Whole genome sequencing-based drug resistance predictions of multidrug-resistant Mycobacterium tuberculosis isolates from Tanzania.

Background: Rifampicin- or multidrug-resistant (RR/MDR) Mycobacterium tuberculosis complex (MTBC) strains account for considerable morbidity and mortality globally. WGS-based prediction of drug resistance may guide clinical decisions, especially for the design of RR/MDR-TB therapies. Methods: We compared WGS-based drug resistance-predictive mutations for 42 MTBC isolates from MDR-TB patients in Tanzania with the MICs of 14 antibiotics measured in the Sensititre™ MycoTB assay. An isolate was phenotypically categorized as resistant if it had an MIC above the epidemiological-cut-off (ECOFF) value, or as susceptible if it had an MIC below or equal to the ECOFF. Results: Overall, genotypically non-wild-type MTBC isolates with high-level resistance mutations (gNWT-R) correlated with isolates with MIC values above the ECOFF. For instance, the median MIC value (mg/L) for rifampicin-gNWT-R strains was >4.0 (IQR 4.0-4.0) compared with 0.5 (IQR 0.38-0.50) in genotypically wild-type (gWT-S, P < 0.001); isoniazid-gNWT-R >4.0 (IQR 2.0-4.0) compared with 0.25 (IQR 0.12-1.00) among gWT-S (P = 0.001); ethionamide-gNWT-R 15.0 (IQR 10.0-20.0) compared with 2.50 (IQR; 2.50-5.00) among gWT-S (P < 0.001). WGS correctly predicted resistance in 95% (36/38) and 100% (38/38) of the rifampicin-resistant isolates with ECOFFs >0.5 and >0.125 mg/L, respectively. No known resistance-conferring mutations were present in genes associated with resistance to fluoroquinolones, aminoglycosides, capreomycin, bedaquiline, delamanid, linezolid, clofazimine, cycloserine, or p-amino salicylic acid. Conclusions: WGS-based drug resistance prediction worked well to rule-in phenotypic drug resistance and the absence of second-line drug resistance-mediating mutations has the potential to guide the design of RR/MDR-TB regimens in the future.

The magnitude and factors associated with delays in management of smear positive tuberculosis in Dar es Salaam, Tanzania.

OBJECTIVE: To assess the magnitude and factors responsible for delay in TB management. DESIGN: A cross sectional hospital based survey in Dar es Salaam region, May 2006. RESULTS: We interviewed 639 TB patients. A total of 78.4% of patients had good knowledge on TB transmission. Only 35.9% had good knowledge on the symptoms. Patient delay was observed in 35.1% of the patients, with significantly (X2 = 5.49, d.f. = 1, P = 0.019) high proportion in females (41.0%) than in males (31.5%). Diagnosis delay was observed in 52.9% of the patients, with significantly (X2 = 10.1, d.f. = 1, P = 0.001) high proportion in females (62.1%) than in males (47.0%). Treatment delay was observed in 34.4% of patients with no significant differences among males and females. Several risk factors were significantly associated with patient's delays in females but not in males. The factors included not recognizing the following as TB symptoms: night sweat (OR = 1.92, 95% CI 1.20, 3.05), chest pain (OR = 1.62, 95% CI 1.1, 2.37), weight loss (OR = 1.55, 95% CI 1.03, 2.32), and coughing blood (OR = 1.47, 95% CI 1.01, 2.16). Other factors included: living more than 5 Km from a health facility (OR = 2.24, 95% CI 1.41, 3.55), no primary education (OR = 1.74, 95% CI 1.01, 3.05) and no employment (OR = 1.77, 95% CI 1.20, 2.60). In multiple logistic regression, five factors were more significant in females (OR = 2.22, 95% CI 1.14, 4.31) than in males (OR = 0.70, 95% CI 0.44, 1.11). These factors included not knowing that night sweat and chest pain are TB symptoms, a belief that TB is always associated with HIV infection, no employment and living far from a health facility. CONCLUSION: There were significant delays in the management of TB patients which were contributed by both patients and health facilities. However, delays in most of patients were due to delay of diagnosis and treatment in health facilities. The delays at all levels were more common in females than males. This indicates the need for education targeting health seeking behaviour and improvement in health system.

Gridlock from Diagnosis to Treatment of Multidrug-Resistant Tuberculosis (MDR-TB) in Tanzania: Illuminating Potential Factors for Possible Intervention.

SETTINGS: Kibong'oto Infectious Diseases Hospital, Kilimanjaro, Tanzania. OBJECTIVE: Characterise multidrug-resistant tuberculosis (MDR-TB)-treated cases during the scaling up of molecular diagnostics using Xpert MTB/RIF and GenoType MTBDRplus. DESIGN: Retrospective cohort study. RESULTS: A total of 223 MDR-TB patients were referred to the Kibong'oto Infectious Disease Hospital from January 2013 through December 2014. Four cities-Dar es Salaam, Mbeya, Mwanza, and Tanga-contributed 144 (65%) of referrals. Of the total referred patients, HIV coinfection was found in 92 (41%) and 180 (81%) had history of previous TB treatment. Molecular drug susceptibility testing (DST) contributed 201 (91%) of referrals and resulted in a shorter time from diagnosis to start of treatment, 30 days (95% confidence interval [CI], 26-37), compared to conventional phenotypic DST, 212 days (95% CI, 151-272; P<.001). Molecular DST found higher proportions of MDR-TB children and people living with HIV without prior treatment, 5 (12%) and 24 (56%), respectively, compared to those with previous treatment for TB, 4 (2%) and 68 (38%), respectively. The median CD4 count correspondingly was 131 cells/µl (IQR, 109-131) and 200 cells/µl (IQR, 94-337) for MDR-TB diagnosed by phenotypic and molecular diagnostics (P=.70). Despite the more rapid time to treatment initiation among patients diagnosed by molecular DST, treatment outcomes, including time to sputum culture conversion, did not differ compared to those diagnosed with conventional phenotypic DST. Regardless of the method of diagnosis, MDR-TB/HIV coinfected patients who died had lower CD4 counts (mean 86 ± 87 cells/µl) than survivors (mean 274 ± 224 cells/µl; P=.02). CONCLUSION: Molecular diagnostics appear to speedup the time to treatment initiation, but may not improve other treatment outcomes.