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Keywords:

  • tuberculosis;
  • child contacts;
  • preventive therapy;
  • policy–practice gap
  • tuberculose;
  • contacts de l’enfant;
  • traitement préventif;
  • lacune dans la pratique de politique
  • Tuberculosis: contactos: niños;
  • terapia preventiva;
  • brecha entre política y práctica

Abstract

  1. Top of page
  2. Abstract
  3. Introduction
  4. Search strategy and selection criteria
  5. Preventive therapy in children: benefits and safety
  6. Prioritising children for prophylactic treatment
  7. Barriers to IPT implementation in high-burden settings
  8. Overcoming the barriers
  9. Conclusion
  10. References

Young children living with a tuberculosis patient are at high risk of Mycobacterium tuberculosis infection and disease. WHO guidelines promote active screening and isoniazid (INH) preventive therapy (PT) for such children under 5 years, yet this well-established intervention is seldom used in endemic countries. We review the literature regarding barriers to implementation of PT and find that they are multifactorial, including difficulties in screening, poor adherence, fear of increasing INH resistance and poor acceptability among primary caregivers and healthcare workers. These barriers are largely resolvable, and proposed solutions such as the adoption of symptom-based screening and shorter drug regimens are discussed. Integrated multicomponent and site-specific solutions need to be developed and evaluated within a public health framework to overcome the policy–practice gap and provide functional PT programmes for children in endemic settings.

Les jeunes enfants vivant avec un patient tuberculeux sont à haut risque d’infection par Mycobacterium tuberculosis et de la maladie. Les directives de l’OMS recommandent le dépistage actif et le traitement préventif à l’isoniazide pour de tels enfants de moins de cinq ans, mais cette intervention bien établie est rarement utilisée dans les pays endémiques. Nous passons en revue la littérature concernant les obstacles à l’implémentation d’un traitement préventif et trouvons qu’ils sont multifactoriels, comprenant les difficultés en matière de dépistage, la faible adhésion, la crainte de l’augmentation de la résistance à l’isoniazide et la faible acceptabilité chez les principaux dispensateurs de soins et les agents de la santé. Ces obstacles peuvent en grande partie être résolus et les solutions proposées telles que l’adoption du dépistage basé sur les symptômes et des schémas thérapeutiques plus courts sont discutées. Les solutions intégrées multi-composantes et spécifiques au site doivent être développées et évaluées dans un cadre de santé publique pour surmonter le fossé entre politique et pratique et pour fournir des programmes fonctionnels de thérapie préventive pour les enfants dans les milieux endémiques.

Los niños que viven con enfermos de tuberculosis (TB) tienen un alto riesgo de contraer la infección por Mycobacterium tuberculosis y desarrollar la enfermedad. Las guías de la OMS promueven una búsqueda activa y una terapia preventiva con isoniazida en niños menores de cinco años en situación de riesgo, pero esta intervención rara vez se utiliza en países endémicos. Hemos revisado la literatura existente sobre las barreras para la implementación de la terapia preventiva y hemos encontrado que son multifactoriales, e incluyen las dificultades en el cribado, una mala adherencia, el miedo de aumentar la resistencia a la isoniazida y una mala aceptación por parte de los trabajadores sanitarios de los servicios primarios. Estas barreras son, en su mayoría, franqueables, por lo que se discuten propuestas con soluciones tales como la adopción de un cribado basado en síntomas y regímenes de medicación más cortos. Es necesario desarrollar soluciones integradas con componentes múltiples y específicos para cada emplazamiento, y evaluarlas dentro de un marco de sanidad pública que se sobreponga a la brecha entre la política y la práctica, con el fin de poder ofrecer programas funcionales de terapia preventiva para aquellos niños que viven en zonas endémicas.


Introduction

  1. Top of page
  2. Abstract
  3. Introduction
  4. Search strategy and selection criteria
  5. Preventive therapy in children: benefits and safety
  6. Prioritising children for prophylactic treatment
  7. Barriers to IPT implementation in high-burden settings
  8. Overcoming the barriers
  9. Conclusion
  10. References

It is estimated that around 10% of the world’s tuberculosis (TB) cases occur in children (0–14 years of age) (Nelson & Wells 2004). This may be much higher in endemic countries where the actual burden of TB disease in children is unclear because comprehensive surveillance data are not routinely reported (Rekha & Swaminathan 2007) Nevertheless, from epidemiological, clinical and autopsy data, it is evident that TB is a major cause of morbidity and mortality in children in high-burden countries, which is increasing with the dual TB/HIV epidemic (Chintu et al. 2002; Marais et al. 2007; Hesseling et al. 2009).

The recently revised WHO Stop TB Strategy recognises the need for a greater focus on children (WHO 2006b, 2010a), especially on those living with a TB case as they experience a high risk of TB infection and disease (Sinfield et al. 2006; Marais et al. 2009; Triasih et al. 2012). The childhood TB subgroup of the WHO Stop TB partnership has facilitated a number of important initiatives aimed at greater emphasis on childhood TB by National TB programmes (NTP) This includes screening children living with an infectious case followed by the provision of preventive therapy (PT) for those cleared of TB disease (WHO 2006a, 2010c). However, for a variety of reasons, these recommendations, including PT provision, are rarely fully implemented in high-burden countries. This is important, as a large proportion of childhood TB occurred in children younger than 5 years who would have been eligible for PT (Du Preez et al. 2011).

Search strategy and selection criteria

  1. Top of page
  2. Abstract
  3. Introduction
  4. Search strategy and selection criteria
  5. Preventive therapy in children: benefits and safety
  6. Prioritising children for prophylactic treatment
  7. Barriers to IPT implementation in high-burden settings
  8. Overcoming the barriers
  9. Conclusion
  10. References

References for this review were identified through searches of PubMed using the following terms individually or in combination ‘tuberculosis’, ‘childhood’, ‘child’, ‘infection’, ‘latent’, ‘disease’, ‘epidemiology’, ‘risk factors’, ‘preventive therapy’, ‘chemoprophylaxis’, ‘prophylaxis’, ‘isoniazid’ and ‘multi drug-resistance’. Guidelines for childhood tuberculosis developed by the WHO were reviewed. All articles and guidelines resulting from these searches and relevant references cited in those articles were reviewed. Articles included were not limited by date.

In this review, we discuss the potential of PT as a method to prevent childhood TB in high-burden countries, barriers to its implementation and possible solutions. We also highlight areas for further research.

Preventive therapy in children: benefits and safety

  1. Top of page
  2. Abstract
  3. Introduction
  4. Search strategy and selection criteria
  5. Preventive therapy in children: benefits and safety
  6. Prioritising children for prophylactic treatment
  7. Barriers to IPT implementation in high-burden settings
  8. Overcoming the barriers
  9. Conclusion
  10. References

Current strategies to reduce the burden of TB in children in endemic countries focus on the identification and treatment of infectious adult cases and Bacillus Calmette–Guerin (BCG) vaccination (Marais et al. 2009). These methods are insufficient to control childhood TB (Lawn et al. 2006). The need for child contact focused TB prevention measures are emphasised by a recent study from Guinea-Bissau that reported a 66% higher mortality among children exposed to TB at home than unexposed children from the same community (Gomes et al. 2011). PT, a well-established intervention that remains largely underutilised, presents an attractive option.

The benefits of PT have been recognised since the 1950s (Hsu 1956): PT reduces the risk of developing TB disease in infected individuals and reduces the reservoir of M. tuberculosis in the community (Landry & Menzies 2008). A decision analysis study based on data from sub-Saharan Africa suggested that 90% of TB disease could be avoided over a 10-year period if 30% of M. tuberculosis infection was successfully treated (Heymann 1993). Moreover, modelling studies indicate that to attain TB eradication by 2050, preventive measures must be included in TB programmes (Dye & Williams 2008). The most widely adopted PT regimen is isoniazid preventive therapy (IPT), daily isoniazid (INH) for at least 6 months. This regimen has been rigorously studied in large randomised-controlled trials (RCT) and long-term prospective observational studies that find high efficacy (>90% with good adherence) against progression to TB disease in infected adults, children and HIV-infected individuals (Hsu 1984; Bucher et al. 1999; Landry & Menzies 2008).

In general, IPT is safe and well tolerated by children and adolescents; major potential serious adverse events (SAE), including hepatotoxicity and pyridoxine deficiency, are rare in children (Donald 2010). An RCT of 926 children comparing regimens of PT reported no SAE, including in those who received 9 months of INH alone (Spyridis et al. 2007). Retrospective data from 564 children receiving IPT reported an incidence rate for hepatotoxicity of 0.18%, (Nakajo et al. 1989) while other studies involving over 2000 children receiving IPT reported no discontinuation of treatment owing to hepatotoxicity (Hsu 1984; Frydenberg & Graham 2009). Any increases in liver transaminase levels in children taking INH are mild, not requiring cessation of treatment (Spyridis et al. 1979). Clinical pyridoxine deficiency is also rarely seen in children (Mcilleron et al. 2009). IPT remains safe even when doses are increased from 5 to 10 mg/kg, as has been recently recommended (WHO 2010d).

A further benefit of IPT is cost effectiveness. A modelling study, focused on children from countries with high rates of INH resistance, showed that with a rate of disease progression of >9%, PT regimens including INH or rifampicin (RIF) singularly or in combination are more cost effective than no treatment (Finnell et al. 2009). Further studies in Europe, sub-Saharan Africa and Australia all conclude that screening and IPT are worthwhile public health interventions (Bell et al. 1999; Macintyre et al. 2000; Diel et al. 2005). These studies did not include children. However, owing to the relatively increased risk of disease progression in children, and the similar efficacy of IPT, it is expected that cost effectiveness would be even greater than in adults.

Prioritising children for prophylactic treatment

  1. Top of page
  2. Abstract
  3. Introduction
  4. Search strategy and selection criteria
  5. Preventive therapy in children: benefits and safety
  6. Prioritising children for prophylactic treatment
  7. Barriers to IPT implementation in high-burden settings
  8. Overcoming the barriers
  9. Conclusion
  10. References

The literature is consistent in describing factors associated with an increased risk of M. tuberculosis infection and disease in children and therefore identifies those who would benefit from PT. Studies have shown that children exposed to patients who are sputum positive and/or have extensive lung involvement are at high risk of infection. Children who sleep in close proximity to a source case and those whose source case is a female family member are also at increased risk, more than five times higher in some reports (Lockman et al. 1999; Kenyon et al. 2002; Lienhardt et al. 2003).

Following infection, infants and young children (<5 years) are at the highest risk of progression to disease. Review of the pre-chemotherapy literature shows that 40–50% of infected infants (0–11 months), 10–20% of children aged 1 year and 10% of children aged 2–4 years progress to disease (Marais et al. 2004). Further, HIV-infected children are at much higher risk (20-fold) of TB disease than uninfected children (Lockman et al. 1999; Hesseling et al. 2009) and have poorer health outcomes overall (Rekha & Swaminathan 2007). Malnutrition is also associated with an increased risk of disease development (Cegielski & Mcmurray 2004; Marais et al. 2009).

Barriers to IPT implementation in high-burden settings

  1. Top of page
  2. Abstract
  3. Introduction
  4. Search strategy and selection criteria
  5. Preventive therapy in children: benefits and safety
  6. Prioritising children for prophylactic treatment
  7. Barriers to IPT implementation in high-burden settings
  8. Overcoming the barriers
  9. Conclusion
  10. References

Barrier: Screening children for preventive therapy

Studies in developed and developing countries show that the most effective means of case identification is at the household contact level (Zachariah et al. 2003; Becerra et al. 2005). Screening allows for detection of those who are eligible for PT as well as early detection of active TB in household contacts of any age. Potential screening tools to differentiate between TB disease, TB infection and TB exposure are variably recommended and include clinical assessment, investigations for evidence of immune response to M. tuberculosis [tuberculin skin test (TST) or an interferon gamma release assay (IGRA)], and chest x-ray (Marais et al. 2009). These investigations have limitations: children who are TST or IGRA negative may still be infected and at risk of disease progression (Bergamini et al. 2009), while chest x-rays are variably interpreted even by experienced radiologists and very few radiological features are sensitive or specific for infection or disease (Marais et al. 2009).

Screening of child contacts is rarely carried out in high-burden settings. A lack of tuberculin and x-ray materials and equipment, lack of staff expertise to interpret diagnostic results, the need for a minimum of two appointments to complete screening, transport and time costs for the patients and their families and high healthcare worker (HCW) workload have all been identified as barriers to screening (Zachariah et al. 2003; Kruk et al. 2008). Owing to these and other factors, high-burden countries have reported extremely poor compliance with screening and initiation of IPT. In Thailand, screening compliance was only 52% (Tornee et al. 2005). In Malawi, only 21% of adult sputum-positive cases with young children were informed about the need to screen their children, and only 9% of 365 children were actually screened for TB (Claessens et al. 2002). In another Malawian study, of actively screened child contacts, 39% of children came to the hospital for screening, of which only 40% (16% of total) returned for screening results or medication (Zachariah et al. 2003). The need for chest x-rays as part of screening was identified as an important barrier. A further Malawian study found that, despite the provision of clear information to sputum smear–positive TB cases in the local language and using illustrations, only 8% of child case contacts were brought for screening (Nyirenda et al. 2006).

Barrier: Adherence to prophylactic treatment

Poor adherence is an important barrier to PT programmes; non-adherence may decrease treatment effectiveness by 50–80% (American Thoracic Society and Center for Disease Control 2000). Current recommendations for IPT duration are for 6 or 9 months, with large trials showing 9 months of treatment to be most beneficial when considering adherence rates (Landry & Menzies 2008). However, acceptable adherence (over 80% of all medication taken) (le Roux et al. 2009) is rarely achieved, and reported rates range from 20% to 60% (Alperstein et al. 1998; Marais et al. 2006b; Van Zyl et al. 2006). Factors associated with poor adherence include transportation costs, very young age (<1 year), living in large households, treatment duration, culture, and knowledge and attitudes towards TB disease and PT (Alperstein et al. 1998; Marais et al. 2006b; le Roux et al. 2009).

Barrier: Drug resistance and preventive therapy

Implementation of PT programmes often face resistance from HCWs owing to concern over the development of primary resistance if patients with TB disease are given PT (Tornee et al. 2005). There is no evidence of an increased risk of primary resistance with the use of IPT in adults (Balcells et al. 2006). In children, the risk of primary resistance is likely to be negligible: children tend to develop paucibacilliary disease, with bacterial loads of between 104 and 105, reducing the chance of resistant organisms (Marais et al. 2009; Schaaf & Marais 2011).

For child contacts of Multidrug resistant (MDR)-TB patients, evidence-based guidelines for PT regimens are lacking (Schaaf & Marais 2011). Current WHO guidelines do not recommend the use of second-line anti-TB drugs for children in contact with MDR-TB patients; instead, they recommend that children <5 years of age be closely followed for a minimum of 2 years and initiated on appropriate TB treatment if necessary (WHO 2006b). The literature indicates that standard PT regimens are inadequate to prevent progression to disease, and regimens need to be tailored to the susceptibility profile of the source case (Schaaf et al. 2002; Sneag et al. 2007; Tochon et al. 2011). However, this approach requires drug sensitivity testing (DST) which is often unavailable, especially in high-burden low-resource countries.

Barrier: Primary caregiver acceptability

Qualitative research suggests that poor primary caregiver (PCG) acceptability of PT is associated with low-risk perception of TB disease, the influence of friends, lack of knowledge regarding the purpose of PT (and TB disease in general) and poor health service accessibility (Carey et al. 1997; Alperstein et al. 1998; Tornee et al. 2005; Marais et al. 2006b). It has also been suggested that the importance of ongoing treatment of a healthy child is difficult to emphasise to PCGs; one study found 31% of PCGs did not believe their doctors when they were told that treatment was necessary (Alperstein et al. 1998).

Barrier: Healthcare worker acceptability

Research has shown surprisingly low levels of acceptability and knowledge of PT in HCWs. In Australia, 17% of PCGs were told by their doctors not to give PT to their children (Alperstein et al. 1998), while in India, in a setting where PT had been emphasised, only 27% of cases were told of the need to screen and treat their child contacts by a HCW (Banu Rekha et al. 2009). In America, international medical graduates were significantly less likely to prescribe PT to a recent converter and to believe that PT was protective against TB disease compared to American medical graduates (Hirsch-Moverman et al. 2006). In South Africa, it was found that HCWs lacked knowledge and experience of IPT (Lester et al. 2010). Qualitative investigation gives further insight. Indian HCWs claimed poor guidelines and system difficulties made PT programmes hard to implement, and fear of being blamed for causing unnecessary adverse events in children was also mentioned (Banu Rekha et al. 2009). Thai doctors cited fears of adverse events and expressed concern over an increase in resistance to INH and a lack of resources to conduct proper screening (Tornee et al. 2005).

Overcoming the barriers

  1. Top of page
  2. Abstract
  3. Introduction
  4. Search strategy and selection criteria
  5. Preventive therapy in children: benefits and safety
  6. Prioritising children for prophylactic treatment
  7. Barriers to IPT implementation in high-burden settings
  8. Overcoming the barriers
  9. Conclusion
  10. References

Screening – possible solutions: symptom-based screening

Recognition of barriers associated with screening in high-burden countries, especially a lack of tuberculin and chest x-ray materials at healthcare facilities, led to the adoption of a symptom-based screening approach by the WHO (Kruk et al. 2008). This approach is based on initial screening of children for TB-associated symptoms; asymptomatic children are directly eligible for IPT, while symptomatic children require further investigation to rule out TB disease before IPT can be initiated (Figure 1) (WHO 2006a). Symptom-based screening negates the need for the TST, instead adopting contact with an infectious case as a proxy for infection. This is reasonable: child case contact studies show high rates of infection in this population group (Kruk et al. 2008; Rutherford et al. 2012; Triasih et al. 2012); negative TST results do not rule out infection (Bergamini et al. 2009); and the time to TST conversion means that a repeat test is recommended in TST-negative children (National Tuberculosis Controllers Association 2005). This places more pressure on resources, families and HCWs (Kruk et al. 2008).

image

Figure 1.  WHO algorithm for symptom-based screening (WHO 2006a). The original WHO guidelines recommended isoniazid 5 mg/kg daily (WHO 2006a). This has since been revised to 10 mg/kg daily for 6 months for children (WHO 2010c).

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Evidence from South Africa suggests that symptom-based screening is safe (Marais et al. 2006a; Kruk et al. 2008). Investigation of 252 actively screened child case contacts revealed 33 children with disease of whom 25 had symptoms (Kruk et al. 2008). The remaining eight asymptomatic children presented with hilar adenopathy only. In a further study, investigation of signs and symptoms associated with TB disease in children found that 20 of 81 children diagnosed with TB disease by chest x-ray were asymptomatic, and chest x-ray findings of the asymptomatic cases showed evidence of primary complex only (Marais et al. 2006a). These studies show that symptom-based screening would miss some children with primary lung involvement on chest x-ray. However, pre-chemotherapeutic literature suggests that transient, asymptomatic hilar adenopathy is a component of the primary complex and rarely leads to disease development, being more indicative of recent infection and low bacterial load (Marais et al. 2004, 2009). Further, very few cases of TB disease developed (5 from 1394 – 0.36%) in a large trial in the 1950s, where children with evidence of hilar adenopathy or paratracheal involvement were treated with 12 months of INH only (Ferebee et al. 1957). As countries begin to update their National TB guidelines, many are switching to symptom-based screening for child contacts, especially in Africa (S. Graham, Personal communication) More research on the acceptability and utility of symptom-based screening is required.

The recent emphasis of IPT for HIV-infected patients has led to considerable research in screening methods that may provide relevant insights into child contact screening issues (Bassett et al. 2010; Cain et al. 2010). Like children, HIV-infected patients are at high risk of disease progression. Further, problems associated with the accuracy of diagnosis and acceptability of screening and IPT provision are seen in both populations (Cain et al. 2010; Lester et al. 2010). Large, multisite studies using culture as a gold standard have found combinations of symptoms alone to have satisfactory sensitivity for selecting those HIV-infected patients who can be placed directly on IPT (Cain et al. 2010). More recent studies have consolidated these findings (Getahun et al. 2011; Gupta et al. 2011) and have also found symptom-based screening to reduce TB cases and TB-related deaths and to be more cost effective than screening approaches that include a chest x-ray (Samandari et al. 2011). Indeed, symptom-based screening is now the recommended WHO policy for HIV-infected patients (WHO 2010b). Similar prospective studies are urgently needed in children.

Symptom-based screening allows for screening to be conducted in peripheral health clinics instead of hospitals or specialised clinics. This reduces the transport and time costs experienced by the child’s PCG by creating a single-day screening algorithm. It also eliminates the need for expensive healthcare resources and staff expertise that are often not available in low-income countries. Adoption of this approach could significantly improve the feasibility of PT in resource-limited countries. This can be illustrated with an example from Malawi. In 1998, there were 9462 cases of sputum smear–positive TB treated in Malawi (Harries et al. 2002). Assuming the national average of 0.78 children <5 years of age per household, 7380 children would be eligible for IPT or TB treatment in 1 year. Under the current system, these would be assessed and followed up at the district hospital level – meaning each hospital in Malawi would need to screen approximately 300 children per year. However, using the symptom-based screening approach, the process could be decentralised to the peripheral health centre level, and each centre would only need to screen 14 children per year. Depending on the TB prevalence in their catchment areas, this number may be higher.

Adherence – possible solution: alternative drug regimens

Rifampicin and pyrazinamide (PZA) have been suggested to decrease the duration of PT and improve adherence (Mitchison 2000). Current evidence supports the use of shorter drug regimens, showing them to be as safe and efficacious as INH-based regimens, with the exception of PZA (Table 1). Regimens that include PZA show unacceptably high rates of hepatotoxicity in non-HIV-infected adults but may not necessarily pose a problem for children. Studies in children taking PZA for 2 months as part of regimens for TB disease have reported very low rates of SAE (Biddulph 1990; Padmini et al. 1993; Donald 2010). Further, a study including 423 immigrants found PZA-associated hepatotoxicity to be correlated with age: the odds of hepatotoxicity rising by 1.07 times per year of age increase (Priest et al. 2004), and a study investigating PT found drug-associated hepatitis increased significantly with age, from <1% in those aged 0–19 years to 5% in those aged 60 years or more (Ormerod & Horsfield 1996).

Table 1.   Evidence for the efficacy and safety of alternative prophylactic drug regimens
ReferencesStudy populationRegimenEfficacySide effects
  1. R, rifampicin; H, isoniazid; Z, pyrazinamide; P, rifapentine: RCT, randomised-controlled trials; TB, tuberculosis; AE, Adverse events; RD, Risk difference; RR, Relative risk.

Sterling et al. (2011) Open-label, randomised non-inferiority trial United States, Canada, Brazil, Spain N = 77313PH weekly vs. 9H daily3PH weekly was non-inferior to 9H daily for TB disease development (cumulative proportion of TB disease in 3PH group; 0.19%, cumulative proportion of TB disease in 9H group; 0.43%)Rates of treatment discontinuation owing to AE were significantly higher in 3PH weekly group (4.9%vs. 3.7%P = 0.009) Rates of investigator assessed drug-induced hepatotoxicity were significantly lower in the 3PH group (0.4%vs. 2.7%P ≤ 0.01)
Bright-Thomas et al. (2010) Cohort United Kingdom 334 children aged <16 years3RH0.96 cases of active TB/1000 person yearsNo adverse events
Spyridis et al. (2007) RCT Greece 926 children <15 years9H vs. 4RH or 3RHNo TB disease in any group.No adverse events
Cook et al. (2006) Non-randomised observational study America 459 adults and children2RZ daily or twice weekly or 4–6R daily vs. 9HNot reportedNo difference in severe heptatoxicity between short and long course groups (6.1%vs. 2.0%; P = 0.09)
Gao et al. (2006) Meta-analysis 6 trials N = 40532–3RZ vs. 6–12HNo difference in TB disease (HIV-infected patients’ pooled risk difference, 0%; 95% CI, −1–2 and HIV non-infected patients’ pooled risk difference, 0%; 95% CI, −2–1)AE in 2RZ significantly higher in HIV non-infected patients (2RZ RD, 29%; 95% CI, 13–46 and 6H RD, 7%; 95% CI, 4–10) No difference in AE for HIV-infected patients
Ena and Valls (2005) Meta-analysis 5 trials 1926 adults3RH vs. 6–12HNo difference in TB disease (pooled risk difference = 0% 95% CI, −1–2%)No difference in AE (pooled risk difference, −1%; 95% CI, −4–2%)
McElroy et al. (2005) Cross-sectional survey 8087 patients2ZNot reportedHigh liver transaminases in 25.6% Hepatitis in 18.7% 7 deaths 23 hospitalisations
Priest et al. (2004) Cohort America 423 adults2RZ twice weeklyNot reportedHepatotoxicity in 6.9% levels of liver transaminases >10 times the upper normal limit in 4.3% 2 hospitalisations
Whalen et al. (1997) RCT Uganda 2736 HIV-infected adultsPlacebo vs. 6H, 3RH, 3RHZTB disease Incidence lower in intervention groups compared with placebo. 6H (RR, 0.33; 95% CI, 0.14–0.77) 3RH (RR, 0.40; 95% CI, 0.18–0.86) 3RHZ (RR, 0.51; 95% CI, 0.24–1.08) No difference in efficacy between the 3 interventionsHigher AE in intervention groups compared to placebo (5% placebo, 11% H, 10% HR and 25% HRZ) Only serious adverse events in 3HRZ
Magdorf et al. (1994) Pilot RCT Germany 150 children2RZ vs. 4R, vs. 6HTB disease in one child, 2RZ group5 developed AE. 3 in 6H and 1 each in 4R and 2RZ

Evidence from numerous studies shows that shorter PT regimens increase adherence. A study from South Africa found that children prescribed RIF and INH for 3 months were much more likely to be adherent compared to children prescribed INH for 6 months (Odds ratio, 4.27; 95% CI, 2.40–10.36) (Van Zyl et al. 2006), while an RCT of 926 children found significantly better adherence to 4 months of RIF and INH when compared to 9 months of INH only (Spyridis et al. 2007). Another RCT conducted in three sites among 802 patients reported that those taking RIF for 4 months were more likely to complete treatment compared to those randomised to INH for 9 months (Relative risk, 4.3; 95% CI, 2.7–6.8) (Trajman et al. 2010). Use of another rifamycin, rifapentine, may also help improve adherence. In a recent trial, once-weekly rifapentine plus INH for 3 months was as effective as daily INH for 9 months and had a higher treatment completion rate (Sterling et al. 2011). Alternative PT regimens may also allow for easier procurement of medication, especially in resource-limited settings: the Global Drug Facility provides easily accessible rifapentine suitable for PT (WHO 2012).

Other methods to increase adherence levels have shown promise. Supervised PT in South African children significantly increased adherence levels (Odds ratio, 4.43; 95% CI, 1.47–13.72) (Van Zyl et al. 2006). In the UK, a shorter regimen (3 months of RIF and INH vs. 6 months of INH) was associated with increased adherence, with those able to choose their preferred regimen being less likely to default treatment (Odds ratio, 0.43; 95% CI, 0.3–0.6) (Rennie et al. 2007). In the USA, the use of special child targeted calendars to record treatment compliance and a reward at the end of each completed month increased adherence significantly (Cass et al. 2005). Finally, adherence to treatment increased by 34% in a study which adopted home visits by a specialised nurse to educate and encourage mothers to continue the treatment for their children (Salleras Sanmarti et al. 1993).

Acceptability of healthcare workers and primary caregivers

Investigations regarding interventions to increase the acceptability of PT by PCGs and HCWs are lacking. It is clear that new innovative thinking to develop interventions is required. Possibilities include education and continued support. These were shown to be effective for increasing adherence of INH in American children, and it is likely that they also affected parental acceptability (although this was not reported) (Salleras Sanmarti et al. 1993). Educational programmes have also shown success in increasing PCG and HCW acceptability in other preventive activities (Horwood et al. 2010). Site-specific research to identify levels of acceptability and reasons for non-compliance to prescribing medication by HCW and administering medication by PCG is needed.

Further research: site-specific investigations and interventions

Important questions remain regarding evidence-based guidelines for PT in children including: management of child contacts of MDR-TB patients; the optimal duration of PT for children at high risk of progression to disease living in settings where the risk of reinfection is high; and effectiveness and tolerability of novel, short-duration PT regimens. However, the major challenge continues to be the implementation of guidelines, whether current or revised versions in the future, so that an intervention with proven efficacy will also have established effectiveness. The development of successful PT programmes may require site-specific investigations (Table 2). We suggest the adoption of a comprehensive public health framework that identifies all gaps between WHO recommendations for child case contact management and current onsite practice at TB clinics (Hill et al. 2011). Interventions based on findings can then be developed and assessed for impact and cost effectiveness. Policy based on outputs from focused research will enable effective, achievable PT programmes to be established in high- burden settings.

Table 2.   Summary of barriers and possible solutions and research to improve the performance of prophylactic treatment programmes
BarriersPossible solutions
Little emphasis placed on childhood tuberculosis (TB)National TB programmes to prioritise child TB activities
High burden of screening and preventive therapy (PT) in endemic settingsFocus screening and PT to the highest risk groups, for example, children <3 years and HIV-infected children in contact with a sputum smear–positive case
Screening is burdensome on resources in endemic settingsEvaluate the safety and acceptability of symptom-based screening
Poor adherence to screening by primary caregiver (PCG)Conduct site-specific investigation of barriers to screening adherence by PCGs
Long duration of PTAdopt short treatment regimens shown to be safe in children
Poor acceptability of PT by healthcare worker (HCW)Conduct site-specific investigation of barriers to PT acceptability by HCWs
Poor acceptability of PT by PCGsConduct site-specific investigation of barriers to PT acceptability by PCGs

Conclusion

  1. Top of page
  2. Abstract
  3. Introduction
  4. Search strategy and selection criteria
  5. Preventive therapy in children: benefits and safety
  6. Prioritising children for prophylactic treatment
  7. Barriers to IPT implementation in high-burden settings
  8. Overcoming the barriers
  9. Conclusion
  10. References

Screening, management and implementation of PT programmes for child TB contacts have great potential to reduce TB incidence and TB-related mortality in young children. PT is a proven and effective intervention but it is rarely implemented in high-burden settings. Review of the literature highlights that while barriers to effective screening and PT programmes are multifactorial, they are also largely resolvable. The potential of a symptom-based screening approach and of alternative PT regimens should be considered by NTP. Site-specific policy–practice gaps need to be evaluated within a public health framework, and novel approaches to overcome poor adherence and acceptability require development, implementation and evaluation.

References

  1. Top of page
  2. Abstract
  3. Introduction
  4. Search strategy and selection criteria
  5. Preventive therapy in children: benefits and safety
  6. Prioritising children for prophylactic treatment
  7. Barriers to IPT implementation in high-burden settings
  8. Overcoming the barriers
  9. Conclusion
  10. References
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