BACKGROUND:Randomized trials of long-acting injectable antiretroviral therapy (ART) in persons with human immunodeficiency virus (HIV) who face challenges with adherence to oral medication are lacking. METHODS:We conducted an open-label, randomized trial involving persons with HIV who had inadequate adherence to ART (a persistent HIV-1 RNA level of >200 copies per milliliter or loss to follow-up). Participants received up to 24 weeks of adherence support, conditional economic incentives, and standard care with oral ART (step 1). Participants who had an HIV-1 RNA level of 200 copies per milliliter or lower in step 1 were randomly assigned in a 1:1 ratio to either continue standard care or switch to monthly injections of long-acting cabotegravir plus rilpivirine with or without oral lead-in therapy (step 2). The primary outcome was regimen failure, defined as confirmed virologic failure (two consecutive HIV-1 RNA measurements of >200 copies per milliliter) or treatment discontinuation during step 2. RESULTS:In step 1 of the trial, we enrolled 453 participants; the median age was 40 years, 63% were Black, and 29% had been assigned female sex at birth. In step 2, a total of 306 participants underwent randomization; 152 were assigned to receive cabotegravir-rilpivirine and 154 to receive standard care. Step 2 randomization was stopped early on the basis of the superiority of cabotegravir-rilpivirine to standard care in secondary outcomes at a prespecified analysis performed after a median follow-up of 48 weeks. The cumulative incidence of regimen failure by week 48 was 22.8% in the cabotegravir-rilpivirine group and 41.2% in the standard-care group (difference, -18.4 percentage points; 98.4% confidence interval [CI], -32.4 to -4.3; P = 0.002). The cumulative incidence of an adverse event was 43.5% in the cabotegravir-rilpivirine group and 42.4% in the standard-care group (difference, 1.1 percentage points; 95% CI, -12.7 to 15.0). Resistance-associated mutations developed in 2 participants with confirmed virologic failure in each group. CONCLUSIONS:Monthly injections of long-acting cabotegravir-rilpivirine were superior to standard oral ART in reducing the risk of regimen failure among persons with HIV who had adherence challenges. (Funded by the National Institute of Allergy and Infectious Diseases; LATITUDE ClinicalTrials.gov number, NCT03635788.).
Sweat monitoring is gaining increasing attention as a key component of next-generation health technologies. In this study, we developed a compact and flexible wearable sensor based on microelectromechanical systems (MEMS) technology for real-time sweat rate measurement. The sensor detects thermal dissipation of a heat source due to sweat flow within a microchannel, allowing for non-invasive and continuous monitoring. It consists of a microheater and two temperature sensors placed symmetrically upstream and downstream along the microchannel wall. When sweat enters the channel, the convective flow causes a temperature difference between the two sensors, which varies according to the sweat rate. Numerical simulations using finite element analysis were conducted to optimize the sensor geometry, particularly the spacing between the heater and the temperature sensors. The device was fabricated by patterning Cr-Au electrodes onto a flexible polyimide substrate and forming a PDMS microchannel over the sensing area. During exercise experiments, the device was attached to the upper arm of a participant, and the sensor output was recorded wirelessly using a compact data acquisition system. The results showed a clear increase in sweat rate during exercise and a gradual decay during the post-exercise recovery phase. These results demonstrate that the developed device can reliably capture temporal changes in sweat rate, making it a promising candidate for wearable applications in personalized health monitoring and fitness tracking.
BACKGROUND:Despite advancements in tuberculosis diagnostics, many cases remain unconfirmed because of challenges in conventional sputum-based testing. This study aimed to evaluate the diagnostic accuracy of tongue swab sampling as a non-invasive alternative for tuberculosis diagnosis using Xpert MTB/RIF Ultra (Ultra). METHODS:We conducted a large-scale, multicountry, prospective diagnostic accuracy study of Ultra using tongue swabs in people with presumptive pulmonary tuberculosis. Participants were enrolled consecutively at primary health centres and hospitals across eight countries from June 26, 2023, to Feb 15, 2024, and the study was coordinated by three consortia. Eligible participants were individuals aged 12 years or older or 18 years or older, according to the consortium involved, with presumptive pulmonary tuberculosis or at least one risk factor for tuberculosis and a positive tuberculosis screening test at the select consortia. Standardised tongue swab collection and processing protocols were used in all countries. Sensitivity and specificity with 95% CI values were calculated against sputum liquid or solid culture (primary) and sputum Ultra (secondary) reference standards using Wilson's score method. Fisher's exact tests were used for subgroup comparisons, with p values < 0·05 considered statistically significant. FINDINGS:Among the 1844 participants included in the analysis, 389 tested positive and 1455 tested negative for pulmonary tuberculosis based on the primary sputum culture reference standard. 871 (47·2%) participants were female and 973 (52·7%) were male, with a mean age of 43 years (range 12-90). Among the 1844 participants, 399 (21·7%) were enrolled in Viet Nam, 166 (9·0%) in India, 427 (23·2%) in South Africa, 271 (14·7%) in the Philippines, 138 (7·5%) in Nigeria, 102 (5·5%) in Zambia, 175 (9·5%) in Uganda, and 166 (9·0%) in Peru. Tongue swab Ultra testing showed a sensitivity of 65·6% (95% CI 60·6-70·3) and specificity of 98·5% (95% CI 97·7-99·1) against the culture-based reference standard. Sensitivity estimates varied across collection centres and were higher in individuals without HIV than in those living with HIV (68·4% vs 50·0%; absolute difference 18·4 percentage points [95% CI 3·3-33·4]). When sputum Ultra was used as the reference standard, sensitivity was 75·4% (95% CI 69·0-78·8). Tongue swab Ultra showed higher sensitivity than sputum smear microscopy. Invalid or error result rates were variable and high at certain sites (range 0-16%). INTERPRETATION:Tongue swabs are a promising sample type for rapid diagnostic tests for tuberculosis, with moderate sensitivity and high specificity when Ultra was used as the reference standard. However, further research is needed to optimise protocols for Ultra testing and develop assays tailored to tongue swab specimens. Adoption of tongue swab-based molecular testing could expand tuberculosis diagnostics access, especially for populations unable to produce sputum, thus supporting global tuberculosis elimination goals. FUNDING:National Institute of Allergy and Infectious Diseases, United States Agency for International Development.
When the acquired immunodeficiency syndrome emerged in the 1980s, the United States National Institutes of Health established research networks to conduct clinical trials with the pharmaceutical industry to identify effective antiretroviral therapeutics. The clinical trials networks included laboratory centers with academic pharmacology laboratories measuring drug concentrations to allow for the estimation of pharmacokinetic parameters and correlation with pharmacodynamic outcomes. Adoption of comprehensive quality assurance initiatives was key to ensuring the integrity of pharmacology sampling and laboratory data provided by clinical sites and laboratories. Subsequently, this infrastructure facilitated rapid responses to co-infection pathogens such as hepatitis C virus, Mycobacterium tuberculosis, and severe acute respiratory syndrome coronavirus 2. In 2008, the Center for Integrated Global Biomedical Sciences at the University at Buffalo was awarded the initial National Institute of Allergy and Infectious Diseases contract for the Clinical Pharmacology Quality Assurance Program. Since 2015, over 4,500 tutorial certificates for research staff and laboratories have been awarded on topics including the conduct of clinical pharmacology research protocols and bioanalytical method validation for antiretroviral assays. A bioanalytical peer review program for ensuring the quality of the assay methods has approved over 350 assays for > 100 analytes in 21 human biological matrices. An ISO-17043 accredited external proficiency testing program has completed 35 rounds for 15 analytes. Also, a laboratory assessment program was established that utilizes international laboratory and regulatory standards, and multiple mechanisms for training, assistance and guidance to participants. This report summarizes the development of the CPQA program over the last decade.
BACKGROUND:Combined intramuscular long-acting cabotegravir-rilpivirine is the first long-acting combination antiretroviral therapy regimen approved for adults with HIV. The International Maternal Pediatric Adolescent AIDS Clinical Trials Network (IMPAACT 2017)-More Options for Children and Adolescents (MOCHA) study assessed safety, acceptability, tolerability, antiviral activity, and pharmacokinetics of these drugs in adolescents with HIV-1. Here we present secondary outcome data up to week 48. METHODS:In this phase 1/2, open-label, non-comparative, dose-finding trial conducted at 18 sites across Botswana, South Africa, Thailand, Uganda, and the USA, virologically suppressed (HIV-1 RNA <50 copies per mL) adolescents (aged 12-17 years; weight ≥35 kg) with HIV-1 switched prestudy antiretrovirals to 4 weeks of daily oral 30 mg cabotegravir and 25 mg rilpivirine, followed by 600 mg cabotegravir and 900 mg rilpivirine long-acting intramuscular (3 mL each) injections in the contralateral gluteus medius at week 4 and week 8, and then every 8 weeks. Secondary outcomes assessed here were grade 3 or worse adverse event, virological failure (including HIV-1 RNA ≥50 copies per mL and ≥200 copies per mL per the US Food and Drug Administration snapshot algorithm), and pharmacokinetic measures including cabotegravir and rilpivirine predose concentration assessment. This trial is registered with ClinicalTrials.gov, NCT03497676. FINDINGS:Between July 26, 2021, and Aug 27, 2022, 44 of 55 participants who had participated in cohort 1 and 100 of 115 screened study-naive participants were enrolled into cohort 2 of the study. 74 (51%) of 144 participants were female and 70 (49%) male, median age was 15 years (range 12-17), BMI 19·5 kg/m2 (16·0-34·3), weight 48·5 kg (35·2-100·9). 132 (92%) had vertical HIV acquisition. Of 144 enrolled participants, 142 received at least one injection, 140 completed week 48, and 140 received the expected seven injections through to week 48. Of 142 participants with at least one injection, 48 (34%) experienced injection-site reaction, mostly grade 1 resolving within 7 days. 43 (38%) of 140 participants experienced drug-related adverse events; two experienced grade 3 or worse adverse events (one abscess with pain 3 days after injection; one abscess 6 weeks after injection). The most common drug-related non-injection-site reaction adverse events were headache (three), rash (three), and nausea (two). After week 48, one participant experienced a grade 4 adverse event (anaphylaxis per site; post-injection reaction per Clinical Management Committee) that resolved but led to study drug discontinuation. No virological failures occurred through to week 48. Median week 48 observed predose concentrations were 2·77 μg/mL for cabotegravir (IQR 1·99-3·55) and 67·9 ng/mL for rilpivirine (52·8-82·4), approximating those in adults and exceeding the protein-adjusted IC90 of 0·166 μg/mL and 12 ng/mL, respectively. INTERPRETATION:Week 48 data from the first virologically suppressed adolescents with HIV-1 who switched from daily oral to intramuscular cabotegravir and intramuscular rilpivirine every 8 weeks showed favourable safety, pharmacokinetics, and virological suppression informing both real-world use, where approved, and ongoing regulatory submissions, where approval is pending. FUNDING:National Institutes of Health and ViiV Healthcare.
