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Randy M Stalter,1 Vidya Atluri,2 Fan Xia,1 Katherine K Thomas,3 Kristine F Lan,2 Alexander L Greninger,4 Rena C Patel2 1Department of Epidemiology, University of Washington, Seattle, WA, USA; 2Department of Medicine, University of Washington, Seattle, WA, USA; 3Department of Global Health, University of Washington, Seattle, WA, USA; 4Department of Laboratory Medicine and Pathology, University of Washington, Seattle, WA, USACorrespondence: Randy M StalterDepartment of Epidemiology, University of Washington, UW Box 359927 325 Ninth Avenue, Seattle, WA, 98104, USA, Tel +1-412-760-8134, Email rstalter@uw.eduPurpose: To examine associations between male sex and SARS-CoV-2 test positivity, severe COVID-19 disease, and death in a single-site cohort, and assess whether male sex impacts risk for severe COVID-19 disease through socioeconomic status (SES), comorbidities, or inflammation.Materials and Methods: We conducted a retrospective cohort study with data collected from University of Washington Medicine EMR from March 1 to September 29, 2020. All persons, regardless of age, were included if they had a conclusive diagnostic COVID-19 PCR test result. Our exposure was sex assigned at birth. We used Poisson regression to assess associations between sex and COVID-19 test positivity, disease severity and COVID-19 related death, and linear regression to compare viral cycle threshold at the first positive test. We conducted mediation analyses to assess interventional indirect effects of male sex on severe COVID-19 risk through socioeconomic status (SES, based on area deprivation and insurance type), comorbidities, and inflammation status. Models controlled for age and race/ethnicity.Results: Of 32,919 males and 34,733 females included, 1469 (4.5%) and 1372 (4.0%) tested positive for SARS-CoV-2, respectively. Males were 14% more likely to test positive (RR = 1.14; 95% CI: 1.06– 1.23), had 80% higher risk for severe COVID-19 disease (RR = 1.80; 95% CI: 1.39– 2.33) and had 58% higher risk for death (RR = 1.58; 95% CI: 1.10– 2.26) compared to females after adjusting for age and race/ethnicity. Mediation analyses indicated non-significant interventional indirect effects of male sex on severe COVID-19 disease through elevated inflammatory markers, SES and comorbidities, but the greatest effect was through the inflammation pathway.Conclusion: Males appear to be at higher risk at all steps of the continuum of COVID-19 illness. The strongest mediating signal, albeit non-significant, is with inflammatory pathways. Further elucidation of causal pathways linking sex and COVID-19 severity is needed in larger cohorts.Keywords: SARS-CoV-2, disease severity, mediation, sex-based differences

Background: Confounding introduced by individuals' sexual risk behavior is potentially a significant source of bias in HIV-1 prevention intervention studies. To more completely account for sexual behaviors when assessing the efficacy of the monthly dapivirine ring, a new longer-acting HIV-1 prevention option for women, we estimated per-sex-act risk reduction associated with product use., Methods: We conducted a secondary analysis of data from MTN-020/ASPIRE, a phase 3, randomized, placebo-controlled efficacy trial of the dapivirine ring that recruited HIV-uninfected, African women aged 18-45 years. With cumulative sex acts as the time scale, we used multivariable Cox regression with inverse probability of censoring weights to estimate HIV-1 risk reduction associated with a rate of dapivirine release indicative of consistent product use., Results: Women in the dapivirine ring group (n = 1187) had an estimated incidence rate of 2.3 (95% confidence interval [CI], 1.8-3.1) HIV-1 acquisition events per 10 000 sex acts versus 3.6 (95% CI, 2.9-4.4) per 10 000 acts in the placebo group (n = 1187). Dapivirine release indicative of consistent ring use was associated with a 63% (95% CI, 33%-80%) per-sex-act HIV-1 risk reduction., Conclusions: These results support the efficacy of the dapivirine vaginal ring for HIV-1 prevention and help to inform decision-making for women, providers, and policymakers regarding product use., Clinical Trials Registration: NCT01617096., Competing Interests: Potential conflicts of interest . C. W. H. has received grant support from Merck and Gilead Sciences; is a co-inventer of two issued U.S. patents related to microbicides; and is founder of Prionde BioPharma, LLC, a microbicide company. T. P. P. has received grant support from Gilead Sciences, MSD, and the South African Medical Research Council; and participates on advisory boards for the Dual Protection Pill (DPP) Consortium and the Maximizing Options to Advance Informed Choice for HIV Prevention (MOSAIC) project. A. D. S. has received consulting fees from the Magee Women’s Research Institute. S. L. H. has received consulting fees from Merck. M. M. has received grant support from ViiV Healthcare, GSK, and Gilead Sciences; royalties from Elsevier; and consulting fees and honoraria from Bio-Rad. L. G. B. has received honoraria from ViiV Healthcare, Gilead Sciences and Merck Pty Ltd. J. M. B. is an employee of Gilead Sciences, outside the present work. E. R. B. has received payment for participation on Data Safety Monitoring Boards for Merck and the Adolescent Trials Network and is a paid statistical editor for JID. All other authors report no potential conflicts. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed., (© The Author(s) 2023. Published by Oxford University Press on behalf of Infectious Diseases Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

The large COVID-19 outbreaks in prisons in the Washington (USA) State Department of Corrections (WADOC) system during 2020 highlighted the need for a new public health approach to prevent and control COVID-19 transmission in the system's 12 facilities. WADOC and the Washington State Department of Health (WADOH) responded by strengthening partnerships through dedicated corrections-focused public health staff, improving cross-agency outbreak response coordination, implementing and developing corrections-specific public health guidance, and establishing collaborative data systems. The preexisting partnerships and trust between WADOC and WADOH, strengthened during the COVID-19 response, laid the foundation for a collaborative response during late 2021 to the largest tuberculosis outbreak in Washington State in the past 20 years. We describe challenges of a multiagency collaboration during 2 outbreak responses, as well as approaches to address those challenges, and share lessons learned for future communicable disease outbreak responses in correctional settings.

Depression is a common cause of morbidity globally and can impact adherence to medications, posing challenges to medication-based HIV prevention. The objectives of this work are to describe the frequency of depression symptoms in a cohort of 499 young women in Kampala, Uganda and to determine the association of depression symptoms with use of HIV pre-exposure prophylaxis (PrEP). Mild or greater depression, assessed by the patient health questionnaire (PHQ-9), was experienced by 34% of participants at enrollment. Participants with mild depression symptoms tended to uptake PrEP, request PrEP refills, and adhere to PrEP with similar frequency to women with no/minimal signs of depression. These findings highlight opportunities to leverage existing HIV prevention programs to identify women who may benefit from mental health services and may not otherwise be screened. Trial registration: ClinicalTrials.gov identifier: NCT03464266..

During 2014-2020, no tuberculosis (TB) cases were reported within the Washington state prison system. However, during July 2021-June 2022, 25 TB cases were reported among persons incarcerated or formerly incarcerated in two Washington state prisons. Phylogenetic analyses of whole genome sequencing data indicated that Mycobacterium tuberculosis isolates from all 11 patients with culture-confirmed TB were closely related, suggesting that these cases represented a single outbreak. The median infectious period for 12 patients who were considered likely contagious was 170 days. As of November 15, 2022, the Washington State Department of Corrections (WADOC) and Washington State Department of Health (WADOH), with technical assistance from CDC, had identified 3,075 contacts among incarcerated residents and staff members at five state prisons, and 244 contacts without a known TB history received a diagnosis of latent TB infection (LTBI). Persons who were evaluated for TB disease were isolated; those receiving a diagnosis of TB then initiated antituberculosis therapy. Persons with LTBI were offered treatment to prevent progression to TB disease. This ongoing TB outbreak is the largest in Washington in 20 years. Suspension of annual TB screening while limited resources were redirected toward the COVID-19 response resulted in delayed case detection that facilitated TB transmission. In addition, fear of isolation might discourage residents and staff members from reporting symptoms, which likely also leads to delayed TB diagnoses. Continued close collaboration between WADOC and WADOH is needed to end this outbreak and prevent future outbreaks., Competing Interests: All authors have completed and submitted the International Committee of Medical Journal Editors form for disclosure of potential conflicts of interest. Lara B. Strick reports travel support from the Infectious Diseases Society of America to attend their annual meeting as a speaker. Lana Dov serves in an uncompensated position as the president of the National TB Nurse Coalition. No other potential conflicts of interest were disclosed.

Low perceived HIV risk is a barrier to effective pre-exposure prophylaxis (PrEP) use among African adolescent girls and young women (AGYW). Single-item risk perception measures are stigmatizing and alienating to AGYW and may not predict PrEP use. There is a need for a tool capturing domains of perceived HIV risk and salience that align with PrEP use among AGYW. This HIV PrEP study was conducted in Kampala, Uganda. We developed and piloted the 9-item "HIV Salience and Perception" (HPS) scale (range: 9-36); higher scores indicate beliefs of higher vulnerability to HIV. We administered the scale to Ugandan AGYW participating in an ongoing cohort study at enrollment, one, three and six months. PrEP dispensing was measured quarterly and adherence was measured daily via Wisepill (high adherence: ≥80% of expected pill bottle openings). We assessed scale performance and used generalized estimating equations to determine associations between scale score and PrEP use. Among 499 AGYW, 54.1% of our sample was ≥ 20 years (range:16-25). The median HPS score was 18 (range:8-33; α = 0.77). Higher score was associated with PrEP dispensing (aRR = 1.07 per point increase; 95% CI = 1.01-1.13; p-value = 0.02) in the overall cohort and among only those ≥ 20 years (aRR = 1.10; 95% CI = 1.03-1.19; p-value = 0.01). We did not observe an association between scale score and PrEP adherence. AGYW scoring higher on a novel HPS scale were more likely to initiate and obtain PrEP refills through 6 months. This scale may capture drivers of PrEP dispensing and could inform PrEP delivery and counseling for AGYW., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: Accurate diagnosis of coronavirus disease 2019 is essential to limiting transmission within healthcare settings. The aim of this study was to identify patient demographic and clinical characteristics that could impact the clinical sensitivity of the nasopharyngeal severe acute respiratory syndrome coronavirus-2 (SARS-CoV2) reverse transcription polymerase chain reaction (RT-PCR) test., Methods: We conducted a retrospective, matched case-control study of patients who underwent repeated nasopharyngeal SARS-CoV2 RT-PCR testing at a tertiary care academic medical center between March 1 and July 23, 2020. The primary endpoint was conversion from negative to positive PCR status within 14 days. We conducted conditional logistic regression modeling to assess the associations between demographic and clinical features and conversion to test positivity., Results: Of 51,116 patients with conclusive SARS-CoV2 nasopharyngeal RT-PCR results, 97 patients converted from negative to positive within 14 days. We matched those patients 1:2 to 194 controls by initial test date. In multivariate analysis, clinical suspicion for a respiratory infection (adjusted odds ratio [aOR] 20.9, 95% confidence interval [CI]: 3.1-141.2) and lack of pulmonary imaging (aOR 4.7, 95% CI: 1.03-21.8) were associated with conversion, while a lower burden of comorbidities trended toward an increased odds of conversion (aOR 2.2, 95% CI: 0.9-5.3)., Conclusions: Symptoms consistent with a respiratory infection, especially in relatively healthy individuals, should raise concerns about a clinical false-negative result. We have identified several characteristics that should be considered when creating institutional infection prevention guidelines in the absence of more definitive data and should be included in future studies., (© 2022 Wiley Periodicals LLC.)

Background: Globally, women have higher herpes simplex virus type 2 (HSV-2) prevalence than men; data from observational studies suggest a possible association of HSV-2 acquisition with use of intramuscular depot medroxyprogesterone acetate (DMPA-IM)., Methods: Within a randomized trial of the effect of 3 contraceptive methods-DMPA-IM, a copper intrauterine device (IUD), and a levonorgestrel (LNG) implant-on human immunodeficiency virus (HIV) acquisition, we assessed HSV-2 acquisition. HSV-2 and HIV seronegative women, aged 16-35 years, and seeking effective contraception were followed for 12-18 months at 12 sites in Eswatini, Kenya, South Africa, and Zambia from 2015 to 2018. HSV-2 serologic testing was done at enrollment and final study visits. Intention-to-treat analysis using Poisson regression with robust standard errors compared HSV-2 incidence by contraceptive method., Results: At baseline, 4062 randomized women were HSV-2 seronegative, of whom 3898 (96.0%) had a conclusive HSV-2 result at their final study visit. Of these, 614 (15.8%) acquired HSV-2, at an incidence of 12.4/100 person-years (p-y): 10.9/100 p-y among women assigned DMPA-IM, 13.7/100 p-y the copper IUD, and 12.7/100 p-y the LNG implant. Incidence rate ratios (IRR) for HSV-2 acquisition were 0.80 (95% confidence interval [CI], .65-.97) for DMPA-IM compared with copper IUD, 0.86 (95% CI, .71-1.05) for DMPA-IM compared with LNG implant, and 1.08 (95% CI, .89-1.30) for copper IUD compared with LNG implant. HSV-2 acquisition risk was significantly increased among women who also acquired HIV during follow-up (IRR 3.55; 95% CI, 2.78-4.48)., Conclusions: In a randomized trial, we found no association between HSV-2 acquisition and use of 3 contraceptive methods., Trial Registration: ClinicalTrials.gov number NCT02550067., Competing Interests: Potential conflicts of interest. E. A. B. reports support for the present manuscript from the WHO Department of RH. D. D. reports support for the present manuscript from National Institute of Mental Health paid to the institution and grants or contracts outside of the conduct of the study from the National Institute of Allergy and Infectious Diseases paid to the institution. J. B. reports grants or contracts outside of the conduct of the study from National Institutes of Health paid to the institution; personal consulting fees from Gilead, Janssen, and Merck; employee/stock/options from Gilead; donation of study medication from Gilead and IPM; and employee outside of the submitted work for Gilead Sciences. R. S. reports direct travel reimbursements and travel scholarships for Conference on Retroviruses and Opportunistic Infections, AIDS, Infectious Diseases Society for Obstetrics and Gynecology, and International Society for Pharmacoepidemiology conferences. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed., (© The Author(s) 2021. Published by Oxford University Press for the Infectious Diseases Society of America.)

Introduction: Contraceptive implants containing etonogestrel and levonorgestrel have emerged as popular contraceptive options among women in areas of high HIV burden in sub-Saharan Africa. However, recent pharmacokinetic data have shown drug-drug interactions between implants and efavirenz-containing antiretroviral therapy (ART), reducing the effectiveness of the implants. Here, we evaluated pregnancy incidence in 6-month intervals following implant initiation among women using efavirenz and contraceptive implants to assess whether the risk of breakthrough pregnancy is higher after specific periods of implant use., Methods: We used data from a retrospective longitudinal analysis of women living with HIV ages 18-45 years in western Kenya who attended HIV-care facilities between 2011 and 2015. We used Cox proportional hazard models to compute hazard ratios (HRs) for breakthrough pregnancy by implant type and ART regimen. Depending on the model, we adjusted for socio-demographic and clinical factors, programme, site and interaction between calendar time and ART regimen. We utilized inverse probability weights (IPWs) to account for three sampling phases (electronic medical record [EMR], chart review and phone interview) and calculated overall parameter estimates., Results: Women contributed 14,768 woman-years from the largest sampling phase (EMR). The median age was 31 years. Women used etonogestrel implants for 26-69% of the time and levonorgestrel implants for 7-31% of the time, depending on the sampling phase. Women used efavirenz, nevirapine or no ART for 27-33%, 40-46% and 15-26% of follow-ups, respectively. When combining sampling phases, there was little evidence to suggest that the relative hazard of pregnancy among efavirenz-containing ART users relative to nevirapine-containing ART changed with length of time on implants: IPW-adjusted HR of 3.1 (CI: [1.5; 6.4]) at 12 months, 3.4 (CI: [1.8; 6.3]) at 24 months, 3.8 (CI: [1.9; 7.7]) at 36 months and 4.2 (CI: [1.6; 11.1]) at 48 months (interaction p-value = 0.88). Similarly, no significant change in HRs over time was found when comparing women not using ART to nevirapine-containing ART users (interaction p-value = 0.49)., Conclusions: We did not find evidence to suggest implants being more fallible from drug-drug interactions with efavirenz at later time intervals of implant use. Thus, we would not recommend shortening the duration of implant use or replacing implants sooner when concomitantly used with efavirenz., (© 2022 The Authors. Journal of the International AIDS Society published by John Wiley & Sons Ltd on behalf of the International AIDS Society.)

Introduction : Pregnancy is a period of elevated HIV risk in high-burden settings, motivating the need for prevention tools that are both safe for use and effective during pregnancy. Oral pre-exposure prophylaxis (PrEP) containing tenofovir disoproxil fumarate (TDF) is recommended by the World Health Organization, including for pregnant and postpartum women at substantial risk of HIV infection. Although TDF use during pregnancy appears generally safe, data on PrEP use during pregnancy remain limited. Areas covered : We provide an overview of the clinical pharmacology and efficacy of daily TDF-based PrEP and summarize current evidence on the safety of PrEP use by pregnant HIV-uninfected women. We synthesize relevant studies assessing pregnancy outcomes among pregnant women who are living with HIV (WLHIV) and using TDF-based therapy. Finally, we make comparison to the safety profiles of other emerging HIV prevention options. Expert opinion : The current evidence indicates that TDF/FTC PrEP use is not associated with increased risk of adverse pregnancy and early infant growth outcomes. While safety data are generally reassuring, there is need for continued accrual of data on growth and pregnancy outcomes in PrEP research, implementation projects, and controlled pharmacokinetic studies to support current evidence and to understand concentration-efficacy relationship in pregnant women.

New tools are needed to support pre-exposure prophylaxis (PrEP) adherence for human immunodeficiency virus (HIV) prevention, including those that enable real-time feedback. In a large, completed PrEP trial, adequate urine tenofovir levels measured using a novel immunoassay predicted HIV protection and showed good sensitivity and specificity for detectable plasma tenofovir., (© The Author(s) 2020. Published by Oxford University Press for the Infectious Diseases Society of America.)

Recent studies among men who have sex with men suggest that sexual behaviors associated with risk of sexually transmitted infections increase following initiation of pre-exposure prophylaxis (PrEP) for HIV prevention. We used longitudinal data from HIV-uninfected participants (n = 1013) enrolled in an open-label study of PrEP delivered to Ugandan and Kenyan heterosexual HIV serodiscordant couples to understand the association between PrEP initiation and HIV risk-related sexual behaviors among these couples. In the month following PrEP initiation, the mean number of monthly sex acts within couples decreased from 7.9 to 6.9 (mean difference: - 1.1; 95% CI - 1.5, - 0.7) and the proportion of couples having condomless sex decreased from 65% to 32% (percentage point change: - 33%; 95% CI - 37%, - 30%); these behaviors then remained relatively constant over 2 years. We found no evidence of sexual risk compensation following PrEP initiation within African serodiscordant couples. However, roughly a third of couples continued to engage in condomless sex during follow up, emphasizing the importance of continued PrEP use to sustain HIV protection.

Objectives: To evaluate pharmacokinetics and pharmacogenetics of contraceptive implant progestin concentrations in HIV-positive women initiating efavirenz (EFV)-containing or nevirapine (NVP)-containing antiretroviral therapy (ART)., Design: We analyzed stored samples from women self-reporting implant use in the Partners PrEP Study., Methods: Plasma samples collected every 6 months were analyzed for levonorgestrel and etonogestrel concentrations. Progestin concentrations from samples collected after ART initiation were compared with pre-ART concentrations for intraindividual comparisons. We used adjusted linear mixed models to compare hormone concentrations between individuals on EFV and NVP to a no ART group. We then evaluated whether possessing certain alleles with known or possible influences on EFV, NVP, or progestin metabolism were associated with changes in progestin concentrations or modified the association between ART use and progestin concentrations., Results: Our analysis included 11 women who initiated EFV, 13 who initiated NVP, and 36 who remained ART-naive. In the EFV group, the adjusted geometric mean ratio (aGMR) of levonorgestrel was 0.39 [90% confidence intervals (0.31, 0.49); P < 0.001] and the etonogestrel aGMR was 0.51 (0.34, 0.76; P = 0.006) compared with the control group. No difference was observed in the NVP group compared with controls [levonorgestrel 0.93 (0.74, 1.18); P = 0.64; etonogestrel 1.07 (0.77, 1.50); P = 0.73]. Possession of four allele variants were found to result in further reductions in progestin concentrations among those receiving EFV., Conclusion: Concomitant use of EFV significantly reduces levonorgestrel or etonogestrel concentrations by 61 and 49%, respectively, compared with no ART use. We also report allelic variants in hepatic enzymes that influenced the extent of the observed drug-interaction between progestins and EFV.

Background: Understanding and meeting the reproductive health needs of adolescents living with HIV (ALHIV) is a growing concern since advances in antiretroviral therapy mean that many ALHIV are now living into adulthood and starting to have sex., Methods: We conducted a mixed-methods study in the Copperbelt Province of Zambia to advance our understanding of the reproductive health needs of ALHIV and to assess the extent to which these needs are being met. We conducted in-depth interviews (IDIs) with 32 ALHIV from two HIV clinics, 23 with their caregivers, and 10 with clinic staff. ALHIV were interviewed twice. We used the data from the qualitative interviews to create a cross-sectional survey that we conducted with 312 ALHIV in three HIV clinics., Findings: The vast majority of ALHIV reported they wanted to have children in the future but lacked knowledge about preventing mother-to-child transmission. Some sexually active adolescents used condoms, although they wanted more information about and access to non-condom methods. Many ALHIV reported that their first sexual encounters were forced. Religious beliefs prevented some caregivers from discussing premarital sex and contraception with ALHIV. Clinic staff and caregivers had mixed views about integrating contraceptive counseling and method provision into HIV care and treatment services. Few sexually active ALHIV reported that they disclosed their HIV status to their sexual partners and few reported that they knew their sexual partner's status., Conclusions: ALHIV are in dire need of comprehensive sexual and reproductive health services and information including a range of contraceptive methods to prevent pregnancy, knowledge about preventing mother-to-child transmission and having a healthy pregnancy, skills related to HIV disclosure and condom negotiation to prevent horizontal transmission, and screening for sexual violence for both males and females if services are available., Competing Interests: The authors have declared that no competing interests exist.

Little is known about adherence to antiretroviral therapy (ART) among adolescents in sub-Saharan Africa, where the majority of the world's HIV-positive adolescents reside. We assessed individual, household, and HIV self-management characteristics associated with a 48-hour treatment gap in the preceding 3 months, and a pharmacy medication possession ratio (MPR) that assessed the number of ART pills dispensed divided by the number of ART pills required in the past 6 months, among 285 Zambians, ages 15-19 years. Factors significantly associated with a 48-hour treatment gap were being male, not everyone at home being aware of the adolescent's HIV status, and alcohol use in the past month. Factors associated with an MPR < 90% included attending the clinic alone, alcohol use in the past month, and currently not being in school. Findings support programs to strengthen adolescents' HIV management skills with attention to alcohol use, family engagement, and the challenges adolescents face transitioning into adulthood, especially when they are no longer in school.

Background: Adolescents living with HIV (ALHIV) experience less favorable antiretroviral therapy (ART) outcomes than other age groups. First-line treatment failure complicates ART management as second-line regimens can be costlier and have greater pill burdens. Understanding predictors of switching ART regimens and adherence among adolescents on second-line ART may help to prevent poor treatment outcomes., Methods: A quantitative survey was administered to 309 ALHIV attending 3 ART clinics in the Copperbelt Province, Zambia. Medical chart data, including pharmacy refill data, were abstracted. Associations between being on second-line ART and sociodemographic, psychosocial and ART adherence characteristics were tested. Cox proportional hazards models were used to estimate the effect of baseline ART variables on time to switching., Results: Ten percent of participants were on second-line regimens. Compared with ALHIV on first-line ART, adolescents on second-line regimens were older (P = 0.02), out of school due to completion of secondary studies (P = 0.04) and on ART longer (P = 0.03). Adolescents on second-line regimens were more likely to report missing ≥48 consecutive hours of drugs in the last 3 months (P = 0.01). Multivariable analysis showed that adolescents who initiated ART with efavirenz-based regimens were more likely to switch to second-line than those put on nevirapine-based regimens (hazard ratio = 2.6; 95% confidence interval: 1.1-6.4)., Conclusions: Greater support is needed for ALHIV who are on second-line regimens. Interventions for older adolescents that bridge the gap between school years and young adulthood would be helpful. More research is needed on why ALHIV who start on efavirenz-based regimens are more likely to switch within this population.

Results of recent microbicide and pre-exposure prophylaxis clinical trials have shown adherence to be a significant challenge with new HIV prevention technologies. As the vaginal ring containing dapivirine moves into two open label follow-on studies (HOPE/MTN-025 and DREAM) and other antiretroviral-based and multi-purpose prevention technology ring products advance through the development pipeline, there is a need for more accurate and reliable measures of adherence to microbicide ring products. We previously conducted a comprehensive landscape analysis to identify new technologies that could be applied to adherence measurement of vaginal rings containing antiretrovirals. To explore attitudes and perceptions towards the approaches that we identified, we conducted a survey of stakeholders with experience and expertise in microbicide and HIV prevention clinical trials. From May to July 2015 an electronic survey was distributed via email to 894 stakeholders; a total of 206 eligible individuals responded to at least one question and were included in the data analysis. Survey respondents were presented with various objective measures and asked about their perceived acceptability to trial participants, feasibility of implementation by study staff, usefulness for measuring adherence and ethical concerns. Methods that require no additional input from the participant and require no modifications to the existing ring product (i.e., measurement of residual drug or excipient, or a vaginal analyte that enters the ring) were viewed as being more acceptable to trial participants and more feasible to implement in the field. Respondents saw value in using objective measures to provide real-time feedback on adherence. However, approaches that involve unannounced home visits for sample collection or spot checks of ring use, which could provide significant value to adherence feedback efforts, were met with skepticism. Additional research on the acceptability of these methods to potential trial participants and trial staff is recommended.

Introduction: Poor adherence to product use has been observed in recent trials of antiretroviral (ARV)-based oral and vaginal gel HIV prevention products, resulting in an inability to determine product efficacy. The delivery of microbicides through vaginal rings is widely perceived as a way to achieve better adherence but vaginal rings do not eliminate the adherence challenges exhibited in clinical trials. Improved objective measures of adherence are needed as new ARV-based vaginal ring products enter the clinical trial stage., Methods: To identify technologies that have potential future application for vaginal ring adherence measurement, a comprehensive literature search was conducted that covered a number of biomedical and public health databases, including PubMed, Embase, POPLINE and the Web of Science. Published patents and patent applications were also searched. Technical experts were also consulted to gather more information and help evaluate identified technologies. Approaches were evaluated as to feasibility of development and clinical trial implementation, cost and technical strength., Results: Numerous approaches were identified through our landscape analysis and classified as either point measures or cumulative measures of vaginal ring adherence. Point measurements are those that give a measure of adherence at a particular point in time. Cumulative measures attempt to measure ring adherence over a period of time., Discussion: Approaches that require modifications to an existing ring product are at a significant disadvantage, as this will likely introduce additional regulatory barriers to the development process and increase manufacturing costs. From the point of view of clinical trial implementation, desirable attributes would be high acceptance by trial participants, and little or no additional time or training requirements on the part of participants or clinic staff. We have identified four promising approaches as being high priority for further development based on the following measurements: intracellular drug levels, drug levels in hair, the accumulation of a vaginal analyte that diffuses into the ring, and the depletion of an intrinsic ring constituent., Conclusions: While some approaches show significant promise over others, it is recommended that a strategy of using complementary biometric and behavioural approaches be adopted to best understand participants' adherence to ARV-based ring products in clinical trials.

Objectives: A longer-acting injectable contraceptive that lasts for 6 months would be a valuable addition to the contraceptive method mix and ideal for women who are interested in spacing births and/or uncertain about their future reproductive plans. Here we review past applications of drug delivery technologies to injectable contraceptives as well as recent advancements in sustained drug delivery technologies that hold promise for the development of a new longer-acting injectable contraceptive product., Study Design: A global landscape analysis was conducted, promising sustained drug delivery technologies, and research opportunities and partnerships were established with experts in the fields of contraception and drug delivery to identify new approaches in developing a longer-acting injectable contraceptive product., Results: The landscape analysis confirmed that a number of existing polymer systems, such as poly-lactic-co-glycolic acid and poly(epsilon-caprolactone), remain promising candidates for application to a longer-acting injectable product. Novel polymers and materials also hold promise for achieving longer release profiles and/or having other advantages over existing polymer systems, but products using these materials could potentially have longer roads to regulatory approval. Additionally, recent advancements in the manufacturing process of microspheres may benefit the development of a longer-acting injectable contraceptive., Conclusion: The design of any new injectable product must take into account the limitations of current injectable contraceptives and address concerns that women may have for a longer-acting product. FHI 360 is supporting several research collaborations for proof of concept of various drug delivery approaches for achieving longer-acting product that fits an established target product profile., (Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.)

Introduction: Worldwide, HIV-related mortality among adolescents living with HIV (ALHIV) increased by 50% from 2005 to 2012 and is attributed in part to a lack of support for adolescent retention to care and adherence to antiretroviral therapy (ART). This vulnerability reinforces the need to better understand incomplete ART adherence among ALHIV, particularly in sub-Saharan Africa, where the majority of the world's 2.1 million ALHIV reside., Methods: From December 2011 to February 2012, we conducted in-depth interviews with 32 ALHIV (aged 15 to 18) and 23 of their adult caregivers in the Copperbelt Province of Zambia. Interviews were transcribed and translated. An iterative qualitative process was used to code and analyze the data and main themes were summarized regarding the barriers to and facilitators of ART adherence., Results: More than a quarter of ALHIV reported missing a day or more of ART (ranging from one day to six months). Barriers to ART adherence included fear of disclosure and anticipated stigma. Few youth were willing to take their drugs outside of the home, which led to missed doses of ART. Similarly, families tended to manage HIV within the home only. As a result, although caregivers and families were often the greatest source of emotional and instrumental support, they coped with HIV in isolation of other potential support from their communities, schools or churches. Factors that supported ART adherence included attending clinic-sponsored youth groups, wanting to maintain one's health and using phone and clock alarms. Involvement of adult caregivers in HIV management varied greatly and was often based on the age and health status of the youth. Some caregivers struggled with letting the adolescents assume responsibility for their medication, and ALHIV had few self-management skills and tools to help them regularly take ART., Conclusions: These data highlight the importance of families and home environments in supporting adherence to ART among ALHIV. Skill-building and family-based interventions to prepare ALHIV and their adult caregivers for HIV self-management and HIV status disclosure by youth are of paramount importance. Future research and programmes also need to address the fears adolescents and families have regarding HIV-related stigma that shape young peoples' adherence behaviours.

Background: Currently more than 340,000 individuals are receiving long-term hemodialysis (HD) therapy for end-stage renal disease and therefore are particularly vulnerable to influenza, prone to more severe influenza outcomes, and less likely to achieve seroprotection from standard influenza vaccines. Influenza vaccine adjuvants, chemical or biologic compounds added to a vaccine to boost the elicited immunologic response, may help overcome this problem., Study Design: Economic stochastic decision analytic simulation model., Setting & Participants: US adult HD population., Model, Perspective, & Timeframe: The model simulated the decision to use either an adjuvanted or nonadjuvanted vaccine, assumed the societal perspective, and represented a single influenza season, or 1 year., Intervention: Adjuvanted influenza vaccine at different adjuvant costs and efficacies. Sensitivity analyses explored the impact of varying influenza clinical attack rate, influenza hospitalization rate, and influenza-related mortality., Outcomes: Incremental cost-effectiveness ratio of adjuvanted influenza vaccine (vs nonadjuvanted) with effectiveness measured in quality-adjusted life-years., Results: Adjuvanted influenza vaccine would be cost-effective (incremental cost-effectiveness ratio <$50,000/quality-adjusted life-year) at a $1 adjuvant cost (on top of the standard vaccine cost) when adjuvant efficacy (in overcoming the difference between influenza vaccine response in HD patients and healthy adults) ≥60% and economically dominant (provides both cost savings and health benefits) when the $1 adjuvant's efficacy is 100%. A $2 adjuvant would be cost-effective if adjuvant efficacy was 100%., Limitations: All models are simplifications of real life and cannot capture all possible factors and outcomes., Conclusions: Adjuvanted influenza vaccine with adjuvant cost ≤$2 could be a cost-effective strategy in a standard influenza season depending on the potency of the adjuvant., (Copyright © 2011 National Kidney Foundation, Inc. Published by Elsevier Inc. All rights reserved.)