The affordability for patients of a new universal MDR-TB coverage model in China.
Ruan YZ, Li RZ, Wang XX, Wang LX, Sun Q, Chen C, Xu CH, Su W, Zhao J, Pang Y, Cheng J, Wang Q, Fu YT, Huan ST, Chen MT, Scano F,Floyd K, Chin DP, Fitzpatrick C.
Int J Tuberc Lung Dis. 2016 May;20(5):638-44. doi: 10.5588/ijtld.15.0413.
BACKGROUND: China has piloted a new model of universal coverage for multidrug-resistant tuberculosis (MDR-TB), designed to rationalize hospital use of drugs and tests and move away from fee-for-service payment towards a standard package with financial protection against catastrophic health costs.
OBJECTIVE: To evaluate the affordability to patients of this new model.
DESIGN: This was an observational study of 243 MDR-TB cases eligible for enrolment on treatment under the project. We assessed the affordability of the project from the perspective of households, with a focus on catastrophic costs.
RESULTS: Of the 243 eligible cases, 172 (71%) were enrolled on treatment; of the 71 cases not enrolled, 26 (37%) cited economic reasons. The 73 surveyed cases paid an average of RMB 5977 (US$920) out-of-pocket in search costs incurred outside the pilot model. Within the pilot, they paid another RMB 2094 (US$322) in medical fees and RMB 5230 (US$805) in direct non-medical costs. Despite 90% reimbursement of medical fees, 78% of households experienced catastrophic costs, including indirect costs.
CONCLUSION:The objectives of the pilot model are aligned with health reform in China and universal health coverage globally. Enrollment would almost certainly be higher with 100% reimbursement of medical fees, but patient enablers will be required to truly eliminate catastrophic costs.
A performance evaluation of MTBDRplus version 2 for the diagnosis of multidrug-resistant tuberculosis.
Seifert M, Ajbani K, Georghiou SB, Catanzaro D, Rodrigues C, Crudu V, Victor TC, Garfein RS, Catanzaro A, Rodwell TC.
Int J Tuberc Lung Dis. 2016 May;20(5):631-7. doi: 10.5588/ijtld.15.0788.
OBJECTIVE:To evaluate the performance of a recently updated rapid molecular diagnostic test, GenoType(®) MTBDRplus version 2, designed to detect drug resistance in both acid-fast bacilli (AFB) smear-negative and -positive specimens.
DESIGN: Sputum samples from 1128 patients at risk for multidrug-resistant tuberculosis (MDR-TB) were tested using MTBDRplus v2 and compared with reference standard MGIT™ 960™ drug susceptibility testing. The relationship of participant human immunodeficiency virus (HIV) status, diabetic status, previous treatment, and smear gradation to the likelihood of obtaining an interpretable result was assessed using logistic regression.
RESULTS:The sensitivity and specificity of MTBDRplus v2 for detecting MDR-TB, when compared to a reference standard, were respectively 96.0% (95%CI 93.5-97.6) and 99.2% (95%CI 97.0-99.9) in AFB smear-positive specimens and 82.8% (95%CI 63.5-93.5) and 98.3% (95%CI 89.9-99.9) in AFB smear-negative specimens. A dose-response relationship was observed between the proportion of interpretable test results and AFB smear bacterial load after adjusting for age, sex, body mass index, HIV status, previous treatment and diabetic status.
CONCLUSION:While MTBDRplus v2 performs well among both AFB smear-positive and -negative specimens, smear gradation appears to influence both the probability of obtaining an interpretable result and test sensitivity, indicating a significant association between bacillary load and test performance.
A Multi-Center Non-inferiority Evaluation of Hain GenoType MTBDRplus Version 2 and Nipro NTM+MDRTB line probe assays for the diagnosis of Rifampin and Isoniazid Resistance.
Nathavitharana RR, Hillemann D, Schumacher SG, Schlueter B, Ismail N, Vally Omar S, Sikhondze W, Havumaki J, Valli E, Boehme C, Denkinger CM.
J Clin Microbiol. 2016 Apr 13. pii: JCM.00251-16. [Epub ahead of print]
INTRODUCTION:Under 30% of MDR-TB patients are currently diagnosed due to laboratory constraints. Molecular diagnostics enable rapid and simplified diagnosis. Newer version line probe assays have not been evaluated against the WHO-endorsed GenoType® MTBDRplus(HainV1) for the rapid detection of rifampin (RIF) and isoniazid (INH) resistance.
METHODS:A two-phase non-inferiority study was conducted in two supra-national reference laboratories to allow head-to-head comparisons of two new tests (HainV2, Nipro) to HainV1. In phase 1, results for 379 test strains were compared to a composite reference standard using phenotypic DST and targeted sequencing. In phase 2, results for 644 sputum samples were compared to phenotypic DST.
RESULTS:Using a challenging set of strains in phase 1, sensitivity and specificity for HainV1, HainV2 and Nipro for RIF resistance detection were 90.3%/98.5%, 90.3%/98.5% and 92.0%/98.5% respectively and 89.1%/99.4%, 89.1%/99.4% and 89.6%/100.0% for INH resistance detection. Testing of sputa in phase 2 yielded a sensitivity and specificity of 97.1%/97.1%, 98.2%/97.8% and 96.5%/97.5% for RIF and 94.4%/96.4%, 95.4%/98.8% and 94.9%/97.6% for INH. Overall indeterminate rates were low but there was a higher rate of indeterminate results with Nipro compared to HainV1 and V2 in samples with low smear-grade.
CONCLUSION:Non-inferiority of HainV2 and Nipro to HainV1 was demonstrated for RIF and INH resistance detection in isolates and sputum specimens. These results support WHO endorsement of HainV2 and Nipro assays for MDR-TB detection.
Comparison of effectiveness and safety of imipenem/clavulanate- versus meropenem/clavulanate-containing regimens in the treatment of MDR- and XDR-TB.
Tiberi S, Sotgiu G, D’Ambrosio L, Centis R, Abdo Arbex M, Alarcon Arrascue E, Alffenaar JW, Caminero JA, Gaga M, Gualano G, Skrahina A, Solovic I, Sulis G, Tadolini M, Alarcon Guizado V, De Lorenzo S, Roby Arias AJ, Scardigli A, Akkerman OW, Aleksa A, Artsukevich J, Auchynka V,Bonini EH, Chong Marín FA, Collahuazo López L, de Vries G, Dore S, Kunst H, Matteelli A, Moschos C, Palmieri F, Papavasileiou A, Payen MC,Piana A, Spanevello A, Vargas Vasquez D, Viggiani P, White V, Zumla A, Migliori GB.
Eur Respir J. 2016 Apr 13. pii: ERJ-00214-2016. doi: 10.1183/13993003.00214-2016. [Epub ahead of print]
No large study to date has ever evaluated the effectiveness, safety and tolerability of imipenem/clavulanateversusmeropenem/clavulanate to treat multidrug- and extensively drug-resistant tuberculosis (MDR- and XDR-TB). The aim of this observational study was to compare the therapeutic contribution of imipenem/clavulanateversusmeropenem/clavulanate added to background regimens to treat MDR- and XDR-TBcases.84 patients treated with imipenem/clavulanate-containing regimens showed a similar median number of antibiotic resistances (8versus8) but more fluoroquinolone resistance (79.0%versus48.9%, p<0.0001) and higher XDR-TB prevalence (67.9%versus49.0%, p=0.01) in comparison with 96 patients exposed to meropenem/clavulanate-containing regimens. Patients were treated with imipenem/clavulanate- and meropenem/clavulanate-containing regimens for a median (interquartile range) of 187 (60-428)versus85 (49-156) days, respectively.Statistically significant differences were observed on sputum smear and culture conversion rates (79.7%versus94.8%, p=0.02 and 71.9%versus94.8%, p<0.0001, respectively) and on success rates (59.7%versus77.5%, p=0.03). Adverse events to imipenem/clavulanate and meropenem/clavulanate were reported in 5.4% and 6.5% of cases only.Our study suggests that meropenem/clavulanate is more effective than imipenem/clavulanate in treating M/XDR-TB patients.
The Impact of a Line Probe Assay Based Diagnostic Algorithm on Time to Treatment Initiation and Treatment Outcomes for Multidrug Resistant TB Patients in Arkhangelsk Region, Russia.
Eliseev P, Balantcev G, Nikishova E, Gaida A, Bogdanova E, Enarson D, Ornstein T, Detjen A, Dacombe R, Gospodarevskaya E, Phillips PP, Mann G,Squire SB, Mariandyshev A.
PLoS One. 2016 Apr 7;11(4):e0152761. doi: 10.1371/journal.pone.0152761. eCollection 2016.
BACKGROUND: In the Arkhangelsk region of Northern Russia, multidrug-resistant (MDR) tuberculosis (TB) rates in new cases are amongst the highest in the world. In 2014, MDR-TB rates reached 31.7% among new cases and 56.9% among retreatment cases. The development of new diagnostic tools allows for faster detection of both TB and MDR-TB and should lead to reduced transmission by earlier initiation of anti-TB therapy.
STUDY AIM: The PROVE-IT (Policy Relevant Outcomes from Validating Evidence on Impact) Russia study aimed to assess the impact of the implementation of line probe assay (LPA) as part of an LPA-based diagnostic algorithm for patients with presumptive MDR-TB focusing on time to treatment initiation with time from first-care seeking visit to the initiation of MDR-TB treatment rather than diagnostic accuracy as the primary outcome, and to assess treatment outcomes. We hypothesized that the implementation of LPA would result in faster time to treatment initiation and better treatment outcomes.
METHODS: A culture-based diagnostic algorithm used prior to LPA implementation was compared to an LPA-based algorithm that replaced BacTAlert and Löwenstein Jensen (LJ) for drug sensitivity testing. A total of 295 MDR-TB patients were included in the study, 163 diagnosed with the culture-based algorithm, 132 with the LPA-based algorithm.
RESULTS: Among smear positive patients, the implementation of the LPA-based algorithm was associated with a median decrease in time toMDR-TB treatment initiation of 50 and 66 days compared to the culture-based algorithm (BacTAlert and LJ respectively, p<0.001). In smear negative patients, the LPA-based algorithm was associated with a median decrease in time to MDR-TB treatment initiation of 78 days when compared to the culture-based algorithm (LJ, p<0.001). However, several weeks were still needed for treatment initiation in LPA-based algorithm, 24 days in smear positive, and 62 days in smear negative patients. Overall treatment outcomes were better in LPA-based algorithm compared to culture-based algorithm (p = 0.003). Treatment success rates at 20 months of treatment were higher in patients diagnosed with the LPA-based algorithm (65.2%) as compared to those diagnosed with the culture-based algorithm (44.8%). Mortality was also lower in the LPA-based algorithm group (7.6%) compared to the culture-based algorithm group (15.9%). There was no statistically significant difference in smear and culture conversion rates between the two algorithms.
CONCLUSION:The results of the study suggest that the introduction of LPA leads to faster time to MDR diagnosis and earlier treatment initiation as well as better treatment outcomes for patients with MDR-TB. These findings also highlight the need for further improvements within the health system to reduce both patient and diagnostic delays to truly optimize the impact of new, rapid diagnostics.
External Quality Assessment for Tuberculosis Diagnosis and Drug Resistance in the European Union: A Five Year Multicentre Implementation Study.
Nikolayevskyy V, Hillemann D, Richter E, Ahmed N, van der Werf MJ, Kodmon C, Drobniewski F, Ruesch-Gerdes S; ERLTB-Net Network.
PLoS One. 2016 Apr 7;11(4):e0152926. doi: 10.1371/journal.pone.0152926. eCollection 2016.
BACKGROUND: External quality assurance (EQA) systems are essential to ensure accurate diagnosis of TB and drug-resistant TB. The implementation of EQA through organising regular EQA rounds and identification of training needs is one of the key activities of the European TB reference laboratory network (ERLTB-Net). The aim of this study was to analyse the results of the EQA rounds in a systematic manner and to identify potential benefits as well as common problems encountered by the participants.
METHODS: The ERLTB-Net developed seven EQA modules to test laboratories’ proficiency for TB detection and drug susceptibility testing using both conventional and rapid molecular tools. All National TB Reference laboratories in the European Union and European Economic Area (EU/EEA) Member States were invited to participate in the EQA scheme.
RESULTS: A total of 32 National TB Reference laboratories participated in six EQA rounds conducted in 2010-2014. The participation rate ranged from 52.9% – 94.1% over different modules and rounds. Overall, laboratories demonstrated very good proficiency proving their ability to diagnose TB and drug-resistant TB with high accuracy in a timely manner. A small number of laboratories encountered problems with identification of specific Non-tuberculous Mycobacteria (NTMs) (N = 5) and drug susceptibility testing to Pyrazinamide, Amikacin, Capreomycin, and Ethambutol (N = 4).
CONCLUSIONS: The European TB Reference laboratories showed a steady and high level of performance in the six EQA rounds. A network such as ERLTB-Net can be instrumental in developing and implementing EQA and in establishing collaboration between laboratories to improve the diagnosis of TB in the EU/EEA.
Comparison of Xpert MTB/RIF Assay and GenoType MTBDRplus DNA Probes for Detection of Mutations Associated with Rifampicin Resistance in Mycobacterium tuberculosis.
Rahman A, Sahrin M, Afrin S, Earley K, Ahmed S, Rahman SM, Banu S.
PLoS One. 2016 Apr 7;11(4):e0152694. doi: 10.1371/journal.pone.0152694. eCollection 2016.
BACKGROUND: GeneXpert MTB/RIF (Xpert) and Genotype MTBDRplus (DRplus) are two World Health Organization (WHO) endorsed probe based molecular drug susceptibility testing (DST) methods for rapid diagnosis of drug resistant tuberculosis. Both methods target the same 81 bp Rifampicin Resistance Determining Region (RRDR) of bacterial RNA polymerase β subunit (rpoB) for detection of Rifampicin (RIF) resistance associated mutations using DNA probes. So there is a correspondence of the probes of each other and expected similarity of probe binding.
METHODS: We analyzed 92 sputum specimens by Xpert, DRplus and LJ proportion method (LJ-DST). We compared molecular DSTs with gold standard LJ-DST. We wanted to see the agreement level of two molecular methods for detection of RIF resistance associated mutations. The 81bp RRDR region of rpoB gene of discrepant cases between the two molecular methods was sequenced by Sanger sequencing.
RESULTS: The agreement of Xpert and DRplus with LJ-DST for detection of RIF susceptibility was found to be 93.5% and 92.4%, respectively. We also found 92.4% overall agreement of two molecular methods for the detection of RIF susceptibility. A total of 84 out of 92 samples (91.3%) had agreement on the molecular locus of RRDR mutation by DRplus and Xpert. Sanger sequencing of 81bp RRDR revealed that Xpert probes detected seven of eight discrepant cases correctly and DRplus was erroneous in all the eight cases.
CONCLUSION: Although the overall concordance with LJ-DST was similar for both Xpert and DRplus assay, Xpert demonstrated more accuracy in the detection of RIF susceptibility for discrepant isolates compared with DRplus. This observation would be helpful for the improvement of probe based detection of drug resistance associated mutations especially rpoB mutation in M. tuberculosis.
Management and treatment outcomes of patients enrolled in MDR-TB treatment in Viet Nam.
Phuong NT, Nhung NV, Hoa NB, Thuy HT, Takarinda KC, Tayler-Smith K, Harries AD.
Public Health Action. 2016 Mar 21;6(1):25-31. doi: 10.5588/pha.15.0068. Epub 2016 Feb 11.
SETTING: The programmatic management of drug-resistant tuberculosis (TB) in Viet Nam has been rapidly scaled up since 2009.
OBJECTIVES: To document the annual numbers of patients enrolled for multidrug-resistant tuberculosis (MDR-TB) treatment during 2010-2014and to determine characteristics and treatment outcomes of patients initiating treatment during 2010-2012.
DESIGN: A retrospective cohort study using national reports and data from the national electronic data system for drug-resistant TB.
RESULTS: The number of patients enrolled annually for MDR-TB treatment increased from 97 in 2010 to 1522 in 2014. The majority of patients were middle-aged men who had pulmonary disease and had failed a retreatment regimen; 77% had received ⩾2 courses of TB treatment. Favourable outcomes (cured and treatment completed) were attained in 73% of patients. Unfavourable outcomes included loss to follow-up (12.5%), death (8%) and failure (6.3%). Having had ⩾2 previous treatment courses and being human immunodeficiency virus-positive were associated with unfavourable outcomes.
CONCLUSION: Increasing numbers of patients are being treated for MDR-TB each year with good treatment outcomes under national programme management in Viet Nam. However, there is a need to increase case detection-currently at 30% of the estimated 5100 MDR-TBcases per year, reduce adverse outcomes and improve monitoring and evaluation.
Assessing Local Risk of Rifampicin-Resistant Tuberculosis in KwaZulu-Natal, South Africa Using Lot Quality Assurance Sampling.
Heidebrecht CL, Podewils LJ, Pym A, Mthiyane T, Cohen T.
PLoS One. 2016 Apr 6;11(4):e0153143. doi: 10.1371/journal.pone.0153143. eCollection 2016.
BACKGROUND: KwaZulu-Natal (KZN) has the highest burden of notified multidrug-resistant tuberculosis (MDR TB) and extensively drug-resistant (XDR) TB cases in South Africa. A better understanding of spatial heterogeneity in the risk of drug-resistance may help to prioritize local responses.
METHODS: Between July 2012 and June 2013, we conducted a two-way Lot Quality Assurance Sampling (LQAS) study to classify the burden of rifampicin (RIF)-resistant TB among incident TB cases notified within the catchment areas of seven laboratories in two northern and one southern district of KZN. Decision rules for classification of areas as having either a high- or low-risk of RIF resistant TB (based on proportion of RIF resistance among all TB cases) were based on consultation with local policy makers.
RESULTS: We classified five areas as high-risk and two as low-risk. High-risk areas were identified in both Southern and Northern districts, with the greatest proportion of RIF resistance observed in the northernmost area, the Manguzi community situated on the Mozambique border.
CONCLUSION: Our study revealed heterogeneity in the risk of RIF resistant disease among incident TB cases in KZN. This study demonstrates the potential for LQAS to detect geographic heterogeneity in areas where access to drug susceptibility testing is limited.
Presumptive treatment of multidrug-resistant tuberculosis in household contacts.
Parr JB, Rich ML, Keshavjee S, Franke MF, Mitnick CD, Bayona J, Becerra MC.
Int J Tuberc Lung Dis. 2016 Mar;20(3):370-5. doi: 10.5588/ijtld.15.0433.
SETTING: Multidrug-resistant tuberculosis (MDR-TB) is a growing global health threat that often requires presumptive treatment in the absence of drug susceptibility testing (DST) results.
OBJECTIVE: To compare two approaches to the treatment of MDR-TB contacts with no DST results who develop TB disease.
DESIGN: We conducted a retrospective cohort study of adults treated for TB disease who were contacts of patients living with MDR-TB. Subjects had been treated according to one of two presumptive treatment strategies: 1) regimens containing exclusively first-line drugs, and 2) regimens that included both first- and second-line drugs that were adjusted if and when DST results became available. The primary endpoint was a composite of death and treatment failure.
RESULTS: Household contacts of MDR-TB patients who developed TB disease and were treated with first-line regimens were significantly more likely to experience unfavorable end-of-treatment outcomes than those treated with presumptive MDR-TB regimens (RR 2.88, 95%CI 1.24-6.68).
CONCLUSION: Household contacts of MDR-TB patients who develop TB disease but have no DST results should receive regimens containing second-line drugs selected based on the infecting strain of the index patient. Regimens containing only first-line anti-tuberculosis drugs significantly increase the risk of unfavorable outcomes.
Direct tuberculosis drug susceptibility testing: time-saving and cost-effective in detecting MDR-TB.
Zhang T, Lv CF, Wang J, Zheng WB, Lu LZ, Liu SJ, Bao J.
Int J Tuberc Lung Dis. 2016 Mar;20(3):323-8. doi: 10.5588/ijtld.15.0637.
BACKGROUND: Recent advances have made molecular diagnosis of tuberculosis (TB) and drug susceptibility testing (DST) possible, but the high costs involved present a huge challenge. The refinement and improvement of affordable methods therefore remain a priority. Conventional indirect DST is inexpensive and reliable, but time-consuming. A direct DST method for the direct testing of sputum samples without culture has been developed to reduce the time required for DST, but there have been conflicting results.
METHODS AND RESULTS: Direct and indirect DST against isoniazid and rifampicin were performed on 208 sputum smear-positive specimens, 186 from newly diagnosed patients and 22 from previously treated patients; respectively 169 and 180 of the direct and indirect DST results were reportable. In comparison with indirect DST, direct DST resulted in a saving of on average 10.5 days. The time to direct DST results was inversely correlated with the number of acid-fast bacilli in the sputum samples.
CONCLUSION: Direct DST is highly sensitive, reliable, cost-effective and time-saving in comparison with indirect DST.
Dilemma of managing asymptomatic children referred with ‘culture-confirmed’ drug-resistant tuberculosis.
Loveday M, Sunkari B, Marais BJ, Master I, Brust JC.
Arch Dis Child. 2016 Apr 4. pii: archdischild-2015-310186. doi: 10.1136/archdischild-2015-310186. [Epub ahead of print]
BACKGROUND: The diagnosis of drug-resistant tuberculosis (DR-TB) in children is challenging and treatment is associated with many adverse effects.
OBJECTIVE: We aimed to assess if careful observation, without initiation of second-line treatment, is safe in asymptomatic children referred with ‘culture-confirmed’ DR-TB.
SETTING: KwaZulu-Natal, South Africa-an area with high burdens of HIV, TB and DR-TB.
DESIGN, INTERVENTION AND MAIN OUTCOME MEASURES: We performed an outcome review of children with ‘culture-confirmed’ DR-TB who were not initiated on second-line TB treatment, as they were asymptomatic with normal chest radiographs on examination at our specialist referral hospital. Children were followed up every other month for the first year, with a final outcome assessment at the end of the study.
RESULTS: In total, 43 asymptomatic children with normal chest radiographs were reviewed. The median length of follow-up until final evaluation was 549 days (IQR 259-722 days); most (34; 83%) children were HIV uninfected. Resistance patterns included 9 (21%) monoresistant and 34 (79%) multidrug-resistant (MDR) strains. Fifteen children (35%) had been treated with first-line TB treatment, prior to presentation at our referral hospital. At the final evaluation, 34 (80%) children were well, 7 (16%) were lost to follow-up, 1 (2%) received MDR-TB treatment and 1 (2%) died of unknown causes. The child who received MDR-TB treatment developed new symptoms at the 12-month review and responded well to second-line treatment.
CONCLUSIONS: Bacteriological evaluation should not be performed in the absence of any clinical indication. If drug-resistant Mycobacterium tuberculosis is detected in an asymptomatic child with a normal chest radiograph, close observation may be an appropriate strategy, especially in settings where potential laboratory error and poor record keeping are constant challenges.
Migration-related tuberculosis: epidemiology and characteristics of tuberculosis cases originating outside the European Union and European Economic Area, 2007 to 2013.
Ködmön C, Zucs P, van der Werf MJ.
Euro Surveill. 2016;21(12). doi: 10.2807/1560-7917.ES.2016.21.12.30164.
Migrants arriving from high tuberculosis (TB)-incidence countries may pose a significant challenge to TB control programmes in the host country. TB surveillance data for 2007-2013 submitted to the European Surveillance System were analysed. Notified TB cases were stratified by origin and reporting country. The contribution of migrant TB cases to the TB epidemiology in EU/EEA countries was analysed. Migrant TB cases accounted for 17.4% (n = 92,039) of all TB cases reported in the EU/EEA in 2007-2013, continuously increasing from 13.6% in 2007 to 21.8% in 2013. Of 91,925 migrant cases with known country of origin, 29.3% were from the Eastern Mediterranean, 23.0% from south-east Asia, 21.4% from Africa, 13.4% from the World Health Organization European Region (excluding EU/EEA), and 12.9% from other regions. Of 46,499 migrant cases with known drug-susceptibility test results, 2.9% had multidrug-resistant TB, mainly (51.7%) originating from the European Region. The increasing contribution of TB in migrants from outside the EU/EEA to the TB burden in the EU/EEA is mainly due to a decrease in native TB cases. Especially in countries with a high proportion of TB cases in non-EU/EEA migrants, targeted prevention and control initiatives may be needed to progress towards TB elimination.
What can we offer to 3 million MDRTB household contacts in 2016?
BMC Med. 2016 Apr 1;14(1):64. doi: 10.1186/s12916-016-0610-x.
The diagnosis of multidrug resistant tuberculosis (MDR-TB) in any individual is the beginning of a prolonged and difficult therapeutic journey. It also marks the moment from which to begin consideration of how to manage close contacts. Preventive therapy for drug-susceptible latent tuberculosis infection has been demonstrated to be effective at reducing the risk of future disease; the stakes are higher when considering prevention of MDR-TB because treatment of active disease is more prolonged and toxic and much less effective. This has encouraged exploration of the potential utility of preventive therapy, with second-line agents, in reducing future incident drug-resistant TB.Three clinical trials of preventive therapy for contacts of patients with MDR-TB are starting in 2015/16; results will not be available until at least 2020, so what should be offered to exposed contacts in the interim?A recent policy brief, arising from a global consultation meeting of international experts, recommended preventive therapy based upon very limited available observational data. However the many known unknowns associated with this approach, include the high proportion of index-contact pairs with discordant drug susceptibility profiles and (even if susceptibilities are shared) the lack of data supporting the use of the selected agents in the treatment of latent infection (rather than active disease).It is important to acknowledge that the alternative to offering preventive therapy is not doing nothing. On the contrary, identified contacts should be maintained under close, active surveillance for 24 months, enabling early detection of active disease in the small proportion amongst whom this may occur. Such patients should benefit from less extensive disease at diagnosis and early access to individualized therapeutic regimens with improved treatment outcomes. Moreover the vast majority of contacts that do not develop disease will benefit from avoidance of potentially toxic, unnecessary therapy.Whether preventive therapy or close observation are implemented, national programmes should maintain a register of all contacts, interventions and 24 month outcomes; these will provide important performance metrics for programmatic management of MDRTB. If harmonized and standardized internationally, such a register could rapidly yield a wealth of observational data, to complement the trial results of the future.
A call to action: Addressing the reproductive health needs of women with drug-resistant tuberculosis.
Schnippel K, Ndjeka N, Conradie F, Berhanu R, Claasen Z, Banoo S, Firnhaber C.
S Afr Med J. 2016 Mar 17;106(4):333-4. doi: 10.7196/SAMJ.2016.v106i4.10205.
Although there is substantial risk to maternal and neonatal health in the situation of pregnancy during treatment for rifampicin-resistant tuberculosis (RR-TB), there is little evidence to guide clinicians as to how to manage this complexity. Of the 49 680 patients initiated on RR-TB treatment from 2009 to 2014 in South Africa, 47% were women and 80% of them were in their reproductive years (15 – 44). There is an urgent need for increased evidence of the safety of RR-TB treatment during pregnancy, increased access to contraception during RR-TB treatment, and inclusion of reproductive health in research on the prevention and treatment of TB.
Assessment of treatment response in tuberculosis.
Rockwood N, du Bruyn E, Morris T, Wilkinson RJ.
Expert Rev Respir Med. 2016 Mar 31:1-12. [Epub ahead of print]
Antibiotic treatment of tuberculosis has a duration of several months. There is significant variability of the host immune response and the pharmacokinetic-pharmacodynamic properties of Mycobacterium tuberculosis sub-populations at the site of disease. A limitation of sputum-based measures of treatment response may be sub-optimal detection and monitoring of Mycobacterium tuberculosis sub-populations. Potential biomarkers and surrogate endpoints should be benchmarked against hard clinical outcomes (failure/relapse/death) and may need tailoring to specific patient populations. Here, we assess the evidence supporting currently utilized and future potential host and pathogen-based models and biomarkers for monitoring treatment response in active and latent tuberculosis. Biomarkers for monitoring treatment response in extrapulmonary, pediatric and drug resistant tuberculosis are research priorities.
Propensity Score-Based Approaches to Confounding by Indication in Individual Patient Data Meta-Analysis: Non-Standardized Treatment for Multidrug Resistant Tuberculosis.
Fox GJ, Benedetti A, Mitnick CD, Pai M, Menzies D; Collaborative Group for Meta-Analysis of Individual Patient Data in MDR-TB.
PLoS One. 2016 Mar 29;11(3):e0151724. doi: 10.1371/journal.pone.0151724. eCollection 2016.
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.
Rationing tests for drug-resistant tuberculosis – who are we prepared to miss?
Martin LJ, Roper MH, Grandjean L, Gilman RH, Coronel J, Caviedes L, Friedland JS, Moore DA.
BMC Med. 2016 Mar 23;14(1):30. doi: 10.1186/s12916-016-0576-8.
BACKGROUND:Early identification of patients with drug-resistant tuberculosis (DR-TB) increases the likelihood of treatment success and interrupts transmission. Resource-constrained settings use risk profiling to ration the use of drug susceptibility testing (DST). Nevertheless, no studies have yet quantified how many patients with DR-TB this strategy will miss.
METHODS: A total of 1,545 subjects, who presented to Lima health centres with possible TB symptoms, completed a clinic-epidemiological questionnaire and provided sputum samples for TB culture and DST. The proportion of drug resistance in this population was calculated and the data was analysed to demonstrate the effect of rationing tests to patients with multidrug-resistant TB (MDR-TB) risk factors on the number of tests needed and corresponding proportion of missed patients with DR-TB.
RESULTS: Overall, 147/1,545 (9.5 %) subjects had culture-positive TB, of which 32 (21.8 %) had DR-TB (MDR, 13.6 %; isoniazid mono-resistant, 7.5 %; rifampicin mono-resistant, 0.7 %). A total of 553 subjects (35.8 %) reported one or more MDR-TB risk factors; of these, 506 (91.5 %; 95 % CI, 88.9-93.7 %) did not have TB, 32/553 (5.8 %; 95 % CI, 3.4-8.1 %) had drug-susceptible TB, and only 15/553 (2.7 %; 95 % CI, 1.5-4.4 %) hadDR-TB. Rationing DST to those with an MDR-TB risk factor would have missed more than half of the DR-TB population (17/32, 53.2 %; 95 % CI, 34.7-70.9).
CONCLUSIONS: Rationing DST based on known MDR-TB risk factors misses an unacceptable proportion of patients with drug-resistance in settings with ongoing DR-TB transmission. Investment in diagnostic services to allow universal DST for people with presumptive TB should be a high priority.
Mycobacterium tuberculosis whole genome sequencing and protein structure modelling provides insights into anti-tuberculosis drug resistance.
Phelan J, Coll F, McNerney R, Ascher DB, Pires DE, Furnham N, Coeck N, Hill-Cawthorne GA, Nair MB, Mallard K, Ramsay A, Campino S,Hibberd ML, Pain A, Rigouts L, Clark TG.
BMC Med. 2016 Mar 23;14(1):31. doi: 10.1186/s12916-016-0575-9.
BACKGROUND: Combating the spread of drug resistant tuberculosis is a global health priority. Whole genome association studies are being applied to identify genetic determinants of resistance to anti-tuberculosis drugs. Protein structure and interaction modelling are used to understand the functional effects of putative mutations and provide insight into the molecular mechanisms leading to resistance.
METHODS: To investigate the potential utility of these approaches, we analysed the genomes of 144 Mycobacterium tuberculosis clinical isolates from The Special Programme for Research and Training in Tropical Diseases (TDR) collection sourced from 20 countries in four continents. A genome-wide approach was applied to 127 isolates to identify polymorphisms associated with minimum inhibitory concentrations for first-line anti-tuberculosis drugs. In addition, the effect of identified candidate mutations on protein stability and interactions was assessed quantitatively with well-established computational methods.
RESULTS: The analysis revealed that mutations in the genes rpoB (rifampicin), katG (isoniazid), inhA-promoter (isoniazid), rpsL (streptomycin) and embB (ethambutol) were responsible for the majority of resistance observed. A subset of the mutations identified in rpoB and katG were predicted to affect protein stability. Further, a strong direct correlation was observed between the minimum inhibitory concentration values and the distance of the mutated residues in the three-dimensional structures of rpoB and katG to their respective drugs binding sites.
CONCLUSIONS: Using the TDR resource, we demonstrate the usefulness of whole genome association and convergent evolution approaches to detect known and potentially novel mutations associated with drug resistance. Further, protein structural modelling could provide a means of predicting the impact of polymorphisms on drug efficacy in the absence of phenotypic data. These approaches could ultimately lead to novel resistance mutations to improve the design of tuberculosis control measures, such as diagnostics, and inform patient management.
The Burden of Drug-Resistant Tuberculosis in Papua New Guinea: Results of a Large Population-Based Survey.
Aia P, Kal M, Lavu E, John LN, Johnson K, Coulter C, Ershova J, Tosas O, Zignol M, Ahmadova S, Islam T.
PLoS One. 2016 Mar 22;11(3):e0149806. doi: 10.1371/journal.pone.0149806. eCollection 2016.
BACKGROUND: Reliable estimates of the burden of multidrug-resistant tuberculosis (MDR-TB) are crucial for effective control and prevention of tuberculosis (TB). Papua New Guinea (PNG) is a high TB burden country with limited information on the magnitude of the MDR-TB problem.
METHODS: A cross-sectional study was conducted in four PNG provinces: Madang, Morobe, National Capital District and Western Province. Patient sputum samples were tested for rifampicin resistance by the Xpert MTB/RIF assay and those showing the presence of resistance underwent phenotypic susceptibility testing to first- and second-line anti-TB drugs including streptomycin, isoniazid, rifampicin, ethambutol, pyrazinamide, ofloxacin, amikacin, kanamycin and capreomycin.
RESULTS: Among 1,182 TB patients enrolled in the study, MDR-TB was detected in 20 new (2.7%; 95% confidence intervals [CI] 1.1-4.3%) and 24 previously treated (19.1%; 95%CI: 8.5-29.8%) TB cases. No case of extensively drug-resistant TB (XDR-TB) was detected. Thirty percent (6/20) of new and 33.3% (8/24) of previously treated cases with MDR-TB were detected in a single cluster in Western Province.
CONCLUSION: In PNG the proportion of MDR-TB in new cases is slightly lower than the regional average of 4.4% (95%CI: 2.6-6.3%). A large proportion of MDR-TB cases were identified from a single hospital in Western Province, suggesting that the prevalence of MDR-TB across the country is heterogeneous. Future surveys should further explore this finding. The survey also helped strengthening the use of smear microscopy and Xpert MTB/RIF testing as diagnostic tools for TB in the country.
Linezolid as a potentially effective drug for the treatment of multidrug-resistant tuberculosis in Japan.
Yi L, Yoshiyama T, Okumura M, Morimoto K, Sasaki Y, Shiraishi Y, Ogata H, Mitarai S.
Jpn J Infect Dis. 2016 Mar 18. [Epub ahead of print]
Linezolid (LZD) is classified as a WHO group 5 drug used in the treatment of tuberculosis (TB). Although its efficacy and long-term safety have not yet been established, it is being increasingly used in the treatment of multidrug resistant tuberculosis (MDR-TB) and extensive multidrug-resistant tuberculosis (XDR-TB). The current study is a single-center retrospective clinical analysis of hospitalized M/XDR-TB patients in Fukujuji Hospital involving 26 patients (18 males and 8 females) consecutively treated with combinations of anti-TB drugs including LZD from 2009 to 2015. The sputum culture results were negative after using LZD for an average period of 28.0 ± 12.0 (average ± SD) days. LZD was reduced or withdrawn in eleven cases due to adverse effects. Nineteen cases including three XDR-TB cases were operated on, and their TB was healed following surgery. The average time from the initiation of LZD therapy to surgery was 87.6 ± 38.7 (average ± SD) days. Favorable clinical outcome was maintained in twenty-three surviving patients, while three patients died during treatment because of end stage cancer and aspiration pneumonia. Our study showed that LZD might be clinically effective in the treatment of M/XDR-TB cases in Japan.
Rights and Responsibilities of Tuberculosis Patients, and the Global Fund: A Qualitative Study.
PLoS One. 2016 Mar 21;11(3):e0151321. doi: 10.1371/journal.pone.0151321. eCollection 2016.
BACKGROUND: Implementation of the Charter to protect patients’ rights is an important criterion to achieve patient-centered approach and receive financial support from the Global Fund. Our study aims to explore the knowledge of tuberculosis (TB) patients about their rights and responsibilities at the Chest Disease Unit of the Bahawal Victoria Hospital, Bahawalpur, Pakistan.
METHODS: This was a qualitative study. The data from purposefully selected TB patients was collected by in-depth interviews. Eligibility criteria included confirmed diagnosis of TB and enrollment in the TB program. A pilot tested interview protocol was based upon the objectives of the study, and was used uniformly in each interview to maintain the consistency. The sample size was limited by applying the saturation criteria. All interviews were audiotaped and transcribed verbatim. Inductive thematic content analysis was applied to analyze the data and draw conclusions.
RESULTS: Out of the total 16 patients, four were female, and seven were illiterate. Eight patients were known cases of multi-drug resistant TB. Analysis of the data yielded seven themes; tuberculosis care services, moral support and stigmatization, dignity and privacy, complaints, fear of losing job, information sharing and compliance to the treatment plan, and contribution to eradicate TB. First five represented the rights section while latter two were related to the responsibilities section of the Charter.
CONCLUSION: Discriminatory access to TB care services and the right to privacy were two major concerns identified in this study. However, the respondents recognized their responsibilities as a TB patient. To ensure uninterrupted investment from the Global Fund, there is a need to implement fair TB care policies which support human rights-based approach.