 2-12 weeks postpartum will be assigned to this arm if receiving one of the following ARV drug combinations and starting postpartum contraceptives: atazanavir/ritonavir/tenofovir, darunavir/cobicistat, atazanavir/cobicistat, or efavirenz AND starting combined oral contraceptives formulated with ethinyl estradiol; or atazanavir/ritonavir/tenofovir, efavirenz, atazanavir/cobicistat, or darunavir/cobicistat AND starting etonogestrel implant. Note: As of February 2016, the study will no longer enroll women receiving atazanavir/ritonavir/tenofovir or efavirenz AND starting etonogestrel implant.

Study Status

Recruiting

Start Date: March 2003

Completed Date:

Phase: Phase 4

Type: Interventional

Design:

Primary Outcome: Drug parameter: Area under the curve from 0 to 12 hours (AUC 0-12)

Secondary Outcome: Ratio of cord blood concentration to maternal blood concentration

Study sponsors, principal investigator, and references

Principal Investigator: Mark Mirochnick, MD

Lead Sponsor: National Institute of Allergy and Infectious Diseases (NIAID)

Collaborator: Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)

More information:https://clinicaltrials.gov/show/NCT00042289

Loutfy MR, Walmsley SL. Treatment of HIV infection in pregnant women: antiretroviral management options. Drugs. 2004;64(5):471-88. Review.

Best BM, Mirochnick M, Capparelli EV, Stek A, Burchett SK, Holland DT, Read JS, Smith E, Hu C, Spector SA, Connor JD; PACTG P1026s Study Team. Impact of pregnancy on abacavir pharmacokinetics. AIDS. 2006 Feb 28;20(4):553-60.

Stek AM, Mirochnick M, Capparelli E, Best BM, Hu C, Burchett SK, Elgie C, Holland DT, Smith E, Tuomala R, Cotter A, Read JS. Reduced lopinavir exposure during pregnancy. AIDS. 2006 Oct 3;20(15):1931-9.

Aweeka FT, Stek A, Best BM, Hu C, Holland D, Hermes A, Burchett SK, Read J, Mirochnick M, Capparelli EV; International Maternal Pediatric Adolescent AIDS Clinical Trials Group (IMPAACT) P1026s Protocol Team. Lopinavir protein binding in HIV-1-infected pregnant women. HIV Med. 2010 Apr;11(4):232-8. doi: 10.1111/j.1468-1293.2009.00767.x. Epub 2009 Dec 3.

Mirochnick M, Best BM, Stek AM, Capparelli EV, Hu C, Burchett SK, Rossi SS, Hawkins E, Basar M, Smith E, Read JS; IMPAACT 1026s Study Team. Atazanavir pharmacokinetics with and without tenofovir during pregnancy. J Acquir Immune Defic Syndr. 2011 Apr 15;56(5):412-9. doi: 10.1097/QAI.0b013e31820fd093.

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