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The global transition to use of dolutegravir (DTG) in WHO-preferred regimens for HIV treatment is limited by lack of knowledge on use in pregnancy. Here we assessed the relationship between drug concentrations (pharmacokinetics, PK), including in breastmilk, and impact on viral suppression when initiated in the third trimester (T3). In DolPHIN-1, HIV-infected treatment-naïve pregnant women (28-36 weeks of gestation, age 26 (19-42), weight 67kg (45-119), all Black African) in Uganda and South Africa were randomised 1:1 to dolutegravir (DTG) or efavirenz (EFV)-containing ART until 2 weeks post-partum (2wPP), between 9th March 2017 and 16th January 2018, with follow-up until six months postpartum. The primary endpoint was pharmacokinetics of DTG in women and breastfed infants; secondary endpoints included maternal and infant safety and viral suppression. Intensive pharmacokinetic sampling of DTG was undertaken at day 14 and 2wPP following administration of a medium-fat breakfast, with additional paired sampling between maternal plasma and cord blood, breastmilk and infant plasma. No differences in median baseline maternal age, gestation (31 vs 30 weeks), weight, obstetric history, viral load (4.5 log10 copies/mL both arms) and CD4 count (343 vs 466 cells/mm3) were observed between DTG (n = 29) and EFV (n = 31) arms. Although DTG Ctrough was below the target 324ng/mL (clinical EC90) in 9/28 (32%) mothers in the third trimester, transfer across the placenta (121% of plasma concentrations) and into breastmilk (3% of plasma concentrations), coupled with slower elimination, led to significant infant plasma exposures (3-8% of maternal exposures). Both regimens were well-tolerated with no significant differences in frequency of adverse events (two on DTG-ART, one on EFV-ART, all considered unrelated to drug). No congenital abnormalities were observed. DTG resulted in significantly faster viral suppression (P = 0.02) at the 2wPP visit, with median time to <50 copies/mL of 32 vs 72 days. Limitations related to the requirement to initiate EFV-ART prior to randomisation, and to continue DTG for only two weeks postpartum. Despite low plasma DTG exposures in the third trimester, transfer across the placenta and through breastfeeding was observed in this study, with persistence in infants likely due to slower metabolic clearance. HIV RNA suppression <50 copies/mL was twice as fast with DTG compared to EFV, suggesting DTG has potential to reduce risk of vertical transmission in mothers who are initiated on treatment late in pregnancy. clinicaltrials.gov NCT02245022.

A 65-year-old male presented after a positive Cologuard testing. He was asymptomatic at presentation, with no reported complaints of fever, chills, abdominal pain, diarrhea, constipation, hematochezia, or unexpected weight loss. CT imaging of the abdomen and pelvis revealed a 2 cm mass at the rectosigmoid junction with a single enlarged lymph node nearby measuring 2.7 x 1.6 cm, raising suspicion for regional metastatic adenopathy. He underwent a colonoscopy, which confirmed a rectosigmoid mass. Biopsy results showed adenocarcinoma of the colon. Consequently, the patient was scheduled for a laparoscopic sigmoidectomy with low anterior resection. The pathology of the surgical specimen confirmed adenocarcinoma, moderately differentiated, associated with a component of poorly differentiated large cell neuroendocrine carcinoma, with the neuroendocrine component best developed in the lymph node metastasis. Although the patient did not meet the standard criteria for mixed neuroendocrine-non-neuroendocrine neoplasm (MiNEN) tumors, treatment was administered using chemotherapeutic agents typically reserved for MiNENs. He was treated with platinum-based doublet with good response and has been in remission for one and a half years. This report highlights the importance of flexible therapeutic approaches when pathology marginally deviates from the standard established criteria, illustrating that tailoring treatment to the specific pathology can provide considerable patient benefits.

Introduction HPTN 083 demonstrated the superiority of long‐acting cabotegravir (CAB‐LA) versus daily oral emtricitabine/tenofovir disoproxil fumarate (TDF/FTC) as pre‐exposure prophylaxis (PrEP) among cisgender men and transgender women who have sex with men (MSM/TGW). HPTN 083 provided the first opportunity to understand experiences with injectable PrEP in a clinical trial. Methods Participants from two US sites (Chicago, IL and Atlanta, GA) and one international site (Rio de Janeiro, Brazil) were purposively sampled for individual qualitative interviews (N = 40), between November 2019 and March 2020, to explore trial experiences, barriers to adherence and other factors that may have impacted study implementation or outcomes. The blinded phase ended early due to efficacy; this analysis includes interviews conducted prior to unblinding with three groups defined by adherence (i.e. injection visit attendance): adherent (n = 27), non‐adherent (n = 12) and early discontinuers (n = 1). Data were organized using NVivo software and analysed using content analysis. Results Participants (mean age: 27) were primarily cisgender MSM (90%) and Black/African American (60%). Reasons for trial enrolment and PrEP use included a preference for using HIV prevention medication versus treatment in the event of HIV acquisition; the ability to enhance health via study‐related education and services; access to a novel, convenient HIV prevention product at no cost; and contributing to MSM/TGW communities through research. Participants contrasted positive experiences with study staff with their routine clinical care, and emphasized increased scheduling flexibility, thorough communication, non‐judgemental counselling and open, affirming environments (e.g. compassion, less stigma) as adherence facilitators. Injection experiences were positive overall; some described early injection‐related anxiety, which abated with time and when given some measure of control (e.g. pre‐injection countdown), and minimal injection site discomfort. Some concerns and misperceptions about injectable PrEP were reported. Barriers to adherence, across all adherence categories, included structural factors (e.g. financial constraints, travel) and competing demands (e.g. work schedules). Conclusions Respondents viewed injectable PrEP trial participation as a positive experience and a means of enhancing wellbeing. Study site flexibility and affirming clinic environments, inclusive of non‐judgemental counselling, were key facilitators of adherence. To support injection persistence, interventions that address structural barriers and promote flexible means of injection delivery may be most effective.

BackgroundEvaluating long-term efficacy, safety and pharmacokinetics of long-acting cabotegravir + rilpivirine (CAB+RPV LA) in sub-Saharan African populations is important because of the region’s unique demographics and antiretroviral therapy resistance patterns.ObjectivesTo describe the 96-week efficacy, safety and pharmacokinetics of CAB+RPV LA in South African participants from the pooled FLAIR and ATLAS-2M Phase 3/3b randomised studies.MethodPrimary endpoint: proportion of participants with plasma HIV-1 RNA levels ≥ 50 copies/mL at Week 96. Secondary endpoints: proportion of participants with plasma HIV-1 RNA levels < 50 copies/mL, confirmed virological failure (CVF; two consecutive plasma HIV-1 RNA ≥ 200 copies/mL), adverse events and pharmacokinetics.ResultsSixty-six participants were included, (CAB+RPV LA, n = 49; current oral antiretroviral regimen [CAR], n = 17). Forty-five (92%) on CAB+RPV LA and 15 (88%) on CAR maintained HIV-1 RNA levels < 50 copies/mL. At Week 96, two participants, one in each arm, had CVF. Ninety per cent on CAB+RPV LA and 76% on CAR of participants experienced an adverse event; six (12%) of which were drug-related (CAB+RPV LA: n = 6). Injection-site reactions were common (78% [Grade 1: 80%; Grade 2: 20%]). CAB and RPV trough plasma concentrations remained above respective in vitro protein-adjusted 90% inhibitory concentrations following all doses.ConclusionThis subgroup analysis of South African participants demonstrated durable efficacy, acceptable safety profile and pharmacokinetics of injectable CAB+RPV LA up to 96 weeks, consistent with long-term data from other regions and studies.

Microbial communities present in body fluids can assist in distinguishing between types of body fluids. Metagenomic studies have reported bacterial genera which are core to specific body fluids and are greatly influenced by geographical location and ethnicity. Bacteria in body fluids could also be due to bacterial infection; hence, it would be worthwhile taking into consideration bacterial species associated with diseases. The present review reports bacterial species characteristic of diseased and healthy body fluids across geographical locations, and bacteria described in forensic studies, with the aim of collating a set of bacteria to serve as the core species-specific markers for forensic body fluid identification. The most widely reported saliva-specific bacterial species are Streptococcus salivarius, Prevotella melaninogenica, Neisseria flavescens, with Fusobacterium nucleatum associated with increased diseased state. Lactobacillus crispatus and Lactobacillus iners are frequently dominant in the vaginal microbiome of healthy women. Atopobium vaginae, Prevotella bivia, and Gardnerella vaginalis are more prevalent in women with bacterial vaginosis. Semen and urine-specific bacteria at species level have not been reported, and menstrual blood bacteria are indistinguishable from vaginal fluid. Targeting more than one bacterial species is recommended for accurate body fluid identification. Although metagenomic sequencing provides information of a broad microbial profile, the specific bacterial species could be used to design biosensors for rapid body fluid identification. Validation of microbial typing methods and its application in identifying body fluids in a mixed sample would allow regular use of microbial profiling in a forensic workflow.

In this randomized, controlled trial involving women in South Africa and Uganda, twice-yearly subcutaneous lenacapavir was superior to daily oral emtricitabine–tenofovir disoproxil fumarate in preventing HIV infection.

People with HIV (PWH) are understudied in COVID-19 vaccine trials, leaving knowledge gaps on whether the identified immune correlates of protection also hold in PWH. CoVPN 3008 (NCT05168813) enrolled predominantly PWH and reported lower COVID-19 incidence for a Hybrid vs. Vaccine Group (baseline SARS-CoV-2-positive and one mRNA-1273 dose vs. negative and two doses). Using case-cohort sampling, antibody markers at enrolment (M0) and four weeks post-final vaccination (Peak) are assessed as immune correlates of COVID-19. For the Hybrid Group [ n  = 287 (195 PWH)], all M0 markers inversely correlate with COVID-19 through 230 days post-Peak, with 50% inhibitory dilution BA.4/5 neutralizing antibody titer (nAb-ID50 BA.4/5) the strongest and only independent correlate (HR per 10-fold increase=0.46, 95% CI 0.28, 0.75; P  = 0.002). For the Vaccine Group [ n  = 115 (86 PWH)], Peak nAb-ID50 BA.4/5 correlates with reduced COVID-19 risk (1.9%, 1.1%, and 0.3% at titers 10, 100, and 1000 AU/ml) through 92, but not 165, days post-Peak. Using multivariable Cox analysis of binding and nAb, nAb titers predict COVID-19 in PWH. Two doses of a 100-µg Ancestral strain mRNA vaccine in baseline-SARS-CoV-2-negative individuals elicit sufficient cross-reacting Omicron antibodies to reduce COVID-19 incidence for 90 days post-Peak, but viral evolution and waning antibodies abrogate this protection thereafter. Using data from the CoVPN 3008 study, the authors show that the neutralizing antibody correlate of risk holds in people living with HIV. However, the nAb correlate was weaker and shorter-lived in a vaccine-immunity versus hybrid-immunity population.

Melanoma is a type of skin cancer originating in the melanocytes and is recognized as one of the most severe and challenging forms of skin cancer to treat. Tyrosinase-related protein 1 (TYRP1) is a crucial protein involved in melanin production and is notably overexpressed in melanoma cells. Recently, TYRP1 has been identified as a prospective target in CAR T-Cell therapy, particularly for CD28 receptor binding, to treat patients with rare and cutaneous melanoma subtypes. We hypothesize that the receptor binds to a specific orientation to form a strong interaction. This study aims to elucidate the binding mechanism between CD28+ CAR-T cells and TYRP1-expressing melanoma cells to aid in developing novel therapeutics against melanoma. Initially, molecular docking simulations of CD28 and TYRP1 receptors were conducted. Subsequently, YASARA software was used to perform molecular dynamics simulations of the CD28-TYRP1 complex. The computational analysis revealed strong and stable hook-like interactions between the two receptors, formed at druggable sites as suggested by the P2Rank web server. This investigation into T cell receptor interactions will significantly enhance CAR-T cell therapy's effectiveness for treating cutaneous and rare melanoma subtypes.