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BACKGROUND: There are currently no Food and Drug Administration-approved treatments for female sexual arousal disorder (FSAD), which is physiologically analogous to male erectile dysfunction. AIMS: The study sought to test the systemic and local genital safety of topical sildenafil cream, 3.6% (sildenafil cream) among healthy premenopausal women with FSAD and their sexual partners over a 12-week treatment period. METHODS: This was a phase 2b, exploratory, randomized, placebo-controlled, double-blind study of sildenafil cream among healthy premenopausal women with FSAD. Safety was assessed by the frequency and incidence of treatment-emergent adverse events (TEAEs) among participants and their sexual partners. Participants recorded the incidence of TEAEs in a daily eDiary (electronic diary). Sexual partners were contacted within 72 hours of each sexual event in which investigational product was used. All participants used placebo cream for 1 month, during a single-blind run-in period, and then if eligible, were randomized 1:1 to sildenafil cream or placebo cream. Participants used their assigned investigational product over a 12-week double-blind dosing period. They attended monthly follow-up visits, in which their eDiary TEAE data were reviewed by the study staff and graded for severity and relationship to study product. OUTCOMES: The frequency and incidence of TEAEs among participants and their sexual partners. RESULTS: During the 12-week double-blind dosing period, there were 78 TEAEs reported by 29 of 99 sildenafil-assigned participants and 65 TEAEs reported by 28 of 94 placebo-assigned participants (P = .76). All TEAEs were mild or moderate in severity. The most common treatment-related TEAE among active and placebo-assigned participants was application site discomfort. There were no differences in the number of treatment-related TEAEs among sildenafil cream vs placebo cream users (P > .99). Four sildenafil cream participants and 3 placebo cream participants discontinued the study due to TEAEs involving application site discomfort (P > .99). There were 9 TEAEs reported by 7 of 91 sexual partners exposed to sildenafil cream vs 4 TEAEs reported by 4 of 84 sexual partners exposed to placebo cream (P = .54). CLINICAL IMPLICATIONS: These data support further clinical development of topical sildenafil cream for the treatment of FSAD. STRENGTHS AND LIMITATIONS: Safety was assessed among participants and their sexual partners after 1357 and 1160 sexual experiences in which sildenafil cream or placebo cream were used, respectively. The phase 2b study was powered for the primary objectives of efficacy, rather than safety. CONCLUSION: These data demonstrate that topically applied sildenafil cream was safe and well tolerated by exposed users and their sexual partners.
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Introduction: Globally, many young women face the overlapping burden of HIV infection and unintended pregnancy. Protection against both may benefit from safe and effective multipurpose prevention technologies. Methods: Healthy women ages 18-34 years, not pregnant, seronegative for HIV and hepatitis B surface antigen, not using hormonal contraception, and at low risk for HIV were randomized 2:2:1 to continuous use of a tenofovir/levonorgestrel (TFV/LNG), TFV, or placebo intravaginal ring (IVR). In addition to assessing genital and systemic safety, we determined TFV concentrations in plasma and cervicovaginal fluid (CVF) and LNG levels in serum using tandem liquid chromatography-mass spectrometry. We further evaluated TFV pharmacodynamics (PD) through ex vivo CVF activity against both human immunodeficiency virus (HIV)-1 and herpes simplex virus (HSV)-2, and LNG PD using cervical mucus quality markers and serum progesterone for ovulation inhibition. Results: Among 312 women screened, 27 were randomized to use one of the following IVRs: TFV/LNG (n = 11); TFV-only (n = 11); or placebo (n = 5). Most screening failures were due to vaginal infections. The median days of IVR use was 68 [interquartile range (IQR), 36-90]. Adverse events (AEs) were distributed similarly among the three arms. There were two non-product related AEs graded >2. No visible genital lesions were observed. Steady state geometric mean amount (ssGMA) of vaginal TFV was comparable in the TFV/LNG and TFV IVR groups, 43,988 ng/swab (95% CI, 31,232, 61,954) and 30337â ng/swab (95% CI, 18,152, 50,702), respectively. Plasma TFV steady state geometric mean concentration (ssGMC) was <10â ng/ml for both TFV IVRs. In vitro, CVF anti-HIV-1 activity showed increased HIV inhibition over baseline following TFV-eluting IVR use, from a median of 7.1% to 84.4% in TFV/LNG, 15.0% to 89.5% in TFV-only, and -27.1% to -20.1% in placebo participants. Similarly, anti-HSV-2 activity in CVF increased >50 fold after use of TFV-containing IVRs. LNG serum ssGMC was 241â pg/ml (95% CI 185, 314) with rapid rise after TFV/LNG IVR insertion and decline 24-hours post-removal (586â pg/ml [95% CI 473, 726] and 87â pg/ml [95% CI 64, 119], respectively). Conclusion: TFV/LNG and TFV-only IVRs were safe and well tolerated among Kenyan women. Pharmacokinetics and markers of protection against HIV-1, HSV-2, and unintended pregnancy suggest the potential for clinical efficacy of the multipurpose TFV/LNG IVR. Clinical Trial Registration: NCT03762382 [https://clinicaltrials.gov/ct2/show/NCT03762382].
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Background: New multi-purpose prevention technology (MPT) products are needed to prevent human immunodeficiency virus (HIV) and herpes simplex virus type 2 (HSV2). In this study, we evaluated a fast-dissolve insert that may be used vaginally or rectally for prevention of infection. Objective: To describe the safety, acceptability, multi-compartment pharmacokinetics (PK), and in vitro modeled pharmacodynamics (PD) after a single vaginal dose of an insert containing tenofovir alafenamide (TAF) and elvitegravir (EVG) in healthy women. Methods: This was a Phase I, open-label, study. Women (n=16) applied one TAF (20mg)/EVG (16mg) vaginal insert and were randomized (1:1) to sample collection time groups for up to 7 days post dosing. Safety was assessed by treatment-emergent adverse events (TEAEs). EVG, TAF and tenofovir (TFV) concentrations were measured in plasma, vaginal fluid and tissue, and TFV-diphosphate (TFV-DP) concentration in vaginal tissue. PD was modeled in vitro by quantifying the change in inhibitory activity of vaginal fluid and vaginal tissue against HIV and HSV2 from baseline to after treatment. Acceptability data was collected by a quantitative survey at baseline and post treatment. Results: The TAF/EVG insert was safe, with all TEAEs graded as mild, and acceptable to participants. Systemic plasma exposure was low, consistent with topical delivery, while high mucosal levels were detected, with median TFV vaginal fluid concentrations exceeding 200,000 ng/mL and 1,000 ng/mL for up to 24 hours and 7 days post dosing, respectively. All participants had vaginal tissue EVG concentrations of > 1 ng/mg at 4 and 24 hours post dosing. The majority had tissue TFV-DP concentrations exceeding 1000 fmol/mg by 24 - 72 hours post dosing. Vaginal fluid inhibition of HIV-1 and HSV-2 in vitro significantly increased from baseline and was similarly high at 4 and 24 hours post dosing. Consistent with high tissue TFV-DP concentrations, p24 HIV antigen production from ectocervical tissues infected ex vivo with HIV-1 significantly decreased from baseline at 4 hours post dosing. HSV-2 production from tissue also decreased post treatment. Conclusions: A single dose of TAF/EVG inserts met PK benchmarks, with PK data supporting an extended window of high mucosal protection. PD modeling supports mucosal protection against both HIV-1 and HSV-2. The inserts were safe and highly acceptable. Clinical trial registration: ClinicalTrials.gov, identifier NCT03762772.
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Fármacos Anti-HIV , Infecções por HIV , HIV-1 , Humanos , Feminino , Fármacos Anti-HIV/efeitos adversos , Tenofovir/efeitos adversos , AlaninaRESUMO
BACKGROUND: With an unplanned pregnancy rate of 50% or more in many countries, there is an urgent need for contraceptives that are more accessible and acceptable. To meet the growing demand for new contraceptives, ZabBio developed ZB-06, a vaginal film containing HC4-N, a human contraceptive antibody that inactivates sperm. OBJECTIVE: This study aimed to assess the potential contraceptive activity of the ZB-06 film using a surrogate assessment for contraceptive efficacy, the postcoital test. We also assessed clinical safety of film use among healthy heterosexual couples. Serum, cervical mucus, and vaginal fluid HC4-N antibody concentrations and sperm agglutination potency were determined after single film use. Changes in the concentration of soluble proinflammatory cytokines and vaginal Nugent score after film use were measured as subclinical safety endpoints. STUDY DESIGN: This was a phase 1, first-in-woman, open-label, proof-of-concept, postcoital test and safety study. RESULTS: A total of 20 healthy women were enrolled in the study, and 8 heterosexual couples completed all study visits. The product was safe for both female participants and their male sexual partners. The postcoital test performed on ovulatory cervical mucus at baseline (no product use) revealed a mean of 25.9 (±30.6) progressively motile sperm per high-power field. After use of a single ZB-06 film before intercourse, this number dropped to 0.04 (±0.06) progressively motile sperm per high-power field (P<.0001). At the follow-up postcoital test visit approximately 1 month later (no product use), a mean of 47.4 (±37.4) progressively motile sperm per high-power field was observed, indicating contraceptive reversibility. CONCLUSION: A single dose of the ZB-06 film applied before intercourse was safe and met efficacy surrogate benchmarks of excluding progressively motile sperm from ovulatory cervical mucus. These data indicate that ZB-06 is a viable contraceptive candidate warranting further development and testing.
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Dispositivos Anticoncepcionais Femininos , Espermicidas , Gravidez , Humanos , Masculino , Feminino , Anticoncepcionais , Espermicidas/farmacologia , Sêmen , VaginaRESUMO
BACKGROUND: While oral pre-exposure prophylaxis (PrEP) has been shown to reduce the risk of HIV, challenges such as adhering to a daily-dosing regimen and persistence have emerged as barriers for at-risks populations in South Africa. This qualitative research sought to investigate perceptions of and preferences for a long-acting, biodegradable implantable PrEP product designed to address these barriers. METHODS: To identify and understand motivators, barriers, and preferences for the PrEP implant, we conducted qualitative in-depth interviews (IDIs) among health care providers (HCPs) and target end-users (young women, adolescent girls, and female sex workers) in urban and rural/peri-urban regions of Gauteng Province, South Africa. The IDIs focused on defining values, beliefs, habits, lifestyles, influencers, and information channels for potential PrEP implant end-users. RESULTS: We conducted 36 IDIs across health care providers and target end-user respondent segments. Respondents had generally positive reactions to the PrEP implant. Most end-users felt that some undesirable aspects of the implant (e.g., side effects, pain during insertion, potential scarring, and inability to remove implant) would be offset by having a highly effective, and long-lasting HIV prevention product. Although some HCPs believed the implantable PrEP would lead to increases in promiscuity and risky sexual behavior, most HCPs saw value in the PrEP implant's long duration of protection, its biodegradability, and the likelihood of higher adherence relative to oral PrEP. CONCLUSIONS: This study is a first step toward further research needed to demonstrate the demand for a biodegradable, long-acting implantable PrEP and suggests such a product would be accepted by end-users and HCPs in South Africa. This study indicates the need to develop more convenient, discreet, long-acting, and highly effective biomedical HIV prevention options for at-risk populations.
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Infecções por HIV , Profissionais do Sexo , Feminino , Humanos , Adolescente , África do Sul , Pesquisa Qualitativa , Infecções por HIV/tratamento farmacológico , Infecções por HIV/prevenção & controleRESUMO
Multipurpose prevention technologies (MPTs), which prevent sexually transmitted infection(s) and unintended pregnancy, are highly desirable to women. In this randomized, placebo-controlled, phase I study, women used a placebo or tenofovir (TFV) and levonorgestrel (LNG) intravaginal ring (IVR), either continuously or cyclically (three, 28-day cycles with a 3 day interruption in between each cycle), for 90 days. Sixty-eight women were screened; 47 were randomized to 4 arms: TFV/LNG or placebo IVRs used continuously or cyclically (4:4:1:1). Safety was assessed by adverse events and changes from baseline in mucosal histology and immune mediators. TFV concentrations were evaluated in multiple compartments. LNG concentration was determined in serum. Modeled TFV pharmacodynamic antiviral activity was evaluated in vaginal and rectal fluids and cervicovaginal tissue ex vivo. LNG pharmacodynamics was assessed with cervical mucus quality and anovulation. All IVRs were safe with no serious adverse events nor significant changes in genital tract histology, immune cell density or secreted soluble proteins from baseline. Median vaginal fluid TFV concentrations were >500 ng/mg throughout 90d. TFV-diphosphate tissue concentrations exceeded 1,000 fmol/mg within 72hrs of IVR insertion. Mean serum LNG concentrations exceeded 200 pg/mL within 2h of TFV/LNG use, decreasing quickly after IVR removal. Vaginal fluid of women using TFV-containing IVRs had significantly greater inhibitory activity (87-98% versus 10% at baseline; p<0.01) against HIV replication in vitro. There was a >10-fold reduction in HIV p24 antigen production from ectocervical tissues after TFV/LNG exposure. TFV/LNG IVR users had significantly higher rates of anovulation, lower Insler scores and poorer/abnormal cervical mucus sperm penetration. Most TFV/LNG IVR users reported no change in menstrual cycles or fewer days of and/or lighter bleeding. All IVRs were safe. Active rings delivered high TFV concentrations locally. LNG caused changes in cervical mucus, sperm penetration, and ovulation compatible with contraceptive efficacy. Trial registration: ClinicalTrials.gov #NCT03279120.
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Anovulação , Anticoncepcionais , Dispositivos Anticoncepcionais Femininos , Levanogestrel , Tenofovir , Anovulação/induzido quimicamente , Antivirais , Anticoncepcionais/uso terapêutico , Difosfatos , Feminino , Proteína do Núcleo p24 do HIV , Infecções por HIV , Humanos , Levanogestrel/uso terapêutico , Masculino , Sêmen , Tenofovir/uso terapêuticoRESUMO
BACKGROUND: Hormonal changes during the menstrual cycle play a key role in shaping immunity in the cervicovaginal tract. Cervicovaginal fluid contains cytokines, chemokines, immunoglobulins, and other immune mediators. Many studies have shown that the concentrations of these immune mediators change throughout the menstrual cycle, but the studies have often shown inconsistent results. Our understanding of immunological correlates of the menstrual cycle remains limited and could be improved by meta-analysis of the available evidence. METHODS: We performed a systematic review and meta-analysis of cervicovaginal immune mediator concentrations throughout the menstrual cycle using individual participant data. Study eligibility included strict definitions of the cycle phase (by progesterone or days since the last menstrual period) and no use of hormonal contraception or intrauterine devices. We performed random-effects meta-analyses using inverse-variance pooling to estimate concentration differences between the follicular and luteal phases. In addition, we performed a new laboratory study, measuring select immune mediators in cervicovaginal lavage samples. RESULTS: We screened 1570 abstracts and identified 71 eligible studies. We analyzed data from 31 studies, encompassing 39,589 concentration measurements of 77 immune mediators made on 2112 samples from 871 participants. Meta-analyses were performed on 53 immune mediators. Antibodies, CC-type chemokines, MMPs, IL-6, IL-16, IL-1RA, G-CSF, GNLY, and ICAM1 were lower in the luteal phase than the follicular phase. Only IL-1α, HBD-2, and HBD-3 were elevated in the luteal phase. There was minimal change between the phases for CXCL8, 9, and 10, interferons, TNF, SLPI, elafin, lysozyme, lactoferrin, and interleukins 1ß, 2, 10, 12, 13, and 17A. The GRADE strength of evidence was moderate to high for all immune mediators listed here. CONCLUSIONS: Despite the variability of cervicovaginal immune mediator measurements, our meta-analyses show clear and consistent changes during the menstrual cycle. Many immune mediators were lower in the luteal phase, including chemokines, antibodies, matrix metalloproteinases, and several interleukins. Only interleukin-1α and beta-defensins were higher in the luteal phase. These cyclical differences may have consequences for immunity, susceptibility to infection, and fertility. Our study emphasizes the need to control for the effect of the menstrual cycle on immune mediators in future studies.
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Elafina , beta-Defensinas , Feminino , Fator Estimulador de Colônias de Granulócitos , Humanos , Imunoglobulinas , Fatores Imunológicos , Interferons , Proteína Antagonista do Receptor de Interleucina 1 , Interleucina-16 , Interleucina-1alfa , Interleucina-6 , Interleucinas , Lactoferrina , Ciclo Menstrual , Muramidase , ProgesteronaRESUMO
Multipurpose prevention technology intravaginal rings (MPT IVRs) may offer a promising solution for addressing women's multiple sexual and reproductive health needs. We describe MPT IVR acceptability perspectives and examine user experiences of 25 cisgender women aged 18-34 years enrolled in a phase IIa randomized, partially blinded, placebo-controlled evaluation of tenofovir-based IVRs with and without contraceptive co-formulation. All took part in an individual, audio-recorded, semi-structured qualitative interview. A thematic analysis of transcribed interviews was completed in MaxQDA. Participants shared little to no knowledge of or experience with IVRs prior to joining the study. Four MPT IVR themes were identified: physical well-being, method reliability, personal management, and societal endorsement. Commonly cited of concern, but less described as being experienced, were physical discomforts (e.g., painful insertion/removal; inability to carry out daily activities/chores; foreign body sensation; expulsion; sexual interference, or debilitating side effects). Uncertainty regarding efficacy influenced perspectives about intended prevention benefits. Personal choices in managing reproduction and sexual behaviors had to be congruent with sociocultural values and norms for acceptance beyond the individual user level. Participants viewed broader community acceptance as likely to be mixed given community opposition to the use of modern family planning methods. They also shared concerns that IVR use could lead to infertility, especially among nulliparous women, or that it would encourage premarital sex or high-risk sexual behaviors among adolescent and young women. While a MPT IVR may not be suitable for all women, first-hand testimonials could help influence collective receptivity. Additional community acceptability research is needed. Clinical Trial Registration The study is registered at http://ClinicalTrials.gov under the identifier NCT03762382.
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Dispositivos Anticoncepcionais Femininos , Infecções por HIV , Adolescente , Feminino , Humanos , Gravidez , Infecções por HIV/prevenção & controle , Reprodutibilidade dos Testes , Comportamento Sexual , TenofovirRESUMO
In a phase-IIa trial, we investigated the influence of 90 days continuous-delivery tenofovir (TFV) intravaginal rings (IVRs) with/without levonorgestrel (LNG) on the genital microbiota of Kenyan women. Eligible women (n = 27; 18-34 years; negative for HIV, sexually transmitted infections, and Amsel-bacterial vaginosis) were randomized 2:2:1 to use of IVRs containing TFV, TFV/LNG, or placebo. Using vaginal wall and IVR swabs at IVR insertion and removal, the genital microbial composition was determined using 16S rRNA gene sequencing. The presence of Candida spp. was determined using qPCR. The vaginal total bacterial burden appeared to decrease with TFV and TFV/LNG IVR use (log100.57 and log100.27 decrease respectively; p > 0.05). The TFV/LNG IVR was more 'stabilizing': 50% of the participants' microbiota community state types remained unchanged and 50% shifted towards higher Lactobacillus abundance. Specifically, TFV/LNG IVR use was accompanied by increased abundances of Lactobacillus gasseri/hominis/johnsonii/taiwanensis (16.3-fold) and L. fermentum/reuteri/vaginalis (7.0-fold; all p < 0.01). A significant shift in the overall microbial α-diversity or ß-diversity was not observed for either IVR, and IVR use did not influence Candida spp. prevalence. TFV/LNG and TFV IVRs did not adversely affect the genital microbiota and are safe to use. Our findings support further studies assessing their efficacy in preventing HIV/HSV-2 and unintended pregnancies.
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Infecções por HIV , Microbiota , Administração Intravaginal , Feminino , Infecções por HIV/tratamento farmacológico , Infecções por HIV/prevenção & controle , Humanos , Quênia/epidemiologia , Levanogestrel/efeitos adversos , RNA Ribossômico 16S , Tenofovir/efeitos adversos , VaginaRESUMO
Vitrified, or "frozen", donor eggs can either be fertilized and cultured for fresh transfer (group 1), or fertilized and cryopreserved for transfer in a "frozen embryo transfer" cycle (group 2). This study compared the pregnancy rates between the two groups. Frozen donor egg cycles (N = 1213) were analyzed at the World Egg Bank. The outcome studied was clinical pregnancy rate. Cycles included only single embryo transfers (ET) without preimplantation genetic testing (PGT). A total of 600 cycles met the inclusion criteria. Group 1 included 409 cycles and group 2 had 191 cycles. There was no statistical significance in clinical pregnancy rate between the two groups (38.63% vs 32.46%, p = 0.14). Mean embryo age was higher in group 2 (5.1 vs. 5.4 days, p < 0.01). The compounding effect of vitrification when applied to two distinct stages (oocyte and embryo), has not been studied. When comparing the two groups, we found no difference in pregnancy rate. However, there was a trend towards fewer pregnancies in group 2. A larger study should be done to determine the validity of this result (Ramadan et al. in Fertil Steril, 2020).
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Blastocisto , Criopreservação , Feminino , Humanos , Oócitos , Gravidez , Taxa de Gravidez , VitrificaçãoRESUMO
For adolescent girls (AG) and young women (YW), adherence barriers may limit the effectiveness of daily oral HIV pre-exposure prophylaxis (PrEP). Due to its low-burden and long-lasting product attributes, PrEP implants could remove some of the critical adherence barriers of oral PrEP products for individuals at risk of HIV. To explore stated preferences for a long-acting PrEP implant, we conducted a quantitative survey and discrete choice experiment with AG (ages 15-17), YW (18-34), and female sex workers (FSW; ≥ 18) in Gauteng Province, South Africa. We completed 600 quantitative surveys across the three subgroups of women. Respondents stated preference for an implant that provided longer HIV protection (24 months versus 6 months) and required a single insertion. They stated that they preferred a biodegradable implant that could be removed within 1 month of insertion. Respondents had no preference for a particular insertion location. Overall, 78% of respondents said they would be likely (33%) or very likely (45%) to use a PrEP implant were one available, with the majority (82%) stating preference for a product that would provide dual protection against HIV and unintended pregnancies. To reduce their risk of HIV, AG, YW, and FSW in our survey reported a strong willingness to use long-acting, highly-effective, dissolvable PrEP implants.
RESUMEN: Las niñas adolescentes (NA) y mujeres jóvenes (MJ), pueden enfrentar barreras de adherencia que limitan la eficacia de la profilaxis oral previa a la exposición al VIH (PrEP). Ya que el implante de PrEP es un producto que requiere de poca intervención de la usuaria y es de larga duración, podría eliminar algunas de las barreras de adherencia más importantes en el uso de los productos orales de PrEP para aquellas personas en riesgo de infección de VIH. Para explorar las preferencias declaradas en cuanto al implante de PrEP de acción prolongada, llevamos a cabo una encuesta cuantitativa y un experimento de elección discreta (DCE) con NA (de 15 a 17 años), MJ (de 18 a 34 años) y mujeres trabajadoras del sexo (MTS; ≥ 18 años) en la provincia de Gauteng, Sudáfrica. Administramos 600 encuestas cuantitativas en los tres subgrupos de mujeres. Los resultados indican la preferencia por un implante que proporciona una protección contra el VIH más prolongada (24 meses a comparación con 6 meses) y que requiere de una única inserción. Las participantes afirmaron que prefieren un implante biodegradable que puede retirarse un mes después de su inserción. Las participantes no tenían preferencia por un sitio específico de inserción. En general, el 78% de las participantes indicaron que probablemente (33%) o muy probablemente (45%) utilizarían un implante de PrEP si estuviera disponible, y la mayoría (82%) manifestó su preferencia por un producto que proporcionaba una doble protección contra el VIH y el embarazo no deseado. Para reducir el riesgo de contraer el VIH, las NA, MJ y MTS participantes se mostraron muy dispuestas a utilizar implantes de PrEP de larga duración, altamente eficaces y disolubles.
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Fármacos Anti-HIV , Infecções por HIV , Profilaxia Pré-Exposição , Profissionais do Sexo , Adolescente , Fármacos Anti-HIV/uso terapêutico , Feminino , Infecções por HIV/prevenção & controle , Humanos , Profilaxia Pré-Exposição/métodos , Gravidez , África do Sul/epidemiologia , Inquéritos e QuestionáriosRESUMO
Background: A relationship between the vaginal microbiota and tenofovir (TFV) concentrations and activity after topical administration has been previously reported. Objective: CONRAD A15-138 was a randomized, placebo-controlled Phase I study aimed at characterizing the safety, pharmacokinetics (PK), and pharmacodynamics (PD) of TFV and levonorgestrel (LNG) administered through a vaginal ring (IVR) for 90 days. Herein, we describe changes from baseline in the vaginal microbiota with IVR use and the impact of the vaginal microbiota on mucosal TFV PK. Methods: The study screened 68 participants and randomized 47 (37 TFV/LNG, 10 placebo), assessing the vaginal microbiota by sequencing the V3-V4 regions of 16S rRNA genes prior to IVR insertion and monthly for 3 months. Concentrations of TFV in vaginal fluid (VF), and TFV and TFV-diphosphate (TFV-DP) in vaginal tissue, and modeled PD against HIV-1 in vitro were measured before and after treatment. Results: There were no clinically significant changes in relative abundance of vaginal bacterial phylotypes from pre-insertion baseline at any month among active and placebo IVR users. There were no significant changes in community state type (CST) with IVR use. Participants with diverse, anaerobic CST IVA/B microbiota had higher in vivo release of TFV from the IVR compared to women with Lactobacillus-dominated (LbD) microbiota, who had expected in vivo TFV release rates. Median VF TFV concentrations were significantly higher among women with CST IVA/B microbiota in months 1 (3,135 ng/mg VF) and 2 (3,800 ng/mg). Women with LbD microbiota had significantly higher median VF TFV concentration (1,423 ng/mg) and median TFV (103 ng/mg) and TFV-DP (5,877 fmol/mg) tissue concentrations versus women with CST IVA/B microbiota at month 3. All women demonstrated a significant increase from pre-insertion baseline of in vitro HIV-1 inhibition by VF (p values <0.05). PD differences in tissue according to CST, however, were not statistically significant. Conclusion: TFV/LNG IVR use did not change the vaginal microbiota nor increase the incidence of CST IVA/B. Vaginal microbiota, and in particular CST IVA/B, possibly through increased vaginal pH, impacted in vivo TFV release and cervicovaginal (CV) PK, but both PK and PD data suggest CV protection against HIV-1. Clinical Trial Registration: ClinicalTrials.gov (#NCT03279120).
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Fármacos Anti-HIV , Dispositivos Anticoncepcionais Femininos , Infecções por HIV , Microbiota , Fármacos Anti-HIV/uso terapêutico , Feminino , Infecções por HIV/tratamento farmacológico , Infecções por HIV/prevenção & controle , Humanos , Levanogestrel/uso terapêutico , RNA Ribossômico 16S/genética , Tenofovir/farmacocinética , Tenofovir/uso terapêuticoRESUMO
OBJECTIVE: To describe and compare systemic and local pharmacokinetics (PK) and cervicovaginal (CV) pharmacodynamics (PD) of oral tenofovir disoproxil fumarate (TDF) in combination with emtricitabine (FTC) with tenofovir (TFV) intravaginal ring (IVR). DESIGN: Phase I, randomized, parallel-group study. Women (n = 22) used TDF/FTC oral tablets daily or TFV IVR continuously and were assessed at baseline and 14 days. METHODS: TFV and FTC concentrations were measured in plasma, CV fluid (CVF), and CV tissue. TFV-diphosphate and FTC-triphosphate were assessed in CV tissue. In vitro PD antiviral activities of TFV and FTC (using in vivo concentration ranges) were modeled in the CVF and by infecting CV tissue explants ex vivo with HIV-1BaL. RESULTS: Adverse events (AEs) were more common with oral TDF/FTC use (P < 0.01). The median CVF TFV concentrations were 106 ng/mL after use of TFV IVR vs. 102 ng/mL for TDF/FTC. The median TFV and TFV-diphosphate concentrations in CV tissue were >100-fold higher among IVR users. The median CVF FTC concentrations were 103 ng/mL. FTC and FTC-triphosphate were detected in all CV tissues from TDF/FTC users. HIV inhibitory activity of CVF increased significantly with treatment in both cohorts (P < 0.01) but was higher in TFV IVR users (P < 0.01). In vitro inhibition of tissue infection with ex vivo administration of TFV and FTC was dose dependent, with maximal efficacy achieved with 10 µg/mL TFV, 1 µg/mL FTC, and 0.1 µg/mL of TFV and FTC combined. CONCLUSIONS: Both products were safe and increased mucosal HIV inhibitory activity. In addition to systemic protection, oral TDF/FTC displays a PK/PD profile compatible with CV mucosal antiviral activity. TFV IVR resulted in fewer AEs, lower TFV plasma concentrations, higher CVF and tissue TFV and TFV-DP concentrations, and greater anti-HIV activity in CVF.
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Fármacos Anti-HIV , Infecções por HIV , Administração Intravaginal , Administração Oral , Emtricitabina/farmacologia , Emtricitabina/uso terapêutico , Feminino , Genitália , Infecções por HIV/tratamento farmacológico , Infecções por HIV/prevenção & controle , Humanos , TenofovirRESUMO
BACKGROUND: Bacterial vaginosis-a condition defined by a shift from Lactobacillus dominance to a polymicrobial, anaerobic bacterial community-increases the risk of acquiring sexually transmitted infections and other complications of the female reproductive tract. Antibiotic treatment frequently fails to return the microbiome to an optimal Lactobacillus-dominated state. No criteria currently exist to identify the patients likely to experience treatment failure. OBJECTIVE: We sought to identify the pretreatment community signatures associated with treatment failure through 16S ribosomal RNA gene analysis. STUDY DESIGN: Twenty-eight women who were enrolled in an oral metronidazole treatment trial of bacterial vaginosis were studied. Cervicovaginal lavage samples were collected before metronidazole treatment and at 7 and 30 days posttreatment. Cervicovaginal lavage DNA was amplified and sequenced using a paired-end, V4 region 2×150 MiSeq run. RESULTS: Of the 28 women, 25% failed to clear bacterial vaginosis; 35.7% demonstrated a transient clearance, shifting to community-type 2 (Lactobacillus iners dominant) at visit 2 only; 7.1% demonstrated a delayed clearance, reaching community-type 2 at the final visit only; and 32.1% of patients experienced sustained bacterial vaginosis clearance. Examination of the community composition and structure demonstrated that both the richness and the evenness were significantly lower for the women who experienced sustained clearance, whereas the women who failed to clear bacterial vaginosis possessed the highest median levels of richness, evenness, and diversity pretreatment. Soluble immune factors in the lower reproductive tract improved significantly following a shift from community-type 4 to a Lactobacillus-dominant microbiome, with the samples categorized as community-type 2 possessing significantly higher levels of secretory leukocyte protease inhibitor, growth-regulated alpha protein, and macrophage inflammatory protein-3 and significantly lower levels of intercellular adhesion molecule-1. Although the shifts to Lactobacillus dominance improved the markers of mucosal tissue health, these gains were only temporary among the women who experienced recurrence. CONCLUSION: Assemblies of highly diverse microbiota are associated with the enhanced resilience of bacterial vaginosis to standard metronidazole treatment. These communities may be foundational to treatment resistance or simply an indication of a well-established community made possible by canonical biofilm-forming taxa. Future studies must target the transcriptional activity of these communities under the pressure of antibiotic treatment to resolve the mechanisms of their resistance.
Assuntos
Antibacterianos/uso terapêutico , Metronidazol/uso terapêutico , Vagina/microbiologia , Vaginose Bacteriana/tratamento farmacológico , Adulto , Feminino , Humanos , Lactobacillus , Estudos Longitudinais , Microbiota , Recidiva , Falha de Tratamento , Vaginose Bacteriana/diagnóstico , Vaginose Bacteriana/microbiologiaRESUMO
BACKGROUND: Daily oral emtricitabine (FTC, F)/tenofovir disoproxil fumarate (TDF) combination is approved for HIV pre-exposure prophylaxis (PrEP) in men and women. Tenofovir alafenamide fumarate (TAF) is a newer, more potent prodrug of tenofovir (TFV), and in combination with FTC, has recently been approved for prevention of HIV through rectal transmission. METHODS: This Phase I, prospective, interventional, randomized study was conducted in three clinical sites: PROFAMILIA, Santo Domingo, Dominican Republic; University of Pittsburgh and Eastern Virginia Medical School. We assessed the multi-compartmental pharmacokinetics (primary outcome) and safety (secondary outcome) among HIV uninfected women randomized to F/TDF (200mg/300mg) or F/TAF (200mg/25mg; F/TAF25) (n=24) in a single dose phase (SDP) and F/TDF, F/TAF (200mg/10mg; F/TAF10), or F/TAF25 (n=75) in a multiple dose (14 daily doses) phase (MDP). We described PK parameters in plasma, peripheral blood mononuclear cells (PBMCs), and cervicovaginal (CV) and rectal fluids and tissues. ClinicalTrials.gov #NCT02904369, completed. FINDINGS: Recruitment for the study began on 5 October 2016. The first participant was enrolled on 6 October 2016 and the last participant completed the study 21 November 2017. PLASMA: TFV concentrations area under curve (AUC) were ~20 fold lower following F/TAF versus F/TDF. TFV-diphosphate (TFV-DP) AUC concentrations in PBMCs were 7-fold higher with F/TAF25 versus F/TDF. Median TFV-DP concentrations in vaginal tissue (4hours post last dose) were approximately 6-fold higher with F/TAF25 versus F/TDF. TFV and TFV-DP were lower with F/TAF versus F/TDF in rectal tissue. Concentrations of FTC and FTC-triphosphate (FTC-TP) were similar across matrices and treatment arms. Gastrointestinal adverse events (AEs) occurred more frequently in F/TDF users (44.0%) than in either F/TAF group (11.5 and 12.0%). INTERPRETATION: F/TAF was safe and well-tolerated. TFV-DP concentrations were higher in PBMCs and similar or higher (4h post dose) in female genital tract tissues for F/TAF versus F/TDF. High FTC and FTC-TP concentrations in all compartments support the potential of F/TAF as a new PrEP combination for women.
RESUMO
Bacterial vaginosis is a condition associated with adverse reproductive outcomes and characterized by a shift from a Lactobacillus-dominant vaginal microbiota to a polymicrobial microbiota, consistently colonized by strains of Gardnerella vaginalis. Metronidazole is the first-line treatment; however, treatment failure and recurrence rates remain high. To understand complex interactions between Gardnerella vaginalis and Lactobacillus involved in efficacy, here we develop an ordinary differential equation model that predicts bacterial growth as a function of metronidazole uptake, sensitivity, and metabolism. The model shows that a critical factor in efficacy is Lactobacillus sequestration of metronidazole, and efficacy decreases when the relative abundance of Lactobacillus is higher pre-treatment. We validate results in Gardnerella and Lactobacillus co-cultures, and in two clinical cohorts, finding women with recurrence have significantly higher pre-treatment levels of Lactobacillus relative to bacterial vaginosis-associated bacteria. Overall results provide mechanistic insight into how personalized differences in microbial communities influence vaginal antibiotic efficacy.
Assuntos
Antibacterianos/administração & dosagem , Metronidazol/administração & dosagem , Microbiota , Vaginose Bacteriana/tratamento farmacológico , Bactérias/classificação , Bactérias/efeitos dos fármacos , Bactérias/genética , Bactérias/crescimento & desenvolvimento , Estudos de Coortes , Feminino , Gardnerella vaginalis/efeitos dos fármacos , Gardnerella vaginalis/genética , Gardnerella vaginalis/crescimento & desenvolvimento , Humanos , Lactobacillus/efeitos dos fármacos , Lactobacillus/genética , Lactobacillus/crescimento & desenvolvimento , Microbiota/efeitos dos fármacos , Resultado do Tratamento , Vagina/efeitos dos fármacos , Vagina/microbiologia , Vaginose Bacteriana/microbiologiaRESUMO
While vitamin D insufficiency is known to impact a multitude of health outcomes, including HIV-1, little is known about the role of vitamin D-mediated immune regulation in the female reproductive tract (FRT). We performed a pilot clinical study of 20 women with circulating 25(OH)D levels <62.5 nmol/L. Participants were randomized into either weekly or daily high-dose oral vitamin D supplementation groups. In addition to serum vitamin D levels, genital mucosal endpoints, including soluble mediators, immune cell populations, gene expression, and ex vivo HIV-1 infection, were assessed. While systemic vitamin D levels showed a significant increase following supplementation, these changes translated into modest effects on the cervicovaginal factors studied. Paradoxically, post-supplementation vitamin D levels were decreased in cervicovaginal fluids. Given the strong correlation between vitamin D status and HIV-1 infection and the widespread nature of vitamin D deficiency, further understanding of the role of vitamin D immunoregulation in the female reproductive tract is important.
Assuntos
Suplementos Nutricionais , Suscetibilidade a Doenças/imunologia , Genitália Feminina/imunologia , Infecções por HIV/imunologia , HIV-1/imunologia , Fatores Imunológicos , Mucosa/imunologia , Estado Nutricional/fisiologia , Deficiência de Vitamina D/imunologia , Vitamina D/administração & dosagem , Vitamina D/farmacologia , 25-Hidroxivitamina D 2/sangue , Adulto , Feminino , Humanos , Pessoa de Meia-Idade , Mucosa/citologia , Projetos Piloto , Vitamina D/metabolismo , Vitamina D/fisiologia , Adulto JovemRESUMO
The development of topical inserts for the prevention of sexually transmitted infections (STIs), particularly human immunodeficiency virus (HIV), represents a promising alternative to oral and parenteral pre-exposure prophylaxis (PrEP) dosage forms. They may be used for vaginal and/or rectal administration of a variety of agents with antiviral activity. Topical inserts deliver drugs to the portal of viral entry, i.e., the genital or rectal mucosa, with low systemic exposure, and therefore are safer and have fewer side effects than systemic PrEP agents. They may dissolve fast, releasing the active drugs within minutes of insertion, or slowly for long-acting drug delivery. Furthermore, they are user-friendly being easy to administer, discreet and highly portable. They are also economical and easy to manufacture at scale and to distribute, with excellent stability and shelf-life. Altogether, topical inserts represent a particularly promising form of drug delivery for HIV and STI prevention. Highlighted within this review are end-user acceptability research dedicated to understanding preferred attributes for this form of drug delivery, advantages and disadvantages of the formulation platform options, considerations for their development, clinical assessment of select placebo prototypes, future directions, and the potential impact of this dosage form on the HIV prevention landscape.
RESUMO
OBJECTIVE: Endogenous and exogenous contraceptive hormones may affect mucosal pharmacokinetics (PKs) of topical antiretrovirals such as tenofovir. We present PK data from healthy women using tenofovir vaginal gel, at baseline (follicular and luteal phases) and after oral contraceptive pill (OCP) or depot medroxyprogesterone acetate (DMPA) use. METHODS: CONRAD A10-114 was a prospective, interventional, open-label, parallel study. We enrolled 74 women and 60 completed the study (32 and 28 who selected OCPs or DMPA, respectively). Participants used 2 doses of tenofovir gel separated by 2 hours, without intercourse, and were examined 3 or 11 hours after the last dose. We assessed pharmacokinetics in plasma, cervicovaginal (CV) aspirate, and vaginal tissue. RESULTS: In general, there were no significant differences in mucosal tenofovir and tenofovir diphosphate concentrations (P > 0.23) in the follicular and luteal phases, except for lower mean tenofovir tissue concentrations (P < 0.01) in the follicular phase. Tenofovir concentrations significantly decreased in CV aspirate (P < 0.01) after contraceptive use, but overall remained very high (>10 ng/mL). Mean tissue tenofovir diphosphate increased to 6229 fmol/mg after DMPA use compared with 3693 and 1460 fmol/mg in the follicular and luteal phases, respectively (P < 0.01). The molecular conversion of tenofovir into tenofovir diphosphate was more effective in DMPA users (molecular ratio of 2.02 versus 0.65 luteal phase, P < 0.01). CONCLUSIONS: Both menstrual cycle phase and exogenous hormones affect topical tenofovir mucosal and systemic PKs. However, high levels of tenofovir and tenofovir diphosphate were observed in the CV mucosa in the presence or absence of OCPs and DMPA, with tissue levels exceeding benchmarks of predicted mucosal anti-HIV efficacy (tenofovir >1.00 ng/mL in CV aspirate and tenofovir diphosphate >1000 fmol/mg).
Assuntos
Fármacos Anti-HIV/farmacocinética , Anticoncepcionais Femininos/farmacocinética , Infecções por HIV/prevenção & controle , Acetato de Medroxiprogesterona/farmacocinética , Tenofovir/farmacocinética , Cremes, Espumas e Géis Vaginais/farmacocinética , Administração Intravaginal , Adulto , Fármacos Anti-HIV/administração & dosagem , Anticoncepcionais Femininos/administração & dosagem , Interações Medicamentosas , Feminino , Voluntários Saudáveis , Humanos , Acetato de Medroxiprogesterona/administração & dosagem , Ciclo Menstrual/efeitos dos fármacos , Pessoa de Meia-Idade , Estudos Prospectivos , Tenofovir/administração & dosagem , Resultado do Tratamento , Cremes, Espumas e Géis Vaginais/administração & dosagem , Adulto JovemRESUMO
BACKGROUND: Adherence is critical for successful topical, vaginally delivered anti-retroviral (ARV)-based HIV pre-exposure prophylaxis (PrEP). Quantitating systemic or tissue ARV levels through LC-MS/MS is currently viewed as the most reliable measure of adherence. However, for placebo-controlled trials, this is a high cost analysis that measures adherence only in the drug treatment group. A desirable marker of adherence is one that is measured in both placebo and drug treatment groups using a simple on-site clinical laboratory test, which allows necessary interventions for supporting participant adherence. Our objective was to develop adherence markers for four vaginal placebo products currently used as microbicide delivery systems: gel, film, insert, and intravaginal ring. Excipient and spectroscopy-based approaches were used for preclinical development of the placebo markers and subsequently validated by the CONRAD 135 study. The study collected vaginal swabs collected each day for 1 week post vaginal application of gel, film, or insert in the clinic with or without sex. Intravaginal rings were collected after 1 day, 7, and 30 days of use. RESULTS: Placebo gel, film, and insert in vaginal swabs were successfully detected by specific excipient colorimetric or probe-based assays for hydroxyethylcellulose, glycerin, and sorbitol respectively, as well as spectroscopy-based prediction models. The range of detection for gel, film, and insert in swabs collected up to 16 h post vaginal application was 70-100% of the total swabs per time point, with some markers showing potential for longer duration. Decreasing residual glycerin levels and increasing bioanalyte penetration of vaginally used intravaginal rings showed significant changes between 1 and 30 days of use. CONCLUSIONS: We demonstrated clinical proof-of-concept that adherence markers for placebo product can be measured using simple, lower cost approaches. Measuring adherence in both placebo and drug arms of a HIV PrEP study would better inform future trial designs.