Publications by authors named "Charles Horsburgh"

16 Publications

  • Page 1 of 1

Prevalence and risk factors associated with latent tuberculosis infection among household contacts of smear positive pulmonary tuberculosis patients in South India.

Trop Med Int Health 2021 Dec 26;26(12):1645-1651. Epub 2021 Oct 26.

Department of Preventive & Social Medicine, JIPMER, Puducherry, India.

Objective: We aimed to determine the prevalence and find the risk factors associated with latent tuberculosis infection (LTBI) among the household contacts (HHC) of pulmonary TB patients.

Methods: This cohort study was conducted from 2014 to 2019. Pretested standardised questionnaires and tools were used for data collection. The prevalence of LTBI among HHCs of TB patients was summarised as proportion with 95% confidence interval (CI). Mixed-effects generalised linear modelling function (meglm) in STATA with family Poisson and log link was performed to find the factors associated with LTBI.

Results: In total, 1523 HHC of pulmonary TB patients were included in the study. Almost all HHC shared their residence with the index case (IC) for more than a year; 25% shared the same bed with the IC. The prevalence of LTBI among the HHC of TB patients was 52.6% (95% CI: 50.1-55.1%). In an adjusted model, we found that among HHC belonging to the age group of 19-64 years (aIRR = 1.2; 95% CI: 1.1-1.3; p-value: 0.02), to the age group >65 years (aIRR = 1.4, 95% CI: 1.1-1.9, p-value: 0.02) and sharing the same bed with the IC (aIRR = 1.2, 95% CI: 1.1-1.3, p value: 0.04) were independent determinants of LTBI among the HHC.

Conclusion: One in two household contacts of TB patients have latent tuberculosis infection. This underscores the need of targeted contact screening strategies, effective contact tracing and testing using standardised methods in high TB burden settings.
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http://dx.doi.org/10.1111/tmi.13693DOI Listing
December 2021

Comparison of profile and treatment outcomes between elderly and non-elderly tuberculosis patients in Puducherry and Tamil Nadu, South India.

PLoS One 2021 27;16(8):e0256773. Epub 2021 Aug 27.

Department of Preventive & Social Medicine, JIPMER, Puducherry, India.

The rising geriatric population and the increased susceptibility of this age group to tuberculosis (TB), the deadliest single infectious agent, is bothersome for India. This study tried to explore the demographic and treatment outcome differences between the elderly (aged 60 years and above) and non-elderly TB (<60 years) patients from South India. This study was part of a large ongoing cohort study under the RePORT India consortium. Newly diagnosed TB patients recruited into the cohort between 2014 and 2018 were included in this study. Pretested and standardized questionnaire and tools were used to collect data and were stored securely for the entire cohort. Required demographic, anthropometric and treatment related variables were extracted from this database and analyzed using Stata version 14.0. Prevalence of elderly TB was summarized as percentage with 95% confidence interval (CI). Generalized linear modelling was attempted to find the factors associated with elderly TB. A total of 1,259 eligible TB patients were included into this present study. Mean (SD) of the participants in the elderly and non-elderly group was 65.8 (6.2) and 40.2 (12.0) respectively. Prevalence of elderly TB was 15.6% (95%CI: 13.6%-17.6%) with nearly 71% belonging to 60-69 age category. Male sex, OBC caste, poor education, unemployment, marriage, alcohol consumption and unable to work as per Karnofsky score were found to be significantly associated with an increased prevalence of elderly TB. Unfavorable outcomes (12% vs 6.5%, p value: 0.018), including death (9.3% vs 3.4%, p value: 0.001) were significantly higher among the elderly group when compared to their non-elderly counterparts. The current TB programme should have strategies to maintain follow up with due attention to adverse effects, social support and outcomes. Additional research should focus on predictors for unfavorable outcomes among the elderly TB group and explore ways to handle the same. Rendering adequate social support from the health system side and family side would be a good start.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0256773PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8396735PMC
August 2021

Antibiotics and fecundability among female pregnancy planners: a prospective cohort study.

Hum Reprod 2021 09;36(10):2761-2768

Department of Epidemiology, Boston University School of Public Health, Boston, MA, USA.

Study Question: To what extent is female preconception antibiotic use associated with fecundability?

Summary Answer: Preconception antibiotic use overall was not appreciably associated with fecundability.

What Is Known Already: Antibiotics are commonly used by women and are generally thought to be safe for use during pregnancy. However, little is known about possible effects of antibiotic use on fecundability, the per-cycle probability of conception. Previous research on this question has been limited to occupational rather than therapeutic exposure.

Study Design, Size, Duration: We analyzed data from an Internet-based preconception cohort study of 9524 female pregnancy planners aged 21-45 years residing in the USA and Canada who had been attempting to conceive for six or fewer cycles at study entry. Participants enrolled between June 2013 and September 2020 and completed baseline and bimonthly follow-up questionnaires for up to 12 months or until a reported pregnancy, whichever came first. The questions pertaining to antibiotic type and indication were added to the PRESTO questionnaires in March 2016.

Participants/materials, Setting, Methods: We assessed antibiotic use in the previous 4 weeks at baseline and on each follow-up questionnaire. Participants provided the name of the specific antibiotic and the indication for use. Antibiotics were classified based on active ingredient (penicillins, macrolides, nitrofurantoin, nitroimidazole, cephalosporins, sulfonamides, quinolones, tetracyclines, lincosamides), and indications were classified by type of infection (respiratory, urinary tract, skin, vaginal, pelvic, and surgical). Participants reported pregnancy status on follow-up questionnaires. We used proportional probabilities regression to estimate fecundability ratios (FR), the per-cycle probability of conception comparing exposed with unexposed individuals, and 95% confidence intervals (CI), adjusting for sociodemographics, lifestyle factors, and reproductive history.

Main Results And The Role Of Chance: Overall, women who used antibiotics in the past 4 weeks at baseline had similar fecundability to those who had not used antibiotics (FR: 0.98, 95% CI: 0.89-1.07). Sulfonamides and lincosamides were associated with slightly increased fecundability (FR: 1.39, 95% CI: 0.90-2.15, and FR: 1.58 95% CI: 0.96-2.60, respectively), while macrolides were associated with slightly reduced fecundability (FR: 0.70, 95% CI: 0.47-1.04). Analyses of the indication for antibiotic use suggest that there is likely some confounding by indication.

Limitations, Reasons For Caution: Findings were imprecise for some antibiotic classes and indications for use owing to small numbers of antibiotic users in these categories. There are likely heterogeneous effects of different combinations of indications and treatments, which may be obscured in the overall null results, but cannot be further elucidated in this analysis.

Wider Implications Of The Findings: There is little evidence that use of most antibiotics is associated with reduced fecundability. Antibiotics and the infections they treat are likely associated with fecundability through differing mechanisms, resulting in their association with increased fecundability in some circumstances and decreased fecundability in others.

Study Funding/competing Interest(s): This study was supported through funds provided by the Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health (R01-HD086742, R21-HD072326). L.A.W. has received in-kind donations from Swiss Precision Diagnostics, Sandstone Diagnostics, Fertility Friend, and Kindara for primary data collection in PRESTO. The other authors have no conflicts of interest to disclose.

Trial Registration Number: N/A.
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http://dx.doi.org/10.1093/humrep/deab173DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8581385PMC
September 2021

Directly Observed Therapy to Measure Adherence to Tuberculosis Medication in Observational Research: Protocol for a Prospective Cohort Study.

JMIR Res Protoc 2021 Jun 16;10(6):e24510. Epub 2021 Jun 16.

Section of Infectious Diseases, Boston Medical Center, Boston, MA, United States.

Background: A major challenge for prospective, clinical tuberculosis (TB) research is accurately defining a metric for measuring medication adherence.

Objective: We aimed to design a method to capture directly observed therapy (DOT) via mobile health carried out by community workers. The program was created specifically to measure TB medication adherence for a prospective TB cohort in Western Cape Province, South Africa.

Methods: Community workers collect daily adherence data on mobile smartphones. Participant-level adherence, program-level adherence, and program function are systematically monitored to assess DOT program implementation. A data dashboard allows for regular visualization of indicators. Numerous design elements aim to prevent or limit data falsification and ensure study data integrity.

Results: The cohort study is ongoing and data collection is in progress. Enrollment began on May 16, 2017, and as of January 12, 2021, a total of 236 participants were enrolled. Adherence data will be used to analyze the study's primary aims and to investigate adherence as a primary outcome.

Conclusions: The DOT program includes a mobile health application for data collection as well as a monitoring framework and dashboard. This approach has potential to be adapted for other settings to improve the capture of medication adherence in clinical TB research.

Trial Registration: Clinicaltrials.gov NCT02840877; https://clinicaltrials.gov/ct2/show/NCT02840877.
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http://dx.doi.org/10.2196/24510DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8277341PMC
June 2021

Alcohol and Tobacco Use in a Tuberculosis Treatment Cohort during South Africa's COVID-19 Sales Bans: A Case Series.

Int J Environ Res Public Health 2021 05 19;18(10). Epub 2021 May 19.

Section of Infectious Diseases, Department of Medicine, Boston Medical Center, Boston, MA 02119, USA.

Background: South Africa temporarily banned alcohol and tobacco sales for about 20 weeks during the COVID-19 lockdown. We described changes in alcohol and tobacco consumption after implementation of these restrictions among a small number of participants in a tuberculosis treatment cohort.

Method: The timeline follow-back procedure and Fägerstrom test for nicotine dependence was used to collect monthly alcohol and tobacco use information. We report changes in heavy drinking days (HDD), average amount of absolute alcohol (AA) consumed per drinking day, and cigarettes smoked daily during the alcohol and tobacco ban compared to use prior to the ban.

Results: Of the 61 participants for whom we have pre-ban and within-ban alcohol use information, 17 (27.9%) reported within-ban alcohol use. On average, participants reported one less HDD per fortnight (interquartile range (IQR): -4, 1), but their amount of AA consumed increased by 37.4 g per drinking occasion (IQR: -65.9 g, 71.0 g). Of 53 participants who reported pre-ban tobacco use, 17 (32.1%) stopped smoking during the ban. The number of participants smoking >10 cigarettes per day decreased from 8 to 1.

Conclusions: From these observations, we hypothesize that policies restricting alcohol and tobacco availability seem to enable some individuals to reduce their consumption. However, these appear to have little effect on the volume of AA consumed among individuals with more harmful patterns of drinking in the absence of additional behavior change interventions.
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http://dx.doi.org/10.3390/ijerph18105449DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8161406PMC
May 2021

Evaluation of factors influencing Mycobacterium tuberculosis complex recovery and contamination rates in MGIT960.

Indian J Tuberc 2020 Oct 19;67(4):466-471. Epub 2020 Jul 19.

Department of Microbiology, Jawaharlal Institute of Postgraduate Medical Education and Research (JIPMER), Pondicherry, India. Electronic address:

Background: Tuberculosis (TB) is a major public health problem worldwide. Contamination rate and poor recovery of Mycobacterium tuberculosis complex (MTBC) in MGIT960 culture may affect the early diagnosis of TB. Evidence is needed to determine the factors associated with contamination rates and MTBC recovery in MGIT960. Hence, we undertook this study to compare the factors influencing MTBC culture positivity and contamination rates in MGIT960 in patients with Pulmonary tuberculosis (PTB).

Methods: A total of 849 sputum samples from newly diagnosed smear-positive TB cases enrolled into the Regional Prospective Observational Research for Tuberculosis India cohort between May 2014 to March 2017 were analyzed. Samples were inoculated into MGIT960 and positive cultures were examined for the presence of MTBC by immunochromatographic test for detection of MPT64 antigen.

Results: Of the 849 cases, 811 (95.5%) were culture positive for MTBC, 23 (2.7%) were culture negative and 15 (1.8%) were contaminated. Salivary sputum showed significantly less culture yield compared to mucopurulent/blood stained samples (p = 0.021). Sputum from individuals <20 or ≥60 years showed lower culture yield of 93.9%, compared to those aged 20-59years (98.2%) (p = 0.002). Based on smear grading, culture isolation of MTBC by MGIT960 was 86.1%, 93.6% and 99.5% for negative, scanty and positive (1+/2+/3+) samples, respectively (p ≤ 0.0001). Sputum from HIV negative patients showed higher culture yield, compared to HIV positive patients (p ≤ 0.0001). Chest X-Ray revealed that patient with cavity showed higher culture isolation of MTBC compared to patients without cavity (p = 0.035). Contamination rates were higher in smear negatives (6.0%), compared to scanty (2.1%) and smear positives (1.1%) (p = 0.007). However, delay in transport of the specimen to the laboratory was the only independent factor significantly associated with increase in culture contamination.

Conclusion: Our results highlight that extremes of age, smear negativity, HIV infection, sputum quality and cavitation significantly influence the culture yield of MTBC, whereas transport duration and smear grading affected the contamination rates in MGIT960. Hence, addressing these factors may improve the diagnostic performance of MGIT960.
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http://dx.doi.org/10.1016/j.ijtb.2020.07.016DOI Listing
October 2020

Using Cure Models to Estimate the Serial Interval of Tuberculosis With Limited Follow-up.

Am J Epidemiol 2020 11;189(11):1421-1426

Serial interval (SI), defined as the time between symptom onset in an infector and infectee pair, is commonly used to understand infectious diseases transmission. Slow progression to active disease, as well as the small percentage of individuals who will eventually develop active disease, complicate the estimation of the SI for tuberculosis (TB). In this paper, we showed via simulation studies that when there is credible information on the percentage of those who will develop TB disease following infection, a cure model, first introduced by Boag in 1949, should be used to estimate the SI for TB. This model includes a parameter in the likelihood function to account for the study population being composed of those who will have the event of interest and those who will never have the event. We estimated the SI for TB to be approximately 0.5 years for the United States and Canada (January 2002 to December 2006) and approximately 2.0 years for Brazil (March 2008 to June 2012), which might imply a higher occurrence of reinfection TB in a developing country like Brazil.
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http://dx.doi.org/10.1093/aje/kwaa090DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7731991PMC
November 2020

Pediatric Multidrug-resistant Tuberculosis in Kyiv City, Ukraine.

J Epidemiol Glob Health 2019 03;9(1):56-61

Department of Medicine, The Miriam Hospital, Providence, RI, USA.

Few reports have described pediatric Multidrug-resistant Tuberculosis (MDR-TB) in the former Soviet republics, despite the fact that these countries have the highest proportion of TB cases that are MDR. We aimed to examine pediatric MDR-TB in Ukraine. This retrospective cohort study included all children <18 years of age who started undergoing MDR-TB treatment between January 1, 2011 and July 31, 2016 at Kyiv City Pediatric TB Hospital. From each child's clinical chart, we abstracted demographic and clinical data. Using Fisher's exact test, we compared characteristics between children with microbiologically confirmed vs. probable (i.e., clinically diagnosed) MDR-TB. The study population included 20 children with a median age of 5 years. At diagnosis, 12 (60%) had intrathoracic lymphadenopathy as their only radiographic abnormality, and two (10%) were asymptomatic. Children with confirmed MDR-TB were more likely to be adolescents or have radiologic abnormalities in addition to intrathoracic lymphadenopathy. Median treatment duration was 20 months. Eighteen (90%) children were treated successfully. The remaining two were transferred to another facility, and their final outcomes were unknown. The excellent outcomes in this cohort are consistent with high treatment success rates for pediatric MDR-TB reported in other parts of the world.
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http://dx.doi.org/10.2991/jegh.k.190225.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7024600PMC
March 2019

Brief Report: Assessing the Association Between Changing NRTIs When Initiating Second-Line ART and Treatment Outcomes.

J Acquir Immune Defic Syndr 2018 04;77(4):413-416

Center for Global Health and Development, Boston University, Boston, MA.

Background: After first-line antiretroviral therapy failure, the importance of change in nucleoside reverse transcriptase inhibitor (NRTI) in second line is uncertain due to the high potency of protease inhibitors used in second line.

Setting: We used clinical data from 6290 adult patients in South Africa and Zambia from the International Epidemiologic Databases to Evaluate AIDS (IeDEA) Southern Africa cohort.

Methods: We included patients who initiated on standard first-line antiretroviral therapy and had evidence of first-line failure. We used propensity score-adjusted Cox proportional-hazards models to evaluate the impact of change in NRTI on second-line failure compared with remaining on the same NRTI in second line. In South Africa, where viral load monitoring was available, treatment failure was defined as 2 consecutive viral loads >1000 copies/mL. In Zambia, it was defined as 2 consecutive CD4 counts <100 cells/mm.

Results: Among patients in South Africa initiated on zidovudine (AZT), the adjusted hazard ratio for second-line virologic failure was 0.25 (95% confidence interval: 0.11 to 0.57) for those switching to tenofovir (TDF) vs. remaining on AZT. Among patients in South Africa initiated on TDF, switching to AZT in second line was associated with reduced second-line failure (adjusted hazard ratio = 0.35 [95% confidence interval: 0.13 to 0.96]). In Zambia, where viral load monitoring was not available, results were less conclusive.

Conclusions: Changing NRTI in second line was associated with better clinical outcomes in South Africa. Additional clinical trial research regarding second-line NRTI choices for patients initiated on TDF or with contraindications to specific NRTIs is needed.
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http://dx.doi.org/10.1097/QAI.0000000000001611DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5825249PMC
April 2018

Latent Tuberculosis Infection Testing Practices in Long-Term Care Facilities, Boston, Massachusetts.

J Am Geriatr Soc 2017 Jun 3;65(6):1145-1151. Epub 2017 May 3.

Department of Epidemiology, School of Public Health, Boston University, Boston, Massachusetts.

Objectives: To describe latent tuberculosis infection (LTBI) testing practices in long-term care facilities (LTCFs).

Design: Retrospective cohort study.

Setting: Three Boston-area LTCFs.

Participants: Residents admitted between January 1 and December 31, 2011.

Measurements: Resident demographic characteristics, comorbidities, LTCF stay, and LTBI testing and treatment.

Results: Data for 291 LTCF residents admitted in 2011 were reviewed. Of the 257 without a history of LTBI and with documentation of testing, 162 (63%) were tested; 114 of 186 (61%) with a stay less than 90 days and 48 of 71 (68%) with a stay of 90 days or longer were tested. Of 196 residents with data on prior LTBI testing, 39 (19.9%) had LTBI; 12 of these (30.8%) were diagnosed at the LTCF. Hispanic participants were more likely than black participants to undergo LTBI testing (adjusted odds ratio (aOR) = 2.4, P = .003). Having a length of stay of less than 90 days (aOR = 0.7, P < .001) and history of illicit drug use (aOR = 0.7, P < .001) were associated with lower odds of LTBI testing.

Conclusion: One-fifth of LTCF residents had LTBI, but testing was not always performed. The high prevalence of LTBI in older adults combined with the risk of an outbreak if a case of tuberculosis occurs in a LTCF make LTBI testing and treatment an important prevention opportunity. The importance of LTBI testing in LTCFs needs to be reinforced.
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http://dx.doi.org/10.1111/jgs.14696DOI Listing
June 2017

Increased risk of active tuberculosis after cancer diagnosis.

J Infect 2017 06 31;74(6):590-598. Epub 2017 Mar 31.

Department of Clinical Epidemiology, Aarhus University Hospital, Aarhus, Denmark; Department of Epidemiology, Boston University School of Public Health, Boston, MA, USA.

Background: Cancer may increase risk of active tuberculosis but evidence is sparse. We therefore examined tuberculosis risk in patients with incident cancer using Danish nationwide medical databases.

Methods: We conducted a matched follow-up study comparing risk of active tuberculosis in cancer-exposed individuals to that in a general population comparison cohort, matched on gender, age, and country of origin, in different follow-up intervals using Cox regression.

Findings: We identified 290,944 patients with incident cancer and 871,147 matched comparison cohort members during 1 January, 2004-30 November, 2013. After adjusting for comorbidities, the overall adjusted hazard ratio (aHR) for tuberculosis among cancer patients was 2.48 (95% confidence interval [CI]: 1.99-3.10). The highest tuberculosis risks were observed following cancers of the aerodigestive tract (aHR = 8.12; 95% CI: 4.33-15.22), tobacco-related cancers (aHR = 5.01; 95% CI: 3.37-7.44), and hematological cancers (aHR = 4.88; 95% CI: 2.27-10.48). Tuberculosis risk was highly elevated within the first year after cancer diagnosis (aHR = 4.14; 95% CI: 2.88-5.96), with a 6.78-fold increased aHR for cancer patients receiving cytostatics or radiotherapy. Beyond five years of observation, the overall aHR for tuberculosis remained at 2.66 (95% CI: 1.22-5.81).

Interpretation: Cancer is a clinical predictor for increased risk of active tuberculosis, probably related to decreased infection barriers, immunosuppression, and shared risk factors.
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http://dx.doi.org/10.1016/j.jinf.2017.03.012DOI Listing
June 2017

Risk factors for postoperative pneumonia after lung cancer surgery and impact of pneumonia on survival.

Respir Med 2015 Oct 17;109(10):1340-6. Epub 2015 Jul 17.

Department of Clinical Epidemiology, Institute of Clinical Medicine, Aarhus University Hospital, Aarhus, Denmark.

Objective: Little is known about risk factors and prognosis for postoperative pneumonia (POP) in patients undergoing therapeutic lung cancer (LC) surgery.

Methods: We followed a nationwide population-based cohort of 7479 patients with LC surgery in Denmark 1995-2011. We used logistic regression analysis to examine risk factors for POP within 30 days after surgery. Subsequent survival in patients with POP was analyzed with Cox regression.

Results: We identified 268 (3.6%) patients with POP. Important risk factors included advanced age (age ≥80 years: (adjusted odds ratio [aOR] = 3.64; 95% CI: 2.17-6.12) as compared to patients aged 50-59 years), previous pneumonia (aOR = 2.68; 95% CI: 2.02-3.56), obesity (aOR = 1.91; 95% CI: 0.99-3.69), chronic pulmonary disease (aOR = 1.90; 95% CI: 1.40-2.57), alcoholism (aOR = 1.56; 95% CI: 0.81-3.01), and atrial fibrillation (aOR = 1.42; 95% CI: 0.82-2.45). Overall thoracoscopic surgery halved the risk of POP and the highest risk of POP was seen in pneumonectomy performed in open thoracotomy. Among patients surviving the 30-day postoperative period, 31-365 day mortality was 21.6% in POP patients vs. 16.8% in non-POP patients, and 1-5-year mortality was 62.2% vs. 53.0%. Adjusted 31-365 day hazard ratio (HR) of death with POP was 1.31 (95% CI: 1.00-1.73), and 1-5 year HR was 1.22 (95% CI 0.98-1.53).

Conclusion: Major risk factors for POP following LC surgery are advanced age, previous pneumonia, obesity, chronic pulmonary disease, alcoholism, and atrial fibrillation. POP is a clinical marker for decreased LC survival.
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http://dx.doi.org/10.1016/j.rmed.2015.07.008DOI Listing
October 2015

Primary Capreomycin Resistance Is Common and Associated With Early Mortality in Patients With Extensively Drug-Resistant Tuberculosis in KwaZulu-Natal, South Africa.

J Acquir Immune Defic Syndr 2015 Aug;69(5):536-43

*Department of Medicine, Division of Pulmonary, Allergy, and Critical Care Medicine, Columbia University College of Physicians and Surgeons, New York, NY; †Department of Epidemiology, Columbia Mailman School of Public Health, New York, NY; ‡Centre for AIDS Programme of Research in South Africa (CAPRISA), Durban, South Africa; §Department of Microbiology, National Health Laboratory Service (NHLS), Durban, South Africa; ‖Department of Medical Microbiology, School of Laboratory Medicine and Medical Sciences, University of KwaZulu-Natal, Durban, South Africa; ¶DR-TB Department, King Dinuzulu Hospital, Department of Health, Sydenham, South Africa; and #Department of Epidemiology, Boston University School of Public Health, Boston, MA.

Background: Capreomycin is a key antimycobacterial drug in treatment of extensively drug-resistant tuberculosis (XDR-TB). Drug-susceptibility testing (DST) for capreomycin is not routinely performed in newly diagnosed XDR-TB in South Africa. We performed this study to assess the prevalence, clinical significance, and molecular epidemiology of capreomycin resistance in newly diagnosed patients with XDR-TB in KwaZulu-Natal, South Africa.

Methods: Retrospective cohort study of consecutive patients with XDR-TB admitted to a TB referral hospital without previous XDR-TB treatment. A subset of isolates had extended DST (including capreomycin), mutational analysis, and IS6110 restriction fragment length polymorphism assays.

Results: A total of 216 eligible patients with XDR-TB were identified. The majority were treated with capreomycin (72%), were young (median age: 35.5 years), and were female (56%). One hundred five (76%) were HIV+, and 109 (66%) were on antiretroviral therapy. A subset of 52 patients had full DST. A total of 47/52 (90.4%) patients with XDR-TB were capreomycin resistant. Capreomycin-resistant patients experienced worse mortality and culture conversion than capreomycin susceptible, although this difference was not statistically significant. The A1401G mutation in the rrs gene was associated with capreomycin resistance. The majority of capreomycin-resistant strains were F15/LAM4/KZN lineage (80%), and clustering was common in these isolates (92.5%).

Conclusions: Capreomycin resistance is common in patients with XDR-TB in KwaZulu-Natal, is predominantly because of ongoing province-wide transmission of a highly resistant strain, and is associated with high mortality. Capreomycin should be included in routine DST in all patients with XDR-TB. New drug regimens that do not include injectable agents should be operationally tested as empiric treatment in XDR-TB.
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http://dx.doi.org/10.1097/QAI.0000000000000650DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4501864PMC
August 2015

The cost-effectiveness of improved hepatitis C virus therapies in HIV/hepatitis C virus coinfected patients.

AIDS 2014 Jan;28(3):365-76

aSection of Infectious Diseases, Department of Medicine, Boston Medical Center bDepartment of Epidemiology, Boston University School of Public Health, Boston, Massachusetts cDepartment of Public Health, Weill Cornell Medical College, New York, New York dDivision of General Medicine, Massachusetts General Hospital eDivision of Infectious Diseases, Massachusetts General Hospital fDepartment of Global Health and Population gDepartment of Health Policy and Management, Harvard School of Public Health, Boston, Massachusetts, USA.

Objectives: To evaluate the effectiveness and cost-effectiveness of strategies to treat hepatitis C virus (HCV) in HIV/HCV coinfected patients in the United States.

Participants: Simulated cohort of HIV/HCV genotype 1 coinfected, noncirrhotic, HCV treatment-naive individuals enrolled in US HIV guideline-concordant care.

Design/interventions: Monte Carlo simulation comparing five strategies: no treatment; dual therapy with pegylated-interferon (PEG) and ribavirin (RBV); 'PEG/RBV trial' in which all patients initiate dual therapy and switch to triple therapy upon failure; 'IL28B triage' in which patients initiate either dual therapy or triple therapy based on their IL28B allele type; and PEG/RBV and telaprevir (TPV) triple therapy. Sensitivity analyses varied efficacies and costs and included a scenario with interferon (IFN)-free therapy.

Main Measures: Sustained virologic response (SVR), life expectancy, discounted quality-adjusted life expectancy (QALE), lifetime medical costs, and incremental cost-effectiveness ratios (ICERs) in $/quality-adjusted life years (QALY) gained.

Results: 'PEG/RBV trial,' 'IL28B triage,' and 'triple therapy' each provided 72% SVR and extended QALE compared with 'dual therapy' by 1.12, 1.14, and 1.15 QALY, respectively. The ICER of 'PEG/RBV trial' compared with 'dual therapy' was $37 500/QALY. 'IL28B triage' and 'triple therapy' provided little benefit compared with 'PEG/RBV trial,' and both had ICERs exceeding $300 000/QALY. In sensitivity analyses, IFN-free treatment attaining 90% SVR had an ICER less than $100 000/QALY compared with 'PEG/RBV trial' when its cost was $109 000 or less (125% of the cost of PEG/RBV/TVR).

Conclusion: HCV protease inhibitors are most efficiently used in HIV/HCV coinfection after a trial of PEG/RBV, sparing protease inhibitors for those who attain rapid virologic response and SVR. The cost-effectiveness of IFN-free regimens for HIV/HCV coinfection will depend on the cost of these therapies.
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http://dx.doi.org/10.1097/QAD.0000000000000093DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4045405PMC
January 2014

High incidence of hospital admissions with multidrug-resistant and extensively drug-resistant tuberculosis among South African health care workers.

Ann Intern Med 2010 Oct;153(8):516-22

Boston University School of Medicine and School of Public Health, Boston, Massachusetts, USA.

Background: Nosocomial transmission has been described in extensively drug-resistant tuberculosis (XDR-TB) and HIV co-infected patients in South Africa. However, little is known about the rates of drug-resistant tuberculosis among health care workers in countries with high tuberculosis and HIV burden.

Objective: To estimate rates of multidrug-resistant tuberculosis (MDR-TB) and XDR-TB hospitalizations among health care workers in KwaZulu-Natal, South Africa.

Design: Retrospective study of patients with drug-resistant tuberculosis who were admitted from 2003 to 2008 for the initiation of drug-resistant tuberculosis therapy.

Setting: A public tuberculosis referral hospital in KwaZulu-Natal, South Africa.

Participants: 231 health care workers and 4151 non-health care workers admitted for initiation of MDR-TB or XDR-TB treatment.

Measurements: Hospital admission rates and hospital admission incidence rate ratios.

Results: Estimated incidence of MDR-TB hospitalization was 64.8 per 100,000 health care workers versus 11.9 per 100,000 non-health care workers (incidence rate ratio, 5.46 [95% CI, 4.75 to 6.28]). Estimated incidence of XDR-TB hospitalizations was 7.2 per 100,000 health care workers versus 1.1 per 100,000 non-health care workers (incidence rate ratio, 6.69 [CI, 4.38 to 10.20]). A higher percentage of health care workers than non-health care workers with MDR-TB or XDR-TB were women (78% vs. 47%; P < 0.001), and health care workers were less likely to report previous tuberculosis treatment (41% vs. 92%; P < 0.001). HIV infection did not differ between health care workers and non-health care workers (55% vs. 57%); however, among HIV-infected patients, a higher percentage of health care workers were receiving antiretroviral medications (63% vs. 47%; P < 0.001).

Limitation: The study had an observational retrospective design, is subject to referral bias, and had no information on type of health care work or duration of occupational exposure to tuberculosis.

Conclusion: Health care workers in this HIV-endemic area were substantially more likely to be hospitalized with either MDR-TB or XDR-TB than were non-health care workers. The increased risk may be explained by occupational exposure, underlining the urgent need for tuberculosis infection-control programs.
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http://dx.doi.org/10.7326/0003-4819-153-8-201010190-00008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3074259PMC
October 2010

Prevention of tuberculosis in Bacille Calmette-Guérin-primed, HIV-infected adults boosted with an inactivated whole-cell mycobacterial vaccine.

AIDS 2010 Mar;24(5):675-85

Infectious Disease and International Health, Dartmouth Medical School, Hanover, New Hampshire, USA.

Objective: To determine whether a multiple-dose series of an inactivated whole cell mycobacterial vaccine, Mycobacterium vaccae, can prevent HIV-associated tuberculosis.

Design And Methods: The DarDar trial was a randomized, placebo-controlled, double-blind trial. The study was carried in an outpatient facility in Dar es Salaam, Tanzania. HIV-infected patients with CD4 cell counts of at least 200 cells/microl and a Bacille Calmette-Guérin scar were chosen for the study. The intervention was carried out by random 1:1 assignment to five intradermal doses of M. vaccae or placebo. Tuberculin skin tests were performed, and patients with reactions of at least 5 mm were administered isoniazid for 6 months. The main outcome measures were disseminated (primary endpoint), definite, and probable tuberculosis (secondary endpoints).

Results: Two thousand thirteen individuals were randomized (1006 to M. vaccae, 1007 to placebo) and followed every 3 months for a median of 3.3 years. The trial was terminated early because of slow accrual of cases of disseminated tuberculosis and significant protection against definite tuberculosis. Hazard ratios were disseminated tuberculosis 0.52 (95% confidence interval 0.21-1.34; seven cases in M. vaccae, 13 cases in placebo; log-rank P = 0.16), definite tuberculosis 0.61 (95% confidence interval 0.39-0.96; 33 cases in M. vaccae, 52 cases in placebo; P = 0.03), and probable tuberculosis 1.17 (95% confidence interval 0.76-1.80; 48 cases in M. vaccae, 40 cases in placebo; P = 0.46). Immunization was well tolerated, with no adverse effect on CD4 cell count or HIV viral load, and no increase in the rate of serious adverse events.

Conclusion: Administration of a multiple-dose series of M. vaccae to HIV-infected adults with childhood Bacille Calmette-Guérin immunization is safe and is associated with significant protection against definite tuberculosis. These results provide evidence that immunization with a whole cell mycobacterial vaccine is a viable strategy for the prevention of HIV-associated tuberculosis.
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http://dx.doi.org/10.1097/QAD.0b013e3283350f1bDOI Listing
March 2010
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