SettingKibong’oto National Tuberculosis Hospital (KNTH), Kilimanjaro, Tanzania.ObjectiveCharacterize the diagnostic process and interim treatment outcomes from patients treated for multidrug-resistant tuberculosis (MDR-TB) in Tanzania.DesignA retrospective cohort study was performed among all patients treated at KNTH for pulmonary MDR-TB between November 2009 and September 2011.ResultsSixty-one culture-positive MDR-TB patients initiated therapy, 60 (98%) with a prior history of TB treatment. Forty-one (67%) were male and 9 (14%) were HIV infected with a mean CD4 count of 424 (±106) cells/µl. The median time from specimen collection to MDR-TB diagnosis and from diagnosis to initiation of MDR-TB treatment was 138 days (IQR 101–159) and 131 days (IQR 32–233), respectively. Following treatment initiation four (7%) patients died (all HIV negative), 3 (5%) defaulted, and the remaining 54 (89%) completed the intensive phase. Most adverse drug reactions were mild to moderate and did not require discontinuation of treatment. Median time to culture conversion was 2 months (IQR 1–3) and did not vary by HIV status. In 28 isolates available for additional second-line drug susceptibility testing, fluoroquinolone, aminoglycoside and para-aminosalicylic acid resistance was rare yet ethionamide resistance was present in 9 (32%).ConclusionThe majority of MDR-TB patients from this cohort had survived a prolonged referral process, had multiple episodes of prior TB treatment, but did not have advanced AIDS and converted to culture negative early while completing an intensive inpatient regimen without serious adverse event. Further study is required to determine the clinical impact of second-line drug susceptibility testing and the feasibility of alternatives to prolonged hospitalization.

Coadministration of efavirenz, tenofovir and emtricitabine with a standard first-line TB treatment regimen did not significantly alter the pharmacokinetic parameters of these drugs and was tolerated well by Tanzanian TB patients who are coinfected with HIV.

BACKGROUND: Post-TB lung disease (PTLD) is an important but under-recognised chronic respiratory disease in high TB burden settings such as Tanzania.METHODS: This was a cross-sectional survey of adults within 2 years of completion of TB treatment in Kilimanjaro, Tanzania. Data were collected using questionnaires (symptoms and exposures), spirometry and chest radiographs to assess outcome measures, which were correlated with daily life exposures, including environment and diet.RESULTS: Of the 219 participants enrolled (mean age: 45 years ± 10; 193 88% males), 98 (45%) reported chronic respiratory symptoms; 46 (22%) had received treatment for TB two or more times; and HIV prevalence was 35 (16%). Spirometric abnormalities were observed in 146 (67%). Chest X-ray abnormalities occurred in 177 (86%). A diagnosis of PTLD was made in 200 (91%), and half had clinically relevant PTLD. The prevalence of mMRC ≥Grade 3 chronic bronchitis and dyspnoea was respectively 11% and 26%. Older age, multiple episodes of TB and poverty indicators were linked with clinically relevant PTLD.CONCLUSIONS: We found a substantial burden of PTLD in adults who had recently completed TB treatment in Tanzania. There is a pressing need to identify effective approaches for both the prevention and management of this disease.

Therapeutic drug monitoring may improve multidrug-resistant tuberculosis (MDR-TB) treatment outcomes. Levofloxacin demonstrates significant individual pharmacokinetic variability. Thus, we sought to develop and validate a high-performance liquid chromatography (HPLC) method with ultraviolet (UV) detection for levofloxacin in patients on MDR-TB treatment. The HPLC-UV method is based on a solid phase extraction (SPE) and a direct injection into the HPLC system. The limit of quantification was 0.25 μg/mL, and the assay was linear over the concentration range of 0.25—15 μg/mL (y = 0.5668x—0.0603, R2 = 0.9992) for the determination of levofloxacin in plasma. The HPLC-UV methodology achieved excellent accuracy and reproducibility along a clinically meaningful range. The intra-assay RSD% of low, medium, and high quality control samples (QC) were 1.93, 2.44, and 1.90, respectively, while the inter-assay RSD% were 3.74, 5.65, and 3.30, respectively. The mean recovery was 96.84%. This method was then utilized to measure levofloxacin concentrations from patients’ plasma samples from a retrospective cohort of consecutive enrolled subjects treated for MDR-TB at the national TB hospital in Tanzania during 5/3/2013–8/31/2015. Plasma was collected at 2 hours after levofloxacin administration, the time of estimated peak concentration (eCmax) treatment. Forty-one MDR-TB patients had plasma available and 39 had traceable programmatic outcomes. Only 13 (32%) patients had any plasma concentration that reached the lower range of the expected literature derived Cmax with the median eCmax being 5.86 (3.33–9.08 μg/ml). Using Classification and Regression Tree analysis, an eCmax ≥7.55 μg/mL was identified as the threshold which best predicted cure. Analyzing this CART derived threshold on treatment outcome, the time to sputum culture conversion was 38.3 ± 22.7 days vs. 47.8 ± 26.5 days (p = 0.27) and a greater proportion were cured, in 10 out of 15 (66.7%) vs. 6 out of 18 (33.3%) (p = 0.06) respectively. Furthermore, one patient with an eCmax/minimum inhibitory concentration (MIC) of only 1.13 acquired extensively drug resistant (XDR)-TB while undergoing treatment. The individual variability of levofloxacin concentrations in MDR-TB patients from Tanzania supports further study of the application of onsite therapeutic drug monitoring and MIC testing.

SummaryData on antituberculosis drug-induced hepatotoxicity in sub Saharan Africa are limited, probably because liver function tests are not carried out routinely during tuberculosis treatment in most African countries. We monitored the liver function of 112 Tanzanian hospitalized pulmonary tuberculosis patients during the first 2 months (i.e. the intensive phase) of tuberculosis treatment. The rate of hepatotoxicity in our study was 0.9% (95% CI 0.04-4.3%). It is encouraging to find a lower rate of antituberculosis drug-induced hepatotoxicity than one would expect based on the high prevalence of risk factors such as HIV and hepatitis B.