Multidrug-Resistant Tuberculosis Treatment Outcomes in Relation to Treatment and Initial Versus Acquired Second-Line Drug Resistance.

BACKGROUND: Resistance to second-line drugs develops during treatment of multidrug-resistant (MDR) tuberculosis, but the impact on treatment outcome has not been determined. METHODS: Patients with MDR tuberculosis starting second-line drug treatment were enrolled in a prospective cohort study. Sputum cultures were analyzed at a central reference laboratory. We compared subjects with successful and poor treatment outcomes in terms of (1) initial and acquired resistance to fluoroquinolones and second-line injectable drugs (SLIs) and (2) treatment regimens. RESULTS: Of 1244 patients with MDR tuberculosis, 973 (78.2%) had known outcomes and 232 (18.6%) were lost to follow-up. Among those with known outcomes, treatment succeeded in 85.8% with plain MDR tuberculosis, 69.7% with initial resistance to either a fluoroquinolone or an SLI, 37.5% with acquired resistance to a fluoroquinolone or SLI, 29.3% with initial and 13.0% with acquired extensively drug-resistant tuberculosis (P < .001 for trend). In contrast, among those with known outcomes, treatment success increased stepwise from 41.6% to 92.3% as the number of drugs proven effective increased from ≤1 to ≥5 (P < .001 for trend), while acquired drug resistance decreased from 12% to 16% range, depending on the drug, down to 0%-2% (P < .001 for trend). In multivariable analysis, the adjusted odds of treatment success decreased 0.62-fold (95% confidence interval, .56-.69) for each increment in drug resistance and increased 2.1-fold (1.40-3.18) for each additional effective drug, controlling for differences between programs and patients. Specific treatment, patient, and program variables were also associated with treatment outcome. CONCLUSIONS: Increasing drug resistance was associated in a logical stepwise manner with poor treatment outcomes. Acquired resistance was worse than initial resistance to the same drugs. Increasing numbers of effective drugs, specific drugs, and specific program characteristics were associated with better outcomes and less acquired resistance.

Impact of HIV on mortality among patients treated for tuberculosis in Lima, Peru: a prospective cohort study.

BACKGROUND: Human immunodeficiency virus (HIV)-associated tuberculosis deaths have decreased worldwide over the past decade. We sought to evaluate the effect of HIV status on tuberculosis mortality among patients undergoing treatment for tuberculosis in Lima, Peru, a low HIV prevalence setting. METHODS: We conducted a prospective cohort study of patients treated for tuberculosis between 2005 and 2008 in two adjacent health regions in Lima, Peru (Lima Ciudad and Lima Este). We constructed a multivariate Cox proportional hazards model to evaluate the effect of HIV status on mortality during tuberculosis treatment. RESULTS: Of 1701 participants treated for tuberculosis, 136 (8.0%) died during tuberculosis treatment. HIV-positive patients constituted 11.0% of the cohort and contributed to 34.6% of all deaths. HIV-positive patients were significantly more likely to die (25.1 vs. 5.9%, P < 0.001) and less likely to be cured (28.3 vs. 39.4%, P = 0.003). On multivariate analysis, positive HIV status (hazard ratio [HR] = 6.06; 95% confidence interval [CI], 3.96-9.27), unemployment (HR = 2.24; 95% CI, 1.55-3.25), and sputum acid-fast bacilli smear positivity (HR = 1.91; 95% CI, 1.10-3.31) were significantly associated with a higher hazard of death. CONCLUSIONS: We demonstrate that positive HIV status was a strong predictor of mortality among patients treated for tuberculosis in the early years after Peru started providing free antiretroviral therapy. As HIV diagnosis and antiretroviral therapy provision are more widely implemented for tuberculosis patients in Peru, future operational research should document the changing profile of HIV-associated tuberculosis mortality.

Targeted drug-resistance testing strategy for multidrug-resistant tuberculosis detection, Lima, Peru, 2005-2008.

The Peruvian National Tuberculosis Control Program issued guidelines in 2006 specifying criteria for culture and drug-susceptibility testing (DST), including district-level rapid DST. All patients referred for culture and DST in 2 districts of Lima, Peru, during January 2005-November 2008 were monitored prospectively. Of 1,846 patients, 1,241 (67.2%) had complete DST results for isoniazid and rifampin; 419 (33.8%) patients had multidrug-resistant (MDR) TB at the time of referral. Among patients with new smear-positive TB, household contact and suspected category I failure were associated with MDR TB, compared with concurrent regional surveillance data. Among previously treated patients with smear-positive TB, adult household contact, suspected category II failure, early relapse after category I, and multiple previous TB treatments were associated with MDR TB, compared with concurrent regional surveillance data. The proportion of MDR TB detected by using guidelines was higher than that detected by a concurrent national drug-resistance survey, indicating that the strategy effectively identified patients for DST.

Scale-up of multidrug-resistant tuberculosis laboratory services, Peru.

Over the past 10 years, the Peruvian National Tuberculosis (TB) Program, the National Reference Laboratory (NRL), Socios en Salud, and US partners have worked to strengthen the national TB laboratory network to support treatment of multidrug-resistant TB. We review key lessons of this experience. The preparation phase involved establishing criteria for drug susceptibility testing (DST), selecting appropriate DST methods, projecting the quantity of DST and culture to ensure adequate supplies, creating biosafe laboratory facilities for DST, training laboratory personnel on methods, and validating DST methods at the NRL. Implementation involved training providers on DST indications, validating conventional and rapid first-line DST methods at district laboratories, and eliminating additional delays in specimen transport and result reporting. Monitoring included ongoing quality control and quality assurance procedures. Hurdles included logistics, coordinating with policy, competing interests, changing personnel, communications, and evaluation. Operational research guided laboratory scale-up and identified barriers to effective capacity building.

A web-based laboratory information system to improve quality of care of tuberculosis patients in Peru: functional requirements, implementation and usage statistics.

BACKGROUND: Multi-drug resistant tuberculosis patients in resource-poor settings experience large delays in starting appropriate treatment and may not be monitored appropriately due to an overburdened laboratory system, delays in communication of results, and missing or error-prone laboratory data. The objective of this paper is to describe an electronic laboratory information system implemented to alleviate these problems and its expanding use by the Peruvian public sector, as well as examine the broader issues of implementing such systems in resource-poor settings. METHODS: A web-based laboratory information system "e-Chasqui" has been designed and implemented in Peru to improve the timeliness and quality of laboratory data. It was deployed in the national TB laboratory, two regional laboratories and twelve pilot health centres. Using needs assessment and workflow analysis tools, e-Chasqui was designed to provide for improved patient care, increased quality control, and more efficient laboratory monitoring and reporting. RESULTS: Since its full implementation in March 2006, 29,944 smear microscopy, 31,797 culture and 7,675 drug susceptibility test results have been entered. Over 99% of these results have been viewed online by the health centres. High user satisfaction and heavy use have led to the expansion of e-Chasqui to additional institutions. In total, e-Chasqui will serve a network of institutions providing medical care for over 3.1 million people. The cost to maintain this system is approximately US$0.53 per sample or 1% of the National Peruvian TB program's 2006 budget. CONCLUSION: Electronic laboratory information systems have a large potential to improve patient care and public health monitoring in resource-poor settings. Some of the challenges faced in these settings, such as lack of trained personnel, limited transportation, and large coverage areas, are obstacles that a well-designed system can overcome. e-Chasqui has the potential to provide a national TB laboratory network in Peru. Furthermore, the core functionality of e-Chasqui as been implemented in the open source medical record system OpenMRS http://www.openmrs.org for other countries to use.

Reducing communication delays and improving quality of care with a tuberculosis laboratory information system in resource poor environments: a cluster randomized controlled trial.

BACKGROUND: Lost, delayed or incorrect laboratory results are associated with delays in initiating treatment. Delays in treatment for Multi-Drug Resistant Tuberculosis (MDR-TB) can worsen patient outcomes and increase transmission. The objective of this study was to evaluate the impact of a laboratory information system in reducing delays and the time for MDR-TB patients to culture convert (stop transmitting). SETTING: 78 primary Health Centers (HCs) in Lima, Peru. Participants lived within the catchment area of participating HCs and had at least one MDR-TB risk factor. The study design was a cluster randomized controlled trial with baseline data. The intervention was the e-Chasqui web-based laboratory information system. Main outcome measures were: times to communicate a result; to start or change a patient's treatment; and for that patient to culture convert. RESULTS: 1671 patients were enrolled. Intervention HCs took significantly less time to receive drug susceptibility test (DST) (median 11 vs. 17 days, Hazard Ratio 0.67 [0.62-0.72]) and culture (5 vs. 8 days, 0.68 [0.65-0.72]) results. The time to treatment was not significantly different, but patients in intervention HCs took 16 days (20%) less time to culture convert (p = 0.047). CONCLUSIONS: The eChasqui system reduced the time to communicate results between laboratories and HCs and time to culture conversion. It is now used in over 259 HCs covering 4.1 million people. This is the first randomized controlled trial of a laboratory information system in a developing country for any disease and the only study worldwide to show clinical impact of such a system. TRIAL REGISTRATION: ClinicalTrials.gov NCT01201941.

[Cost analysis of rapid methods for diagnosis of multidrug resistant tuberculosis in different epidemiologic groups in Perú]. / Análisis de costos de los métodos rápidos para diagnóstico de tuberculosis multidrogorresistente en diferentes grupos epidemiológicos del Perú.

OBJECTIVES: To evaluate the costs of three methods for the diagnosis of drug susceptibility in tuberculosis, and to compare the cost per case of Multidrug-resistant tuberculosis (MDR TB) diagnosed with these (MODS, GRIESS and Genotype MTBDR plus®) in 4 epidemiologic groups in Peru. MATERIALS AND METHODS: In the basis of programmatic figures, we divided the population in 4 groups: new cases from Lima/Callao, new cases from other provinces, previously treated patients from Lima/Callao and previously treated from other provinces. We calculated the costs of each test with the standard methodology of the Ministry of Health, from the perspective of the health system. Finally, we calculated the cost per patient diagnosed with MDR TB for each epidemiologic group. RESULTS: The estimated costs per test for MODS, GRIESS, and Genotype MTBDR plus® were 14.83. 15.51 and 176.41 nuevos soles respectively (the local currency, 1 nuevos sol=0.36 US dollars for August, 2011). The cost per patient diagnosed with GRIESS and MODS was lower than 200 nuevos soles in 3 out of the 4 groups. The costs per diagnosed MDR TB were higher than 2,000 nuevos soles with Genotype MTBDR plus® in the two groups of new patients, and lower than 1,000 nuevos soles in the group of previously treated patients. CONCLUSIONS: In high-prevalence groups, like the previously treated patients, the costs per diagnosis of MDR TB with the 3 evaluated tests were low, nevertheless, the costs with the molecular test in the low- prevalence groups were high. The use of the molecular tests must be optimized in high prevalence areas.

Full impact of laboratory information system requires direct use by clinical staff: cluster randomized controlled trial.

OBJECTIVE: To evaluate the time to communicate laboratory results to health centers (HCs) between the e-Chasqui web-based information system and the pre-existing paper-based system. METHODS: Cluster randomized controlled trial in 78 HCs in Peru. In the intervention group, 12 HCs had web access to results via e-Chasqui (point-of-care HCs) and forwarded results to 17 peripheral HCs. In the control group, 22 point-of-care HCs received paper results directly and forwarded them to 27 peripheral HCs. Baseline data were collected for 15 months. Post-randomization data were collected for at least 2 years. Comparisons were made between intervention and control groups, stratified by point-of-care versus peripheral HCs. RESULTS: For point-of-care HCs, the intervention group took less time to receive drug susceptibility tests (DSTs) (median 9 vs 16 days, p<0.001) and culture results (4 vs 8 days, p<0.001) and had a lower proportion of 'late' DSTs taking >60 days to arrive (p<0.001) than the control. For peripheral HCs, the intervention group had similar communication times for DST (median 22 vs 19 days, p=0.30) and culture (10 vs 9 days, p=0.10) results, as well as proportion of 'late' DSTs (p=0.57) compared with the control. CONCLUSIONS: Only point-of-care HCs with direct access to the e-Chasqui information system had reduced communication times and fewer results with delays of >2 months. Peripheral HCs had no benefits from the system. This suggests that health establishments should have point-of-care access to reap the benefits of electronic laboratory reporting.

Using the e-Chasqui, web-based information system, to determine laboratory guidelines and data available to clinical staff.

13% of all drug susceptibility tests (DSTs) performed at a public laboratory in Peru were duplicate. To determine reasons for duplicate requests an online survey was implemented in the e-Chasqui laboratory information system. Results showed that 59.6% of tests were ordered because clinical staff was unaware of ordering guidelines or of a previous result. This shows a benefit of using a web-based system and the lack of laboratory information available to clinical staff in Peru.

Assessing effects of the e-Chasqui laboratory information system on accuracy and timeliness of bacteriology results in the Peruvian tuberculosis program.

We created a web-based laboratory information system, e-Chasqui to connect public laboratories to health centers to improve communication and analysis. After one year, we performed a pre and post assessment of communication delays and found that e-Chasqui maintained the average delay but eliminated delays of over 60 days. Adding digital verification maintained the average delay, but should increase accuracy. We are currently performing a randomized evaluation of the impacts of e-Chasqui.

Análisis de costos de los métodos rápidos para diagnóstico de Tuberculosis multidrogorresistente en diferentes grupos epidemiológicos del Perú / Cost analysis of rapid methods for diagnosis of multidrug resistant Tuberculosis in different epidemiologic groups in Perú

Objetivos. Evaluar los costos de tres métodos diagnósticos para susceptibilidad a drogas antituberculosas y comparar el costo por caso de tuberculosis multidrogorresistente (TB MDR) diagnosticado con estos (MODS; GRIESS y Genotype MTBDR plus ® en cuatro grupos epidemiológicos en el Perú. Materiales y métodos. En base a cifras programáticas, se dividió a la población en cuatro grupos: pacientes nuevos de Lima/Callao; nuevos de otras provincias; los antes tratados de Lima/Callao y de otras provincias. Se calcularon los costos de cada prueba en base a la metodología estándar utilizada por el Ministerio de Salud, desde la perspectiva de los servicios de salud. Basado en ello, se calculó el costo por paciente TB MDR diagnosticado para cada grupo epidemiológico. Resultados. Los costos estimados por prueba para MODS, GRIESS, y Genotype MTBDR plus ® fueron de 14,83; 15,51 y 176,41 nuevos soles, respectivamente. El costo por paciente TB MDR diagnosticado con GRIESS y MODS fue menor a los 200 nuevos soles en tres de los cuatro grupos. El costo por TB MDR diagnosticado fue de más de 2000 nuevos soles con el Genotype MTBDR plus ® en los dos grupos de pacientes nuevos y, menores a 1000 nuevos soles en los grupos de pacientes antes tratados. Conclusiones. En grupos de alta prevalencia, como son los pacientes antes tratados, los costos por caso diagnosticado de TB MDR con las tres pruebas evaluadas fueron bajos, sin embargo, con la prueba molecular en los grupos de baja prevalencia, fueron elevados. El uso de las pruebas moleculares debe optimizarse en grupos de altas prevalencias.

Objectives.To evaluate the costs of three methods for the diagnosis of drug susceptibility in tuberculosis, and to compare the cost per case of Multidrug-resistant tuberculosis (MDR TB) diagnosed with these (MODS, GRIESS and Genotype MTBDR plus ® in 4 epidemiologic groups in Peru. Materials and methods.In the basis of programmatic figures, we divided the population in 4 groups: new cases from Lima/Callao, new cases from other provinces, previously treated patients from Lima/Callao and previously treated from other provinces. We calculated the costs of each test with the standard methodology of the Ministry of Health, from the perspective of the health system. Finally, we calculated the cost per patient diagnosed with MDR TB for each epidemiologic group. Results. The estimated costs per test for MODS, GRIESS, and Genotype MTBDR plus® were 14.83. 15.51 and 176.41 nuevos soles respectively (the local currency, 1 nuevos sol=0.36 US dollars for August, 2011). The cost per patient diagnosed with GRIESS and MODS was lower than 200 nuevos soles in 3 out of the 4 groups. The costs per diagnosed MDR TB were higher than 2,000 nuevos soles with Genotype MTBDR plus ® in the two groups of new patients, and lower than 1,000 nuevos soles in the group of previously treated patients. Conclusions. In high-prevalence groups, like the previously treated patients, the costs per diagnosis of MDR TB with the 3 evaluated tests were low, nevertheless, the costs with the molecular test in the low- prevalence groups were high. The use of the molecular tests must be optimized in high prevalence areas.