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Mitnick, Carole

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Mitnick

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Carole

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Mitnick, Carole

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2006 - 200932010 - 201714

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Author's Publications: search.filters.isAuthorOfPublication.0f2f2c6d-9d50-498d-aa1f-e73ec1c915da

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Now showing 1 - 10 of 17
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    The need to accelerate access to new drugs for multidrug-resistant tuberculosis
    (World Health Organization, 2015) Cox, Helen S; Furin, Jennifer J; Mitnick, Carole; Daniels, Colleen; Cox, Vivian; Goemaere, Eric
    Abstract Approximately half a million people are thought to develop multidrug-resistant tuberculosis annually. Barely 20% of these people currently receive recommended treatment and only about 10% are successfully treated. Poor access to treatment is probably driving the current epidemic, via ongoing transmission. Treatment scale-up is hampered by current treatment regimens, which are lengthy, expensive, poorly tolerated and difficult to administer in the settings where most patients reside. Although new drugs provide an opportunity to improve treatment regimens, current and planned clinical trials hold little promise for developing regimens that will facilitate prompt treatment scale-up. In this article we argue that clinical trials, while necessary, should be complemented by timely, large-scale, operational research that will provide programmatic data on the use of new drugs and regimens while simultaneously improving access to life-saving treatment. Perceived risks – such as the rapid development of resistance to new drugs – need to be balanced against the high levels of mortality and transmission that will otherwise persist. Doubling access to treatment and increasing treatment success could save approximately a million lives over the next decade.
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    Treatment Outcomes for Adolescents With Multidrug-Resistant Tuberculosis in Lima, Peru
    (SAGE Publications, 2016) Tierney, Dylan; Brooks, Meredith; Manjourides, Justin; Furin, Jennifer J.; Mitnick, Carole
    Treatment outcomes for adolescents with multidrug-resistant tuberculosis are rarely reported and, to date, have been poor. Among 90 adolescents from Lima, Peru, 68 (75.6%) achieved cure or completion of treatment. Unsuccessful treatment was less common in the Peru cohort than previously described in the literature.
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    Time to Culture Conversion and Regimen Composition in Multidrug-Resistant Tuberculosis Treatment
    (Public Library of Science, 2014) Tierney, Dylan B.; Franke, Molly; Becerra, Mercedes; Alcántara Virú, Félix A.; Bonilla, César A.; Sánchez, Epifanio; Guerra, Dalia; Muñoz, Maribel; Llaro, Karim; Palacios, Eda; Mestanza, Lorena; Hurtado, Rocio; Furin, Jennifer J.; Shin, Sonya; Mitnick, Carole
    Sputum cultures are an important tool in monitoring the response to tuberculosis treatment, especially in multidrug-resistant tuberculosis. There has, however, been little study of the effect of treatment regimen composition on culture conversion. Well-designed clinical trials of new anti-tuberculosis drugs require this information to establish optimized background regimens for comparison. We conducted a retrospective cohort study to assess whether the use of an aggressive multidrug-resistant tuberculosis regimen was associated with more rapid sputum culture conversion. We conducted Cox proportional-hazards analyses to examine the relationship between receipt of an aggressive regimen for the 14 prior consecutive days and sputum culture conversion. Sputum culture conversion was achieved in 519 (87.7%) of the 592 patients studied. Among patients who had sputum culture conversion, the median time to conversion was 59 days (IQR: 31–92). In 480 patients (92.5% of those with conversion), conversion occurred within the first six months of treatment. Exposure to an aggressive regimen was independently associated with sputum culture conversion during the first six months of treatment (HR: 1.36; 95% CI: 1.10, 1.69). Infection with human immunodeficiency virus (HR 3.36; 95% CI: 1.47, 7.72) and receiving less exposure to tuberculosis treatment prior to the individualized multidrug-resistant tuberculosis regimen (HR: 1.58; 95% CI: 1.28, 1.95) were also independently positively associated with conversion. Tachycardia (HR: 0.77; 95% CI: 0.61, 0.98) and respiratory difficulty (HR: 0.78; 95% CI: 0.62, 0.97) were independently associated with a lower rate of conversion. This study is the first demonstrating that the composition of the multidrug-resistant tuberculosis treatment regimen influences the time to culture conversion. These results support the use of an aggressive regimen as the optimized background regimen in trials of new anti-TB drugs.
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    Acquired and Transmitted Multidrug Resistant Tuberculosis: The Role of Social Determinants
    (Public Library of Science, 2016) Odone, Anna; Calderon, Roger; Becerra, Mercedes; Zhang, Zibiao; Contreras, Carmen C.; Yataco, Rosa; Galea, Jerome; Lecca, Leonid; Bonds, Matthew; Mitnick, Carole; Murray, Megan
    Although risk factors for multi-drug resistant tuberculosis are known, few studies have differentiated between acquired and transmitted resistance. It is important to identify factors associated with these different mechanisms to optimize control measures. We conducted a prospective cohort study of index TB patients and their household contacts in Lima, Peru to identify risk factors associated with acquired and transmitted resistance, respectively. Patients with higher socioeconomic status (SES) had a 3-fold increased risk of transmitted resistance compared to those with lower SES when acquired resistance served as the baseline. Quality of housing mediated most of the impact of SES.
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    Multidrug-resistant tuberculosis treatment failure detection depends on monitoring interval and microbiological method
    (European Respiratory Society, 2016) Mitnick, Carole; White, Richard A.; Lu, Chunling; Rodriguez, Carly; Bayona, Jaime; Becerra, Mercedes; Burgos, Marcos; Centis, Rosella; Cohen, Theodore; Cox, Helen; D'Ambrosio, Lia; Danilovitz, Manfred; Falzon, Dennis; Gelmanova, Irina Y.; Gler, Maria T.; Grinsdale, Jennifer A.; Holtz, Timothy H.; Keshavjee, Salmaan; Leimane, Vaira; Menzies, Dick; Migliori, Giovanni Battista; Brooks, Meredith; Mishustin, Sergey P.; Pagano, Marcello; Quelapio, Maria I.; Shean, Karen; Shin, Sonya; Tolman, Arielle W.; van der Walt, Martha L.; Van Deun, Armand; Viiklepp, Piret
    Debate persists about monitoring method (culture or smear) and interval (monthly or less frequently) during treatment for multidrug-resistant tuberculosis (MDR-TB). We analysed existing data and estimated the effect of monitoring strategies on timing of failure detection. We identified studies reporting microbiological response to MDR-TB treatment and solicited individual patient data from authors. Frailty survival models were used to estimate pooled relative risk of failure detection in the last 12 months of treatment; hazard of failure using monthly culture was the reference. Data were obtained for 5410 patients across 12 observational studies. During the last 12 months of treatment, failure detection occurred in a median of 3 months by monthly culture; failure detection was delayed by 2, 7, and 9 months relying on bimonthly culture, monthly smear and bimonthly smear, respectively. Risk (95% CI) of failure detection delay resulting from monthly smear relative to culture is 0.38 (0.34–0.42) for all patients and 0.33 (0.25–0.42) for HIV-co-infected patients. Failure detection is delayed by reducing the sensitivity and frequency of the monitoring method. Monthly monitoring of sputum cultures from patients receiving MDR-TB treatment is recommended. Expanded laboratory capacity is needed for high-quality culture, and for smear microscopy and rapid molecular tests.
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    Propensity Score-Based Approaches to Confounding by Indication in Individual Patient Data Meta-Analysis: Non-Standardized Treatment for Multidrug Resistant Tuberculosis
    (Public Library of Science, 2016) Fox, Gregory J.; Benedetti, Andrea; Mitnick, Carole; Pai, Madhukar; Menzies, Dick
    Background: In the absence of randomized clinical trials, meta-analysis of individual patient data (IPD) from observational studies may provide the most accurate effect estimates for an intervention. However, confounding by indication remains an important concern that can be addressed by incorporating individual patient covariates in different ways. We compared different analytic approaches to account for confounding in IPD from patients treated for multi-drug resistant tuberculosis (MDR-TB). Methods: Two antibiotic classes were evaluated, fluoroquinolones—considered the cornerstone of effective MDR-TB treatment—and macrolides, which are known to be safe, yet are ineffective in vitro. The primary outcome was treatment success against treatment failure, relapse or death. Effect estimates were obtained using multivariable and propensity-score based approaches. Results: Fluoroquinolone antibiotics were used in 28 included studies, within which 6,612 patients received a fluoroquinolone and 723 patients did not. Macrolides were used in 15 included studies, within which 459 patients received this class of antibiotics and 3,670 did not. Both standard multivariable regression and propensity score-based methods resulted in similar effect estimates for early and late generation fluoroquinolones, while macrolide antibiotics use was associated with reduced treatment success. Conclusions: In this individual patient data meta-analysis, standard multivariable and propensity-score based methods of adjusting for individual patient covariates for observational studies yielded produced similar effect estimates. Even when adjustment is made for potential confounding, interpretation of adjusted estimates must still consider the potential for residual bias.
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    Issues in design and interpretation of MDR-TB clinical trials: report of the first Global MDR-TB Clinical Trials Landscape Meeting
    (BioMed Central, 2015) Mitnick, Carole; Rusen, ID; Bain, Lisa J; Horsburgh, C Robert
    Recognizing that the current MDR-TB regimen is suboptimal and based on low-quality evidence, the Global MDR-TB Clinical Trials Landscape Meeting was held in December, 2014 to strategize about coordination of research and development of new treatment regimens for this disease that affects millions of people worldwide every year. Sixty international experts on multidrug-resistant tuberculosis (MDR-TB) met in Washington D.C. and Cape Town, South Africa to consider key MDR-TB trial-related issues, including: standardization of definitions; clinical trial capacity building and; regimens optimized to foster compliance, avoid the emergence of resistance and have clinical relevance for special populations, including children and those co-infected with HIV. Underpinning all of this is the generation of a sufficient evidence base to facilitate regulatory approval and improved normative guidance. Participants discussed treatment combinations currently being studied in Phase 2B and Phase 3 trials as well as other promising new regimens and combinations that may be evaluated in the near future. These include regimens designed specifically to enable shorter duration and all-oral treatment as a means of maximizing treatment completion. It is hoped that clear definition of these challenges will facilitate the process of identifying solutions that accelerate progress towards effective, non-toxic treatments that can be programmatically implemented.
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    Programmatic Management of Drug-Resistant Tuberculosis: An Updated Research Agenda
    (Public Library of Science, 2016) Mitnick, Carole; Rodriguez, Carly; Hatton, Marita L.; Brigden, Grania; Cobelens, Frank; Grobusch, Martin P.; Horsburgh, Robert; Lange, Christoph; Lienhardt, Christian; Oren, Eyal; Podewils, Laura J.; Seaworth, Barbara; van den Hof, Susan; Daley, Charles L.; Gebhard, Agnes C.; Wares, Fraser
    Introduction: There are numerous challenges in delivering appropriate treatment for multidrug-resistant tuberculosis (MDR-TB) and the evidence base to guide those practices remains limited. We present the third updated Research Agenda for the programmatic management of drug-resistant TB (PMDT), assembled through a literature review and survey. Methods: Publications citing the 2008 research agenda and normative documents were reviewed for evidence gaps. Gaps were formulated into questions and grouped as in the 2008 research agenda: Laboratory Support, Treatment Strategy, Programmatically Relevant Research, Epidemiology, and Management of Contacts. A survey was distributed through snowball sampling to identify research priorities. Respondent priority rankings were scored and summarized by mean. Sensitivity analyses explored weighting and handling of missing rankings. Results: Thirty normative documents and publications were reviewed for stated research needs; these were collapsed into 56 research questions across 5 categories. Of more than 500 survey recipients, 133 ranked priorities within at least one category. Priorities within categories included new diagnostics and their effect on improving treatment outcomes, improved diagnosis of paucibacillary and extra pulmonary TB, and development of shorter, effective regimens. Interruption of nosocomial transmission and treatment for latent TB infection in contacts of known MDR−TB patients were also top priorities in their respective categories. Results were internally consistent and robust. Discussion Priorities retained from the 2008 research agenda include shorter MDR-TB regimens and averting transmission. Limitations of recent advances were implied in the continued quest for: shorter regimens containing new drugs, rapid diagnostics that improve treatment outcomes, and improved methods of estimating burden without representative data. Conclusion: There is continuity around the priorities for research in PMDT. Coordinated efforts to address questions regarding shorter treatment regimens, knowledge of disease burden without representative data, and treatment for LTBI in contacts of known DR-TB patients are essential to stem the epidemic of TB, including DR-TB.
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    Evaluation of high-dose rifampin in patients with new, smear-positive tuberculosis (HIRIF): study protocol for a randomized controlled trial
    (BioMed Central, 2016) Brooks, Meredith; Lecca, Leonid; Peloquin, Charles; Mitchison, Denis; Seung, Kwonjune; Pagano, Marcello; Coleman, David; Osso, Elna; Coit, Julia; Vargas Vasquez, Dante Elmo; Sanchez Garavito, Epifanio; Calderon, Roger; Contreras, Carmen; Davies, Geraint; Mitnick, Carole
    Background: Evidence has existed for decades that higher doses of rifampin may be more effective, but potentially more toxic, than standard doses used in tuberculosis treatment. Whether increased doses of rifampin could safely shorten treatment remains an open question. Methods/Design The HIRIF study is a phase II randomized trial comparing rifampin doses of 20 and 15 mg/kg/day to the standard 10 mg/kg/day for the first 2 months of tuberculosis treatment. All participants receive standard doses of companion drugs and a standard continuation-phase treatment (4 months, 2 drugs). They are followed for 6 months post treatment. Study participants are adults with newly diagnosed, previously untreated, smear positive (≥2+) pulmonary tuberculosis. The primary outcome is rifampin area under the plasma concentration-time curve (AUC0–24) after at least 14 days of study treatment/minimum inhibitory concentration. 180 randomized participants affords 90 % statistical power to detect a difference of at least 14 mcg/mL*hr between the 20 mg/kg group and the 10 mg/kg group, assuming a loss to follow-up of up to 17 %. Discussion Extant evidence suggests the potential for increased doses of rifampin to shorten tuberculosis treatment duration. Early studies that explored this potential using intermittent, higher dosing were derailed by toxicity. Given the continued large, global burden of tuberculosis with nearly 10 million new cases annually, shortened regimens with existing drugs would offer an important advantage to patients and health systems. Trial registration This trial was registered with clinicaltrials.gov (registration number: NCT01408914) on 2 August 2011.
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    Aggressive Regimens for Multidrug-Resistant Tuberculosis Decrease All-Cause Mortality
    (Public Library of Science, 2013) Mitnick, Carole; Franke, Molly; Rich, Michael; Alcantara Viru, Felix A.; Appleton, Sasha C.; Atwood, Sidney S.; Bayona, Jaime; Bonilla, Cesar; Chalco, Katiuska; Fraser, Hamish S. F.; Furin, Jennifer; Guerra, Dalia; Hurtado, Rocio; Joseph, Keith; Llaro, Karim; Mestanza, Lorena; Mukherjee, Joia; Muñoz, Maribel; Palacios, Eda; Sanchez, Epifanio; Seung, Kwonjune; Shin, Sonya; Sloutsky, Alexander; Tolman, Arielle W.; Becerra, Mercedes
    Rationale: A better understanding of the composition of optimal treatment regimens for multidrug-resistant tuberculosis (MDR-TB) is essential for expanding universal access to effective treatment and for developing new therapies for MDR-TB. Analysis of observational data may inform the definition of an optimized regimen. Objectives: This study assessed the impact of an aggressive regimen–one containing at least five likely effective drugs, including a fluoroquinolone and injectable–on treatment outcomes in a large MDR-TB patient cohort. Methods: This was a retrospective cohort study of patients treated in a national outpatient program in Peru between 1999 and 2002. We examined the association between receiving an aggressive regimen and the rate of death. Measurements and Main Results: In total, 669 patients were treated with individualized regimens for laboratory-confirmed MDR-TB. Isolates were resistant to a mean of 5.4 (SD 1.7) drugs. Cure or completion was achieved in 66.1% (442) of patients; death occurred in 20.8% (139). Patients who received an aggressive regimen were less likely to die (crude hazard ratio [HR]: 0.62; 95% CI: 0.44,0.89), compared to those who did not receive such a regimen. This association held in analyses adjusted for comorbidities and indicators of severity (adjusted HR: 0.63; 95% CI: 0.43,0.93). Conclusions: The aggressive regimen is a robust predictor of MDR-TB treatment outcome. TB policy makers and program directors should consider this standard as they design and implement regimens for patients with drug-resistant disease. Furthermore, the aggressive regimen should be considered the standard background regimen when designing randomized trials of treatment for drug-resistant TB.