Andrea Ries Thurman

Innate Immunity and Inflammatory Response to Trichomonas vaginalis and Bacterial Vaginosis: Relationship to HIV Acquisition

Citation Thurman AR, Doncel GF. Innate immunity and inflammatory response to Trichomonas vaginalis and bacterial vaginosis: relationship to HIV acquisition. Am J Reprod Immunol 2011; 65: 89–98

Multipurpose Prevention Technologies: Biomedical Tools to Prevent HIV-1, HSV-2, and Unintended Pregnancies

Statistics clearly show an unmet need for highly effective contraception, especially in less developed countries. Many of these countries are at the core of the HIV/AIDS epidemic and show very high prevalence rates for other sexually transmitted infections (STIs) such as that caused by HSV-2. A woman at risk of unintended pregnancy due to unprotected intercourse is also at risk for HIV/STI. Owing to their causative interrelationship, combining protection against these conditions will result in enhanced prevention and health benefits. Existing multipurpose prevention modalities such as condoms and physical barriers, albeit efficacious, face cultural hurdles that have so far hindered their widespread use. Success has recently been demonstrated in large clinical trials, demonstrating proof of concept of microbicides in reducing the incidence of HIV-1 and HSV-2 among at-risk populations. The challenge heretofore is to refine these products to make them more potent, convenient, accessible, and acceptable. Potent antiviral drugs released topically in the female reproductive tract by innovative delivered systems and formulations will provide safe, effective, and acceptable multipurpose prevention tools. This paper provides an overview of existing and novel approaches to multipurpose prevention strategies.

Depot Medroxyprogesterone Acetate Increases Immune Cell Numbers and Activation Markers in Human Vaginal Mucosal Tissues

The relationship between exogenous contraceptive hormones and permissiveness of the female genital tract to human immunodeficiency virus type 1 (HIV-1) is the subject of renewed debate. To better characterize the effect of depot medroxyprogesterone acetate (DMPA) on HIV-1 cellular targets and epithelial integrity in the vagina, we compared leukocyte populations, markers of activation and proliferation, and the density of intercellular junctional proteins in the vaginal epithelium of women during the follicular and luteal phases of the menstrual cycle and approximately 12 weeks after receiving a DMPA injection. This prospective cohort study involved 15 healthy women. Vaginal biopsies were obtained in the follicular and luteal phases of the menstrual cycle, and approximately 12 weeks following a 150-mg intramuscular injection of DMPA. Leukocyte populations, activation phenotype, and epithelial tight junction and adherens proteins were evaluated by immunohistochemistry. After receiving DMPA, the numbers of CD45, CD3, CD8, CD68, HLA-DR, and CCR5 bearing immune cells were significantly (p<0.05) increased in vaginal tissues, compared to the follicular and/or luteal phases of untreated cycles. There were no significant differences in immune cell populations between the follicular and luteal phases of the control cycle. There were also no statistically significant differences in epithelial thickness and density of epithelial tight junction and adherens proteins among the follicular, luteal, and post-DMPA treatment sampling points. In this pilot study, vaginal immune cell populations were significantly altered by exogenous progesterone, resulting in increased numbers of T cells, macrophages, and HLA-DR- and CCR5-positive cells.

Role of Semen in HIV-1 Transmission: Inhibitor or facilitator?

Citation Doncel GF, Joseph T, Thurman AR. Role of semen in HIV‐1 transmission: inhibitor or facilitator? Am J Reprod Immunol 2011; 65: 292–301

Intravaginal rings as delivery systems for microbicides and multipurpose prevention technologies

There is a renewed interest in delivering pharmaceutical products via intravaginal rings (IVRs). IVRs are flexible torus-shaped drug delivery systems that can be easily inserted and removed by the woman and that provide both sustained and controlled drug release, lasting for several weeks to several months. In terms of women’s health care products, it has been established that IVRs effectively deliver contraceptive steroids and steroids for the treatment of postmenopausal vaginal atrophy. A novel application for IVRs is the delivery of antiretroviral drugs for the prevention of human immunodeficiency virus (HIV) genital infection. Microbicides are antiviral drugs delivered topically for HIV prevention. Recent reviews of microbicide IVRs have focused on technologies in development and optimizing ring design. IVRs have several advantages, including the ability to deliver sustained drug doses for long periods of time while bypassing first pass metabolism in the gut. IVRs are discreet, woman-controlled, and do not require a trained provider for placement or fitting. Previous data support that women and their male sexual partners find IVRs highly acceptable. Multipurpose prevention technology (MPT) products provide protection against unintended/mistimed pregnancy and reproductive tract infections, including HIV. Several MPT IVRs are currently in development. Early clinical testing of new microbicide and MPT IVRs will require a focus on safety, pharmacokinetics and pharmacodynamics. Specifically, IVRs will have to deliver tissue concentrations of drugs that are pharmacodynamically active, do not cause mucosal alterations or inflammation, and do not change the resident microbiota. The emergence of resistance to antiretrovirals will need to be investigated. IVRs should not disrupt intercourse or have high rates of expulsion. Herein, we reviewed the microbicide and MPT IVRs currently in development, with a focus on the clinical aspects of IVR assessment and the challenges facing microbicide and MPT IVR product development, clinical testing, and implementation. The information in this review was drawn from PubMed searches and a recent microbicide/MPT product development workshop organized by CONRAD.

Bacterial Vaginosis and Subclinical Markers of Genital Tract Inflammation and Mucosal Immunity

Bacterial vaginosis (BV) has been linked to an increased risk of human immunodeficiency virus (HIV) acquisition and transmission in observational studies, but the underlying biological mechanisms are unknown. We measured biomarkers of subclinical vaginal inflammation, endogenous antimicrobial activity, and vaginal flora in women with BV and repeated sampling 1 week and 1 month after completion of metronidazole therapy. We also compared this cohort of women with BV to a healthy control cohort without BV. A longitudinal, open label study of 33 women with a Nugent score of 4 or higher was conducted. All women had genital swabs, cervicovaginal lavage (CVL) fluid, and cervicovaginal biopsies obtained at enrollment and received 7 days of metronidazole treatment. Repeat sampling was performed approximately 1 week and 1 month after completion of therapy. Participants baseline samples were compared to a healthy, racially matched control group (n=13) without BV. The CVL from women with resolved BV (Nugent 0-3) had significantly higher anti-HIV activity, secretory leukocyte protease inhibitor (SLPI), and growth-related oncogene alpha (GRO-α) levels and their ectocervical tissues had significantly more CD8 cells in the epithelium. Women with persistent BV after treatment had significantly higher levels of interleukin-1β, tumor necrosis factor alpha (TNF-α), and intercellular adhesion molecule 1 (ICAM-1) in the CVL. At study entry, participants had significantly greater numbers of CCR5(+) immune cells and a higher CD4/CD8 ratio in ectocervical tissues prior to metronidazole treatment, compared to a racially matched cohort of women with a Nugent score of 0-3. These data indicate that BV is associated with changes in select soluble immune mediators, an increase in HIV target cells, and a reduction in endogenous antimicrobial activity, which may contribute to the increased risk of HIV acquisition.

Effects of Hormonal Contraception on Antiretroviral Drug Metabolism Pharmacokinetics and Pharmacodynamics.

Among women, human immunodeficiency virus type 1 (HIV‐1) infection is most prevalent in those of reproductive age. These women are also at risk of unintended or mistimed pregnancies. Hormonal contraceptives (HCs) are one of the most commonly used methods of family planning worldwide. Therefore, concurrent use of HC among women on antiretroviral medications (ARVs) is increasingly common. ARVs are being investigated and have been approved for pre‐exposure prophylaxis (PrEP), and therefore, drug–drug interactions must also be considered in HIV‐1‐negative women who want to prevent both unintended pregnancy and HIV‐1 infection. This article will review four main interactions: (i) the effect of HCs on ARV pharmacokinetics (PK) and pharmacodynamics (PD) during therapy, (ii) the effect of ARVs on HC PK and PD, (iii) the role of drug transporters on drug–drug interactions, and (iv) ongoing research into the effect of HCs on pre‐exposure prophylaxis PK and PD.

Vaginal cytokines do not differ between postmenopausal women with and without symptoms of vulvovaginal irritation.

ObjectiveThe aim of this exploratory pilot study was to determine if there are differences in vaginal cytokine levels between postmenopausal women with and without vulvovaginal irritative symptoms (itching, burning, or pain). MethodsPostmenopausal women (n = 34) not using hormone therapy and presenting with or without symptoms of vulvovaginal irritation were asked to volunteer for this study. Each participant underwent a vaginal examination and screening for vaginitis using Amsel criteria, pH, and light microscopy. A vaginal lavage with 5.0 mL of sterile saline was carried out, and a peripheral blood sample was obtained. The vaginal lavage and serum samples were assayed for interleukin (IL)-1&bgr;, IL-6, IL-8, and tumor necrosis factor-&agr; by specific enzyme-linked immunosorbent assays. Results were adjusted for total protein concentration and presented as the amount of cytokines per protein (pg/&mgr;g protein). Statistical analysis was performed using SAS version 9.3 (SAS Institute, Cary, NC). The means and SDs of all variables among women with and without vulvovaginal irritation were compared using independent-samples Student’s t test. ResultsA total of 26 postmenopausal women were enrolled into the study (symptomatic, n = 15; asymptomatic, n = 11). The mean (SD) vaginal pH for all participants was 5.9 (1.2). There were no significant differences (P > 0.05) in age, age at menopause, vaginal pH, and vaginal and serum cytokines and chemokines (IL-1&bgr;, IL-6, IL-8, and tumor necrosis factor-&agr;) among symptomatic versus asymptomatic women. IL-8 was the most abundant vaginal cytokine, with mean (SD) vaginal IL-8 levels being 4.1 (3.4) and 3.1 (3.9) pg/&mgr;g protein in the symptomatic versus asymptomatic groups, respectively (P = 0.55). There were no significant linear correlations (P > 0.05) between serum and vaginal cytokine levels for all endpoints. ConclusionsThe presence or absence of postmenopausal vulvovaginal symptoms does not significantly differentiate vaginal inflammatory markers. Serum and vaginal cytokines are not significantly linearly correlated among postmenopausal women with and without symptoms commonly associated with vaginal atrophy, implying that this is a local reaction.

Post-cesarean delivery infectious morbidity: Focus on preoperative antibiotics and methicillin-resistant Staphylococcus aureus

BACKGROUND Randomized controlled trials show that administering preoperative antibiotics prior to cesarean delivery (CD) significantly reduces the incidence of post-CD infectious morbidity. Methicillin-resistant Staphylococcus aureus (MRSA) has become prevalent in obstetrics and gynecology. The objective of this trial is to examine infectious morbidity in a clinical setting before versus after implementation of a preoperative antibiotic policy and, further, to describe the organisms cultured from CD wound infections. METHODS We used a retrospective chart review of women delivering by CD before and after implementation of preoperative antibiotic policy. RESULTS Prior to instituting the preoperative antibiotic policy, the incidence of post-CD infectious morbidity was 20.7% and dropped to 8.5% after the policy was established (P < .001). Study cohorts were similar (P > .05) in several risk factors for infection. MRSA was the most common organism isolated from post-CD wound infections (18/34, 53%). Endomyometritis accounted for the majority of post-CD infections (143/191, 74.9%), and most infections occurred within 7 days of CD (170/191, 89.0%). CONCLUSION The incidence of post-CD infectious complications decreased after a policy of administering preoperative antibiotics was instituted. MRSA was the most common organism isolated from post-CD wound infections. Further studies into the benefit of MRSA coverage in CD preoperative antibiotic regimens are needed.

Medroxyprogesterone acetate and estradiol cypionate injectable suspension (Cyclofem) monthly contraceptive injection: steady-state pharmacokinetics

BACKGROUND Cyclofem is a combined injectable contraceptive, containing medroxyprogesterone acetate (MPA) and estradiol cypionate. The objective was to characterize the steady-state pharmacokinetics (PK) using tandem liquid chromatography/mass spectrometry and compare these data to a previous PK study of this formulation in US women. STUDY DESIGN Fifteen ovulatory, surgically sterile women received three Cyclofem injections, once every 28 days, with serum PK measurements on 23 separate days. Trough levels of estradiol and MPA were obtained on Days 1, 29 and 57, prior to each of the three injections. Steady-state concentrations of MPA and estradiol were assessed during the third treatment month on Days 58, 60, 62, 64, 67, 69, 71, 75, 78 and 85. MPA and serum progesterone levels were measured during the follow-up phase to assess MPA clearance (Days 92, 99, 106, 113, 120, 127, 134 and 141) and return of ovulation (Days 103, 106, 131 and 134). RESULTS In the steady state, mean serum MPA concentrations peaked at 1.31 ng/mL at 4.1 days. Mean estradiol levels peaked at 254 pg/mL by 3.3 days. Ovulation was suppressed for at least 77 days post third injection in all but one woman. CONCLUSIONS Once monthly injections of Cyclofem resulted in contraceptive levels of MPA without accumulation of hormones, consistent with a previous US study.