Treatment of Drug-Resistant Tuberculosis. An Official ATS/CDC/ERS/IDSA Clinical Practice Guideline.

Background: The American Thoracic Society, U.S. Centers for Disease Control and Prevention, European Respiratory Society, and Infectious Diseases Society of America jointly sponsored this new practice guideline on the treatment of drug-resistant tuberculosis (DR-TB). The document includes recommendations on the treatment of multidrug-resistant TB (MDR-TB) as well as isoniazid-resistant but rifampin-susceptible TB.Methods: Published systematic reviews, meta-analyses, and a new individual patient data meta-analysis from 12,030 patients, in 50 studies, across 25 countries with confirmed pulmonary rifampin-resistant TB were used for this guideline. Meta-analytic approaches included propensity score matching to reduce confounding. Each recommendation was discussed by an expert committee, screened for conflicts of interest, according to the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) methodology.Results: Twenty-one Population, Intervention, Comparator, and Outcomes questions were addressed, generating 25 GRADE-based recommendations. Certainty in the evidence was judged to be very low, because the data came from observational studies with significant loss to follow-up and imbalance in background regimens between comparator groups. Good practices in the management of MDR-TB are described. On the basis of the evidence review, a clinical strategy tool for building a treatment regimen for MDR-TB is also provided.Conclusions: New recommendations are made for the choice and number of drugs in a regimen, the duration of intensive and continuation phases, and the role of injectable drugs for MDR-TB. On the basis of these recommendations, an effective all-oral regimen for MDR-TB can be assembled. Recommendations are also provided on the role of surgery in treatment of MDR-TB and for treatment of contacts exposed to MDR-TB and treatment of isoniazid-resistant TB.

The RNA chaperone La promotes pre-tRNA maturation via indiscriminate binding of both native and misfolded targets.

Non-coding RNAs have critical roles in biological processes, and RNA chaperones can promote their folding into the native shape required for their function. La proteins are a class of highly abundant RNA chaperones that contact pre-tRNAs and other RNA polymerase III transcripts via their common UUU-3'OH ends, as well as through less specific contacts associated with RNA chaperone activity. However, whether La proteins preferentially bind misfolded pre-tRNAs or instead engage all pre-tRNA substrates irrespective of their folding status is not known. La deletion in yeast is synthetically lethal when combined with the loss of tRNA modifications predicted to contribute to the native pre-tRNA fold, such as the N2, N2-dimethylation of G26 by the methyltransferase Trm1p. In this work, we identify G26 containing pre-tRNAs that misfold in the absence of Trm1p and/or La (Sla1p) in Schizosaccharomyces pombe cells, then test whether La preferentially associates with such tRNAs in vitro and in vivo. Our data suggest that La does not discriminate a native from misfolded RNA target, and highlights the potential challenges faced by RNA chaperones in preferentially binding defective substrates.

Bridging populations-sexual risk behaviors and HIV prevalence in clients and partners of female sex workers, Bangkok, Thailand 2007.

The aim of this study is to estimate HIV prevalence and assess sexual behaviors in a high-risk and difficult-to-reach population of clients of female sex workers (FSWs). A modified variation of respondent-driven sampling was conducted among FSWs in Bangkok, where FSWs recruited 3 FSW peers, 1 client, and 1 nonpaying partner. After informed consent was obtained, participants completed a questionnaire, were HIV-tested, and were asked to return for results. Analyses were weighted to control for the design of the survey. Among 540 FSWs, 188 (35%) recruited 1 client, and 88 (16%) recruited 1 nonpaying partner. Clients' median age was 38 years. HIV prevalence was 20% and was associated with younger age at first sexual experience [relative risk (RR) = 3.10, 95% confidence interval (CI) 1.16-8.24] and condom use during last sexual encounter with regular partner (RR = 3.97, 95% CI 1.09-14.61). Median age of nonpaying partners was 34 years, and HIV prevalence was 15.1%. There were 56 discordant FSW-client pairs and 14 discordant FSW-nonpaying partner pairs. Condom use was relatively high among discordant FSW-client pairs (90.1%) compared to discordant FSW-nonpaying partner pairs (18.7%). Results suggest that sexual partners of FSWs have a high HIV prevalence and can be a bridge for HIV transmission to other populations. Findings also highlight the importance of initiating surveillance and targeted programs for FSW partners, and demonstrate a recruitment method for hard-to-reach populations.

Introduction and evaluation of multidrug-resistant tuberculosis supplemental surveillance in the United States.

The current tuberculosis (TB) case reporting system for the United States, the Report of Verified Case of TB (RVCT), has minimal capture of multidrug-resistant (MDR) TB treatment and adverse events. Data were abstracted in five states using the form for 13 MDR TB patients during 2012-2015. The Centers for Disease Control and Prevention Guidelines for Evaluating Public Health Surveillance Systems were used to evaluate attributes of the form. Unstructured interviews with pilot sites and stakeholders provided qualitative feedback. The form was acceptable, simple, stable, representative, and provided high-quality data but was not flexible or timely. For the 13 patients on whom data were collected, the median duration of treatment with an injectable medication was 216 days (IQR 203-252). Six (46%) patients reported a side effect requiring a medication change and eight (62%) had a side effect present at treatment completion. A standardized MDR TB supplemental surveillance form was well received by stakeholders whose feedback was critical to making modifications. The finalized form will be implemented nationally in 2020 and will provide MDR TB treatment and morbidity data in the United States to help ensure patients with MDR TB receive the most effective treatment regimens with the least toxic drugs.

Estimating False-Recent Classification for the Limiting-Antigen Avidity EIA and BED-Capture Enzyme Immunoassay in Vietnam: Implications for HIV-1 Incidence Estimates.

Laboratory tests that can distinguish recent from long-term HIV infection are used to estimate HIV incidence in a population, but can potentially misclassify a proportion of long-term HIV infections as recent. Correct application of an assay requires determination of the proportion false recents (PFRs) as part of the assay characterization and for calculating HIV incidence in a local population using a HIV incidence assay. From April 2009 to December 2010, blood specimens were collected from HIV-infected individuals attending nine outpatient clinics (OPCs) in Vietnam (four from northern and five from southern Vietnam). Participants were living with HIV for ≥1 year and reported no antiretroviral (ARV) drug treatment. Basic demographic data and clinical information were collected. Specimens were tested with the BED capture enzyme immunoassay (BED-CEIA) and the Limiting-antigen (LAg)-Avidity EIA. PFR was estimated by dividing the number of specimens classified as recent by the total number of specimens; 95% confidence intervals (CI) were calculated. Specimens that tested recent had viral load testing performed. Among 1,813 specimens (north, n = 942 and south, n = 871), the LAg-Avidity EIA PFR was 1.7% (CI: 1.2-2.4) and differed by region [north 2.7% (CI: 1.8-3.9) versus south 0.7% (CI: 0.3-1.5); p = .002]. The BED-CEIA PFR was 2.3% (CI: 1.7-3.0) and varied by region [north 3.4% (CI: 2.4-4.7) versus south 1.0% (CI: 0.5-1.2), p < .001]. Excluding specimens with an undetectable VL, the LAg-Avidity EIA PFR was 1.2% (CI: 0.8-1.9) and the BED-CEIA PFR was 1.7% (CI: 1.2-2.4). The LAg-Avidity EIA PFR was lower than the BED-CEIA PFR. After excluding specimens with an undetectable VL, the PFR for both assays was similar. A low PFR should facilitate the implementation of the LAg-Avidity EIA for cross-sectional incidence estimates in Vietnam.

Treatment of Active Tuberculosis in Chicago, 2008-2011: The Role of Public Health Departments.

OBJECTIVE: Evaluate differences in TB outcomes among different provider types in Chicago, IL. METHODS: We retrospectively reviewed all TB cases reported to the Chicago Department of Public Health (CDPH) from 2008 through 2011. Provider type was stratified into three groups: public, public-private, and private providers. Multivariate regression was used to evaluate treatment duration and time to sputum culture conversion. A Cox proportional hazard model was used to assess treatment completion. RESULTS: Of 703 cases, 203 (28.9%), 314 (44.7%), and 186 (26.5%) were treated by public, public-private and private providers, respectively. Adjusted regression showed private provider patients had a 48-day (95% CI 22.0-74.3) increase in treatment duration and a 30-day (95% C.I. 9.5-51.1) increase in time to sputum culture conversion. Cox model showed increased risk of remaining on treatment was associated with extra-pulmonary TB (aHR 0.78, 95% C.I. 0.62-0.98), being foreign-born (aHR 0.74, 95% C.I. 0.58-0.95), and any drug resistance (aHR 0.59, 95% C.I. 0.46-0.76). There were no differences in outcomes between public and public-private providers. CONCLUSION: Patients treated solely in the private sector had prolonged time to sputum culture conversion and treatment duration which lead to increased cost for treatment, prolonged infectiousness, potential for transmission, and the possibility for increased medication side effects.

Clinical Impact on Tuberculosis Treatment Outcomes of Discordance Between Molecular and Growth-Based Assays for Rifampin Resistance, California 2003-2013.

Background. Data from international settings suggest that isolates of Mycobacterium tuberculosis with rpoB mutations testing phenotypically susceptible to rifampin (RIF) may have clinical significance. We analyzed treatment outcomes of California patients with discordant molecular-phenotypic RIF results. Methods. We included tuberculosis (TB) patients, during 2003-2013, whose specimens tested RIF susceptible phenotypically but had a rpoB mutation determined by pyrosequencing. Demographic data were abstracted from the California TB registry. Phenotypic drug-susceptibility testing, medical history, treatment, and outcomes were abstracted from medical records. Results. Of 3330 isolates tested, 413 specimens had a rpoB mutation (12.4%). Of these, 16 (3.9%) had molecular-phenotypic discordant RIF results. Seven mutations were identified: 511Pro, 516Phe, 526Asn, 526Ser (AGC and TCC), 526Cys, and 533Pro. Fourteen (88%) had isoniazid (INH) resistance, 6 of whom were also phenotypically resistant to ethambutol (EMB) and/or pyrazinamide (PZA). Five patients (25%), 1 with 511Pro and 4 with 526Asn, relapsed or failed treatment. The initial regimen for 3 patients was RIF, PZA, and EMB; 1 patient received RIF, PZA, EMB, and a fluoroquinolone (FQN); and 1 patient received RIF, EMB, FQN, and some second-line medications. Upon retreatment with an expanded regimen, 3 (75%) patients completed treatment, 1 patient moved before treatment completion, and 1 patient continues on treatment. The remaining 11 patients had a successful outcome with 9 having received a FQN and/or a rifamycin. Conclusions. Rifampin molecular-phenotypic discordance was rare, and most isolates had INH resistance. Patients who did not receive an expanded regimen had poor outcomes. These mutations may have clinical importance, and expanded treatment regimens should be considered.

Completion Rate and Side-Effect Profile of Three-Month Isoniazid and Rifapentine Treatment for Latent Tuberculosis Infection in an Urban County Jail.

In an urban jail population, 3 months of isoniazid and rifapentine (3HP) was associated with an 85% latent tuberculosis infection treatment completion rate compared with 18% in a standard 9-month isoniazid treatment group. Among the 91 patients who started 3HP therapy, there were 2 treatment discontinuations from adverse drug reactions.

Performance and comparison of self-reported STI symptoms among high-risk populations - MSM, sex workers, persons living with HIV/AIDS - in El Salvador.

Resource-limited countries have limited laboratory capability and rely on syndromic management to diagnose sexually transmitted infections (STIs). We aimed to estimate the sensitivity, specificity and positive predictive value (PPV) of STI syndromic management when used as a screening method within a study setting. Men who have sex with men (MSM), female sex workers (FSWs) and people living with HIV/AIDS (PLWHA) participated in a behavioural surveillance study. Data were obtained on demographics, sexual behaviours, STI history and service utilisation. Biological specimens were tested for genital inflammatory infections (Neisseria gonorrhoeae [GC], Chlamydia trachomatis [CT], Mycoplasma genitalium [MG], Trichomonas vaginalis [TV]) and genital ulcerative infection (syphilis and Herpes simplex virus-2). There was a high prevalence of Herpes simplex virus-2 (MSM 48.1%, FSW 82.0% and PLWHA 84.4%). Most participants reported no ulcerative symptoms and the majority of men reported no inflammatory symptoms. Sensitivity and PPV were poor for inflammatory infections among PLWHA and MSM. Sensitivity in FSWs for inflammatory infections was 75%. For ulcerative infections, sensitivity was poor, but specificity and PPV were high. Reliance on self-reported symptoms may not be an effective screening strategy for these populations. STI prevention studies should focus on symptom recognition and consider routine screening and referral for high-risk populations.

The effects of topical vitamin K on bruising after laser treatment.

BACKGROUND: Pulsed dye laser treatment and other cosmetic procedures result in significant bruising. Claims have been made regarding the efficacy of topical vitamin K in both preventing and speeding the clearing of bruising; however, well-controlled studies are lacking. OBJECTIVE: The purpose of this study is to evaluate the effects of topical vitamin K versus placebo in the prevention and clearing of laser-induced purpura. METHODS: A total of 22 patients were enrolled in this double-blind randomized placebo-controlled study. The patients were divided into pretreatment and posttreatment groups; the 11 patients in the former group applied vitamin K cream to half of their face and vehicle alone to the other half of their face twice daily for 2 weeks before laser treatment. The latter group followed the same procedure for 2 weeks after laser treatment. On day 0, all subjects underwent laser treatment for facial telangiectases using a 585-nm pulsed dye laser. Bruising was rated by the both the patient and physician by means of a visual analogue scale on days 0, 3, 7, 10, 14, and 17. RESULTS: The side of the face treated with topical vitamin K before laser therapy showed no significant difference in bruising as compared to placebo. However, the side of the face treated with vitamin K cream after laser treatment had significantly lower scores of bruising severity when compared with the side treated with placebo. CONCLUSION: Although pretreatment with vitamin K did not prevent bruising after laser treatment, use of vitamin K cream after laser treatment did reduce the severity of bruising, particularly in the initial days of application.