Effectiveness of double-dose dolutegravir in people receiving rifampin-based tuberculosis treatment: an observational, cohort study of people with HIV from six countries.

BACKGROUND: Tenofovir-lamivudine-dolutegravir (TLD) is the preferred first-line antiretroviral therapy (ART) regimen. An additional 50 mg dose of dolutegravir (TLD + 50) is required with rifampin-containing tuberculosis (TB) co-treatment. There are limited data on the effectiveness of TLD + 50 in individuals with TB/HIV. METHODS: Prospective, observational cohort study at 12 sites in Haiti, Kenya, Malawi, South Africa, Uganda, Zimbabwe. Participants starting TLD and rifampin-containing TB treatment were eligible. Primary outcome was HIV-1 RNA ≤1000 copies/mL at end of TB treatment. FINDINGS: We enrolled 91 participants with TB/HIV: 75 (82%) ART-naïve participants starting TLD after a median 15 days on TB treatment, 10 (11%) ART-naïve participants starting TLD and TB treatment, 5 (5%) starting TB treatment after a median 3.3 years on TLD, and 1 (1%) starting TB treatment and TLD after changing from efavirenz/lamivudine/tenofovir. Median age was 37 years, 35% female, median CD4 count 120 cells/mm3 (IQR 50-295), 87% had HIV-1 RNA >1000 copies/mL. Two participants died during TB treatment. Among 89 surviving participants, 80 were followed to TB treatment completion, including 7 who had no HIV-1 RNA result due to missed visits. Primary virologic outcome was assessed in 73 participants, of whom 69 (95%, 95% CI 89-100%) had HIV-1 RNA ≤1000 copies/mL. No dolutegravir resistance mutations were detected among four participants with HIV-1 RNA >1000 copies/mL. INTERPRETATION: In routine programmatic settings, concurrent rifampin-containing TB treatment and TLD + 50 was feasible, well-tolerated, and achieved high rates of viral suppression in a cohort of predominantly ART-naïve people with TB/HIV.

Genotype-Phenotype Characterization of Serial Mycobacterium tuberculosis Isolates in Bedaquiline-Resistant Tuberculosis.

BACKGROUND: Emerging resistance to bedaquiline (BDQ) threatens to undermine advances in the treatment of drug-resistant tuberculosis (DRTB). Characterizing serial Mycobacterium tuberculosis (Mtb) isolates collected during BDQ-based treatment can provide insights into the etiologies of BDQ resistance in this important group of DRTB patients. METHODS: We measured mycobacteria growth indicator tube (MGIT)-based BDQ minimum inhibitory concentrations (MICs) of Mtb isolates collected from 195 individuals with no prior BDQ exposure who were receiving BDQ-based treatment for DRTB. We conducted whole-genome sequencing on serial Mtb isolates from all participants who had any isolate with a BDQ MIC >1 collected before or after starting treatment (95 total Mtb isolates from 24 participants). RESULTS: Sixteen of 24 participants had BDQ-resistant TB (MGIT MIC ≥4 µg/mL) and 8 had BDQ-intermediate infections (MGIT MIC = 2 µg/mL). Participants with pre-existing resistance outnumbered those with resistance acquired during treatment, and 8 of 24 participants had polyclonal infections. BDQ resistance was observed across multiple Mtb strain types and involved a diverse catalog of mmpR5 (Rv0678) mutations, but no mutations in atpE or pepQ. Nine pairs of participants shared genetically similar isolates separated by <5 single nucleotide polymorphisms, concerning for potential transmitted BDQ resistance. CONCLUSIONS: BDQ-resistant TB can arise via multiple, overlapping processes, including transmission of strains with pre-existing resistance. Capturing the within-host diversity of these infections could potentially improve clinical diagnosis, population-level surveillance, and molecular diagnostic test development.

1-Year Incidence of Tuberculosis Infection and Disease Among Household Contacts of Rifampin- and Multidrug-Resistant Tuberculosis.

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.

Modelling the impact of CD4 testing on mortality from TB and cryptococcal meningitis among patients with advanced HIV disease in nine countries.

INTRODUCTION: Despite antiretroviral therapy (ART) scale-up among people living with HIV (PLHIV), those with advanced HIV disease (AHD) (defined in adults as CD4 count <200 cells/mm3 or clinical stage 3 or 4), remain at high risk of death from opportunistic infections. The shift from routine baseline CD4 testing towards viral load testing in conjunction with "Test and Treat" has limited AHD identification. METHODS: We used official estimates and existing epidemiological data to project deaths from tuberculosis (TB) and cryptococcal meningitis (CM) among PLHIV-initiating ART with CD4 <200 cells/mm3 , in the absence of select World Health Organization recommended diagnostic or therapeutic protocols for patients with AHD. We modelled the reduction in deaths, based on the performance of screening/diagnostic testing and the coverage and efficacy of treatment/preventive therapies for TB and CM. We compared projected TB and CM deaths in the first year of ART from 2019 to 2024, with and without CD4 testing. The analysis was performed for nine countries: South Africa, Kenya, Lesotho, Mozambique, Nigeria, Uganda, Zambia, Zimbabwe and the Democratic Republic of Congo. RESULTS: The effect of CD4 testing comes through increased identification of AHD and consequent eligibility for protocols for AHD prevention, diagnosis and management; algorithms for CD4 testing avert between 31% and 38% of deaths from TB and CM in the first year of ART. The number of CD4 tests required per death averted varies widely by country from approximately 101 for South Africa to 917 for Kenya. CONCLUSIONS: This analysis supports retaining baseline CD4 testing to avert deaths from TB and CM, the two most deadly opportunistic infections among patients with AHD. However, national programmes will need to weigh the cost of increasing CD4 access against other HIV-related priorities and allocate resources accordingly.

Factors associated with prevalent Mycobacterium tuberculosis infection and disease among adolescents and adults exposed to rifampin-resistant tuberculosis in the household.

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.

The association between comorbidities and coronavirus disease 2019 hospitalization among people with HIV differs by age.

OBJECTIVES: To determine whether factors associated with coronavirus disease 2019 (COVID-19) hospitalization among people with HIV (PWH) differ by age stratum. DESIGN: Retrospective cohort study. METHODS: All adult PWH with a positive SARS-CoV-2 PCR in a public safety-net health system between 1 March 2020 and 28 February 2021 and a Veterans Affairs Medical Center between 1 1 March 2020 and 15 November 2020 in Atlanta, Georgia were included. We performed multivariable logistic regression to determine demographic and clinical factors associated with COVID-19 hospitalization overall and stratified by age less than 50 and at least 50 years. RESULTS: Three hundred and sixty-five PWH (mean age 49 years, 74% cisgender male, 82% black) were included. Ninety-six percent were on antiretroviral therapy (ART), 87% had CD4 + T-cell count at least 200 cells/µl, and 89% had HIV-1 RNA less than 200 copies/ml. Overall, age [adjusted odds ratio (aOR) 95% confidence interval (CI) 1.07 (1.04-1.10)], later date of SARS-CoV-2 infection [aOR 0.997 (0.995-1.00)], heart disease [aOR 2.27 (1.06-4.85)], and history of hepatitis C virus (HCV) [aOR 2.59 (1.13-5.89)] were associated with COVID-19 hospitalization. Age-adjusted comorbidity burden was associated with 30% increased risk of hospitalization [aOR 1.30 (1.11-1.54)]. Among 168 PWH less than 50 years old, older age [aOR 1.09 (1.01-1.18)] and no ART use [aOR 40.26 (4.12-393.62)] were associated with hospitalization; age-adjusted comorbidity burden was not ( P  = 0.25). Among 197 PWH at least 50, older age [aOR 1.10 (1.04-1.16)], heart disease [aOR 2.45 (1.04-5.77)], history of HCV [aOR 3.52 (1.29-9.60)], and age-adjusted comorbidity burden [aOR 1.36 (1.12-1.66)] were associated with hospitalization. CONCLUSION: Comorbidity burden is more strongly associated with COVID-19 hospitalization among older, rather than younger, PWH. These findings may have important implications for risk-stratifying COVID-19 therapies and booster recommendations in PWH.

Case-Finding Strategies for Drug-Resistant Tuberculosis: Protocol for a Scoping Review.

BACKGROUND: Transmission of drug-resistant tuberculosis (DR-TB) is ongoing. Finding individuals with DR-TB and initiating treatment as early as possible is important to improve patient clinical outcomes and to break the chain of transmission to control the pandemic. To our knowledge systematic reviews assessing effectiveness, cost-effectiveness, acceptability, and feasibility of different case-finding strategies for DR-TB to inform research, policy, and practice have not been conducted, and it is unknown whether enough research exists to conduct such reviews. It is unknown whether case-finding strategies are similar for DR-TB and drug-susceptible TB and whether we can draw on findings from drug-susceptible reviews to inform decisions on case-finding strategies for DR-TB. OBJECTIVE: This protocol aims to describe the available literature on case-finding for DR-TB and to describe case-finding strategies. METHODS: We will screen systematic reviews, trials, qualitative studies, diagnostic test accuracy studies, and other primary research that specifically sought to improve DR-TB case detection. We will exclude studies that invited individuals seeking care for TB symptoms, those including individuals already diagnosed with TB, or laboratory-based studies. We will search the academic databases including MEDLINE, Embase, The Cochrane Library, Africa-Wide Information, CINAHL, Epistemonikos, and PROSPERO with no language or date restrictions. We will screen titles, abstracts, and full-text articles in duplicate. Data extraction and analyses will be performed using Excel (Microsoft Corp). RESULTS: We will provide a narrative report with supporting figures or tables to summarize the data. A systems-based logic model, developed from a synthesis of case-finding strategies for drug-susceptible TB, will be used as a framework to describe different strategies, resulting pathways, and enhancements of pathways. The search will be conducted at the end of 2021. Title and abstract screening, full text screening, and data extraction will be undertaken from January to June 2022. Thereafter, analysis will be conducted, and results compiled. CONCLUSIONS: This scoping review will chart existing literature on case-finding for DR-TB-this will help determine whether primary studies on effectiveness, cost-effectiveness, acceptability, and feasibility of different case-finding strategies for DR-TB exist and will help formulate potential questions for a systematic review. We will also describe case-finding strategies for DR-TB and how they fit into a model of case-finding pathways for drug-susceptible TB. This review has some limitations. One limitation is the diverse, inconsistent use of intervention terminology within the literature, which may result in missing relevant studies. Poor reporting of intervention strategies may also cause misunderstanding and misclassification of interventions. Lastly, case-finding strategies for DR-TB may not fit into a model developed from strategies for drug-susceptible TB. Nevertheless, such a situation will provide an opportunity to refine the model for future research. The review will guide further research to inform decisions on case-finding policies and practices for DR-TB. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/40009.

Estimating severe acute respiratory coronavirus virus 2 (SARS-CoV-2) seroprevalence from residual clinical blood samples, January-March 2021.

We describe severe acute respiratory coronavirus virus 2 (SARS-CoV-2) IgG seroprevalence and antigenemia among patients at a medical center in January-March 2021 using residual clinical blood samples. The overall seroprevalences were 17% by infection and 16% by vaccination. Spent or residual samples are a feasible alternative for rapidly estimating seroprevalence or monitoring trends in infection and vaccination.

Impact of the COVID-19 pandemic on TB services at ART programmes in low- and middle-income countries: a multi-cohort survey.

INTRODUCTION: COVID-19 stretched healthcare systems to their limits, particularly in settings with a pre-existing high burden of infectious diseases, including HIV and tuberculosis (TB). We studied the impact of COVID-19 on TB services at antiretroviral therapy (ART) clinics in low- and middle-income countries. METHODS: We surveyed ART clinics providing TB services in the International Epidemiology Databases to Evaluate AIDS (IeDEA) consortium in Africa and the Asia-Pacific until July 2021 (TB diagnoses until the end of 2021). We collected site-level data using standardized questionnaires. RESULTS: Of 46 participating ART clinics, 32 (70%) were in Africa and 14 (30%) in the Asia-Pacific; 52% provided tertiary care. Most clinics (85%) reported disrupted routine HIV care services during the pandemic, both in Africa (84%) and the Asia-Pacific (86%). The most frequently reported impacts were on staff (52%) and resource shortages (37%; protective clothing, face masks and disinfectants). Restrictions in TB health services were observed in 12 clinics (26%), mainly reduced access to TB diagnosis and postponed follow-up visits (6/12, 50% each), and restrictions in TB laboratory services (22%). Restrictions of TB services were addressed by dispensing TB drugs for longer periods than usual (7/12, 58%), providing telehealth services (3/12, 25%) and with changes in directly observed therapy (DOT) (e.g. virtual DOT, 3/12). The number of TB diagnoses at participating clinics decreased by 21% in 2020 compared to 2019; the decline was more pronounced in tertiary than primary/secondary clinics (24% vs. 12%) and in sites from the Asia-Pacific compared to Africa (46% vs. 14%). In 2021, TB diagnoses continued to decline in Africa (-8%) but not in the Asia-Pacific (+62%) compared to 2020. During the pandemic, new infection control measures were introduced or intensified at the clinics, including wearing face masks, hand sanitation and patient triage. CONCLUSIONS: The COVID-19 pandemic led to staff shortages, reduced access to TB care and delays in follow-up visits for people with TB across IeDEA sites in Africa and the Asia-Pacific. Increased efforts are needed to restore and secure ongoing access to essential TB services in these contexts.

Real-world use and outcomes of dolutegravir-containing antiretroviral therapy in HIV and tuberculosis co-infection: a site survey and cohort study in sub-Saharan Africa.

INTRODUCTION: Dolutegravir is being scaled up globally as part of antiretroviral therapy (ART), but for people with HIV and tuberculosis co-infection, its use is complicated by a drug-drug interaction with rifampicin requiring an additional daily dose of dolutegravir. This represents a disadvantage over efavirenz, which does not have a major drug-drug interaction with rifampicin. We sought to describe HIV clinic practices for prescribing concomitant dolutegravir and rifampicin, and characterize virologic outcomes among patients with tuberculosis co-infection receiving dolutegravir or efavirenz. METHODS: Within the four sub-Saharan Africa regions of the International epidemiology Databases to Evaluate AIDS consortium, we conducted a site survey (2021) and a cohort study (2015-2021). The cohort study used routine clinical data and included patients newly initiating or already receiving dolutegravir or efavirenz at the time of tuberculosis diagnosis. Patients were followed from tuberculosis diagnosis until viral suppression (<1000 copies/ml), a competing event (switching ART regimen; loss to program/death) or administrative censoring at 12 months. RESULTS: In the survey, 86 of 90 (96%) HIV clinics in 18 countries reported prescribing dolutegravir to patients who were receiving rifampicin as part of tuberculosis treatment, with 77 (90%) reporting that they use twice-daily dosing of dolutegravir, of which 74 (96%) reported having 50 mg tablets available to accommodate twice-daily dosing. The cohort study included 3563 patients in 11 countries, with 67% newly or recently initiating ART. Among patients receiving dolutegravir (n = 465), the cumulative incidence of viral suppression was 58.9% (95% confidence interval [CI]: 54.3-63.3%), switching ART regimen was 4.1% (95% CI: 2.6-6.2%) and loss to program/death was 23.4% (95% CI: 19.7-27.4%). Patients receiving dolutegravir had improved viral suppression compared with patients receiving efavirenz who had a tuberculosis diagnosis before site dolutegravir availability (adjusted subdistribution hazard ratio [aSHR]: 1.47, 95% CI: 1.28-1.68) and after site dolutegravir availability (aSHR 1.28, 95% CI: 1.08-1.51). CONCLUSIONS: At a programmatic level, dolutegravir was being widely prescribed in sub-Saharan Africa for people with HIV and tuberculosis co-infection with a dose adjustment for the drug-drug interaction with rifampicin. Despite this more complex regimen, our cohort study revealed that dolutegravir did not negatively impact viral suppression.

Nucleocapsid Antigenemia Is a Marker of Acute SARS-CoV-2 Infection.

Detecting severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is essential for diagnosis, treatment, and infection control. Polymerase chain reaction (PCR) fails to distinguish acute from resolved infections, as RNA is frequently detected after infectiousness. We hypothesized that nucleocapsid in blood marks acute infection with the potential to enhance isolation and treatment strategies. In a retrospective serosurvey of inpatient and outpatient encounters, we categorized samples along an infection timeline using timing of SARS-CoV-2 testing and symptomatology. Among 1860 specimens from 1607 patients, the highest levels and frequency of antigenemia were observed in samples from acute SARS-CoV-2 infection. Antigenemia was higher in seronegative individuals and in those with severe disease. In our analysis, antigenemia exhibited 85.8% sensitivity and 98.6% specificity as a biomarker for acute coronavirus disease 2019 (COVID-19). Thus, antigenemia sensitively and specifically marks acute SARS-CoV-2 infection. Further study is warranted to determine whether antigenemia may aid individualized assessment of active COVID-19.

The Impact of Churn on HIV Outcomes in a Southern United States Clinical Cohort.

Background: Persons with human immunodeficiency virus (PWH) may experience a cycle of engaging and disengaging in care referred to as "churn." While human immunodeficiency virus (HIV) churn is predicted to be more prevalent in the southern United States (US), it has not been well characterized in this region. Methods: We conducted a retrospective cohort study involving PWH newly establishing care at a large urban clinic in Atlanta, Georgia, from 2012 to 2017, with follow-up data collected through 2019. The primary exposure was churn, defined as a ≥12-month gap between routine clinic visits or viral load (VL) measurements. We compared HIV metrics before and after churn and assessed the risk of future churn or loss to follow-up. Results: Of 1303 PWH newly establishing care, 81.7% were male and 84.9% were Black; 200 (15.3%) experienced churn in 3.3 years of median follow-up time. The transmissible viremia (TV) rate increased from 28.6% prechurn to 66.2% postchurn (P < .0001). The 122 PWH having TV on reengagement had delayed time to subsequent viral suppression (adjusted hazard ratio, 0.59 [95% confidence interval {CI}, .48-.73]), and PWH returning to care contributed disproportionately to the community viral load (CVL) (proportion of CVL/proportion of patients, 1.96). Churn was not associated with an increased risk of subsequent churn (adjusted odds ratio [aOR], 1.53 [95% CI, .79-2.97]) or loss to follow-up (aOR, 1.04 [95% CI, .60-1.79]). Conclusions: The rate of churn in a southern US clinic was high, and those who experienced churn had increased TV at reentry and disproportionately contributed to the CVL and likely contributing to ongoing HIV transmission.

High Prevalence of Tuberculosis Infection and Disease in Child Household Contacts of Adults With Rifampin-resistant Tuberculosis.

BACKGROUND: Household contact (HHC) investigation is an important strategy to identify individuals with tuberculosis (TB) exposure, infection and disease, including those who may benefit from tuberculosis preventive therapy (TPT). Data in children exposed to rifampin-resistant TB are limited. METHODS: In preparation for and to inform the feasibility of an interventional trial, HHC of adults with pulmonary rifampin-resistant TB from high TB-burden countries were evaluated in a cross-sectional study. Using interferon-gamma release assay and study-specific and 2015 international consensus definitions of intrathoracic TB in children, we evaluated the prevalence and predictors of TB infection and disease in child (<15 years) HHCs. RESULTS: Of 303 child HHCs, median age (range) 7 years (0-14), 57% [95% confidence interval (CI): 50%-64%] had a positive interferon-gamma release assay result (TB infected). TB infection was associated with the index case smoking (P = 0.034), being the parent or sleeping in the same room (P = 0.002) and the child HHC being age ≥5 years and having attended school (P = 0.013). Four had study-defined confirmed TB and 9 had probable TB, a prevalence of 4.3% (95% CI: 2.6%-7.1%). Using the international consensus definitions, 4 had confirmed TB and 49 had unconfirmed TB, a prevalence of 17.2% (95% CI: 12.9%-22.4%). Twenty (7%) children had received TPT. CONCLUSIONS: The prevalence of TB infection and disease was high in child HHC exposed to rifampin-resistant TB. Few children had routinely received TPT. High-quality evidence is needed to inform strong recommendations for and access to TPT in children exposed to TB resistant to rifampin.

Patient Experiences with Telemedicine for HIV Care During the First COVID-19 Wave in Atlanta, Georgia.

We explored experiences with telemedicine among persons with HIV (PWH) during the first wave of the coronavirus disease 2019 (COVID-19) pandemic. A convenience sample of adults (>18 years) receiving care in an urban clinic in Atlanta were invited to participate. Patients completed a structured survey that assessed the usefulness, quality, satisfaction, and concerns with telemedicine services (telephone calls) received during the first wave of the COVID-19 pandemic (March-May 2020). Demographic, plasma HIV-1 RNA, and CD4+ T cell count data were obtained through medical chart abstraction. Bootstrapped t-tests and chi-square tests were used to examine differences in patient experiences by age, sex, and race. Of 406 PWH contacted, 101 completed the survey (median age 55 years, 84% men, 77% Black, 98% virally suppressed, median CD4 count 572 cells/µL). The main HIV care disruptions experienced were delays in follow-up visits (40%), difficulty getting viral load measured (35%), and difficulty accessing antiretroviral therapy (21%). Participant ratings for quality (median score 6.5/7), usefulness (median score 6.0/7), and satisfaction (median score 6.3/7) with telemedicine were high. However, 28% of patients expressed concerns about providers' ability to examine them and about the lack of laboratory tests. More women had concerns about providers' ability to examine them (92% vs. 50%, p = .005) and about the safety of their personal information (69% vs. 23%, p = .002) compared with men. No age or race differences were observed. Although PWH are generally satisfied with telephone-based telemedicine, concerns with its use were notable, particularly among women. Future HIV telemedicine models should address these.

Tuberculosis treatment within differentiated service delivery models in global HIV/TB programming.

INTRODUCTION: Providing more convenient and patient-centred options for service delivery is a priority within global HIV programmes. These efforts improve patient satisfaction and retention and free up time for providers to focus on new HIV diagnoses or severe illness. Recently, the coronavirus disease 2019 (COVID-19) pandemic precipitated expanded eligibility criteria for these differentiated service delivery (DSD) models to decongest clinics and protect patients and healthcare workers. This has resulted in dramatic scale-up of DSD for antiretroviral therapy, cotrimoxazole and tuberculosis (TB) preventive treatment. While TB treatment among people living with HIV (PLHIV) has traditionally involved frequent, facility-based management, TB treatment can also be adapted within DSD models. Such adaptations could include electronic tools to ensure appropriate clinical management, treatment support, adherence counselling and adverse event (AE) monitoring. In this commentary, we outline considerations for DSD of TB treatment among PLHIV, building on best practices from global DSD model implementation for HIV service delivery. DISCUSSION: In operationalizing TB treatment in DSD models, we consider the following: what activity is being done, when or how often it takes place, where it takes place, by whom and for whom. We discuss considerations for various programme elements including TB screening and diagnosis; medication dispensing; patient education, counselling and support; clinical management and monitoring; and reporting and recording. General approaches include multi-month dispensing for TB medications during intensive and continuation phases of treatment and standardized virtual adherence and AE monitoring. Lastly, we provide operational examples of TB treatment delivery through DSD models, including a conceptual model and an early implementation experience from Zambia. CONCLUSIONS: COVID-19 has catalysed the rapid expansion of differentiated patient-centred service delivery for PLHIV. Expanding DSD models to include TB treatment can capitalize on existing platforms, while providing high-quality, routine treatment, follow-up and patient education and empowerment.

TCA cycle remodeling drives proinflammatory signaling in humans with pulmonary tuberculosis.

The metabolic signaling pathways that drive pathologic tissue inflammation and damage in humans with pulmonary tuberculosis (TB) are not well understood. Using combined methods in plasma high-resolution metabolomics, lipidomics and cytokine profiling from a multicohort study of humans with pulmonary TB disease, we discovered that IL-1ß-mediated inflammatory signaling was closely associated with TCA cycle remodeling, characterized by accumulation of the proinflammatory metabolite succinate and decreased concentrations of the anti-inflammatory metabolite itaconate. This inflammatory metabolic response was particularly active in persons with multidrug-resistant (MDR)-TB that received at least 2 months of ineffective treatment and was only reversed after 1 year of appropriate anti-TB chemotherapy. Both succinate and IL-1ß were significantly associated with proinflammatory lipid signaling, including increases in the products of phospholipase A2, increased arachidonic acid formation, and metabolism of arachidonic acid to proinflammatory eicosanoids. Together, these results indicate that decreased itaconate and accumulation of succinate and other TCA cycle intermediates is associated with IL-1ß-mediated proinflammatory eicosanoid signaling in pulmonary TB disease. These findings support host metabolic remodeling as a key driver of pathologic inflammation in human TB disease.

Performance of GeneXpert MTB/RIF for Diagnosing Tuberculosis Among Symptomatic Household Contacts of Index Patients in South Africa.

BACKGROUND: We describe the performance of GeneXpert MTB/RIF (Xpert) for diagnosing tuberculosis (TB) among symptomatic household contacts (HHCs) of rifampicin-resistant and drug-sensitive index cases. METHODS: We conducted a cross-sectional study among HHCs of recently diagnosed (<2 weeks) smear-positive and Xpert-positive index cases in the Bojanala District, South Africa. The HHCs were screened for TB symptoms; persons with ≥1 TB symptom provided 1 sputum for smear microscopy, Xpert, and mycobacterial growth indicator tube (MGIT) culture. Diagnostic test performance of Xpert was determined using MGIT as the reference standard. RESULTS: From August 2013 to July 2015, 619 HHCs from 216 index cases were enrolled: 60.6% were female, median age was 22 years (interquartile range, 9-40), and 126 (20.4%) self-reported/tested human immunodeficiency virus positive. A total of 54.3% (336 of 619) of contacts had ≥1 TB symptom (cough, fever, night sweats, weight loss), 297 of 336 (88.4%) of which provided a sputum; 289 (97.3%) had complete testing and 271 were included in the analysis. In total, 42 (6.8%) of 619 HHCs had microbiologically confirmed TB. The MGIT identified 33 HHCs as positive for Mycobacterium tuberculosis; of these, 7 were positive on Xpert resulting in a sensitivity of 21.2% (95% confidence interval [CI], 9.0-38.9), specificity of 98.3% (95% CI, 95.6-99.5), positive predictive value of 63.6% (95% CI, 30.8-89.1), and negative predictive value of 90.0 (95% CI, 85.7-93.4). CONCLUSIONS: Among symptomatic HHCs investigated for TB, Xpert performed suboptimally compared with MGIT culture. The poor performance of Xpert for diagnosing TB suggests that a more sensitive test, such a Xpert Ultra or culture, may be needed to improve yield of contact investigation, where feasible.

Resistance to Mycobacterium tuberculosis Infection Among Household Contacts: A Multinational Study.

BACKGROUND: Some contacts of patients with tuberculosis remain negative on tests for tuberculosis infection, despite prolonged exposure, suggesting they might be resistant to Mycobacterium tuberculosis infection. The objective of this multinational study was to estimate the proportion of household contacts resistant to M. tuberculosis (resisters). METHODS: We conducted a longitudinal study enrolling index patients enrolled in treatment for pulmonary multidrug- or rifampin-resistant tuberculosis and their household contacts. Contacts were tested for tuberculosis infection with a tuberculin skin test (TST) and interferon-gamma release assay (IGRA) at baseline and after 1 year. Exposure was quantified based on index patients' infectiousness, index patient and household contact interaction, and age. We explored multiple definitions of resistance to tuberculosis infection by varying TST negativity cutoffs (0 vs <5 mm), classification of missing test results, and exposure level. RESULTS: In total, 1016 contacts were evaluated from 284 households; 572 contacts aged ≥5 years had TST and longitudinal IGRA results available. And 77 (13%) or 71 (12%) contacts were classified as resisters with a <5 mm or 0 mm TST threshold, respectively. Among 263 highly exposed contacts, 29 (11%) or 26 (10%) were classified as resisters using TST cutoffs of <5 mm and 0 mm, respectively. The prevalence of resisters did not differ substantially by sex, age, human immunodeficiency virus (HIV) coinfection, or comorbid conditions. CONCLUSIONS: At least 10% of household contacts can be classified as resistant to tuberculosis infection, depending on the definition used, including those with high exposure. Further studies to understand genetic or immunologic mechanisms underlying the resister phenotype may inform novel strategies for therapeutics and vaccines.

Drug susceptibility patterns of Mycobacterium tuberculosis from adults with multidrug-resistant tuberculosis and implications for a household contact preventive therapy trial.

BACKGROUND: Drug susceptibility testing (DST) patterns of Mycobacterium tuberculosis (MTB) from patients with rifampicin-resistant tuberculosis (RR-TB) or multidrug-resistant TB (MDR-TB; or resistant to rifampicin and isoniazid (INH)), are important to guide preventive therapy for their household contacts (HHCs). METHODS: As part of a feasibility study done in preparation for an MDR-TB preventive therapy trial in HHCs, smear, Xpert MTB/RIF, Hain MTBDRplus, culture and DST results of index MDR-TB patients were obtained from routine TB programs. A sputum sample was collected at study entry and evaluated by the same tests. Not all tests were performed on all specimens due to variations in test availability. RESULTS: Three hundred eight adults with reported RR/MDR-TB were enrolled from 16 participating sites in 8 countries. Their median age was 36 years, and 36% were HIV-infected. Routine testing on all 308 were confirmed as having RR-TB, but only 75% were documented as having MDR-TB. The majority of those not classified as having MDR-TB were because only rifampicin resistance was tested. At study entry (median 59 days after MDR-TB treatment initiation), 280 participants (91%) were able to produce sputum for the study, of whom 147 (53%) still had detectable MTB. All but 2 of these 147 had rifampicin DST done, with resistance detected in 89%. Almost half (47%) of the 147 specimens had INH DST done, with 83% resistance. Therefore, 20% of the 280 study specimens had MDR-TB confirmed. Overall, DST for second-line drugs were available in only 35% of the 308 routine specimens and 15% of 280 study specimens. CONCLUSIONS: RR-TB was detected in all routine specimens but only 75% had documented MDR-TB, illustrating the need for expanded DST beyond Xpert MTB/RIF to target preventive therapy for HHC.