Download Randomized, Controlled Trial of Oral Ribavirin for Japanese

MAJOR ARTICLE
Randomized, Controlled Trial of Oral Ribavirin
for Japanese Encephalitis in Children in Uttar
Pradesh, India
Rashmi Kumar,1 Piyush Tripathi,1 Madan Baranwal,1 Sudhakar Singh,1 Sanjeev Tripathi,1 and Gopa Banerjee2
Departments of 1Pediatrics and 2Microbiology, Chhatrapati Shahuji Maharaj Medical University, Lucknow, Uttar Pradesh, India
(See the editorial commentary by Chapman on pages 407–9)
Background. Japanese encephalitis is associated with high rates of mortality and disabling sequelae. To date,
no specific antiviral has proven to be of benefit for this condition. We attempted to determine the efficacy of oral
ribavirin treatment for reducing early mortality among children with Japanese encephalitis in Uttar Pradesh, India.
Methods. Children (age, 6 months to 15 years) who had been hospitalized with acute febrile encephalopathy
(a ⭐2-week history of fever plus altered sensorium) were tested for the presence of immunoglobulin M antibodies
to Japanese encephalitis virus with commercial immunoglobulin M capture enzyme-linked immunosorbent assay.
Children with positive results were randomized to receive either ribavirin (10 mg/kg per day in 4 divided doses
for 7 days) or placebo syrup through nasogastric tube or by mouth. The primary outcome was early mortality;
secondary outcome measures were early (at hospital discharge; normal or nearly normal, independent functioning,
dependent, vegetative state, or death) outcome, time to resolution of fever, time to resumption of oral feeding,
duration of hospitalization, and late outcome (⭓3 months after hospital discharge). The study was double-blind,
and analysis was by intention to treat.
Results. A total of 153 patients were enrolled during a 3-year period; 70 patients received ribavirin, and 83
received placebo. There was no statistically significant difference between the 2 groups in the early mortality rate:
19 (27.1%) of 70 ribavirin recipients and 21 (25.3%) of 83 placebo recipients died (odds ratio, 1.10; 95% confidence
interval, 0.5–2.4). No statistically significant differences in secondary outcome measures were found.
Conclusions. For the dosage schedule used in our study, oral ribavirin has no effect in reducing early mortality
associated with Japanese encephalitis.
Trial registration. ClinicalTrials.gov identifier: NCT00216268.
Japanese encephalitis (JE) is, at present, the single most
important cause of viral encephalitis in Asia [1]. In
addition to causing acute illness with a high mortality
rate, the disease may leave survivors with major mental
and physical disabilities, placing an enormous load on
the very families who are least equipped to bear the
burden of a handicapped child [2]. As with other flaviviruses, there is no known specific antiviral therapy
for the infection. A double-blind, placebo-controlled
Received 3 June 2008; accepted 23 September 2008; electronically published
14 January 2009.
Reprints or correspondence: Prof. Rashmi Kumar, Dept. of Pediatrics, Chhatrapati
Shahuji Maharaj Medical University, Lucknow (UP), India 226003 (rashmik2005
@gmail.com).
Clinical Infectious Diseases 2009; 48:400–6
2009 by the Infectious Diseases Society of America. All rights reserved.
1058-4838/2009/4804-0005$15.00
DOI: 10.1086/596309
400 • CID 2009:48 (15 February) • Kumar et al.
trial of administration of IFN-a-2a to Vietnamese children indicated no benefit [3]. There is, therefore, an
urgent need for antiviral drug trials involving this devastating disease [4].
The drug ribavirin (1-b-d-ribofuranosyl-1,2,4-triazole-3-carboxamide) is a broad-spectrum antiviral
agent, a synthetic nucleoside compound with ribose
and triazole moieties that bears striking structural similarity to guanosine and inosine [5]. Ribavirin likely has
multiple mechanisms of action, but these have not been
fully elucidated. It appears to interfere with RNA and
DNA synthesis, inhibiting protein synthesis and viral
replication [6]. The drug is being marketed for human
consumption and is approved for use for acute bronchiolitis caused by respiratory syncytial virus and for
chronic hepatitis C [7].
Several in vitro [8–11] and animal [12–14] studies
have demonstrated that ribavirin has an effect on pathogenic
flaviviruses, including JE virus and West Nile virus. Human
studies of ribavirin have been conducted for Lassa fever [15],
Argentinian hemorrhagic fever [16, 17], hemorrhagic fever with
renal syndrome [18], hantavirus pulmonary syndrome [19–21],
influenza [22], severe acute respiratory syndrome [23], subacute sclerosing panencephalitis [24], La Crosse encephalitis
[25], West Nile encephalitis [26], and HIV/AIDS [27]. However,
placebo-controlled trials examining the efficacy and safety of
this agent are rare, and those that have demonstrated efficacy
are even more so [15–18]. In certain South Asian countries,
ribavirin is used empirically to treat JE [28, 29]. Here, we report
the results of, to our knowledge, the first randomized, doubleblind, placebo-controlled trial of ribavirin for treatment of JE.
METHODS
Study site. The study was performed in the pediatric wards
of Chhatrapati Shahuji Maharaj Medical University in Lucknow, the capital city of Uttar Pradesh—the “northern state,”
India’s most populous state and also one of its poorest, with
the lowest human development indices [30]. Chhatrapati Shahuji Maharaj Medical University is a teaching hospital that
caters mostly to poor and severely ill persons from the city and
surrounding districts, extending up to Nepal.
Objective. We aimed to evaluate the benefit of the antiviral
drug ribavirin on the outcome of JE.
Prior approval was obtained from the Institutional Ethics
Committee and Drug Controller General of India. Consent and
adverse event forms were completed for each patient.
Screening. During the period from July 2005 through November 2007, we actively tested children who had been hospitalized with acute febrile encephalopathy for JE during every
monsoon or postmonsoon season (i.e., July through November). Inclusion criteria for testing were age of 16 months and
the presence of acute febrile encephalopathy, which was defined
as a ⭐2-week history of fever plus altered sensorium in a previously healthy child. Exclusion criteria for testing were as follows: (1) a firm diagnosis of bacterial or tuberculous meningitis
based on examination of CSF specimens or imaging findings,
or (2) frank hepatic encephalopathy with jaundice. Children
who met the aforementioned criteria were considered to have
acute encephalitis and underwent IgM ELISA testing of CSF
specimens (if available) or blood specimens. Testing was performed the morning after hospital admission, and attempts
were made to have the ELISA results within 24 h after hospital
admission. Patients from the pediatric wards of Baba Raghav
Das Medical College (Gorakhpur, India) in 2006 and Vivekanand Hospital (Lucknow) in 2007 were also screened using
similar criteria.
ELISAs. We tested for the presence of IgM against JE virus
by IgM capture ELISA with use of the JE Chex kit (Excyton).
The test results showed complete concordance with conventional ELISA results [31] and takes 3 h to perform. Only patients with an index value of ⭓100 were considered to have
JE. On 3 occasions, kits marketed by Inbios USA and Panbio
Australia were used instead.
Drug and placebo. Ribavirin and placebo syrup were obtained from Lupin, the sole manufacturer of ribavirin in India,
in identical 30-mL bottles. The placebo contained all of the
ingredients of the ribavirin syrup except the active principle.
Only a small code number on the bottles (10001 or 10002 for
the first lot and 10003 or 10004 for the second lot) differentiated
the drug and placebo bottles
Randomization procedure. Generation of the allocation sequence was performed by a member of the study team who
worked in the laboratory. Sequential numbers ending with the
digits of either 1 or 2 were taken from a random number table.
The numbers (1 or 2 ) were written in the same sequence on
sheets of paper, which were folded and then placed in identical
envelopes and sealed. The envelopes were numbered sequentially starting from 1.
As soon as it was known that a patient had tested positive
for JE virus, he or she was randomized to a study arm. The
next envelope was opened by the project’s medical officer. If
the envelope had a sheet bearing the number 1, a bottle coded
10001 was assigned to the patient; if the sheet bore the number
2, a bottle of syrup coded 10002 was assigned. In 2006, a second
lot of bottles coded 10003 and 10004 was received, and sheets
bearing numbers 3 and 4 were used in the same way.
Blinding. The code provided by the company in a sealed
envelope was kept locked and was revealed only at the end of
the study, after analysis. The person who generated the sequence
was not involved with clinical assessment for severity or outcome of illness. In November 2007, after data collection was
complete, the codes were linked (i.e., the envelopes bearing
information about the code were opened by a third person,
who was not involved in the study, who told us which of the
codes 10001 and 10002 were the same as codes 10003 and
10004). This allowed us to analyze the data.
Enrollment, treatment, and diagnostic evaluation. After
randomization, written consent was obtained from the patient’s
guardian by the medical officer working in the project. A detailed history and the findings of physical and neurological
examinations were recorded on predesigned data collection
forms. Predetermined definitions for conditions such as acute
febrile encephalopathy, acute encephalitis, and elevated intracranial tension were used. A standardized diagnostic evaluation
for patients with suspected acute encephalitis was adopted. At
hospital admission, we performed complete blood cell counts;
examination of CSF specimens for cell count and determination
Ribavirin for Japanese Encephalitis • CID 2009:48 (15 February) • 401
Figure 1. Flow chart of a study of patients with Japanese encephalitis
(JE). BM, bacterial meningitis; LAMA, left hospital against medical advice;
TBM, tuberculous meningitis.
of sugar and protein levels; Gram stain and bacterial culture;
smear and rapid tests for malaria; determination of the blood
urea, serum electrolytes, and creatinine levels; and liver function
tests. CT was performed whenever possible. Treatment of the
patients was supportive and included use of antipyretics and
anticonvulsants, nursing care, and administration of intravenous fluids and cerebral dehydrants, as needed. Intravenous
ceftriaxone (100 mg/kg per day in 2 divided doses) was usually
administered for a week. Ribavirin or placebo syrup was given
through a nasogastric tube or orally once the child was conscious, at a dosage of 10 mg/kg per day in 4 divided doses for
7 days. Records of the codes on the ribavirin bottle were kept.
In 2006, ventilators became available, and many children received mechanical ventilation support as the need arose.
Follow-up and outcome. The patients were observed daily
until they were discharged from the hospital. Intake of ribavirin
(or placebo) syrup was checked daily. The primary outcome
measured was mortality rate in the hospital. Note was also made
402 • CID 2009:48 (15 February) • Kumar et al.
of time after commencement of treatment (in days) to resolution of fever and to resumption of oral feeding and total
duration of hospitalization. In general, patients were discharged
from the hospital once they could be fed by mouth and were
afebrile. Hemoglobin and reticulocyte concentrations were
again determined at hospital discharge or after 7–10 days if the
child remained in the hospital, and any decreases in the hemoglobin concentration were noted.
In many cases, the family of the patient preferred to take
the child home once the outcome appeared to be hopeless. This
was referred to as “leaving against medical advice.” In such
cases, leaving against medical advice was equated with death
in the hospital. In some cases, patients did not wait for discharge but just left the hospital without informing the hospital
staff. Such patients were called “absconders.” If the patient was
discharged from the hospital, the patient’s functional status at
the time of discharge was recorded in terms of ability to comprehend speech, to feed, to speak, and to walk.
After discharge from the hospital, the patients were given
appointments for revisit every 3 months. If they did not attend
the visit, a postal reminder was sent. In 2006 and 2007, the
families of many patients possessed mobile phones, and a reminder could be made via telephone. At each visit, the functional status was assessed through a specially designed outcome
questionnaire, a complete neurological examination was performed, and any other problems were noted. In some cases,
outcome questionnaires were filled out via telephone interviews. From December 2007 through February 2008, 2 trained
field workers actually visited the homes of patients and filled
out the outcome questionnaires for survivors. Outcome was
classified as normal or near normal, independent functioning,
dependent, vegetative, or death, in accordance with the Glasgow
Outcome Scale [32].
Sample size. The mortality rate for JE is ∼35% (it was 37%
in a previous study [33] and was quoted to be 30% in a recent
review [34]). To detect a decrease in the mortality rate of 20%
with 95% confidence and 80% power, sample size per group
totaled to 72 [35].
Data management and analysis. Baseline clinical features
at hospital admission were compared between the ribavirin and
placebo arms. The primary outcome factor (early mortality)
was based on the sum of deaths in the hospital plus patients
who left the hospital against medical advice in a poor general
condition. Secondary outcome factors were time to resolution
of fever, time until the patient could start feeding orally, duration of hospital stay, and early and late outcomes. Outcomes
in the 2 groups were also dichotomized as “good” (i.e., normal,
near normal, or independent functioning) or “bad” (death,
leaving against medical advice in a poor general condition, lack
of independent functioning, or vegetative state). These comparisons were made both at the time of hospital discharge (early
Table 1.
Clinical and laboratory features of ribavirin and placebo groups at hospital admission.
Characteristic
Demographic characteristic
Age, mean months SD
Male sex
Mean weight-for-age percentage SD
Clinical characteristic
Ribavirin group
(n p 70)
Placebo group
(n p 83)
90.5 32.9
59 (84.3)
92.2 33.6
62 (74.7)
74.0 12.39
74.4 12.13
Duration of illness, mean days SD
7.8 4.9
Mean GCS SD
Convulsions
Increased generalized muscle tone
Focal deficit
7.1
70
35
25
Extrapyramidal signs
Gastric bleeding
Fundus blurring or papilledema, proportion of patients (%)
S/o increased intracranial tensiona
b
Hyperventilation
Decerebrate posturing
Biological characteristic
Hemoglobin concentration, mean g/dL SD
Total leukocyte count, mean cells ⫻ 106/L SD
2.54
(100)
(50.0)
(35.7)
18 (25.7)
22 (31.4)
10/50 (20.0)
2.63
(98.8)
(48.1)
(43.4)
30 (36.1)
30 (36.1)
9/58 (15.5)
12 (17.1)
8 (9.6)
15 (21.4)
12 (17.1)
33 (39.7)
13 (15.7)
11.5 1.85
11.0 1.75
11.36 5.67
Mean neutrophil percentage SD
Platelet count, mean cells ⫻ 10 9/L SD
CSF cell count, mean cells/mm3 SD
ALT level, mean U/L SD
7.8 4.4
6.9
82
40
36
68.0 10.68
160 42
9.62 4.13
66.39 12.17
186 75
41.5 62.52
55.7 74.72
43.3 87.57
69.6 122.19
Protein level, mean g/dL SD
Receipt of ventilator support
6.9 1.28
5 (7.1)
6.7 1.22
5 (6.0)
Enrollment from other hospitals
Duration of drug or placebo treatment, mean days SD
Complete treatment course received
Adverse event during treatment
Anemia
5 (7.1)
5.7 1.9
41 (58.6)
6 (7.2)
5.6 2.0
47 (56.7)
5 (7.1)
4 (4.8)
4 (5.7)
0 (0)
0 (0)
1 (1.2)
3 (3.6)
3 (3.6)
Anemia plus an increase in the reticulocyte count
Hepatomegaly
Splenomegaly
NOTE. Data are no. (%) of patients, unless otherwise indicated. The Mann-Whitney U test was used for
continuous nonparametric data, and the x2 test was used for categorical data. Differences were statistically
nonsignificant unless otherwise indicated. ALT, alanine aminotransferase; GCS, Glasgow Coma Score.
a
b
Bradycardia with hypertension and/or abnormal breathing pattern.
P ! .05.
outcome) and after ⭓3 months of follow-up (late outcome).
Patients whose conditions were normal or near normal at hospital discharge were considered to have good late outcomes,
without regard to the 3-month follow-up data. Kaplan Meier
survival curves were generated. Data were analyzed on an intention-to-treat basis.
RESULTS
The study was launched in April 2005. By July 2005, the ribavirin and placebo bottles had been arranged and JE IgM
ELISA kits has been obtained. From August through October
2005, a severe epidemic of JE occurred in the eastern districts
of the state. During 2005–2007, from July through November,
a total of 791 patients with acute febrile encephalopathy who
fulfilled the inclusion criteria for testing were admitted to the
hospital. Of these patients, 162 patients met the exclusion criteria for testing. Of the remaining 629 patients, 577 could be
tested for JE virus IgM; 161 had positive results, of whom only
153 could be randomized and enrolled. Of the 153 patients,
77 were enrolled in 2005, 37 were enrolled in 2006, and 39
were enrolled in 2007. Seventy-five patients were determined
to have tested positive for IgM with use of CSF specimens, and
84 were determined to have tested positive with use of serum
specimens. Twelve patients were enrolled from the other hosRibavirin for Japanese Encephalitis • CID 2009:48 (15 February) • 403
Table 2. Outcomes for children with Japanese encephalitis who received either ribavirin or placebo.
Outcome
Early mortality, no. (%) of patients
Early mortality among 48 patients with hyperventilation,
proportion of patients (%)
Ribavirin group
(n p 70)
Placebo group
(n p 83)
OR (95% CI)
19 (27.1)
21 (25.3)
1.10 (0.5–2.41)
0.38 (0.09–1.57)
9/15 (60.0)
12/33 (36.4)
Early mortality among patients who received ⭓2 days
of treatment, proportion of patients (%)
14/65 (21.5)
13/75 (17.3)
0.76 (0.3–1.9)
Good early outcome, proportion of patients (%)
28/70 (40.0)
32/82 (39.0)
1.04 (0.5–2.11)
Good late outcome, proportion of patients (%)
Time to resolution of fever, median days (IQR)
27/66 (40.9)
5.0 (3–8)
26/79 (32.9)
4.0 (2–7)
1.41 (0.68–2.95)
…
Time to resumption of oral feeding, median days (IQR)
Duration of hospitalization, median days (IQR)
4 (3–8)
9 (4–13)
5 (3–7)
10 (5–15)
…
…
Duration of follow-up, median months (IQR)
9 (3–22)
7 (3–14)
…
NOTE. IQR, interquartile range.
pitals. Of the enrolled patients, 137 tested positive with use of
the Excyton kit, and 16 tested positive with use of other kits.
Once randomization was performed, informed consent was
obtained for all children. All started receiving either the drug
or placebo and were observed until they either were discharged,
absconded, left the hospital against medical advice, or died. A
total of 4 patients absconded from the hospital; all but 1 of
these 4 had cases that had improved to nearly “normal,” and
the early outcome was classified as good.
Figure 1 presents a flow chart for patients in each study arm.
Eighty-three patients received bottles coded either 10001 or
10003 (placebo), and 70 patients received bottles coded either
10002 or 10004 (ribavirin).
Table 1 presents the baseline and treatment characteristics
of the 2 groups. There were no statistically significant differences between the 2 groups with the exception of hyperventilation, which occurred more frequently in the placebo group.
Thirteen patients received !2 days of ribavirin syrup, and 3
patients received !1 day of ribavirin syrup. There were no
treatment-related deaths, and no unblinding occurred.
A total of 28 patients died in the hospital, and 12 left against
medical advice in a very poor general condition. Thus, the
overall early mortality rate was 26.1% (40 of 153 children). Of
these 40 children, 19 were in the ribavirin group, and 21 were
in the placebo group. The early mortality rates were 33.7% (26
of 77 children) in 2005, 10.8% (4 of 37) in 2006, and 25.6%
(10 of 39) in 2007. We confirmed that 10 of the 12 patients
who left the hospital against medical advice died soon after
discharge from the hospital.
After we excluded the 40 patients with early mortality, an
attempt was made to observe the remaining 113 patients after
they had left the hospital, but only 98 (86.7%) could be observed for at least 3 months. The longest period of follow-up
was 30 months. The remaining 15 patients were untraceable,
404 • CID 2009:48 (15 February) • Kumar et al.
but the outcome was determined to be either normal or nearly
normal at hospital discharge for 7 of these patients, who we
classified as having good late outcomes. Therefore, analysis for
late outcome was possible for 145 patients.
Table 2 compares the outcome factors in the 2 groups. There
were no statistically significant differences in early mortality,
early and late outcomes (when dichotomized into good and
bad outcomes), time to resolution of fever, time to resumption
of oral feeding, or duration of hospital stay. If the 2 patients
who left the hospital against medical advice and who could not
be confirmed to have died were counted as survivors, the OR
for mortality with drug would be 1.09 (95% CI, 0.49–2.42;
P p .817).
Figure 2. Probabilities of survival for 153 patients, according to therapy. P p .9, by log rank test. Gray bar, ribavirin recipients; black bar,
placebo recipients.
Figure 2 shows the Kaplan Meier survival curves for the
ribavirin and placebo groups. Again, no statistically significant
differences between groups were found.
There were no serious adverse events attributable to ribavirin
therapy. Five patients (4 in the ribavirin arm and 1 in placebo
arm) experienced a mild increase in reticulocyte count, as well
as a decrease in the hemoglobin concentration of 1.5%–2.8%.
Four patients (1 in the ribavirin arm and 3 in the placebo arm)
experienced a decrease in the hemoglobin concentration alone
of 2–4.2 g/dL, which was probably due to the illness itself. The
decrease in the hemoglobin concentration occurred a median
of 20 days (range, 0–22 days) after commencement of treatment, and the increase in the reticulocyte count occurred a
median of 3 days (range, 3–21 days) after commencement of
treatment. Three patients in the placebo group but none in the
ribavirin group developed hepatomegaly and splenomegaly
during the course of their hospital stay. Treatment did not have
to be discontinued in any case.
DISCUSSION
Our study found that nasogastric or oral ribavirin treatment
(10 mg/kg per day in 4 divided doses for 7 days) did not affect
the outcome in children with JE. The OR for early mortality
and early and late outcomes in patients who received drug and
placebo were close to 1, and there were no statistically significant differences between groups in the secondary outcomes.
Ribavirin recipients and placebo recipients were comparable
in that there were no statistically significant differences in their
demographic characteristics or clinical or laboratory findings,
with the exception of hyperventilation, which was more common among placebo recipients. However, after stratification for
hyperventilation, no statistically significant differences in mortality rate were observed between the 2 groups.
Many infections may produce an illness similar to JE, which
is why we enrolled only patients with laboratory-confirmed
disease. A cutoff index value of 1100 allowed us to exclude
patients with infections due to other flaviviruses. The kit used
was evaluated by Jacobson et al. [36], who reported a sensitivity
and specificity of 96.7% and 65.3%, respectively. However, Jacobson and colleagues used only serum samples and have themselves argued that the accuracy would be better if they had
tested only persons with acute encephalitis syndrome.
Other strengths of the study are that randomization and
blinding procedures were followed precisely. Although bottles
were not coded individually, no unblinding actually occurred.
Because our study involved only hospitalized patients, the patients could all be observed carefully until they were discharged
from the hospital or died. The primary outcome—early mortality—was easily measurable and verifiable. After hospital discharge, great effort was made to locate survivors for follow-up
assessments. The duration of follow-up after discharge varied,
because enrollments occurred over a 30-month period. We expect that most of the improvements in survivors occur during
the first 3 months after the onset of illness; therefore, we attempted to perform follow-up assessment for at least 3 months.
Children with a good outcome at the time of hospital discharge
were classified as having good late outcomes, even if they could
not be followed up, because it was seen that, apart from possible
development of epilepsy, such patients usually did not have
cases that would deteriorate after discharge.
Our enrolled patients received a variable number of ribavirin
doses. However, these differences would equal out between the
2 groups because of randomization. Intention-to-treat analysis
was performed; thus, once patients were randomized, they were
all followed up for outcome.
Another possible reason for the lack of response to ribavirin
may be that treatment with the drug could not be started early
enough. JE becomes clinically distinct only once convulsions
or coma sets in; before this happens, the features are nonspecific. Neurological damage may occur rapidly after viral invasion of the brain and may be minimally amenable to repair.
Once specific symptoms begin, the illness may have a compact
clinical course, often with swift mortality. Travel to the city
from far-flung rural areas would be initiated only after specific
symptoms appear and could take time.
It is also possible that adequate drug concentrations were
not achieved. We used a dosage of drug that is somewhat similar
to that recommended for children with typical viral infections
[37] and for which safety and pharmacokinetic data in children
are available [38]. Nasogastric or oral ribavirin syrup was used
because it was thought that ethics approval and blinding for
use of the intravenous formulation would not be possible in
our circumstances. In a study of children with HIV infection,
Connor et al. [38] reported a mean level of CSF penetration
of ribavirin of 70% and found minimal adverse effects, with
mean trough CSF levels of 1.5 and 3.0 mmol/L after administration of oral ribavirin at dosages of 6 and 10 mg/kg per day,
respectively. It is also possible that levels of the drug in CSF
may be higher in patients with acute CNS infections such as
JE as a result of disruption of the blood-brain barrier. On the
other hand, delivery of drug through the gastrointestinal route
in a seriously sick child does not guarantee absorption. Because
it was not possible to measure serum or CSF levels of ribavirin,
more cannot be said about this.
Effective antiviral treatment of JE remains an urgent need.
Although ribavirin administered by the gastrointestinal route
at the dosage used in this study was not found to be effective
in decreasing the rate of early mortality associated with JE,
higher doses and other routes of administration should be
assessed.
Ribavirin for Japanese Encephalitis • CID 2009:48 (15 February) • 405
Acknowledgments
We thank Lupin Pharmaceuticals, for providing the ribavirin and placebo
syrup, the consultant physicians of the Department of Pediatrics, CSM
Medical University, and of BRD Medical College, for their cooperation.
Financial support. Indian Council of Medical Research (5/8/7/13/
2001-ECDI).
Potential conflicts of interest. All authors: no conflicts.
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