Treatment outcomes of patients with MDR-TB in Nepal on a current programmatic standardised regimen:retrospective single-centre study

OBJECTIVES: The objectives of this study were to evaluate treatment in patients on current programmatic multidrug-resistant tuberculosis (MDR-TB) regimen and verify eligibility for the 9-month regimen and therapeutic drug monitoring (TDM). METHODS: We performed a retrospective chart review of patients with MDR-TB receiving standardised regimen at the German Nepal TB Project Clinic, Nepal, between 2014 and 2016. Eligibility for the 9-month regimen and indications for TDM were evaluated. RESULTS: Out of 107 available patients' medical records, 98 were included. In this centre, the MDR-TB treatment success rates were 69.0% in 2015, 86.6% in 2016 and 86.5% in 2017. The median time to sputum smear conversion was 60 days (60-90 IQR) and culture conversion was 60 days (60-90 IQR). Observed side effects did not impact treatment outcomes. No difference in treatment success rates was observed between patients with predisposing risk factors and those without. Only 49% (36/74) of patients were eligible for the 9-month regimen and 23 patients for TDM according to American Thoracic Society guideline criteria. CONCLUSIONS: Nepalese patients with MDR-TB on ambulatory care had good treatment outcome after programmatic treatment. Implementation of the new WHO oral MDR-TB treatment regimen may further improve treatment results. The 9-month regimen and TDM should be considered as part of programmatic care

Ambulatory-Based Standardized Therapy for Multi-Drug Resistant Tuberculosis: Experience from Nepal, 2005–2006

OBJECTIVE: The aim of this study was to describe treatment outcomes for multi-drug resistant tuberculosis (MDR-TB) outpatients on a standardized regimen in Nepal. METHODOLOGY: Data on pulmonary MDR-TB patients enrolled for treatment in the Green Light Committee-approved National Programme between 15 September 2005 and 15 September 2006 were studied. Standardized regimen was used (8Z-Km-Ofx-Eto-Cs/16Z-Ofx-Eto-Cs) for a maximum of 32 months and follow-up was by smear and culture. Drug susceptibility testing (DST) results were not used to modify the treatment regimen. MDR-TB therapy was delivered in outpatient facilities for the whole course of treatment. Multivariable analysis was used to explain bacteriological cure as a function of sex, age, initial body weight, history of previous treatment and the region of report. PRINCIPAL FINDINGS: In the first 12-months, 175 laboratory-confirmed MDR-TB cases (62% males) had outcomes reported. Most cases had failed a Category 2 first-line regimen (87%) or a Category 1 regimen (6%), 2% were previously untreated contacts of MDR-TB cases and 5% were unspecified. Cure was reported among 70% of patients (range 38%-93% by Region), 8% died, 5% failed treatment, and 17% defaulted. Unfavorable outcomes were not correlated to the number of resistant drugs at baseline DST. Cases who died had a lower mean body weight than those surviving (40.3 kg vs 47.2 kg, p<0.05). Default was significantly higher in two regions [Eastern OR = 6.2; 95%CL2.0-18.9; Far West OR = 5.0; 95%CL1.0-24.3]. At logistic regression, cure was inversely associated with body weight <36 kg [Adj.OR = 0.1; 95%CL0.0-0.3; ref. 55-75 kg] and treatment in the Eastern region [Adj.OR = 0.1; 95%CL0.0-0.4; ref. Central region]. CONCLUSIONS: The implementation of an ambulatory-based treatment programme for MDR-TB based on a fully standardized regimen can yield high cure rates even in resource-limited settings. The determinants of unfavorable outcome should be investigated thoroughly to maximize likelihood of successful treatment

Evaluation of saliva as a potential alternative sampling matrix for therapeutic drug monitoring of levofloxacin in MDR-TB patients

Saliva may be a useful alternative matrix for monitoring levofloxacin concentrations in multi-drug resistant TB patients. The objectives of this study were: a) to evaluate the correlation between plasma and salivary Lfx concentrations in MDR-TB patients; and b) to gauge the possibility of using saliva as an alternative sampling matrix for therapeutic drug monitoring of Lfx in TB endemic areas. This was a prospective pharmacokinetic study that enrolled MDR-TB patients receiving levofloxacin (Lfx; 750-1000mg once daily dosing) under standardized treatment regimen in Nepal. Paired blood and saliva samples were collected at steady state. Lfx concentrations were quantified using liquid chromatography- tandem mass spectrometry. Pharmacokinetic parameters were calculated using non-compartmental kinetics. Lfx drug exposure was evaluated in 23 MDR-TB patients. During the first month, the median (IQR) area under the concentration-time curve (AUC0-24) was 67.09 (53.93-98.37) mg*h/L in saliva and 99.91 (76.80-129.70) mg*h/L in plasma, and the saliva plasma (S/P) ratio was 0.69 (0.53-0.99). Similarly, during the second month, the median (IQR) AUC0-24 was 75.63 (61.45-125.5) mg*h/L in saliva and 102.7 (84.46-131.9) mg*h/L in plasma with a S/P ratio of 0.73 (0.66-1.18). Furthermore, large inter-and intra-individual variabilities in Lfx concentrations were observed. This study could not demonstrate a strong correlation between plasma and saliva Lfx levels. Despite a good Lfx penetration in saliva, the variability in individual saliva-to-plasma ratios limits the use of saliva as a valid substitute for plasma. Nevertheless, saliva could be useful in semi-quantitatively predicting Lfx plasma levels

A novel sputum transport solution eliminates cold chain and supports routine tuberculosis testing in Nepal

This preliminary study evaluated the transport reagent OMNIgene SPUTUM (OMS) in a real-world, resource-limited setting: a zonal hospital and national tuberculosis (TB) reference laboratory, Nepal. The objectives were to: (1) assess the performance of OMS for transporting sputum from peripheral sites without cold chain stabilization; and (2) compare with Nepal’s standard of care (SOC) for Mycobacterium tuberculosis smear and culture diagnostics. Sixty sputa were manually split into a SOC sample (airline-couriered to the laboratory, conventional processing) and an OMS sample (OMS added at collection, no cold chain transport or processing). Smear microscopy and solid culture were performed. Transport was 0–8 days. Forty-one samples (68%) were smear-positive using both methods. Of the OMS cultures, 37 (62%) were positive, 22 (36%) were negative, and one (2%) was contaminated. Corresponding SOC results were 32 (53%), 21 (35%), and seven (12%). OMS “rescued” six (i.e., missed using SOC) compared with one rescue using SOC. Of smear-positives, six SOC samples produced contaminated cultures whereas only one OMS sample was contaminated. OMS reduced culture contamination from 12% to 2%, and improved TB detection by 9%. The results suggest that OMS could perform well as a no cold chain, long-term transport solution for smear and culture testing. The findings provide a basis for larger feasibility studies

Evaluation of saliva as a potential alternative sampling matrix for therapeutic drug monitoring of levofloxacin in patients with multidrug-resistant tuberculosis

Saliva may be a useful alternative matrix for monitoring levofloxacin concentrations in multidrug-resistant tuberculosis (MDR-TB) patients. The objectives of this study were (i) to evaluate the correlation between plasma and salivary levofloxacin (Lfx) concentrations in MDR-TB patients and (ii) to gauge the possibility of using saliva as an alternative sampling matrix for therapeutic drug monitoring of Lfx in areas where TB is endemic. This was a prospective pharmacokinetic study that enrolled MDR-TB patients receiving levofloxacin (750- to 1,000-mg once-daily dosing) under standardized treatment regimen in Nepal. Paired blood and saliva samples were collected at steady state. Lfx concentrations were quantified using liquid chromatography-tandem mass spectrometry. Pharmacokinetic parameters were calculated using noncompartmental kinetics. Lfx drug exposures were evaluated in 23 MDR-TB patients. During the first month, the median (interquartile range [IQR]) areas under the concentration-time curve from 0 to 24 h (AUC 0–24 ) were 67.09 (53.93 to 98.37) mg ⋅ h/liter in saliva and 99.91 (76.80 to 129.70) mg ⋅ h/liter in plasma, and the saliva plasma (S/P) ratio was 0.69 (0.53 to 0.99). Similarly, during the second month, the median (IQR) AUC 0–24 were 75.63 (61.45 to 125.5) mg ⋅ h/liter in saliva and 102.7 (84.46 to 131.9) mg ⋅ h/liter in plasma, with an S/P ratio of 0.73 (0.66 to 1.18). Furthermore, large inter- and intraindividual variabilities in Lfx concentrations were observed. This study could not demonstrate a strong correlation between plasma and saliva Lfx levels. Despite a good Lfx penetration in saliva, the variability in individual saliva-to-plasma ratios limits the use of saliva as a valid substitute for plasma. Nevertheless, saliva could be useful in semiquantitatively predicting Lfx plasma levels. (This study has been registered at ClinicalTrials.gov under identifier NCT03000517.

MDR-TB treatment centers and sub-centers in Nepal.

<p>Footnote <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0008313#pone-0008313-g001" target="_blank">Figure 1:</a> In 2005–2006, not all the health centres were functioning. The 175 cases included in this study were under care at 17 clinics (Bhaktapur, Bheri, Bir, Genetup, Haraicha, HelpHand, INF_Banke, KohalpurMC, Mahakali, Mangalbare, NATA, NMC, NTC, Patan, RTC, Stupa, and TUTH).</p

Characteristics of the study population.

<p>SD = Standard Deviation; IQR = Inter Quartile Range.</p