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| 2. |
- Dorlo, Thomas P C, et al.
(författare)
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Failure of miltefosine in visceral leishmaniasis is associated with low drug exposure.
- 2014
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Ingår i: Journal of Infectious Diseases. - : Oxford University Press (OUP). - 0022-1899 .- 1537-6613. ; 210:1, s. 146-53
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Recent reports indicated high miltefosine treatment failure rates for visceral leishmaniasis (VL) on the Indian subcontinent. To further explore the pharmacological factors associated with these treatment failures, a population pharmacokinetic-pharmacodynamic study was performed to examine the relationship between miltefosine drug exposure and treatment failure in a cohort of Nepalese patients with VL.METHODS: Miltefosine steady-state blood concentrations at the end of treatment were analyzed using liquid chromatography tandem mass spectrometry. A population pharmacokinetic-pharmacodynamic analysis was performed using nonlinear mixed-effects modeling and a logistic regression model. Individual estimates of miltefosine exposure were explored for their relationship with treatment failure.RESULTS: The overall probability of treatment failure was 21%. The time that the blood concentration was >10 times the half maximal effective concentration of miltefosine (median, 30.2 days) was significantly associated with treatment failure: each 1-day decrease in miltefosine exposure was associated with a 1.08-fold (95% confidence interval, 1.01-1.17) increased odds of treatment failure.CONCLUSIONS: Achieving a sufficient exposure to miltefosine is a significant and critical factor for VL treatment success, suggesting an urgent need to evaluate the recently proposed optimal allometric miltefosine dosing regimen. This study establishes the first evidence for a drug exposure-effect relationship for miltefosine in the treatment of VL.
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- Dorlo, Thomas P C, et al.
(författare)
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Reply to Arya and Agarwal.
- 2013
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Ingår i: Clinical Infectious Diseases. - : Oxford University Press (OUP). - 1058-4838 .- 1537-6591. ; 57:6, s. 917-8
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Tidskriftsartikel (refereegranskat)
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| 5. |
- Mahendradhata, Yodi, et al.
(författare)
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The incremental cost-effectiveness of engaging private practitioners to refer tuberculosis suspects to DOTS services in Jogjakarta, Indonesia
- 2010
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Ingår i: American Journal of Tropical Medicine and Hygiene. - : American Society of Tropical Medicine and Hygiene. - 0002-9637 .- 1476-1645. ; 82:6, s. 1131-1139
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Tidskriftsartikel (refereegranskat)abstract
- We aimed to evaluate the incremental cost-effectiveness of engaging private practitioners (PPs) to refer tuberculosis (TB) suspects to public health centers in Jogjakarta, Indonesia. Effectiveness was assessed for TB suspects notified between May 2004 and April 2005. Private practitioners referred 1,064 TB suspects, of which 57.5% failed to reach a health center. The smear-positive rate among patients reaching a health center was 61.8%. Two hundred eighty (280) out of a total of 1,306 (21.4%) new smear-positive cases were enrolled through the PPs strategy. The incremental cost-effectiveness ratio per smear-positive case successfully treated for the PPs strategy was US$351.66 (95% CI 322.84-601.33). On the basis of an acceptability curve using the National TB control program's willingness-to-pay threshold (US$448.61), we estimate the probability that the PPs strategy is cost-effective at 66.8%. The strategy of engaging PPs was incrementally cost-effective, although under specific conditions, most importantly a well-functioning public directly observed treatment, short-course (DOTS) program.
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- Ostyn, Bart, et al.
(författare)
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Failure of miltefosine treatment for visceral leishmaniasis in children and men in South-East Asia.
- 2014
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Ingår i: PLOS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 9:6, s. e100220-
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: High frequency of relapse in miltefosine-treated visceral leishmaniasis (VL) patients in India and Nepal followed up for twelve months.OBJECTIVE: To identify epidemiological and clinical risk factors for relapse of VL in patients recently treated with standard dosing of miltefosine in India and Nepal.DESIGN: Prospective observational study in three Primary Health Centers and one reference center in Muzaffarpur district, Bihar, India; and two zonal hospitals and a university hospital in South-east Nepal; records of all consenting patients diagnosed with VL and treated with miltefosine according to the current treatment guidelines of the Kala azar elimination program between 2009 and 2011.RESULTS: We compared the clinical records of 78 cases of relapse with those of 775 patients who had no record of subsequent relapse. Relapse was 2 times more common amongst male patients (IRR 2.14, 95% CI 1.27-3.61), and 2 to 3 times more frequent in the age groups below 15 compared to the over 25 year olds (age 10 to 14: IRR 2.53; 95% CI 1.37-4.65 and Age 2 to 9: IRR 3.19; 95% CI 1.77-5.77). History of earlier VL episodes, or specific clinical features at time of diagnosis such as duration of symptoms or spleen size were no predictors of relapse.CONCLUSIONS: Young age and male gender were associated with increased risk of VL relapse after miltefosine, suggesting that the mechanism of relapse is mainly host-related i.e. immunological factors and/or drug exposure (pharmacokinetics). The observed decrease in efficacy of miltefosine may be explained by the inclusion of younger patients compared to the earlier clinical trials, rather than by a decreased susceptibility of the parasite to miltefosine. Our findings highlight the importance of proper clinical trials in children, including pharmacokinetics, to determine the safety, efficacy, drug exposure and therapeutic response of new drugs in this age group.
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- Rijal, Suman, et al.
(författare)
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Increasing failure of miltefosine in the treatment of Kala-azar in Nepal and the potential role of parasite drug resistance, reinfection, or noncompliance.
- 2013
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Ingår i: Clinical Infectious Diseases. - : Oxford University Press (OUP). - 1058-4838 .- 1537-6591. ; 56:11, s. 1530-8
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Miltefosine (MIL), the only oral drug for visceral leishmaniasis (VL), is currently the first-line therapy in the VL elimination program of the Indian subcontinent. Given the paucity of anti-VL drugs and the looming threat of resistance, there is an obvious need for close monitoring of clinical efficacy of MIL.METHODS: In a cohort study of 120 VL patients treated with MIL in Nepal, we monitored the clinical outcomes up to 12 months after completion of therapy and explored the potential role of drug compliance, parasite drug resistance, and reinfection.RESULTS: The initial cure rate was 95.8% (95% confidence interval [CI], 92.2-99.4) and the relapse rate at 6 and 12 months was 10.8% (95% CI, 5.2-16.4) and 20.0% (95% CI, 12.8-27.2) , respectively. No significant clinical risk factors of relapse apart from age <12 years were found. Parasite fingerprints of pretreatment and relapse bone marrow isolates within 8 patients were similar, suggesting that clinical relapses were not due to reinfection with a new strain. The mean promastigote MIL susceptibility (50% inhibitory concentration) of isolates from definite cures was similar to that of relapses. Although more tolerant strains were observed, parasite resistance, as currently measured, is thus not likely involved in MIL treatment failure. Moreover, MIL blood levels at the end of treatment were similar in cured and relapsed patients.CONCLUSIONS: Relapse in one-fifth of the MIL-treated patients observed in our study is an alarming signal for the VL elimination campaign, urging for further review and cohort monitoring.
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- Uranw, Surendra, et al.
(författare)
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Adherence to miltefosine treatment for visceral leishmaniasis under routine conditions in Nepal.
- 2013
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Ingår i: Tropical medicine & international health. - : Wiley. - 1360-2276 .- 1365-3156. ; 18:2, s. 179-87
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVE: To assess patient adherence to unsupervised single-drug miltefosine treatment for visceral leishmaniasis and to identify the factors influencing adherence.METHODS: This is a prospective cohort study of 171 patients with Visceral leishmaniasis (VL) in three healthcare settings in Nepal. Adherence was assessed through pill count, checking of treatment cards and adherence questionnaires, as well as miltefosine concentration measurements at the end of treatment. Poor adherence was defined as less than 90% of required capsules taken.RESULTS: Patient adherence to miltefosine was 83%. Predictors of adherence were being the male sex (OR = 2.60, 95% CI 1.02-6.67) and knowing the duration of treatment (OR = 3.05, 95% CI 1.16-8.04). Adherence was also better for patients who were literate and knew the side effects of treatment. Gastrointestinal side effects and negligence after the resolution of clinical symptoms of VL were the main reasons for poor adherence. Poor adherence was associated (though not statistically significant) with future relapse.CONCLUSION: Effective counselling during the treatment, a short take-home message on VL and on side effects and action of miltefosine, and follow-up visits are the best way to prevent poor adherence. Single end-of-treatment measurements of miltefosine concentrations as objective assessment of adherence would only be useful in addition to the subjective assessments when substantial doses of miltefosine have been missed.
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