Randomized Controlled Trial of Clinical Guidelines Versus Interactive Decision-Support for Improving Medical Trainees' Confidence with Latent Tuberculosis Care.

BACKGROUND: In order to eliminate tuberculosis (TB) in the USA, primary care providers must take on an expanded role in the diagnosis and management of latent tuberculosis infection (LTBI). Clinical practice guidelines and recommendations exist for LTBI management, but there is a need for innovative tools to improve medical students' and residents' knowledge of evidence-based practices for LTBI testing and treatment. OBJECTIVE: To assess the impact of LTBI-ASSIST, a free online decision support aid, as a novel educational tool and mechanism of delivering clinical practice guidelines for medical trainees. DESIGN: A single site, randomized controlled trial of trainees delivered by electronic survey. INTERVENTIONS: Medical students and Internal Medicine residents at the Johns Hopkins University School of Medicine. PARTICIPANTS: Participants were randomized in 1:1 ratio to receive the US clinical practice guidelines and recommendations for Latent TB management (control arm) or the guidelines plus an introduction to LTBI-ASSIST (LTBI-ASSIST arm) as they completed a case-based knowledge assessment and reported confidence with domains of LTBI care. MAIN MEASURES: (1) Proportion of questions answered correctly on a case-based knowledge assessment; (2) change in reported confidence with domains of LTBI care. KEY RESULTS: One hundred and thirty participants completed the knowledge assessment. Those randomized to receive the LTBI-ASSIST Tool performed better on the case-based knowledge assessment with a mean score of 75.9% (95% CI: 70.6-81.1), compared to 57.4% (52.8-62.0) in the group that received the guidelines only (p <0.001). Similarly, the LTBI-ASSIST group reported a higher change in confidence (measured as post-assessment confidence minus pre-assessment confidence), compared to the control group, in six of the seven domains of LTBI care. CONCLUSIONS: LTBI-ASSIST can be an effective supplement to existing guidelines in educating medical trainees and helping providers find evidence-based, guideline-supported answers for questions encountered in clinical practice. TRIAL REGISTRATION: NIH Clinical Trial Registry No. NCT05772065.

Potential Effects of the Coronavirus Disease 2019 (COVID-19) Pandemic on Human Immunodeficiency Virus (HIV) Transmission: A Modeling Study in 32 US Cities.

BACKGROUND: The degree to which the 2019 novel coronavirus disease (COVID-19) pandemic will affect the US human immunodeficiency virus (HIV) epidemic is unclear. METHODS: We used the Johns Hopkins Epidemiologic and Economic Model to project HIV infections from 2020 to 2025 in 32 US metropolitan statistical areas (MSAs). We sampled a range of effects of the pandemic on sexual transmission (0-50% reduction), viral suppression among people with HIV (0-40% reduction), HIV testing (0-50% reduction), and pre-exposure prophylaxis use (0-30% reduction), and indexed reductions over time to Google Community Mobility Reports. RESULTS: Simulations projected reported diagnoses would drop in 2020 and rebound in 2021 or 2022, regardless of underlying incidence. If sexual transmission normalized by July 2021 and HIV care normalized by January 2022, we projected 1161 (1%) more infections from 2020 to 2025 across all 32 cities than if COVID-19 had not occurred. Among "optimistic" simulations in which sexual transmission was sharply reduced and viral suppression was maintained we projected 8% lower incidence (95% credible interval: 14% lower to no change). Among "pessimistic" simulations where sexual transmission was largely unchanged but viral suppression fell, we projected 11% higher incidence (1-21% higher). MSA-specific projections are available at www.jheem.org?covid. CONCLUSIONS: The effects of COVID-19 on HIV transmission remain uncertain and differ between cities. Reported diagnoses of HIV in 2020-2021 are likely to correlate poorly with underlying incidence. Minimizing disruptions to HIV care is critical to mitigating negative effects of the COVID-19 pandemic on HIV transmission.

Evaluation of the Latent Tuberculosis Care Cascade Among Public Health Clinics in the United States.

BACKGROUND: Tuberculosis (TB) elimination within the United States will require scaling up TB preventive services. Many public health departments offer care for latent tuberculosis infection (LTBI), although gaps in the LTBI care cascade are not well quantified. An understanding of these gaps will be required to design targeted public health interventions. METHODS: We conducted a cohort study through the Tuberculosis Epidemiologic Studies Consortium (TBESC) within 15 local health department (LHD) TB clinics across the United States. Data were abstracted on individuals receiving LTBI care during 2016-2017 through chart review. Our primary objective was to quantify the LTBI care cascade, beginning with LTBI testing and extending through treatment completion. RESULTS: Among 23 885 participants tested by LHDs, 46% (11 009) were male with a median age of 31 (interquartile range [IQR] 20-46). A median of 35% of participants were US-born at each site (IQR 11-78). Overall, 16 689 (70%) received a tuberculin skin test (TST), 6993 (29%) received a Quantiferon (QFT), and 1934 (8%) received a T-SPOT.TB; 5% (1190) had more than one test. Among those tested, 2877 (12%) had at least one positive test result (3% among US-born, and 23% among non-US-born, P < .01). Of 2515 (11%) of the total participants diagnosed with LTBI, 1073 (42%) initiated therapy, of whom 817 (76%) completed treatment (32% of those with LTBI diagnosis). CONCLUSIONS: Significant gaps were identified along the LTBI care cascade, with less than half of individuals diagnosed with LTBI initiating therapy. Further research is needed to better characterize the factors impeding LTBI diagnosis, treatment initiation, and treatment completion.

Tuberculosis treatment adherence in the era of COVID-19.

BACKGROUND: In-person directly observed therapy (DOT) is commonly used for tuberculosis (TB) treatment monitoring in the US, with increasing usage of video-DOT (vDOT). We evaluated the impact of COVID-19 on TB treatment adherence, and utilization and effectiveness of vDOT. METHODS: We abstracted routinely collected data on individuals treated for TB disease in Baltimore, Maryland between April 2019 and April 2021. Our primary outcomes were to assess vDOT utilization and treatment adherence, defined as the proportion of prescribed doses (7 days/week) verified by observation (in-person versus video-DOT), comparing individuals in the pre-COVID and COVID (April 2020) periods. RESULTS: Among 52 individuals with TB disease, 24 (46%) received treatment during the COVID-19 pandemic. vDOT utilization significantly increased in the COVID period (18/24[75%]) compared to pre-COVID (12/28[43%], p = 0.02). Overall, median verified adherence was similar pre-COVID and COVID periods (65% versus 68%, respectively, p = 0.96). Adherence was significantly higher overall when using vDOT (median 86% [IQR 70-98%]) compared to DOT (median 59% [IQR 55-64%], p < 0.01); this improved adherence with vDOT was evident in both the pre-COVID (median 98% vs. 58%, p < 0.01) and COVID period (median 80% vs. 62%, p = 0.01). CONCLUSION: vDOT utilization increased during the COVID period and was more effective than in-person DOT at verifying ingestion of prescribed treatment.

What Will It Take to End HIV in the United States? : A Comprehensive, Local-Level Modeling Study.

BACKGROUND: The Ending the HIV Epidemic (EHE) initiative aims to reduce incident HIV infections by 90% over a span of 10 years. The intensity of interventions needed to achieve this for local epidemics is unclear. OBJECTIVE: To estimate the effect of HIV interventions at the city level. DESIGN: A compartmental model of city-level HIV transmission stratified by age, race, sex, and HIV risk factor was developed and calibrated. SETTING: 32 priority metropolitan statistical areas (MSAs). PATIENTS: Simulated populations in each MSA. INTERVENTION: Combinations of HIV testing and preexposure prophylaxis (PrEP) coverage among those at risk for HIV, plus viral suppression in persons with diagnosed HIV infection. MEASUREMENTS: The primary outcome was the projected reduction in incident cases from 2020 to 2030. RESULTS: Absent intervention, HIV incidence was projected to decrease by 19% across all 32 MSAs. Modest increases in testing (1.25-fold per year), PrEP coverage (5 percentage points), and viral suppression (10 percentage points) across the population could achieve reductions of 34% to 67% by 2030. Twenty-five percent PrEP coverage, testing twice a year on average, and 90% viral suppression among young Black and Hispanic men who have sex with men (MSM) achieved similar reductions (13% to 68%). Including all MSM and persons who inject drugs could reduce incidence by 48% to 90%. Thirteen of 32 MSAs could achieve greater than 90% reductions in HIV incidence with large-scale interventions that include heterosexuals. A web application with location-specific results is publicly available (www.jheem.org). LIMITATION: The COVID-19 pandemic was not represented. CONCLUSION: Large reductions in HIV incidence are achievable with substantial investment, but the EHE goals will be difficult to achieve in most locations. An interactive model that can help policymakers maximize the effect in their local environments is presented. PRIMARY FUNDING SOURCE: National Institutes of Health.

Using Innovation to Address Adolescent and Young Adult Health Disparities in Pelvic Inflammatory Disease: Design of the Technology Enhanced Community Health Precision Nursing (TECH-PN) Trial.

New approaches to pelvic inflammatory disease (PID) care among adolescents and young adults (AYAs) that optimize self-care and personalize treatment are warranted to address age and racial-ethnic PID-related health disparities. Here we describe the 13-month preliminary feasibility and acceptability outcomes of recruitment, retention, and intervention delivery for Technology Enhanced Community Health Precision Nursing (TECH-PN) randomized controlled trial. Urban AYAs 13-25 years assigned female sex at birth with acute mild-moderate PID provided baseline and follow-up interview data and vaginal specimens for sexually transmitted infection (STI), cytokine, and microbiota assessment. All participants received medications and text-messaging support. Participants were block randomized to either control or intervention. Control participants received 1 community nursing visit with self-management for interim care per national guidelines. Intervention participants received unlimited precision care services driven by interim STI and macrolide resistance testing results by an advanced practice provider. In the first 13 months, 75.2% patients were eligible, and 76.1% of eligible patients enrolled. Of the participants, 94% completed the intervention and 96%, 91%, and 89%, respectively, completed their 14-, 30-, and 90-day visits. Baseline laboratory results revealed infection rates that were highest for Mycoplasma genitalium (45%) followed by Chlamydia trachomatis (31%). Preliminary enrollment, STI, intervention delivery, and retention data demonstrate the feasibility and acceptability of the TECH-PN intervention and support rationale for precision care for PID among urban AYAs. ClinicalTrials.gov Identifier. NCT03828994.

New Strategies in Clinical Guideline Delivery: Randomized Trial of Online, Interactive Decision Support Versus Guidelines for Human Immunodeficiency Virus Treatment Selection by Trainees.

BACKGROUND: Support for clinicians in human immunodeficiency virus (HIV) medicine is critical given national HIV-provider shortages. The US Department of Health and Human Services (DHHS) guidelines are comprehensive but complex to apply for antiretroviral therapy (ART) selection. Human immunodeficiency virus antiretroviral selection support and interactive search tool (HIV-ASSIST) (www.hivassist.com) is a free tool providing ART decision support that could augment implementation of clinical practice guidelines. METHODS: We conducted a randomized study of medical trainees at Johns Hopkins University, in which participants were asked to select an ART regimen for 10 HIV case scenarios through an electronic survey. Participants were randomized to receive either DHHS guidelines alone, or DHHS guidelines and HIV-ASSIST to support their decision making. ART selections were graded "appropriate" if consistent with DHHS guidelines, or concordant with regimens selected by HIV experts at 4 academic institutions. RESULTS: Among 118 trainees, participants randomized to receive HIV-ASSIST had a significantly higher percentage of appropriate ART selections compared to those receiving DHHS guidelines alone (percentage of appropriate responses in DHHS vs HIV-ASSIST arms: median [Q1, Q3], 40% [30%, 50%] vs 90% [80%, 100%]; P < .001). The effect was seen for all case types, but most pronounced for complex cases involving ART-experienced patients with ongoing viremia (DHHS vs HIV-ASSIST: median [Q1, Q3], 0% [0%, 33%] vs 100% [66%, 100%]). CONCLUSIONS: Trainees using HIV-ASSIST were significantly more likely to choose appropriate ART regimens compared to those using guidelines alone. Interactive decision support tools may be important to ensure appropriate implementation of HIV guidelines. CLINICAL TRIALS REGISTRATION: NCT04080765.

Xpert Mycobacterium tuberculosis/Rifampicin-Detected Rifampicin Resistance is a Suboptimal Surrogate for Multidrug-resistant Tuberculosis in Eastern Democratic Republic of the Congo: Diagnostic and Clinical Implications.

BACKGROUND: Rifampicin (RIF) resistance is highly correlated with isoniazid (INH) resistance and used as proxy for multidrug-resistant tuberculosis (MDR-TB). Using MTBDRplus as a comparator, we evaluated the predictive value of Xpert MTB/RIF (Xpert)-detected RIF resistance for MDR-TB in eastern Democratic Republic of the Congo (DRC). METHODS: We conducted a cross-sectional study involving data from new or retreatment pulmonary adult TB cases evaluated between July 2013 and December 2016. Separate, paired sputa for smear microscopy and MTBDRplus were collected. Xpert testing was performed subject to the availability of Xpert cartridges on sample remnants after microscopy. RESULTS: Among 353 patients, 193 (54.7%) were previously treated and 224 (63.5%) were MTBDRplus TB positive. Of the 224, 43 (19.2%) were RIF monoresistant, 11 (4.9%) were INH monoresistant, 53 (23.7%) had MDR-TB, and 117 (52.2%) were RIF and INH susceptible. Overall, among the 96 samples detected by MTBDRplus as RIF resistant, 53 (55.2%) had MDR-TB. Xpert testing was performed in 179 (50.7%) specimens; among these, 163 (91.1%) were TB positive and 73 (44.8%) RIF resistant. Only 45/73 (61.6%) Xpert-identified RIF-resistant isolates had concomitant MTBDRplus-detected INH resistance. Xpert had a sensitivity of 100.0% (95% CI, 92.1-100.0) for detecting RIF resistance but a positive-predictive value of only 61.6% (95% CI, 49.5-72.8) for MDR-TB. The most frequent mutations associated with RIF and INH resistance were S531L and S315T1, respectively. CONCLUSIONS: In this high-risk MDR-TB study population, Xpert had low positive-predictive value for the presence of MDR-TB. Comprehensive resistance testing for both INH and RIF should be performed in this setting.

Impact of diagnostic strategies for tuberculosis using lateral flow urine lipoarabinomannan assay in people living with HIV.

BACKGROUND: Tuberculosis is the primary cause of hospital admission in people living with HIV, and the likelihood of death in the hospital is unacceptably high. The Alere Determine TB LAM Ag test (AlereLAM) is a point-of-care test and the only lateral flow lipoarabinomannan assay (LF-LAM) assay currently commercially available and recommended by the World Health Organization (WHO). A 2019 Cochrane Review summarised the diagnostic accuracy of LF-LAM for tuberculosis in people living with HIV. This systematic review assesses the impact of the use of LF-LAM (AlereLAM) on mortality and other patient-important outcomes. OBJECTIVES: To assess the impact of the use of LF-LAM (AlereLAM) on mortality in adults living with HIV in inpatient and outpatient settings. To assess the impact of the use of LF-LAM (AlereLAM) on other patient-important outcomes in adults living with HIV, including time to diagnosis of tuberculosis, and time to initiation of tuberculosis treatment. SEARCH METHODS: We searched the Cochrane Infectious Diseases Group Specialized Register; the Cochrane Central Register of Controlled Trials (CENTRAL); MEDLINE (PubMed); Embase (Ovid); Science Citation Index Expanded (Web of Science), BIOSIS Previews, Scopus, LILACS; ProQuest Dissertations and Theses; ClinicalTrials.gov; and the WHO ICTRP up to 12 March 2021. SELECTION CRITERIA: Randomized controlled trials that compared a diagnostic intervention including LF-LAM with diagnostic strategies that used smear microscopy, mycobacterial culture, a nucleic acid amplification test such as Xpert MTB/RIF, or a combination of these tests. We included adults (≥ 15 years) living with HIV. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed trials for eligibility, extracted data, and analysed risk of bias using the Cochrane tool for assessing risk of bias in randomized studies. We contacted study authors for clarification as needed. We used risk ratio (RR) with 95% confidence intervals (CI). We used a fixed-effect model except in the presence of clinical or statistical heterogeneity, in which case we used a random-effects model. We assessed the certainty of the evidence using GRADE. MAIN RESULTS: We included three trials, two in inpatient settings and one in outpatient settings. All trials were conducted in sub-Saharan Africa and assessed the impact of diagnostic strategies that included LF-LAM on mortality when the test was used in conjunction with other tuberculosis diagnostic tests or clinical assessment for clinical decision-making in adults living with HIV. Inpatient settings  In inpatient settings, the use of LF-LAM testing as part of a tuberculosis diagnostic strategy likely reduces mortality in people living with HIV at eight weeks compared to routine tuberculosis diagnostic testing without LF-LAM (pooled RR 0.85, 95% CI 0.76 to 0.94; 5102 participants, 2 trials; moderate-certainty evidence). That is, people living with HIV who received LF-LAM had 15% lower risk of mortality. The absolute effect was 34 fewer deaths per 1000 (from 14 fewer to 55 fewer). In inpatient settings, the use of LF-LAM testing as part of a tuberculosis diagnostic strategy probably results in a slight increase in the proportion of people living with HIV who were started on tuberculosis treatment compared to routine tuberculosis diagnostic testing without LF-LAM (pooled RR 1.26, 95% CI 0.94 to 1.69; 5102 participants, 2 trials; moderate-certainty evidence).  Outpatient settings In outpatient settings, the use of LF-LAM testing as part of a tuberculosis diagnostic strategy may reduce mortality in people living with HIV at six months compared to routine tuberculosis diagnostic testing without LF-LAM (RR 0.89, 95% CI 0.71 to 1.11; 2972 participants, 1 trial; low-certainty evidence). Although this trial did not detect a difference in mortality, the direction of effect was towards a mortality reduction, and the effect size was similar to that in inpatient settings.  In outpatient settings, the use of LF-LAM testing as part of a tuberculosis diagnostic strategy may result in a large increase in the proportion of people living with HIV who were started on tuberculosis treatment compared to routine tuberculosis diagnostic testing without LF-LAM (RR 5.44, 95% CI 4.70 to 6.29, 3022 participants, 1 trial; low-certainty evidence). Other patient-important outcomes Assessment of other patient-important and implementation outcomes in the trials varied. The included trials demonstrated that a higher proportion of people living with HIV were able to produce urine compared to sputum for tuberculosis diagnostic testing; a higher proportion of people living with HIV were diagnosed with tuberculosis in the group that received LF-LAM; and the incremental diagnostic yield was higher for LF-LAM than for urine or sputum Xpert MTB/RIF. AUTHORS' CONCLUSIONS: In inpatient settings, the use of LF-LAM as part of a tuberculosis diagnostic testing strategy likely reduces mortality and probably results in a slight increase in tuberculosis treatment initiation in people living with HIV. The reduction in mortality may be due to earlier diagnosis, which facilitates prompt treatment initiation. In outpatient settings, the use of LF-LAM testing as part of a tuberculosis diagnostic strategy may reduce mortality and may result in a large increase in tuberculosis treatment initiation in people living with HIV. Our results support the implementation of LF-LAM to be used in conjunction with other WHO-recommended tuberculosis diagnostic tests to assist in the rapid diagnosis of tuberculosis in people living with HIV.

Multicenter Study of the Accuracy of the BD MAX Multidrug-resistant Tuberculosis Assay for Detection of Mycobacterium tuberculosis Complex and Mutations Associated With Resistance to Rifampin and Isoniazid.

BACKGROUND: Tuberculosis (TB) control is hindered by absence of rapid tests to identify Mycobacterium tuberculosis (MTB) and detect isoniazid (INH) and rifampin (RIF) resistance. We evaluated the accuracy of the BD MAX multidrug-resistant (MDR)-TB assay (BD MAX) in South Africa, Uganda, India, and Peru. METHODS: Outpatient adults with signs/symptoms of pulmonary TB were prospectively enrolled. Sputum smear microscopy and BD MAX were performed on a single raw sputum, which was then processed for culture and phenotypic drug susceptibility testing (DST), BD MAX, and Xpert MTB/RIF (Xpert). RESULTS: 1053 participants with presumptive TB were enrolled (47% female; 32% with human immunodeficiency virus). In patients with confirmed TB, BD MAX sensitivity was 93% (262/282 [95% CI, 89-95%]); specificity was 97% (593/610 [96-98%]) among participants with negative cultures on raw sputa. BD MAX sensitivity was 100% (175/175 [98-100%]) for smear-positive samples (fluorescence microscopy), and 81% (87/107 [73-88%]) in smear-negative samples. Among participants with both BD MAX and Xpert, sensitivity was 91% (249/274 [87-94%]) for BD MAX and 90% (246/274 [86-93%]) for Xpert on processed sputa. Sensitivity and specificity for RIF resistance compared with phenotypic DST were 90% (9/10 [60-98%]) and 95% (211/222 [91-97%]), respectively. Sensitivity and specificity for detection of INH resistance were 82% (22/27 [63-92%]) and 100% (205/205 [98-100%]), respectively. CONCLUSIONS: The BD MAX MDR-TB assay had high sensitivity and specificity for detection of MTB and RIF and INH drug resistance and may be an important tool for rapid detection of TB and MDR-TB globally.

Evaluating the Concordance of Clinician Antiretroviral Prescribing Practices and HIV-ASSIST, an Online Clinical Decision Support Tool.

BACKGROUND: Individualized selection of antiretroviral (ARV) therapy is complex, considering drug resistance, comorbidities, drug-drug interactions, and other factors. HIV-ASSIST (www.hivassist.com) is a free, online tool that provides ARV decision support. HIV-ASSIST synthesizes patient and virus-specific attributes to rank ARV combinations based upon a composite objective of achieving viral suppression and maximizing tolerability. OBJECTIVE: To evaluate concordance of HIV-ASSIST recommendations with ARV selections of experienced HIV clinicians. DESIGN: Retrospective cohort study. PATIENTS: New and established patients at the Johns Hopkins Bartlett HIV Clinic and San Francisco Veterans Affairs HIV Clinic completing clinic visits were included. Chart reviews were conducted of the most recent clinic visit to generate HIV-ASSIST recommendations, which were compared to prescribed regimens. MAIN MEASURES: For each provider-prescribed regimen, we assessed its corresponding HIV-ASSIST "weighted score" (scale of 0 to 10 +, scores of < 2.0 are preferred), rank within HIV-ASSIST's ordered listing of ARV regimens, and concordance with the top five HIV-ASSIST ranked outputs. KEY RESULTS: Among 106 patients (16% female), 23 (22%) were ARV-naïve. HIV-ASSIST outputs for ARV-naïve patients were 100% concordant with prescribed regimens (median rank 1 [IQR 1-3], median weighted score 1.1 [IQR 1-1.2]). For 18 (17%) ARV-experienced patients with ongoing viremia, HIV-ASSIST outputs were 89% concordant with prescribed regimens (median rank 2 [IQR 1-3], median weighted score 1 [IQR 1-1.2]). For 65 (61.3%) patients that were suppressed on a current ARV regimen, HIV-ASSIST recommendations were concordant 88% of the time (median rank 1 [IQR 1-1], median weighted score 1.1 [IQR 1-1.6]). In 18% of cases, HIV-ASSIST weighted score suggested that the prescribed regimen would be considered "less preferred" (score > 2.0) than other available alternatives. CONCLUSION: HIV-ASSIST is an educational decision support tool that provides ARV recommendations concordant with experienced HIV providers from two major academic centers for a diverse set of patient scenarios.

Prevalence, Predictors, and Successful Treatment Outcomes of Xpert MTB/RIF-identified Rifampicin-resistant Tuberculosis in Post-conflict Eastern Democratic Republic of the Congo, 2012-2017: A Retrospective Province-Wide Cohort Study.

BACKGROUND: Multidrug-resistant tuberculosis (MDR-TB) jeopardizes global TB control. The prevalence and predictors of Rifampicin-resistant (RR) TB, a proxy for MDR-TB, and the treatment outcomes with standard and shortened regimens have not been assessed in post-conflict regions, such as the South Kivu province in the eastern Democratic Republic of the Congo (DRC). We aimed to fill this knowledge gap and to inform the DRC National TB Program. METHODS: of adults and children evaluated for pulmonary TB by sputum smear microscopy and Xpert MTB/RIF (Xpert) from February 2012 to June 2017. Multivariable logistic regression, Kaplan-Meier estimates, and multivariable Cox regression were used to assess independent predictors of RR-TB and treatment failure/death. RESULTS: Of 1535 patients Xpert-positive for TB, 11% had RR-TB. Independent predictors of RR-TB were a positive sputum smear (adjusted odds ratio [aOR] 2.42, 95% confidence interval [CI] 1.63-3.59), retreatment of TB (aOR 4.92, 95% CI 2.31-10.45), and one or more prior TB episodes (aOR 1.77 per episode, 95% CI 1.01-3.10). Over 45% of RR-TB patients had no prior TB history or treatment. The median time from Xpert diagnosis to RR-TB treatment initiation was 12 days (interquartile range 3-60.2). Cures were achieved in 30/36 (83%) and 84/114 (74%) of patients on 9- vs 20/24-month MDR-TB regimens, respectively (P = .06). Predictors of treatment failure/death were the absence of directly observed therapy (DOT; adjusted hazard ratio [aHR] 2.77, 95% CI 1.2-6.66) and any serious adverse drug event (aHR 4.28, 95% CI 1.88-9.71). CONCLUSIONS: Favorable RR-TB cure rates are achievable in this post-conflict setting with a high RR-TB prevalence. An expanded Xpert scale-up; the prompt initiation of shorter, safer, highly effective MDR-TB regimens; and treatment adherence support are critically needed to optimize outcomes.

Lateral flow urine lipoarabinomannan assay for detecting active tuberculosis in people living with HIV.

BACKGROUND: The lateral flow urine lipoarabinomannan (LF-LAM) assay Alere Determine™ TB LAM Ag is recommended by the World Health Organization (WHO) to help detect active tuberculosis in HIV-positive people with severe HIV disease. This review update asks the question, "does new evidence justify the use of LF-LAM in a broader group of people?", and is part of the WHO process for updating guidance on the use of LF-LAM. OBJECTIVES: To assess the accuracy of LF-LAM for the diagnosis of active tuberculosis among HIV-positive adults with signs and symptoms of tuberculosis (symptomatic participants) and among HIV-positive adults irrespective of signs and symptoms of tuberculosis (unselected participants not assessed for tuberculosis signs and symptoms).The proposed role for LF-LAM is as an add on to clinical judgement and with other tests to assist in diagnosing tuberculosis. SEARCH METHODS: We searched the Cochrane Infectious Diseases Group Specialized Register; MEDLINE, Embase, Science Citation Index, Web of Science, Latin American Caribbean Health Sciences Literature, Scopus, the WHO International Clinical Trials Registry Platform, the International Standard Randomized Controlled Trial Number Registry, and ProQuest, without language restriction to 11 May 2018. SELECTION CRITERIA: Randomized trials, cross-sectional, and observational cohort studies that evaluated LF-LAM for active tuberculosis (pulmonary and extrapulmonary) in HIV-positive adults. We included studies that used the manufacturer's recommended threshold for test positivity, either the updated reference card with four bands (grade 1 of 4) or the corresponding prior reference card grade with five bands (grade 2 of 5). The reference standard was culture or nucleic acid amplification test from any body site (microbiological). We considered a higher quality reference standard to be one in which two or more specimen types were evaluated for tuberculosis diagnosis and a lower quality reference standard to be one in which only one specimen type was evaluated. DATA COLLECTION AND ANALYSIS: Two review authors independently extracted data using a standardized form and REDCap electronic data capture tools. We appraised the quality of studies using the Quality Assessment of Diagnostic Accuracy Studies-2 (QUADAS-2) tool and performed meta-analyses to estimate pooled sensitivity and specificity using a bivariate random-effects model and a Bayesian approach. We analyzed studies enrolling strictly symptomatic participants separately from those enrolling unselected participants. We investigated pre-defined sources of heterogeneity including the influence of CD4 count and clinical setting on the accuracy estimates. We assessed the certainty of the evidence using the GRADE approach. MAIN RESULTS: We included 15 unique studies (nine new studies and six studies from the original review that met the inclusion criteria): eight studies among symptomatic adults and seven studies among unselected adults. All studies were conducted in low- or middle-income countries. Risk of bias was high in the patient selection and reference standard domains, mainly because studies excluded participants unable to produce sputum and used a lower quality reference standard.Participants with tuberculosis symptomsLF-LAM pooled sensitivity (95% credible interval (CrI) ) was 42% (31% to 55%) (moderate-certainty evidence) and pooled specificity was 91% (85% to 95%) (very low-certainty evidence), (8 studies, 3449 participants, 37% with tuberculosis).For a population of 1000 people where 300 have microbiologically-confirmed tuberculosis, the utilization of LF-LAM would result in: 189 to be LF-LAM positive: of these, 63 (33%) would not have tuberculosis (false-positives); and 811 to be LF-LAM negative: of these, 174 (21%) would have tuberculosis (false-negatives).By clinical setting, pooled sensitivity was 52% (40% to 64%) among inpatients versus 29% (17% to 47%) among outpatients; and pooled specificity was 87% (78% to 93%) among inpatients versus 96% (91% to 99%) among outpatients. Stratified by CD4 cell count, pooled sensitivity increased, and specificity decreased with lower CD4 cell count.Unselected participants not assessed for signs and symptoms of tuberculosisLF-LAM pooled sensitivity was 35% (22% to 50%), (moderate-certainty evidence) and pooled specificity was 95% (89% to 96%), (low-certainty evidence), (7 studies, 3365 participants, 13% with tuberculosis).For a population of 1000 people where 100 have microbiologically-confirmed tuberculosis, the utilization of LF-LAM would result in: 80 to be LF-LAM positive: of these, 45 (56%) would not have tuberculosis (false-positives); and 920 to be LF-LAM negative: of these, 65 (7%) would have tuberculosis (false-negatives).By clinical setting, pooled sensitivity was 62% (41% to 83%) among inpatients versus 31% (18% to 47%) among outpatients; pooled specificity was 84% (48% to 96%) among inpatients versus 95% (87% to 99%) among outpatients. Stratified by CD4 cell count, pooled sensitivity increased, and specificity decreased with lower CD4 cell count. AUTHORS' CONCLUSIONS: We found that LF-LAM has a sensitivity of 42% to diagnose tuberculosis in HIV-positive individuals with tuberculosis symptoms and 35% in HIV-positive individuals not assessed for tuberculosis symptoms, consistent with findings reported previously. Regardless of how people are enrolled, sensitivity is higher in inpatients and those with lower CD4 cell, but a concomitant lower specificity. As a simple point-of-care test that does not depend upon sputum evaluation, LF-LAM may assist with the diagnosis of tuberculosis, particularly when a sputum specimen cannot be produced.

Impact of Providing Preexposure Prophylaxis for Human Immunodeficiency Virus at Clinics for Sexually Transmitted Infections in Baltimore City: An Agent-based Model.

BACKGROUND: Preexposure prophylaxis (PrEP) greatly reduces the risk of human immunodeficiency virus (HIV) acquisition, but its optimal delivery strategy remains uncertain. Clinics for sexually transmitted infections (STIs) can provide an efficient venue for PrEP delivery. METHODS: To quantify the added value of STI clinic-based PrEP delivery, we used an agent-based simulation of HIV transmission among men who have sex with men (MSM). We simulated the impact of PrEP delivery through STI clinics compared with PrEP delivery in other community-based settings. Our primary outcome was the projected 20-year reduction in HIV incidence among MSM. RESULTS: Assuming PrEP uptake and adherence of 60% each, evaluating STI clinic attendees and delivering PrEP to eligible MSM reduced HIV incidence by 16% [95% uncertainty range, 14%-18%] over 20 years, an impact that was 1.8 (1.7-2.0) times as great as that achieved by evaluating an equal number of MSM recruited from the community. Comparing strategies where an equal number of MSM received PrEP in each strategy (ie, evaluating more individuals for PrEP in the community-based strategy, because MSM attending STI clinics are more likely to be PrEP eligible), the reduction in HIV incidence under the STI clinic-based strategy was 1.3 (1.3-1.4) times as great as that of community-based delivery. CONCLUSIONS: Delivering PrEP to MSM who attend STI clinics can improve efficiency and effectiveness. If high levels of adherence can be achieved in this population, STI clinics may be an important venue for PrEP implementation.

Challenges in the Evaluation of Interventions to Improve Engagement Along the HIV Care Continuum in the United States: A Systematic Review.

In the United States (US), there are high levels of disengagement along the HIV care continuum. We sought to characterize the heterogeneity in research studies and interventions to improve care engagement among people living with diagnosed HIV infection. We performed a systematic literature search for interventions to improve HIV linkage to care, retention in care, reengagement in care and adherence to antiretroviral therapy (ART) in the US published from 2007-mid 2015. Study designs and outcomes were allowed to vary in included studies. We grouped interventions into categories, target populations, and whether results were significantly improved. We identified 152 studies, 7 (5%) linkage studies, 33 (22%) retention studies, 4 (3%) reengagement studies, and 117 (77%) adherence studies. 'Linkage' studies utilized 11 different outcome definitions, while 'retention' studies utilized 39, with very little consistency in effect measurements. The majority (59%) of studies reported significantly improved outcomes, but this proportion and corresponding effect sizes varied substantially across study categories. This review highlights a paucity of assessments of linkage and reengagement interventions; limited generalizability of results; and substantial heterogeneity in intervention types, outcome definitions, and effect measures. In order to make strides against the HIV epidemic in the US, care continuum research must be improved and benchmarked against an integrated, comprehensive framework.

Cost-effectiveness of CRAG-LFA screening for cryptococcal meningitis among people living with HIV in Uganda.

BACKGROUND: Cryptococcal meningitis (CM) constitutes a significant source of mortality in resource-limited regions. Cryptococcal antigen (CRAG) can be detected in the blood before onset of meningitis. We sought to determine the cost-effectiveness of implementing CRAG screening using the recently developed CRAG lateral flow assay in Uganda compared to current practice without screening. METHODS: A decision-analytic model was constructed to compare two strategies for cryptococcal prevention among people living with HIV with CD4 < 100 in Uganda: No cryptococcal screening vs. CRAG screening with WHO-recommended preemptive treatment for CRAG-positive patients. The model was constructed to reflect primary HIV clinics in Uganda, with a cohort of HIV-infected patients with CD4 < 100 cells/uL. Primary outcomes were expected costs, DALYs, and incremental cost-effectiveness ratios (ICERs). We evaluated varying levels of programmatic implementation in secondary analysis. RESULTS: CRAG screening was considered highly cost-effective and was associated with an ICER of $6.14 per DALY averted compared to no screening (95% uncertainty range: $-20.32 to $36.47). Overall, implementation of CRAG screening was projected to cost $1.52 more per person, and was projected to result in a 40% relative reduction in cryptococcal-associated mortality. In probabilistic sensitivity analysis, CRAG screening was cost-effective in 100% of scenarios and cost saving (ie cheaper and more effective than no screening) in 30% of scenarios. Secondary analysis projected a total cost of $651,454 for 100% implementation of screening nationally, while averting 1228 deaths compared to no screening. CONCLUSION: CRAG screening for PLWH with low CD4 represents excellent value for money with the potential to prevent cryptococcal morbidity and mortality in Uganda.