Download Efficacy of Miltefosine in the Treatment of Visceral

MAJOR ARTICLE
Efficacy of Miltefosine in the Treatment
of Visceral Leishmaniasis in India After a
Decade of Use
Shyam Sundar,1,a Anup Singh,1,a Madhukar Rai,1 Vijay K. Prajapati,1 Avinash K. Singh,1 Bart Ostyn,2 Marleen Boelaert,2
Jean-Claude Dujardin,2,3 and Jaya Chakravarty1
1
Department of Medicine, Institute of Medical Sciences, Banaras Hindu University, Varanasi, India; and 2Institute of Tropical Medicine, and
Department of Biomedical Sciences, Antwerp University, Belgium
3
Background. Miltefosine is the only oral drug available for treatment of Indian visceral leishmaniasis (VL),
which was shown to have an efficacy of 94% in a phase III trial in the Indian subcontinent. Its unrestricted use
has raised concern about its continued effectiveness. This study evaluates the efficacy and safety of miltefosine for
the treatment of VL after a decade of use in India.
Methods. An open-label, noncomparative study was performed in which 567 patients received oral miltefosine (50 mg for patients weighing <25 kg, 100 mg in divided doses for those weighing ≥25 kg, and 2.5 mg per kg
for those aged <12 years, daily for 28 days) in a directly observed manner. Patients were followed up for 6 months
to see the response to therapy.
Results. At the end of treatment the initial cure rate was 97.5% (intention to treat), and 6 months after the
end of treatment the final cure rate was 90.3%. The overall death rate was 0.9% (5 of 567), and 2 deaths were
related to drug toxicity. Gastrointestinal intolerance was frequent (64.5%). The drug was interrupted in 9 patients
(1.5%) because of drug-associated adverse events.
Conclusions. As compared to the phase III trial that led to registration of the drug a decade ago, there is a
substantial increase in the failure rate of oral miltefosine for treatment of VL in India.
Miltefosine is the first orally effective agent for treating
leishmaniasis. It was first approved in India, in 2002, for
the treatment of visceral leishmaniasis (VL), following a
phase III multicenter study [1, 2]. Since then, it has been
registered in various other countries in different parts of
the world and has been used in the treatment of nearly
all forms of leishmaniasis, although with a variable rate
of efficacy [3, 4]. Because of its ease of use and the possibility for ambulatory care, the VL elimination program
in India, Nepal, and Bangladesh has recommended
Received 15 January 2012; accepted 2 April 2012; electronically published 9
May 2012.
a
S. S. and A. S. contributed equally to this work.
Correspondence: Shyam Sundar, MD, Dept of Medicine, Institute of Medical
Sciences, Banaras Hindu University, Varanasi 221005, India (drshyamsundar@
hotmail.com).
Clinical Infectious Diseases 2012;55(4):543–50
© The Author 2012. Published by Oxford University Press on behalf of the Infectious
Diseases Society of America. All rights reserved. For Permissions, please e-mail:
[email protected].
DOI: 10.1093/cid/cis474
miltefosine as the first-line drug for treatment in this
region [5]. More than a decade has passed since the
pivotal phase III trial leading to the registration of miltefosine in India was done. During 2002–2006, the drug
was available over the counter in many private pharmacies, and prescribing practice and drug use was rather
irrational, with many incomplete dosages and poor adherence [5]. Currently, the drug is made available only
in public hospitals, through the National VL Control
Program, and patients are provided the supply of drugs
for 1 week at a time. We commissioned this study to
evaluate miltefosine efficacy in Bihar, India, an area of
VL endemicity, 10 years after the pivotal phase III trial.
The study was performed in a dedicated research clinic
where directly observed therapy was conducted.
MATERIALS AND METHODS
Study Design
An open-label, noncomparative study was done at the
Muzaffarpur site of the Kala Azar Medical Research
Miltefosine for Leishmaniasis
•
CID 2012:55 (15 August)
•
543
Center (KAMRC), Institute of Medical Sciences, Banaras
Hindu University, from September 2009 through November
2010. The study was approved by the Ethical Committee of
the Institute of Medical Sciences and by the Institute of Tropical Medicine of Antwerp, Belgium. Written informed consent
was obtained from adult patients and from the guardians of
patients aged <18 years. All authors participated fully in the
design of the study, had access to all study data, and take
responsibility for data analysis.
Study Drug
Miltefosine (Paladin Labs, Canada, 50-mg and 10-mg capsules) was administered orally for 28 days as directly observed
therapy after meals in the following doses: 100 mg daily (one
50-mg capsule in the morning and one 50-mg capsule in the
evening after meals), for patients weighing >25 kg; 50 mg
every morning, for patients weighing ≤25 kg; and 2.5 mg/kg
daily in divided doses, for patients aged <12 years.
Study Patients
Females and males aged 6–70 years were eligible if they had
symptoms and signs suggestive of VL (ie, fever with chills, rigor,
and splenomegaly) with Leishmania parasites demonstrable in
splenic-aspirate smears. Splenic-aspirate smears were each read
by 2 observers in a blinded fashion. Parasites in splenic-aspirate
smears were graded on a log scale, from 0 (defined as 0 parasites
per 1000 high-power fields in oil immersion) to ≥6 (defined as
>100 parasites per high-power field in oil immersion) [6]. Criteria for exclusion were current pregnancy; current breast-feeding;
seropositivity for human immunodeficiency virus; presence of a
serious illness or concurrent infectious disease, such as tuberculosis or bacterial pneumonia; granulocyte count <1000 granulocytes/mm3; hemoglobin level <5.0 g/dL; platelet count <40 000
platelets/mm3; hepatic transaminase levels >5 the normal level;
total bilirubin level >2.0 mg/dL; serum creatinine level above the
upper normal limit; prothrombin time >5 seconds above
control; and/or inability of the subject or guardian to provide
written informed consent.
parameters, were recorded weekly. The assessment for initial
cure, at day 29, consisted of a clinical examination, including
measurement of body temperature and weight, assessment of
liver and spleen size, and evaluation of hematological and biochemical parameters. Splenic aspiration was repeated, and
smears of aspirates were examined for Leishmania parasites
(LD bodies). If splenic-aspirate smears on day 29 showed a
parasite density grading of ≥2 (ie, 1–10 parasites per 100 highpower fields), treatment was considered to have failed, and
patients were provided rescue treatment; if there were no parasites, patients were assumed to have achieved parasitological
cure and were discharged from the clinic. Those with a grade
of ≥1 (1–10 parasites per 1000 high-power fields) were discharged but recalled on day 44 to repeat the splenic-aspirate
smear, and persistence of parasites meant that treatment had
failed. “Initial cure” was defined as resolution of fever, regression of splenic enlargement, and return of laboratory values to
normal ranges at the end of treatment and absence of parasites
in splenic-aspirate smears at day 29 (or at day 44 for those
with a grade of ≥1). All patients with initial cure were discharged from the clinic and invited for a follow-up visit 6
months after treatment to assess final cure. They were assessed
by clinical examination and hematological and biochemical
evaluation. “Final cure” was defined as the absence of signs or
symptoms of relapse at 6 months in those with initial cure. If
at any point during follow-up or at the 6-month visit a relapse
was suspected, a new parasitological evaluation with a splenicaspirate smear was done to document relapse. “Treatment
failure” was defined as either the lack of initial cure or relapse.
Patients with treatment failure were given rescue treatment
with amphotericin B (0.75 mg/kg administered in 15 daily
infusions).
Safety End Points
Treatment was discontinued and subjects were given rescue
treatment if an adverse event if grade ≥3 Common Toxicity
Criteria were detected [7], except for cases of elevated hepatic
enzyme levels [2].
Study Protocol
Statistical Analysis
Once patients fulfilled the inclusion and exclusion criteria and
provided consent, they were admitted for the full duration of
treatment at the KAMRC research clinic. Because of the long
half-life of miltefosine and its known teratogenic potential,
women of childbearing age were asked to practice contraception during treatment and for an additional 3 months after
completion of treatment. Treatment was directly observed by a
clinic nurse, who observed the swallowing of the pills. Vital
signs, such as body temperature, pulse rate, and blood pressure, were recorded daily. Other parameters, such as body
weight, spleen size, and hematological and biochemical
The data were analyzed by the statistical software package
SPSS (version 16.0). Continuous variables are presented as
mean values ± SD, and frequencies with their respective percentages are given for categorical variables. The comparison
between the mean values for patients at baseline and day 29
was done by a paired t test and the Wilcoxon signed ranked
test. For comparison of clinical outcomes between treatmentnaive patients and those with relapse after prior antileishmanial treatment, the independent 2-sample t test and the
Mann-Whitney U test was used. A P value of <.05 was considered statistically significant.
544
•
CID 2012:55 (15 August)
•
Sundar et al
Table 1. Comparison of Clinical and Laboratory Data at Baseline and Day 29 Among Indian Patients With Visceral Leishmaniasis Who
Received Miltefosine Therapy
Variable
Baseline (n = 567)
Day 29 (n = 553)
Change From Baseline to
Day 29 (n = 553)
…
Age, years
Mean ± SD
24.2 ± 16.0
…
Median (range)
18 (6–70)
…
…
Age ≥12 years
Sex
432 (75.2)
…
…
Male
333 (58.7)
…
…
Female
Had relapse
234 (41.3)
40 (7.05)
…
…
…
…
47.2 ± 52.3
30 (3–365)
…
…
…
…
36.1 ± 14.2
37
37 ± 14
37
0.5 ± 5.2
1
2.3 ± 1.2
2
…
…
…
…
4.5 ± 3.2
4
0.4 ± 1.1
0
−4.1 ± 2.5
−4
8.3 ± 1.8
8
10.3 ± 1.5
10
1.9 ± 1.4
2
3452.4 ± 1576
3100
9303.4 ± 3587.8
8800
5857 ± 3471.2
5200
127 670.2 ± 65 140.6
323 083.2 ± 110 442
195 379.1 ± 112 871.3
Median
118 000
305 000
184 000
Creatinine level, mg/dL
Mean ± SD
0.8 ± 0.2
0.75 ± 0.3
−0.03 ± 0.3
0.8
0.7
−0.05
8.2 ± 5.9
8.8 ± 5.8
−0.6 ± 5.9
9
9
0
60.7 ± 39.6
41.3 ± 25.3
−19.6 ± 44.4
49
34
−2
40.3 ± 25.8
40.8 ± 23.2
0.5 ± 39.3
34
37
0
P Value
Illness duration, days
Mean ± SD
Median (range)
Body weight, kg
<.0001
Mean ± SD
Median
Splenic aspirate score
Mean ± SD
Median
Spleen size, cm below left costal margin
<.0001
Mean ± SD
Median
Hemoglobin level, g/dL
<.0001
Mean ± SD
Median
WBC count, cells/mm3
<.0001
Mean ± SD
Median
Platelet count, platelets/mm3
Mean ± SD
<.0001
Median
BUN level, mg/dL
Mean ± SD
Median
AST level, IU/mL
Mean ± SD
Median
ALT level, IU/mL
Mean ± SD
Median
.009
.018
<.0001
.016
Data are No. (%) of patients, unless otherwise indicated.
Abbreviations: ALT, alanine aminotransferase; AST, aspartate aminotransferase; BUN, blood urea nitrogen; SD, standard deviation; WBC, white blood cell.
RESULTS
A total of 760 patients were screened and assessed for eligibility for treatment with miltefosine. Of these, 567 fulfilled the
eligibility criteria and were enrolled in the study. Clinical characteristics and laboratory values at baseline are shown in
Table 1. Therapy in 9 patients was stopped prematurely
(Figure 1). Of these patients, 1 later died (see below), and the
Miltefosine for Leishmaniasis
•
CID 2012:55 (15 August)
•
545
Figure 1.
Flow of patients through the study.
other 8 were given rescue therapy (15 infusions of amphotericin B in a dose of 0.75 mg/kg). Four patients withdrew
consent. There were 2 deaths recorded during the course of
the treatment. The patient mentioned above developed repeated vomiting and severe pancytopenia during the third week of
therapy and later went into shock and finally died. The death
was possibly related to the study drug. Another patient had
sudden death on the fourth day of therapy, probably because
of a cardiac event.
Finally, 553 of 567 patients were available for parasitological
assessment of initial cure at day 29 (or day 44). Three more
patients died before the assessment at the final cure end point
546
•
CID 2012:55 (15 August)
•
Sundar et al
(180 days after treatment). There was no loss to follow-up
during the study (see Figure 1 flowchart).
Efficacy
All the 553 evaluable patients were afebrile at day 29 and
showed remarkable regression of spleen size and significant
improvement in clinical and hematological tests (Table 1).
No parasites were demonstrated by splenic-aspirate smear;
thus, an initial cure was achieved in all patients who completed therapy (Table 2). This resulted in an initial cure rate
of 97.5% (553 of 567; 95% confidence interval [CI],
96.3%–98.8%).
Table 2. Clinical Outcomes Among Indian Patients With Visceral Leishmaniasis Who Received Miltefosine Therapy
Variable
Table 3. Adverse Events Among Indian Patients With Visceral
Leishmaniasis Who Received Miltefosine Therapy
Patients, No. (%) (n = 567)
a
Drug stopped because of adverse events
9 (1.4)
Withdrew consent
Death
4 (0.7)
5b (0.8)
Adverse Event
Vomiting
Any
95% Confidence
Interval
Value (n = 567)
366 (64.55)
60.6–68.5
366 (64.55)
60.6–68.5
Initial cure
553 (97.5)
Duration of 1–2 days
Relapse
Final cure
39c (6.8)
512 (90.3)
CTC gradea
Grade 1
254 (44.79)
40.7–48.9
Grade 2
112 (19.75)
16.5–23.0
a
Includes 1 patient who died later, after treatment was stopped because of
an adverse event; this patient’s outcome is included among the data in the
row “Death.”
b
1 (0.01)
37 (6.52)
−.16 to .52
4.5–8.6
CTC gradea
Grade 1
30 (5.29)
3.4–7.1
Grade 2
5 (0.08)
Grade 4
Rigors
2 (0.03)
Grade 3
Diarrhea
Any
Two died during treatment, and 3 died during follow-up.
c
Includes 1 patient who had relapse and later died; this patient’s outcome is
included among the data in the row “Death.”
During the 6-month follow-up, 39 of these 553 patients
(7.24%) relapsed with recurrence of fever, increase in spleen
size, worsening of laboratory values, and presence of parasites
demonstrated by repeat splenic-aspirate smear. Additionally,
there were 3 deaths. One involved a patient for whom relapse
was diagnosed at 5 months of follow-up, in association with a
grade ≥4 splenic aspirate; he later died from severe pancytopenia and grade 3 renal dysfunction. Two other patients died
during the course of follow-up: one died after developing severe
pancytopenia 1 week after the end of treatment, and another
committed suicide 4 months after the end of treatment. The
remaining 512 patients showed consistent clinical and biochemical improvement at the 6-month follow-up visit and were
classified as having achieved a definitive cure. This yielded a
final cure rate of 90.3% (512 of 567; 95% CI, 87.9%–92.7%).
There was no statistically significant difference in baseline
clinical and laboratory characteristics between patients who relapsed and those who attained final cure (data not shown). All
patients who relapsed after miltefosine treatment were successfully treated with amphotericin B, except for the patient who
died before rescue treatment could be started.
Of 567 patients, 78 (13.7%) had a history of previously failed
antileishmanial treatment. Of these 78, 67 (85.8%) were definitely cured, and 8 patients (10.2%) relapsed; for 2 patients,
treatment was stopped because of adverse events, and 1 patient
withdrew consent. The cure rate among previously treated patients was not significantly different from that among treatment-naive patients, for whom the rate was 91% (445 of 489).
Any
Duration of 1–2 days
AST level
.1–1.7
−.13 to .84
35 (6.17)
4.2–8.2
35 (6.17)
4.2–8.2
Change from baseline, U/L, mean (%)
Day 7
Day 14
0.96 (2.3)
−15.08 (37.4)
−19.6 (32.2)
Day 29
−2.6 to 4.5b
−19.0 to 11.5b
−23.0 to −15.7b
a
CTC grade
Grade 1
325 (57.31)
53.2–61.4
Grade 2
190 (33.50)
29.6–37.4
21 (3.70)
2.1–5.2
Grade 3
ALT level
Change from baseline, U/L, mean (%)
Day 7
9.84 (23.3)
6.7–12.6b
Day 14
7.26 (17.2)
3.7–10.3b
Day 29
CTC gradea
0.5 (1.2)
−2.7 to 3.7b
Grade 1
343 (60.49)
56.4–64.5
Grade 2
Grade 3
121 (21.34)
20 (3.52)
18.0–24.7
2.0–5.0
Serum creatinine level
Change from baseline, mg/dL, mean (%)
Day 7
−0.02 (2.7)
−.03 to −.0002b
Day 14
−0.02 (2.7)
−.03 to −.0002b
Day 29
CTC gradea
−0.03 (3.7)
−.054 to −.005b
Grade 1
166 (29.27)
25.5–33.0
Grade 2
Grade 3
10 (1.76)
6 (1.05)
.7–2.8
.2–1.9
Data are No. (%) of patients, unless otherwise indicated.
Adverse Events
Signs and symptoms with toxicity grading are given in
Table 3. Gastrointestinal intolerance was the most common
Abbreviations: ALT, alanine aminotransferase; AST, aspartate aminotransferase; CTC, Common Toxicity Criteria.
a
Specified in [7].
b
For the mean change.
Miltefosine for Leishmaniasis
•
CID 2012:55 (15 August)
•
547
were lost to follow-up until the assessment of final cure at 6
months. The main findings of the current study as compared
to findings from the phase III trial during 1999–2000 were a
significant decline in the final cure rate, from 94% to approximately 90% (P = .04), and a doubling of the relapse rate, from
3% (9 of 291) to 6.8% (39 of 567) (P = .02) [2]. As this cure
rate was achieved under conditions whereby the drug was administered as directly observed therapy, even lower cure rates
can be expected in patients receiving home-based therapy currently being practiced in the VL elimination program in India,
Nepal, and Bangladesh. The related low adherence would ultimately facilitate emergence of drug-resistant strains, and we
recommend the use of directly observed therapy in this
program. A potential explanation to our findings could be the
presence of miltefosine-resistant parasites in our cohort of
patients. Miltefosine is highly susceptible to the development
of resistance because of its long half-life, and this was verified
in experimental studies [8]. We cannot confirm that this phenomenon occurred in the present study because in vitro susceptibility studies of clinical isolates of present patients are still
in progress.
Our findings are consistent with those of a recent phase IV
study of miltefosine for treatment of VL in Bangladesh, where
the cure rates were 71.8% and 85% in intention-to-treat and
per-protocol analyses, respectively [9]. Weekly supply of the
drug without direct observation might have contributed to the
lower efficacy. These findings from Bangladesh is particularly
adverse event, with vomiting in 64.5% of patients and diarrhea
in 6.5%. However, these side effects were mild (grade 1 or 2)
in most patients. Miltefosine had to be stopped for only 3
patients because of severe gastrointestinal intolerance, one of
whom died.
The results of laboratory tests are summarized in Table 3.
Mean renal function did not change significantly at the end of
the therapy, compared with baseline. However, 6 patients (1%)
had a grade 3 increase in serum creatinine concentration. In 2
patients, miltefosine was stopped for this reason. In the other
4, renal dysfunction was only detected at the end of therapy;
in 3, tests repeated 1 week later revealed an improved condition, whereas the fourth patient, who had concomitant pancytopenia, died 1 week after treatment. Five more patients had a
treatment switch because of other serious adverse events (see
Figure 1).
There was significant improvement in hemoglobin, leukocyte,
and platelet levels with the resolution of disease (Table 1).
DISCUSSION
Miltefosine has been used mainly in the Indian subcontinent,
and its efficacy is significantly lower in eastern Africa
(Table 4). This study examined the efficacy and safety of miltefosine in a carefully monitored cohort of Indian patients 10
years after the pivotal phase III trial was done [2]. The drug
was taken under direct observation, and no enrolled patients
Table 4.
Result of Various Clinical Trials of Miltefosine for Treatment of Visceral Leishmaniasis
Study, by Cohort Age
Country
Patients, No.
Cure,a % (95% CI)
Relapse, % (95% CI)
96.7 (90.2–103.1)
3.3 (−3.1 to 9.8)
94.3 (91.7–96.9)
81.9 (79.6–84.1)
3.0 (1.1–4.9)
3.9 (2.8–5.0)
Adults
India
Sundar et al [2]
Bhattacharya et al [19]
India
India
Ritmeijer et al [21]
Ethiopia
290c
60.0 (54.4–65.6)
10.3 (6.8–13.8)
Rahman et al [9]
Rijal et ald
Bangladesh
Nepal
977
101
71.8 (69.0–74.6)
…
9.7 (7.9–11.6)
…
…
…
82.1 (74.7–89.6)
11.8 (5.6–18.2)
…
…
72.3 (63.5–81.0)
21.8 (13.7–29.8)
At 6 months
At 12 months
Children
11.1 (−3.4 to 25.6)
93.8 (88.4–99.1)
…
3.8 (−.4 to 7.9)
…
…
44
93.2 (85.7–100.6)
2.3 (−2.1 to 6.7)
…
20
95.0 (85.4–104.5)
0
Bhattacharya et al [12]
Singh et al [20]
India
India
Treatment naive
Previously treated
Computed on an intention-to-treat basis.
b
Restricted to patients who took 100 mg/kg of miltefosine.
c
Also includes patients with human immunodeficiency virus infection.
d
Conducted during 2008–2010 (unpublished data).
e
Restricted to patients who took 2.5 mg/kg of miltefosine for 4 weeks.
•
CID 2012:55 (15 August)
•
18e
83.3 (66.1–100.5)
India
548
299
1132
80
…
Sundar et al [11]
Abbreviation: CI, confidence interval.
a
30b
Jha et al [18]
Sundar et al
intriguing because the drug had not been introduced there at
the time our study was conducted. Also, in a small cohort of
101 patients treated with miltefosine in Nepal, the cure rates
at 6 and 12 months were 82.1% and 72.3%, respectively, and
the relapse frequencies at 6 and 12 months were 11.8% and
21.8%, respectively (Rijal et al, unpublished data). We followed
all patients for 1 year after treatment in our study site in India,
and only 1 patient had relapse between 6 and 12 months.
Thus, for India, a 6-month follow-up period appears to be sufficient to estimate the final cure rate. The findings from the
Bangladesh and Nepal studies, in addition to our own findings, indicate the vulnerability of miltefosine to lose its
effectiveness.
A substantial proportion of patients (65%) in the cohort developed adverse events, which was seen consistently across the
clinical studies of miltefosine for treatment of VL [10–12]. In
most patients, these side effects are transient, lasting for 1–2
days. Transient asymptomatic elevation of hepatic enzyme
levels, although occurring in a large proportion, is rarely noticed
by the patient and does not lead to discontinuation of the drug.
Because miltefosine is the only oral antileishmanial drug, it
was sold over the counter in India. In the VL elimination
program, VL patients without contraindications for miltefosine
use are provided with weekly supplies until end of treatment.
Because of its potential teratogenicity and its long half-life, only
nonpregnant women who agree for contraception for the duration of treatment and further 3 months are eligible. A significant
proportion of patients discontinue the treatment prematurely
and are not traceable [13]. One of the important reasons for
this discontinuation is the high incidence of side effects, as was
observed in this study. Gastrointestinal intolerance plays an important role in noncompliance if patients are not forewarned
and counseled about the impending adverse events.
The increasing relapse rates during miltefosine therapy may
well be the reflection of suboptimal use in terms of dose and
duration in the few years since its commercialization, reminding us of the declining efficacy of pentavalent antimonials [14].
It surely emphasizes the need for training and supervision of
correct treatment prescription practices among healthcare staff,
for measures to improve treatment adherence among patients,
and for tools for monitoring treatment outcomes and drug resistance (if any) among patients. Furthermore, we need to understand the mechanism leading to miltefosine tolerance and
the steps to prevent and overcome this phenomenon.
This is a clinical study limited by the fact that direct testing
of isolates for miltefosine resistance was not performed, and,
thus, this study does not provide proof of a change in
outcome due to miltefosine resistance.
It remains a relevant question whether a course correction
is required at this stage of the VL elimination program, in
view of the availability of alternative regimens, namely, single-
dose liposomal amphotericin B therapy [15] or multidrug
therapy, which have the distinct advantage of a shorter course
and better compliance [16, 17].
Notes
Acknowledgments. We are grateful to Mr N. Tiwary for statistical
analysis.
Financial support. This work was supported by the European Commission–funded project Kaladrug-R (EC-FP7-222895) and by the Sitaram
Memorial Trust, Muzaffarpur.
Potential conflicts of interest. S. S. has received grant support for clinical trials and travel funds to attend scientific meetings from Paladin Labs,
Institute for One World Health, and GlaxoSmithKline, and his institute
has received grants from Bharat Serum and Vaccine Ltd. All other authors
report no potential conflicts.
All authors have submitted the ICMJE Forms for Disclosure of Potential
Conflicts of Interest. Conflicts that the editors consider relevant to the
content of the manuscript have been disclosed.
References
1. Sundar S, Rosenkaimer F, Makharia MK, et al. Trial of oral miltefosine for visceral leishmaniasis. Lancet 1998; 352:1821–3.
2. Sundar S, Jha TK, Thakur CP, et al. Oral miltefosine for Indian visceral leishmaniasis. N Eng J Med 2002; 347:1739–46.
3. Soto J, Arana BA, Toledo J, et al. Miltefosine for new world cutaneous
leishmaniasis. Clin Infect Dis 2004; 38:1266–72.
4. Soto J, Toledo J, Gutierrez P, et al. Treatment of American cutaneous
leishmaniasis with miltefosine, an oral agent. Clin Infect Dis 2001; 33:
E57–61.
5. Sundar S, Mondal D, Rijal S, et al. Implementation research to
support the initiative on the elimination of kala azar from Bangladesh,
India and Nepal—the challenges for diagnosis and treatment. Trop
Med Int Health 2008; 13:2–5.
6. Chulay JD, Bryceson AD. Quantitation of amastigotes of Leishmania
donovani in smears of splenic aspirates from patients with visceral
leishmaniasis. Am J Trop Med Hyg 1983; 32:475–9.
7. Cancer Therapy Evaluation Program. Common toxicity criteria. Rockville, MD. National Cancer Institute, 2002. Available at: http://ctep.
cancer.gov/reporting/index.html. Accessed 7 October 2009.
8. Perez-Victoria FJ, Sanchez-Cañete MP, Seifert K, et al. Mechanisms of
experimental resistance of Leishmania to miltefosine: implications for
clinical use. Drug Resist Updat 2006; 9:26–39.
9. Rahman M, Ahmed BN, Faiz MA, et al. Phase IV trial of miltefosine
in adults and children for treatment of visceral leishmaniasis (kalaazar) in Bangladesh. Am J Trop Med Hyg 2011; 85:66–9.
10. Sundar S, Makharia A, More DK, et al. Short-course of oral miltefosine for treatment of visceral leishmaniasis. Clin Infect Dis, 2000;
31:1110–3.
11. Sundar S, Jha TK, Sindermann H, Junge K, Bachmann P, Berman J.
Oral miltefosine treatment in children with mild to moderate Indian
visceral leishmaniasis. Pediatr Infect Dis J 2003; 22:434–8.
12. Bhattacharya SK, Jha TK, Sundar S, et al. Efficacy and tolerability of
miltefosine for childhood visceral leishmaniasis in India. Clin Infect
Dis 2004; 38:217–21.
13. Sundar S, Murray H. Availability of miltefosine for the treatment of
kala-azar in India. Bull World Health Organ 2005; 83:5.
14. Sundar S, Thakur BB, Tandon AK, et al. Clinicoepidemiological study
of drug resistance in Indian kala-azar. Br Med J 1994; 308:307.
15. Sundar S, Chakravarty J, Agarwal D, Rai M, Murray HW. Single-dose
liposomal amphotericin B for visceral leishmaniasis in India. N Engl
J Med 2010; 362:504–12.
Miltefosine for Leishmaniasis
•
CID 2012:55 (15 August)
•
549
16. Sundar S, Rai M, Chakravarty J, et al. New treatment approach in
Indian visceral leishmaniasis: single-dose liposomal amphotericin B followed by short-course oral miltefosine. Clin Infect Dis 2008; 47:1000–6.
17. Sundar S, Sinha PK, Rai M, et al. Comparison of short-course multidrug treatment with standard therapy for visceral leishmaniasis in
India: an open-label, non-inferiority, randomised controlled trial.
Lancet 2011; 377:477–86.
18. Jha TK, Sundar S, Thakur CP, et al. Miltefosine, an oral agent, for the
treatment of Indian visceral leishmaniasis. N Engl J Med 1999;
341:1795–800.
550
•
CID 2012:55 (15 August)
•
Sundar et al
19. Bhattacharya SK, Sinha PK, Sundar S, et al. Phase 4 trial of miltefosine
for the treatment of Indian visceral leishmaniasis. J Infect Dis 2007;
196:591–98.
20. Singh UK, Prasad R, Mishra OP, et al. Miltefosine in children with
visceral leishmaniasis: a prospective, multicentric, crosssectional study.
Indian J Pediatr 2006; 73:1077–80.
21. Ritmeijer K, Dejenie A, Assefa Y, et al. A comparison of miltefosine
and sodium stibogluconate in treatment of visceral leishmaniasis in an
Ethiopian population with high prevalence of HIV infection. Clin
Infect Dis 2006; 43:357–64.