Table 1

What are the options for treating latent TB infection in children?

CitationStudy groupStudy type (level of evidence)OutcomeKey resultsComments
Ormerod (1998)19Children (0–15 years) with household TB contacts and new migrants from high TB prevalence countries with:
1. Heaf test grade 2–3 (no BCG), or
2. Heaf test grade 3–4 (previous BCG), or
3. TST conversion, or
4. Healed lesion on CXR

1981–1983: Daily 9RH (n=220)
1984–1986: Daily 6RH (n=119)
1987–1988: Daily 4RH (n=53)
1989–1996: Daily 3RH (n=79)
Observational study (level 2c)Drug AE


Treatment efficacy
1981–1986: 4 had therapy modified due to nausea; all had normal LFTs. None had therapy stopped due to AE

Reduction in proportion of paediatric TB notifications after prophylaxis was introduced (1981–1983 24.9% vs 4.3% 1993–1996)
No increase in the proportion of paediatric TB notifications with 3RH and 4RH
AE were not described in detail

Dose:
R (10 mg/kg/day)
H (10 mg/kg/day)
McNab et al (2000)10Aboriginal adults and children
No defined inclusion criteria

1992–1995: 6R2H2 with DOT
1986–1989: daily 12H (historical controls)

6R2H2 (n=591; 89% ≤19 years)
12H (n=403; 71% ≤19 years)
Cohort study (level 2b)Treatment completion

Drug AE









Treatment efficacy
6R2H2: 82%; 12H: 19% (p<0.0001)


Treatment discontinuation due to AE:
 ▸ Age 0–9 years: 6R2H2 92/1000 vs 12H 23/1000 patient-years (p<0.0001)*
 ▸ Age 10–19 years: 6R2H2 61/1000 vs 12H 37/1000 patient-years (p=0.014)*
Higher rates of GI (nausea), neurological (headache) and miscellaneous (fatigue) AE in 6R2H2 group
Skin allergy and hepatitis rate similar in both groups
No hospital admission or death in either group

Rate of TB:
 ▸ Age 0–9 years: 0.7/1000 6R2H2 vs 12.7/1000 patient-years 12H (p<0.001)
 ▸ Age 10–19 years: 1.7/1000 6R2H2 vs 8.2/1000 patient-years 12H (p<0.05)
Dose:
6R2H2 (R 10 mg/kg/day, H 15 mg/kg/day)
9H (15 mg/kg/day)
Tortajada et al (2005)14Children and adults (<35 years) with:
 ▸ Recent TST conversion
 ▸ Exposure >6 h/day to patient with smear-positive TB
 ▸ Immunosuppressed with daily exposure to TB

6H (n=199; 18% 1–19 years) vs
2RZ (n=153; 17% 1–19 years)
Open labelled multicentre, randomised, comparative and prospective trial (level 1b)Treatment completion

Treatment compliance

Drug AE



Treatment efficacy
73% 6H vs 70% 2RZ (p=0.73) (all age groups)


Daily adherence: 77% 6H vs 82% 2RZ (p=0.21)


0/56 hepatotoxicity (in those aged 1–19 years)
At least one AE: 41% 6H vs 59% 2RZ (p<0.001) (all age groups)

No cases of active TB at 24-week follow-up
Short duration of follow-up (24 weeks)

Dose:
6H (5 mg/kg/day)
2RZ (R 10 mg/kg/day, Z 25 mg/kg/day)
Page et al (2006)15Children and adults with LTBI


Daily 9H (small proportion received 9H2 with DOT) vs daily 4R

9H (n=770; 21% <18 years) vs 4R (n=1379; 7% <18 years)
Retrospective cohort study (level 2b)Treatment completion

Drug AE





Treatment efficacy
72% 4R vs 53% 9H (all age groups) (p<0.001)


Recognised AE: 11% 9H vs 8% 4R (p=0.02)
Permanent discontinuation due to AE: 4.6% 9H vs 1.9% 4R (p<0.001)
Hepatotoxicity: 1.8% 9H vs 0.08% 4R (p<0.001)
No difference in types of adverse reactions between the 2 groups

Cases of active TB: 1/1379 4R vs 0/770 9H (p=0.46)†
Higher percentage of patients in 9H received DOT (5% vs 1%)

Dose not specified
Lardizabal et al (2006)16Children and adults with LTBI

2000–2001: treated with 9H
2002: offered 9H or 4R

4R (n=261) vs 9H (n=213)
74% aged 1–24 years
Retrospective review (level 2c)Treatment completion

Drug AE




Treatment efficacy
53.1% 9H vs 80.5% 4R (all age groups) (p<0.0001)


Treatment discontinuation due to AE: 6.1% 9H vs 3.1% 4R (p=0.12)
Hepatotoxicity: 3/213 cases 9H vs 0/261 cases 4R (p=0.049)*
No significant difference between age groups and risk of AE

No patients were referred to clinic for assessment for active TB
Unknown proportion of children included in study

Dose not specified
Cook et al (2006)11Children and adults with LTBI
Daily or twice-weekly§ 2RZ (if ≥3 years old) vs daily 4R (6R if <15 years old) vs daily 9H
§DOT if 2×/week 2RZ

2RZ (n=278; n=8 0–14 years) vs 4R (n=32) vs 9H (n=149)
Observational study (level 2c)Treatment completion

Drug AE
76.6% 2RZ vs 87.5% 4R/6R vs 65.8% 9H


Hepatotoxicity:
 ▸ All age groups: 2RZ 57/278 (20.5%) vs 4R 0/32 (0%) vs 9H 17/149 (11.4%)
 ▸ Grade 3 or 4 hepatotoxicity in 6.1% 2RZ vs 2.0% 9H (p=0.08)
Treatment discontinuation due to AE:
 ▸ Age 0–14 years: 2RZ 1/8 due to hepatotoxicity
 ▸ Higher in short course group vs 9H group (p=0.001)
13 patients in 2RZ group changed to 4R and completed treatment

Dose:
2RZ (Z 15 mg/kg/day, R 10 mg/kg/day)
2R2Z2 (Z 50 mg/kg, R 10 mg/kg/day)
4R (10 mg/kg/day)
9H (10 mg/kg/day)
van Zyl et al (2006)8Children <5 years with adult household PTB contact (n=181)
 ▸ 2 TB disease
 ▸ 72 infected
 ▸ 105 exposed
 ▸ 2 incompletely evaluated

6H (n=105)
3RH (n=72)
Note:
 ▸ Chemoprophylaxis for MDR contact for remaining 4 children
 ▸ DOT for 32 children (unknown treatment group)
Retrospective study (level 2c)Treatment completion27.6% 6H vs 66.6% 3RH (p<0.0001)Dose not specified
Rennie et al (2007)9Children and adults (≤35 years) with LTBI defined as:
 ▸ Positive TST, and
 ▸ Normal CXR and inflammatory markers, and
 ▸ No clinical evidence of TB

Daily 6H (n=277) vs daily 3RH (n=314)
Note: n=50 school referrals with mean age of 12.9 years
Retrospective audit (level 2c)Treatment completion

Drug AE



Cost
Treatment ‘failure’ greater with 6H regimen (p<0.001)


Hepatotoxity: 5.8% 6H vs 5.1% 3RH (p=0.84)
Treatment discontinuation due to AE: all in 6H group in those aged <15 years

Cost per patient: 6H 1.6 times higher than 3RH
78.7% of patients chose 3RH over 6H when offered a choice of regimen

Dose:
6H (5 mg/kg/day)
3RH (H 5 mg/kg/day, R 10 mg/kg/day)
Spyridis et al (2007)13Children (<15 years) with LTBI



Period 1: 1995–1998
Daily 9H (n=232) vs daily 4RH (n=238)
7–11-year follow-up

Period 2: 1999–2002
Daily 4RH (n=236) vs daily 3RH (n=220)
3–7-year follow-up
Prospective randomised study (level 1b)Treatment compliance


Drug AE






Treatment efficacy
Period 1: 4RH (92%) vs 9H (86%) (p=0.011)
Period 2: No significant difference in compliance for 3RH vs 4RH (p=0.510)

Rate of AE:
 ▸ GI: 6.5% 9H vs 0.7% 4RH (p<0.0001)*
 ▸ Transient increase in liver enzymes: 6% 9H vs 1.2% RH (p<0.0001)*
In RH group 1.3% rash, 0.7% photosensitivity
Treatment discontinuation due to AE: none in both groups

Proportion of compliant patients who developed CXR changes suggestive of active TB:
 ▸ 24% 9H vs 11.8% 4RH (p<0.0001)*
 ▸ 13.6% 4RH vs 11% 3RH (p=0.079)*
No clinical disease observed in either group
Dose:
9H (10 mg/kg/day)
4RH/3RH (R 10 mg/kg/day, H 10 mg/kg/day)
Li et al (2010)17Children and adults with LTBI (n=2530 <15 years)

Daily or twice-weekly 9H
(n=14030; 2430 (17%) <15 years) vs 6 Rifamycin (n=1005; 100 (10%) <15 years)
Retrospective cohort study (level 2b)Treatment completion

Drug AE
Aged <15 years: 1023/2430 (42.1%) 9H vs 55/100 (55.0%) 6R (p=0.01)‡

Treatment discontinuation due to AE:
 ▸ Age <15 years: 6.7% 6R vs 1.1% 9H (p<0.001)
 ▸ In all age groups: Of those who did not complete treatment the proportion with an AE was 5.8–6.8 times higher in 6R group than 9H group
70.5% in 9H group received DOT vs 85.7% 6R

Dose not specified
Bright-Thomas et al (2010)20Children (<16 years) with LTBI

Daily 3RH (n=252)
Retrospective cohort study (level 2b)Treatment compliance

Drug AE


Treatment efficacy
No significant non-compliance detected (non-compliance not defined)

Hepatitis: No significant cases requiring treatment discontinuation

Cases of active TB:
 ▸ 3/252 (1.2%) developed active TB
 ▸ 0.964/1000 person years (95% CI 0.0199 to 2.816)
82 patients lost to follow-up

Dose not specified
Sterling et al (2011)12Adults (≥12 years) (2001–2008) and children (2–11 years) (2005–2008) with a history of contact with culture-confirmed TB within 2 years of recruitment

Weekly rifapentine plus isoniazid for 3 months (rifapentine with DOT (n=3986) vs self-administered 9H (n=3745))
Prospective, open-label, randomised trial (level 1b)Treatment completion

Drug AE





Treatment efficacy
82.1% 3 months of rifapentine and isoniazid vs 69.0% 9H (p<0.001)

Hepatotoxicity: 2.7% 9H vs 0.4% 3RH (p<0.001)
Hypersensitivity: 3.8% 3RH vs 0.5% 9H (p<0.001)
No significant difference for grade 3 or 4 AE or risk of death
Permanent discontinuation due to AE: 4.9% 3RH vs 3.7% 9H (p=0.009)

Proportion of compliant patients who developed TB: 6/2682 (0.2%) 9H vs 5/3376 (0.1%) 3RH (p=0.49)*
3RH was non-inferior to 9H regimen (UL of the 95% CI of the difference <0.75%)
Unknown proportion of children included in the study

Dose:
3 months rifapentine plus H (rifapentine 900 mg with incremental adjustment for subjects weighing ≤50 kg, H 15–25 mg/kg/day)
9H (5–15 mg/kg/day)
  • *Calculated using data extracted from published paper.

  • †One patient developed TB lymphadenitis 1 year later.

  • ‡Calculated using data provided by the authors.

  • The number preceding the drug abbreviations denotes months, eg 9RH – 9 months of rifampicin and isoniazid.

  • AE, adverse effect; CXR, chest x-ray; DOT, directly observed therapy; GI, gastrointestinal; H, isoniazid, H2, twice weekly isoniazid; LFT, liver function test; LTBI, latent TB infection; MDR, multi-drug-resistant; PTB, pulmonary tuberculosis; R, rifampicin; R2, twice weekly rifampicin; TB, tuberculosis; TST, tuberculin skin test; UL, upper limit; Z, pyrazinamide; Z2, twice weekly pyrazinamide.