TB Modeling and Translational Epi Group

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- June 2017 -

Improving active case finding for tuberculosis in South Africa: informing innovative implementation approaches in the context of the Kharitode trial through formative research. (2017). Kerrigan D., West N., Tudor C., Hanrahan CF., Lebina L., Msandiwa R., Mmolawa L., Martinson N., Dowdy D, Health research policy and systems, 15, 42

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BACKGROUND: Tuberculosis (TB) is the leading infectious killer worldwide, with approximately 1.8 million deaths in 2015. While effective treatment exists, implementation of active case finding (ACF) methods to identify persons with active TB in a timely and cost-effective manner continues to be a major challenge in resource-constrained settings. Limited qualitative work has been conducted to gain an in-depth understanding of implementation barriers. METHODS: Qualitative research was conducted to inform the development of three ACF strategies for TB to be evaluated as part of the Kharitode cluster-randomised trial being conducted in a rural province of South Africa. This included 25 semi-structured in-depth interviews among 8 TB patients, 7 of their household members and 10 clinic health workers, as well as 4 focus group discussions (2 rural and 2 main town locations) with 6-8 participants each (n = 27). Interviews and focus group discussions explored the context, advantages and limitations, as well as the implications of three ACF methods. Content analysis was utilised to document salient themes regarding their feasibility, acceptability and potential effectiveness. RESULTS: Study participants (TB patients and community members) reported difficulty identifying TB symptoms and seeking care in a timely fashion. In turn, all stakeholder groups felt that more proactive case finding strategies would be beneficial. Clinic-based strategies (including screening all patients regardless of visit purpose) were seen as the most acceptable method based on participants' preference ranking of the ACF strategies. However, given the resource constraints experienced by the public healthcare system in South Africa, many participants doubted whether it would be the most effective strategy. Household outreach and incentive-based strategies were described as promising, but participants reported some concerns (e.g. stigma in case of household-based and ethical concerns in the case of incentives). Participants offered insights into how to optimise each strategy, tailoring implementation to community needs (low TB knowledge) and realities (financial constraints, transport, time off from work). CONCLUSIONS: Findings suggest different methods of TB ACF are likely to engage different populations, highlighting the utility of a comprehensive approach. TRIAL REGISTRATION: Clinicaltrials.gov ( NCT02808507 ). Registered June 1, 2016. The participants in this formative study are not trial participants.

- May 2017 -

Reply to Anthony et al., "Protecting Pyrazinamide, a Priority for Improving Outcomes in Multidrug-Resistant Tuberculosis Treatment". (2017). Fofana MO., Dowdy DW, Antimicrobial agents and chemotherapy, 61

The Impact of Preexposure Prophylaxis Among Men Who Have Sex With Men: An Individual-Based Model. (2017). Kasaie P., Pennington J., Shah MS., Berry SA., German D., Flynn CP., Beyrer C., Dowdy DW, Journal of acquired immune deficiency syndromes (1999), 75, 175-183

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OBJECTIVES: Preexposure prophylaxis (PrEP) is recommended for preventing HIV infection among individuals at high risk, including men who have sex with men (MSM). Although its individual-level efficacy is proven, questions remain regarding population-level impact of PrEP implementation. DESIGN: We developed an agent-based simulation of HIV transmission among MSM, accounting for demographics, sexual contact network, HIV disease stage, and use of antiretroviral therapy. We use this framework to compare PrEP delivery strategies in terms of impact on HIV incidence and prevalence. RESULTS: The projected reduction in HIV incidence achievable with PrEP reflects both population-level coverage and individual-level adherence (as a proportion of days protected against HIV transmission). For example, provision of PrEP to 40% of HIV-negative MSM reporting more than one sexual partner in the last 12 months, taken with sufficient adherence to provide protection on 40% of days, can reduce HIV incidence by 9.5% (95% uncertainty range: 8%-11%) within 5 years. However, if this could be increased to 80% coverage on 80% of days (eg, through mass campaigns with a long-acting injectable formulation), a 43% (42%-44%) reduction in HIV incidence could be achieved. Delivering PrEP to MSM at high risk for HIV acquisition can augment population-level impact up to 1.8-fold. CONCLUSIONS: If highly ambitious targets for coverage and adherence can be achieved, PrEP can substantially reduce HIV incidence in the short-term. Although the reduction in HIV incidence largely reflects the proportion of person-years protected, the efficiency of PrEP delivery can be enhanced by targeting high-risk populations.

Prevalence of Kaposi's sarcoma in patients with AIDS and associated factors, Sao Paulo-SP, Brazil, 2003-2010. (2017). Tancredi MV., Pinto VM., Silva MHD., Pimentel SR., Silva TSBD., Ito SMA., Golub JE., Toscano ALCC, Epidemiologia e servicos de saude : revista do Sistema Unico de Saude do Brasil, 26, 379-387

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OBJECTIVE: to estimate the prevalence of Kaposi's sarcoma (KS) in patients with AIDS and identify the associated factors to the occurrence of this neoplasm. METHODS: this is a cross-sectional study with notification data from two AIDS reference centers in Sao Paulo-SP, Brazil, from January, 2003 to March, 2010; probabilistic linkage and multiple logistic regression methods were applied. RESULTS: among 3,557 AIDS cases, 213 (6%) presented KS; 95.3% of them occurred in males; male sex (OR=3.1; 95%CI=1.4;6.6), age at the AIDS diagnosis >28 years old (OR=1.6; 95%CI=1.0;2.6), MSM (OR=3.2; 95%CI=2.0;4.9), prior use of HAART (OR=0.4; 95%CI=0.3;0.5), AIDS diagnosis between 2007-2010 (OR=0.3; 95%CI=0.2;0.4), and CD4+ T-cell counting under 200cells/mm3 (OR=16.0; 95%CI=6.0;42.7) and 200-500cells/mm(3) (OR=2,5; 95%CI=1.1;6.4) were associated to the occurrence of KS. CONCLUSION: KS has a high prevalence in Sao Paulo-SP; strategies for early HIV diagnosis may reduce this prevalence.

Comparing Drivers and Dynamics of Tuberculosis in California, Florida, New York, and Texas. (2017). Shrestha S., Hill AN., Marks SM., Dowdy DW, American journal of respiratory and critical care medicine, 196, 1050-1059

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RATIONALE: There is substantial state-to-state heterogeneity in tuberculosis (TB) in the United States; better understanding this heterogeneity can inform effective response to TB at the state level, the level at which most TB control efforts are coordinated. OBJECTIVES: To characterize drivers of state-level heterogeneity in TB epidemiology in the four U.S. states that bear half the country's TB burden: California, Florida, New York, and Texas. METHODS: We constructed an individual-based model of TB in the four U.S. states and calibrated the model to state-specific demographic and age- and nativity-stratified TB incidence data. We used the model to infer differences in natural history of TB and in future projections of TB. MEASUREMENTS AND MAIN RESULTS: We found that differences in both demographic makeup (particularly the size and composition of the foreign-born population) and TB transmission dynamics contribute to state-level differences in TB epidemiology. The projected median annual rate of decline in TB incidence in the next decade was substantially higher in Texas (3.3%; 95% range, -5.6 to 10.9) than in California (1.7%; 95% range, -3.8 to 7.1), Florida (1.5%; 95% range, -7.4 to 14), and New York (1.9%; 95% range, -6.4 to 9.8). All scenarios projected a flattening of the decline in TB incidence by 2025 without additional resources or interventions. CONCLUSIONS: There is substantial state-level heterogeneity in TB epidemiology in the four states, which reflect both demographic factors and potential differences in the natural history of TB. These differences may inform resource allocation decisions in these states.

Strategies to Accelerate HIV Care and Antiretroviral Therapy Initiation After HIV Diagnosis: A Randomized Trial. (2017). Hoffmann CJ., Mabuto T., Ginindza S., Fielding KL., Kubeka G., Dowdy DW., Churchyard GJ., Charalambous S, Journal of acquired immune deficiency syndromes (1999), 75, 540-547

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OBJECTIVE: Determine the effectiveness of strategies to increase linkage to care after testing HIV positive at mobile HIV testing in South Africa. DESIGN: Unmasked randomized controlled trial. METHODS: Recruitment of adults testing HIV positive and not currently in HIV care occurred at 7 mobile HIV counseling and testing units in urban, periurban, and rural South Africa with those consenting randomized 1:1:1:1 into 1 of 4 arms. Three strategies were compared with standard of care (SOC): point-of-care CD4 count testing (POC CD4), POC CD4 plus longitudinal strengths-based counseling (care facilitation; CF), and POC CD4 plus transport reimbursement (transport). Participants were followed up telephonically and through clinic records and analyzed with an intention-to-treat analysis. RESULTS: From March 2013 to October 2014, 2558 participants were enrolled, of whom 160 were excluded postrandomization. Compared with the SOC arm where 298 (50%) reported having entered care, linkage to care was 319 (52%) for POC CD4, hazard ratio (HR) 1.0 [95% confidence interval (CI): 0.89 to 1.2, P = 0.6]; 331 (55%) for CF, HR: 1.1 (95% CI: 0.84 to 1.3, P = 0.2); and 291 (49%) for transport, HR 0.97 (95% CI: 0.83 to 1.1, P = 0.7). Linkage to care verified with clinical records that occurred for 172 (29%) in the SOC arm; 187 (31%) in the POC CD4 arm, HR: 1.0 (95% CI: 0.86 to 1.3, P = 0.6); 225 (38%) in the CF arm, HR: 1.4 (95% CI: 1.1 to 1.7, P = 0.001); and 180 (31%) in the transport arm, HR: 1.1 (95% CI: 0.88 to 1.3, P = 0.5). CONCLUSIONS: CF improved verified linkage to care from 29% to 38%.

- March 2017 -

The epidemiology, pathogenesis, transmission, diagnosis, and management of multidrug-resistant, extensively drug-resistant, and incurable tuberculosis. (2017). Dheda K., Gumbo T., Maartens G., Dooley KE., McNerney R., Murray M., Furin J., Nardell EA., London L., Lessem E., Theron G., van Helden P., Niemann S., Merker M., Dowdy D., Van Rie A., Siu GK., Pasipanodya JG., Rodrigues C., Clark TG., Sirgel FA., Esmail A., Lin HH., Atre SR., Schaaf HS., Chang KC., Lange C., Nahid P., Udwadia ZF., Horsburgh CR Jr., Churchyard GJ., Menzies D., Hesseling AC., Nuermberger E., McIlleron H., Fennelly KP., Goemaere E., Jaramillo E., Low M., Jara CM., Padayatchi N., Warren RM, The Lancet. Respiratory medicine

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Global tuberculosis incidence has declined marginally over the past decade, and tuberculosis remains out of control in several parts of the world including Africa and Asia. Although tuberculosis control has been effective in some regions of the world, these gains are threatened by the increasing burden of multidrug-resistant (MDR) and extensively drug-resistant (XDR) tuberculosis. XDR tuberculosis has evolved in several tuberculosis-endemic countries to drug-incurable or programmatically incurable tuberculosis (totally drug-resistant tuberculosis). This poses several challenges similar to those encountered in the pre-chemotherapy era, including the inability to cure tuberculosis, high mortality, and the need for alternative methods to prevent disease transmission. This phenomenon mirrors the worldwide increase in antimicrobial resistance and the emergence of other MDR pathogens, such as malaria, HIV, and Gram-negative bacteria. MDR and XDR tuberculosis are associated with high morbidity and substantial mortality, are a threat to health-care workers, prohibitively expensive to treat, and are therefore a serious public health problem. In this Commission, we examine several aspects of drug-resistant tuberculosis. The traditional view that acquired resistance to antituberculous drugs is driven by poor compliance and programmatic failure is now being questioned, and several lines of evidence suggest that alternative mechanisms-including pharmacokinetic variability, induction of efflux pumps that transport the drug out of cells, and suboptimal drug penetration into tuberculosis lesions-are likely crucial to the pathogenesis of drug-resistant tuberculosis. These factors have implications for the design of new interventions, drug delivery and dosing mechanisms, and public health policy. We discuss epidemiology and transmission dynamics, including new insights into the fundamental biology of transmission, and we review the utility of newer diagnostic tools, including molecular tests and next-generation whole-genome sequencing, and their potential for clinical effectiveness. Relevant research priorities are highlighted, including optimal medical and surgical management, the role of newer and repurposed drugs (including bedaquiline, delamanid, and linezolid), pharmacokinetic and pharmacodynamic considerations, preventive strategies (such as prophylaxis in MDR and XDR contacts), palliative and patient-orientated care aspects, and medicolegal and ethical issues.

Drug-resistant tuberculosis in 2017: at a crossroads. (2017). Dowdy DW., Theron G., Tornheim JA., Kendall EA, The Lancet. Respiratory medicine

Identifying barriers to and facilitators of tuberculosis contact investigation in Kampala, Uganda: a behavioral approach. (2017). Ayakaka I., Ackerman S., Ggita JM., Kajubi P., Dowdy D., Haberer JE., Fair E., Hopewell P., Handley MA., Cattamanchi A., Katamba A., Davis JL, Implementation science : IS, 12, 33

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BACKGROUND: The World Health Organization recommends routine household tuberculosis contact investigation in high-burden countries but adoption has been limited. We sought to identify barriers to and facilitators of TB contact investigation during its introduction in Kampala, Uganda. METHODS: We collected cross-sectional qualitative data through focus group discussions and interviews with stakeholders, addressing three core activities of contact investigation: arranging household screening visits through index TB patients, visiting households to screen contacts and refer them to clinics, and evaluating at-risk contacts coming to clinics. We analyzed the data using a validated theory of behavior change, the Capability, Opportunity, and Motivation determine Behavior (COM-B) model, and sought to identify targeted interventions using the related Behavior Change Wheel implementation framework. RESULTS: We led seven focus-group discussions with 61 health-care workers, two with 21 lay health workers (LHWs), and one with four household contacts of newly diagnosed TB patients. We, in addition, performed 32 interviews with household contacts from 14 households of newly diagnosed TB patients. Commonly noted barriers included stigma, limited knowledge about TB among contacts, insufficient time and space in clinics for counselling, mistrust of health-center staff among index patients and contacts, and high travel costs for LHWs and contacts. The most important facilitators identified were the personalized and enabling services provided by LHWs. We identified education, persuasion, enablement, modeling of health-positive behaviors, incentivization, and restructuring of the service environment as relevant intervention functions with potential to alleviate barriers to and enhance facilitators of TB contact investigation. CONCLUSIONS: The use of a behavioral theory and a validated implementation framework provided a comprehensive approach for systematically identifying barriers to and facilitators of TB contact investigation. The behavioral determinants identified here may be useful in tailoring interventions to improve implementation of contact investigation in Kampala and other similar urban settings.

MDR-TB treatment as prevention: The projected population-level impact of expanded treatment for multidrug-resistant tuberculosis. (2017). Kendall EA., Azman AS., Cobelens FG., Dowdy DW, PloS one, 12, e0172748

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BACKGROUND: In 2013, approximately 480,000 people developed active multidrug-resistant tuberculosis (MDR-TB), while only 97,000 started MDR-TB treatment. We sought to estimate the impact of improving access to MDR-TB diagnosis and treatment, under multiple diagnostic algorithm and treatment regimen scenarios, on ten-year projections of MDR-TB incidence and mortality. METHODS: We constructed a dynamic transmission model of an MDR-TB epidemic in an illustrative East/Southeast Asian setting. Using approximate Bayesian computation, we investigated a wide array of potential epidemic trajectories consistent with current notification data and known TB epidemiology. RESULTS: Despite an overall projected decline in TB incidence, data-consistent simulations suggested that MDR-TB incidence is likely to rise between 2015 and 2025 under continued 2013 treatment practices, although with considerable uncertainty (median 17% increase, 95% Uncertainty Range [UR] -38% to +137%). But if, by 2017, all identified active TB patients with previously-treated TB could be tested for drug susceptibility, and 85% of those with MDR-TB could initiate MDR-appropriate treatment, then MDR-TB incidence in 2025 could be reduced by 26% (95% UR 4-52%) relative to projections under continued current practice. Also expanding this drug-susceptibility testing and appropriate MDR-TB treatment to treatment-naive as well as previously-treated TB cases, by 2020, could reduce MDR-TB incidence in 2025 by 29% (95% UR 6-55%) compared to continued current practice. If this diagnosis and treatment of all MDR-TB in known active TB cases by 2020 could be implemented via a novel second-line regimen with similar effectiveness and tolerability as current first-line therapy, a 54% (95% UR 20-74%) reduction in MDR-TB incidence compared to current-practice projections could be achieved by 2025. CONCLUSIONS: Expansion of diagnosis and treatment of MDR-TB, even using current sub-optimal second-line regimens, is expected to significantly decrease MDR-TB incidence at the population level. Focusing MDR diagnostic efforts on previously-treated cases is an efficient first-step approach.

- February 2017 -

Vitamin A and D Deficiencies Associated With Incident Tuberculosis in HIV-Infected Patients Initiating Antiretroviral Therapy in Multinational Case-Cohort Study. (2017). Tenforde MW., Yadav A., Dowdy DW., Gupte N., Shivakoti R., Yang WT., Mwelase N., Kanyama C., Pillay S., Samaneka W., Santos B., Poongulali S., Tripathy S., Riviere C., Berendes S., Lama JR., Cardoso SW., Sugandhavesa P., Christian P., Semba RD., Campbell TB., Gupta A, Journal of acquired immune deficiency syndromes (1999), 75, e71-e79

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INTRODUCTION: Numerous micronutrients have immunomodulatory roles that may influence risk of tuberculosis (TB), but the association between baseline micronutrient deficiencies and incident TB after antiretroviral therapy (ART) initiation in HIV-infected individuals is not well characterized. METHODS: We conducted a case-cohort study (n = 332) within a randomized trial comparing 3 ART regimens in 1571 HIV treatment-naive adults from 9 countries. A subcohort of 30 patients was randomly selected from each country (n = 270). Cases (n = 77; main cohort = 62, random subcohort = 15) included patients diagnosed with TB by 96 weeks post-ART initiation. We determined pretreatment concentrations of vitamin A, carotenoids, vitamin B6, vitamin B12, vitamin D, vitamin E, and selenium. We measured associations between pretreatment micronutrient deficiencies and incident TB using Breslow-weighted Cox regression models. RESULTS: Median pretreatment CD4 T-cell count was 170 cells/mm; 47.3% were women; and 53.6% Black. In multivariable models after adjusting for age, sex, country, treatment arm, previous TB, baseline CD4 count, HIV viral load, body mass index, and C-reactive protein, pretreatment deficiency in vitamin A (adjusted hazard ratio, aHR 5.33, 95% confidence interval, CI: 1.54 to 18.43) and vitamin D (aHR 3.66, 95% CI: 1.16 to 11.51) were associated with TB post-ART. CONCLUSIONS: In a diverse cohort of HIV-infected adults from predominantly low- and middle-income countries, deficiencies in vitamin A and vitamin D at ART initiation were independently associated with increased risk of incident TB in the ensuing 96 weeks. Vitamin A and D may be important modifiable risk factors for TB in high-risk HIV-infected patients starting ART in resource-limited highly-TB-endemic settings.

Describing the global burden of MDR-TB: missing cases or different metrics? (2017). Murrill M., Dowdy DW, The international journal of tuberculosis and lung disease : the official journal of the International Union against Tuberculosis and Lung Disease, 21, 1

- January 2017 -

Challenges in the Evaluation of Interventions to Improve Engagement Along the HIV Care Continuum in the United States: A Systematic Review. (2017). Risher KA., Kapoor S., Daramola AM., Paz-Bailey G., Skarbinski J., Doyle K., Shearer K., Dowdy D., Rosenberg E., Sullivan P., Shah M, AIDS and behavior, 21, 2101-2123

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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.

Priority-Setting for Novel Drug Regimens to Treat Tuberculosis: An Epidemiologic Model. (2017). Kendall EA., Shrestha S., Cohen T., Nuermberger E., Dooley KE., Gonzalez-Angulo L., Churchyard GJ., Nahid P., Rich ML., Bansbach C., Forissier T., Lienhardt C., Dowdy DW, PLoS medicine, 14, e1002202

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BACKGROUND: Novel drug regimens are needed for tuberculosis (TB) treatment. New regimens aim to improve on characteristics such as duration, efficacy, and safety profile, but no single regimen is likely to be ideal in all respects. By linking these regimen characteristics to a novel regimen's ability to reduce TB incidence and mortality, we sought to prioritize regimen characteristics from a population-level perspective. METHODS AND FINDINGS: We developed a dynamic transmission model of multi-strain TB epidemics in hypothetical populations reflective of the epidemiological situations in India (primary analysis), South Africa, the Philippines, and Brazil. We modeled the introduction of various novel rifampicin-susceptible (RS) or rifampicin-resistant (RR) TB regimens that differed on six characteristics, identified in consultation with a team of global experts: (1) efficacy, (2) duration, (3) ease of adherence, (4) medical contraindications, (5) barrier to resistance, and (6) baseline prevalence of resistance to the novel regimen. We compared scale-up of these regimens to a baseline reflective of continued standard of care. For our primary analysis situated in India, our model generated baseline TB incidence and mortality of 157 (95% uncertainty range [UR]: 113-187) and 16 (95% UR: 9-23) per 100,000 per year at the time of novel regimen introduction and RR TB incidence and mortality of 6 (95% UR: 4-10) and 0.6 (95% UR: 0.3-1.1) per 100,000 per year. An optimal RS TB regimen was projected to reduce 10-y TB incidence and mortality in the India-like scenario by 12% (95% UR: 6%-20%) and 11% (95% UR: 6%-20%), respectively, compared to current-care projections. An optimal RR TB regimen reduced RR TB incidence by an estimated 32% (95% UR: 18%-46%) and RR TB mortality by 30% (95% UR: 18%-44%). Efficacy was the greatest determinant of impact; compared to a novel regimen meeting all minimal targets only, increasing RS TB treatment efficacy from 94% to 99% reduced TB mortality by 6% (95% UR: 1%-13%, half the impact of a fully optimized regimen), and increasing the efficacy against RR TB from 76% to 94% lowered RR TB mortality by 13% (95% UR: 6%-23%). Reducing treatment duration or improving ease of adherence had smaller but still substantial impact: shortening RS TB treatment duration from 6 to 2 mo lowered TB mortality by 3% (95% UR: 1%-6%), and shortening RR TB treatment from 20 to 6 mo reduced RR TB mortality by 8% (95% UR: 4%-13%), while reducing nonadherence to the corresponding regimens by 50% reduced TB and RR TB mortality by 2% (95% UR: 1%-4%) and 6% (95% UR: 3%-10%), respectively. Limitations include sparse data on key model parameters and necessary simplifications to model structure and outcomes. CONCLUSIONS: In designing clinical trials of novel TB regimens, investigators should consider that even small changes in treatment efficacy may have considerable impact on TB-related incidence and mortality. Other regimen improvements may still have important benefits for resource allocation and outcomes such as patient quality of life.

- December 2016 -

Second line drug susceptibility testing to inform the treatment of rifampin-resistant tuberculosis: a quantitative perspective. (2016). Kendall EA., Cohen T., Mitnick CD., Dowdy DW, International journal of infectious diseases : IJID : official publication of the International Society for Infectious Diseases, 56, 185-189

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Treatment failure and resistance amplification are common among patients with rifampin-resistant tuberculosis (TB). Drug susceptibility testing (DST) for second-line drugs is recommended for these patients, but logistical difficulties have impeded widespread implementation of second-line DST in many settings. To provide a quantitative perspective on the decision to scale up second-line DST, we synthesize literature on the prevalence of second-line drug resistance, the expected clinical and epidemiologic benefits of using second-line DST to ensure that patients with rifampin-resistant TB receive effective regimens, and the costs of implementing (or not implementing) second-line DST for all individuals diagnosed with rifampin-resistant TB. We conclude that, in most settings, second-line DST could substantially improve treatment outcomes for patients with rifampin-resistant TB, reduce transmission of drug-resistant TB, prevent amplification of drug resistance, and be affordable or even cost-saving. Given the large investment made in each patient treated for rifampin-resistant TB, these payoffs would come at relatively small incremental cost. These anticipated benefits likely justify addressing the real challenges faced in implementing second-line DST in most high-burden settings.

Expected effects of adopting a 9 month regimen for multidrug-resistant tuberculosis: a population modelling analysis. (2016). Kendall EA., Fojo AT., Dowdy DW, The Lancet. Respiratory medicine, 5, 191-199

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BACKGROUND: In May, 2016, WHO endorsed a 9 month regimen for multidrug-resistant tuberculosis that is cheaper and potentially more effective than the conventional, longer (20-24 month) therapy. We aimed to investigate the population-level implications of scaling up this new regimen. METHODS: In this population modelling analysis, we developed a dynamic transmission model to simulate the introduction of this short-course regimen as an instantaneous switch in 2016. We projected the corresponding percentage reduction in the incidence of multidrug-resistant tuberculosis by 2024 compared with continued use of longer therapy. In the primary analysis in a representative southeast Asian setting, we assumed that the short-course regimen would double treatment access (through savings in resources or capacity) and achieve long-term efficacy at levels seen in preliminary cohort studies. We then did extensive sensitivity analyses to explore a range of alternative scenarios. FINDINGS: Under the optimistic assumptions in the primary analysis, the incidence of multidrug-resistant tuberculosis in 2024 would be 3.3 (95% uncertainty range 2.2-5.6) per 100 000 population with the short-course regimen and 4.3 (2.9-7.6) per 100 000 population with continued use of longer therapy-ie, the short-course regimen could reduce incidence by 23% (10-38). Incidence would be reduced by 14% (4-28) if the new regimen affected only treatment effectiveness and by 11% (3-24) if it affected only treatment availability. Under more pessimistic assumptions, the short-course regimen would have minimal effect and even potential for harm-eg, when 30% of patients are ineligible for the new regimen because of second-line drug resistance, we projected a change in incidence of -2% (-20 to +28). The new regimen's effect was greater in settings with more ongoing transmission of multidrug-resistant tuberculosis, but results were otherwise similar across settings with different levels of tuberculosis incidence and prevalence of multidrug resistance. INTERPRETATION: The short-course regimen has potential to substantially lessen the multidrug-resistant tuberculosis epidemic, but this effect depends on its long-term efficacy, its ability to expand treatment access, and the role of second-line drug resistance. FUNDING: US National Institutes of Health and Bill & Melinda Gates Foundation.

Minding the Gap: Specimen Referral Systems for Diagnosis of Infectious Diseases. (2016). Dowdy DW, Clinical infectious diseases : an official publication of the Infectious Diseases Society of America, 64, 804-805

A Multistrain Mathematical Model To Investigate the Role of Pyrazinamide in the Emergence of Extensively Drug-Resistant Tuberculosis. (2016). Fofana MO., Shrestha S., Knight GM., Cohen T., White RG., Cobelens F., Dowdy DW, Antimicrobial agents and chemotherapy, 61

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Several infectious diseases of global importance-e.g., HIV infection and tuberculosis (TB)-require prolonged treatment with combination antimicrobial regimens typically involving high-potency core agents coupled with additional companion drugs that protect against the de novo emergence of mutations conferring resistance to the core agents. Often, the most effective (or least toxic) companion agents are reused in sequential (first-line, second-line, etc.) regimens. We used a multistrain model of Mycobacterium tuberculosis transmission in Southeast Asia to investigate how this practice might facilitate the emergence of extensive drug resistance, i.e., resistance to multiple core agents. We calibrated this model to regional TB and drug resistance data using an approximate Bayesian computational approach. We report the proportion of data-consistent simulations in which the prevalence of pre-extensively drug-resistant (pre-XDR) TB-defined as resistance to both first-line and second-line core agents (rifampin and fluoroquinolones)-exceeds predefined acceptability thresholds (1 to 2 cases per 100,000 population by 2035). The use of pyrazinamide (the most effective companion agent) in both first-line and second-line regimens increased the proportion of simulations in which the prevalence exceeded the pre-XDR acceptability threshold by 7-fold compared to a scenario in which patients with pyrazinamide-resistant TB received an alternative drug. Model parameters related to the emergence and transmission of pyrazinamide-resistant TB and resistance amplification were among those that were the most strongly correlated with the projected pre-XDR prevalence, indicating that pyrazinamide resistance acquired during first-line treatment subsequently promotes amplification to pre-XDR TB under pyrazinamide-containing second-line treatment. These findings suggest that the appropriate use of companion drugs may be critical to preventing the emergence of strains resistant to multiple core agents.

Clinical and epidemiological characteristics associated with unfavorable tuberculosis treatment outcomes in TB-HIV co-infected patients in Brazil: a hierarchical polytomous analysis. (2016). Prado TN., Rajan JV., Miranda AE., Dias ED., Cosme LB., Possuelo LG., Sanchez MN., Golub JE., Riley LW., Maciel EL, The Brazilian journal of infectious diseases : an official publication of the Brazilian Society of Infectious Diseases, 21, 162-170

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BACKGROUND: TB patients co-infected with HIV have worse treatment outcomes than non-coinfected patients. How clinical characteristics of TB and socioeconomic characteristics influence these outcomes is poorly understood. Here, we use polytomous regression analysis to identify clinical and epidemiological characteristics associated with unfavorable treatment outcomes among TB-HIV co-infected patients in Brazil. METHODS: TB-HIV cases reported in the Brazilian information system (SINAN) between January 1, 2001 and December 31, 2011 were identified and categorized by TB treatment outcome (cure, default, death, and development of MDR TB). We modeled treatment outcome as a function of clinical characteristics of TB and patient socioeconomic characteristics by polytomous regression analysis. For each treatment outcome, we used cure as the reference outcome. RESULTS: Between 2001 and 2011, 990,017 cases of TB were reported in SINAN, of which 93,147 (9.4%) were HIV co-infected. Patients aged 15-19 (OR=2.86; 95% CI: 2.09-3.91) and 20-39 years old (OR=2.30; 95% CI: 1.81-2.92) were more likely to default on TB treatment than those aged 0-14 years old. In contrast, patients aged >/=60 years were more likely to die from TB (OR=2.22; 95% CI: 1.43-3.44) or other causes (OR=2.86; 95% CI: 2.14-3.83). Black patients were more likely to default on TB treatment (OR=1.33; 95% CI: 1.22-1.44) and die from TB (OR=1.50; 95% CI: 1.29-1.74). Finally, alcoholism was associated with all unfavorable outcomes: default (OR=1.94; 95% CI: 1.73-2.17), death due to TB (OR=1.46; 95% CI: 1.25-1.71), death due to other causes (OR=1.38; 95% CI: 1.21-1.57) and MDR-TB (OR=2.29; 95% CI: 1.46-3.58). CONCLUSIONS: Socio-economic vulnerability has a significant effect on treatment outcomes among TB-HIV co-infected patients in Brazil. Enhancing social support, incorporation of alcohol abuse screening and counseling into current TB surveillance programs and targeting interventions to specific age groups are interventions that could improve treatment outcomes.

Cost and cost-effectiveness of tuberculosis treatment shortening: a model-based analysis. (2016). Gomez GB., Dowdy DW., Bastos ML., Zwerling A., Sweeney S., Foster N., Trajman A., Islam MA., Kapiga S., Sinanovic E., Knight GM., White RG., Wells WA., Cobelens FG., Vassall A, BMC infectious diseases, 16, 726

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BACKGROUND: Despite improvements in treatment success rates for tuberculosis (TB), current six-month regimen duration remains a challenge for many National TB Programmes, health systems, and patients. There is increasing investment in the development of shortened regimens with a number of candidates in phase 3 trials. METHODS: We developed an individual-based decision analytic model to assess the cost-effectiveness of a hypothetical four-month regimen for first-line treatment of TB, assuming non-inferiority to current regimens of six-month duration. The model was populated using extensive, empirically-collected data to estimate the economic impact on both health systems and patients of regimen shortening for first-line TB treatment in South Africa, Brazil, Bangladesh, and Tanzania. We explicitly considered 'real world' constraints such as sub-optimal guideline adherence. RESULTS: From a societal perspective, a shortened regimen, priced at USD1 per day, could be a cost-saving option in South Africa, Brazil, and Tanzania, but would not be cost-effective in Bangladesh when compared to one gross domestic product (GDP) per capita. Incorporating 'real world' constraints reduces cost-effectiveness. Patient-incurred costs could be reduced in all settings. From a health service perspective, increased drug costs need to be balanced against decreased delivery costs. The new regimen would remain a cost-effective option, when compared to each countries' GDP per capita, even if new drugs cost up to USD7.5 and USD53.8 per day in South Africa and Brazil; this threshold was above USD1 in Tanzania and under USD1 in Bangladesh. CONCLUSION: Reducing the duration of first-line TB treatment has the potential for substantial economic gains from a patient perspective. The potential economic gains for health services may also be important, but will be context-specific and dependent on the appropriate pricing of any new regimen.

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