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Thierry Wirth, Philip Supply, Stefan Niemann and colleagues analyze 4,987 Mycobacterium tuberculosis strains of the Beijing lineage isolated from 99 countries. They report whole-genome sequencing of 110 representative strains, characterize global population structure and reconstruct the evolutionary history of this lineage. Mycobacterium tuberculosis strains of the Beijing lineage are globally distributed and are associated with the massive spread of multidrug-resistant (MDR) tuberculosis in Eurasia. Here we reconstructed the biogeographical structure and evolutionary history of this lineage by genetic analysis of 4,987 isolates from 99 countries and whole-genome sequencing of 110 representative isolates. We show that this lineage initially originated in the Far East, from where it radiated worldwide in several waves. We detected successive increases in population size for this pathogen over the last 200 years, practically coinciding with the Industrial Revolution, the First World War and HIV epidemics. Two MDR clones of this lineage started to spread throughout central Asia and Russia concomitantly with the collapse of the public health system in the former Soviet Union. Mutations identified in genes putatively under positive selection and associated with virulence might have favored the expansion of the most successful branches of the lineage.

Drug resistance is a challenge for the global control of tuberculosis. We examined mortality in patients with tuberculosis from high-burden countries, according to concordance or discordance of results from drug susceptibility testing done locally and in a reference laboratory. This multicentre cohort study was done in Côte d'Ivoire, Democratic Republic of the Congo, Kenya, Nigeria, South Africa, Peru, and Thailand. We collected Mycobacterium tuberculosis isolates and clinical data from adult patients aged 16 years or older. Patients were stratified by HIV status and tuberculosis drug resistance. Molecular or phenotypic drug susceptibility testing was done locally and at the Swiss National Center for Mycobacteria, Zurich, Switzerland. We examined mortality during treatment according to drug susceptibility test results and treatment adequacy in multivariable logistic regression models adjusting for sex, age, sputum microscopy, and HIV status. We obtained M tuberculosis isolates from 871 patients diagnosed between 2013 and 2016. After exclusion of 237 patients, 634 patients with tuberculosis were included in this analysis; the median age was 33·2 years (IQR 26·9–42·5), 239 (38%) were women, 272 (43%) were HIV-positive, and 69 (11%) patients died. Based on the reference laboratory drug susceptibility test, 394 (62%) strains were pan-susceptible, 45 (7%) monoresistant, 163 (26%) multidrug-resistant (MDR), and 30 (5%) had pre-extensively or extensively drug resistant (pre-XDR or XDR) tuberculosis. Results of reference and local laboratories were concordant for 513 (81%) of 634 patients and discordant for 121 (19%) of 634. Overall, sensitivity to detect any resistance was 90·8% (95% CI 86·5–94·2) and specificity 84·3% (80·3–87·7). Mortality ranged from 6% (20 of 336) in patients with pan-susceptible tuberculosis treated according to WHO guidelines to 57% (eight of 14) in patients with resistant strains who were under-treated. In logistic regression models, compared with concordant drug susceptibility test results, the adjusted odds ratio of death was 7·33 (95% CI 2·70–19·95) for patients with discordant results potentially leading to under-treatment. Inaccurate drug susceptibility testing by comparison with a reference standard leads to under-treatment of drug-resistant tuberculosis and increased mortality. Rapid molecular drug susceptibility test of first-line and second-line drugs at diagnosis is required to improve outcomes in patients with MDR tuberculosis and pre-XDR or XDR tuberculosis. National Institutes of Allergy and Infectious Diseases, Swiss National Science Foundation, Swiss National Center for Mycobacteria.

Tuberculosis (TB) mortality declined in the northern hemisphere over the last 200 years, but peaked during the Russian (1889) and the Spanish (1918) influenza pandemics. We studied the impact of these two pandemics on TB mortality. We retrieved historic data from mortality registers for the city of Bern and countrywide for Switzerland. We used Poisson regression models to quantify the excess pulmonary TB (PTB) mortality attributable to influenza. Yearly PTB mortality rates increased during both influenza pandemics. Monthly influenza and PTB mortality rates peaked during winter and early spring. In Bern, for an increase of 100 influenza deaths (per 100,000 population) monthly PTB mortality rates increased by a factor of 1.5 (95%Cl 1.4-1.6, p<0.001) during the Russian, and 3.6 (95%Cl 0.7-18.0, p = 0.13) during the Spanish pandemic. Nationally, the factor was 2.0 (95%Cl 1.8-2.2, p<0.001) and 1.5 (95%Cl 1.1-1.9, p = 0.004), respectively. We did not observe any excess cancer or extrapulmonary TB mortality (as a negative control) during the influenza pandemics. We demonstrate excess PTB mortality during historic influenza pandemics in Switzerland, which supports a role for influenza vaccination in PTB patients in high TB incidence countries.

Timely descriptions of HIV service characteristics and their evolution over time across diverse settings are important for monitoring the scale-up of evidence-based program strategies, understanding the implementation landscape, and examining service delivery factors that influence HIV care outcomes. The International epidemiology Databases to Evaluate AIDS (IeDEA) consortium undertakes periodic cross-sectional surveys on service availability and care at participating HIV treatment sites to characterize trends and inform the scientific agenda for HIV care and implementation science communities. IeDEA's 2020 general site assessment survey was developed through a consultative, 18-month process that engaged diverse researchers in identifying content from previous surveys that should be retained for longitudinal analyses and in developing expanded and new content to address gaps in the literature. An iterative review process was undertaken to standardize the format of new survey questions and align them with best practices in survey design and measurement and lessons learned through prior IeDEA site assessment surveys. The survey questionnaire developed through this process included eight content domains covered in prior surveys (patient population, staffing and community linkages, HIV testing and diagnosis, new patient care, treatment monitoring and retention, routine HIV care and screening, pharmacy, record-keeping and patient tracing), along with expanded content related to antiretroviral therapy (differentiated service delivery and roll-out of dolutegravir-based regimens); mental health and substance use disorders; care for pregnant/postpartum women and HIV-exposed infants; tuberculosis preventive therapy; and pediatric/adolescent tuberculosis care; and new content related to Kaposi's sarcoma diagnostics, the impact of COVID-19 on service delivery, and structural barriers to HIV care. The survey was distributed to 238 HIV treatment sites in late 2020, with a 95% response rate. IeDEA's approach for site survey development has broad relevance for HIV research networks and other priority health conditions.

Background Tuberculosis (TB) affects people’s quality of life (QoL). We prospectively monitored physical and mental health-related QoL over time in people with TB in the Southern African region with a high HIV and TB burden. Methods Adults aged ≥ 15 years with pulmonary TB were enrolled in five cohorts in Malawi, Mozambique, South Africa, Zambia, and Zimbabwe from October 2022 to September 2024. We assessed six QoL outcomes using validated instruments at the start (baseline), end of treatment, and 6 months post-treatment: symptoms of depression (PHQ-9), mental and physical health (SF-12 mental, SF12-MC, SF-12 physical component, SF12-PC), physical fitness (6-Minute Walk Test, 6MWT; 1-min Sit-To-Stand Test, STST), and respiratory health (Saint-George-Respiratory-Questionnaire, SGRQ). Missing QoL scores were imputed with multivariate imputation by chained equations. We compared the proportion of participants with impaired QoL, defining impairment based on outcome-specific cut-off values. We also estimated changes in QoL scores and examined their associations with baseline characteristics using Bayesian multivariable regression models. Results We included 1438 participants with a median follow-up of 344 days (interquartile range [IQR] 183–373). The median age was 39 years (IQR 30–50); 67% were male, and 39% living with HIV. At baseline, 49% had symptoms of depression, 73% had impaired mental health and 92% impaired physical health-related QoL, 68–74% had reduced physical fitness (68%: 6MWT, 74%: STST), and 78% impaired respiratory health. All QoL outcomes improved by the end of treatment, notably depressive symptoms (48% to 5%), mental health-related QoL (73% to 28%), and respiratory health (78% to 11%). Most QoL impairments continued to decrease post-treatment, especially physical and respiratory health; depressive symptoms remained below 5%. Across QoL domains and study visits, better outcomes were associated with age < 30 (83% probability), and worse outcomes with female gender (86%) and a prior TB history (89%). Living with HIV and alcohol drinking were associated with worse QoL only at baseline (88% and 87%). Conclusions TB negatively impacts QoL across physical, mental, and social domains, including post-treatment. The study highlights the need for integrated mental and physical healthcare and rehabilitation during TB treatment and beyond, especially for high-risk populations, to address the long-term impact of TB on QoL.

In settings with high tuberculosis (TB) endemicity, distinct genotypes of the Mycobacterium tuberculosis complex (MTBC) often differ in prevalence. However, the factors leading to these differences remain poorly understood. Here we studied the MTBC population in Dar es Salaam, Tanzania over a six-year period, using 1,082 unique patient-derived MTBC whole-genome sequences (WGS) and associated clinical data. We show that the TB epidemic in Dar es Salaam is dominated by multiple MTBC genotypes introduced to Tanzania from different parts of the world during the last 300 years. The most common MTBC genotypes deriving from these introductions exhibited differences in transmission rates and in the duration of the infectious period, but little differences in overall fitness, as measured by the effective reproductive number. Moreover, measures of disease severity and bacterial load indicated no differences in virulence between these genotypes during active TB. Instead, the combination of an early introduction and a high transmission rate accounted for the high prevalence of L3.1.1, the most dominant MTBC genotype in this setting. Yet, a longer co-existence with the host population did not always result in a higher transmission rate, suggesting that distinct life-history traits have evolved in the different MTBC genotypes. Taken together, our results point to bacterial factors as important determinants of the TB epidemic in Dar es Salaam.

Introduction Increasing evidence indicates the benefits of patient and public involvement (PPI) in medical research, and PPI is increasingly expected by funders and publishers. We conducted a mapping review of studies reporting examples of PPI implementation in HIV research, and developed an online evidence map to guide HIV researchers. Methods We systematically searched Medline and Embase up until 18 August 2024, including search terms with variations for PPI and HIV. We extracted information from identified studies in duplicate and analysed the data descriptively and qualitatively to describe types of PPI models and reported benefits, challenges, and mitigation strategies. This study was co‐initiated and co‐led by people living with HIV. Results We identified 17 studies reporting PPI in HIV research between 1992 and August 2024. Most PPI examples informed prospective clinical studies, but also qualitative research, questionnaire development, research priority setting and surveys. Ten studies described the number and characteristics of PPI members involved. We observed four PPI models, from a model that solely engaged PPI members for a specific task to a model whereby PPI representatives were integrated into the study team with decision‐making authority. Benefits reported included wider dissemination of research results, better understanding of research material and results, and higher levels of trust and learning between researcher and communities. The most commonly reported challenges were the lack of specific resources for PPI, differing levels of knowledge and expertise, concern about HIV status disclosure, and lack of diversity of the PPI team. Uneven power dynamics, tensions, and differing expectations between stake‐holder groups were also frequently noted. Conclusions This mapping review summarizes published examples of PPI in HIV research for various phases of research. There is a clear need to strengthen the reporting on PPI processes in HIV research, for example by following the Guidance for Reporting Involvement of Patients and the Public (GRIPP) 2 guidelines, and developing guidance on its hands‐on implementation. We embedded PPI from study inception onwards, which potentially pre‐empted some of the challenges reported in the reviewed examples. The resulting online evidence map is a starting point to guide researchers on integrating PPI into their own research.

IntroductionAnti-retroviral therapy (ART) simplification strategies are needed for treatment-experienced people with HIV (PWH) and multidrug-resistant viruses. These individuals are commonly treated with boosted ART regimens and are thereby at risk for harmful drug-drug interactions (DDI). In this trial, we aim to assess the efficacy of the combination doravirine, dolutegravir and lamivudine (DOR/DTG/3TC) among people with a history of virological failure who receive boosted ART.Methods and analysisB-Free is a multistage, randomised, multicentre, open-label, non-inferiority trial, embedded within the Swiss HIV Cohort Study and conducted in collaboration with cohorts of PWH in the Netherlands and France. Cohort participants with a history of ART change due to virologic failure and who maintain HIV virologic suppression with an ART regimen consisting of a pharmacological booster and at least two drugs from classes other than nucleoside reverse transcriptase inhibitors are included. Patients with major drug resistance mutations against DTG or DOR and individuals with chronic hepatitis B virus infection are not eligible for the study. Individuals are randomised 1:1 to either receiving co-formulated DTG/3TC and DOR once daily or continuing their boosted ART regimen. The primary outcome is the proportion of individuals lacking virologic control (HIV-RNA ≥50 cp/mL) at 48 weeks, according to the Food and Drug Administration snapshot algorithm. Changes in DDI burden (assessed using a DDI score), treatment satisfaction (assessed using the HIV Treatment Satisfaction Questionnaire), quality of life and mental health represent key secondary outcomes. Additional secondary outcomes include the proportion of individuals developing new resistance-associated mutations and changes in quality of life and mental health. In a qualitative substudy, we will conduct semistructured interviews with a subset of participants to assess their expectations and experiences towards HIV treatment and clinical research in general. Enrolling 210 individuals will provide 80% power to demonstrate non-inferiority, defined as less than 8% absolute increase in loss of viral suppression in individuals randomised to DOR/DTG/3TC (one-sided type I error rate of 0.025).Ethics and disseminationThe study was approved by the competent ethics committees (reference number BASEC 2023–01060) and the regulatory authority Swissmedic (reference number 701655) in Switzerland before the enrolment of the first participant. Approval by the European Medicines Agency and local ethical committees in the Netherlands and France will be obtained prior to including participants in these countries. Participant’s written informed consent is obtained by the investigators before enrolment. The results of all major B-Free study outcomes will be submitted to peer-reviewed journals that enable Open Access publication.Trial registration numberSwiss National Clinical Trials Portal (SNCTP000005686, registered on 06 November 2023) and Clinicaltrials.gov (NCT06037564, registered on 07 September 2023).

IntroductionTuberculosis (TB) is a leading infectious cause of death globally. It is the most common opportunistic infection in people living with HIV, and the most common cause of their morbidity and mortality. Following TB treatment, surviving individuals may be at risk for post-TB lung disease. The TB Sentinel Research Network (TB-SRN) provides a platform for coordinated observational TB research within the International epidemiology Databases to Evaluate AIDS (IeDEA) consortium.Methods and analysisThis prospective, observational cohort study will assess treatment and post-treatment outcomes of pulmonary TB (microbiologically confirmed or clinically diagnosed) among 2600 people aged ≥15 years, with and without HIV coinfection, consecutively enrolled at 16 sites in 11 countries, across 6 of IeDEA’s global regions. Data regarding clinical and sociodemographic factors, mental health, health-related quality of life, pulmonary function, and laboratory and radiographic findings will be collected using standardised questionnaires and data collection tools, beginning from the initiation of TB treatment and through 12 months after the end of treatment. Data will be aggregated for proposed analyses.Ethics and disseminationEthics approval was obtained at all implementing study sites, including the Vanderbilt University Medical Center Human Research Protections Programme. Participants will provide informed consent; for minors, this includes both adolescent assent and the consent of their parent or primary caregiver. Protections for vulnerable groups are included, in alignment with local standards and considerations at sites. Procedures for requesting use and analysis of TB-SRN data are publicly available. Findings from TB-SRN analyses will be shared with national TB programmes to inform TB programming and policy, and disseminated at regional and global conferences and other venues.

Introduction In 2016, the World Health Organization recommended differentiated service delivery (DSD) as a client‐centred approach to simplify HIV care in frequency and intensity, thus reducing the clinic visit burden on individuals and HIV programmes. We describe the scale of DSD implementation among HIV facilities in low‐ and middle‐income countries (LMICs) in Latin America, Africa and the Asia‐Pacific before the COVID‐19 pandemic. Methods We analysed facility‐level survey data from HIV care facilities participating in the International epidemiology Databases to Evaluate AIDS consortium in 2019. We used descriptive statistics to summarise the availability of DSD, multi‐month dispensing (MMD) and DSD for HIV treatment models. We explored factors associated with DSD implementation using multivariable models. Results We included 175 facilities in the Asia‐Pacific (n = 30), Latin America (n = 8), Central Africa (n = 21), East Africa (n = 74), Southern Africa (n = 28) and West Africa (n = 14). Overall, 133 facilities (76%) reported implementing DSD. Of these, 91% offered DSD for HIV treatment, 61% for HIV testing and 59% for antiretroviral therapy (ART) initiation. The most common duration of ART refills for clinically stable clients was 3MMD, (70%), followed by monthly (14%) and 6MMD (10%). Facility‐based individual models were the most frequently available DSD for the HIV treatment model (82%), followed by client‐managed group models (60%). Out‐of‐facility individual models were available at 48% of facilities. Facility‐based individual models were particularly common among facilities in East (92%) and Southern Africa (96%). Facilities in medium and high HIV prevalence countries, and those with 3MMD, were more likely to implement DSD. Conclusions In 2019, DSD was available in most HIV care facilities globally but was not evenly implemented across regions and HIV services. Most offered facility‐based DSD for HIV treatment models and 3MMD for clinically stable clients. Efforts to expand DSD for HIV testing and ART initiation and to offer longer MMD can improve long‐term retention in care of people living with HIV in LMICs, while further alleviating the operational burden on healthcare services. These findings from the pre‐COVID‐19 era underline the need for strengthening DSD in HIV care, which remains at the centre of current efforts towards client‐centred care.