Pre-exposure Prophylaxis Use by Breastfeeding HIV-Uninfected Women: A Prospective Short-Term Study of Antiretroviral Excretion in Breast Milk and Infant Absorption
As pre-exposure prophylaxis (PrEP) becomes more widely used in heterosexual populations, an important consideration is its safety in infants who are breastfed by women taking PrEP. We investigated whether tenofovir and emtricitabine are excreted into breast milk and then absorbed by the breastfeedin...
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| creator | Mugwanya, Kenneth K Hendrix, Craig W Mugo, Nelly R Marzinke, Mark Katabira, Elly T Ngure, Kenneth Semiyaga, Nulu B John-Stewart, Grace Muwonge, Timothy R Muthuri, Gabriel Stergachis, Andy Celum, Connie L Baeten, Jared M |
| description | As pre-exposure prophylaxis (PrEP) becomes more widely used in heterosexual populations, an important consideration is its safety in infants who are breastfed by women taking PrEP. We investigated whether tenofovir and emtricitabine are excreted into breast milk and then absorbed by the breastfeeding infant in clinically significant concentrations when used as PrEP by lactating women.
We conducted a prospective short-term, open-label study of daily oral emtricitabine-tenofovir disoproxil fumarate PrEP among 50 HIV-uninfected breastfeeding African mother-infant pairs between 1-24 wk postpartum (ClinicalTrials.gov Identifier: NCT02776748). The primary goal was to quantify the steady-state concentrations of tenofovir and emtricitabine in infant plasma ingested via breastfeeding. PrEP was administered to women through daily directly observed therapy (DOT) for ten consecutive days and then discontinued thereafter. Non-fasting peak and trough samples of maternal plasma and breast milk were obtained at drug concentration steady states on days 7 and 10, and a single infant plasma sample was obtained on day 7. Peak blood and breast milk samples were obtained 1-2 h after the maternal DOT PrEP dose, while maternal trough samples were obtained at the end of the PrEP dosing interval (i.e., 23 to 24 h) after maternal DOT PrEP dose. Tenofovir and emtricitabine concentrations were quantified using liquid chromatography-tandem mass spectrometry (LC-MS/MS) assays. Of the 50 mother-infant pairs enrolled, 48% were ≤12 wk and 52% were 13-24 wk postpartum, and median maternal age was 25 y (interquartile range [IQR] 22-28). During study follow-up, the median (IQR) daily reported frequency of infant breastfeeding was 15 times (12 to 18) overall, 16 (14 to 19) for the ≤12 weeks, and 14 (12 to 17) for the 13-24 wk infant age groups. Overall, median (IQR) time-averaged peak concentrations in breast milk were 3.2 ng/mL (2.3 to 4.7) for tenofovir and 212.5 ng/mL (140.0 to 405.0) for emtricitabine. Similarly, median (IQR) time-averaged trough concentrations in breast milk were 3.3 ng/mL (2.3 to 4.4) for tenofovir and 183.0 ng/mL (113.0 to 250.0) for emtricitabine, reflecting trough-to-peak breast milk concentration ratios of 1.0 for tenofovir and 0.8 for emtricitabine, respectively. In infant plasma, tenofovir was unquantifiable in 46/49 samples (94%), but emtricitabine was detectable in 47/49 (96%) (median [IQR] concentration: 13.2 ng/mL [9.3 to 16.7]). The estimated equivalent doses |
| doi_str_mv | 10.1371/journal.pmed.1002132 |
| format | Article |
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We conducted a prospective short-term, open-label study of daily oral emtricitabine-tenofovir disoproxil fumarate PrEP among 50 HIV-uninfected breastfeeding African mother-infant pairs between 1-24 wk postpartum (ClinicalTrials.gov Identifier: NCT02776748). The primary goal was to quantify the steady-state concentrations of tenofovir and emtricitabine in infant plasma ingested via breastfeeding. PrEP was administered to women through daily directly observed therapy (DOT) for ten consecutive days and then discontinued thereafter. Non-fasting peak and trough samples of maternal plasma and breast milk were obtained at drug concentration steady states on days 7 and 10, and a single infant plasma sample was obtained on day 7. Peak blood and breast milk samples were obtained 1-2 h after the maternal DOT PrEP dose, while maternal trough samples were obtained at the end of the PrEP dosing interval (i.e., 23 to 24 h) after maternal DOT PrEP dose. Tenofovir and emtricitabine concentrations were quantified using liquid chromatography-tandem mass spectrometry (LC-MS/MS) assays. Of the 50 mother-infant pairs enrolled, 48% were ≤12 wk and 52% were 13-24 wk postpartum, and median maternal age was 25 y (interquartile range [IQR] 22-28). During study follow-up, the median (IQR) daily reported frequency of infant breastfeeding was 15 times (12 to 18) overall, 16 (14 to 19) for the ≤12 weeks, and 14 (12 to 17) for the 13-24 wk infant age groups. Overall, median (IQR) time-averaged peak concentrations in breast milk were 3.2 ng/mL (2.3 to 4.7) for tenofovir and 212.5 ng/mL (140.0 to 405.0) for emtricitabine. Similarly, median (IQR) time-averaged trough concentrations in breast milk were 3.3 ng/mL (2.3 to 4.4) for tenofovir and 183.0 ng/mL (113.0 to 250.0) for emtricitabine, reflecting trough-to-peak breast milk concentration ratios of 1.0 for tenofovir and 0.8 for emtricitabine, respectively. In infant plasma, tenofovir was unquantifiable in 46/49 samples (94%), but emtricitabine was detectable in 47/49 (96%) (median [IQR] concentration: 13.2 ng/mL [9.3 to 16.7]). The estimated equivalent doses an infant would ingest daily from breastfeeding were 0.47 μg/kg (IQR 0.35 to 0.71) for tenofovir and 31.9 μg/kg (IQR 21.0 to 60.8) for emtricitabine, translating into a <0.01% and 0.5% relative dose when compared to the 6 mg/kg dose that is proposed for therapeutic treatment of infant HIV infection and for prevention of infant postnatal HIV infection; a dose that has not shown safety concerns. No serious adverse effects were recorded during study follow-up. The key study limitation was that only a single infant sample was collected to minimize venipunctures for the children. However, maternal daily DOT and specimen collection at drug concentration steady state provided an adequate approach to address the key research question. Importantly, there was minimal variation in breast milk concentrations of tenofovir and emtricitabine (respective median trough-to-peak concentration ratio ~1), demonstrating that infants were exposed to consistent drug dosing via breast milk.
In this short-term study of daily directly observed oral PrEP in HIV-uninfected breastfeeding women, the estimated infant doses from breast milk and resultant infant plasma concentrations for tenofovir and emtricitabine were 12,500 and >200-fold lower than the respective proposed infant therapeutic doses, and tenofovir was not detected in 94% of infant plasma samples. These data suggest that PrEP can be safely used during breastfeeding with minimal infant drug exposure.
ClinicalTrials.gov, Identifier: NCT02776748.</description><identifier>ISSN: 1549-1676</identifier><identifier>ISSN: 1549-1277</identifier><identifier>EISSN: 1549-1676</identifier><identifier>DOI: 10.1371/journal.pmed.1002132</identifier><identifier>PMID: 27676257</identifier><language>eng</language><publisher>United States: Public Library of Science</publisher><subject>Administration, Oral ; Anti-HIV Agents - pharmacokinetics ; Babies ; Baby foods ; Biology and Life Sciences ; Breast feeding ; Breast Feeding - adverse effects ; Breastfeeding & lactation ; Drug dosages ; Emtricitabine - pharmacokinetics ; Epidemiology ; Female ; Health aspects ; HIV ; HIV Infections - prevention & control ; Human immunodeficiency virus ; Humans ; Infections ; Infectious diseases ; Lactation ; Medical research ; Medicine ; Medicine and Health Sciences ; Milk ; Milk, Human - chemistry ; Patient outcomes ; People and Places ; Physiological absorption ; Physiological aspects ; Plasma ; Pre-Exposure Prophylaxis - methods ; Prophylaxis ; Prospective Studies ; Short term ; Studies ; Tenofovir - pharmacokinetics ; Womens health</subject><ispartof>PLoS medicine, 2016-09, Vol.13 (9), p.e1002132-e1002132</ispartof><rights>COPYRIGHT 2016 Public Library of Science</rights><rights>2016 Public Library of Science. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited: Mugwanya KK, Hendrix CW, Mugo NR, Marzinke M, Katabira ET, Ngure K, et al. (2016) Pre-exposure Prophylaxis Use by Breastfeeding HIV-Uninfected Women: A Prospective Short-Term Study of Antiretroviral Excretion in Breast Milk and Infant Absorption. PLoS Med 13(9): e1002132. doi:10.1371/journal.pmed.1002132</rights><rights>2016 Mugwanya et al 2016 Mugwanya et al</rights><rights>2016 Public Library of Science. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited: Mugwanya KK, Hendrix CW, Mugo NR, Marzinke M, Katabira ET, Ngure K, et al. (2016) Pre-exposure Prophylaxis Use by Breastfeeding HIV-Uninfected Women: A Prospective Short-Term Study of Antiretroviral Excretion in Breast Milk and Infant Absorption. PLoS Med 13(9): e1002132. doi:10.1371/journal.pmed.1002132</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c764t-56e38b31fdfe0ec771644e6f25be111c6d6771089b05129dee42fad34dbb35793</citedby><cites>FETCH-LOGICAL-c764t-56e38b31fdfe0ec771644e6f25be111c6d6771089b05129dee42fad34dbb35793</cites><orcidid>0000-0003-2243-9789 ; 0000-0001-5208-7468 ; 0000-0002-8478-9234</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC5038971/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC5038971/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,315,729,782,786,866,887,2106,2932,23875,27933,27934,53800,53802</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/27676257$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><contributor>Mofenson, Lynne Meryl</contributor><creatorcontrib>Mugwanya, Kenneth K</creatorcontrib><creatorcontrib>Hendrix, Craig W</creatorcontrib><creatorcontrib>Mugo, Nelly R</creatorcontrib><creatorcontrib>Marzinke, Mark</creatorcontrib><creatorcontrib>Katabira, Elly T</creatorcontrib><creatorcontrib>Ngure, Kenneth</creatorcontrib><creatorcontrib>Semiyaga, Nulu B</creatorcontrib><creatorcontrib>John-Stewart, Grace</creatorcontrib><creatorcontrib>Muwonge, Timothy R</creatorcontrib><creatorcontrib>Muthuri, Gabriel</creatorcontrib><creatorcontrib>Stergachis, Andy</creatorcontrib><creatorcontrib>Celum, Connie L</creatorcontrib><creatorcontrib>Baeten, Jared M</creatorcontrib><title>Pre-exposure Prophylaxis Use by Breastfeeding HIV-Uninfected Women: A Prospective Short-Term Study of Antiretroviral Excretion in Breast Milk and Infant Absorption</title><title>PLoS medicine</title><addtitle>PLoS Med</addtitle><description>As pre-exposure prophylaxis (PrEP) becomes more widely used in heterosexual populations, an important consideration is its safety in infants who are breastfed by women taking PrEP. We investigated whether tenofovir and emtricitabine are excreted into breast milk and then absorbed by the breastfeeding infant in clinically significant concentrations when used as PrEP by lactating women.
We conducted a prospective short-term, open-label study of daily oral emtricitabine-tenofovir disoproxil fumarate PrEP among 50 HIV-uninfected breastfeeding African mother-infant pairs between 1-24 wk postpartum (ClinicalTrials.gov Identifier: NCT02776748). The primary goal was to quantify the steady-state concentrations of tenofovir and emtricitabine in infant plasma ingested via breastfeeding. PrEP was administered to women through daily directly observed therapy (DOT) for ten consecutive days and then discontinued thereafter. Non-fasting peak and trough samples of maternal plasma and breast milk were obtained at drug concentration steady states on days 7 and 10, and a single infant plasma sample was obtained on day 7. Peak blood and breast milk samples were obtained 1-2 h after the maternal DOT PrEP dose, while maternal trough samples were obtained at the end of the PrEP dosing interval (i.e., 23 to 24 h) after maternal DOT PrEP dose. Tenofovir and emtricitabine concentrations were quantified using liquid chromatography-tandem mass spectrometry (LC-MS/MS) assays. Of the 50 mother-infant pairs enrolled, 48% were ≤12 wk and 52% were 13-24 wk postpartum, and median maternal age was 25 y (interquartile range [IQR] 22-28). During study follow-up, the median (IQR) daily reported frequency of infant breastfeeding was 15 times (12 to 18) overall, 16 (14 to 19) for the ≤12 weeks, and 14 (12 to 17) for the 13-24 wk infant age groups. Overall, median (IQR) time-averaged peak concentrations in breast milk were 3.2 ng/mL (2.3 to 4.7) for tenofovir and 212.5 ng/mL (140.0 to 405.0) for emtricitabine. Similarly, median (IQR) time-averaged trough concentrations in breast milk were 3.3 ng/mL (2.3 to 4.4) for tenofovir and 183.0 ng/mL (113.0 to 250.0) for emtricitabine, reflecting trough-to-peak breast milk concentration ratios of 1.0 for tenofovir and 0.8 for emtricitabine, respectively. In infant plasma, tenofovir was unquantifiable in 46/49 samples (94%), but emtricitabine was detectable in 47/49 (96%) (median [IQR] concentration: 13.2 ng/mL [9.3 to 16.7]). The estimated equivalent doses an infant would ingest daily from breastfeeding were 0.47 μg/kg (IQR 0.35 to 0.71) for tenofovir and 31.9 μg/kg (IQR 21.0 to 60.8) for emtricitabine, translating into a <0.01% and 0.5% relative dose when compared to the 6 mg/kg dose that is proposed for therapeutic treatment of infant HIV infection and for prevention of infant postnatal HIV infection; a dose that has not shown safety concerns. No serious adverse effects were recorded during study follow-up. The key study limitation was that only a single infant sample was collected to minimize venipunctures for the children. However, maternal daily DOT and specimen collection at drug concentration steady state provided an adequate approach to address the key research question. Importantly, there was minimal variation in breast milk concentrations of tenofovir and emtricitabine (respective median trough-to-peak concentration ratio ~1), demonstrating that infants were exposed to consistent drug dosing via breast milk.
In this short-term study of daily directly observed oral PrEP in HIV-uninfected breastfeeding women, the estimated infant doses from breast milk and resultant infant plasma concentrations for tenofovir and emtricitabine were 12,500 and >200-fold lower than the respective proposed infant therapeutic doses, and tenofovir was not detected in 94% of infant plasma samples. These data suggest that PrEP can be safely used during breastfeeding with minimal infant drug exposure.
ClinicalTrials.gov, Identifier: NCT02776748.</description><subject>Administration, Oral</subject><subject>Anti-HIV Agents - pharmacokinetics</subject><subject>Babies</subject><subject>Baby foods</subject><subject>Biology and Life Sciences</subject><subject>Breast feeding</subject><subject>Breast Feeding - adverse effects</subject><subject>Breastfeeding & lactation</subject><subject>Drug dosages</subject><subject>Emtricitabine - pharmacokinetics</subject><subject>Epidemiology</subject><subject>Female</subject><subject>Health aspects</subject><subject>HIV</subject><subject>HIV Infections - prevention & control</subject><subject>Human immunodeficiency virus</subject><subject>Humans</subject><subject>Infections</subject><subject>Infectious diseases</subject><subject>Lactation</subject><subject>Medical research</subject><subject>Medicine</subject><subject>Medicine and Health Sciences</subject><subject>Milk</subject><subject>Milk, Human - chemistry</subject><subject>Patient outcomes</subject><subject>People and Places</subject><subject>Physiological absorption</subject><subject>Physiological aspects</subject><subject>Plasma</subject><subject>Pre-Exposure Prophylaxis - methods</subject><subject>Prophylaxis</subject><subject>Prospective Studies</subject><subject>Short term</subject><subject>Studies</subject><subject>Tenofovir - pharmacokinetics</subject><subject>Womens health</subject><issn>1549-1676</issn><issn>1549-1277</issn><issn>1549-1676</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2016</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><sourceid>ABUWG</sourceid><sourceid>AFKRA</sourceid><sourceid>AZQEC</sourceid><sourceid>BENPR</sourceid><sourceid>CCPQU</sourceid><sourceid>DWQXO</sourceid><sourceid>DOA</sourceid><recordid>eNqVk9tu1DAQhiMEoqXwBggsISG4yGI7zokLpKUqdKVCK3rg0nKS8a6XrB1sp9p9Hl4Uh6ZVF-0FKBdJJt__z3gmE0XPCZ6QJCfvlqa3WrSTbgXNhGBMSUIfRPskZWVMsjx7eO95L3ri3DIwJS7x42iP5iFI03w_-nVmIYZ1Z1xvAZ1Z0y02rVgrhy4doGqDPloQzkuARuk5Op5dxZdaaQm1hwZ9NyvQ79F0ELouxNQ1oPOFsT6-ALtC575vNshINNVeWfDWXCsrWnS0rsObMhopPWZAX1T7AwndoJmWQns0rZyx3QA9jR5J0Tp4Nt4PostPRxeHx_HJ6efZ4fQkrvOM-TjNICmqhMhGAoY6z0nGGGSSphUQQuqsyUIMF2WFU0LLBoBRKZqENVWVpHmZHEQvb3y71jg-9tdxUtCSsZSWRSBmN0RjxJJ3Vq2E3XAjFP8TMHbOhfWqboHjNOQvCpbjFDPMSKiBEZmxvCA1rqkMXh_GbH0VRliD9qE1W6bbX7Ra8Lm55ilOijInweDNaGDNzx6c5yvlamhbocH0Q91JmtKCUBrQV3-hu083UnMRDhCGbELeejDlU5ZTSos8Hah4BzUHDaFIo0GqEN7iJzv4cDWwUvVOwdstQWA8rP1c9M7x2fm3_2C__jt7erXNvr7HLkC0fuFM2w-_o9sG2Q1Yhw1wFuTdAAnmw57edpoPe8rHPQ2yF_eHfye6XczkN2RwN4s</recordid><startdate>20160927</startdate><enddate>20160927</enddate><creator>Mugwanya, Kenneth K</creator><creator>Hendrix, Craig W</creator><creator>Mugo, Nelly R</creator><creator>Marzinke, Mark</creator><creator>Katabira, Elly T</creator><creator>Ngure, Kenneth</creator><creator>Semiyaga, Nulu B</creator><creator>John-Stewart, Grace</creator><creator>Muwonge, Timothy R</creator><creator>Muthuri, Gabriel</creator><creator>Stergachis, Andy</creator><creator>Celum, Connie L</creator><creator>Baeten, Jared M</creator><general>Public Library of Science</general><general>Public Library of Science (PLoS)</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>IOV</scope><scope>ISN</scope><scope>ISR</scope><scope>3V.</scope><scope>7TK</scope><scope>7X7</scope><scope>7XB</scope><scope>88E</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>ABUWG</scope><scope>AFKRA</scope><scope>AZQEC</scope><scope>BENPR</scope><scope>CCPQU</scope><scope>DWQXO</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>K9.</scope><scope>M0S</scope><scope>M1P</scope><scope>PIMPY</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PRINS</scope><scope>7X8</scope><scope>5PM</scope><scope>DOA</scope><scope>CZK</scope><orcidid>https://orcid.org/0000-0003-2243-9789</orcidid><orcidid>https://orcid.org/0000-0001-5208-7468</orcidid><orcidid>https://orcid.org/0000-0002-8478-9234</orcidid></search><sort><creationdate>20160927</creationdate><title>Pre-exposure Prophylaxis Use by Breastfeeding HIV-Uninfected Women: A Prospective Short-Term Study of Antiretroviral Excretion in Breast Milk and Infant Absorption</title><author>Mugwanya, Kenneth K ; Hendrix, Craig W ; Mugo, Nelly R ; Marzinke, Mark ; Katabira, Elly T ; Ngure, Kenneth ; Semiyaga, Nulu B ; John-Stewart, Grace ; Muwonge, Timothy R ; Muthuri, Gabriel ; Stergachis, Andy ; Celum, Connie L ; Baeten, Jared M</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c764t-56e38b31fdfe0ec771644e6f25be111c6d6771089b05129dee42fad34dbb35793</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2016</creationdate><topic>Administration, Oral</topic><topic>Anti-HIV Agents - pharmacokinetics</topic><topic>Babies</topic><topic>Baby foods</topic><topic>Biology and Life Sciences</topic><topic>Breast feeding</topic><topic>Breast Feeding - adverse effects</topic><topic>Breastfeeding & lactation</topic><topic>Drug dosages</topic><topic>Emtricitabine - pharmacokinetics</topic><topic>Epidemiology</topic><topic>Female</topic><topic>Health aspects</topic><topic>HIV</topic><topic>HIV Infections - prevention & control</topic><topic>Human immunodeficiency virus</topic><topic>Humans</topic><topic>Infections</topic><topic>Infectious diseases</topic><topic>Lactation</topic><topic>Medical research</topic><topic>Medicine</topic><topic>Medicine and Health Sciences</topic><topic>Milk</topic><topic>Milk, Human - chemistry</topic><topic>Patient outcomes</topic><topic>People and Places</topic><topic>Physiological absorption</topic><topic>Physiological aspects</topic><topic>Plasma</topic><topic>Pre-Exposure Prophylaxis - methods</topic><topic>Prophylaxis</topic><topic>Prospective Studies</topic><topic>Short term</topic><topic>Studies</topic><topic>Tenofovir - pharmacokinetics</topic><topic>Womens health</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Mugwanya, Kenneth K</creatorcontrib><creatorcontrib>Hendrix, Craig W</creatorcontrib><creatorcontrib>Mugo, Nelly R</creatorcontrib><creatorcontrib>Marzinke, Mark</creatorcontrib><creatorcontrib>Katabira, Elly T</creatorcontrib><creatorcontrib>Ngure, Kenneth</creatorcontrib><creatorcontrib>Semiyaga, Nulu B</creatorcontrib><creatorcontrib>John-Stewart, Grace</creatorcontrib><creatorcontrib>Muwonge, Timothy R</creatorcontrib><creatorcontrib>Muthuri, Gabriel</creatorcontrib><creatorcontrib>Stergachis, Andy</creatorcontrib><creatorcontrib>Celum, Connie L</creatorcontrib><creatorcontrib>Baeten, Jared M</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Gale In Context: Opposing Viewpoints</collection><collection>Gale In Context: Canada</collection><collection>Gale In Context: Science</collection><collection>ProQuest Central (Corporate)</collection><collection>Neurosciences Abstracts</collection><collection>Health & Medical Collection</collection><collection>ProQuest Central (purchase pre-March 2016)</collection><collection>Medical Database (Alumni Edition)</collection><collection>Hospital Premium Collection</collection><collection>Hospital Premium Collection (Alumni Edition)</collection><collection>ProQuest Central (Alumni) (purchase pre-March 2016)</collection><collection>ProQuest Central (Alumni Edition)</collection><collection>ProQuest Central UK/Ireland</collection><collection>ProQuest Central Essentials</collection><collection>ProQuest Central</collection><collection>ProQuest One Community College</collection><collection>ProQuest Central Korea</collection><collection>Health Research Premium Collection</collection><collection>Health Research Premium Collection (Alumni)</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>Health & Medical Collection (Alumni Edition)</collection><collection>Medical Database</collection><collection>Access via ProQuest (Open Access)</collection><collection>ProQuest One Academic Eastern Edition (DO NOT USE)</collection><collection>ProQuest One Academic</collection><collection>ProQuest One Academic UKI Edition</collection><collection>ProQuest Central China</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><collection>DOAJ Directory of Open Access Journals</collection><collection>PLoS Medicine</collection><jtitle>PLoS medicine</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Mugwanya, Kenneth K</au><au>Hendrix, Craig W</au><au>Mugo, Nelly R</au><au>Marzinke, Mark</au><au>Katabira, Elly T</au><au>Ngure, Kenneth</au><au>Semiyaga, Nulu B</au><au>John-Stewart, Grace</au><au>Muwonge, Timothy R</au><au>Muthuri, Gabriel</au><au>Stergachis, Andy</au><au>Celum, Connie L</au><au>Baeten, Jared M</au><au>Mofenson, Lynne Meryl</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Pre-exposure Prophylaxis Use by Breastfeeding HIV-Uninfected Women: A Prospective Short-Term Study of Antiretroviral Excretion in Breast Milk and Infant Absorption</atitle><jtitle>PLoS medicine</jtitle><addtitle>PLoS Med</addtitle><date>2016-09-27</date><risdate>2016</risdate><volume>13</volume><issue>9</issue><spage>e1002132</spage><epage>e1002132</epage><pages>e1002132-e1002132</pages><issn>1549-1676</issn><issn>1549-1277</issn><eissn>1549-1676</eissn><abstract>As pre-exposure prophylaxis (PrEP) becomes more widely used in heterosexual populations, an important consideration is its safety in infants who are breastfed by women taking PrEP. We investigated whether tenofovir and emtricitabine are excreted into breast milk and then absorbed by the breastfeeding infant in clinically significant concentrations when used as PrEP by lactating women.
We conducted a prospective short-term, open-label study of daily oral emtricitabine-tenofovir disoproxil fumarate PrEP among 50 HIV-uninfected breastfeeding African mother-infant pairs between 1-24 wk postpartum (ClinicalTrials.gov Identifier: NCT02776748). The primary goal was to quantify the steady-state concentrations of tenofovir and emtricitabine in infant plasma ingested via breastfeeding. PrEP was administered to women through daily directly observed therapy (DOT) for ten consecutive days and then discontinued thereafter. Non-fasting peak and trough samples of maternal plasma and breast milk were obtained at drug concentration steady states on days 7 and 10, and a single infant plasma sample was obtained on day 7. Peak blood and breast milk samples were obtained 1-2 h after the maternal DOT PrEP dose, while maternal trough samples were obtained at the end of the PrEP dosing interval (i.e., 23 to 24 h) after maternal DOT PrEP dose. Tenofovir and emtricitabine concentrations were quantified using liquid chromatography-tandem mass spectrometry (LC-MS/MS) assays. Of the 50 mother-infant pairs enrolled, 48% were ≤12 wk and 52% were 13-24 wk postpartum, and median maternal age was 25 y (interquartile range [IQR] 22-28). During study follow-up, the median (IQR) daily reported frequency of infant breastfeeding was 15 times (12 to 18) overall, 16 (14 to 19) for the ≤12 weeks, and 14 (12 to 17) for the 13-24 wk infant age groups. Overall, median (IQR) time-averaged peak concentrations in breast milk were 3.2 ng/mL (2.3 to 4.7) for tenofovir and 212.5 ng/mL (140.0 to 405.0) for emtricitabine. Similarly, median (IQR) time-averaged trough concentrations in breast milk were 3.3 ng/mL (2.3 to 4.4) for tenofovir and 183.0 ng/mL (113.0 to 250.0) for emtricitabine, reflecting trough-to-peak breast milk concentration ratios of 1.0 for tenofovir and 0.8 for emtricitabine, respectively. In infant plasma, tenofovir was unquantifiable in 46/49 samples (94%), but emtricitabine was detectable in 47/49 (96%) (median [IQR] concentration: 13.2 ng/mL [9.3 to 16.7]). The estimated equivalent doses an infant would ingest daily from breastfeeding were 0.47 μg/kg (IQR 0.35 to 0.71) for tenofovir and 31.9 μg/kg (IQR 21.0 to 60.8) for emtricitabine, translating into a <0.01% and 0.5% relative dose when compared to the 6 mg/kg dose that is proposed for therapeutic treatment of infant HIV infection and for prevention of infant postnatal HIV infection; a dose that has not shown safety concerns. No serious adverse effects were recorded during study follow-up. The key study limitation was that only a single infant sample was collected to minimize venipunctures for the children. However, maternal daily DOT and specimen collection at drug concentration steady state provided an adequate approach to address the key research question. Importantly, there was minimal variation in breast milk concentrations of tenofovir and emtricitabine (respective median trough-to-peak concentration ratio ~1), demonstrating that infants were exposed to consistent drug dosing via breast milk.
In this short-term study of daily directly observed oral PrEP in HIV-uninfected breastfeeding women, the estimated infant doses from breast milk and resultant infant plasma concentrations for tenofovir and emtricitabine were 12,500 and >200-fold lower than the respective proposed infant therapeutic doses, and tenofovir was not detected in 94% of infant plasma samples. These data suggest that PrEP can be safely used during breastfeeding with minimal infant drug exposure.
ClinicalTrials.gov, Identifier: NCT02776748.</abstract><cop>United States</cop><pub>Public Library of Science</pub><pmid>27676257</pmid><doi>10.1371/journal.pmed.1002132</doi><orcidid>https://orcid.org/0000-0003-2243-9789</orcidid><orcidid>https://orcid.org/0000-0001-5208-7468</orcidid><orcidid>https://orcid.org/0000-0002-8478-9234</orcidid><oa>free_for_read</oa></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 1549-1676 |
| ispartof | PLoS medicine, 2016-09, Vol.13 (9), p.e1002132-e1002132 |
| issn | 1549-1676 1549-1277 1549-1676 |
| language | eng |
| recordid | cdi_plos_journals_1829445298 |
| source | MEDLINE; DOAJ Directory of Open Access Journals; Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals; Public Library of Science (PLoS) Journals Open Access; PubMed Central |
| subjects | Administration, Oral Anti-HIV Agents - pharmacokinetics Babies Baby foods Biology and Life Sciences Breast feeding Breast Feeding - adverse effects Breastfeeding & lactation Drug dosages Emtricitabine - pharmacokinetics Epidemiology Female Health aspects HIV HIV Infections - prevention & control Human immunodeficiency virus Humans Infections Infectious diseases Lactation Medical research Medicine Medicine and Health Sciences Milk Milk, Human - chemistry Patient outcomes People and Places Physiological absorption Physiological aspects Plasma Pre-Exposure Prophylaxis - methods Prophylaxis Prospective Studies Short term Studies Tenofovir - pharmacokinetics Womens health |
| title | Pre-exposure Prophylaxis Use by Breastfeeding HIV-Uninfected Women: A Prospective Short-Term Study of Antiretroviral Excretion in Breast Milk and Infant Absorption |
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