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Background: Determining factors affecting the transmission of rifampicin (RR) and multidrug-resistant (MDR) Mycobacterium tuberculosis complex strains under standardized tuberculosis (TB) treatment is key to control TB and prevent the evolution of drug resistance., Methods: We combined bacterial whole genome sequencing (WGS) and epidemiological investigations for 37% (n = 195) of all RR/MDR-TB patients in Cameroon (2012-2015) to identify factors associated with recent transmission., Results: Patients infected with a strain resistant to high-dose isoniazid, and ethambutol had 7.4 (95% CI 2.6-21.4), and 2.4 (95% CI 1.2-4.8) times increased odds of being in a WGS-cluster, a surrogate for recent transmission. Furthermore, age between 30 and 50 was positively correlated with recent transmission (adjusted OR 3.8, 95% CI 1.3-11.4). We found high drug-resistance proportions against three drugs used in the short standardized MDR-TB regimen in Cameroon, i.e. high-dose isoniazid (77.4%), ethambutol (56.9%), and pyrazinamide (43.1%). Virtually all strains were susceptible to fluoroquinolones, kanamycin, and clofazimine, and treatment outcomes were mostly favourable (87.5%)., Conclusion: Pre-existing resistance to high-dose isoniazid, and ethambutol is associated with recent transmission of RR/MDR strains in our study. A possible contributing factor for this observation is the absence of universal drug susceptibility testing in Cameroon, likely resulting in prolonged exposure of new RR/MDR-TB patients to sub-optimal or failing first-line drug regimens., (© 2021. The Author(s).)

We sought to compare the effectiveness of two World Health Organization (WHO)-recommended regimens for the treatment of rifampin- or multidrug-resistant (RR/MDR) tuberculosis (TB): a standardised regimen of 9-12 months (the "shorter regimen") and individualised regimens of ≥20 months ("longer regimens").We collected individual patient data from observational studies identified through systematic reviews and a public call for data. We included patients meeting WHO eligibility criteria for the shorter regimen: not previously treated with second-line drugs, and with fluoroquinolone- and second-line injectable agent-susceptible RR/MDR-TB. We used propensity score matched, mixed effects meta-regression to calculate adjusted odds ratios and adjusted risk differences (aRDs) for failure or relapse, death within 12 months of treatment initiation and loss to follow-up.We included 2625 out of 3378 (77.7%) individuals from nine studies of shorter regimens and 2717 out of 13 104 (20.7%) individuals from 53 studies of longer regimens. Treatment success was higher with the shorter regimen than with longer regimens (pooled proportions 80.0% versus 75.3%), due to less loss to follow-up with the former (aRD -0.15, 95% CI -0.17- -0.12). The risk difference for failure or relapse was slightly higher with the shorter regimen overall (aRD 0.02, 95% CI 0-0.05) and greater in magnitude with baseline resistance to pyrazinamide (aRD 0.12, 95% CI 0.07-0.16), prothionamide/ethionamide (aRD 0.07, 95% CI -0.01-0.16) or ethambutol (aRD 0.09, 95% CI 0.04-0.13).In patients meeting WHO criteria for its use, the standardised shorter regimen was associated with substantially less loss to follow-up during treatment compared with individualised longer regimens and with more failure or relapse in the presence of resistance to component medications. Our findings support the need to improve access to reliable drug susceptibility testing., Competing Interests: Conflict of interest: S. Abidi has nothing to disclose. Conflict of interest: J. Achar has nothing to disclose. Conflict of interest: M.M. Assao Neino has nothing to disclose. Conflict of interest: D. Bang has nothing to disclose. Conflict of interest: A. Benedetti has nothing to disclose. Conflict of interest: S. Brode reports grants from Insmed and the Canadian Institutes for Health Research, personal fees for educational presentations from Boehringer Ingelheim and AstraZeneca, outside the submitted work. Conflict of interest: J.R. Campbell has nothing to disclose. Conflict of interest: E. Casas has nothing to disclose. Conflict of interest: F. Conradie has nothing to disclose. Conflict of interest: G. Dravniece has nothing to disclose. Conflict of interest: P. du Cros reports he was previously a member of the steering committee and protocol writing committee for the PRACTECAL randomised controlled trial of three novel 6-month MDR-TB regimens; and has undertaken a paid consultancy between TB Alliance and Burnet Institute to investigate applicability of the TB-Nix regimen (a novel short MDR-TB regimen) to Papua New Guinea. Conflict of interest: D. Falzon has nothing to disclose. Conflict of interest: E. Jaramillo has nothing to disclose. Conflict of interest: C. Kuaban has nothing to disclose. Conflict of interest: Z. Lan has nothing to disclose. Conflict of interest: C. Lange reports personal fees for lectures from Chiesi, Gilead, Janssen, Lucane, Novartis, Oxoid, Berlin-Chemie and Thermo Fisher, outside the submitted work. Conflict of interest: P.Z. Li has nothing to disclose. Conflict of interest: M. Makhmudova has nothing to disclose. Conflict of interest: A.K.J. Maug has nothing to disclose. Conflict of interest: D. Menzies has nothing to disclose. Conflict of interest: G.B. Migliori has nothing to disclose. Conflict of interest: A. Miller reports that The Eli Lilly Foundation MDR-TB Partnership provided partial salary support in 2015–2016 through a grant to Salmaan Keshavjee, Harvard Medical School, although none of the work in the current paper or analysis was supported through that mechanism; the grant also paid for travel to a meeting in July of 2016. Conflict of interest: B. Myrzaliev has nothing to disclose. Conflict of interest: N. Ndjeka has nothing to disclose. Conflict of interest: J. Noeske has nothing to disclose. Conflict of interest: N. Parpieva has nothing to disclose. Conflict of interest: A. Piubello has nothing to disclose. Conflict of interest: V. Schwoebel has nothing to disclose. Conflict of interest: W. Sikhondze has nothing to disclose. Conflict of interest: R. Singla has nothing to disclose. Conflict of interest: M.B. Souleymane has nothing to disclose. Conflict of interest: A. Trébucq has nothing to disclose. Conflict of interest: A. Van Deun has nothing to disclose. Conflict of interest: K. Viney has nothing to disclose. Conflict of interest: K. Weyer has nothing to disclose. Conflict of interest: B.J. Zhang has nothing to disclose. Conflict of interest: F. Ahmad Khan reports grants from the World Health Organization during the conduct of the study., (The content of this work is copyright of the authors or their employers. Design and branding are copyright ©ERS 2020.)

Background . Cameroon this last decade continues to present a low contribution of M. africanum and M. bovis in human tuberculosis (TB), while M. bovis was prevalent in cattle but all these pieces of information only concerned West and Center regions. Methods . We carried out the first study in Adamaoua, one of the most rearing regions of Cameroon, on the genetic structure and drug susceptibility of the MTBC strains isolated from newly diagnosed sputum smear-positive patients aged 15 years and above. For that purpose, spoligotyping, a modified 15 standard MIRU/VNTR loci typing, and the proportion method were used. Results . Four hundred and thirty-seven MTBC isolates were analyzed by spoligotyping. Of these, 423 were identified as M. tuberculosis , within the Cameroon family being dominant with 278 (65.7%) isolates; twelve (2.75%) isolates were classified as M. africanum and two as M. bovis . MIRU/VNTR typing of the most prevalent sublineage (SIT 61) suggested that this lineage is not a unique clone as thought earlier but could constitute a group of strains implicated to different pocket of TB transmission. Only M. tuberculosis sublineages were associated with antituberculosis drug resistance. Conclusion . These results showed the weak contribution of M. africanum and M. bovis to human active pulmonary tuberculosis in Cameroon even in the rearing region., Competing Interests: With the submission of this manuscript, the authors would like to undertake the responsibility that, for this submitted manuscript, they did not receive reimbursements, fees, funding, or salary from an organization that may in any way gain or lose financially from the publication of this manuscript, either now or in the future. They did not hold any stocks or shares in an organization that may in any way gain or lose financially from the publication of this manuscript, either now or in the future. Moreover they did not hold or were currently applying for any patents relating to the content of the manuscript or even received reimbursements, fees, funding, or salary from an organization that holds or had applied for patents relating to the content of the manuscript. To the best of their knowledge, they did not have any other financial and nonfinancial competing interests.

Background: In the 1990s, resistance rates of 15% for streptomycin-resistance and 0.6% for multidrug-resistance (MDR) were reported from the Central Region of Cameroon. This work assesses drug resistant tuberculosis in this region 12 years after reorganization of the National Tuberculosis Control Program (NTCP)., Methods: This cross-sectional study was conducted from April 2010 to March 2011 in Jamot Hospital in Yaoundé, Cameroon. Only patients with smear positive pulmonary tuberculosis were included. Sputa were cultured and subsequently underwent drug susceptibility testing (DST). All consenting individuals were tested for their HIV status., Results: A total of 665 smear positive pulmonary tuberculosis patients were enrolled. The HIV prevalence was 28.5% (95%CI [25.2-32.1]). Of the 582 sputa that grew Mycobacterium tuberculosis complex species, DST results were obtained for 576. The overall resistance rate was 10.9% (63/576). The overall resistance rates for single drug resistance were: isoniazid-resistance 4.7% (27/576), streptomycin-resistance 3.3% (19/576), rifampicin-resistance 0.2% (1/576), kanamycin-resistance 0.2% (1/576) and ofloxacin-resistance 0.2% (1/576). The MDR rate was 1.1% (6/576) and no extensively drug resistant tuberculosis (XDR) was detected., Conclusions: The data show that reorganization of the NTCP resulted in a strong decrease in streptomycin-resistance and suggest that it prevented the emergence of XDR in the Central Region of Cameroon.

Background: The potential of genetic testing to rapidly diagnose drug resistance has lead to the development of new diagnostic assays. However, prior to implementation in a given setting, the association of specific mutations with specific drug resistance phenotypes should be evaluated. The purpose of this study was to evaluate molecular markers in predicting drug resistance in the Central Region of Cameroon., Results: From April 2010 and March 2011, 725 smear positive pulmonary tuberculosis patients were enrolled and all positive cultures were tested for drug susceptibility. A total of 63 drug resistant and 100 drug sensitive Mycobacterium tuberculosis complex clinical isolates were screened for genetic mutations in katG, inhA, ahpC, rpoB, rpsL, rrs, gidB and embCAB loci using DNA sequencing. Of the 44 isoniazid resistant (INHR) isolates (24 high level, 1 μg/ml and 20 low level, 0.2 μg/ml), 73% (32/44) carried the katG315 and/or the -15 inhA promoter mutations. Of the 24 high level INHR, 17 (70.8%) harbored katG315 mutation, 1 a point mutation (-15C → T) in the inhA promoter and 6 were (25.0%) wild types. Thus, for INHR high level detection, katG315 mutation had a specificity and a sensitivity of 100% and 70.8% respectively. Of the 20 low level INHR, 10 (50.0%) had a -15C → T mutation in the inhA promoter region, and 1 (2.2%) a -32G → A mutation in the ahpC promoter region. All of the 7 rifampicin resistant (RIFR) isolates carried mutations in the rpoB gene (at codons Ser531Leu (71.4%), His526Asp (14.3%), and Asp516Val (14.3%)). Of the 27 streptomycin resistant (SMR) isolates, 7 carried mutations at the rpsL and the gidB genes. 1 of the 2 ethambutol resistant (EMBR) isolates displayed a mutation in embB gene., Conclusion: This study provided the first molecular investigation assessing the correlation of phenotypic to genotypic characteristics on MTB isolates from the Central Region of Cameroon using DNA sequencing. Mutations on rpoB, katG315 and -15 point mutations in inhA promoter loci could be used as markers for RIF and INH -resistance detection respectively.

Background: We investigated the determinants of sputum culture non-conversion following intensive phase of treatment, and assessed the effects on the outcome among patients treated for a first episode of smear positive tuberculosis (TB)., Methods: This was a prospective cohort study spanning October 2009 to May 2012, among patients treated for a first episode of smear positive pulmonary tuberculosis in the Chest service of the Yaounde Jamot Hospital, Cameroon. Logistic regressions models were used to relate baseline characteristics with non-conversion of sputum cultures after the intensive phase of treatment., Results: A total of 953 patients were admitted to the service during the study period, including 97 (10.2%) who had a positive sputum smear at the end of the intensive phase of anti-tuberculosis treatment. Eighty-six patients with persistent of smear positive sputa at the end of intensive phase of TB treatment were included, among whom 46 (53%) had positive sputum culture for Mycobacterium tuberculosis (C+). The absence of haemoptysis [adjusted odd ratio 4.65 (95% confidence intervals: 1.14-18.95)] and current smoking [7.26 (1.59-33.23)] were the main determinants of sputum culture non-conversion. Of the 46C + patients, 7 (15%) were resistant to at least one anti-tuberculosis drug. Treatment failure rate was 28% among C + patients and 8% among C- patients (p = 0.023). The sensitivity and specificity were 78.6% and 55.4% for culture non-conversion after intensive treatment, in predicting anti-TB treatment failure., Conclusions: Failure rate is high among patients with positive sputum culture after intensive treatment, even in the absence of multi-drug resistant bacilli. Treatment should be closely monitored in these patients and susceptibility to anti-tuberculosis drugs tested in the presence of persistent positive smears following the intensive phase of treatment.

Setting: Seven district hospitals in the Adamaoua Region of Cameroon, June 2009 to May 2010., Objectives: To identify species among Mycobacterium tuberculosis complex (MTC) strains responsible for pulmonary tuberculosis (PTB) and determine their susceptibility to anti-tuberculosis drugs., Design: Sputum specimens were collected from 509 consecutively admitted adults and cultured. Identification of cultured strains was mainly based on culture growth characteristics and standard biochemical tests with spoligotyping for confirmation on a subset of strains. Drug susceptibility testing was performed using the indirect proportion method., Results: Growth of MTC strains occurred in specimens of 445/509 (87.4%) patients: 433 (97.3%) were identified as M. tuberculosis, 10 (2.3%) as M. africanum and 2 (0.4%) as M. bovis. The overall resistance rate was 7.9%, with 7.3% resistance in new cases and 21.1% in previously treated cases. Isoniazid resistance in new cases was most common (4.2%), followed by streptomycin (3.3%), rifampicin (1.9%) and ethambutol (0.9%). Multidrug-resistant tuberculosis was more frequent in previously treated than in new cases (10.5% vs. 1.4%, P < 0.05)., Conclusion: Although the Adamaoua Region is a stock-farming area, M. tuberculosis is the predominant MTC species responsible for PTB. Anti-tuberculosis drug resistance in new and previously treated cases is well established, underscoring the need to reinforce the DOTS strategy.

Genetic assessment by spoligotyping of 565 Mycobacterium tuberculosis complex strains collected from the Western Region of Cameroon between 2004 and 2005 has confirmed the establishment of the "Cameroon family" as the leading cause of tuberculosis in 45.9% of cases and evidenced the rapid quasi extinction of Mycobacterium africanum, isolated in 3.3% of tuberculosis cases.

Objectives: To identify clinical, radiological and microbiological factors associated with the non conversion of sputum smears in new smear positive cases of pulmonary tuberculosis after two months of treatment and to evaluate the influence of non-smear conversion on treatment outcomes., Design: A prospective cohort study., Setting: Tuberculosis centre of Hôpital Jamot in Yaoundé- Cameroon from April 2006 to September 2007., Subjects: A total of 413 patients were studied., Main Outcome Measures: Sputum smear status at two months of treatment, favourable treatment outcome (cured, treatment completed), unfavourable treatment outcome (death, treatment failure, default from treatment) and transferred out., Results: A total of 413 patients were studied; There were 234 (56.8%) males and 178 (43.2%) females with a mean age of 33 years (range 9.80 years). Sputum smears did not convert in 55 (13.4%) patients at the end of two months of treatment. Logistic regression analysis showed that age above or equal to 40 years (OR=2.716, 95% CI:1.412-5.223, p=0.003), and a bacillary load of 3+ on pre-treatment sputum smears (OR=1.955; 95% CI: 1.039-3.68, p=0.037) were significantly associated with non conversion of sputum smears at the end of two months of treatment. Persistent positive smears at the end of two months of treatment were significantly associated with unfavourable treatment outcomes (p=0.025) especially default during the course of treatment., Conclusion: In Yaoundé, Cameroon, non conversion of positive sputum smears in new patients with pulmonary tuberculosis at the end of two months of treatment is associated with an unfavourable outcome particularly defaulting later in the course of treatment. Non conversion of sputum smears at two months of treatment is significantly associated with age above or equal to 40 years and the presence of numerous bacilli (3+) on pre-treatment sputum smears. Patients with these factors who do not smear convert after two months of treatment should be given a fully supervised treatment for the entire duration of therapy so as to prevent in particular treatment default.

A preliminary investigation of the genetic biodiversity of Mycobacterium tuberculosis complex strains in Cameroon, a country with a high prevalence of tuberculosis, described a group of closely related M. tuberculosis strains (the Cameroon family) currently responsible for more than 40% of smear-positive pulmonary tuberculosis cases. Here, we used various molecular methods to study the genetic characteristics of this family of strains. Cameroon family M. tuberculosis strains (i) are part of the major genetic group 2 and lack the TbD1 region like other families of epidemic strains, (ii) lack spacers 23, 24, and 25 in their direct repeat (DR) region, (iii) have an identical number of repeats in 8 of 12 variable-number tandem repeats of mycobacterial interspersed repetitive unit (MIRU-VNTR) loci, (iv) have similar IS6110-restriction fragment length polymorphism (RFLP) multiband patterns (10 to 15 copies) with seven common IS6110 bands, (v) do not have an IS6110 element in their DR locus, and (vi) have four IS6110 elements in open reading frames (adenylate cyclase, phospholipase C, moeY, and ATP binding genes). Analysis by spoligotyping, MIRU-VNTR, and IS6110-RFLP typing methods revealed differences not observed in previous studies; polymorphism as assessed by MIRU-VNTR typing was lower than suggested by spoligotyping, and in rare cases, strains with identical IS6110-RFLP patterns had spoligotypes differing by as much as 15 spacers. Our findings confirm the recent expansion of this family in Cameroon and indicate that the interpretation of molecular typing results has to be adapted to the characteristics of the strain population within each setting. The knowledge of this particular genotype, with its large involvement in tuberculosis in Cameroon, allows greater refinement of tuberculosis transmission studies by interpreting data in the context of this geographic area.

We analyzed DNA polymorphisms in 455 Mycobacterium tuberculosis complex isolates from 455 patients to evaluate the biodiversity of tubercle bacilli in Ouest province, Cameroon. The phenotypic and genotypic identification methods gave concordant results for 99.5% of M. tuberculosis isolates (413 strains) and for 90% of Mycobacterium africanum isolates (41 strains). Mycobacterium bovis was isolated from only one patient. Analysis of regions of difference (RD4, RD9, and RD10) proved to be an accurate and rapid method of distinguishing between unusual members of the M. tuberculosis complex. Whereas M. africanum strains were the etiologic agent of tuberculosis in 56% of cases 3 decades ago, our results showed that these strains now account for just 9% of cases of tuberculosis. We identified a group of closely genetically related M. tuberculosis strains that are currently responsible for >40% of smear-positive pulmonary tuberculosis cases in this region of Cameroon. These strains shared a spoligotype lacking spacers 23, 24, and 25 and had highly related IS6110 ligation-mediated (LM) PCR patterns. They were designated the "Cameroon family." We did not find any significant association between tuberculosis-causing species or strain families and patient characteristics (sex, age, and human immunodeficiency virus status). A comparison of the spoligotypes of the Cameroon strains with an international spoligotype database (SpolDB3) containing 11,708 patterns from >90 countries, showed that the predominant spoligotype in Cameroon was limited to West African countries (Benin, Senegal, and Ivory Coast) and to the Caribbean area.

Setting: All 15 district hospitals of the West Province of Cameroon, between July 1997 and June 1998., Objective: To determine the prevalences of initial and acquired resistance to the main anti-tuberculosis drugs 2 years after the implantation of a tuberculosis control programme in the province., Methods: A total of 615 adults consecutively admitted to the 15 district hospitals with sputum smear-positive pulmonary tuberculosis were systematically studied. Sputum specimens collected from each patient were cultured on Lowenstein-Jensen medium. Testing of susceptibility to the major anti-tuberculosis drugs was performed by the indirect proportion method., Results: Growth of Mycobacterium tuberculosis complex strains was obtained from specimens of 566 (92%) of the 615 patients. The overall resistance rate (one or more drugs) was 26.9%, with initial resistance being 19.7% (86/437) and acquired resistance 51.1% (66/129). Initial resistance to isoniazid was the most common (12.1%), followed by streptomycin (11.7%), ethambutol (2.5%) and rifampicin (2.1%). Initial resistance was noted as 13.5% to one drug, 4.3% to two, 1.1% to three and 0.7% to four. Acquired resistance to isoniazid was the most frequent (41.1%), followed by streptomycin (26.4%), rifampicin (14.7%) and ethambutol (9.3%). Acquired resistance was 25.6% to one drug, 14.7% to two, 7% to three and 3.9% to four., Conclusion: The proportion of resistant tuberculosis in the West Province is quite high. This underscores the need for the improvement of the control programme by introducing the DOTS strategy.

To evaluate the current prevalence of initial and acquired resistance to the main antituberculosis drugs in Yaounde, isolates of M. tuberculosis complex obtained from sputum cultures of 602 adult patients with pulmonary tuberculosis (516 new cases and 86 old cases) consecutively admitted into the tuberculosis centre of Hôpital JAMOT from July 1994 to December 1995 were studied. The susceptibility of isolates to the major antituberculosis drugs was tested by the indirect proportion method. The overall resistance rate (1 or more drugs) was 35.2%, with initial resistance 31.8% (164 of 516) and acquired resistance 55.8% (48 of 86). Initial resistance to streptomycin was the most frequent (20.5%), followed by isoniazid 12.4%), thiacetazone (5.6%), rifampicine (0.8%) and ethambutol (0.4%). Initial resistance was noted as 25% to 1 drug, 5.8% to 2 drugs, 0.8% to 3 drugs and 0.2% to 4 drugs. Acquired resistance to isoniazid was the most frequent (45.3%), followed by streptomycin (40.7%), rifampicine (30.2%), thiacetazone (10.5%) and ethambutol (9.3%). Acquired resistance was found as 13.9% to one drug, 19.8% to 2 drugs, 12.8% to 3 drugs and 9.3% to 4 drugs. A combined resistance to rifampicine and isoniazid in the same patient was noted in 0.8% of the new cases and in 26.7% of the old cases. These high rates af antituberculosis drug resistance in Yaounde underline the urgent need to reestablish a tuberculosis control programme in Cameroon.