A phase 1, randomized, placebo-controlled study to evaluate the safety and immunogenicity of an mRNA-based RSV prefusion F protein vaccine in healthy younger and older adults.

Respiratory Syncytial Virus (RSV) causes lower respiratory tract infections that can be severe and sometimes fatal. The risk for severe RSV infection is highest in infants and older adults. A safe and effective RSV vaccine for older adults represents a serious unmet medical need due to higher morbidity and mortality in this age group. In this randomized, partially double-blind, placebo-controlled, phase 1 dose-escalation study, we evaluated the safety, tolerability and immunogenicity of an investigational messenger ribonucleic acid (mRNA) vaccine encoding the RSV fusion protein (F) stabilized in the prefusion conformation. The study was conducted in healthy younger adults (ages ≥18 and ≤49 years) and healthy older adults (ages ≥60 and ≤79 years). Participants received mRNA-1777 (V171) or placebo as a single intramuscular dose. For each dose level, three sentinel participants were administered open-label mRNA-1777 (V171). Seventy-two younger adults were randomized and administered 25, 100, or 200 µg mRNA-1777 (V171) or placebo, and 107 older adults were randomized and administered 25, 100, 200 or 300 µg mRNA-1777 (V171) or placebo. Primary objectives were safety and tolerability and secondary objectives included humoral and cell-mediated immunogenicity. All dose levels of mRNA-1777 (V171) were generally well tolerated and no serious adverse events related to the vaccine were reported. Immunization with mRNA-1777 (V171) elicited a humoral immune response as measured by increases in RSV neutralizing antibody titers, serum antibody titers to RSV prefusion F protein, D25 competing antibody titers to RSV prefusion F protein, and cell-mediated immune responses to RSV-F peptides.

Condylomata Acuminata (Anogenital Warts) Contain Accumulations of HIV-1 Target Cells That May Provide Portals for HIV Transmission.

Background: Condylomata acuminata (anogenital warts [AGWs]) are prevalent in human immunodeficiency virus (HIV)-infected individuals and sexually active populations at risk for HIV acquisition and have been associated with HIV transmission. We compared AGW specimens to control tissue specimens for abundance, types, and location of HIV target cells and for susceptibility to HIV infection in vitro, to provide biologic evidence that AGWs facilitate HIV transmission. Methods: We used immunohistologic staining to identify HIV target cells in AGW and control specimens. We also inoculated HIV in vitro into AGW and control specimens from HIV-negative men and assessed infection by means of TZM-bl and p24 assays. Results: CD1a+ dendritic cells, CD4+ T cells, and macrophages were significantly more abundant in the epidermis of AGW specimens than control specimens. These HIV target cells also often appeared in large focal accumulations in the dermis of AGW specimens. Two of 8 AGW specimens versus 0 of 8 control specimens showed robust infection with HIV in vitro. Conclusions: Compared with normal skin, AGWs contain significantly higher concentrations of HIV target cells that may be susceptible to HIV infection. Condylomata may thus promote HIV transmission, especially in the setting of typical lesion vascularity and friability. Prevention or treatment of AGWs may decrease the sexual transmission of HIV.

Facilitators of and barriers to high-resolution anoscopy adherence among men who have sex with men: a qualitative study.

Background Anal cancer is a rare malignancy that disproportionately affects men who have sex with men (MSM) and HIV-infected people. Anal cancer is associated with human papillomavirus (HPV) in upward of 90% of cases and is preceded by pre-cancerous changes in cells of the anal canal. High-resolution anoscopy (HRA) is used for the detection, treatment and continued monitoring of anal dysplasia. Practice guidelines regarding anal cancer prevention vary by jurisdiction and institution, and patient engagement is low for high-risk populations such as MSM. The purpose of this study is to characterise perceptions among MSM of barriers to and facilitators of their adherence to HRA follow-up recommendations. METHODS: Surveys and in-person focus groups with MSM who were either adherent or non-adherent to HRA follow-up recommendations at a Federally Qualified Health Centre in Boston, MA, which specialises in sexual and gender minority care, were conducted. Facilitators of and barriers to follow-up were identified by deductive content analysis. RESULTS: Focus group participants identified the following barriers to and facilitators of HRA follow up: (1) patient-level beliefs about HPV-related disease or HRA, ability to engage in care, internalised stigma and physical discomfort; (2) provider-level knowledge and expertise, communication skills and relationship-building with patient; and (3) systems-level societal stigma and healthcare system inefficiencies. CONCLUSIONS: Reinforcing facilitators of and reducing barriers to HRA follow up may improve adherence among MSM. This includes improvements to: patient education, provider training to increase knowledge and cultural sensitivity, public awareness about HPV-related anal cancer, physical discomfort associated with HRA and systems inefficiencies.

Facilitators of and barriers to HPV vaccination among sexual and gender minority patients at a Boston community health center.

BACKGROUND: Young sexual minority individuals have lower human papillomavirus (HPV) vaccine completion rates than the general population, and little is known about how gender minority people perceive HPV vaccination. The aim of this study was to qualitatively identify patient-, provider-, and systems-level barriers and facilitators for HPV vaccination among sexual and gender minority (SGM) people. METHODS: Fifteen SGM-identified individuals, ages 23-26, were recruited at an urban community health center in Boston, MA, that specializes in care for SGM. Participants were enrolled in a study that utilized surveys and in-person focus groups. During focus groups, participants were asked to describe their perceived barriers and facilitators for completion of HPV vaccination. RESULTS: Fourteen participants reported having a sexual minority identity, and five participants reported having a gender minority identity. Participants described the following factors influencing HPV vaccination: (1) at the patient level, low HPV-related knowledge and lack of engagement in care were associated with less vaccination, whereas fear of HPV-related disease motivated vaccination; (2) at the provider level, knowledge and SGM cultural-competence related to HPV was associated with patient willingness to be vaccinated; (3) at the systems level, SGM identity-affirming healthcare settings were associated with increased vaccination, whereas historical trends in HPV vaccine marketing selectively for cisgender women and lack of public awareness of HPV-related disease among SGM were associated with decreased vaccincation. CONCLUSION: Our study identified internal and external barriers for HPV vaccination related among SGM patients. These findings highlight the need to increase public awareness about the risks of HPV-related disease among SGM and educate SGM youth about HPV-related disease and vaccine importance. Finally, this study supports the need for future interventions to cultivate SGM-competent providers and SGM identity-affirming healthcare settings as a way to increase HPV vaccination.

Test performance and acceptability of self- versus provider-collected swabs for high-risk HPV DNA testing in female-to-male trans masculine patients.

BACKGROUND: High-risk human papillomavirus (hrHPV) causes virtually all cervical cancers. Trans masculine (TM) people (those assigned female at birth who identify with a gender other than female) have low uptake of conventional cervical cancer screening. Self-collected hrHPV DNA testing has high levels of acceptability among cisgender (non-transgender) females and may support increased cervical cancer screening uptake in TM individuals. OBJECTIVE: To assess the test performance and acceptability of self-collected vaginal specimens in comparison to provider-collected cervical swabs for hrHPV DNA detection in TM individuals ages 21-64 years. METHODS: Between March 2015-September 2016, 150 TM participants with a cervix (mean age = 27.5 years; SD = 5.7) completed a one-time study visit comprised of a self-report survey, self-collected vaginal HPV DNA swab, clinician-administered cervical HPV swab, and brief interview on acceptability of clinical procedures. Participants were randomized to complete either self- or provider-collection first to minimize ordering effects. Self- and provider-collected samples were tested for 13 hrHPV DNA types using a DNA Hybridization Assay. The primary outcome variable was the concordance (kappa statistic) and performance (sensitivity, specificity) of self-collected vaginal HPV DNA specimens versus provider-collected cervical HPV swabs as the gold standard. RESULTS: Of the 131 participants completing both the self- and provider-collected HPV tests, 21 cases of hrHPV were detected by the provider cervical swab (gold standard; 16.0% hrHPV prevalence); 15 of these cases were accurately detected by the self-collected vaginal swab (71.4% concordance) (Kappa = 0.75, 95% Confidence Interval [CI]: 0.59, 0.92; p<0.001). Compared to the provider-collected cervical hrHPV DNA sample (gold standard), the self-collected vaginal hrHPV DNA test demonstrated a sensitivity of 71.4% (95% CI: 0.52, 0.91; p = 0.0495) and specificity of 98.2% (95% CI: 0.96, 1.00; p<0.0001). Over 90% of participants endorsed a preference for the self-collected vaginal swab over provider-collected cervical swab. CONCLUSION: Self-collected vaginal swabs are highly acceptable to TM as a means to test for hrHPV DNA. Test performance of this self-collection method for hrHPV detection in TM is consistent with previous studies in cisgender females. Self-collected vaginal swab testing for hrHPV DNA represents a reasonable and patient-centered strategy for primary cervical cancer screening in TM patients unwilling to undergo provider collection of specimens via speculum exam.

Comparing self- and provider-collected swabbing for HPV DNA testing in female-to-male transgender adult patients: a mixed-methods biobehavioral study protocol.

BACKGROUND: Cervical cancer, nearly all cases of which are caused by one of several high-risk strains of the human papillomavirus (hr-HPV), leads to significant morbidity and mortality in individuals with a cervix. Trans masculine (TM) individuals were born with female reproductive organs and identify as male, man, transgender man, or another diverse gender identity different from their female assigned sex at birth. Routine preventive sexual health screening of TM patients is recommended, including screening for cervical cancer and other sexually transmitted infections (STIs); however, as many as one in three TM patients are not up-to-date per recommended U.S. GUIDELINES: Among cisgender (non-transgender) women, self-swab hr.-HPV DNA testing as a primary cervical cancer screening method and self-swab specimen collection for other STIs have high levels of acceptability. No study has yet been conducted to compare the performance and acceptability of self- and provider-collected swabs for hr.-HPV DNA testing and other STIs in TM patients. METHODS: This article describes the study protocol for a mixed-methods biobehavioral investigation enrolling 150 sexually active TM to (1) assess the clinical performance and acceptability of a vaginal self-swab for hr.-HPV DNA testing compared to provider cervical swab and cervical cytology, and (2) gather acceptability data on self-collected specimens for other STIs. Study participation entails a one-time clinical visit at Fenway Health in Boston, MA comprised of informed consent, quantitative assessment, venipuncture for syphilis testing and HIV (Rapid OraQuick) testing, randomization, collection of biological specimens/biomarkers, participant and provider satisfaction survey, and qualitative exit interview. Participants are compensated $100. The primary study outcomes are concordance (kappa statistic) and performance (sensitivity and specificity) of self-collected vaginal HPV DNA specimens vs provider-collected cervical HPV swabs as a gold standard. DISCUSSION: This study addresses critical gaps in current clinical knowledge of sexual health in TM patients, including comparing alternative strategies for screening and diagnosis of cervical cancer, hr.-HPV, and other STIs. Findings have implications for improving the delivery of sexual health screening to this often overlooked and underserved patient population. Less-invasive patient-centered strategies may also generalize to other at-risk cisgender female populations that face barriers to timely and needed STI and cervical cancer screening. TRIAL REGISTRATION: ClinicalTrials.gov ID: NCT02401867.

Pharmacodynamic correlations using fresh and cryopreserved tissue following use of vaginal rings containing dapivirine and/or maraviroc in a randomized, placebo controlled trial.

BACKGROUND: The ex vivo challenge assay is a bio-indicator of drug efficacy and was utilized in this randomized, placebo controlled trial as one of the exploratory endpoints. Fresh and cryopreserved tissues were evaluated for human immunodeficiency virus (HIV) infection and pharmacokinetic (PK)/pharmacodynamic (PD) relationships. METHODS: HIV-negative women used vaginal rings containing 25 mg dapivirine (DPV)/100 mg maraviroc (MVC) (n = 12), DPV only (n = 12), MVC only (n = 12), or placebo (n = 12) for 28 days. Blood plasma, cervicovaginal fluid (CVF), and cervical biopsies were collected for drug quantification and the ex vivo challenge assay; half (fresh) were exposed immediately to HIV while the other half were cryopreserved, thawed, then exposed to HIV. HIV replication was monitored by p24 enzyme-linked immunosorbent assay from culture supernatant. Data were log-transformed and analyzed by linear least squared regression, nonlinear Emax dose-response model and Satterthwaite t test. RESULTS: HIV replication was greater in fresh compared to cryopreserved tissue (P = 0.04). DPV was detected in all compartments, while MVC was consistently detected only in CVF. Significant negative correlations between p24 and DPV levels were observed in fresh cervical tissue (P = 0.01) and CVF (P = 0.03), but not plasma. CVF MVC levels showed a significant negative correlation with p24 levels (P = 0.03); drug levels in plasma and tissue were not correlated with HIV suppression. p24 levels from cryopreserved tissue did not correlate to either drug from any compartment. CONCLUSION: Fresh tissue replicated HIV to greater levels and defined PK/PD relationships while cryopreserved tissue did not. The ex vivo challenge assay using fresh tissue could prioritize drugs being considered for HIV prevention.

Phase 1 Safety, Pharmacokinetics, and Pharmacodynamics of Dapivirine and Maraviroc Vaginal Rings: A Double-Blind Randomized Trial.

BACKGROUND: Variable adherence limits effectiveness of daily oral and intravaginal tenofovir-containing pre-exposure prophylaxis. Monthly vaginal antiretroviral rings are one approach to improve adherence and drug delivery. METHODS: MTN-013/IPM 026, a multisite, double-blind, randomized, placebo-controlled trial in 48 HIV-negative US women, evaluated vaginal rings containing dapivirine (DPV) (25 mg) and maraviroc (MVC) (100 mg), DPV only, MVC only, and placebo used continuously for 28 days. Safety was assessed by adverse events. Drug concentrations were quantified in plasma, cervicovaginal fluid (CVF), and cervical tissue. Cervical biopsy explants were challenged with HIV ex vivo to evaluate pharmacodynamics. RESULTS: There was no difference in related genitourinary adverse events between treatment arms compared with placebo. DPV and MVC concentrations rose higher initially before falling more rapidly with the combination ring compared with relatively stable concentrations with the single-drug rings. DPV concentrations in CVF were 1 and 5 log10 greater than cervical tissue and plasma for both rings. MVC was consistently detected only in CVF. DPV and MVC CVF and DPV tissue concentrations dropped rapidly after ring removal. Cervical tissue showed a significant inverse linear relationship between HIV replication and DPV levels. CONCLUSIONS: In this first study of a combination microbicide vaginal ring, all 4 rings were safe and well tolerated. Tissue DPV concentrations were 1000 times greater than plasma concentrations and single drug rings had more stable pharmacokinetics. DPV, but not MVC, demonstrated concentration-dependent inhibition of HIV-1 infection in cervical tissue. Because MVC concentrations were consistently detectable only in CVF and not in plasma, improved drug release of MVC rings is needed.

Cost-effectiveness of surveillance strategies after treatment for high-grade anal dysplasia in high-risk patients.

BACKGROUND: Anal cancer is one of the most common cancers affecting human immunodeficiency virus (HIV)-infected male patients. Currently, there is no consensus on posttreatment surveillance of HIV-infected men who have sex with men (MSM) who have been treated for high-grade intraepithelial neoplasia (HGAIN), the likely precursor to anal cancer. OBJECTIVE: The aim of this study was to assess the cost-effectiveness of a range of strategies for anal cancer surveillance in HIV-infected MSM previously treated for HGAIN. METHODS: We developed a Markov model to project quality-adjusted life expectancy, lifetime costs, and the incremental cost-effectiveness ratios of 5 strategies using high-resolution anoscopy (HRA) and/or anal cytology testing after treatment. RESULTS: Performing HRA alone at 6- and 12-month visits was associated with a cost-effectiveness ratio of $4446 per quality-adjusted life year gained. In comparison, combined HRA and anal cytology at both visits provided greater health benefit at a cost of $17,373 per quality-adjusted life year gained. Our results were robust over a number of scenarios and assumptions including patients' level of immunosuppression. Results were most sensitive to test characteristics and cost, as well as progression rates of normal to HGAIN and HGAIN to cancer. CONCLUSIONS: Our results suggest that combined HRA and anal cytology at 6 and 12 months may be a cost-effective surveillance strategy after treatment of HGAIN in HIV-infected MSM.

Safety and efficacy of topical cidofovir to treat high-grade perianal and vulvar intraepithelial neoplasia in HIV-positive men and women.

OBJECTIVE: To evaluate the safety and efficacy of topical cidofovir for treatment of high-grade squamous perianal intraepithelial neoplasia (PAIN) and vulvar intraepithelial neoplasia (VIN) lesions in HIV-positive individuals. DESIGN: Phase IIa prospective multicenter trial conducted at eight clinical sites through the AIDS Malignancy Consortium. METHODS: : HIV-positive patients with biopsy-proven high-grade PAIN that was at least 3 cm were enrolled. PAIN biopsy specimens were assessed for human papillomavirus (HPV) using PCR and type-specific HPV probing. Participants applied 1% topical cidofovir to PAIN and VIN (if present) for six 2-week cycles. Results were designated as complete response (CR), partial response (PR) (>50% reduction in size), stable disease, or progressive disease (PD). RESULTS: Twenty-four men and nine women (eight with high-grade VIN as well) were enrolled. Mean age was 44 years and mean CD4 cell count was 412 cells/µl. HPV DNA (most commonly HPV16) was detected in all pretreatment study specimens. Twenty six (79%) participants completed treatment per protocol: CR, five (15%); PR, 12 (36%), stable disease, seven (21%); PD, two (6%) (one with a superficially invasive cancer and one with new area of high-grade PAIN). Treatment was well tolerated with most common adverse events being mild to moderate affecting lesional skin: pain/burning/irritation (25 patients) and ulceration (13 patients). CONCLUSION: Topical cidofovir had 51% efficacy in the short-term treatment of high-grade PAIN and VIN with acceptable toxicity in HIV-positive individuals. Randomized control studies with more prolonged treatment courses and longer follow-up to assess the durability of the response are needed.

Frequency of occult high-grade squamous intraepithelial neoplasia and invasive cancer within anal condylomata in men who have sex with men.

Human papillomavirus causes anal condylomata, high-grade anal intraepithelial neoplasia, and anal squamous cell cancer. We found high-grade intraepithelial neoplasia or squamous cell cancer in 75 (47%) of 159 HIV-seropositive men who have sex with men (MSM) and in 42 (26%) of 160 HIV-seronegative MSM with anal condylomata meriting surgery (P<.001, determined by use of the chi(2) test). Anal condylomata in MSM often harbor high-grade intraepithelial neoplasia and squamous cell cancer.

Infrared coagulator treatment of high-grade anal dysplasia in HIV-infected individuals: an AIDS malignancy consortium pilot study.

OBJECTIVE: To evaluate prospectively the safety of the infrared coagulator (IRC) as a treatment for anal high-grade squamous intraepithelial lesions (HSILs) in HIV-infected individuals and to seek preliminary evidence for efficacy. METHODS: HIV-infected patients with

Spectrum of human papillomavirus-related dysplasia and carcinoma of the anus in HIV-infected patients.

The incidence of human papillomavirus (HPV)-related anal squamous cell carcinoma is increasing. It is likely that long-standing HIV-related immunosuppression plays a significant role in the pathogenesis of anal carcinoma; however, a direct HIV-HPV interaction has also been implicated. Using cervical cancer prevention as a paradigm, anal Pap smear screening as part of routine HIV preventive care has been proposed to detect and treat precancerous anal lesions in the hope of decreasing anal cancer rates. All HIV-positive patients with invasive cancer of the anal canal, particularly those with CD4+ cell counts greater than 200/microL and those receiving HAART, should be managed in the same manner as their HIV-negative counterparts.

High resolution anoscopy findings for men who have sex with men: inaccuracy of anal cytology as a predictor of histologic high-grade anal intraepithelial neoplasia and the impact of HIV serostatus.

We compared the pathological diagnoses obtained by anal Papanicolaou (Pap) smear with those obtained by anal biopsy or by surgical excision for 153 men who have sex with men (MSM). Analysis of these paired specimens showed that anal Pap smears were an inaccurate predictor of high-grade anal dysplasia, regardless of human immunodeficiency virus (HIV) serostatus. The presence of any abnormal anal cytological finding indicates a potential for high-grade dysplasia on histological examination of MSM.