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Decline in Clinical Efficacy of Oral Miltefosine in Treatment of Post Kala-azar Dermal Leishmaniasis (PKDL) in India.

ABSTRACT: BACKGROUND:Recent studies have shown significant decline in the final cure rate after miltefosine treatment in visceral leishmaniasis. This study evaluates the efficacy of miltefosine in the treatment of post kala-azar dermal leishmaniasis (PKDL) patients recruited over a period of 5 years with 18 months of follow-up. METHODOLOGY:In this study 86 confirmed cases of PKDL were treated with two different dosage regimens of miltefosine (Regimen I- 50mg twice daily for 90 days and Regimen II- 50 mg thrice for 60 days) and the clinical outcome assessed monthly. Cure/relapse was ascertained by clinical and histopathological examination, and measuring parasite burden by quantitative real-time PCR. In vitro susceptibility of parasites towards miltefosine was estimated at both promastigote and amastigote stages. RESULTS:Seventy three of eighty six patients completed the treatment and achieved clinical cure. Approximately 4% (3/73) patients relapsed by the end of 12 months follow-up, while a total of 15% (11/73) relapsed by the end of 18 months. Relapse rate was significantly higher in regimen II (31%) compared to regimen I (10.5%)(P<0.005). Parasite load at the pre-treatment stage was significantly higher (P<0.005) in cases that relapsed compared to the cases that remained cured. In vitro susceptibility towards miltefosine of parasites isolated after relapse was significantly lower (>2 fold) in comparison with the pre-treatment isolates (P<0.005). CONCLUSION:Relapse rate in PKDL following miltefosine treatment has increased substantially, indicating the need of introducing alternate drugs/ combination therapy with miltefosine.

SUBMITTER: Ramesh V

PROVIDER: S-EPMC4619646 | biostudies-literature | 2015

REPOSITORIES: biostudies-literature

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Decline in Clinical Efficacy of Oral Miltefosine in Treatment of Post Kala-azar Dermal Leishmaniasis (PKDL) in India.

Ramesh V V Singh Ruchi R Avishek Kumar K Verma Aditya A Deep Deepak Kumar DK Verma Sandeep S Salotra Poonam P

PLoS neglected tropical diseases 20151022 10

<h4>Background</h4>Recent studies have shown significant decline in the final cure rate after miltefosine treatment in visceral leishmaniasis. This study evaluates the efficacy of miltefosine in the treatment of post kala-azar dermal leishmaniasis (PKDL) patients recruited over a period of 5 years with 18 months of follow-up.<h4>Methodology</h4>In this study 86 confirmed cases of PKDL were treated with two different dosage regimens of miltefosine (Regimen I- 50mg twice daily for 90 days and Regi ...[more]

PMID: 26492039

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Project description:BACKGROUND: Post kala-azar dermal leishmaniasis (PKDL), a dermal sequel of visceral leishmaniasis, caused by Leishmania donovani, constitutes an important reservoir for the parasite. Parallel functioning of counter acting immune responses (Th1/Th2) reflects a complex immunological scenario, suggesting the involvement of additional regulatory molecules in the disease pathogenesis. METHODOLOGY/PRINCIPAL FINDINGS: In the present study, human cytokine/chemokine/receptor specific cDNA array technique was employed to identify modulations in gene expression of host immuno-determinants during PKDL, followed by evaluation of Th17 type responses by analyzing mRNA and protein expression of Th17 markers (IL-23, IL-17, ROR?t) and performing functional assays using Leishmania antigen (TSLA) or recombinant (rec)IL-17. Array analysis identified key immuno-regulatory molecules including cytokines (TNF-?, IFN-?, IL-10, IL-17), chemokines (MCP-1, MIP-1?), apoptotic molecules (FasL, TRAIL, IRF-1) and receptors (CD40, Fas). Up regulation in lesional expression of Th17 markers was observed during PKDL compared to control (IL-17 and IL-23, P?=?0.0008; ROR?t, P?=?0.02). In follow-up samples, chemotherapy significantly down regulated expression of all markers. In addition, lesional expression of IL-17 was confirmed at protein level by Immuno-histochemistry. Further, systemic presence of Th17 responses (IL-17 and IL-23) was observed in plasma samples from PKDL patients. In functional assays, TSLA stimulated the secretion of IL-17 and IL-23 from PBMCs of PKDL patients, while recIL-17 enhanced the production of TNF-? as well as nitric oxide (NO) in PKDL compared to control (TNF-?, P?=?0.0002; NO, P?=?0.0013). Further, a positive correlation was evident between lesional mRNA expression of IL-17 and TNF-? during PKDL. CONCLUSION/SIGNIFICANCE: The results highlight key immune modulators in PKDL and provide evidence for the involvement of Th17 type responses in the disease pathogenesis.

Project description:BackgroundWith widespread resistance to antimonials in Visceral Leishmaniasis (VL) in the Indian subcontinent, Miltefosine (MIL) has been introduced as the first line therapy. Surveillance of MIL susceptibility in natural populations of Leishmania donovani is vital to preserve it and support the VL elimination program.Methodology and principal findingsWe measured in vitro susceptibility towards MIL and paromomycin (PMM) in L. donovani isolated from VL and PKDL, pre- and post-treatment cases, using an amastigote-macrophage model. MIL susceptibility of post-treatment isolates from cured VL cases (n = 13, mean IC(50)±SD = 2.43±1.44 µM), was comparable (p>0.05) whereas that from relapses (n = 3, mean IC(50) = 4.72±1.99 µM) was significantly higher (p = 0.04) to that of the pre-treatment group (n = 6, mean IC(50) = 1.86±0.75 µM). In PKDL, post-treatment isolates (n = 3, mean IC(50) = 16.13±2.64 µM) exhibited significantly lower susceptibility (p = 0.03) than pre-treatment isolates (n = 5, mean IC(50) = 8.63±0.94 µM). Overall, PKDL isolates (n = 8, mean IC(50) = 11.45±4.19 µM) exhibited significantly higher tolerance (p<0.0001) to MIL than VL isolates (n = 22, mean IC(50) = 2.58±1.58 µM). Point mutations in the miltefosine transporter (LdMT) and its beta subunit (LdRos3) genes previously reported in parasites with experimentally induced MIL resistance were not present in the clinical isolates. Further, the mRNA expression profile of these genes was comparable in the pre- and post-treatment isolates. Parasite isolates from VL and PKDL cases were uniformly susceptible to PMM with respective mean IC(50) = 7.05±2.24 µM and 6.18±1.51 µM.ConclusionThe in vitro susceptibility of VL isolates remained unchanged at the end of MIL treatment; however, isolates from relapsed VL and PKDL cases had lower susceptibility than the pre-treatment isolates. PKDL isolates were more tolerant towards MIL in comparison with VL isolates. All parasite isolates were uniformly susceptible to PMM. Mutations in the LdMT and LdRos3 genes as well as changes in the expression of these genes previously correlated with experimental resistance to MIL could not be verified for the field isolates.

Dataset Information

Decline in Clinical Efficacy of Oral Miltefosine in Treatment of Post Kala-azar Dermal Leishmaniasis (PKDL) in India.

Publications

Decline in Clinical Efficacy of Oral Miltefosine in Treatment of Post Kala-azar Dermal Leishmaniasis (PKDL) in India.

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