Pharmacokinetics of Dapivirine Transfer into Blood Plasma, Breast Milk, and Cervicovaginal Fluid of Lactating Women Using the Dapivirine Vaginal Ring

ABSTRACT Breastfeeding (BF) women are an important population for biomedical HIV prevention strategies, but they are rarely included in trials. The 25-mg dapivirine vaginal ring (VR) reduced women’s risk of sexually transmitted HIV infection in two phase 3 trials conducted in Africa. We conducted a phase 1, open-label study (MTN-029/IPM 039) of dapivirine VR use among lactating women in Pittsburgh, PA, and Birmingham, AL, USA. MTN-029/IPM 039 enrolled 16 healthy adult women who had already weaned their infants but were still able to express breast milk. Women were instructed to use the VR continuously for 14 days and provided milk, plasma, and cervicovaginal fluid (CVF) samples for pharmacological analysis. No infants were exposed to the drug, but infant dosage was estimated according to FDA guidance. Adverse events (AEs) were collected at all contacts. The study was completed with 100% participant retention. Median dapivirine concentrations were 676 pg/ml in breast milk, 327 pg/ml in plasma (milk/plasma ratio ∼2.0), and 36.25 ng/mg in CVF. Six participants experienced 10 total AEs, none of which required VR discontinuation. The estimated mean daily infant dosage was 74.3 ng/kg/day. In this first study of dapivirine exposure during lactation, dapivirine VR use was associated with lower concentrations of detectable dapivirine in milk and plasma than in CVF samples and a favorable safety profile. Estimated daily levels of infant dapivirine exposure were also low. Additional studies are needed to evaluate longer periods of dapivirine VR use among BF mother-infant pairs living in regions with higher incidence of sexually transmitted HIV infection. (This study has been registered at ClinicalTrials.gov under registration no. NCT02808949.)

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Pharmacokinetics of Dapivirine Transfer into Blood Plasma, Breast Milk, and Cervicovaginal Fluid of Lactating Women Using the Dapivirine Vaginal Ring

10.31234/osf.io/fvbx7 ◽

2020 ◽

Author(s):

Lungwani Muungo

Keyword(s):

Breast Milk ◽

Hiv Infection ◽

Phase 1 ◽

Adult Women ◽

Open Label ◽

Lactating Women ◽

Express Breast Milk ◽

Sexually Transmitted ◽

Fda Guidance ◽

Favorable Safety

Breastfeeding (BF) women are an important population for biomedicalHIV prevention strategies, but they are rarely included in trials. The 25-mg dapivirinevaginal ring (VR) reduced women’s risk of sexually transmitted HIV infection in twophase 3 trials conducted in Africa. We conducted a phase 1, open-label study (MTN-029/IPM 039) of dapivirine VR use among lactating women in Pittsburgh, PA, andBirmingham, AL, USA. MTN-029/IPM 039 enrolled 16 healthy adult women who hadalready weaned their infants but were still able to express breast milk. Women wereinstructed to use the VR continuously for 14 days and provided milk, plasma, andcervicovaginal fluid (CVF) samples for pharmacological analysis. No infants were exposedto the drug, but infant dosage was estimated according to FDA guidance. Adverseevents (AEs) were collected at all contacts. The study was completed with100% participant retention. Median dapivirine concentrations were 676 pg/ml inbreast milk, 327 pg/ml in plasma (milk/plasma ratio ?2.0), and 36.25 ng/mg in CVF.Six participants experienced 10 total AEs, none of which required VR discontinuation.The estimated mean daily infant dosage was 74.3 ng/kg/day. In this first studyof dapivirine exposure during lactation, dapivirine VR use was associated with lowerconcentrations of detectable dapivirine in milk and plasma than in CVF samples anda favorable safety profile. Estimated daily levels of infant dapivirine exposure werealso low. Additional studies are needed to evaluate longer periods of dapivirine VRuse among BF mother-infant pairs living in regions with higher incidence of sexuallytransmitted HIV infection. (This study has been registered at ClinicalTrials.gov underregistration no. NCT02808949.)

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A236 LINACLOTIDE IS NOT DETECTABLE IN BREAST MILK OF LACTATING WOMEN: AN OPEN-LABEL, PHASE 1 STUDY

Journal of the Canadian Association of Gastroenterology ◽

10.1093/jcag/gwab002.234 ◽

2021 ◽

Vol 4 (Supplement_1) ◽

pp. 285-287

Author(s):

N Crittenden ◽

D McGeeney ◽

Y Assouline-Dayan ◽

K Boutros ◽

M Syrzycka ◽

...

Keyword(s):

Breast Milk ◽

Phase 1 ◽

Cumulative Exposure ◽

Human Breast Milk ◽

Open Label ◽

Idiopathic Constipation ◽

Once Daily ◽

Lactating Women ◽

Amino Acid Peptide ◽

Institutional Review

Abstract Background Linaclotide (LIN) is a guanylate cyclase-C agonist approved to treat adults with irritable bowel syndrome with constipation (IBS-C) and chronic idiopathic constipation (CIC). As LIN is a 14-amino acid peptide, no absorption from the gastrointestinal tract is expected following oral administration. However, LIN levels in human breast milk have not been determined. Aims To determine the levels of LIN and its active metabolite, MM-419447, excreted in breast milk after multiple once-daily doses of LIN (72 µg, 145 μg, or 290 μg) in lactating women. Methods This was a multicenter, open-label, multidose, Phase 1, milk-only lactation study (NCT02220348) in lactating women aged 18–45 years who were actively breastfeeding or pumping for ≥4 weeks and were already taking LIN 72 μg, 145 μg, or 290 μg therapeutically for IBS-C or CIC. Participants continued their LIN dose once daily for the 3 study days, with breast milk extractions at −1 to 0 hours (pre-dose) on Day 1 and −1 to 0 hours and 0–2, 2–4, 4–8, 8–12, 12–16, and 16–24 hours after dosing on Day 3. The pharmacokinetic endpoints were the cumulative amount of LIN and MM-419447 and the percentage dose of LIN excreted into the breast milk over the dosing interval. Adverse events (AEs) were monitored. The study has institutional review board approval. Results Seven women were enrolled in the study (IBS-C, n=1; CIC, n=6) and received LIN (72 μg, n=5; 145 μg, n=1; and 290 μg, n=1). Mean age was 28 (range: 19–35), mean weight was 70 kg (standard deviation [SD]: 12 kg), and mean body mass index was 26 kg/m2 (SD: 4 kg/m2); the majority were white (n=6). Concentrations of LIN and MM-419447 in breast milk samples were below the quantitation limits (<0.25 ng/mL and <1.00 ng/mL, respectively) at all time points for all participants. Cumulative exposure for each dose was 216 μg (72 μg dose), 435 μg (145 μg dose), and 870 μg (290 μg dose). One treatment-emergent AE was reported (mild rash). Conclusions The data collected in this study provide no evidence that breastfeeding infants receive LIN or MM-419447 through breast milk as their concentrations were below the quantitation limit following multiple once-daily doses of LIN 72 μg, 145 μg, or 290 μg. Funding Agencies This study was sponsored by Allergan plc, Dublin, Ireland (prior to acquisition by AbbVie Inc.). Writing and editorial assistance were provided to the authors by Stephanie J. Rippon, MBio, Jane Beck, MA, and Rebecca Fletcher, BA(Hons), of Complete HealthVizion, Inc., Chicago, IL, USA and funded by Allergan plc (prior to acquisition by AbbVie Inc.).

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An open-label phase 1 clinical trial of the anti-α4β7 monoclonal antibody vedolizumab in HIV-infected individuals

Science Translational Medicine ◽

10.1126/scitranslmed.aax3447 ◽

2019 ◽

Vol 11 (509) ◽

pp. eaax3447 ◽

Cited By ~ 19

Author(s):

Michael C. Sneller ◽

Katherine E. Clarridge ◽

Catherine Seamon ◽

Victoria Shi ◽

Marek D. Zorawski ◽

...

Keyword(s):

Clinical Trial ◽

Monoclonal Antibody ◽

Hiv Infection ◽

Phase 1 ◽

Single Subject ◽

Lymphoid Tissues ◽

Plasma Viremia ◽

Open Label ◽

Phase 1 Clinical Trial ◽

Open Label Phase

Despite the substantial clinical benefits of antiretroviral therapy (ART), complete eradication of HIV has not been possible. The gastrointestinal tract and associated lymphoid tissues may play an important role in the pathogenesis of HIV infection. The integrin α4β7 facilitates homing of T lymphocytes to the gut by binding to the mucosal addressin cell adhesion molecule-1 (MAdCAM-1) expressed on venules in gut-associated lymphoid tissue. CD4+ T cells with increased expression of α4β7 are susceptible to HIV infection and may be key players in subsequent virus dissemination. Data from nonhuman primate models infected with simian immunodeficiency virus (SIV) have suggested that blockade of the α4β7/MAdCAM-1 interaction may be effective at preventing SIV infection and may have beneficial effects in animals with established viral infection. To explore whether these findings could be reproduced in HIV-infected individuals after interruption of ART, we conducted an open-label phase 1 clinical trial of vedolizumab, a monoclonal antibody against α4β7 integrin. Vedolizumab infusions in 20 HIV-infected individuals were well tolerated with no serious adverse events related to the study drug. After interruption of ART, the median time to meeting protocol criteria to restart therapy was 13 weeks. The median duration of plasma viremia of <400 copies/ml was 5.4 weeks. Only a single subject in the trial experienced prolonged suppression of plasma viremia after interruption of ART. These results suggest that blockade of α4β7 may not be an effective strategy for inducing virological remission in HIV-infected individuals after ART interruption.

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Excretion of Moxidectin into Breast Milk and Pharmacokinetics in Healthy Lactating Women

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.00311-11 ◽

2011 ◽

Vol 55 (11) ◽

pp. 5200-5204 ◽

Cited By ~ 22

Author(s):

Joan M. Korth-Bradley ◽

Virginia Parks ◽

Stephan Chalon ◽

Ian Gourley ◽

Kyle Matschke ◽

...

Keyword(s):

Breast Milk ◽

Adverse Events ◽

World Health ◽

Terminal Phase ◽

Absolute Amount ◽

Upper Respiratory Tract ◽

Open Label ◽

Time Curve ◽

Lactating Women ◽

Standard Breakfast

ABSTRACTMoxidectin, registered worldwide as a veterinary antiparasitic agent, is currently under development for humans for the treatment of onchocerciasis in collaboration with the World Health Organization. The objective of this study was to assess the pharmacokinetics of moxidectin in healthy lactating women, including the excretion into breast milk. Twelve women, ages 23 to 38 years, weighing 54 to 79 kg, all more than 5 months postpartum, were enrolled, following their plan to wean their infants and provision of informed consent. A single 8-mg, open-label dose was administered orally after consumption of a standard breakfast. Complete milk collection was done for approximately 28 days, and plasma samples were collected for 90 days. Moxidectin concentrations were measured by high-performance liquid chromatography (HPLC) with fluorescence detection, with a validated range of 0.08 to 120 ng/ml. Noncompartmental pharmacokinetic methods were used to find the following results: peak concentration in plasma (Cmax), 87 ± 25 ng/ml; time toCmax(tmax), 4.18 ± 1.59 h; terminal-phase elimination half-life (t1/2), 832 ± 321 h; total area under the concentration-time curve (AUC), 4,046 ± 1,796 ng·h/ml; apparent oral dose clearance (CL/F), 2.35 ± 1.07 l/h; ratio of CL/Fto the terminal-phase disposition rate constant, λz(Vλz/F), 2,526 ± 772 liters; percentage of maternal dose excreted in milk, 0.701 ± 0.299%; absolute amount excreted in milk, 0.056 ± 0.024 mg; relative infant dose, 8.73 ± 3.17% of maternal dose assuming complete absorption; clearance in milk (CLmilk), 0.016 ± 0.009 liter/h. Nine of 12 subjects reported adverse events, all of which were considered treatment emergent but not drug related and were mostly reported during the long outpatient period 8 to 90 days after dose administration. The most frequently reported adverse events were headache and nausea (n= 4), oropharyngeal pain (n= 2), rhinitis, viral pharyngitis, and viral upper respiratory tract infection (n= 2).

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Changes in the profile of newly HIV-diagnosed men who have sex with men, Madrid, 2014 to 2019

Eurosurveillance ◽

10.2807/1560-7917.es.2021.26.47.2001501 ◽

2021 ◽

Vol 26 (47) ◽

Author(s):

Oskar Ayerdi Aguirrebengoa ◽

Mar Vera Garcia ◽

Teresa Puerta López ◽

Petunia Clavo Escribano ◽

Juan Ballesteros Martín ◽

...

Keyword(s):

Hiv Infection ◽

Latin American ◽

Hiv Transmission ◽

Newly Diagnosed ◽

Sexually Transmitted ◽

Behavioural Characteristics ◽

Hiv Prevention Strategies ◽

Young Msm ◽

Sex With Men ◽

Exposure Prophylaxis

Introduction Knowing the factors associated with HIV transmission is necessary in order to design preventive programmes tailored to the epidemiological situation in each region and population. Aim Our objective was to study the sociodemographic, clinical and behavioural characteristics of men who have sex with men (MSM) who were newly diagnosed with HIV infection. Methods We carried out an observational, descriptive, study on all MSM newly diagnosed with HIV infection in one clinic for sexually transmitted infections (STI) and HIV clinic in Madrid between 2014 and 2019. Information on sociodemographic, clinical, and behavioural characteristics of participants per year of diagnosis was collected. Results We detected a total of 1,398 people with HIV infection, 253 of whom were recent seroconverters (rSCV) with a median duration of documented seroconversion of 6 months. From the total, 97.9% infections were sexually transmitted and 2.1% involved injected drugs, i.e. slam practices. The average age was 32.9 years (range: 15.6–74.9), 51.8% were Spanish and 40% Latin American. These diagnoses decreased in Spanish people and increased in Latin Americans during the study period. Of the rSCV, 73.9% had condomless sex under the influence of drugs and 28.9% participated in chemsex sessions. Apps were used by 92.6% rSCV for sexual encounters and 70.4% of them attributed HIV transmission to their use. Conclusions Combination of HIV prevention strategies, as pre-exposure prophylaxis, should be reinforced among young MSM, especially those born in Latin America, those who use drugs for sex, and those who use apps in search of sexual contacts.

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A Technology-Based Intervention Among Young Men Who Have Sex With Men and Nonbinary People (The Conectad@s Project): Protocol for A Vanguard Mixed Methods Study (Preprint)

10.2196/preprints.34885 ◽

2021 ◽

Author(s):

Thiago Silva Torres ◽

Emilia Moreira Jalil ◽

Lara Esteves Coelho ◽

Daniel Rodrigues Barros Bezerra ◽

Cristina Moreira Jalil ◽

...

Keyword(s):

Hiv Infection ◽

Sexually Transmitted Infections ◽

Text Messages ◽

Hiv Care ◽

Sexually Transmitted ◽

Hiv Prevention Strategies ◽

Adherence Intervention ◽

Sex With Men ◽

Prevention Counseling ◽

Biomedical Interventions

BACKGROUND In many parts of the world, including Brazil, uptake for biomedical interventions has been insufficient to reverse the HIV epidemic among key populations at high risk for HIV, including men who have sex with men. Young MSM (YMSM), particularly Black YMSM, have high HIV incidence, low viral suppression, and low preexposure prophylaxis (PrEP) uptake and adherence. Therefore, novel approaches to increase the HIV biomedical interventions uptake by YMSM are urgently needed. OBJECTIVE We describe the Conectad@s Project, which aims to: (1) estimate the prevalence and incidence of HIV and other sexually transmitted infections, the onset of sexual risk behavior, and barriers to biomedical interventions among YMSM aged 18 to 24 years in Rio de Janeiro, Brazil; and (2) conduct a technology-based adherence intervention study to promote a rapid linkage of YMSM to HIV care or prevention, and support and sustain adherence. METHODS A cross-sectional survey will be conducted with 400 YMSM recruited using respondent-driven sampling (RDS) adapted for social media-based sampling, preceded by a formative phase. HIV and sexually transmitted infections testing will be conducted, including early HIV infection biomarker detection. Behavioral, partnership, network, and structural measures will be collected through structured questionnaires. All individuals recruited for the survey will have access to HIV risk assessment, antiretroviral therapy (ART), PrEP, prevention counseling, and a technology-based adherence intervention. Those who accept the adherence intervention will receive weekly text messages via a social networking app (WhatsApp) for 24 weeks, with follow-up data collected over 48 weeks. RESULTS The Conectad@s project has been approved by our local institutional review board (#CAAE 26086719.0.0000.4262) in accordance with all applicable regulations. Questionnaires for the RDS survey and intervention were developed and tested in 2020, formative interviews were conducted in January and February 2021 to guide the development of the RDS, and enrollment is planned to begin in early 2022. CONCLUSIONS The Conectad@s Project is a vanguard study that, for the first time, will apply digital RDS to sample and recruit YMSM in Brazil and rapidly connect them to ART, PrEP, or prevention counseling through a technology-based adherence intervention. RDS will allow us to estimate HIV prevalence among YMSM and measure HIV infection biomarkers in the context of the onset of risky behavior. The data will lay the groundwork to adapt and implement HIV prevention strategies, identify barriers to the earliest HIV infection diagnosis, immediate ART or PrEP initiation, and detect new clusters of HIV transmission. INTERNATIONAL REGISTERED REPORT DERR1-10.2196/34885

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A Technology-Based Intervention Among Young Men Who Have Sex With Men and Nonbinary People (The Conectad@s Project): Protocol for A Vanguard Mixed Methods Study

JMIR Research Protocols ◽

10.2196/34885 ◽

2022 ◽

Vol 11 (1) ◽

pp. e34885

Author(s):

Thiago Silva Torres ◽

Emilia Moreira Jalil ◽

Lara Esteves Coelho ◽

Daniel Rodrigues Barros Bezerra ◽

Cristina Moreira Jalil ◽

...

Keyword(s):

Hiv Infection ◽

Sexually Transmitted Infections ◽

Text Messages ◽

Hiv Care ◽

Sexually Transmitted ◽

Hiv Prevention Strategies ◽

Adherence Intervention ◽

Sex With Men ◽

Prevention Counseling ◽

Biomedical Interventions

Background In many parts of the world, including Brazil, uptake for biomedical interventions has been insufficient to reverse the HIV epidemic among key populations at high risk for HIV, including men who have sex with men. Young MSM (YMSM), particularly Black YMSM, have high HIV incidence, low viral suppression, and low preexposure prophylaxis (PrEP) uptake and adherence. Therefore, novel approaches to increase the HIV biomedical interventions uptake by YMSM are urgently needed. Objective We describe the Conectad@s Project, which aims to: (1) estimate the prevalence and incidence of HIV and other sexually transmitted infections, the onset of sexual risk behavior, and barriers to biomedical interventions among YMSM aged 18 to 24 years in Rio de Janeiro, Brazil; and (2) conduct a technology-based adherence intervention study to promote a rapid linkage of YMSM to HIV care or prevention, and support and sustain adherence. Methods A cross-sectional survey will be conducted with 400 YMSM recruited using respondent-driven sampling (RDS) adapted for social media-based sampling, preceded by a formative phase. HIV and sexually transmitted infections testing will be conducted, including early HIV infection biomarker detection. Behavioral, partnership, network, and structural measures will be collected through structured questionnaires. All individuals recruited for the survey will have access to HIV risk assessment, antiretroviral therapy (ART), PrEP, prevention counseling, and a technology-based adherence intervention. Those who accept the adherence intervention will receive weekly text messages via a social networking app (WhatsApp) for 24 weeks, with follow-up data collected over 48 weeks. Results The Conectad@s project has been approved by our local institutional review board (#CAAE 26086719.0.0000.4262) in accordance with all applicable regulations. Questionnaires for the RDS survey and intervention were developed and tested in 2020, formative interviews were conducted in January and February 2021 to guide the development of the RDS, and enrollment is planned to begin in early 2022. Conclusions The Conectad@s Project is a vanguard study that, for the first time, will apply digital RDS to sample and recruit YMSM in Brazil and rapidly connect them to ART, PrEP, or prevention counseling through a technology-based adherence intervention. RDS will allow us to estimate HIV prevalence among YMSM and measure HIV infection biomarkers in the context of the onset of risky behavior. The data will lay the groundwork to adapt and implement HIV prevention strategies, identify barriers to the earliest HIV infection diagnosis, immediate ART or PrEP initiation, and detect new clusters of HIV transmission. International Registered Report Identifier (IRRID) DERR1-10.2196/34885

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