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Intermittent versus daily therapy for treating tuberculosis in children

  1. Anuradha Bose1,*,
  2. Soumik Kalita2,
  3. Winsley Rose3,
  4. Prathap Tharyan4

Editorial Group: Cochrane Infectious Diseases Group

Published Online: 28 JAN 2014

Assessed as up-to-date: 30 MAY 2013

DOI: 10.1002/14651858.CD007953.pub2


How to Cite

Bose A, Kalita S, Rose W, Tharyan P. Intermittent versus daily therapy for treating tuberculosis in children. Cochrane Database of Systematic Reviews 2014, Issue 1. Art. No.: CD007953. DOI: 10.1002/14651858.CD007953.pub2.

Author Information

  1. 1

    Christian Medical College, Department of Community Health, Vellore, India

  2. 2

    GlaxoSmithKline Consumer Healthcare, Family Nutrition, Gurgaon, Haryana, India

  3. 3

    Christian Medical College, Department of Child Health, Vellore, India

  4. 4

    Christian Medical College, South Asian Cochrane Network & Centre, Prof. BV Moses & ICMR Advanced Centre for Research & Training in Evidence Informed Health Care, Vellore, Tamil Nadu, India

*Anuradha Bose, Department of Community Health, Christian Medical College, Vellore, 632002, India. abose@cmcvellore.ac.in.

Publication History

  1. Publication Status: New
  2. Published Online: 28 JAN 2014

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Characteristics of included studies [ordered by study ID]
Kansoy (Turkey) 1996

MethodsDesign: Randomized, parallel group, single-centre, open-labelled, controlled trial

Trial duration: December 1988 to February 1992 (recruitment)


ParticipantsNumber randomized: 36 children

Age: Five months to 13 years

Gender: Both

Inclusion criteria:

Diagnosed cases of TB fulfilling the following criteria:

  1. Clinical: afternoon fever, excessive sweating, cough, anorexia and weight loss
  2. Epidemiological: direct contact with an adult with TB (sputum positive or negative)
  3. Radiological, parenchymal or mediastinal lymph nodes in chest radiograph
  4. Immunological: Tuberculin test positivity


Exclusion criteria:

Not reported


InterventionsIntervention:

  1. Intermittent Short Course Chemotherapy group (ISCC): Streptomycin, rifampicin and INH daily for two weeks, followed by INH and rifampicin twice-weekly for eight and a half months (N = 18)


Control:

  1. Conventional Chemotherapy group (CC): Daily streptomycin for 40 days, rifampicin for nine months and INH for 12 months (N = 18)


Doses used:

Rifampicin- 15 mg/kg; maximum 600 mg/day; streptomycin- 20 mg/kg IM up to 1 g; INH 15 mg/kg up to 400 mg


OutcomesOutcomes used in this review

  1. Cure (clinical and radiological response to treatment; weight gain)
  2. Death
  3. Relapse
  4. Adherence
  5. Serious adverse events


Outcomes reported and not used in this review

  1. Therapy period for early clinical response
  2. Complete radiological resolution
  3. Mean weight gain


NotesCountry: Turkey

Setting: SSK Tepecik Teaching Hospital, Izmir; outpatients

Funding: Not mentioned

Comments:

  • Follow-up: At the end of the first month of treatment, every three months during the treatment and every six months after the treatment, until one year after treatment completion
  • Compliance: Not reported how compliance was assessed
  • HIV status: Not reported
  • Previous treatment: Not reported
  • Use of concurrent steroids: Not reported (probably not used)


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear risk"Thirty six patients were randomly allocated either to the study group or conventional therapy group"

Method of sequence generation not described

Allocation concealment (selection bias)Unclear riskMethod used to concealment allocation not described

Blinding (performance bias and detection bias)
All outcomes
Unclear riskThe trial was open labelled, and though outcomes are objective, some amount of detection bias is possible due to a degree of subjectivity in diagnosing TB in children. Unclear if outcome assessors were aware of treatment allocation

Incomplete outcome data (attrition bias)
All outcomes
Low riskThe three drop outs after randomization during the follow-up period in the control group due to poor family compliance are reported

Selective reporting (reporting bias)Low riskThe trial protocol is not available but all relevant outcomes addressing the trial objectives were fully reported

Other biasLow riskThe duration of INH in the control arm was for 12 months while INH was given for nine months in the intermittent treatment arm; the two arms are therefore not strictly comparable but this would affect external validity more than internal validity

Kumar (India) 1990

MethodsTrial Design: Randomized, parallel group, single-centre, open-labelled, controlled trial

Trial duration: Not reported


ParticipantsNumber randomized: 76 children

Age: One year to 15 years

Gender: Both

Inclusion criteria:

  1. Children with TB lymphadenopathy (three of: enlargement of lymph nodes-regional or generalized; positive tuberculin skin test (TST; 10 mm or more induration after 72 hours of one tuberculin unit of purified protein derivative); caseous granulomata on histopathology; presence of acid fast bacilli (AFB) in histopathological sections or on stained smears of lymph node aspirates, or cultures
  2. Children with pulmonary TB, (clinical symptoms of pulmonary TB in older children, chest pain or haemoptysis with malaise, fatigue, weakness or weight loss; evidence of consolidation, cavitation, fibrosis, hilar lymph node enlargement, collapse, pleural effusion or pneumothorax on chest radiograph; positive TST; positive for AFB in smears/culture of gastric lavage, deep laryngeal swab or sputum (older children)
  3. Children with disseminated TB (involvement of multiple organs, miliary mottling on chest radiographs, or in addition to radiological features consistent with a diagnosis of TB at an extra-pulmonary site; histopathological evidence of TB in biopsies of lymph nodes or liver; demonstration of AFB in gastric lavage, sputum or tissue biopsies, and positive culture, or both. TST positivity was taken as additional evidence, though not a diagnostic criterion)


Exclusion criteria:

  1. Children who were thought to have only a primary complex in the lung


InterventionsIntervention:

  1. Partially-intermittent regimen: INH, rifampicin, and pyrazinamide given daily for two months followed by INH and rifampicin twice-weekly for four months (N = 39)


Control:

  1. Fully-intermittent regimen: INH, rifampicin and pyrazinamide given twice weekly for two months followed by INH and rifampicin twice weekly for four months (N = 37)


Doses used:

Intermittent regimen: INH 20 to 30 mg/kg body weight /dose; rifampicin 10 to 15 mg/kg body weight/dose; pyrazinamide 50 to 60 mg/kg body weight /dose

Daily regimen: INH 10 to 15 mg/kg body weight/dose; rifampicin 10 to 15 mg/kg body weight/dose; pyrazinamide 20 to 30 mg/kg body weight/dose


OutcomesOutcomes used in this review

  1. Cure (we used the proportions reported as having marked and moderate improvement as defined below)
  2. Death
  3. Relapse
  4. Adherence
  5. Serious adverse events
  6. Adverse events requiring alteration in therapy
  7. Other adverse events


Criteria for improvement

1. General improvement : Disappearance of fever, improvement in appetite and weight gain

2. Pulmonary TB response

    • Marked: "General Improvement, disappearance of cough, radiologic clearance of pulmonary lesions within 3 months of therapy and no appearance of new lesions"
    • Moderate: "General improvement plus partial clearance of radiologic pulmonary lesions within 3 months of therapy and no appearance of fresh lesions"
    • Poor: "No significant general improvement and no radiologic clearance/ increase in size of pulmonary lesions or appearance of new lesions"


3. Tuberculous lymphadenitis response:

    • Marked: General improvement plus reduction in lymph node size within three to four months and no appearance of any new lymph node enlargement
    • Moderate: General improvement plus reduction in lymph node size later than three to four months and no appearance of new lymph nodes enlargement
    • Poor: "Increase in lymph node size or sinus formation or appearance of new lymph node enlargement, not responding to therapy"


4. Disseminated TB response:

    • Same criteria for pulmonary improvement plus regression in size of enlarged organs if complete by three to four months


NotesCountry: India

Setting: Post Graduate Institute of Medical Education and Research, Chandigarh Hospital; outpatients

Funding: Indian Council of Medical Research

Comments:

  • Follow-up: Monthly for first six months, every three months thereafter, chest x-ray at one year of follow-up; 30/76 completed two years of follow-up
  • Compliance: Intermittent therapy was by DOT; compliance assessed by parental reports, verification of colour of urine (orange to red colour due to rifampicin) and pill counts.
  • HIV status: Not reported
  • Previous treatment: All were newly diagnosed
  • Corticocosteroid use: Not reported


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear risk"At enrolment any currency note available was taken and its number was noted. Even numbers were assigned to Regimen A and odd numbers to Regimen B".

Quasi-random assignment

Allocation concealment (selection bias)Unclear riskQuasi-random allocation may lead to selection bias; however, groups were balanced at baseline on important prognostic indicators though the possibility of residual confounding cannot be ruled out

Blinding (performance bias and detection bias)
All outcomes
Low riskThe trial was open labelled, and though outcomes are objective, some amount of detection bias is possible due to a degree of subjectivity in diagnosing TB in children; however, the explicit pre-stated criteria for defining response would have reduced the element of subjectivity

Incomplete outcome data (attrition bias)
All outcomes
Low riskTen withdrawals were reported; 4/37 in the intervention arm and 6/39 in the control arm which was not significantly different. The participants withdrawing from the trial were from families of migrant labourers.

Selective reporting (reporting bias)Low riskThe trial protocol is not available but all relevant outcomes addressing the trial objectives were fully reported.

Other biasLow riskNo other biases detected

Ramachandran (India) 1998

MethodsTrial Design: Randomized, parallel group, single-centre, open-label, stratified (by probability of TB) assessor blinded, controlled trial

Trial duration: 1992 to 1997


ParticipantsNumber randomized: 137 children

Age: One year to 12 years

Gender: Both

Inclusion criteria:

  1. Children with TB categories A & B (Category A-most probably TB: X-ray findings of primary focus plus hilar lymphadenitis, mediastinal adenitis, miliary TB, progressive primary complex: Category B- probably TB: children with a doubtful radiological abnormality with persistent abnormality two weeks after a course of antibiotics)


Exclusion criteria:

  1. Childern with chest X-ray findings of massive pleural effusion or isolated bronchiectasis and those with extrapulmonary TB
  2. More than two weeks of previous anti-TB treatment
  3. Evidence of renal or hepatic disease


InterventionsIntervention:

  1. Intermittent regimen: INH, rifampicin and pyrazinamide three times a week for two months, followed by INH and rifampicin twice weekly for four months (N = 69)


Control:

  1. Daily regimen: INH and Rifampicin daily for nine months (N = 68)


Doses used:

INH 6 mg/kg (maximum 150 mg) for daily phase and 15 mg/kg (maximum 300 mg) for intermittent phases; rifampicin 12 mg/kg (maximum 300 mg); pyrazinamide 45 mg/kg (maximum 1 g)


OutcomesOutcomes used in this review

  1. Cure: Clearance of radiological lesions assessed by an independent radiologist
  2. Death
  3. Relapse
  4. Adherence
  5. Serious adverse events
  6. Adverse events requiring alteration in therapy


Outcomes reported but not used in this review

  1. Response to therapy according to type of radiological lesion


NotesCountry: India

Settings: Tuberculosis Research Centre, Chennai; hospitalized for minimum two weeks or more; then outpatients

Funding: Not stated

  • Follow-up: At one month intervals till the end of the treatments then at six monthly intervals and at 60 months (radiological outcome)
  • Compliance: Direct supervision weekly for daily regimen; all doses supervised in hospital for intermittent regimen
  • HIV status: Not reported
  • Previous treatment: More than two weeks of anti-TB treatment was an exclusion criterion
  • Corticosteroid use: Not reported


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear risk"Patients were randomly allocated"

Method of sequence generation is not stated

Allocation concealment (selection bias)Unclear riskMethod of allocation concealment not reported

Blinding (performance bias and detection bias)
All outcomes
Low risk"An important feature is that all the radiographs were read by a radiologist, an independent assessor, who was not aware of any of the details pertaining to the patients".

Assessor blinding for the primary outcome and the use of objective secondary outcomes reduces the risk of detection bias; the open label design could introduce performance bias but this appears unlikely to have influenced outcome estimates

Incomplete outcome data (attrition bias)
All outcomes
Low riskAll exclusions, deaths, and losses to follow-up were reported. Treatment allocation for one death in the first month attributed to a non-tuberculous cause was not reported; this does not affect relative estimates for deaths due to interventions. 11 children were lost to follow-up for the final follow-up at 60 months; the last available radiographs (all at or after 24 months) were considered for evaluation and included all 137 evaluable participants .

Selective reporting (reporting bias)Low riskThe trial protocol is not available but all relevant outcomes addressing the trial objectives were fully reported.

Other biasLow riskThe intermittent treatment arm used thrice-weekly regimen for the first two months and a twice weekly regimen for the next four months that is a non-standard regimen; Pyrazinamide was used for the first two months in the intermittent regimen and was not used in the 9-month daily regimen. These would affect external validity rather than internal validity

Te Water Naude (South Africa) 2000

MethodsTrial design: Cluster-randomized (by households), single-centre, open labelled, controlled trial

Trial duration: June 1991 to June 1995


ParticipantsNumber randomized: 314 children

Age: < 14 years; (range 13.4 months to 43.2 months)

Gender: Both

Inclusion criteria:

  1. Modified WHO criteria used to diagnose children as having suspected, probable and confirmed cases of intrathoracic TB.


Exclusion criteria:

  1. Home address in a rural area
  2. Previous treatment for TB
  3. More than 30 days of hospitalisation before referral for clinic management
  4. Extrathoracic TB
  5. Lack of consent


InterventionsIntervention:

  1. Intermittent treatment: Twice-weekly INH 15 mg/kg/dose, rifampicin 15 mg/kg/dose and pyrazinamide 55mg/kg/dose for six months (N = 153 randomized; 96 given treatment)


Control:

  1. Daily treatment: Daily INH 10 mg/kg/day, rifampicin 10 mg/kg/day, pyrazinamide 25 mg/kg/day (5 days a week) for six months (N = 161 randomized; 118 given treatment)


OutcomesOutcomes used in this review

  1. Treatment outcome scores (median and range of composite scores from parent's assessment, clinical symptoms, weight gain, chest radiograph scored from -1 to +2 (total scores could range from -4 to +8) and high scores indicate better outcome). Medians and ranges presented and proportions cured were inferred from these.
  2. Death due to any cause
  3. Relapse: assessed by an independent paediatric pulmonologist based on clinical findings (respiratory signs, weight loss), and chest radiographs (serial deterioration despite exclusion of other conditions)
  4. Adherence: participants who took 75% or > of the prescribed doses
  5. Serious adverse events
  6. Adverse events requiring alteration in therapy


Outcomes reported but not used in this review

  1. Days to default for those fully adherent and partially adherent; medians presented
  2. Factors influencing adherence to treatment


NotesCountry: South Africa

Setting: Idas Valley clinic, Stellenbosch district, Western Cape Province; outpatients

Funding: South African Medical Council

Comments:

  • Follow-up: 30 months after starting treatment
  • Compliance: Treatment given by direct supervision by nursing personnel at the clinic or by parents or guardians. Number of doses taken during each four-week period was recorded
  • HIV status: Not reported
  • Previous treatment: Previous treatment was an exclusion criterion for this trial
  • Use of concurrent steroids: Not reported (probably not used)
  • The number of clusters (households) and the numbers in each arm randomized by households were not reported; the analysis in the paper did not account for clustering.
  • Four children in each group had confirmed TB; 82 in the intermittent treatment group and 111 in the daily treatment group had probable TB, and three in the intermittent treatment group and two in the daily treatment group had suspected TB
  • Date for those cured were inferred from the median scores and range of composite scores for the outcome of those considered


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskQuote from report: "Children diagnosed as having tuberculosis were randomized by household unit to receive either intermittent treatment or daily treatment. Randomization was by random number tables."

Quote from discussions and correspondence with first author: "The method of allocation: When a child fulfilled the eligibility criteria, the parent was asked if they would participate in the study. Households were assigned to one or the other group. A random number table was used: an odd number would assign the household to 2x weekly and an even number to 5x weekly".

Comment: It is unclear if the use of odd and even numbers from a random number table would permit unpredictability in treatment allocation

Allocation concealment (selection bias)High riskQuote from report: "Informed consent was obtained after randomisation"

Quote from correspondence with the first author,"Consent was taken after randomization, for purposes of informed choice or consent".

Comment: As informed consent was taken after randomization, allocation was most likely not concealed. Of 153 randomized to intermittent treatment only 95 (62%) were included in the trial after exclusions; of 161 randomized to daily treatment, only 118 (73%) were included in the trial after exclusions (P < 0.05)

Blinding (performance bias and detection bias)
All outcomes
Unclear riskQuote from discussions and correspondence with the first author, "CXR readers were blinded to the regimen of treatment until after the reading was captured. Parental response was recorded by me yes. I saw all the cases clinically."

Comment: The trial was open label, and though outcomes are mostly objective, some amount of detection bias is possible due to a degree of subjectivity in diagnosing TB in children using the composite of parent's report and clinical criteria, though radiological assessments were done blind to allocation

Incomplete outcome data (attrition bias)
All outcomes
Low riskThe proportions completing the trial after initiation of treatment in the intermittent treatment arm 89/95 (94%) and the daily arm 117/118 (99%) were not statistically significantly different. At six months, 163 of 206 randomized evaluable children  were assessed for treatment response (77%); of which 70/89  (79%) were in the arm allocated twice weekly intermittent treatment and 93/117 (79%) were in the daily treatment arm (P = 0.40).

Selective reporting (reporting bias)Low riskThe trial protocol is not available but all relevant outcomes addressing the trial objectives were fully reported.

Other biasUnclear riskQuote from trial report, "Households rather than patients were used in randomisation to avoid confusion in the event of more than one child from a particular household being enrolled".

Quote from correspondence with author: "we randomised by household, but analysed by individual. There were few where there were more than one per household"

Comment: Though the results were not adjusted for clustering; the proportions randomized by household are probably fewer than those individually randomized

 
Characteristics of excluded studies [ordered by study ID]

StudyReason for exclusion

Al-Dossary 2002Not a RCT: prospective cohort

Amrane 1989Not a RCT; controlled clinical trial

Anastasatu 1991Not a RCT; controlled clinical trial comparing two intermittent regimens

Anastasatu 1993Not a RCT; controlled clinical trial comparing two intermittent regimens

Balasubramanian 1990Not a RCT; controlled clinical trial comparing daily regimen with intermittent regimens

Bignall 1974Not a RCT, controlled clinical trial comparing five intermittent regimens

Carter 1954Not a RCT; study is on use of INH in treatment

Comstock 1969Not a RCT; controlled clinical trial comparing two doses of INH for prophylaxis of TB

Comstock 1970Not a RCT; controlled clinical trial aimed at finding the appropriate dosage of INH

Debre 1973Not a RCT; controlled clinical trial of INH chemoprophylaxis

Dingley 1974RCT; compared four daily regimens

Dingley 1982  RCT; compared four daily regimens

Eule 1986RCT: compared four regimens but there was no daily six-month regimen

Ganguin 1973Not a RCT; controlled clinical trial

Garciá López 1989Not a RCT; case series with historical controls

Göçmen 1993Not a RCT: retrospective study

HKCS-BMRC 1991RCT: compared four intermittent regimens

HKTTS/BMRC 1975RCT: compared daily versus intermittent therapy but did not use rifampicin in the intensive phase.

Jawahar 1990Not a RCT: case series

Jawahar 2005RCT: compared intermittent versus daily regimens; included adults and children but separate data for 87 children not available from trial report or from authors

Jindani 2004RCT: adults and adolescents included; no disaggregated results

Karam-Bechara 1994Not a RCT; follow-up study of two cohorts

MRC 1993RCT: compared different daily regimens to treat spinal TB and there is no intermittent regimen.

No authors 1969RCT: compared four different regimens for re-treatment of TB.

No authors 1974  RCT: used only a once-weekly regimen and was aimed at studying the side effects of rifampicin.

No authors 1975RCT: compared two daily followed by intermittent regimens and there was no comparison of daily versus intermittent regimens

No authors 1976RCT: compared three intermittent regimens

No authors 1977aRCT: compared different intermittent regimens

No authors 1977bRCT: compared three intermittent regimens

No authors 1981RCT: compared four different regimens of which one was daily and the other were intermittent. However there was no rifampicin in any of the regimens.

Rajeswari 1995RCT: initial phase of daily and intermittent arms was for three months

Ramachandran 1986Not a RCT: controlled clinical trial

Ramesh 1991Not a RCT; controlled clinical trial

Santha 1989RCT: compared non-standard regimens

STS-BMRC 1985  RCT: compared three regimens of daily therapy for one or two months followed by intermittent therapy for a total treatment duration of six-months.

Swaminathan 2005RCT: only daily treatment arm had rifampicin and INH

Tam 2002RCT: continuation phase had no daily therapy arm

Teo 2002RCT: compared two four-month regimens

TRC 1970Not a RCT: controlled clinical trial

TRC 1997RCT: compared one daily regimen and two intermittent regimens. Included participants 12-62 years of age. Data for children aged 12 to 15 years not available from report or from authors

WHO CCTC 1971RCT: compared daily treatment for three months followed by randomized intermittent treatment; participants were aged 15 to 70 years

WHO CCTC 1973RCT: compared daily treatment for three months followed by randomized intermittent treatment; participants were aged 15 to 70 years

 
Comparison 1. Intermittent versus daily regimens

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Cure (as defined by clinical and radiological improvement): Intention to treat4465Risk Ratio (M-H, Fixed, 95% CI)1.01 [0.94, 1.10]

    1.1 Intermittent (daily 2 weeks, twice-weekly 8.5 months) versus daily treatment (12 months)
136Risk Ratio (M-H, Fixed, 95% CI)1.19 [0.95, 1.50]

    1.2 Intermittent (twice-weekly 6 months) versus daily treatment (daily 2 months, intermittent 4 months)
176Risk Ratio (M-H, Fixed, 95% CI)0.95 [0.77, 1.17]

    1.3 Intermittent (thrice-weekly 2 months, twice-weekly 4 months) versus daily treatment (9 months)
1140Risk Ratio (M-H, Fixed, 95% CI)1.02 [0.91, 1.14]

    1.4 Intermittent (twice-weekly 6 months) versus daily treatment (6 months)
1213Risk Ratio (M-H, Fixed, 95% CI)1.00 [0.88, 1.15]

 2 Cure (as defined by clinical and radiological improvement): Per-protocol (Sensitivity analysis)4441Risk Ratio (M-H, Fixed, 95% CI)0.96 [0.86, 1.06]

    2.1 Intermittent (daily 2 weeks, twice-weekly 8.5 months) versus daily treatment (12 months)
133Risk Ratio (M-H, Fixed, 95% CI)1.0 [0.89, 1.12]

    2.2 Intermittent (twice-weekly 6 months) versus daily treatment (daily 2 months, intermittent 4 months)
165Risk Ratio (M-H, Fixed, 95% CI)1.03 [0.93, 1.15]

    2.3 Intermittent (thrice-weekly 2 months, twice-weekly 4 months) versus daily treatment (9 months)
1137Risk Ratio (M-H, Fixed, 95% CI)0.82 [0.60, 1.12]

    2.4 Intermittent (twice-weekly 6 months) versus daily treatment (6 months)
1206Risk Ratio (M-H, Fixed, 95% CI)0.99 [0.86, 1.14]

 3 Death from any cause4460Risk Ratio (M-H, Fixed, 95% CI)1.52 [0.26, 8.96]

 4 Relapse4449Risk Ratio (M-H, Fixed, 95% CI)3.68 [0.15, 89.33]

 5 Adherence to treatment4458Risk Ratio (M-H, Fixed, 95% CI)1.04 [0.97, 1.11]

 6 Treatment-limiting adverse events4441Risk Ratio (M-H, Fixed, 95% CI)0.40 [0.06, 2.60]

 
Summary of findings for the main comparison. Intermittent short-course anti-TB regimens compared to daily anti-TB regimens for treating TB in children

Intermittent short-course anti-TB regimens compared to daily anti-TB regimens for treating TB in children with TB

Patient or population: Children with TB1
Intervention: Intermittent short-course twice-weekly anti-TB regimens (six to nine months)
Comparison: Daily anti-TB regimens (six to 12 months)

OutcomesIllustrative comparative risks* (95% CI)Relative effect
(95% CI)
No of participants
(trials)
Quality of the evidence
(GRADE)
Comments

Assumed riskCorresponding risk

Daily anti-TB regimensIntermittent short-course anti-TB regimens

Cure

Follow-up: 12 to 30 months
836 per 1000844 per 1000
(786 to 920)
RR 1.01
(0.94 to 1.1)
465
(4 trials)
⊝⊝⊝⊝
very low 2,3,4,5

Death from any cause8 per 100013 per 1000
(2 to 75)
RR 1.52
(0.26 to 8.96)
213
(2 trials)6
⊝⊝⊝⊝
very low,3,7,8,9

Relapse

Follow-up: 12 to 30 months
0 per 10000 per 1000
(0 to 0)
RR 3.68
(0.15 to 89.33)
214
(1 trial)10
⊝⊝⊝⊝
very low 11,12,13

Adherence to treatment840 per 1000874 per 1000
(815 to 932)
RR 1.04 (0.97, 1.11)458
(4 trials)
⊝⊝⊝⊝
very low3,4,14,15

Treatment-limiting adverse events 15 per 10006 per 1000
(1 to 39)
RR 0.4
(0.06 to 2.6)
441
(4 trials)
⊝⊝⊝⊝
very low2,3,4,16

*The basis for the assumed risk is the median control group risk across studies for pooled data and the control group risk for data from single studies. The corresponding risk (and its 95% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).
CI: Confidence interval; RR: Risk ratio.

GRADE Working Group grades of evidence
High quality: Further research is very unlikely to change our confidence in the estimate of effect.
Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.
Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.
Very low quality: We are very uncertain about the estimate.

 1 The data in this table are from Kumar (India) 1990; Kansoy (Turkey) 1996; Ramachandran (India) 1998; and Te Water Naude (South Africa) 2000.
2 Downgraded by 1 for serious risk of bias: None of the trials were free of risk of bias. The trial that contributed the most weight (43%) to the pooled effect estimates (Te Water Naude (South Africa) 2000) was at high risk of selection bias.
3 No serious inconsistency: Statistical heterogeneity was low.
4 Downgraded by 1 for serious indirectness: Two of the trials (Kansoy (Turkey) 1996; Ramachandran (India) 1998) used a longer duration of treatment in the daily treatment arms than in the intermittent arms, and the intermittent arms in Kansoy (Turkey) 1996 and Ramachandran (India) 1998 used non-standard regimens. None used drug combinations and schedules currently recommended for childhood TB.
5 Downgraded by 1 for serious imprecision: The 95% CI of the effect estimate indicated only non-appreciable benefit with both interventions, but the sample size was smaller than the optimal information size for equivalence.
6 Data for deaths are from only two of the four trials as no deaths were reported in Kansoy (Turkey) 1996 and Te Water Naude (South Africa) 2000.
7 Downgraded by 1 for serious risk of bias: The trials were either unclear or at high risk of selection bias.
8 Downgraded by 1 for serious indirectness: Neither control group used drug combinations and schedules currently recommended for childhood TB.
9 Downgraded by 1 for serious imprecision: The number of deaths was very few, and the 95% CI for the risk difference are wide.
10 Data for relapse are from only one trial (Te Water Naude (South Africa) 2000) as no participant was reported to have had a confirmed relapse in Kansoy (Turkey) 1996; Kumar (India) 1990; and Ramachandran (India) 1998 over one to five years of follow-up.
11 No serious study limitations: Only one relapse was reported with intermittent treatment in Te Water Naude (South Africa) 2000. This trial was at high risk of selection bias, but this is unlikely to have introduced bias in relapse estimates.
12 Downgraded by 1 for serious indirectness: The data for relapse comes from only one trial conducted in South Africa nearly 20 years ago and may not generalize to other settings today.
13Downgraded by 2 for serious imprecision: Only one child relapsed and the upper and lower limits of the 95% CI indicate appreciable benefits for both interventions with so significant differences.
14 Downgraded by 1 for serious risk of bias: The trials were open label in design and assessments of adherence were not done blind to treatment allocation The four trials used different methods to assess adherence and different definitions to define those adherent.
15 Downgraded by 1 for serious imprecision: The 95% CI of the pooled effect estimates indicated that the interventions did not appreciably increase adherence.
16 Downgraded by 1 for serious imprecision: Adverse events were infrequent and the 95% CI of the absolute risk difference indicated a non-appreciable difference in the risk of adverse events requiring treatment interruptions with intermittent and with daily treatments.