Reduction of diagnostic and treatment delays reduces rifampicin-resistant tuberculosis mortality in Rwanda.

SETTING: In 2005, in response to the increasing prevalence of rifampicin-resistant tuberculosis (RR-TB) and poor treatment outcomes, Rwanda initiated the programmatic management of RR-TB, including expanded access to systematic rifampicin drug susceptibility testing (DST) and standardised treatment.OBJECTIVE: To describe trends in diagnostic and treatment delays and estimate their effect on RR-TB mortality.DESIGN: Retrospective analysis of individual-level data including 748 (85.4%) of 876 patients diagnosed with RR-TB notified to the World Health Organization between 1 July 2005 and 31 December 2016 in Rwanda. Logistic regression was used to estimate the effect of diagnostic and therapeutic delays on RR-TB mortality.RESULTS: Between 2006 and 2016, the median diagnostic delay significantly decreased from 88 days to 1 day, and the therapeutic delay from 76 days to 3 days. Simultaneously, RR-TB mortality significantly decreased from 30.8% in 2006 to 6.9% in 2016. Total delay in starting multidrug-resistant TB (MDR-TB) treatment of more than 100 days was associated with more than two-fold higher odds for dying. When delays were long, empirical RR-TB treatment initiation was associated with a lower mortality.CONCLUSION: The reduction of diagnostic and treatment delays reduced RR-TB mortality. We anticipate that universal testing for RR-TB, short diagnostic and therapeutic delays and effective standardised MDR-TB treatment will further decrease RR-TB mortality in Rwanda.

Gatifloxacin is superior to levofloxacin and moxifloxacin in shorter treatment regimens for multidrug-resistant TB.

SETTING: Data were collected from patients starting one of the shorter treatment regimens (STRs) for multidrug-resistant tuberculosis (MDR-TB) in Bangladesh, Niger or Cameroon.OBJECTIVE: To estimate the effect of either a gatifloxacin (GFX), moxifloxacin (MFX) or levofloxacin (LVX) based STR on bacteriological effectiveness.DESIGN: Retrospective study of prospectively collected data.RESULTS: Among 1530 patients, bacteriological effectiveness was 96.7% overall. Stratified by treatment with a GFX-, LVX- or MFX-based regimen effectiveness was respectively 97.5%, 95.5% and 94.7%. Compared to those on a GFX-based regimen, the estimated summary odds ratio of having an adverse outcome was more than double (OR 2.05, 95% CI 1.09-3.90) in patients treated with either an LVX-based or MFX-based regimen. After adjusting for initial resistance, patients treated with an LVX-based regimen and MFX-based regimen had respectively a 4.5- and 8.4-fold times larger odds of an adverse bacteriological outcome. None among 859 patients at risk treated with a GFX-based compared to at least 4 of 228 among those on an MFX-based regimen acquired fluoroquinolone resistance.CONCLUSION: GFX-based regimens had superior bacteriological effectiveness than MFX-based or LVX-based regimens. As GFX is currently unavailable in most MDR-TB programs, its reintroduction should be prioritised.

Principles for constructing a tuberculosis treatment regimen: the role and definition of core and companion drugs.

Current World Health Organization guidelines for the formulation of treatment regimens for multidrug-resistant tuberculosis (MDR-TB) pay too little attention to the microbiological activity of anti-tuberculosis drugs. Here, we draw lessons from the pioneering work done on shorter MDR-TB treatment regimens and the current knowledge of the bactericidal and sterilizing properties of the drugs to inform the composition of treatment regimens for MDR-TB. We propose to reserve the term 'core drug' for the one drug in a regimen that contributes most to relapse-free cure. The core drug has both moderate to high bactericidal and sterilizing activity, is given throughout treatment, is well tolerated, and has no cross-resistance with the core drug used in the previous regimen. Currently used core drugs include rifampicin in the first-line 6-month regimen, and fourth-generation fluoroquinolones and bedaquiline in regimens for drug-resistant TB. All other drugs are 'companion drugs', used to avert treatment failure due to acquired drug resistance against the core drug. Some also help further reduce the risk of relapse. Moreover, toxic drugs should be avoided if there is an alternative. A regimen must always include the core drug, plus at least one companion drug with high bactericidal activity, a second bactericidal companion drug, plus two sterilizing companion drugs.

Gatifloxacin for short, effective treatment of multidrug-resistant tuberculosis.

The 9-month regimen for the treatment of multidrug-resistant tuberculosis (MDR-TB) piloted in Bangladesh and used, with modifications, in Cameroon and Niger, has achieved treatment success in a very large proportion of patients; gatifloxacin (GFX) is likely to have played a critical role in this success. Two months after the publication of a study reporting that GFX and not moxifloxacin (MFX) was associated with dysglycaemia, the manufacturer announced the withdrawal of GFX from the market. The findings of that study may have less significance for the majority of MDR-TB patients living in high-incidence countries who are much younger, have a lower risk of dysglycaemia and suffer from a highly fatal condition. The problem of dysglycaemia is not limited to GFX use and may occur with other fluoroquinolones; furthermore, GFX-associated dysglycemia was manageable among those MDR-TB patients in Bangladesh and Niger in whom it occurred. GFX has now become unavailable in Bangladesh, Cameroon, Niger and other countries piloting the shorter MDR-TB regimens, depriving resource-poor countries of an efficacious, effective and inexpensive drug with a demonstrated good safety profile for the given indication. There is little reason not to make GFX available for MDR-TB treatment as long as the superiority of non-GFX-based MDR-TB regimens is not demonstrated.

Specific gyrA gene mutations predict poor treatment outcome in MDR-TB.

OBJECTIVES: Mutations in the gyrase genes cause fluoroquinolone resistance in Mycobacterium tuberculosis. However, the predictive value of these markers for clinical outcomes in patients with MDR-TB is unknown to date. The objective of this study was to determine molecular markers and breakpoints predicting second-line treatment outcomes in M. tuberculosis patients treated with fourth-generation fluoroquinolones. METHODS: We analysed treatment outcome data in relation to the gyrA and gyrB sequences and MICs of ofloxacin, gatifloxacin and moxifloxacin for pretreatment M. tuberculosis isolates from 181 MDR-TB patients in Bangladesh whose isolates were susceptible to injectable drugs. RESULTS: The gyrA 90Val, 94Gly and 94Ala mutations were most frequent, with the highest resistance levels for 94Gly mutants. Increased pretreatment resistance levels (>2 mg/L), related to specific mutations, were associated with lower cure percentages, with no cure in patients whose isolates were resistant to gatifloxacin at 4 mg/L. Any gyrA 94 mutation, except 94Ala, predicted a significantly lower proportion of cure compared with all other gyrA mutations taken together (all non-94 mutants + 94Ala) [OR = 4.3 (95% CI 1.4-13.0)]. The difference in treatment outcome was not explained by resistance to the other drugs. CONCLUSIONS: Our study suggests that gyrA mutations at position 94, other than Ala, predict high-level resistance to gatifloxacin and moxifloxacin, as well as poor treatment outcome, in MDR-TB patients in whom an injectable agent is still effective.

Fluorescein diacetate vital staining allows earlier diagnosis of rifampicin-resistant tuberculosis.

SETTING: Damien Foundation Project, Bangladesh. OBJECTIVE: To evaluate sputum smear fluorescein diacetate (FDA) vital staining to predict culture-defined failure and rifampicin (RMP) resistance. DESIGN: A retrospective, operational study. RESULTS: A total of 1633 episodes of auramine smear-defined late conversion and failure could be evaluated (respectively 640 and 584 on first treatment and 185 and 224 on retreatment). Negative FDA was 95% predictive of negative culture in patients on first treatment, while its positive predictive value was around 95% during retreatment. The predictive value of a positive (not scanty) result for RMP resistance or environmental non-tuberculous mycobacteria (NTM) was at least 90%, except in late converters on first-line treatment; a negative result was over 95% exclusive of the same except in retreatment failures. FDA correctly identified 88-98% of all RMP resistance. CONCLUSIONS: FDA staining increased the proportion of tuberculosis patients put on second-line treatment without receiving the standard first-line retreatment regimen. In our setting, with excellent microscopy, late case presentation and low resistance prevalence, it proved indispensable for efficient culture and referrals of early suspects for rapid drug susceptibility testing (DST). In other settings with low prevalence of NTM and difficult access to accurate and rapid DST, FDA-positive failures might even be considered for immediate start of second-line treatment.

Extension of the intensive phase reduces relapse but not failure in a regimen with rifampicin throughout.

SETTING: Damien Foundation tuberculosis (TB) control projects in Bangladesh. OBJECTIVE: To assess the effectiveness of extending the intensive phase (P1) of treatment by 1 month for patients who are smear-positive after 2 months of a 6-month regimen containing rifampicin (RMP) throughout. DESIGN: Prospective operational study randomising P1 extension for new smear-positive cases with any number of acid-fast bacilli in the 2-month smear (2M+). Smear-defined failures and relapses underwent culture and drug susceptibility testing in addition to DNA sequencing of the rpoB gene before and after treatment. RESULTS: Of 16,708 patients evaluated, 12,967 were smear-negative at 2 months (2M-); 1871 and 1870 2M+ were randomised to no extension or extension. Respectively 0.3% (95%CI 0.2-0.4), 1.2% (95%CI 0.7-1.8) and 2.0% (95%CI 1.4-2.8) smear- and culture-positive failures, and 1.2% (95%CI 1.0-1.4), 2.6% (95%CI 1.9-3.4) and 0.9% (95%CI 0.5-1.4) relapses were detected. Extension significantly reversed the relative risk (RR) of relapse of 2M+ vs. 2M- patients from 2.2 (95%CI 1.6-3.0) to 0.7 (95%CI 0.4-1.2). The RR for failure remained high, at 7.3 (95%CI 4.7-11.5) with and 4.2 (95%CI 2.5-7.2) without extension. More multi-drug resistance was found after extension, but acquired RMP resistance was similar in all arms. The fair sensitivity of the 2-month smear for failure or relapse (40%) was offset by a very low positive predictive value (3%). CONCLUSIONS: Extension of P1 is very inefficient with this 6-month regimen. Operational research should define appropriate algorithms allowing an earlier switch to the next higher regimen for those in need, using follow-up smears for screening.

Xpert® MTB/RIF for national tuberculosis programmes in low-income countries: when, where and how?

Xpert ® MTB/RIF offers new and important possibilities for the diagnosis of sputum smear-negative tuberculosis (TB) and/or rifampicin (RMP) resistance, and many are encouraging rapid and widespread implementation. This simple test can be implemented almost everywhere, and it provides results within a few hours. In low-income countries (LICs), however, its cost, environmental limitations (stable and regular electricity, adequate room temperature) and difficulties involved in supply and maintenance are major obstacles. While it may be suitable for major reference hospitals, operational research is needed to evaluate the test and its additional yield above high-quality smear microscopy and clinical algorithms before its use at the peripheral level. In the meantime, direct microscopy should remain the initial diagnostic test for TB suspects. In most LICs, the prevalence of RMP resistance among new TB patients is very low; an Xpert MTB/RIF result indicating RMP resistance will thus always need confirmation by another test. In a population at high risk of RMP resistance (> 15%), however, the positive predictive value for RMP resistance by Xpert MTB/RIF is high, and identification of RMP resistance is an excellent proxy for multidrug-resistant TB (MDR-TB). The assay should be widely used for this purpose if, and only if, excellent MDR-TB management is available, both for ethical reasons and to reduce the risk of extensively drug-resistant TB.

Drug susceptibility testing proficiency in the network of supranational tuberculosis reference laboratories.

SETTING: The network of supranational tuberculosis reference laboratories (SRLs). OBJECTIVE: To evaluate the annual SRL Rounds 6-14 of proficiency testing for first-line drug susceptibility testing (DST). DESIGN: Panels consisted of 20-30 cultures (including 10 pairs of duplicate strains), aiming at 50% resistance prevalence with a variety of profiles. The 27 SRLs participating in at least one of these rounds were free to use their preferred DST method. A judicial gold standard of at least 80% concordant 'susceptible' or 'resistant' was used to determine sensitivity, specificity and efficiency; otherwise the strain was excluded. RESULTS: Of 600 strains, 10% were excluded from evaluation. The average SRL sensitivity and specificity varied between rounds, without attaining significance or trends. Both sensitivity and specificity remained at >95% for isoniazid (INH), rifampicin (RMP) and streptomycin and at >80% for ethambutol. The 16 SRLs participating in all rounds performed consistently better. CONCLUSION: The rounds succeeded in comparing the proficiency of laboratories, and should be further promoted for DST quality assessment. However, to function with greater precision and to ultimately improve the clinical relevance of DST, the INH and RMP judicial result gold standard also needs to take into account genotypic and treatment outcome information.

Evaluation of tuberculosis control by periodic or routine susceptibility testing in previously treated cases.

SETTING: A national tuberculosis control programme (NTP) disposing of baseline drug resistance rates and using 2EHRZ/6TH in the treatment of new cases. OBJECTIVE: To estimate the extent of drug resistance created by the NTP. DESIGN: Resistance rates in 2EHRZ/6TH failure and relapse cases were compared to baseline, and resistance profiles of repeat isolates were checked. Numbers of observed resistant failures were compared to numbers expected due to pre-existing resistance. Trends of resistance in combined new and previously treated cases were extrapolated. RESULTS: High drug resistance rates were observed. Changes in resistance to streptomycin, the virtual absence of documented acquired resistance and a close match of observed with expected resistant failures all indicated accumulation of primary drug resistance as the main mechanism. Resistance in relapse/failure cases showed a significantly declining trend, and estimated combined drug resistance decreased rapidly. CONCLUSIONS: Drug resistance in previously treated cases seems to consist of passed-on primary rather than true acquired resistance. A one-time survey is thus confusing, but continuous routine testing may constitute the best drug resistance monitoring method. Cases previously treated with short-course chemotherapy may show drug resistance much more frequently than generally assumed, and all should receive a re-treatment regimen. The 2EHRZ/6TH regimen proved very safe under field conditions, causing no 'amplification' towards multidrug resistance and almost no acquired isoniazid resistance. Implementation of this regimen, together with a standardised re-treatment regimen, seemed to rapidly reduce isoniazid as well as multidrug resistance levels, despite the fact that directly observed treatment was not strictly applied.

Directly observed treatment, short-course strategy and multidrug-resistant tuberculosis: are any modifications required?

Multidrug-resistant tuberculosis (MDRTB) should be defined as tuberculosis with resistance to at least isoniazid and rifampicin because these drugs are the cornerstone of short-course chemotherapy, and combined isoniazid and rifampicin resistance requires prolonged treatment with second-line agents. Short-course chemotherapy is a key ingredient in the tuberculosis control strategy known as directly observed treatment, short-course (DOTS). For populations in which multidrug-resistant tuberculosis is endemic, the outcome of the standard short-course chemotherapy regimen remains uncertain. Unacceptable failure rates have been reported and resistance to additional agents may be induced. As a consequence there have been calls for well-functioning DOTS programmes to provide additional services in areas with high rates of multidrug-resistant tuberculosis. These "DOTS-plus for MDRTB programmes" may need to modify all five elements of the DOTS strategy: the treatment may need to be individualized rather than standardized; laboratory services may need to provide facilities for on-site culture and antibiotic susceptibility testing; reliable supplies of a wide range of expensive second-line agents would have to be supplied; operational studies would be required to determine the indications for and format of the expanded programmes; financial and technical support from international organizations and Western governments would be needed in addition to that obtained from local governments.

Drug susceptibility of Mycobacterium tuberculosis in a rural area of Bangladesh and its relevance to the national treatment regimens.

SETTING: Greater Mymensingh District, a rural area of Bangladesh, at the start of the National Tuberculosis Programme (NTP). OBJECTIVES: To determine the prevalence of initial and acquired drug resistance of Mycobacterium tuberculosis, and to assess the appropriateness of the NTP's standard regimens. DESIGN: Sampling of pre-treatment sputum from all newly registered smear-positive cases in five centres covering the area. Culture and susceptibility testing in a supra-national reference laboratory. RESULTS: Initial resistance to isoniazid (H) was 5.4%, and to rifampicin (R) 0.5%. Acquired H and R resistance were 25.9% and 7.4%, respectively. Multidrug resistance (MDR) was observed in one new case only and in 5.6% of previously treated patients. Changing the present NTP indication for retreatment regimen to one month of previous H intake would increase coverage of H-resistant cases from 52% to 89%, adding 6% to drug costs. CONCLUSION: The prevalence of drug resistance is surprisingly low in Bangladesh, but could rise with improving economic conditions. The NTP regimens for smear-positive cases are appropriate, all the more so since the human immunodeficiency virus is virtually absent. Indications for the retreatment regimen should be extended to include all patients treated for at least one month with any drug. The NTP regimen for smear-negative cases runs the risk of leading to MDR under present field conditions.