Homologous and Heterologous Covid-19 Booster Vaccinations.

BACKGROUND: Although the three vaccines against coronavirus disease 2019 (Covid-19) that have received emergency use authorization in the United States are highly effective, breakthrough infections are occurring. Data are needed on the serial use of homologous boosters (same as the primary vaccine) and heterologous boosters (different from the primary vaccine) in fully vaccinated recipients. METHODS: In this phase 1-2, open-label clinical trial conducted at 10 sites in the United States, adults who had completed a Covid-19 vaccine regimen at least 12 weeks earlier and had no reported history of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection received a booster injection with one of three vaccines: mRNA-1273 (Moderna) at a dose of 100 µg, Ad26.COV2.S (Johnson & Johnson-Janssen) at a dose of 5×1010 virus particles, or BNT162b2 (Pfizer-BioNTech) at a dose of 30 µg. The primary end points were safety, reactogenicity, and humoral immunogenicity on trial days 15 and 29. RESULTS: Of the 458 participants who were enrolled in the trial, 154 received mRNA-1273, 150 received Ad26.COV2.S, and 153 received BNT162b2 as booster vaccines; 1 participant did not receive the assigned vaccine. Reactogenicity was similar to that reported for the primary series. More than half the recipients reported having injection-site pain, malaise, headache, or myalgia. For all combinations, antibody neutralizing titers against a SARS-CoV-2 D614G pseudovirus increased by a factor of 4 to 73, and binding titers increased by a factor of 5 to 55. Homologous boosters increased neutralizing antibody titers by a factor of 4 to 20, whereas heterologous boosters increased titers by a factor of 6 to 73. Spike-specific T-cell responses increased in all but the homologous Ad26.COV2.S-boosted subgroup. CD8+ T-cell levels were more durable in the Ad26.COV2.S-primed recipients, and heterologous boosting with the Ad26.COV2.S vaccine substantially increased spike-specific CD8+ T cells in the mRNA vaccine recipients. CONCLUSIONS: Homologous and heterologous booster vaccines had an acceptable safety profile and were immunogenic in adults who had completed a primary Covid-19 vaccine regimen at least 12 weeks earlier. (Funded by the National Institute of Allergy and Infectious Diseases; DMID 21-0012 ClinicalTrials.gov number, NCT04889209.).

MTN-033: a Phase 1 Study Comparing Applicator versus "as Lubricant" Delivery of Rectal Dapivirine Gel.

Data to inform behaviorally congruent delivery of rectal microbicides as lubricants are scant. Dapivirine (DPV) is a nonnucleoside reverse transcriptase inhibitor which has been demonstrated to be well-tolerated and efficacious in multiple clinical trials when used in a vaginal ring formulation. DPV gel administered rectally with an applicator was found to be well-tolerated in a phase 1 clinical trial. MTN-033, a single site, open label, sequence randomized, crossover study, enrolled HIV-negative men to receive 0.05% DPV gel intrarectally using an applicator (2.5 g) and self-administered on an artificial phallus as lubricant (up to 10 g). The study evaluated the pharmacokinetics (in plasma, rectal fluid, and mucosal rectal tissue), safety, acceptability, and pharmacodynamics of DPV gel when applied rectally. Statistical comparisons between methods of application were performed using mixed effects models or Wilcoxon's signed rank tests. Sixteen participants used DPV gel by applicator and 15/16 participants used gel as lubricant (mean, 1.8 g; SD, 0.8). DPV plasma AUC0-24h after use as lubricant was estimated to be 0.41 times the AUC0-24h (95% CI 0.24, 0.88) after use with applicator. While DPV was quantifiable in plasma and luminal fluid, it was not quantifiable in tissue for both applicator and as lubricant administration. No related adverse events (AE) were reported, and 15/15 participants felt the gel was easy to use. Evidence of local delivery and systemic absorption of DPV when dosed as an anal lubricant supports the feasibility and potential for development of lubricant-delivered rectal microbicides. There were no safety concerns associated with use of DPV gel and participants reported finding it easy to use. However, lower DPV exposure in plasma and lack of quantifiable DPV in rectal tissue indicate that higher potency, concentration, and longer half-life antiretrovirals with optimized formulations will be needed to achieve protective tissue concentrations.

Use of a Vaginal Ring Containing Dapivirine for HIV-1 Prevention in Women.

BACKGROUND: Antiretroviral medications that are used as prophylaxis can prevent acquisition of human immunodeficiency virus type 1 (HIV-1) infection. However, in clinical trials among African women, the incidence of HIV-1 infection was not reduced, probably because of low adherence. Longer-acting methods of drug delivery, such as vaginal rings, may simplify use of antiretroviral medications and provide HIV-1 protection. METHODS: We conducted a phase 3, randomized, double-blind, placebo-controlled trial of a monthly vaginal ring containing dapivirine, a non-nucleoside HIV-1 reverse-transcriptase inhibitor, involving women between the ages of 18 and 45 years in Malawi, South Africa, Uganda, and Zimbabwe. RESULTS: Among the 2629 women who were enrolled, 168 HIV-1 infections occurred: 71 in the dapivirine group and 97 in the placebo group (incidence, 3.3 and 4.5 per 100 person-years, respectively). The incidence of HIV-1 infection in the dapivirine group was lower by 27% (95% confidence interval [CI], 1 to 46; P=0.046) than that in the placebo group. In an analysis that excluded data from two sites that had reduced rates of retention and adherence, the incidence of HIV-1 infection in the dapivirine group was lower by 37% (95% CI, 12 to 56; P=0.007) than that in the placebo group. In a post hoc analysis, higher rates of HIV-1 protection were observed among women over the age of 21 years (56%; 95% CI, 31 to 71; P<0.001) but not among those 21 years of age or younger (-27%; 95% CI, -133 to 31; P=0.45), a difference that was correlated with reduced adherence. The rates of adverse medical events and antiretroviral resistance among women who acquired HIV-1 infection were similar in the two groups. CONCLUSIONS: A monthly vaginal ring containing dapivirine reduced the risk of HIV-1 infection among African women, with increased efficacy in subgroups with evidence of increased adherence. (Funded by the National Institutes of Health; ClinicalTrials.gov number, NCT01617096 .).

DELIVER: A Safety Study of a Dapivirine Vaginal Ring and Oral PrEP for the Prevention of HIV During Pregnancy.

BACKGROUND: Pregnancy represents a period of high HIV acquisition risk. Safety data for the monthly dapivirine vaginal ring (DVR) during pregnancy are limited. Here, we report data from the first 2 cohorts of pregnant participants in MTN-042/DELIVER, a phase 3b, randomized, open-label safety trial of DVR and oral tenofovir disoproxil fumarate/emtricitabine (TDF/FTC). MTN-042 is being conducted in 3 cohorts beginning with later gestational ages when risks of drug exposure are less. METHODS: Eligible pregnant individuals aged 18-40 years in Malawi, South Africa, Uganda, and Zimbabwe were randomized 2:1 to monthly DVR or daily TDF/FTC. Participants in cohort 1 initiated product use between 36 weeks 0 days (36 0/7 weeks) and 37 6/7 weeks gestation; participants in cohort 2 initiated product use between 30 0/7 and 35 6/7 weeks gestation. All participants continued product use until delivery or 41 6/7 weeks gestation. Pregnancy outcomes and complications were assessed and summarized using descriptive statistics and compared with local background rates obtained through a separate chart review. RESULTS: One-hundred and fifty participants were enrolled into cohort 1 with 101 randomized to DVR and 49 to TDF/FTC. One-hundred and fifty-seven participants were enrolled into cohort 2 with 106 randomized to DVR and 51 to TDF/FTC. In both cohorts, pregnancy complications were rare and similar to local background rates. CONCLUSION: In this first study of a long-acting HIV prevention agent in pregnancy, adverse pregnancy outcomes and complications were uncommon when DVR and TDF/FTC were used in the third trimester of pregnancy, suggesting a favorable safety profile for both prevention products.

Brief Report: HIV Drug Resistance Assessment Among Women Who Seroconverted During the MTN-025/HOPE Open-Label Extension Dapivirine Vaginal Ring Trial.

BACKGROUND: Clinical trials of dapivirine (DPV) vaginal ring have shown it is safe, effective, and desired by women as an HIV prevention option. The risk of drug resistance is a potential concern for DPV ring users who acquire HIV. We conducted a comprehensive resistance evaluation of plasma samples from the women who seroconverted during the Microbicide Trials Network-025/HIV Open-label Prevention Extension (HOPE) study of DPV ring. METHODS: Plasma collected on the visit at which seroconversion was detected was tested by next-generation sequencing with unique molecular identifiers for non-nucleoside reverse transcriptase inhibitor (NNRTI) drug resistance mutations (DRM) present at ≥1% frequency. Bulk-cloned plasma-derived recombinant HIV was phenotyped in a TZM-bl-based assay for susceptibility to DPV and other NNRTI. HIV-1 RNA was retrospectively quantified in plasma samples collected before HIV seroconversion. RESULTS: Among 38 participants who seroconverted in HOPE, 7 (18%) had NNRTI DRM detected by next-generation sequencing with unique molecular identifiers including A98G, K103N, V106M, E138A, and V179D. Six of 7 samples with NNRTI DRM had <3-fold reduction in susceptibility to DPV. Only 1 sample with K103N and V179I polymorphism had 9-fold reduction in susceptibility to DPV, but this genotype occurred in an individual who did not use DPV ring, likely indicating transmitted resistance. Detection of NNRTI resistance was not higher in individuals who remained on DPV ring >3 months after acquiring HIV infection. CONCLUSIONS: NNRTI resistance among women who seroconverted during HOPE was infrequent and selection of DPV-specific mutations was not detected. DPV ring is considered a safe and effective option for HIV prevention in women.

How a menu of adherence support strategies facilitated high adherence to HIV prevention products among adolescent girls and young women in sub-Saharan Africa: a mixed methods analysis.

INTRODUCTION: Effective use of pre-exposure prophylaxis (PrEP) has been low among adolescent girls and young women (AGYW) in sub-Saharan Africa. The MTN-034/REACH trial offered AGYW a menu of adherence support strategies and achieved high adherence to both daily oral PrEP and the monthly dapivirine vaginal ring. Understanding how these strategies promoted product use could inform the design of adherence support systems in programmatic settings. METHODS: REACH was a randomized crossover trial evaluating the safety of and adherence to the ring and oral PrEP among 247 HIV-negative AGYW (ages 16-21) in South Africa, Uganda and Zimbabwe from January 2019 to September 2021 (NCT03593655). Adherence support included monthly counselling sessions with drug-level feedback (DLF) plus optional daily short message service (SMS) reminders, weekly phone or SMS check-ins, peer support clubs, "peer buddies" and additional counselling. Counsellors documented adherence support choices and counselling content on standardized forms. Through focus groups, serial in-depth interviews (IDIs) and single IDIs (n = 119 total), we explored participants' experiences with adherence support and how it encouraged product use. RESULTS: Participants received counselling at nearly all visits. DLF was provided at 54.3% of sessions and, across sites, 49%-68% received results showing high adherence for oral PrEP, and 73%-89% for the ring. The most popular support strategies were in-person clubs and weekly calls, followed by online clubs, additional counselling and SMS. Preferences differed across sites but were similar for both products. Qualitative results demonstrated that the REACH strategies supported adherence by providing information about HIV and PrEP, continually motivating participants, and supporting the development of behavioural skills and self-efficacy, aligning with the Information, Motivation, and Behavioural Skills (IMB) model. Effectiveness was supported by three foundational pillars: strong interpersonal relationships with counsellors; ongoing, easily accessible support and resources; and establishing trust in the counsellors and study products through counsellor relationships, peer-to-peer exchange and DLF. CONCLUSIONS: Implementation programmes could support effective PrEP use by offering a small menu of counsellor- and peer-based support options that are youth-friendly and developmentally appropriate. The same menu options can support both ring and oral PrEP users, though content should be tailored to the individual products.

Baseline preferences for oral pre-exposure prophylaxis (PrEP) or dapivirine intravaginal ring for HIV prevention among adolescent girls and young women in South Africa, Uganda and Zimbabwe (MTN-034/IPM-045 study).

INTRODUCTION: Adolescent girls and young women (AGYW) in sub-Saharan Africa are disproportionately affected by the HIV epidemic and face an array of challenges using proven behavioral and biomedical prevention methods. To address the urgent need for expanding prevention options, we evaluated the baseline preferences of HIV prevention methods among participants enrolled in the MTN-034/REACH crossover trial along with their stated product preference prior to product initiation. METHODS: AGYW aged 16-21 years were enrolled at 4 study sites: Cape Town and Johannesburg, South Africa; Kampala, Uganda; and Harare, Zimbabwe and randomly assigned to the sequence of using oral PrEP and the dapivirine ring for 6 months each, followed by a choice period in which they could choose either product (or neither) for an additional six months. Eligible AGYW were HIV-negative, not pregnant and using effective contraception for at least two months prior to enrollment. Descriptive statistics were used to summarize demographic and behavioral data while multinomial analysis was used to determine predictors of stated product preference (ring or oral PrEP). RESULTS: Of the 247 AGYW enrolled in REACH, 34% were aged 16-17 and 89% had a primary partner.The median age of sexual debut was 16 years and 40% had ever been pregnant. At screening, 35% of participants were diagnosed with a sexually transmitted infection (STI), 39% had an AUDIT-C score associated with harmful drinking and 11% reported intimate partner violence in the past 6 months. Overall, 28% of participants, had CESD-10 scores suggestive of depressive symptoms (≥12) in the past week. At baseline, similar proportions stated a preference for the ring and oral PrEP (38.1% and 40.5% respectively), with 19% of participants stating they preferred both products equally. Only study site was significantly associated with product preference (P<0.05) with AGYW from Johannesburg having higher odds of preferring the ring and those from Kampala having higher odds of preferring both options equally. CONCLUSIONS: We successfully enrolled African AGYW with a clear unmet need for HIV prevention. The balanced preference between the two products suggests that multiple biomedical prevention options may be appealing to this age group and could address their prevention needs.

Adherence, safety, and choice of the monthly dapivirine vaginal ring or oral emtricitabine plus tenofovir disoproxil fumarate for HIV pre-exposure prophylaxis among African adolescent girls and young women: a randomised, open-label, crossover trial.

BACKGROUND: Half of new HIV acquisitions in Africa occur in adolescent girls and young women. Pre-exposure prophylaxis (PrEP) with oral tenofovir disoproxil fumarate plus emtricitabine or the monthly dapivirine vaginal ring is efficacious but has lower adherence and effectiveness among adolescent girls and young women. We aimed to assess product adherence, safety, and choice of oral PrEP compared with the dapivirine ring among African adolescent girls and young women. METHODS: MTN-034/REACH was a randomised, open-label, phase 2a crossover trial among HIV-seronegative, non-pregnant adolescent girls and young women aged 16-21 years at four clinical research sites in South Africa, Uganda, and Zimbabwe. Participants were randomly assigned (1:1) to either the dapivirine ring or daily oral PrEP (200 mg of emtricitabine and 300 mg of tenofovir disoproxil fumarate) for 6 months, then switched to the other product option for 6 months, followed by a third 6-month period in which participants were given a choice of oral PrEP, the dapivirine ring, or neither. Fixed block randomisation was used, stratified by site. The primary adherence endpoint was use of each product during the randomised periods, with high use defined as tenofovir-diphosphate concentrations greater than or equal to 700 fmol/punch (associated with taking an average of four or more tablets per week in the previous month) and greater than or equal to 4 mg dapivirine released from the returned ring (continuous use for 28 days in the previous month) based on residual drug concentrations. The primary safety endpoint was grade 2 or higher adverse events during each randomised period of 24 weeks of ring and oral PrEP. This trial is registered at ClinicalTrials.gov, NCT03593655. FINDINGS: From Feb 6, 2019 to Sept 9, 2021, 396 adolescent girls and young women were screened, 247 of whom were enrolled and randomly assigned (6 months of the ring followed by 6 months of oral PrEP n=124; 6 months of oral PrEP followed by 6 months of the ring n=123). Median age was 18 years (IQR 17-19). 54 grade 2 or higher product-related adverse events were reported during oral PrEP and five during dapivirine ring use, with no product-related serious adverse events. High adherence was observed in 753 (57%) of the 1316 oral PrEP visits and 806 (57%) of the 1407 dapivirine ring visits. Four women acquired HIV during follow-up. INTERPRETATION: Adherence was moderately high and similar between oral PrEP and the dapivirine ring with favourable safety and tolerability. Oral PrEP and the dapivirine ring are effective, safe, and well tolerated HIV prevention options for adolescent girls and young women who would benefit from a choice of PrEP formulations to meet their needs and preferences. FUNDING: National Institutes of Health.

Immunogenicity of NVX-CoV2373 heterologous boost against SARS-CoV-2 variants.

As part of a multicenter study evaluating homologous and heterologous COVID-19 booster vaccines, we assessed the magnitude, breadth, and short-term durability of binding and pseudovirus-neutralizing antibody (PsVNA) responses following a single booster dose of NVX-CoV2373 in adults primed with either Ad26.COV2.S, mRNA-1273, or BNT162b2 vaccines. NVX-CoV2373 as a heterologous booster was immunogenic and associated with no safety concerns through Day 91. Fold-rises in PsVNA titers from baseline (Day 1) to Day 29 were highest for prototypic D614G variant and lowest for more recent Omicron sub-lineages BQ.1.1 and XBB.1. Peak humoral responses against all SARS-CoV-2 variants were lower in those primed with Ad26.COV2.S than with mRNA vaccines. Prior SARS CoV-2 infection was associated with substantially higher baseline PsVNA titers, which remained elevated relative to previously uninfected participants through Day 91. These data support the use of heterologous protein-based booster vaccines as an acceptable alternative to mRNA or adenoviral-based COVID-19 booster vaccines. This trial was conducted under ClinicalTrials.gov: NCT04889209.

An international, multicenter phase II trial of bortezomib in patients with hepatocellular carcinoma.

BACKGROUND AND RATIONALE: Bortezomib (PS-341, VELCADE®) is a selective inhibitor of the 26S proteasome, an integral component of the ubiquitin-proteasome pathway. This phase II study evaluated the activity and tolerability of bortezomib in unresectable hepatocellular carcinoma (HCC) patients. METHODS: The primary endpoint was confirmed tumor response rate (RR) with secondary endpoints including duration of response, time to disease progression, survival and toxicity. Treatment consisted of bortezomib, 1.3 mg/m2 IV bolus on days 1, 4, 8, and 11 of each 21-day treatment cycle. Eligibility included: no prior systemic chemotherapy, ECOG PS 0-2, Child-Pugh A or B, preserved hematologic, hepatic and neurologic function; prior liver-directed therapy was permitted. RESULTS: Thirty-five patients enrolled and received a median of 2 cycles of treatment (range 1-12). Overall, 24 and 4 patients had a maximum severity of grade 3 and 4 adverse events (AEs), respectively. No treatment related deaths occurred. Only thrombocytopenia (11%) was seen in greater than 10% of patients. One patient achieved a partial response, lasting 13 weeks during treatment and progressed 11.6 months later; two patients received treatment for greater than 6 months. Median time-to-progression was 1.6 months and median survival was 6.0 months. CONCLUSIONS: This international, multicenter trial evaluated bortezomib as monotherapy in unresectable HCC patients. And, despite the lack of significant activity, this report serves as a baseline clinical experience for the development of future dual biologic approaches including bortezomib.

Rapid decline in vaccine-boosted neutralizing antibodies against SARS-CoV-2 Omicron variant.

The Omicron variant of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) exhibits reduced susceptibility to vaccine-induced neutralizing antibodies, requiring a boost to generate protective immunity. We assess the magnitude and short-term durability of neutralizing antibodies after homologous and heterologous boosting with mRNA and Ad26.COV2.S vaccines. All prime-boost combinations substantially increase the neutralization titers to Omicron, although the boosted titers decline rapidly within 2 months from the peak response compared with boosted titers against the prototypic D614G variant. Boosted Omicron neutralization titers are substantially higher for homologous mRNA vaccine boosting, and for heterologous mRNA and Ad26.COV2.S vaccine boosting, compared with homologous Ad26.COV2.S boosting. Homologous mRNA vaccine boosting generates nearly equivalent neutralizing activity against Omicron sublineages BA.1, BA.2, and BA.3 but modestly reduced neutralizing activity against BA.2.12.1 and BA.4/BA.5 compared with BA.1. These results have implications for boosting requirements to protect against Omicron and future variants of SARS-CoV-2. This trial was conducted under ClincalTrials.gov: NCT04889209.

Patterns of distress in US medical students.

BACKGROUND: How multiple forms of psychological distress coexist in individual medical students has not been formally studied. AIM: To explore the prevalence of various forms of distress in medical students and their relationship to recent suicidal ideation or serious thoughts of dropping out of school. METHODS: All medical students at seven US schools were surveyed with standardized instruments to evaluate burnout, depression, stress, mental quality of life (QOL), physical QOL, and fatigue. Additional items explored recent suicidal ideation and serious thoughts of dropping out of medical school. RESULTS: Nearly all (1846/2246, 82%) of medical students had at least one form of distress with 1066 (58%) having ≥3 forms of distress. A dose-response relationship was found between the number of manifestations of distress and recent suicidal ideation or serious thoughts of dropping out. For example, students with 2, 4, or 6 forms of distress were 5, 15, and 24 fold, respectively, more likely to have suicidal ideation than students with no forms of distress assessed. All forms of distress were independently associated with suicidal ideation or serious thoughts of dropping out on multivariable analysis. CONCLUSIONS: Most medical students experience ≥1 manifestation of distress with many experiencing multiple forms of distress simultaneously. The more forms of distress experienced the greater the risk for suicidal ideation and thoughts of dropping out of medical school.

HIV-1 drug resistance among individuals who seroconverted in the ASPIRE dapivirine ring trial.

INTRODUCTION: A potential concern with the use of dapivirine (DPV) for HIV prevention is the selection of a drug-resistant virus that could spread and reduce the effectiveness of non-nucleoside reverse transcriptase (NNRTI)-based first-line antiretroviral therapy. We evaluated HIV-1 seroconversions in MTN-020/ASPIRE for selection of drug resistance and evaluated the genetic basis for observed reductions in susceptibility to DPV. METHODS: MTN-020/ASPIRE was a placebo-controlled, Phase III safety and effectiveness study of DPV ring for HIV-1 prevention conducted at 15 sites in South Africa, Zimbabwe, Malawi and Uganda between 2012 and 2015. Plasma from individuals who seroconverted in ASPIRE was analysed for HIV-1 drug resistance using both population Sanger sequencing and next-generation sequencing (NGS) with unique molecular identifiers to report mutations at ≥1% frequency. DPV susceptibility of plasma-derived recombinant HIV-1 containing bulk-cloned full-length reverse transcriptase sequences from MTN-020/ASPIRE seroconversions was determined in TZM-bl cells. Statistical significance was calculated using the Fisher's exact test. RESULTS: Plasma from all 168 HIV seroconversions were successfully tested by Sanger sequencing; 57 of 71 DPV arm and 82 of 97 placebo (PLB) arm participants had NGS results at 1% sensitivity. Overall, 18/168 (11%) had NNRTI mutations including K101E, K103N/S, V106M, V108I, E138A/G, V179D/I/T and H221Y. Five samples from both arms had low-frequency NNRTI mutations that were not detected by Sanger sequencing. The frequency of NNRTI mutations from the DPV arm (11%) was not different from the PLB arm (10%; p = 0.80). The E138A mutation was detected in both the DPV (3 of 71 [4.2%]) and PLB arm (5 of 97 [5.2%]) and conferred modest reductions in DPV susceptibility in some reverse transcriptase backgrounds but not others. CONCLUSIONS: HIV-1 drug resistance including NNRTI resistance did not differ between the DPV and placebo arms of the MTN-020/ASPIRE study, indicating that drug resistance was not preferentially acquired or selected by the DPV ring and that the preventive benefit of DPV ring outweighs resistance risk.

Acceptability of a Dapivirine Gel Administered Rectally to HIV-1 Seronegative Adults (MTN-033 Study).

We triangulated quantitative and qualitative assessments to evaluate participants' acceptability of 0.05% dapivirine rectal microbicide (RM) gel administered via two separate modalities (a rectal applicator and an artificial phallus for use as a coital simulation device) as part of a Phase I trial (N = 14) among men who have sex with men (MSM) randomized using a 1:1 ratio. Overall, participants reported favorable acceptability of the gel (n = 11; 78.6%), the same or more at the end of the study compared to when they started the study. Additionally, when discussing their preferred administration modality, they noted that both methods had positive qualities but also potential areas of improvement. Our findings underscore the need to create multiple delivery methods for a future microbicide gel (i.e., with and without the need for an applicator) and highlight the importance of offering MSM choices in how biomedical HIV prevention strategies are delivered.

Heterologous SARS-CoV-2 Booster Vaccinations - Preliminary Report.

Background: While Coronavirus disease 2019 (Covid-19) vaccines are highly effective, breakthrough infections are occurring. Booster vaccinations have recently received emergency use authorization (EUA) for certain populations but are restricted to homologous mRNA vaccines. We evaluated homologous and heterologous booster vaccination in persons who had received an EUA Covid-19 vaccine regimen. Methods: In this phase 1/2 open-label clinical trial conducted at ten U.S. sites, adults who received one of three EUA Covid-19 vaccines at least 12 weeks prior to enrollment and had no reported history of SARS-CoV-2 infection received a booster injection with one of three vaccines (Moderna mRNA-1273 100-µg, Janssen Ad26.COV2.S 5×1010 virus particles, or Pfizer-BioNTech BNT162b2 30-µg; nine combinations). The primary outcomes were safety, reactogenicity, and humoral immunogenicity on study days 15 and 29. Results: 458 individuals were enrolled: 154 received mRNA-1273, 150 received Ad26.CoV2.S, and 153 received BNT162b2 booster vaccines. Reactogenicity was similar to that reported for the primary series. Injection site pain, malaise, headache, and myalgia occurred in more than half the participants. Booster vaccines increased the neutralizing activity against a D614G pseudovirus (4.2-76-fold) and binding antibody titers (4.6-56-fold) for all combinations; homologous boost increased neutralizing antibody titers 4.2-20-fold whereas heterologous boost increased titers 6.2-76-fold. Day 15 neutralizing and binding antibody titers varied by 28.7-fold and 20.9-fold, respectively, across the nine prime-boost combinations. Conclusion: Homologous and heterologous booster vaccinations were well-tolerated and immunogenic in adults who completed a primary Covid-19 vaccine regimen at least 12 weeks earlier.

Safety, uptake, and use of a dapivirine vaginal ring for HIV-1 prevention in African women (HOPE): an open-label, extension study.

BACKGROUND: Two phase 3 clinical trials showed that use of a monthly vaginal ring containing 25 mg dapivirine was well tolerated and reduced HIV-1 incidence in women by approximately 30% compared with placebo. We aimed to evaluate use and safety of the dapivirine vaginal ring (DVR) in open-label settings with high background rates of HIV-1 infection, an important step for future implementation. METHODS: We did a phase 3B open-label extension trial of the DVR (MTN-025/HIV Open-label Prevention Extension [HOPE]). Women who were HIV-1-negative and had participated in the MTN-020/ASPIRE phase 3 trial were offered 12 months of access to the DVR at 14 clinical research centres in Malawi, South Africa, Uganda, and Zimbabwe. At each visit (monthly for 3 months, then once every 3 months), women chose whether or not to accept the offer of the ring. Used, returned rings were tested for residual amounts of dapivirine as a surrogate marker for adherence. HIV-1 serological testing was done at each visit. Dapivirine amounts in returned rings and HIV-1 incidence were compared with data from the ASPIRE trial, and safety was assessed. This study is registered with ClinicalTrials.gov, NCT02858037. FINDINGS: Between July 16, 2016, and Oct 10, 2018, of 1756 women assessed for eligibility, 1456 were enrolled and participated in the study. Median age was 31 years (IQR 27-37). At baseline, 1342 (92·2%) women chose to take the DVR; ring acceptance was more than 79% at each visit up until 12 months and 936 (73·2%) of 1279 chose to take the ring at all visits. 12 530 (89·3%) of 14 034 returned rings had residual dapivirine amounts consistent with some use during the previous month (>0·9 mg released) and the mean dapivirine amount released was greater than in the ASPIRE trial (by 0·21 mg; p<0·0001). HIV-1 incidence was 2·7 per 100 person-years (95% CI 1·9-3·8, 35 infections), compared with an expected incidence of 4·4 per 100 person-years (3·2-5·8) among a population matched on age, site, and presence of a sexually transmitted infection from the placebo group of ASPIRE. No serious adverse events or grade 3 or higher adverse events observed were assessed as related to the DVR. INTERPRETATION: High uptake and persistent use in this open-label extension study support the DVR as an HIV-1 prevention option for women. With an increasing number of HIV-1 prophylaxis choices on the horizon, these results suggest that the DVR will be an acceptable and practical option for women in Africa. FUNDING: The Microbicide Trials Network and the National Institute of Allergy and Infectious Diseases, The Eunice Kennedy Shriver National Institute of Child Health and Human Development, and the National Institute of Mental Health, all components of the US National Institutes of Health.

Gabapentin for the management of hot flashes in prostate cancer survivors: a longitudinal continuation Study-NCCTG Trial N00CB.

Hot flashes are a complication of androgen deprivation therapy for prostate cancer. A phase III study showed that use of low-dose gabapentin was well tolerated and moderately decreased the frequency of hot flashes due to androgen deprivation therapy when taken for 4 weeks. The current study, an open-label continuation of the randomized study, examined the efficacy and toxicity of gabapentin when taken for (an additional) 8 weeks. Patients were allowed to start, or continue, gabapentin and to titrate the dose to maximum efficacy, up to 900 mg/d. They were asked to complete a hot flash diary daily and keep weekly logs of toxicity, satisfaction with hot flash control, and quality of life. The moderate reduction in hot flash frequency and severity in the randomized phase of the study appeared to be maintained during this continuation phase. Men originally receiving the placebo or lowest dose of gabapentin (300 mg/d) had improved hot flash control relative to that at the end of the randomized phase. Minimal adverse effects were reported. These findings suggest that low-dose gabapentin is moderately efficacious for at least 12 weeks of hot flash treatment in men undergoing androgen deprivation therapy for prostate cancer and seems to be well tolerated. (NCT00028572)

Factors associated with resilience to and recovery from burnout: a prospective, multi-institutional study of US medical students.

CONTEXT: Burnout is prevalent among medical students and is a predictor of subsequent serious consideration of dropping out of medical school and suicide ideation. Understanding of the factors that protect against burnout is needed to guide student wellness programmes. METHODS: A total of 1321 medical students attending five institutions were studied longitudinally (2006-2007). The surveys included standardised instruments to evaluate burnout, quality of life, fatigue and stress. Additional items explored social support, learning climate, life events, employment status and demographics. Students who did not have burnout at either time-point (resilient students) were compared with those who indicated burnout at one or both time-points (vulnerable students) using a Wilcoxon-Mann-Whitney test or Fisher's exact test. Similarly, the differences between those who recovered and those who were chronically burned out were also compared in students with burnout at the first time-point. Logistic regression modelling was employed to evaluate associations between the independent variables and resiliency to and recovery from burnout. RESULTS: Overall, 792 (60.0%) students completed the burnout inventory at both time-points. No differences in demographic characteristics were observed between resilient (290/792 [36.6%]) and vulnerable (502/792 [63.4%]) students. Resilient students were less likely to experience depression, had a higher quality of life, were less likely to be employed, had experienced fewer stressful life events, reported higher levels of social support, perceived their learning climate more positively and experienced less stress and fatigue (all p < 0.05) than vulnerable students. On multivariable analysis, perceiving student education as a priority for faculty staff, experiencing less stress, not being employed and being a minority were factors independently associated with recovery from burnout. CONCLUSIONS: Modifiable individual factors and learning climate characteristics including employment status, stress level and perceptions of the prioritising of student education by faculty members relate to medical students' vulnerability to burnout.

Development and preliminary psychometric properties of a well-being index for medical students.

BACKGROUND: Psychological distress is common among medical students but manifests in a variety of forms. Currently, no brief, practical tool exists to simultaneously evaluate these domains of distress among medical students. The authors describe the development of a subject-reported assessment (Medical Student Well-Being Index, MSWBI) intended to screen for medical student distress across a variety of domains and examine its preliminary psychometric properties. METHODS: Relevant domains of distress were identified, items generated, and a screening instrument formed using a process of literature review, nominal group technique, input from deans and medical students, and correlation analysis from previously administered assessments. Eleven experts judged the clarity, relevance, and representativeness of the items. A Content Validity Index (CVI) was calculated. Interrater agreement was assessed using pair-wise percent agreement adjusted for chance agreement. Data from 2248 medical students who completed the MSWBI along with validated full-length instruments assessing domains of interest was used to calculate reliability and explore internal structure validity. RESULTS: Burnout (emotional exhaustion and depersonalization), depression, mental quality of life (QOL), physical QOL, stress, and fatigue were domains identified for inclusion in the MSWBI. Six of 7 items received item CVI-relevance and CVI-representativeness of >or=0.82. Overall scale CVI-relevance and CVI-representativeness was 0.94 and 0.91. Overall pair-wise percent agreement between raters was >or=85% for clarity, relevance, and representativeness. Cronbach's alpha was 0.68. Item by item percent pair-wise agreements and Phi were low, suggesting little overlap between items. The majority of MSWBI items had a >or=74% sensitivity and specificity for detecting distress within the intended domain. CONCLUSIONS: The results of this study provide evidence of reliability and content-related validity of the MSWBI. Further research is needed to assess remaining psychometric properties and establish scores for which intervention is warranted.

Brief Report: Phase IIa Safety Study of a Vaginal Ring Containing Dapivirine in Adolescent Young Women.

BACKGROUND: Young women aged 15-24 years are disproportionately affected by the HIV epidemic. Two phase III trials of a vaginal ring containing 25-mg dapivirine demonstrated HIV-1 risk reduction in adult women older than 21 years but not in those aged 18-21 years. Lack of protection was correlated with low adherence. METHODS: In this phase-IIa, randomized, double-blind, placebo-controlled, US, multicenter trial of the dapivirine ring in sexually active females, aged 15-17 years, participants were randomized 3:1 to a dapivirine or placebo ring to be inserted monthly for 6 months (NCT02028338). Primary safety end points included grade 2 product related adverse events and any grade 3 and higher adverse events. Adherence to ring use was assessed by plasma dapivirine concentrations, residual levels in used rings, and self-report. A plasma dapivirine concentration of >95 pg/mL was used to define short-term adherence; a residual ring level of <23.5 mg was used to define long-term adherence. Acceptability was assessed through computer-assisted self-interviews. RESULTS: Ninety-six participants were enrolled across 6 US sites. The median age was 16.0 years. There were no differences in safety outcomes between treatment arms. Adherence to the dapivirine ring was demonstrated by both plasma measurements (87%) and residual drug levels in rings (95%). Forty-two percent (95% confidence interval: 32 to 52) of participants reported that they never removed the ring. Participants noted no discomfort due to the ring at 87% of visits and "liking" the ring at 93% of visits. CONCLUSION: The dapivirine vaginal ring, a promising topical microbicide, was well tolerated and acceptable in young US adolescents.