Antimicrobials in Clinical Practice

Evaluation of efcacy and adherence to INH

preventive therapy in children at risk to develop
active tuberculosis
C.K. Indumathi
a,
*, Gurinder Kumar
b
, Aruna Sethuraman
c
,
Arpana Iyengar
d
a
Associate Professor, Department of Paediatrics, St Johns Medical College Hospital, Bangalore, Karnataka 560024,
India
b
Fellow Student, Department of Paediatric Nephrology, St Johns Medical College Hospital, Bangalore, Karnataka
560024, India
c
Senior Resident, Department of Paediatrics, St Johns Medical College Hospital, Bangalore, Karnataka 560024, India
d
Additional Professor, Department of Pediatric Nephrology, St Johns Medical College Hospital, Bangalore, Karnataka
560024, India
a r t i c l e i n f o
Article history:
Received 4 July 2013
Accepted 15 January 2014
Available online 8 February 2014
Keywords
INH efcacy
Active tuberculosis
Adherence
Children
a b s t r a c t
Objectives: Revised National Tuberculosis Control Program and Indian Academy of Pediat-
rics advocate 6 months of INH Preventive Therapy (IPT) for children less than 6 years who
are in contact with an infectious pulmonary tuberculosis case, irrespective of their BCG or
nutritional status. Isoniazid is also recommended by Indian Pediatric Nephrology group for
children with nephrotic syndrome who are asymptomatic mantoux positive (latent
tuberculosis) and who require steroid therapy. Poor adherence to INH is a major barrier in
implementing IPT. Objective of this study was to evaluate the efcacy of IPT in preventing
active disease in the above groups and to assess the adherence to IPT in these children.
Methods: Prospective study conducted at department of paediatrics at a tertiary care
teaching hospital, from April 2006 to October 2011. Study involved initiation of IPT in
groups mentioned above (group 1 e children less than 6 years in contact with infectious
adults and group 2 e asymptomatic mantoux positive children with nephrotic syndrome
requiring steroid therapy) and follow-up of cohort at regular intervals for development of
active disease and adherence to prescribed therapy.
Results: A total of 50 children were included in the study (group 1 e 31 children and group
2 e 19 children). Forty-three (86%) children completed 6 months of prescribed INH treat-
ment. Mean duration of follow-up was 12.29 (13.13) months post-treatment. None of
children who adhered to treatment developed active disease.
* Corresponding author. Tel.: 91 9448089891; fax: 91 80 2553 0070.
E-mail address: ckindumathi@gmail.com (C.K. Indumathi).
Available online at www.sciencedirect.com
ScienceDirect
j ournal homepage: www. el sevi er. com/ l ocat e/ pi d
p e di a t r i c i nf e c t i o us d i s e a s e 6 ( 2 0 1 4 ) 2 1 e2 4
http://dx.doi.org/10.1016/j.pid.2014.01.001
2212-8328/Copyright 2014, Indian Academy of Pediatrics, Infectious Disease Chapter. All rights reserved.
Conclusions: Our study suggests that IPT is effective in preventing active disease in both
children in contact with infectious adults and those with nephrotic syndrome and latent
infection. Adherence can be enhanced by counseling of parents at the start of therapy and
reemphasis during subsequent follow-ups.
Copyright 2014, Indian Academy of Pediatrics, Infectious Disease Chapter. All rights
reserved.
Tuberculosis (TB) is still a public health problem affecting
one million children per year worldwide with pediatric TB
accounting for 10e20% of total burden of tuberculosis.
1
Chil-
dren are generally the victims of untreated adult Pulmonary
TB (PTB). Pediatric TB can largely be prevented by early diag-
nosis and treatment of sputum positive adult TB and pro-
phylactic treatment in selected exposed/infected (not
diseased) children.
2
When in close contact with sputum positive adults,
40e70% of children under 5 years would develop infection/
active disease.
3
In a 15 year follow-up study from South India,
children less than 4 years in contact with sputum positive
adults were found to have 7 times higher relative risk of
developing infection compared to adults.
2
Proportion of chil-
dren developing active disease following tuberculous infec-
tion depends on the age and underlying immune status. Life
time risk of developing active TB is almost 20e40% in children
less than 2 years, 20% between 2 and 5 years compared to
5e10% risk in adults.
3
Children less than 5 years, experience
rapid disease progression and dissemination as well.
2
Risk of
developing active disease increases almost to 50% with
retroviral infection and other immunosuppressed states. In
pediatric practice, apart from HIV infection, children with
nephrotic syndrome are at increased risk of acquiring TB
infection due to dysregulation of T lymphocytes. They are also
at higher risk of developing active disease in view of concur-
rent steroid therapy. Hence targeting preventive therapy to
these vulnerable groups, i.e., young children less than 5e6
years and immunocompromised children of any age would
help reduce serious mortality and morbidity amongst them.
World Health Organisation and most of TB public health
control programs worldwide including Revised National
Tuberculosis Control Program of India, advocate 6 months of
IPT for children less than 6 years who are in contact with in-
fectious adults.
4,5
INH Preventive Therapy is also recom-
mended by Indian Academy of Pediatrics (IAP) and Indian
pediatric nephrology group for children with nephrotic syn-
drome who are mantoux positive with no active disease
(latent TB) and who require steroid therapy.
6,7
Studies have
shown that IPT has an efcacy of 69e93% in preventing
development of active disease if strictly adhered to.
3
Ran-
domized controlled trials from South Africa have demon-
strated marked reductionin incidence of TB and TB associated
mortality in HIV infected children who received IPT, though
there is no published data of its effectiveness in children with
nephrotic syndrome.
8
Adherence is a crucial component of
prophylactic therapy and INH prophylaxis to be effective,
needs adequate compliance (>80% of prescribed doses to be
taken).
9
Lack of adherence has been recognized as a major
hurdle to IPT and reported adherence rate vary from 20 to
60%.
9,10
Though IPT is an integral part of RNTCP, there are no
Indian studies determining its efcacy in preventing active TB
in children who are exposed to adult infectious PTB. There is
no published data available on its efcacy in nephrotic syn-
drome with latent TB. Similarly there is no information
available on pattern of adherence to IPT in the Indian setting.
Hence the primary objective of this study was to evaluate the
efcacy of IPT in children who are exposed to adult PTB and in
children with nephrotic syndrome having latent TB. Second-
ary objective was to determine the adherence to IPT.
1. Methodology
This prospective longitudinal study was conducted in the
Department of Paediatrics at a tertiary hospital in India from
October 2006 to October 2011. Children were recruited from
the inpatient wards and outpatient clinics of the department.
Ethical clearance was obtained.
1.1. Inclusion criteria
Group 1: Children less than 6 years in contact with infec-
tious PTB with no evidence of active disease (irrespective of
mantoux status).
Group 2: Children (1e18 years) with rst episode of
nephrotic syndrome having latent tuberculosis (mantoux
test induration of >10 mm with no active disease) and
requiring steroids.
1.2. Exclusion criteria
Children with active TB and children in contact with sus-
pected MDRTB.
Screening for active disease in both groups included his-
tory, clinical examination, chest X-ray and sputumygastric
AFB whenever indicatedyfeasible. After excluding active
disease, INH 5 mg/kg/day for 6 months was started as per
RNTCP and IAP protocols at the beginning of the study.
5,6
Later
INH dose was increased to 10 mg/kg/day as per revised rec-
ommendations. Children with nephrotic syndrome were
started on steroids 2 weeks later. Parents were counseled
regarding the concept of IPT (i.e., need to give medicine in the
absence of disease), risk reduction with INH and importance
of strict adherence to treatment to prevent active disease.
They were asked to report immediately to the hospital if they
developed persistent vomiting or jaundice. Children were
followed up once a month for the entire period of 6 months of
treatment and once in 2 months post-treatment at pediatric
p e d i a t r i c i nf e c t i o us d i s e a s e 6 ( 2 0 1 4 ) 2 1 e2 4 22
OPD by the treating pediatrician. At each visit symptoms of
cough, fever, loss of weight were elicited and children were
examined clinically for evidence of active disease like
lymphadenopathy, organomegaly and respiratory signs. Any
symptoms/signs of adverse effects like vomiting/jaundice
were recorded. Liver function tests were done only when
indicated. Adherence to INH and to steroids (group 2) was
checked with parents by recall method, any missing of doses
documented and adherence was reemphasized at each con-
tact. Adherence was classied as reasonable, poor and very
poor (INH taken more than 5 months, 2e4 months and less
than 2 months respectively).
10
2. Results
Out of 60 children who were screened for active disease, 50
children fullling the inclusion criteria were recruited in the
study.
Group 1: There were 31 childreninthis group. Mean age was
33 months (22.38) with a male to female ratio of 1:1.09%.
Mother was the contact in 15 children and father, grand-
parentsandother closefamilymembersconstitutedtherest.
Twenty-eight out of 31 (90.3%) childrencompleted 6 months
of treatment. Adherence was reasonable in28 children, poor
in 1 child (took treatment for 3 months) and very poor in 2
children. Twenty-eight children who completed the treat-
ment were followed up for a mean period of 16 months
(15.95) and none of them developed active disease. There
were no serious side effects like clinical hepatitis.
Group 2: This group consisted of 19 children with rst
episode nephrotic syndrome. Mean age 48 months (37.5),
male to female ratio 1:1.25. Out of 19 children, 4 children
were lost to follow-up and 15 (79%) completed treatment.
Adherence to INH was reasonable in 15 children and very
poor in 4 children. Mean duration of follow-up in those
who completed treatment was 10 months (3.74). In those
who completed treatment, none of them developed active
disease. There was no occurrence of hepatitis.
Overall, out of 50 children who were initiated on IPT, 5 were
lost to follow-up completely and no information was available
ontheir clinical status. Whether they developed active disease
or not could not be ascertained. In 2 children (group A),
treatment was stopped by local practitioners as they felt that
treatment was not required in the absence of symptoms.
However, both came for follow-up later for other illnesses and
had not developed active disease. Remaining 43 (86%) children
had reasonable adherence and completed 6 months of treat-
ment and had received at least 95% doses. Overall, adherence
was reasonable in 43 children, poor in 1 child and very poor in
6 children. None of children who had reasonable adherence
progressed to active disease. The mean period of follow-up
was 12.29 months (13.13). No side effects were reported.
Table 1 depicts the outcome and follow-up of these children.
3. Discussion
INHProphylactic Therapy is the standardof care recommended
byWHOandnational programs worldwideincludingRNTCP, for
prevention of active TB in children (<6 years) exposed to in-
fectious adult PTB. Way back in 1970, Ferebee et al conducted
trials of INH prophylaxis in adults and children with latent
infection and established its effectiveness towards prevention
of active disease.
1
Cochrane analysis of eleven studies consist-
ing of 73,375 patients (children>2 months and adults) receiving
IPT inferred that the relative risk of developing TB was 0.4 (95%
condenceinterval (CI e0.31e0.52)) comparedwithplaceboand
Isoniazid was effective in preventing TB in 60% of people.
11
Studies conducted in children have revealed an efcacy be-
tween 69 and 93%.
3,6
Our study revealed a good outcome in
group 1, where none of 28 children with good adherence
developed active disease, almost reaching 100% efcacy. Our
observation is comparable to Iranian study,
12
which demon-
strated100%efcacy of INHin15 childrenexposedto infectious
adults in preventing the active disease. However both studies
havesmall samplesize. Theeffectivenessof IPTinchildrenwith
nephrotic syndrome and latent TB (group 2) in prevention of
active disease was similar, with none of 15 children with good
adherence progressing from latent infection to active disease.
This has not been reported so far in the literature to the best of
our knowledge.
Most childrenwho are exposed to infectious TB or who have
latent infectionwoulddevelop active disease inrst 2 years and
ideally 2 years of follow-up is required to establish efcacy of
prophylactic INH.
2
Though none of our children developed
active TB, follow-up duration was lesser than Cochrane data
(12.29 (13.13)) months versus >2 years).
11
Duration of follow-
up was 6 months to 2 years in two other studies.
8,12
What decides the outcome of IPT is strict adherence to
treatment. Rate of completion of 6 months IPT ranges from 12
to 70% in different series.
9,10,13,14
In Ethiopian study, only 12%
Table 1 e Outcome of children initiated on IPT.
Group 1 Group 2 Combined
Number (percentage) 31 (62.0%) 19 (38.0 %) 50
Age: mean (range) in months 33 (22.38) 48 ( 37.5) 35.3 (25.3)
Treatment completed: Number (percentage) 28 (90.3%) 15 (78.94%) 43 (86 %)
Children developing active disease in those who completed treatment None None None
Duration of follow-up post-treatment: mean (range) in months 16 (15.95) 10 (3.74) 12.29 (13.13)
Adverse effects Nil Nil Nil
Reasonable adherence 28 (90.3%) 15 (78.94%) 43 (86%)
Poor adherence 1 (3.20%) Nil 1 (2 %)
Very poor adherence 2 (6.5.0%) 4 (21%) 6 (12.0 %)
p e di a t r i c i nf e c t i o us d i s e a s e 6 ( 2 0 1 4 ) 2 1 e2 4 23
of 82 children completed treatment for 6 months.
13
In another
study from South Africa, out of 180 children started on IPT,
20% completed treatment.
10
Spyridis et al, reported 65%
completion rate to 9 months IPT
9
where as an Australian
study revealed 70%completionrate.
14
Reasons put forward for
poor adherence are: parents not being convinced about the
need for treatment in the absence of symptoms, difculty in
continuing treatment for long periods especially when unsu-
pervised. In fact few authors recommend shorter course
therapy with 2 drugs to improve adherence.
9
Striking obser-
vation of our study was, 86%of children completed treatment,
which was higher than these studies. However, completion
rate of our cohort was lesser than the study from Iran, which
had almost 100% adherence.
12
Our study indicates that
adherence can be enhanced by addressing parents awareness
and perception with proper counseling and regular follow-up.
Continuous ongoing communication between parents and
pediatrician is a key factor in determining adherence and in
turn nal outcome.
Though IPT is an integral part of RNTCP, study from TRC,
Chennai, has shown that tracing, screening and provision of
IPT in children <6 years in contact with smear positive adults
is suboptimal.
15
Only 20%of eligible children were initiated on
IPT and there was inadequate documentation of completion
of treatment. Pothukuchi M et al from Andhra Pradesh had
similar observation.
16
4. Limitations of the study
Main limitation of our study is less than optimal duration of
follow-up as discussed earlier. We intend to continue further
follow-up on these children to establish efcacy. Another
drawback of study being, adherence was assessed by recall
method and not by urinary excretion of metabolites or actual
counting of tablets; more objective methods of checking
adherence used by other authors.
9,10
No active interventions
were done to trace children with poor adherence to determine
whether they had developed active disease. Small number
of the study group, especially group 2, is yet another draw-
back. Further studies with a larger number, longer duration of
follow-up and objective adherence assessment would
strengthen our observation.
To conclude, this study suggests that IPT is effective in
preventing active tuberculosis in both TB exposed children
and those with nephrotic syndrome with latent infection.
Completion rate and adherence to IPT can be enhanced by
counseling of parents at the start of therapy and during sub-
sequent follow-ups. It is safe with no major side effects. To the
best of our knowledge, this is the rst study determining the
efcacy of IPT in Indian setting, in both TB exposed and in
children with nephrotic syndrome. Similarly this is the rst
study addressing the adherence to IPT in India.
Contribution
ICK conceived and designed the study. She was also involved
in writing the manuscript. She will act as the guarantor for the
study. GK and AI contributed to management of nephrotic
syndrome. AS was involved in treatment, analysis and inter-
pretation of results.
Conicts of interest
All authors have none to declare.
r e f e r e n c e s
1. Swaminathan S, Rekha B. Pediatric tuberculosis: global
overview and challenges. Clin Infect Dis. 2010;50:S184eS194.
2. Singh V, Patra S. A relook at preventive therapy for
tuberculosis in children. Indian J Pediatr. 2011;78:205e210.
3. Zyl SV, Marais BJ, Hesseling AC, Gie RP, Beyers N, Schaaf HS.
Adherence to anti-tuberculosis chemoprophylaxis and
treatment in children. Int J Tuberc Lung Dis. 2006;10:13e18.
4. World Health Organisation. Tuberculosis in Children: Treatment
of Tuberculosis: Guidelines for National Programs. 3rd ed. Geneva:
WHO; 2003:61e66.
5. http://www.tbcindia.nic.in/Paediatric%20guidelines_New.
pdf.
6. Indian Academy of Pediatrics. Consensus statement on
childhood tuberculosis. Indian Pediatr. 2010;47:41e55.
7. Bagga A. Revised guidelines for management of
steroid-sensitive nephrotic syndrome. Indian J Nephrol.
2008;18:31e39.
8. Gray DM, Cotton M, Young T, Zar H. Impact of Tuberculosis
Preventive Therapy on Tuberculosis and Mortality in HIV-infected
Children (Cochrane Review). The Cochrane Library, Issue 4,
Wiley. 2009.
9. Spyridis NP, Spyridis PG, Aetal Gelesme. The effectiveness of
a 9-month regimen of isoniazid alone versus 3- and 4-month
regimens of isoniazid plus rifampin for treatment of latent
tuberculosis infection in children: results of an 11-year
randomized study. Clin Infect Dis. 2007;45:715e722.
10. Marais BJ, Zyl SV, Schaaf HS, Aardt MV, Gie RP, Beyers N.
Adherence to isoniazid preventive chemotherapy: a
prospective community based study. Arch Dis Child.
2006;91:762e765.
11. Smieja M, Marchetti C, Cook DJ, Smaill FM. Isoniazid for
Preventing Tuberculosis in Non-HIV Infected Persons (Cochrane
Review). Cochrane Library, Issue 1, Wiley. 2010.
12. Aminzadeh Z, Asl RT. A six months follow-up on children less
than 6 years old in contact with smear positive tuberculosis
patients, Varamin City, Tehran, Iran. Int J Prev Med.
2011;2:79e81.
13. Garie KT, Yassin MA, Cuevas LE. Lack of adherence to
isoniazid chemoprophylaxis in children in contact with
adults with tuberculosis in Southern Ethiopia. PLoS One.
2011;6:e 26452.
14. Alperstein G, Morgan KR, Mills K, Daniels L. Compliance with
antituberculous preventive therapy among 6-year-old
children. Aust N Z J Public Health. 1998;22:210e213.
15. BanuRekha VV, Jagarajamma K, Wares F, Chandrasekaran V,
Swaminathan S. Contact tracing and chemoprophylaxis in
Indias RNTCP program a situational analysis. Int J Tuberc Lung
Dis. 2009;13:1507e1512.
16. Pothukuchi M, Nagaraja SB, Kelamane S, et al. Tuberculosis
contact screening and isoniazid preventive therapy in a south
Indian district: operational issues for programmatic
consideration. PLoS One. 2011;6:e22500.
p e d i a t r i c i nf e c t i o us d i s e a s e 6 ( 2 0 1 4 ) 2 1 e2 4 24