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BackgroundThe pharmacokinetics of long-acting rilpivirine has mostly been studied in clinical trials, which do not fully address the uncertainties that arise in routine clinical situations.Aims and methodsOur population analysis aims to establish percentile curves for rilpivirine concentrations in people with HIV (PWH) followed-up in a routine clinical setting, while identifying patient-related factors that may influence rilpivirine exposure. A total of 238 PWH enrolled in our nationwide multicenter observational study contributed to 1038 concentrations (186 and 852 concentrations after oral and intramuscular injection, respectively).ResultsRilpivirine pharmacokinetics were best described by a two-compartment model with an oral to intramuscular relative bioavailability factor. A simple zero-order absorption process was retained for oral administration while a parallel first-order absorption was used for intramuscular administration, with 27.6% of the dose released via a fast absorption pathway and the remaining fraction via a slow absorption pathway. Our model estimated that long-acting rilpivirine reaches steady-state after 2.5 years and has an elimination half-life of 18 weeks, consistent with published estimates. In females, a 45.6% reduction in the proportion of the dose absorbed via the rapid absorption pathway was observed. However, this resulted in no more than 15% difference in trough concentrations (Ctrough) compared to males, which was not considered to be clinically relevant.ConclusionOverall, our model-based simulations showed that only approximately 50% of long-acting rilpivirine Ctrough would be above the 50 ng/mL threshold associated with optimal therapeutic response, while approximately 85% of Ctrough would be above the first quartile of concentrations observed in Phase III trials (32 ng/mL).

Introduction SARS-CoV-2 mainly infects respiratory endothelial cells, which is facilitated through its spike protein binding to heparan sulphate. Calcium dobesilate (CaD) is a well-established, widely available vasoactive and angioprotective drug interacting with heparan sulphate, with the potential to interfere with the uptake of SARS-CoV-2 by epithelial cells. The CADOVID trial aims to evaluate the efficacy and safety of CaD in reducing the SARS-CoV-2 viral load in non-hospitalised adult patients diagnosed with COVID-19, confirmed by a positive SARS-CoV-2 PCR, including its efficacy to reduce the impact of persistent COVID-19 symptoms.Methods and analysis This is a randomised, placebo-controlled, double-blind, monocentric phase II trial. Enrolment began in July 2022. A total of 74 adult patients will be randomly allocated to the CaD arm or the placebo group with a 1:1 ratio, respectively. Participants in the intervention arm will receive two capsules of CaD 500 mg two times per day and the placebo arm will receive two matching capsules of mannitol 312.5 mg two times per day, with a treatment period of 7 days for both arms, followed by a 77-day observational period without treatment administration. Participants will be asked to complete secured online questionnaires using their personal smartphone or other electronic device. These include a COVID-19 questionnaire (assessing symptoms, temperature measurement, reporting of concomitant medication and adverse events), a COVID-19 persistent symptoms’ questionnaire and the Short Form 12-Item (SF-12) survey. SARS-CoV-2 PCR testing will be performed on nasopharyngeal swabs collected on days 1, 4, 8 and 21. The primary endpoint is the reduction from baseline of SARS-CoV-2 viral load determined by RT-PCR at day 4.Ethics and dissemination This trial has received approval by the Geneva Regional Research Ethics Committee (2022-00613) and Swissmedic (701339). Dissemination of results will be through presentations at scientific conferences and publication in scientific journals.Trial registration number NCT05305508; Clinicaltrials.gov; Swiss National Clinical Portal Registry (SNCTP 000004938).

Summary: Background: The efficacy and tolerability of long-acting cabotegravir and rilpivirine were demonstrated in Phase III trials. However, low concentrations combined with other risk factors have been associated with an increased risk of virologic failure. This study aims to verify whether drug concentrations measured in a real-world setting are consistent with those previously reported. Methods: SHCS-879 is a nationwide observational study within the Swiss HIV Cohort Study for the monitoring of people with HIV (PWH) on long-acting cabotegravir plus rilpivirine. Samples were collected from March 2022 to March 2023. Findings: Overall, 725 samples were obtained from 186 PWH. Our data show a large inter-individual variability in cabotegravir and rilpivirine concentrations, with some individuals exhibiting repeatedly low concentrations. Rilpivirine trough concentrations were consistent with those from Phase III trials, while cabotegravir concentrations were lower. The first concentrations quartile was only slightly above the target of 664 ng/mL. Exploratory statistical analyses found 35% (p

Immunocompromised patients (ICPs) have a higher risk of developing severe forms of COVID-19 and experience a higher burden of complications and mortality than the general population. However, recent studies have suggested that the antibody response to SARS-CoV-2 mRNA vaccines could be highly variable among different ICPs. Using a collaborative, monocentric, prospective cohort study, we assessed anti-SARS-CoV-2 spike protein antibody titers following two and three doses of mRNA vaccines in four groups of ICPs (cancer [n = 232]: hematopoietic stem cell transplant [HSCT; n = 126] patients; people living with HIV [PLWH; n = 131]; and lung transplant [LT; n = 39] recipients) treated at Geneva University Hospitals; and healthy individuals (n = 49). After primo-vaccination, the highest anti-S antibody geometric mean titer (IU/mL) was observed in healthy individuals (2417 IU/mL [95% CI: 2327–2500]), the PLWH group (2024 IU/mL [95% CI:1854–2209]) and patients with cancer (840 IU/mL [95% CI: 625–1129]), whereas patients in the HSCT and LT groups had weaker antibody responses (198 IU/mL [95% CI: 108–361] and 7.3 IU/mL [95% CI: 2.5–22]). The booster dose conferred a high antibody response after 1 month in both PLWH (2500 IU/mL) and cancer patients (2386 IU/mL [95% CI: 2182–2500]), a moderate response in HSCT patients (521 IU/mL [95% CI: 306–885]) and a poor response in LT recipients (84 IU/mL [95% CI: 18–389]). Contemporary treatment with immunosuppressive drugs used in transplantation or chemotherapy was associated with a poor response to vaccination. Our findings confirmed the heterogeneity of the humoral response after mRNA vaccines among different ICPs and the need for personalized recommendations for each of these different groups.

This study aims to assess the immunological response and impact on virological control of the mRNA vaccines for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) among people living with HIV (PLWH). In this single-center observational study, all PLWH were offered vaccination with mRNA1273 or BNT162b2. Both anti-N and anti-S1-receptor binding domain (RBD) antibodies were measured together with HIV-1 RNA levels after the first dose (M0) and then at 1 (M1), 2 (M2) and 6 (M6) months later. A total of 131 individuals (median age: 54 years [IQR: 47.0-60.5]; male: 70.2%; median baseline CD4 T-cell: 602/µl [IQR 445.0-825.5]; median nadir CD4 T-cells 223/µl [IQR 111.0-330.0]) were included. All participants were positive for anti-RBD antibodies at 30 days, 60 days and 6 months after the first dose, with no statistical difference between those with HIV-1 RNA below or >20 copies/ml. HIV-1 RNA data were collected for 128 patients at baseline and 30 days after the first dose; for 124 individuals, 30 days after the second dose; and for 83 patients, 6 months after the first dose. Nineteen (14.8%) of 128 had detectable HIV-1 RNA (>20 copies/ml) at M0, 13/128 (10.2%) at M1 (among which 5 were newly detectable), 15/124 (12.1%) at M2 (among which 5 were newly detectable), and 8/83 (9.6%) at M6. No serious adverse effects were reported. All participants elicited antibodies after two doses of mRNA vaccines, with only a minor impact on HIV-1 RNA levels over a 6-month period.

SHCS#879 is an ongoing Switzerland-wide multicenter observational study conducted within the Swiss HIV Cohort Study (SHCS) for the prospective follow-up of people living with HIV (PLWH) receiving long-acting injectable cabotegravir-rilpivirine (LAI-CAB/RPV). All adults under LAI-CAB/RPV and part of SHCS are enrolled in the project. The study addresses an integrated strategy of treatment monitoring outside the stringent frame of controlled clinical trials, based on relevant patient characteristics, clinical factors, potential drug-drug interactions, and measurement of circulating blood concentrations. So far, 91 blood samples from 46 PLWH have been collected. Most individuals are less than 50 years old, with relatively few comorbidities and comedications. The observed concentrations are globally in accordance with the available values reported in the randomized clinical trials. Yet, low RPV concentrations not exceeding twice the reported protein-adjusted 90% inhibitory concentration have been observed. Data available at present confirm a considerable between-patient variability overall. Based on the growing amount of PK data accumulated during this ongoing study, population pharmacokinetic analysis will characterize individual concentration-time profiles of LAI-CAB/RPV along with their variability in a real-life setting and their association with treatment response and tolerability, thus bringing key data for therapeutic monitoring and precision dosage adjustment of this novel long-acting therapy.

This study identified factors associated with adherence to a 6-month isoniazid preventive therapy (IPT) course among adolescents and children living with HIV. Forty adolescents living with HIV and 48 primary caregivers of children living with HIV completed a Likert-based survey to measure respondent opinions regarding access to care, quality of care, preferred regimens, perceived stigma, and confidence in self-efficacy. Sociodemographic data were collected and adherence measured as the average of pill counts obtained while on IPT. The rates of suboptimal adherence (< 95% adherent) were 22.5% among adolescents and 37.5% among the children of primary caregivers. Univariate logistic regression was used to model the change in the odds of suboptimal adherence. Independent factors associated with suboptimal adherence among adolescents included age, education level, the cost of coming to clinic, stigma from community members, and two variables relating to self-efficacy. Among primary caregivers, child age, concerns about stigma, and location preference for meeting a community-health worker were associated with suboptimal adherence. To determine whether these combined factors contributed different information to the prediction of suboptimal adherence, a risk score containing these predictors was constructed for each group. The risk score had an AUC of 0.87 (95% CI: 0.76, 0.99) among adolescents and an AUC of 0.76 (95% CI: 0.62, 0.90), among primary caregivers suggesting that these variables may have complementary predictive utility. The heterogeneous scope and associations of these variables in different populations suggests that interventions aiming to increase optimal adherence will need to be tailored to specific populations and multifaceted in nature. Ideally interventions should address both long-established barriers to adherence such as cost of transportation to attend clinic and more nuanced psychosocial barriers such as perceived community stigma and confidence in self-efficacy.

The emergence and spread of multidrug-resistant tuberculosis (MDR-TB) poses a major threat to the global targets for TB control. In recent years, an evolving science and evidence base for MDR-TB has led to much needed changes in international guidelines promoting the use of newer TB drugs and regimens for MDR-TB, however, there remains a significant implementation gap. Due to the complexity of treating MDR-TB, management of cases is often supported by an expert multidisciplinary team, or clinical expert group. This service is often centralized, and may be delivered through a telemedicine platform. We have implemented a Web-based “store-and-forward” telemedicine service to optimize MDR-TB patient care in Daru, a remote and resource limited setting in Papua New Guinea (PNG). From April 2016 to February 2019, 237 cases were discussed using the service. This encompassed diagnostic (presumptive) and treatment cases, and more recently, support to the scale up of preventative therapy for latent TB infection. There were 75 cases in which the use of Bedaquiline was discussed or mentioned, with a high frequency of discussions occurring in the initial period (26 cases in the first 12 months), which has appeared to decrease as clinicians gained familiarity with use of the drug (15 cases in the last 12 months). This service has supported high quality clinical care and fostered collaboration between clinicians and technical experts in a shared learning environment.