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Hydroxyurea has been shown to potentiate the activity of the antiretroviral nucleoside analogs. A significant complication of AIDS is invasion of the virus into the CNS, resulting in HIV-associated dementia (HAD). Because of the polar nature of these nucleosides and the presence of effluxpumps in the blood-brain barrier, only low CNS drug concentrations are achieved. Introduction of hydroxyurea into the CNS may therefore increase the antiviral activity of these drugs. This study evaluates the accessibility of hydroxyurea to the CNS following oral drug administration. Twelve HIV patients received 800 mg, 1000 mg, or 1200 mg oral hydroxyurea. Cerebrospinal fluid (CSF) and plasma drug concentrations were measured over 8 hours and simultaneously fitted to a pharmacokinetic model. It was determined that CSF hydroxyurea concentrations, corresponding to those found to increase antiretroviral nucleoside activity in vitro, were achieved. [ABSTRACT FROM AUTHOR]

Background: The BASE study (NCT03998176), a phase 4, 48-week (W), single-arm, prospective trial, revealed that the use of bictegravir/emtricitabine/tenofovir alafenamide (B/F/TAF) in people with HIV and substance use disorders (PWH/SUD) was safe and effective without emergent antiretroviral resistance despite incomplete adherence. Here, we present the W96 results., Methods: A retrospective analysis of all participants enrolled in the BASE study was completed from W48 to W96. End points of interest at W96 included the proportion of participants with viral suppression (VS; HIV RNA <50 copies/mL [c/mL]), incidence of protocol-defined virologic failure (PDVF; 2 consecutive ≥400 c/mL), safety, adherence (percentage of days covered [PDC]), retention in care, and prevalence of ongoing substance use., Results: All enrolled BASE participants (n = 43) were included in the W96 analysis. At W48, 21 participants (49%) had achieved VS (intent-to-treat [ITT]). Thirty-six (84%) participants completed W96, with 19 achieving an HIV RNA <50 copies/mL (ITT, 44%; per-protocol, 54%). Seven participants (19%) met PDVF; genotyping was performed on 2, with no evidence of treatment-emergent antiretroviral resistance noted. No safety signals were identified or attributed to B/F/TAF. Adherence to B/F/TAF decreased 18% after W48 (mean PDC: W0-W48, 72%; W48-W96, 54%; P < .01). Participants exhibiting adherence rates of ≥4 doses/wk (PDC ≥57%) were more likely to achieve VS (PDC ≥57%, 84.2%, vs PDC <57%, 15.8%; P < .01). Retention in care remained stable, and participants continued to use substances through W96., Conclusions: At W96, the proportion of PWH/SUD achieving VS with B/F/TAF decreased to 44%, along with an adherence decrease of 18%, with no evidence of treatment-emergent HIV drug resistance occurring., Competing Interests: Potential conflicts of interest. J.P.H. reports research grants from Gilead Sciences, Inc., and consulting for ViiV Healthcare, Merck, and Medscape. S.H.B. reports grants from Gilead Sciences, ViiV Healthcare, and Janssen outside of the submitted work. S.S. reports grants from ViiV Healthcare outside of the submitted work. All other authors report no potential conflicts., (© The Author(s) 2024. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)

Competing Interests: Potential conflicts of interest. The author: research grants to her institution from ViiV Healthcare. The author has submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed.

Rationale: Optimizing pyrazinamide dosing is critical to improve treatment efficacy while minimizing toxicity during tuberculosis treatment. Study 31/AIDS Clinical Trials Group A5349 represents the largest phase 3 randomized controlled therapeutic trial to date for such an investigation. Objectives: We sought to report pyrazinamide pharmacokinetic parameters, risk factors for lower pyrazinamide exposure, and relationships between pyrazinamide exposure and efficacy and safety outcomes. We aimed to determine pyrazinamide dosing strategies that optimize risks and benefits. Methods: We analyzed pyrazinamide steady-state pharmacokinetic data using population nonlinear mixed-effects models. We evaluated the contribution of pyrazinamide exposure to long-term efficacy using parametric time-to-event models and safety outcomes using logistic regression. We evaluated optimal dosing with therapeutic windows targeting ≥95% durable cure and safety within the observed proportion of the primary safety outcome. Measurements and Main Results: Among 2,255 participants with 6,978 plasma samples, pyrazinamide displayed sevenfold exposure variability (151-1,053 mg·h/L). Body weight was not a clinically relevant predictor of drug clearance and thus did not justify the need for weight-banded dosing. Both clinical and safety outcomes were associated with pyrazinamide exposure, resulting in therapeutic windows of 231-355 mg · h/L for the control and 226-349 mg·h/L for the rifapentine-moxifloxacin regimen. Flat dosing of pyrazinamide at 1,000 mg would have permitted an additional 13.1% ( n  = 96) of participants allocated to the control and 9.2% ( n  = 70) to the rifapentine-moxifloxacin regimen dosed within the therapeutic window, compared with the current weight-banded dosing. Conclusions: Flat dosing of pyrazinamide at 1,000 mg/d would be readily implementable and could optimize treatment outcomes in drug-susceptible tuberculosis. Clinical trial registered with www.clinicaltrials.gov (NCT02410772).

Despite available curative treatments, global rates of hepatitis C virus (HCV) infection persist with significant burden in low- and middle-income countries (LMICs). Long-acting (LA) antiviral products are in development. This study explored the challenges and opportunities in LA-HCV treatment across three LMICs: Egypt, Ethiopia and India. The survey focused on understanding barriers and facilitators to treatment, with emphasis on LA treatment preferences. Four-hundred respondents completed a survey including demographics, HCV treatment history and preferences for injections, implants and microarray patches (MAPs) compared to pills. Overall, 78% of respondents were willing to receive injections, 43% were willing to receive implants and 55% were willing to receive MAPs. Marked heterogeneity in acceptability of non-oral treatments was observed. Among respondents who had not previously received HCV treatment, 94%, 43%, and 75% were willing to receive injections, implants, or MAPs, respectively. In contrast, among those already cured by oral HCV treatment, 61%, 40% and 43% were willing to receive injections, implants or MAPs. Other characteristics associated with willingness to receive an injection included urban residence, younger age, male sex, higher education level and taking pills for any reason (all results p < 0.001). The most common concern for all LA modalities was lack of effectiveness. Prior experience with injection or implant increased willingness to receive any LA modality (p < 0.001). Coupled with a point-of-care HCV diagnostic test, availability of and willingness to receive HCV treatment delivered by a LA formulation could simplify and expand treatment access in LMICs and contribute towards global HCV elimination goals., (© 2024 The Author(s). Journal of Viral Hepatitis published by John Wiley & Sons Ltd.)

Description: In March 2020, the White House Coronavirus Task Force determined that clinicians in the United States needed expert treatment guidelines to optimally manage patients with COVID-19, a potentially life-threatening disease caused by a new pathogen for which no specific treatments were known to be effective., Methods: The U.S. Department of Health and Human Services requested that the National Institutes of Health (NIH) take the lead in expeditiously convening a panel of experts to create "living" guidelines that would be widely accessible and capable of frequent updating as important new information became available., Recommendations: The purpose of this article is to expand on the experiences of the NIH COVID-19 Treatment Guidelines Panel (the Panel) over the past 4 years, summarize the Panel's final recommendations for COVID-19, highlight some challenges and unanswered questions about COVID-19 management, and inform future responses to public health emergencies. The Panel was formed in March 2020, and the first iteration of the guidelines was released in April 2020. Now that the public health emergency has ended, the NIH COVID-19 Treatment Guidelines have sunsetted. This role will now fall to professional societies and organizations, such as the American College of Physicians, the Infectious Diseases Society of America, the Pediatric Infectious Diseases Society, and the World Health Organization, all of which have been active in this area., Competing Interests: Disclosures: Disclosure forms are available with the article online.

The Phase 3 randomized controlled trial, TBTC Study 31/ACTG A5349 (NCT02410772) demonstrated that a 4-month rifapentine-moxifloxacin regimen for drug-susceptible pulmonary tuberculosis was safe and effective. The primary efficacy outcome was 12-month tuberculosis disease free survival, while the primary safety outcome was the proportion of grade 3 or higher adverse events during the treatment period. We conducted an analysis of demographic, clinical, microbiologic, radiographic, and pharmacokinetic data and identified risk factors for unfavorable outcomes and adverse events. Among participants receiving the rifapentine-moxifloxacin regimen, low rifapentine exposure is the strongest driver of tuberculosis-related unfavorable outcomes (HR 0.65 for every 100 µg∙h/mL increase, 95%CI 0.54-0.77). The only other risk factors identified are markers of higher baseline disease severity, namely Xpert MTB/RIF cycle threshold and extent of disease on baseline chest radiography (Xpert: HR 1.43 for every 3-cycle-threshold decrease, 95%CI 1.07-1.91; extensive disease: HR 2.02, 95%CI 1.07-3.82). From these risk factors, we developed a simple risk stratification to classify disease phenotypes as easier-, moderately-harder, or harder-to-treat TB. Notably, high rifapentine exposures are not associated with any predefined adverse safety outcomes. Our results suggest that the easier-to-treat subgroup may be eligible for further treatment shortening while the harder-to-treat subgroup may need higher doses or longer treatment., (© 2024. The Author(s).)

Background: One month of daily rifapentine + isoniazid (1HP) is an effective, ultrashort option for tuberculosis prevention in people with human immunodeficiency virus (HIV). However, rifapentine may decrease antiretroviral drug concentrations and increase the risk of virologic failure. AIDS Clinical Trials Group A5372 evaluated the effect of 1HP on the pharmacokinetics of twice-daily dolutegravir., Methods: A5372 was a multicenter, pharmacokinetic study in people with HIV (≥18 years) already on dolutegravir-containing antiretroviral therapy with HIV RNA <50 copies/mL. Participants received daily rifapentine/isoniazid (600 mg/300 mg) for 28 days as part of 1HP. Dolutegravir was increased to 50 mg twice daily during 1HP, and intensive pharmacokinetic sampling was performed on day 0 (before 1HP) and on the final day of 1HP treatment., Results: Thirty-two participants (41% female; 66% Black/African; median [Q1, Q3] age, 42 [34, 49] years) were included in the pharmacokinetic analysis; 31 had HIV RNA <50 copies/mL at the end of 1HP dosing. One participant had an HIV RNA of 160 copies/mL at day 28, with HIV RNA <50 copies/mL upon repeat testing on day 42. The median (Q1, Q3) dolutegravir trough concentration was 1751 ng/mL (1195, 2542) on day 0 versus 1987 ng/mL (1331, 2278) on day 28 (day 28:day 0 geometric mean ratio, 1.05 [90% confidence interval, .93-1.2]; P = .43). No serious adverse events were reported., Conclusions: Dolutegravir trough concentrations with 50 mg twice-daily dosing during 1HP treatment were greater than those with standard-dose dolutegravir once daily without 1HP. These pharmacokinetic, virologic, and safety data provide support for twice-daily dolutegravir use in combination with 1HP for tuberculosis prevention., Clinical Trials Registration: NCT04272242., Competing Interests: Potential conflicts of interest. A.F.L. has contracts for clinical research unrelated to this work from Gilead, ViiV, and Merck; consulting fees from ViiV. A.A. reports grants from Gilead, ViiV, Roche, GSK and MSD unrelated to this work. S.S. reports grants from ViiV unrelated to the present work. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest., (© The Author(s) 2024. Published by Oxford University Press on behalf of Infectious Diseases Society of America. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Rationale: Observational studies suggest that high-dose isoniazid may be efficacious in treating multidrug-resistant tuberculosis. However, its activity against Mycobacterium tuberculosis ( M.tb ) with katG mutations (which typically confer high-level resistance) is not established. Objectives: To characterize the early bactericidal activity (EBA) of high-dose isoniazid in patients with tuberculosis caused by katG -mutated M.tb . Methods: A5312 was a phase IIA randomized, open-label trial. Participants with tuberculosis caused by katG- mutated M.tb were randomized to receive 15 or 20 mg/kg isoniazid daily for 7 days. Daily sputum samples were collected for quantitative culture. Intensive pharmacokinetic sampling was performed on Day 6. Data were pooled across all A5312 participants for analysis (drug-sensitive, inhA -mutated, and katG -mutated M.tb ). EBA was determined using nonlinear mixed-effects modeling. Measurements and Main Results: Of 80 treated participants, 21 had katG -mutated M.tb . Isoniazid pharmacokinetics were best described by a two-compartment model with an effect of NAT2 acetylator phenotype on clearance. Model-derived maximum concentration and area under the concentration-time curve in the 15 and 20 mg/kg groups were 15.0 and 22.1 mg/L and 57.6 and 76.8 mg ⋅ h/L, respectively. Isoniazid bacterial kill was described using an effect compartment and a sigmoidal maximum efficacy relationship. Isoniazid potency against katG -mutated M.tb was approximately 10-fold lower than in inhA -mutated M.tb . The highest dose of 20 mg/kg did not demonstrate measurable EBA, except against a subset of slow NAT2 acetylators (who experienced the highest concentrations). There were no grade 3 or higher drug-related adverse events. Conclusions: This study found negligible bactericidal activity of high-dose isoniazid (15-20 mg/kg) in the majority of participants with tuberculosis caused by katG- mutated M.tb . Clinical trial registered with www.clinicaltrials.gov (NCT01936831).

Introduction: Support staff within social care settings have expressed a need for resources to facilitate end-of-life care planning with people with intellectual disabilities. This study aimed to co-design a preliminary toolkit of end-of-life care planning approaches and resources that can be implemented in adult social care services for people with intellectual disabilities., Methods: An adapted Experience-Based Co-Design process was applied to develop a toolkit for end-of-life care planning with people with intellectual disabilities. A co-design group (the 'All Together Group') met six times from January to October 2023. The group comprised nine people with intellectual disabilities (including four researchers with intellectual disabilities, who also co-facilitated the workshops), five family members, five intellectual disability support staff, two intellectual disability service managers, and five healthcare professionals., Results: The All Together Group tested resources for and approaches to end-of-life care planning with people with intellectual disabilities, based on findings from a scoping review and a focus group study. Easy-read end-of-life care planning forms were deemed overwhelming and complicated, whilst visual and creative approaches were welcomed. Three new visual resources to support illness planning and funeral planning with people with intellectual disabilities were developed: (i) 'When I'm ill' thinking cards; (ii) 'Let's Talk About Funerals' conversation-starter pictures; and (iii) 'My funeral' planning cards. These three resources, alongside three positively evaluated existing resources, were included in a new toolkit for end-of-life care planning with people with intellectual disabilities., Conclusion: Through an iterative, flexible, inclusive, and comprehensive co-design process, a toolkit of three newly developed and three existing resources was created to facilitate support staff in doing end-of-life care planning with people with intellectual disabilities. Following a trialling process with support staff, the final toolkit was made freely available online., Patient or Public Contribution: The research team included four researchers with intellectual disabilities (A.C., D.J., L.J., and R.K.-B). Researchers with intellectual disability have been part of every step of the research process; from study design to data collection and analysis to dissemination of study findings.Intellectual disability service provider representatives (M.W., N.P., and S.S.) were part of the co-design group as well. Two of these representatives were also co-applicants in the overall project (N.P. and S.S.). The co-design group included people with intellectual disabilities, families, intellectual disability support staff and health and social care professionals. The study was supported by a Research Advisory Group comprising a variety of stakeholders, including people with intellectual disabilities families, intellectual disability researchers, representatives from intellectual disability organisations, and policymakers., (© 2024 The Author(s). Health Expectations published by John Wiley & Sons Ltd.)

Background: The optimal dosing strategy for rifampicin in treating drug-susceptible tuberculosis (TB) is still highly debated. In the phase 3 clinical trial Study 31/ACTG 5349 (NCT02410772), all participants in the control regimen arm received 600 mg rifampicin daily as a flat dose. Here, we evaluated relationships between rifampicin exposure and efficacy and safety outcomes., Methods: We analyzed rifampicin concentration time profiles using population nonlinear mixed-effects models. We compared simulated rifampicin exposure from flat- and weight-banded dosing. We evaluated the effect of rifampicin exposure on stable culture conversion at 6 months; TB-related unfavorable outcomes at 9, 12, and 18 months using Cox proportional hazard models; and all trial-defined safety outcomes using logistic regression., Results: Our model-derived rifampicin exposure ranged from 4.57 mg · h/L to 140.0 mg · h/L with a median of 41.8 mg · h/L. Pharmacokinetic simulations demonstrated that flat-dosed rifampicin provided exposure coverage similar to the weight-banded dose. Exposure-efficacy analysis (n = 680) showed that participants with rifampicin exposure below the median experienced similar hazards of stable culture conversion and TB-related unfavorable outcomes compared with those with exposure above the median. Exposure-safety analysis (n = 722) showed that increased rifampicin exposure was not associated with increased grade 3 or higher adverse events or serious adverse events., Conclusions: Flat-dosing of rifampicin at 600 mg daily may be a reasonable alternative to the incumbent weight-banded dosing strategy for the standard-of-care 6-month regimen. Future research should assess the optimal dosing strategy for rifampicin, at doses higher than the current recommendation., Competing Interests: Potential conflicts of interest. The authors: No reported conflicts of interest. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed., (© The Author(s) 2024. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)

Long-acting technologies (LATs) for hepatitis C virus (HCV) are under development as a strategy to improve linkage to care, treatment adherence and outcomes. We conducted a survey of HCV treatment prescribers and HCV policymakers in low- and middle-income countries (LMICs) regarding acceptability and feasibility of HCV LATs. We included one-time intramuscular injection, subdermal implant and transdermal patch as potential LAT options. We surveyed participants regarding optimal health system and patient characteristics, concerns, potential barriers, overall feasibility and preferences for HCV LAT as compared to daily oral medication. Overall, 122 providers and 50 policymakers from 42 LMICs completed the survey. Among providers, 93% (113/122) expressed willingness to prescribe LAT and 72% (88/120) of providers preferred LAT if provided at comparable efficacy, safety and cost as current oral treatments. Of providers preferring HCV LAT to daily oral medication, 67% (59/88) preferred injection, 24% (21/88) preferred patch and 9% (8/88) preferred implant. Only 20% (24/122) would prescribe LAT if it were more costly than oral treatment. In regression analysis, no provider characteristics were associated with preference for LAT over oral treatment. Policymakers reported high likelihood that LAT would be included in treatment guidelines (42/50; 84%) and national drug formularies (39/50; 78%) if efficacy, safety and cost were similar to oral treatment. HCV LATs could advance progress to HCV elimination in LMICs by diversifying treatment options to improve treatment coverage and outcomes. Provider preferences from LMICs are a critical consideration in the development of HCV LATs to ensure its early and equitable availability in LMICs., (© 2024 John Wiley & Sons Ltd.)

The inclusion of adolescents in TB drug trials is essential for the development of safe, child-friendly regimens for the prevention and treatment of TB. TB Trials Consortium Study 31/AIDS Clinical Trials Group A5349 (S31/A5349) enrolled adolescents as young as 12 years old. We assessed investigator and coordinator described facilitators and barriers to adolescent recruitment, enrollment, and retention.Interviews were conducted with six investigators from sites that enrolled adolescent participants and six investigators from non-enrolling sites. Additionally, two focus groups were conducted with study coordinators from enrolling sites and two focus groups with non-enrolling sites. Discussions were transcribed, analyzed, summarized, and summaries were reviewed by Community Research Advisors Group members and research group representatives for content validity.Investigators and coordinators attributed the successful enrollment of adolescents to the establishment and cultivation of external partnerships, flexibility to accommodate adolescents' schedules, staff engagement, recruitment from multiple locations, dedicated recruitment staff working onsite to access potential participants, creation of youth-friendly environments, and effective communications. Non-enrolling sites were mainly hindered by regulations. Suggestions for improvement in future trials focused on study planning and site preparations.Proactive partnerships and collaboration with institutions serving adolescents helped identify and reduce barriers to their inclusion in this trial..

Background: Isoniazid preventive therapy (IPT) is recommended for tuberculosis prevention yet data on the safety of first-trimester pregnancy exposure are limited., Methods: Planned secondary analysis in a TB prevention trial of adverse pregnancy outcomes among participants assigned to 9-month IPT who became pregnant during (IPT-exposed) or after (unexposed) IPT. Regression models compared binary outcomes of a composite adverse outcome (any non-live birth, excluding induced abortion); preterm delivery <37 weeks; and low birth weight <2500 g) among exposure groups. Models were adjusted for latent TB infection, maternal age, CD4 count, and antiretroviral therapy (ART)., Results: In total, 128 participants had a known pregnancy outcome; 39 IPT-exposed and 89 unexposed. At pregnancy outcome, ART use was lower in IPT-exposed (79%) than unexposed women (98%). Overall, 29 pregnancies ended in a composite adverse outcome (25 spontaneous abortions, 2 stillbirths and 2 ectopic pregnancies), 15 preterm deliveries, and 10 infants with low birth weight. IPT was associated with the composite adverse outcome adjusting for covariates at enrollment (adjusted relative risk [aRR] 1.98; 95% confidence interval [CI] 1.15, 3.41), but the effect was attenuated when adjusted for covariates at pregnancy outcome (aRR 1.47; 95% CI .84, 2.55); IPT was not associated with preterm delivery (relative risk [RR] 0.87; 95% CI .32-2.42) or low birth weight (RR 1.01; 95% CI .29, 3.56)., Conclusions: First-trimester IPT exposure was associated with nearly two-fold increased risk of fetal demise, mostly spontaneous abortion, though the association was attenuated when adjusted for covariates proximal to pregnancy outcome including ART use. Further study is needed to inform TB prevention guidelines., Competing Interests: Potential conflicts of interest. A. G. reports Advisory Board roles from NIAID and Indo-US Science and Technology Forum (IUSSTF). M. H. reports institutional research and training grants related to infectious diseases from US NIH; board membership of Botswana-Harvard Partnership through employer; spouse's research grants from NIH related to infectious diseases research. C. A. B. reports institutional grant support for clinical trials from Gilead and DNAe; consulting fees (paid to author) from National Data and Analytics Platform (NDAP), Inc.; honoraria for medical education lectures and travel support (paid to author) from International Antiviral Society–United States (IAS-USA), a non-profit medical education entity; and unpaid positions as Present of the non-profit Conference on Retroviruses and Opportunistic Infections (CROI) Foundation Board, and Secretary/Treasurer of the IAS-USA Board of Directors. R. E. C. reports spouse's stock in Merck. S. S. reports institutional research support from ViiV Healthcare and participation on a Data Safety Monitoring or Advisory board for now completed NIH coronavirus disease (COVID)-related trials. All other authors report no potential conflicts. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed., (© The Author(s) 2023. Published by Oxford University Press on behalf of Infectious Diseases Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: Tuberculosis infection (TBI) and TB disease (TBD) incidence remains poorly described following household contact (HHC) rifampin-/multidrug-resistant TB exposure. We sought to characterize TBI and TBD incidence at 1 year in HHCs and to evaluate TB preventive treatment (TPT) use in high-risk groups., Methods: We previously conducted a cross-sectional study of HHCs with rifampin-/multidrug-resistant TB in 8 high-burden countries and reassessed TBI (interferon-gamma release assay, HHCs aged ≥5 years) and TBD (HHCs all ages) at 1 year. Incidence was estimated across age and risk groups (<5 years; ≥5 years, diagnosed with human immunodeficiency virus [HIV]; ≥5 years, not diagnosed with HIV/unknown, baseline TBI-positive) by logistic or log-binomial regression fitted using generalized estimating equations., Results: Of 1016 HHCs, 850 (83.7%) from 247 households were assessed (median, 51.4 weeks). Among 242 HHCs, 52 tested interferon-gamma release assay-positive, yielding a 1-year 21.6% (95% confidence interval [CI], 16.7-27.4) TBI cumulative incidence. Sixteen of 742 HHCs developed confirmed (n = 5), probable (n = 3), or possible (n = 8) TBD, yielding a 2.3% (95% CI, 1.4-3.8) 1-year cumulative incidence (1.1%; 95% CI, .5-2.2 for confirmed/probable TBD). TBD relative risk was 11.5-fold (95% CI, 1.7-78.7), 10.4-fold (95% CI, 2.4-45.6), and 2.9-fold (95% CI, .5-17.8) higher in age <5 years, diagnosed with HIV, and baseline TBI high-risk groups, respectively, vs the not high-risk group (P = .0015). By 1 year, 4% (21 of 553) of high-risk HHCs had received TPT., Conclusions: TBI and TBD incidence continued through 1 year in rifampin-/multidrug-resistant TB HHCs. Low TPT coverage emphasizes the need for evidence-based prevention and scale-up, particularly among high-risk groups., Competing Interests: Potential conflicts of interest . S. G. and V. M. report grant UM1AI069465 provided by NIAID. S. S. reports research grants from ViiV Healthcare (paid to institution) and unpaid participation as chair of an NIH, NIAID data and safety monitoring board (DSMB). S. Ki. reports grants from NIH (CRDF Global) and unpaid participation on the DRAMATIC Study DSMB. S. Kr. reports receipt of grants CRDF and RePORT India phase II, payment or honoraria from Clinical Care Options, LLC, and travel support from CROI 2022 New Investigator Scholarship. M. D. H. reports NIH research and training grants; travel support from CROI (paid to author); unpaid participation on a Medicins Sans Frontiers DSMB; and a role as board member for the Botswana Harvard Partnership via employer. A. G. reports grants or contracts from NIH, UNITAID, and the Centers for Disease Control and Prevention; travel support from CROI 2023 (paid to author); participation on the NIH/NAID Advisory Council and Indo US Science Technology Governing Board; and roles on the IMPAACT Network TB Scientific Committee and World Health Organization MDR TB Guidelines Committee. U. G. L. reports an ACTG NIH grant to a clinical research site. L. M. reports receipt of clinical trial fees to their institution from Merck Sharp & Dohme Corp, Adagio Therapeutics, Inc, ViiV Healthcare, and Johnson & Johnson. A. C. H. reports grant funding from DAIDS, NIAID, and NIH as one of the protocol chairs. G. C. reports a grant from DAID (paid to their institution). All other authors report no potential conflicts. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed., (© The Author(s) 2023. Published by Oxford University Press on behalf of Infectious Diseases Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Antimalarial medications are recommended for chemoprevention as part of malaria control programs to decrease the morbidity and mortality related to more than 200 million infections each year. We sought to evaluate patient and provider acceptability of malaria chemoprevention in a long-acting formulation. We administered questionnaires to patients and providers in malaria endemic districts in Kenya and Zambia. Questions explored preferences and concerns around long-acting antimalarial formulations compared with oral formulations. We recruited 202 patient respondents (Kenya, n = 102; Zambia, n = 100) and 215 provider respondents (Kenya, n = 105; Zambia, n = 110). Long-acting injection was preferred to oral pills, whereas oral pills were preferred to implant or transdermal administration by patient respondents. Of 202 patient respondents, 80% indicated that they 'definitely would try' malaria chemoprevention offered by injection instead of oral pills. Of parents or guardians, 84% of 113 responded that they 'definitely would' have their child age < 12 years and 90% of 88 'definitely would' have their child ≥12 years receive an injection for malaria prevention. Provider respondents indicated that they would be more likely to prescribe a long-acting injectable product compared with an oral product for malaria chemoprevention in adults (70%), adolescents ages 12 years and older (67%), and children <12 years (81%). Potential for prolonged adverse effects with long-acting products was the highest concern for patient respondents, while higher medication-related cost was cited as the most concerning barrier to implementation by providers. Overall, these findings indicate enthusiasm for the development of long-acting injectable antimalarials to provide individual delivery method options across age groups.

Rationale: We developed a standardized method, possible poor treatment response (PPTR), to help ascertain efficacy endpoints in Study S31/A5349 (NCT02410772), an open-label trial comparing two 4-month rifapentine-based regimens with a standard 6-month regimen for the treatment of pulmonary tuberculosis (TB). Objectives: We describe the use of the PPTR process and evaluate whether the goals of minimizing bias in efficacy endpoint assessment and attainment of relevant data to determine outcomes for all participants were achieved. Methods: A PPTR event was defined as the occurrence of one or more prespecified triggers. Each PPTR required initiation of a standardized evaluation process that included obtaining multiple sputum samples for microbiology. Measurements and Main Results: Among 2,343 participants with culture-confirmed drug-susceptible TB, 454 individuals (19.4%) had a total of 534 individual PPTR events, of which 76.6% were microbiological (positive smear or culture at or after 17 wk). At least one PPTR event was experienced by 92.4% (133 of 144) of participants with TB-related unfavorable outcome and between 13.8% and 14.7% of participants with favorable and not-assessable outcomes. A total of 75% of participants with TB-related unfavorable outcomes had microbiological confirmation of failure to achieve a disease-free cure. Conclusions: Standardized methodologies, such as our PPTR approach, could facilitate unbiased efficacy outcome determinations, improve discrimination between outcomes that are related and unrelated to regimen efficacy, and enhance the ability to conduct pooled analyses of contemporary trials.

Background: Cabotegravir (CAB) + rilpivirine (RPV) dosed intramuscularly monthly or every 2 months is a complete, long-acting (LA) regimen for the maintenance of HIV-1 virologic suppression. Here, we report the antiretroviral therapy as long acting suppression (ATLAS)-2M study week 152 results., Methods: ATLAS-2M is a phase 3b, randomized, multicenter study assessing the efficacy and safety of CAB+RPV LA every 8 weeks (Q8W) versus every 4 weeks (Q4W). Virologically suppressed (HIV-1 RNA <50 copies/mL) individuals were randomized to receive CAB+RPV LA Q8W or Q4W. Endpoints included the proportion of participants with plasma HIV-1 RNA ≥50 copies/mL and <50 copies/mL, incidence of confirmed virologic failure (CVF; 2 consecutive measurements ≥200 copies/mL), safety, and tolerability., Results: A total of 1045 participants received CAB+RPV LA (Q8W, n = 522; Q4W, n = 523). CAB+RPV LA Q8W demonstrated noninferior efficacy versus Q4W dosing, with 2.7% (n = 14) and 1.0% (n = 5) of participants having HIV-1 RNA ≥50 copies/mL, respectively, with adjusted treatment difference being 1.7% (95% CI: 0.1-3.3%), meeting the 4% noninferiority threshold. At week 152, 87% of participants maintained HIV-1 RNA <50 copies/mL (Q8W, 87% [n = 456]; Q4W, 86% [n = 449]). Overall, 12 (2.3%) participants in the Q8W arm and 2 (0.4%) in the Q4W arm had CVF. Eight and 10 participants with CVF had treatment-emergent, resistance-associated mutations to RPV and integrase inhibitors, respectively. Safety profiles were comparable, with no new safety signals observed since week 48., Conclusions: These data demonstrate virologic suppression durability with CAB+RPV LA Q8W or Q4W for ∼3 years and confirm long-term efficacy, safety, and tolerability of CAB+RPV LA as a complete regimen to maintain HIV-1 virologic suppression., Competing Interests: Potential conflicts of interest. E. T. O. has received research support to their institution during the conduct of this study and has served as a consultant for Merck and ViiV Healthcare, outside of the submitted work. E. T. O. joined ViiV Healthcare after the conclusion of the week 152 analysis. G. Richmond received grants for clinical trials from Gilead, TaiMed, Insmed, and ViiV Healthcare, outside the submitted work. G. Rizzardini has received payment/honoraria from Gilead, GSK, MSD, and ViiV Healthcare, outside of the submitted work, and reports participation on a Data Safety Monitoring Board or Advisory Board for ViiV, GSK, and Gilead. A. T. has served as a consultant on advisory boards for GSK and received payment for presentations by GSK and ViiV Healthcare (Nordic countries), outside of the submitted work. S. N. reports consulting fees and payment or honoraria for lectures, presentations, speaker’s bureaus, manuscript writing, or education events from Gilead Sciences, MSD, Janssen, and ViiV Healthcare and support for attending meetings and/or travel from Gilead Sciences, Janssen, and ViiV Healthcare. N. P. reports payment of honoraria for educational events not related to this manuscript. A. W. reports grants and personal fees and honoraria for lectures and presentations from Gilead, Merck, and ViiV Healthcare, outside the submitted work. S. S. reports payments to their institution for clinical trial participation for the submitted work from ViiV Healthcare, salary support for research from the National Institutes of Health (NIH), and participation on a Data and Safety Monitoring Board for NIH. J. R. reports personal fees from Gilead (consulting and payment or honoraria for lectures, presentations, speaker’s bureaus, manuscript writing, or educational events), Janssen (payment or honoraria for lectures, presentations, speaker’s bureaus, manuscript writing, or educational events), Merck (payment or honoraria for lectures, presentations, speaker’s bureaus, manuscript writing, or educational events), Theratechnologies (payment or honoraria for lectures, presentations, speaker’s bureaus, manuscript writing, or educational events), and ViiV Healthcare (consulting and payment or honoraria for lectures, presentations, speaker’s bureaus, manuscript writing, or educational events) and support for attending meetings and/or travel from Gilead and Pfizer, outside of the submitted work. C. H., C. L., R. D., K. Y. S., C. A., and W. R. S. are employees of ViiV Healthcare and stockholders of GSK. K. Y. S. also reports a role as ViiV Employee-Head of Research and Development and as a member of the ViiV Leadership Team. C. M. E., A. A., Y. W., S. L. F., and S. T. are employees and stockholders of GSK. S. L. F. also reports that GSK provides support for travel and registration to conferences as relevant and a patent application with GSK (author is named as an inventor on the patent application for a Method of Treating HIV with Cabotegravir and Rilpivirine). S. T. also reports stocks in Haleon. H. C., V. v. E., R. V. S.-R., and K. V. are employees and stockholders of Janssen, Pharmaceutical Companies of Johnson & Johnson. V. v. E. also reports the following: the US application or Patent Cooperation Treaty international application number 62/870,413 filed on 3 July 2019 (TIP1068USPSP1 Methods of Treating HIV. The disclosure is directed to the use of rilpivirine, or a salt thereof, to treat HIV infections in pediatric subjects). All other authors report no potential conflicts. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed., (© The Author(s) 2023. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)

Background: Understanding factors associated with prevalent Mycobacterium tuberculosis infection and prevalent TB disease in household contacts of patients with drug-resistant tuberculosis (TB) may be useful for TB program staff conducting contact investigations., Methods: Using data from a cross-sectional study that enrolled index participants with rifampin-resistant pulmonary TB and their household contacts (HHCs), we evaluated HHCs age ≥15 years for factors associated with two outcomes: Mycobacterium tuberculosis infection and TB disease. Among HHCs who were not already diagnosed with current active TB disease by the TB program, Mycobacterium tuberculosis infection was determined by interferon-gamma release assay (IGRA). TB disease was adjudicated centrally. We fitted logistic regression models using generalized estimating equations., Results: Seven hundred twelve HHCs age ≥15 years enrolled from 279 households in eight high-TB burden countries were a median age of 34 years, 63% female, 22% current smokers and 8% previous smokers, 8% HIV-positive, and 11% previously treated for TB. Of 686 with determinate IGRA results, 471 tested IGRA positive (prevalence 68.8% (95% Confidence Interval: 64.6%, 72.8%)). Multivariable modeling showed IGRA positivity was more common in HHCs aged 25-49 years; reporting prior TB treatment; reporting incarceration, substance use, and/or a period of daily alcohol use in the past 12 months; sharing a sleeping room or more evenings spent with the index participant; living with smokers; or living in a home of materials typical of low socioeconomic status. Forty-six (6.5% (95% Confidence Interval: 4.6%, 9.0%)) HHCs age ≥15 years had prevalent TB disease. Multivariable modeling showed higher prevalence of TB disease among HHCs aged ≥50 years; reporting current or previous smoking; reporting a period of daily alcohol use in the past 12 months; and reporting prior TB treatment., Conclusion: We identified overlapping and distinct characteristics associated with Mycobacterium tuberculosis infection and TB disease that may be useful for those conducting household TB investigations., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2023 Kim et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Adults with HIV frequently develop a form of mild cognitive impairment known as HIV-associated neurocognitive disorder (HAND), but presumably cognitive decline in older persons with HIV could also be attributable to Alzheimer's disease (AD). However, distinguishing these two conditions in individual patients is exceedingly difficult, as the distinct neural and neuropsychological features are poorly understood and most studies to date have only investigated HAND or AD spectrum (ADS) disorders in isolation. The current study examined the neural dynamics underlying visuospatial processing using magnetoencephalography (MEG) in 31 biomarker-confirmed patients on the ADS, 26 older participants who met criteria for HAND, and 31 older cognitively normal controls. MEG data were examined in the time-frequency domain, and a data-driven approach was utilized to identify the neural dynamics underlying visuospatial processing. Both clinical groups (ADS/HAND) were significantly less accurate than controls on the task and exhibited stronger prefrontal theta oscillations compared to controls. Regarding disease-specific alterations, those with HAND exhibited stronger alpha oscillations than those on the ADS in frontoparietal and temporal cortices. These results indicate both common and unique neurophysiological alterations among those with ADS disorders and HAND in regions serving visuospatial processing and suggest the underlying neuropathological features are at least partially distinct., (© The Author(s) 2022. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: People with human immunodeficiency virus (HIV) and substance use disorder (PWH/SUD) are at higher risk of nonadherence to antiretroviral therapy. Bictegravir/emtricitabine/tenofovir alafenamide (B/F/TAF) exhibits high rates of efficacy with a favorable adverse event profile. The BASE study (NCT03998176) is a phase 4, single-arm study evaluating the effectiveness and safety of B/F/TAF among PWH/SUD., Methods: Viremic (HIV RNA >1000 copies/mL) PWH/SUD initiated B/F/TAF once daily for 48 weeks (W). The primary endpoint was proportion of participants with HIV RNA <50 copies/mL at W24. Secondary endpoints were proportion of participants with HIV-1 RNA <50 copies/mL at W48, safety, B/F/TAF adherence (dried blood spot [DBS] concentrations of emtricitabine triphosphate and tenofovir diphosphate [TFV-DP]), substance use (NIDA-ASSIST), and quality of life (SF-12)., Results: Forty-three participants were enrolled; 95% reported methamphetamine use. Median age was 38 (range, 21-62) years; 21% were female, 81% White, 14% Black, and 16% Hispanic. Thirty-two (74%) and 21 (49%) participants had HIV RNA <50 copies/mL (intention-to-treat) at W24 and W48, respectively. Seven participants (16%) experienced confirmed virologic failure through W48; 1 developed emergent drug resistance (M184V). Fifteen participants (35%) experienced grade ≥3 adverse events. Five participants (12%) reported suicidal ideation; none resulted in discontinuation. Median DBS concentrations were representative of 5-6 doses/week (TFV-DP, 1603 fmol/punches). NIDA-ASSIST scores declined from baseline to W48 with methamphetamine use decreasing most (-7.9 points; -29%), and SF-12 physical/mental scores increased 1.2 and 7.6 points, respectively., Conclusions: B/F/TAF among a high-risk population of PWH/SUD resulted in an initial 72% viral suppression rate at W24 before dropping to 49% at W48 as retention declined. One participant developed emergent drug resistance (M184V)., Competing Interests: Potential conflicts of interest. J. P. H. reports research grants from Gilead Sciences. S. H. B. reports grants from Gilead Sciences, ViiV Healthcare, and Janssen, outside the submitted work. S. S. reports grants from ViiV Healthcare, outside the submitted work. K. K. S. reports research grants from Organon, paid to her institution. All other authors report no potential conflicts., (© The Author(s) 2023. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)

Background: Tuberculosis (TB) Trials Consortium Study 31/AIDS Clinical Trials Group A5349, an international randomized open-label phase 3 noninferiority trial showed that a 4-month daily regimen substituting rifapentine for rifampin and moxifloxacin for ethambutol had noninferior efficacy and was safe for the treatment of drug-susceptible pulmonary TB (DS-PTB) compared with the standard 6-month regimen. We explored results among the prespecified subgroup of people with human immunodeficiency virus (HIV) (PWH)., Methods: PWH and CD4+ counts ≥100 cells/μL were eligible if they were receiving or about to initiate efavirenz-based antiretroviral therapy (ART). Primary endpoints of TB disease-free survival 12 months after randomization (efficacy) and ≥ grade 3 adverse events (AEs) on treatment (safety) were compared, using a 6.6% noninferiority margin for efficacy. Randomization was stratified by site, pulmonary cavitation, and HIV status. PWH were enrolled in a staged fashion to support cautious evaluation of drug-drug interactions between rifapentine and efavirenz., Results: A total of 2516 participants from 13 countries in sub-Saharan Africa, Asia, and the Americas were enrolled. Among 194 (8%) microbiologically eligible PWH, the median CD4+ count was 344 cells/μL (interquartile range: 223-455). The rifapentine-moxifloxacin regimen was noninferior to control (absolute difference in unfavorable outcomes -7.4%; 95% confidence interval [CI] -20.8% to 6.0%); the rifapentine regimen was not noninferior to control (+7.5% [95% CI, -7.3% to +22.4%]). Fewer AEs were reported in rifapentine-based regimens (15%) than the control regimen (21%)., Conclusions: In people with HIV-associated DS-PTB with CD4+ counts ≥100 cells/μL on efavirenz-based ART, the 4-month daily rifapentine-moxifloxacin regimen was noninferior to the 6-month control regimen and was safe., Clinical Trials Registration: NCT02410772., Competing Interests: Potential conflicts of interest. The authorship team members have declared any potential conflicts of interest with respect to the research, authorship, and/or publication of this article. Sanofi's commercial interests did not influence the study design; the collection, analysis, or interpretation of data; the preparation of this manuscript; or the decision to submit this manuscript for publication. A Sanofi technical expert served on the protocol team. A. V. reports unpaid participation on 2 advisory boards for a TB trial of high-dose rifampin (InterTB; St George's Hospital, London), and for a trial of shortened treatment for latent TB (McGill University, Montreal) and other financial or nonfinancial interests as part of this trial, Sanofi (Paris, France, and Bridgewater, NJ, USA) donated rifapentine and all other study drugs, supported shipping of study drugs to all sites, and provided funding support for pharmacokinetic testing. From 2007 until 2016, Sanofi donated a total of $2.9 million to the CDC Foundation to supplement CDC funding for rifapentine research; these funds supported prior TBTC studies of rifapentine but were not part of the support for this trial. This information was included in the main study publication (New England Journal of Medicine, 2021). L. M. reports grants or contracts from Merck Sharpe & Dohme Corp (institution received clinical trial fees), Viiv Healthcare (institution received clinical trial fees), Kowa Pharmaceuticals America (pharmaceutical support on protocol), Sanofi-Aventis (pharmaceutical support on protocol), and Adagio Therapeutics, Inc (institution received clinical trial fees). R. M. S. reports grants or contracts from TB Alliance: Drug regimen optimization for new and existing TB drugs, NIH/NIAID: Novel Biomarkers to Shorten TB Treatment, BMGF: TB Drug Lesion Penetration and Translational Modeling, NIH/NIAID/Rutgers: Impact of Pregnancy on Tuberculosis, BMGF/C-Path: In silico assessment of Adaptive Trial Designs, BMGF/DRI: Accelerating evaluation and development of new combination TB drug treatments, UNITAID/SU: Better Evidence and Formulations for Improved MDR-TB Treatment for Children (BENEFIT Kids), NIH/NIAID: Identifying Optimal Treatment Strategies for Tuberculosis, NIH/NIAID/SU: Optimizing and operationalizing pediatric drug-resistant tuberculosis treatment, and BMGF/C-Path: Model-based meta-analysis of endpoints analyzed in Phase III Quinolones clinical trials; including leadership or fiduciary role in other board, society, committee or advocacy group for Leadership and Operations Center (LOC), AIDS Clinical Trials Group (ACTG), WHO working group: Reaching UNGA HLM on TB targets for ending TB in children and adolescents, and Working Group on New TB Drugs (WGND), Core Member. S. S. reports Research contracts with ViiV Healthcare (paid to institution) and participates for NIH DMSB (unpaid participation). R. E. C. reports contract to institution from Unitaid, grant to institution from National Institutes of Health and Novartis, consultant from Johnson & Johnson and spouse is stockholder for Merck. S. E. D. reports support for attending meetings and/or travel from US CDC contract (provided reimbursement of travel expenses to attend the twice-yearly scientific meetings of the CDC TB Trials Consortium.). I. M. S. is the Vice-Chair for ACTG International. P. N. reports a contract from the CDC TB Trials Consortium. All other authors report no potential conflicts. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed., (© The Author(s) 2022. Published by Oxford University Press on behalf of Infectious Diseases Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Despite virologic suppression, people living with HIV (PLWH) remain at risk for developing cognitive impairment, with aberrations in motor control being a predominant symptom leading to functional dependencies in later life. While the neuroanatomical bases of motor dysfunction have recently been illuminated, the underlying molecular processes remain poorly understood. Herein, we evaluate the predictive capacity of the mitochondrial redox environment on sensorimotor brain-behavior dynamics in 40 virally-suppressed PLWH and 40 demographically-matched controls using structural equation modeling. We used state-of-the-art approaches, including Seahorse Analyzer of mitochondrial function, electron paramagnetic resonance spectroscopy to measure superoxide levels, antioxidant activity assays and dynamic magnetoencephalographic imaging to quantify sensorimotor oscillatory dynamics. We observed differential modulation of sensorimotor brain-behavior relationships by superoxide and hydrogen peroxide-sensitive features of the redox environment in PLWH, while only superoxide-sensitive features were related to optimal oscillatory response profiles and better motor performance in controls. Moreover, these divergent pathways may be attributable to immediate, separable mechanisms of action within the redox environment seen in PLWH, as evidenced by mediation analyses. These findings suggest that mitochondrial redox parameters are important modulators of healthy and pathological oscillations in motor systems and behavior, serving as potential targets for remedying HIV-related cognitive-motor dysfunction in the future., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 The Author(s). Published by Elsevier Inc. All rights reserved.)

Competing Interests: Potential conflicts of interest. C. F. reports serving as a paid consultant for Gilead Sciences, Janssen Pharmaceuticals, Merck Laboratories, and ViiV Healthcare, and chairs the Scientific Advisory Board for Navigen Corporation and Watermark. He also reports payments for expert testimony from WilmerHale and payments for educational lectures with Virology Education and the International Antiviral Association. He is also the co-inventor on two issued patents related to the development of long-acting formulations for delivery of antiretroviral drugs. P. C. reports being an executive committee member for the LEAP study. D. L. T. reports funds to his institution from Unitaid (longevity grant), during the conduct of the study; various NIH grants, outside the submitted work; royalties or licenses from UpToDate; consulting fees for service on scientific advisory boards for Merck and Excision Bio; various payments for expert testimony; serving on an SMC for Merck molnupiravir trials; holding stock or stock options from Excision Bio as scientific advisor; and various CME activities, approved by their university. S. S. reports research grants to her institution from ViiV Healthcare. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed.

A key component of global tuberculosis (TB) control is the treatment of latent TB infection. The use of long-acting technologies to administer TB preventive treatment has the potential to significantly improve the delivery and impact of this important public health intervention. For example, an ideal long-acting treatment could consist of a single dose that could be administered in the clinic (ie, a "1-shot cure" for latent TB). Interest in long-acting formulations for TB preventive therapy has gained considerable traction in recent years. This article presents an overview of the specific considerations and current preclinical advancements relevant for the development of long-acting technologies of TB drugs for treatment of latent infection, including attributes of target product profiles, suitability of drugs for long-acting formulations, ongoing research efforts, and translation to clinical studies., Competing Interests: Potential conflicts of interest. N.C.A. reports research funding from Johns Hopkins University, Janssen, Unitaid, and NIH grants R61AI161809 and 1P30AI094189 and receipt of research materials from Janssen. E.N. reports research funding from Johns Hopkins University, Unitaid, NIH, Janssen, and TB Alliance. He also reports payments for participating in a Janssen advisory board. C.F.M. reports research funding from Unitaid and NIH grant R01 Al134091 and a likely planned patent on INH prodrugs for LA. A.O. is a Director of Tandem Nano Ltd, and co-inventor of several patents relating to drug delivery. A.O. has received research funding from ViiV Healthcare, Merck, Janssen, GSK, Tandem Nano Ltd., and Gilead. He also reports receiving consulting fees from Gilead, ViiV Healthcare, Merck, and Tandem Nano Ltd. S.P.R. reports research funding from Unitaid and report patents related to long-acting therapeutic inventions through the University of Liverpool and is the vice-chair of the nonprofit British Society for Nanomedicine. S.S. reports research funding to her institution from ViiV Healthcare, Unitaid, and NIH grant NIAID R24 AI118397. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed., (© The Author(s) 2022. Published by Oxford University Press on behalf of Infectious Diseases Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

The Brief Rifapentine-Isoniazid Efficacy for TB Prevention/A5279 trial demonstrated a 1-month daily regimen of rifapentine and isoniazid was noninferior to 9 months of isoniazid alone for preventing TB in persons living with HIV (PLWH). Our objective was to evaluate rifapentine pharmacokinetics in trial participants receiving antiretroviral therapy (ART) and perform simulations to compare weight-based rifapentine dosing with a standard, fixed dose. Nonlinear mixed effect modeling was used to estimate rifapentine and 25-desacetyl rifapentine population pharmacokinetic characteristics. The pharmacokinetic model was validated using a nonparametric bootstrap and visual predictive checks. Monte Carlo simulations were performed to compare weight-based and fixed dose regimens. Rifapentine and 25-desacetyl rifapentine concentrations (347 of each; 185 participants) were each described with a one-compartment model with one-way conversion between rifapentine and 25-desacetyl rifapentine. The absorption rate was nearly doubled in fed versus fasting states. Rifapentine clearance was increased 31% in those receiving efavirenz (EFV)-based versus nevirapine-based ART. Metabolite clearance was allometrically scaled with fat-free mass. Simulations showed lower rifapentine exposures with weight-based compared with fixed dosing. With 10 mg/kg weight-based regimens, 26% and 62% of simulated exposures in <35 kg and 35-45 kg weight classes were above target (AUC 0 to 24 h of 257 mg*hr/L); 85% of simulated exposures across all weight classes with fixed dosing were above target. These data support fixed dosing with rifapentine 600 mg daily for TB prevention regardless of weight for PLWH 13 years or older receiving the 4-week regimen and no need for dose adjustment when given with EFV-based ART. Clinical Trials Registration. NCT01404312.

Background: A 4-month regimen containing rifapentine and moxifloxacin has noninferior efficacy compared to the standard 6-month regimen for drug-sensitive tuberculosis. We evaluated the effect of regimens containing daily, high-dose rifapentine on efavirenz pharmacokinetics and viral suppression in patients with human immunodeficiency virus (HIV)-associated tuberculosis (TB)., Methods: In the context of a Phase 3 randomized controlled trial, HIV-positive individuals already virally suppressed on efavirenz--containing antiretroviral therapy (ART) (EFV1), or newly initiating efavirenz (EFV2) received TB treatment containing rifapentine (1200 mg), isoniazid, pyrazinamide, and either ethambutol or moxifloxacin. Mid-interval efavirenz concentrations were measured (a) during ART and TB cotreatment (Weeks 4, 8, 12, and 17, different by EFV group) and (b) when ART was taken alone (pre- or post-TB treatment, Weeks 0 and 22). Apparent oral clearance (CL/F) was estimated and compared. Target mid-interval efavirenz concentrations were > 1 mg/L. Co-treatment was considered acceptable if > 80% of participants had mid-interval efavirenz concentrations meeting this target., Results: EFV1 and EFV2 included 70 and 41 evaluable participants, respectively. The geometric mean ratio comparing efavirenz CL/F with vs without TB drugs was 0.79 (90% confidence interval [CI] .72-.85) in EFV1 and 0.84 [90% CI .69-.97] in EFV2. The percent of participants with mid-interval efavirenz concentrations > 1mg/L in EFV1 at Weeks 0, 4, 8, and 17 was 96%, 96%, 88%, and 89%, respectively. In EFV2, at approximately 4 and 8 weeks post efavirenz initiation, the value was 98%., Conclusions: TB treatment containing high-dose daily rifapentine modestly decreased (rather than increased) efavirenz clearance and therapeutic targets were met supporting the use of efavirenz with these regimens, without dose adjustment., Clinical Trials Registration: NCT02410772., Competing Interests: Potential conflicts of interest. The authorship team members have declared (below or attached) any potential conflicts of interest with respect to the research, authorship, and/or publication of this article. Sanofi commercial interests did not influence the study design; the collection, analysis, or interpretation of data; the preparation of this manuscript; or the decision to submit this manuscript for publication. A Sanofi technical expert served on the protocol team. N. M. reports a grant to the institution for pneumonia research from Pfizer and a subaward to collect specimens to validate a TB diagnostic from Roche. L. M. reports grants or contracts from Merck Sharpe & Dohme (institution received clinical trial fees), ViiV Healthcare (institution received clinical trial fees), Kowa Pharmaceuticals America (pharmaceutical support on protocol), and Sanofi-Aventis (pharmaceutical support on protocol) outside of the submitted work. S. S. reports research grant support to the institution from ViiV Healthcare outside of the submitted work and support for attending meetings and/or travel from the National Institutes of Health (NIH). C. V. F. reports being a member of the Safety Monitoring Committee for Division of Microbiology and Infectious Diseases (DMID), NIAID, NIH, for 2 protocols on (1) an influenza virus challenge study and (2) a safety and pharmacokinetics of single doses of an antifungal, VT-1598 (no payments are made to institution or personally for service on this SMC). R. E. C. reports consulting fees from Sanofi. U. L. reports funding support for travel to ACTG Annual Network Meeting from AIDS Clinical Trials Group. A. A. V. reports working with a group at CDC that perform TB trials. The group has collaborated with pharmaceutical partners. Sanofi collaborated in Study 31/A5349 and provided support for testing PK of TB drugs, and provided drugs for the trial. All other authors report no potential conflicts. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed., (© The Author(s) 2021. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.)