Cabotegravir for the prevention of HIV-1 in women: results from HPTN 084, a phase 3, randomised clinical trial.

BACKGROUND: Oral pre-exposure prophylaxis has been introduced in more than 70 countries, including many in sub-Saharan Africa, but women experience considerable barriers to daily pill-taking, such as stigma, judgement, and the fear of violence. Safe and effective long-acting agents for HIV prevention are needed for women. We aimed to evaluate the safety and efficacy of injectable cabotegravir compared with daily oral tenofovir diphosphate plus emtricitabine (TDF-FTC) for HIV prevention in HIV-uninfected women. METHODS: HPTN 084 was a phase 3, randomised, double-blind, double-dummy, active-controlled, superiority trial in 20 clinical research sites in seven countries in sub-Saharan Africa. Participants were eligible for enrolment if they were assigned female sex at birth, were aged 18-45 years, reported at least two episodes of vaginal intercourse in the previous 30 days, were at risk of HIV infection based on an HIV risk score, and agreed to use a long-acting reversible contraceptive method. Participants were randomly assigned (1:1) to either active cabotegravir with TDF-FTC placebo (cabotegravir group) or active TDF-FTC with cabotegravir placebo (TDF-FTC group). Study staff and participants were masked to study group allocation, with the exception of the site pharmacist who was responsible for study product preparation. Participants were prescribed 5 weeks of daily oral product followed by intramuscular injections every 8 weeks after an initial 4-week interval load, alongside daily oral pills. Participants who discontinued injections were offered open-label daily TDF-FTC for 48 weeks. The primary endpoints of the study were incident HIV infection in the intention-to-treat population, and clinical and laboratory events that were grade 2 or higher in all women who had received at least one dose of study product. This study is registered with ClinicalTrials.gov, NCT03164564. FINDINGS: From Nov 27, 2017, to Nov 4, 2020, we enrolled 3224 participants (1614 in the cabotegravir group and 1610 in the TDF-FTC group). Median age was 25 years (IQR 22-30); 1755 (54·7%) of 3209 had two or more partners in the preceding month. 40 incident infections were observed over 3898 person-years (HIV incidence 1·0% [95% CI 0·73-1·40]); four in the cabotegravir group (HIV incidence 0·2 cases per 100 person-years [0·06-0·52]) and 36 in the TDF-FTC group (1·85 cases per 100 person-years [1·3-2·57]; hazard ratio 0·12 [0·05-0·31]; p<0·0001; risk difference -1·6% [-1·0% to -2·3%]. In a random subset of 405 TDF-FTC participants, 812 (42·1%) of 1929 plasma samples had tenofovir concentrations consistent with daily use. Injection coverage was 93% of the total number of person-years. Adverse event rates were similar across both groups, apart from injection site reactions, which were more frequent in the cabotegravir group than in the TDF-FTC group (577 [38·0%] of 1519 vs 162 [10·7%] of 1516]) but did not result in injection discontinuation. Confirmed pregnancy incidence was 1·3 per 100 person-years (0·9-1·7); no congenital birth anomalies were reported. INTERPRETATION: Although both products for HIV prevention were generally safe, well tolerated, and effective, cabotegravir was superior to TDF-FTC in preventing HIV infection in women. FUNDING: National Institute of Allergy and Infectious Diseases, ViiV Healthcare, and the Bill & Melinda Gates Foundation. Additional support was provided through the National Institute of Mental Health, the National Institute on Drug Abuse, and the Eunice Kennedy Shriver National Institute of Child Health and Human Development. ViiV Healthcare and Gilead Sciences provided pharmaceutical support.

Examining Associations Between Mental Health, IPV Exposure, HIV Risk Behaviors, and PrEP Use in South African Women: An Analysis of Data from the Charisma Study.

Intimate partner violence (IPV) has been associated with poorer mental health outcomes and increased human immunodeficiency virus (HIV) risk behaviors. We examine the relations between IPV, mental health symptomology (defined as psychological distress and alcohol misuse), and engagement in HIV risk behaviors among a sample of South African women who participated in a randomized controlled trial of CHARISMA, an intervention to increase women's agency to use oral pre-exposure prophylaxis (PrEP) safely and consistently as well as mitigate relationship challenges. We also examined the impact of trial participation on women's mental health, as well as the impact of psychological distress on the effectiveness of the CHARISMA intervention. Mental health symptomology and IPV exposure were prevalent and associated with some HIV risk and protective behaviors. Trial participation reduced psychological distress. There was no evidence for mental health symptomology impacting the effectiveness of the CHARISMA intervention.

Changes in relationships, HIV risk, and feelings towards PrEP: findings from a qualitative explanatory study among participants in the CHARISMA intervention trial.

BACKGROUND: Intimate partner violence (IPV) and other relationship-based challenges have been demonstrated to reduce women's ability to use pre-exposure prophylaxis (PrEP) effectively for HIV prevention. The Community Health Clinical Model for Agency in Relationships and Safer Microbicide Adherence (CHARISMA) intervention was designed to mitigate these challenges and increase South African women's agency to use PrEP. The CHARISMA randomized controlled trial did not identify statistically significant differences in PrEP adherence or relationship dynamics between the intervention and control arms. As such, the aim of this explanatory qualitative sub-study was to understand women's experiences with the CHARISMA trial and explore reasons for the null results. METHODS: Twelve CHARISMA trial participants were purposively selected to participate in serial in-depth interviews, which took place at the trial end and 3 months later. Participants represented individuals who had received each of the three counselling modules, 1) healthy communication counselling, 2) PrEP disclosure counselling, or 3) IPV counselling, as well as those in the control arm who received IPV standard-of-care counselling. RESULTS: A thematic case analysis revealed numerous positive relationship outcomes among intervention participants, including identifying and ending unhealthy relationships, gaining a sense of personal empowerment, and enacting more positive behaviors and HIV risk reduction strategies in subsequent relationships. These positive shifts were occasionally described as contributing to decisions to discontinue PrEP use, which may partly explain the limited impact of the intervention on PrEP adherence. CONCLUSIONS: Future investigations of counselling interventions addressing relationship-based barriers to PrEP use should account for changing risk dynamics and need for PrEP.

Topical Anesthetics for Analgesia in Acute Corneal Abrasion: Eye Care Providers Survey.

STUDY OBJECTIVES: To evaluate the current attitudes of ophthalmologists and optometrists regarding topical anesthetic (TA) use in the emergency department (ED) for analgesia in corneal abrasions. METHODS: A survey was distributed through email to ophthalmologists and optometrists, and their responses were deidentified. Three scenarios were presented involving the addition of tetracaine in addition to usual care in the setting of uncomplicated corneal abrasion. A 250-character space for comments and demographic questionnaire followed. A chi-square test, Fisher exact test, or sign test, at a significance level of 0.05, was used. RESULTS: Of the 978 individuals surveyed, 486 responded (MD/DOs: 47.1% and ODs: 52.9%). Topical anesthetic favorability significantly decreased with shorter practice length when the patient was only examined by an ED provider. Topical anesthetic favorability was significantly impacted by respondents' degree type. When respondents were posed with using TAs if the respondents were the patient, the respondents were 22.6% more likely to use TA when compared with their answers in the scenario where the ED provider examined the patient and 20.0% more likely when compared with the scenario where a MD/OD examined the patient. Most did not support tetracaine use. CONCLUSIONS: Although treating pain is associated with improved quality of life, most respondents did not support TA use in the ED. Practice length and degree type significantly impacted responses. Respondents were more inclined to use TAs when the respondents were the patient. Results suggest that eye care providers need additional research data supporting safety before routine use in the ED, given the potential for adverse events with TAs.

Nationwide analysis of unplanned conversion during minimally invasive distal pancreatectomy for pancreatic adenocarcinoma.

BACKGROUND: Utilization of minimally-invasive distal pancreatectomy (MIDP) for pancreatic adenocarcinoma has increased. While unplanned conversion to an open procedure during MIDP is associated with inferior short-term outcomes, the long-term consequences of conversion have not been adequately examined. METHODS: Patients with pancreatic adenocarcinoma undergoing MIDP were selected from the National Cancer Database (2010-2015) and subdivided based on the occurrence of unplanned conversion. Post-operative outcomes and overall survival (OS) were examined. Conversion was additionally compared to a matched group of planned open resections. RESULTS: Among 592 patients undergoing attempted MIDP, unplanned conversion occurred in 23.1%. Despite increased 90-day mortality among patients experiencing conversion, there was no difference in median OS between groups (25.0 vs 27.8 months, p = 0.095). For patients undergoing conversion, post-operative outcomes and long-term survival were similar when compared to a propensity-matched group of patients undergoing planned open resection. On multivariable analysis, treatment at an academic facility (OR 0.63) and a robotic approach (OR 0.50) were both significantly associated with completed MIDP. CONCLUSION: Despite inferior post-operative outcomes compared to successful MIDP, unplanned conversion did not result in significantly reduced long term survival. MIDP can be attempted selectively but treatment at experienced centers via a robotic approach should be considered.

"The role of case management in HIV treatment adherence: HPTN 078".

Adherence to care and antiretroviral therapy is challenging, especially for people living with HIV (PLWH) with additional co-occurring risk factors. Case management interventions, including motivational interviewing (MI), show promise to improve HIV treatment adherence, but few studies have examined how such interventions are delivered to or experienced by PLWH who have been reengaged in care. We conducted qualitative interviews with six case managers and 110 PLWH exiting from a randomized study (HPTN 078) who received a MI-based case management intervention in addition to standard patient-navigation services, or standard services only. Our study provided greater insight into the main findings from HPTN 078, including an in-depth description of the multiple barriers to adherence faced by this largely "out-of-care" population, as well as a more nuanced understanding of the benefits and challenges of implementing MI. A blend of MI plus more intensive interventions may be needed for PLWH facing multiple structural barriers.

Integration of a Relationship-focused Counseling Intervention with Delivery of the Dapivirine Ring for HIV Prevention to Women in Johannesburg: Results of the CHARISMA Pilot Study.

Biomedical, female-initiated HIV prevention methods can help reduce disproportionately high HIV rates among women in sub-Saharan Africa, but male partner resistance and intimate partner violence (IPV) may impact ability to ensure effective use. To support consistent use of the dapivirine vaginal ring (VR), we pilot-tested the impact of the CHARISMA relationship counseling intervention ("CHARISMA") with women enrolled in the multi-site open-label Microbicide Trials Network (MTN) 025/HOPE trial at the Wits Reproductive Health and HIV Research Institute (Wits RHI) site in Johannesburg, South Africa. Lay counselors used a 42-item tool with five subscales to assess relationships and IPV and provide tailored counseling at enrolment, followed by a booster counselling session at Month 1 and follow-up checks at Months 3 and 6. We evaluated potential impact by examining self-reported ring disclosure to partners, partner clinic attendance, self-reported incident social harms (SH) and IPV, and biomarkers of ring adherence at Wits RHI. We subsequently compared these outcomes at three comparator HOPE study sites using multivariable regression models. Comparator study sites were purposively selected as those most similar to Wits RHI for baseline characteristics identified a priori. At Wits RHI, 95 of 96 (99%) HOPE participants enrolled into the CHARISMA pilot study. Mean age was 30, 36.8% lived with a partner, and 85.3% received their partner's financial support. During the six months of pilot study follow-up, participants reported: ring use disclosure to partners at 72.7% visits; 4.3% partners attending the research clinic; one partner-related SH; and 9.5% experienced incident IPV. The mean level of dapivirine released from returned used rings was 3.4 mg (SD 1.56), suggesting moderate adherence. Participants in the CHARISMA pilot had high background prevalence and incidence of IPV but were nevertheless able to adhere to ring use, and some male partners came to the research clinic. In adjusted regression models, compared to Wits RHI, partner clinic attendance was lower at all comparator sites; and significantly so at Site A (aRR 0.12, 95% CI 0.00-0.98). Sites B and C had lower levels of dapivirine released (suggesting lower adherence), but this difference was not significant. Site B women were more likely to report ring disclosure to partners at FU visits (aRR 1.12, 95% CI 1.00-1.25). IPV reported during follow-up was significantly lower at Site B (aRR 0.20, 95% CI 0.04-0.98, p = 0.047). CHARISMA taught women skills to decide on levels of ring-use disclosure to partners or others; therefore it is difficult to interpret differences in ring disclosure to partners with other sites. Similarly, CHARISMA heightened participants' awareness of abuse, possibly increasing IPV reports. Testing CHARISMA under fully-powered controlled conditions will improve understanding of its impact on women's relationships and ability to use female-initiated HIV prevention methods.

Exploring individual-level barriers to HIV medication adherence among men who have sex with men in the HIV Prevention Trials Network (HPTN 065) study.

African-American men who have sex with men (MSM) with HIV are more likely to have unsuppressed viral load than other racial/ethnic groups. HPTN 065 Study, completed in 2015, consisted of five interconnected study components conducted at clinics in Bronx, New York and Washington, D.C. Participants completed surveys with questions related to socio-demographic factors and individual-level HIV medication adherence barriers, such as forgetting doses or fear of taking medications in front of others. Descriptive analyses and ordinal logistic regression with robust standard errors were conducted. Fifty-seven per cent of participants (N = 359) were African-American (57.1%) and roughly 40% had no more than a high school education. Mean age was 48 years. Overall, MSM with viral load suppression identified fewer individual-level barriers to adherence (p < .01) and individuals with depressive symptoms identified a greater number of barriers to adherence (p < .01). Compared to African-Americans, white MSM had a lower likelihood of identifying barriers to adherence (p < .05). Findings suggest that individual-level barriers to HIV medication adherence are common among MSM, irrespective of time since diagnosis and viral suppression. Race-specific interventions which address intersectional stigma are needed to improve health outcomes among African-American MSM, who bear much of the burden of poor HIV outcomes in the United States.

Acceptability and feasibility of the CHARISMA counseling intervention to support women's use of pre-exposure prophylaxis: results of a pilot study.

BACKGROUND: Women may need or seek male partner approval to safely and consistently use oral antiretroviral pre-exposure prophylaxis (PrEP) or vaginal microbicides. We developed CHARISMA, a counseling intervention to support women's relationships and their ability to consistently use HIV prevention products. METHODS: In a pilot study with 95 female participants in Johannesburg, South Africa, lay counselors implemented CHARISMA, assessing participants' relationship(s) with their male partner(s) and barriers or facilitators to HIV prevention method use, and then providing tailored, interactive counseling. We conducted study participant surveys and clinic staff interviews to evaluate CHARISMA's feasibility and acceptability. RESULTS: The CHARISMA pilot study indicates that a two-session relationship counseling intervention with 6-month follow-up to support women's ability to safely and effectively use vaginal microbicides was generally acceptable and feasible. Most participants thought CHARISMA was relevant, helpful, and about the right length, and that it had a positive impact on their relationships with their partners and their product use. Staff estimated that the intervention took 1.5-2 h to implement at enrollment and 45 min to an hour for the month 1 visit. They thought that overall CHARISMA was generally feasible to implement. CONCLUSIONS: Findings from this study suggest several lessons learned that may be relevant to others developing interventions supporting women's use of oral PrEP or vaginal microbicides. The use of lay counselors instead of nurses to deliver counseling appeared to be successful, but the counselors experienced significant stress from hearing about participants' traumatic experiences and required emotional support to avoid burnout. Although staff and participants felt that having multiple intervention sessions over time was valuable, a similar level of intensity may not be feasible in other settings. Further research is needed to determine an intervention delivery mode and follow-up period that optimally balances participant needs and clinic resources. Male engagement was a challenge, as it has been in previous studies of vaginal microbicides. Alternative strategies to reach men that do not require them to come to the clinic or rely on their female partners may be more effective.

Examining stigma, social support, and gender differences in unsuppressed HIV viral load among participants in HPTN 065.

Successful navigation of the HIV care continuum is necessary to maintain viral suppression. We explored gender-stratified correlates of being virally unsuppressed in the Prevention for Positives (P4P) component of HPTN 065. The outcome of interest was unsuppressed viral load (> 40 copies/mL) among individuals already living with HIV. Correlates included medication adherence factors, social support and stigma. Logistic regression models were stratified by gender (N = 673). Men-specific correlates of being virally unsuppressed included opposite-sex partners, older age and HIV disclosure stigma. Women-specific correlates included time since diagnosis, and personal-level barriers to medication adherence. When more individuals knew about their HIV status, women had over twice the likelihood of being virally unsuppressed; no such association was seen among men. Additionally, higher levels of social support were not associated with viral suppression among women. Interventions should consider gender-specific approaches to engaging social support in de-stigmatization of HIV and promotion of medication adherence and subsequent viral suppression.

'Either You Float or You Drown:' The Role of Social Ties and Stigma in Lived Experiences of the HIV Care Continuum in HPTN 065.

HPTN 065 utilized financial incentives to promote viral suppression among HIV-positive participants. Exit interviews were conducted in a sub-study of participants in Washington, DC and Bronx, NY. The present analyses explored lived experiences of social ties and stigma as individuals navigated the HIV care continuum, including gender differences in lived experiences. Using viral load data and informed by stages-of-change theory, participants were categorized into "Low-Adherers (n = 13)", "Action (n = 29)" and "Maintenance (n = 31)" stages. Secondary analyses of qualitative data were informed by grounded theory, and instances of social ties and stigma discussed by participants were quantified with descriptive statistics. Participants (N = 73) were mostly male (64%), African American (58%), with yearly income under $10,000 (52%). Low-adherers identified fewer, and sometimes more combative social ties than those in other adherence stages. Maintainers identified supportive ties as motivation for medication adherence (68%) but relied less on them for motivation than individuals in other adherence stages. Low-adherers described current experiences of stigma related to being diagnosed with HIV more than other adherence stages (23%). Individuals in Action reported stigma related to disclosing their HIV status to others (52%), while individuals in Maintenance mostly stigmatized others engaging in "risky" behaviors (32%). Findings suggest that women may perceive greater HIV stigma than men, perceive less supportive social ties, and were the majority of Low-adherers. Gender-informed approaches can facilitate community de-stigmatization of HIV, as African American women may be at greater risk of negative HIV health outcomes.

Acceptability of Long-Acting Injectable Cabotegravir (CAB LA) in HIV-Uninfected Individuals: HPTN 077.

Long-acting injectable PrEP could offer an alternative to daily oral PrEP, improve adherence and protection, if found acceptable, safe and effective. HPTN 077 evaluated injectable cabotegravir safety, tolerability and pharmacokinetics among HIV-uninfected males and females in sequentially-enrolled cohorts of two dosing strategies. We compared acceptability of product attributes, prevention preferences and future interest in injectable PrEP (FIIP) by region, sex-at-birth, arm and cohort and used multivariable analysis to identify FIIP determinants. Baseline injectable PrEP preferences were higher in non-U.S. sites and increased in both regions over time. In multivariable models, FIIP was most strongly associated with acceptability of product attributes, was higher in non-U.S. sites and more altruistic participants. Treatment arm and report of pain were not associated with FIIP. Injectable acceptability was highest in non-U.S. sites. Preferences for injectable versus other PrEP methods were higher among U.S. males than females, but higher among males and females in non-U.S. settings.

Depression and Sexual Trauma Among Adolescent Girls and Young Women in HIV-Prevention Research in Tanzania.

PURPOSE: Clinical trials are necessary to test HIV-prevention strategies among adolescent girls and young women in sub-Saharan Africa. Psychosocial risk factors that increase girls' and young women's vulnerability for HIV may also impact their experiences in clinical trials. A better understanding of psychosocial risks among girls and young women enrolled in HIV-prevention research is needed. This analysis explores depression and sexual trauma among adolescent girls and young women enrolled in a mock microbicide trial in Tanzania. METHODS: We collected cross-sectional data from 135 HIV-negative adolescent girls and young women between 15 and 21 in Dar es Salaam, Tanzania enrolled in a mock microbicide trial. Depression, sexual behavior, and sexual trauma were measured. Sexual trauma and demographic variables were entered into a multivariate binomial logistic regression model predicting depression. FINDINGS: Overall, 27% of participants had moderate-to-severe depression. The most commonly endorsed items were anhedonia (lack of interest/pleasure) and low mood, which were reported by 78% of participants. Thoughts of suicide or self-harm were endorsed by 17% of participants. Coerced/forced first sex was reported by 42% of participants. Participants reporting coerced/forced first sex had 3.16 times the likelihood of moderate-to-severe depression. CONCLUSIONS: Depression and coerced/forced sex were common among participants in an HIV-prevention mock clinical trial in Tanzania. When enrolling adolescent girls and young women in HIV-prevention trials in sub-Saharan Africa, our research suggests the need for a trauma-informed approach, referrals for trauma and depression, and interventions that address the impact of depression and trauma on HIV prevention, clinical trial adherence, and clinical outcomes.

Influences on seeking a contraceptive method among adolescent women in three cities in Nigeria.

BACKGROUND: Despite international support for increasing access to contraceptives among adolescents, gaps in use still exist worldwide. Past research has identified barriers to use across all levels of the socioecological model including restrictive policies, a lack of youth friendly services, and knowledge gaps. This study was conducted to further identify influences on contraceptive use among adolescent girls in Nigeria in hopes of guiding future policies and programs. METHODS: In 2018, 12 focus group discussions (FGD) were conducted in three cities in Nigeria with young women ages 15-24 with the objective of determining what and who influence adolescents' contraceptive seeking behaviors. A vignette structure was used to identify perceptions on injunctive and descriptive community norms that influence adolescent contraceptive behaviors. The FGDs were conducted by members of the University of Ibadan Centre for Population and Reproductive Health (CPRH) and analyzed by a researcher at the University of North Carolina-Chapel Hill's Carolina Population Center using a thematic analysis approach. RESULTS: Participants identified community level resistance to sex and contraceptive use among unmarried adolescents though also acknowledged that these adolescent behaviors are still occurring despite established norms. Concerns about side effects and the preservation of fertility were frequently attached to contraceptive use and pointed to as a reason for community resistance to contraceptive use among this population. Participants saw peers, parents and partners as influencers on a girl's decision to seek a method, though each were believed to play a different role in that decision. CONCLUSION: The findings show that that despite barriers created by established injunctive norms, young women with a supportive social network can access contraceptive methods despite these barriers. By harnessing the influence of peers, partners and parents, the Nigerian family planning efforts can strive to improve the health and well-being of young people.

Stakeholder acceptability of adolescent participation in clinical trials for biomedical HIV prevention products: considerations from Tanzania and India.

Researchers and advocates have increasingly called for adolescent participation in clinical trials for new HIV prevention products, particularly adolescent girls in areas most affected by the epidemic. However, recent trials have highlighted the challenges for young women and adolescents to be able to effectively use new products that require daily dosing. This analysis provides a highly relevant context for this challenging environment by examining community members acceptability of adolescent girls' participation in clinical trials for new HIV prevention products. We conducted 41 in-depth interviews in Dar es Salaam, Tanzania and Pune, India with 22 key informants (KIs). Cultural perspectives on adolescent sexuality varied between countries, with KIs in Tanzania more readily acknowledging adolescent girls' sexual activity than KIs in India. KIs in both countries felt strongly adolescents must be well-informed about research concepts prior to participation, and emphasis should be given to preventative misconception. Despite concern in both countries that the trials might be seen as encouraging sexual behavior, KIs in Tanzania overwhelmingly supported adolescent inclusion, whereas KIs in India were more cautious. Involving adolescent girls in clinical trials for new HIV prevention products is potentially acceptable, although meaningful community engagement will be necessary.

Contrast-Induced Nephropathy in Ischemic Stroke Patients Undergoing Computed Tomography Angiography: CINISter Study.

GOAL: Computed tomography angiography (CTA) is a well-tolerated, noninvasive study of the intracranial vascular circulation; however, contrast-induced nephropathy (CIN) has been reported in 5%-7% of patients undergoing CTA. Limited studies have evaluated the risks of CIN in patients undergoing CTA. Our study was designed to evaluate the prevalence and risk factors for CIN in patients with ischemic stroke who receive a CTA. MATERIALS AND METHODS: Single-center, nested, case-control study of patients with ischemic stroke who received a CTA between June 18, 2012 and January 1, 2016. Patients were grouped based on development of CIN. FINDINGS: A total of 209 patients were included in the final analysis (178 controls, 31 cases). The prevalence of CIN during the time period studied was 14.8% (95% confidence interval [CI]: 10.2-20.2). A higher proportion of patients who developed CIN had a history of diabetes mellitus (37 [20.56%] versus 15 [48.39%]; P = .0009) and reported taking no medications prior to admission (35 [19.44%] versus 11 [35.48%]; P = .0458). However, a lower proportion of patients who developed CIN had a history of smoking (59 [32.78] versus 3 [9.68]; P = .0091). After statistical adjustment, only a history of diabetes (odds ratio [OR] 4.15 [95% CI: 1.765, 9.754), taking no medications prior to admission (OR 3.56 [95% CI: 1.417, 8.941]) and a self-reported history of smoking (OR 0.204 [95% CI: 0.057, 0.721]) remained associated with the development of CIN. CONCLUSIONS: Those patients with a history of diabetes mellitus or not taking medications prior to admission should be monitored closely for the development of contrast-induced nephropathy CIN.

Safety, tolerability, and pharmacokinetics of long-acting injectable cabotegravir in low-risk HIV-uninfected individuals: HPTN 077, a phase 2a randomized controlled trial.

BACKGROUND: Cabotegravir (CAB) is a novel strand-transfer integrase inhibitor being developed for HIV treatment and prevention. CAB is formulated both as an immediate-release oral tablet for daily administration and as a long-acting injectable suspension (long-acting CAB [CAB LA]) for intramuscular (IM) administration, which delivers prolonged plasma exposure to the drug after IM injection. HIV Prevention Trials Network study 077 (HPTN 077) evaluated the safety, tolerability, and pharmacokinetics of CAB LA in HIV-uninfected males and females at 8 sites in Brazil, Malawi, South Africa, and the United States. METHODS AND FINDINGS: HPTN 077 was a double-blind, placebo-controlled phase 2a trial. Healthy individuals age 18-65 years at low HIV risk were randomized (3:1) to receive CAB or placebo (PBO). In the initial oral phase, participants received 1 daily oral tablet (CAB or PBO) for 4 weeks. Those without safety concerns in the oral phase continued and received injections in the injection phase (Cohort 1: 3 injections of CAB LA 800 mg or 0.9% saline as PBO IM every 12 weeks for 3 injection cycles; Cohort 2: CAB LA 600 mg or PBO IM for 5 injection cycles; the first 2 injections in Cohort 2 were separated by 4 weeks, the rest by 8 weeks). The primary analysis included weeks 5 to 41 of study participation, encompassing the injection phase. The cohorts were enrolled sequentially. Primary outcomes were safety and tolerability. Secondary outcomes included pharmacokinetics and events occurring during the oral and injection phases. Between February 9, 2015, and May 27, 2016, the study screened 443 individuals and enrolled 110 participants in Cohort 1 and 89 eligible participants in Cohort 2. Participant population characteristics were as follows: 66% female at birth; median age 31 years; 27% non-Hispanic white, 41% non-Hispanic black, 24% Hispanic/Latino, 3% Asian, and 6% mixed/other; and 6 transgender men and 1 transgender woman. Twenty-two (11%) participants discontinued the oral study product; 6 of these were for clinical or laboratory adverse events (AEs). Of those who received at least 1 CAB LA injection, 80% of Cohort 1 and 92% of Cohort 2 participants completed all injections; injection course completion rates were not different from those in the PBO arm. Injection site reactions (ISRs) were common (92% of Cohort 1 and 88% of Cohort 2 participants who received CAB LA reported any ISR). ISRs were mostly Grade 1 (mild) to Grade 2 (moderate), and 1 ISR event (Cohort 1) led to product discontinuation. Grade 2 or higher ISRs were the only AEs reported more commonly among CAB LA recipients than PBO recipients. Two Grade 3 (severe) ISRs occurred in CAB recipients, 1 in each cohort, but did not lead to product discontinuation in either case. Seven incident sexually transmitted infections were diagnosed in 6 participants. One HIV infection occurred in a participant 48 weeks after last injection of CAB LA: CAB was not detectable in plasma both at the time of first reactive HIV test and at the study visit 12 weeks prior to the first reactive test. Participants in Cohort 2 (unlike Cohort 1) consistently met prespecified pharmacokinetic targets of at least 95% of participants maintaining CAB trough concentrations above PA-IC90, and 80% maintaining trough concentrations above 4× PA-IC90. Study limitations include a modest sample size, a short course of injections, and a low-risk study population. CONCLUSIONS: In this study, CAB LA was well tolerated at the doses and dosing intervals used. ISRs were common, but infrequently led to product discontinuation. CAB LA 600 mg every 8 weeks met pharmacokinetic targets for both male and female study participants. The safety and pharmacokinetic results observed support the further development of CAB LA, and efficacy studies of CAB LA for HIV treatment and prevention are in progress. TRIAL REGISTRATION: ClinicalTrials.gov Registry: ClinicalTrials.gov Trial number: NCT02178800.

The Role of Financial Incentives Along the Antiretroviral Therapy Adherence Continuum: A Qualitative Sub-study of the HPTN 065 (TLC-Plus) Study.

The stages of change (SOC) theory suggests individuals adapt incrementally to behaviors like adherence, requiring different strategies over the behavior change continuum. Offering financial incentives (FIs) is one strategy to motivate adherence. This qualitative sub-study examined adherence barriers and the role of FIs to increase viral suppression (VS) among HIV Prevention Trials Network (HPTN) 065 study participants categorized into SOC-related adherence stages based on changes from baseline to follow-up viral load tests. Of 73 participants, most were in Maintenance stage (n = 31), defined as having achieved VS throughout HPTN 065, or in Action stage (n = 29), defined as moving from virally unsuppressed to suppressed in 50% or more of tests. Only 13 were Low Adherers, having achieved VS in fewer than 50% of tests. The latter group faced substantial social and structural adherence barriers. Participants in the Action stage made positive changes to adherence routines to achieve VS. Those in Maintenance were less incentivized by FIs, as they were already committed. Results from this sub-study suggest FI effectiveness may vary across the SOC continuum, with greatest impact for those initiating antiretroviral or without explicit adherence routines. FIs may be insufficient to overcome strong social or structural barriers, and unnecessary for those intrinsically committed to remaining adherent.

Health Disparities in the Appropriate Management of Cryptorchidism.

OBJECTIVE: To assess regional practices in management of cryptorchidism with regard to timely fixation by the current recommended age of 18 months. STUDY DESIGN: A retrospective study was performed. Charts of all patients who underwent surgical correction for cryptorchidism by a pediatric general surgeon or urologist within a tertiary pediatric hospital in an urban setting were systematically reviewed. RESULTS: We identified 1209 patients with cryptorchidism. The median age of surgical correction was 3.7 years (IQR: 1.4, 7.7); only 27% of patients had surgical correction before 18 months of age. Forty-six percent of our patients were white, 40% were African American, and 8% were Hispanic. African American and Hispanic patients were less likely to undergo timely repair (P?=?.01), as were those with public or no insurance (P?

Cardiovascular mortality among liver transplant recipients with nonalcoholic steatohepatitis in the United States-a retrospective study.

Nonalcoholic steatohepatitis (NASH) has become an increasingly important indication for liver transplantation (LT), and there has been a particular concern of excessive cardiovascular-related mortality in this group. Using the United Network for Organ Sharing-Standard Transplant Analysis and Research (UNOS STAR) dataset, we reviewed data on 56,995 adult transplants (January 2002 through June 2013). A total of 3,170 NASH liver-only recipients were identified and were matched with 3,012 non-NASH HCV+ and 3,159 non-NASH HCV- controls [matched 1:1 based on gender, age at LT (±3 years), and MELD score (±3)]. Cox regression analysis revealed significantly lower hazard of all-cause (HR 0.669; P < 0.0001) and cardiovascular-related mortality (HR 0.648; P < 0.0001) in the NASH compared to the non-NASH group after adjusting for diabetes, BMI, and race. Relative to the non-NASH HCV-positive group, NASH group has lower hazard of all-cause (HR 0.539; P < 0.0001) and cardiovascular-related mortality (HR 0.491; P < 0001). A lower hazard of all-cause mortality (HR 0.844; P = 0.0094) was also observed in NASH patients compared to non-NASH HCV-negative group, but cardiovascular mortality was similar (HR 0.892; P = 0.3276). LT recipients with NASH have either lower or similar risk of all-cause and cardiovascular-related mortality compared to its non-NASH counterparts after adjusting for diabetes, BMI, and race.