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Keywords:

  • tuberculosis;
  • co-morbidity;
  • HIV;
  • malnutrition;
  • first-line drugs;
  • literature review
  • tuberculose;
  • co-morbidité;
  • VIH;
  • malnutrition;
  • médicaments de première ligne;
  • revue de la littérature
  • Tuberculosis;
  • co-morbilidad;
  • VIH;
  • desnutrición;
  • medicamentos primera línea de tratamiento;
  • revisión literaria

Summary

  1. Top of page
  2. Summary
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. References

Objective  To determine the frequency and manifestations of adverse events associated with recommended first-line anti-TB drugs in children.

Method  Literature review.

Results  Overall, children tolerate anti-TB drugs very well when using currently recommended dosages. Serious adverse events are rare and even mild symptoms such as nausea or vomiting are uncommon. There are occasional case reports of severe hepatotoxicity.

Conclusions  Surveillance and reporting of adverse events will need to be improved when recommended dosages of the main first-line anti-TB therapy for children are increased. Co-morbidities such as HIV infection and severe malnutrition may affect the incidence and complicate the management of possible adverse events to anti-TB therapy.

Objectif:  Déterminer la fréquence et les manifestations des événements indésirables associés aux antituberculeux de première ligne recommandés chez les enfants.

Méthode:  Revue de la littérature.

Résultats:  En général, les enfants tolèrent très bien les médicaments anti-TB lors de l’utilisation des doses recommandées actuellement. Les effets indésirables graves sont rares et même des symptômes bénins tels que nausées ou vomissements sont rares. Il existe quelques reports de cas d’hépatotoxicité sévères.

Conclusions:  La surveillance et la notification des événements indésirables devraient être améliorées si les doses recommandées des principaux anti-TB de première ligne pour les enfants devraient être augmentées. Des co-morbidités telles que l’infection VIH et la malnutrition sévère pourraient influer sur l’incidence et compliquer la prise en charge des effets indésirables possibles dans la thérapie anti-TB.

Objetivos:  Determinar la frecuencia y manifestaciones de los efectos adversos asociados a los medicamentos recomendados como primera línea de tratamiento para TB en niños.

Método:  Revisión literaria.

Resultados:  En general, los niños toleran los medicamentos anti-TB muy bien cuando se utilizan las dosis actualmente recomendadas. Los eventos adversos serios son raros e incluso los síntomas leves como las nauseas o vómitos son poco comunes. Hay reportes ocasionales de hepatotoxicidad severa.

Conclusiones: Es necesario mejorar la vigilancia y el reporte de eventos adversos si se aumentasen las dosis recomendadas de las terapias anti-TB de primera línea para niños. La co-morbilidad de otras patologías tales como la infección por VIH o la desnutrición severa podrían afectar la incidencia y complicar el manejo de posibles eventos adversos de la terapia antituberculosa.


Introduction

  1. Top of page
  2. Summary
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. References

An estimated 1 million children develop tuberculosis (TB) worldwide each year but difficulties with confirming diagnosis and previous poor surveillance in high-burden countries means that it is difficult to know the true burden. Childhood TB has not been regarded as important within the global TB control strategy, because most cases are not infectious, but this view is changing. Childhood TB is increasingly recognized as an important cause of morbidity and mortality, and as an important sentinel event indicating ongoing transmission in the community. The World Health Organization (WHO) has now published guidelines for the management of childhood TB and directed National TB Control Programmes to routinely report child TB data and outcomes (World Health Organization 2006a,b).

There are some data from TB-endemic countries where children represent 10% to more than 30% of the total caseload being treated for TB (van et al. 1999; Harries et al. 2002; Nelson & Wells 2004; Oeltmann et al. 2008). The numbers of children receiving TB treatment has increased markedly in HIV-endemic communities (Harries et al. 1997). The majority of children being treated for TB in the world live in resource-limited TB endemic countries where surveillance and reporting of adverse reactions to anti-TB therapy are poor or non-existent, and co morbidities such as malnutrition and HIV infection are common. This adds emphasis to the important issue that recommended dosages of anti-TB therapy for children must be safe and well tolerated.

Data from resource-limited settings suggest that treatment adherence is poor in children (van et al. 1999; Harries et al. 2002; Oeltmann et al. 2008). Adverse reactions to anti-TB drugs could potentially cause significant morbidity as well as adversely affect treatment adherence and outcomes (Oeltmann et al. 2008; Tostmann et al. 2008) and management of TB in HIV-infected children is complicated by the addition of other medications with potential toxicities. Finally, recommended drug dosages for children are currently under review and may be increased for isoniazid (INH), rifampicin (RMP) and pyrazinamide (PZA), as they were recently for ethambutol (EMB) (Donald et al. 2006; World Health Organization 2006c; Hill et al. 2008). We aimed to review the frequency and manifestations of toxicities in children to currently recommended first-line anti-TB therapy.

Methods

  1. Top of page
  2. Summary
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. References

Articles were identified through Pub Med by use of the ‘Clinical Queries’ framework. The search strategy employed was as follows: (antitubercul* agents OR tuberculosis OR rifampicin OR isoniazid OR pyrazinamide OR ethambutol OR streptomycin and (adverse drug reaction OR adverse effect OR side effect OR poisoning OR toxicity). The search was initially limited to English language and humans and ‘all child (0–18 years)’ and then expanded to all ages. Search was limited initially to review article OR randomized controlled trial. A similar strategy was adopted to search EMBASE databases and the Cochrane Library Reference. Reference lists were hand searched and relevant articles that provided specific data from children of tolerance or drug-related adverse events were retrieved. Case reports or series describing adverse reactions in children were not included if they did not also provide background information that allowed estimation of the prevalence of the event among a larger study population of children receiving anti-TB treatment.

Recommended drug dosages for children

Table 1 lists doses of first-line anti-TB drugs and Table 2 lists treatment regimens for children as currently recommended by WHO. Recommended dosages of INH, RIF and PZA are currently being reviewed (Hill et al. 2008). Recommendations for EMB are as per recent review and revision (Donald et al. 2006; World Health Organization 2006c). WHO guidelines no longer recommend the use of thiacetazone.

Table 1.   Recommended doses of first-line anti-TB drugs for children until 2008
DrugRecommended dose
DailyThree times weekly
Dose and range (mg/kg body weight)Maximum (mg)Dose and range (mg/kg body weight)Daily maximum (mg)
  1. Source: Guidance for national tuberculosis programmes on the management of tuberculosis in children (World Health Organization 2006a). N.B. Recommended dosages for isoniazid, rifampicin and pyrazinamide were increased in 2009.

  2. †The recommended daily dose of ethambutol is higher in children (20 mg/kg) than in adults (15 mg/kg), because the pharmacokinetics are different. Although ethambutol was frequently omitted from treatment regimens for children in the past, due in part to concerns about the difficulty of monitoring for toxicity (particularly for optic neuritis) in young children, a literature review indicates that it is safe in children at a dose of 20 mg/kg (range 15–25 mg/kg) daily (Donald et al. 2006).

Isoniazid5 (4–6)30010 (8–12)
Rifampicin10 (8–12)60010 (8–12)600
Pyrazinamide25 (20–30)35 (30–40)
EthambutolChildren 20 (15–25)†30 (25–35)
Adults 15 (15–20)
Streptomycin15 (12–18)15 (12–18)
Table 2.   Recommended treatment regimens for children in each TB diagnostic category
TB diagnostic categoryTB casesRegimen†
Intensive phaseContinuation phase
  1. E, ethambutol; H, isoniazid; R, rifampicin; S, streptomycin; Z, pyrazinamide.

  2. †Direct observation of drug administration is recommended during the initial phase of treatment and whenever the continuation phase contains rifampicin.

  3. ‡In comparison with the treatment regimen for patients in diagnostic category I, ethambutol may be omitted during the initial phase of treatment for patients with non-cavitary, smear-negative pulmonary TB who are known to be HIV-negative, patients known to be infected with fully drug-susceptible bacilli and young children with primary TB.

  4. §This regimen (2HRZE/6HE) may be associated with a higher rate of treatment failure and relapse compared with the 6-month regimen with rifampicin in the continuation phase.

  5. ¶In comparison with the treatment regimen for patients in diagnostic category I, streptomycin replaces ethambutol in the treatment of TB meningitis.

IIINew smear-negative pulmonary TB (other than in category I)2HRZ‡4HR or 6HE
Less severe forms of extrapulmonary TB
INew smear-positive Pulmonary TB2HRZE4HR or 6HE§
New smear-negative pulmonary TB with extensive parenchymal involvement
Severe forms of extrapulmonary TB (other than TB meningitis see below)
Severe concomitant HIV disease
ITB meningitis2RHZS¶4RH
IIPreviously treated smear-positive pulmonary TB2HRZES/1HRZE5HRE
 Release
 Treatment after interruption
 Treatment failure

Co-factors and toxicity

Studies of anti-TB drugs among large populations that include mainly adults but also children consistently report that advancing age is associated with higher rates of toxicity (Kopanoff et al. 1978; Reed & Blumer 1983; Ormerod & Horsfield 1996; Nolan et al. 1999; Tostmann et al. 2008). This review focuses mainly on reports from children, presenting some data from adults as examples to illustrate this contrast. Other important factors that potentially influence likelihood of toxicity to an anti-TB drug are dosage, duration of therapy, daily or intermittent regimen, concurrent use of other drugs including anti-TB drugs, presence of TB disease, severity of TB disease, and co-morbidities such as HIV infection or liver disease. This information is included wherever possible in the presentation of the data.

Results

  1. Top of page
  2. Summary
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. References

Isoniazid

There are two major adverse reactions to INH: neurologic and hepatic. Both are rare in children. The level of INH at any given dosage in children and adults depends on whether the patient is a fast, intermediate or slow acetylator. This is determined by the N-acetyltransferase 2 genotype which differs between ethnic groups (Schaaf et al. 2005; Kubota et al. 2007; Possuelo et al. 2008). Slow acetylator status has been associated with more adverse reactions to INH (Parthasarathy et al. 1986; Possuelo et al. 2008; Tostmann et al. 2008).

Hepatitis is the most serious adverse reaction and there are occasional case reports of severe INH-induced hepatitis and hepatic failure in children receiving doses of less than 10 mg/kg (Palusci et al. 1995; Lobato et al. 2008). Subclinical, asymptomatic transient transaminase elevation in the first few months of chemoprophylaxis is observed in 5–10% of children receiving INH, the highest rates being reported in adolescents (Beaudry et al. 1974; Litt et al. 1976; Rapp et al. 1978; Spyridis et al. 1979; Magdorf et al. 1994). One study reported transient transaminase elevation as more common in those receiving 9 months (6%) than in those receiving 3–4 months of prophylaxis (1.2%) (Spyridis et al. 1979). In contrast, symptomatic hepatotoxicity resulting in discontinuation of therapy is very uncommon in children. Jaundice was reported in one child and discontinuation of therapy in two of a total of 1 451 children from four studies using INH prophylaxis at 10 mg/kg (Beaudry et al. 1974; Nakajo et al. 1989; Palusci et al. 1995; Spyridis et al. 2007). Similarly, large studies involving over 2 000 children receiving 10–20 mg/kg INH prophylaxis did not report a single case of discontinuation due to hepatotoxicity (Rapp et al. 1978; Dash et al. 1980; Hsu 1984). These reports on INH hepatotoxicity were all from low TB-endemic, resource-rich settings.

INH competes with vitamin B6 (pyridoxine) in its action as a cofactor in the synthesis of synaptic neurotransmitters. Resulting dose-related neurologic side effects include peripheral neuropathy, ataxia and paresthesia. Children receiving INH are less susceptible to developing pyridoxine deficiency or peripheral neuritis than adults, even at doses up to 20 mg/kg (Morales & Lincoln 1957; Robson & Sullivan 1963). A study in children in USA found 13% to be vitamin B6 deficient on assay with a higher incidence in those receiving more than 10 mg/kg daily, but none had clinical features of pyridoxine deficiency (Pellock et al. 1985). Similarly, no cases of clinical pyridoxine deficiency were identified in studies of children in Zaire and South Africa receiving 3–15 mg/kg daily (Mbala et al. 1998; McIlleron et al. 2009). In contrast to these data in children, clinical vitamin B6 deficiency was reported in 2% of adults receiving low-dose (3–5 mg/kg) INH therapy daily and in 10% or more of those receiving around 20 mg/kg daily (Pellock et al. 1985). Pyridoxine supplementation with INH therapy is not routinely recommended for children but is recommended for those with nutritional deficiencies such as severely malnourished or HIV-infected children (World Health Organization 2006a).

INH is used in combination with RMP as chemoprophylaxis and it may be difficult to know which drug is responsible for an adverse event. Experience with the combination is largely in low TB-endemic settings and there are a number of reports from Western Europe. A prospective, randomized, controlled study of treatment of latent TB in children over an 11-year period detected no serious drug related adverse effects (Spyridis et al. 2007). Of 232 patients that received INH for 9 months, 6.5% developed nausea/epigastric pain and 6% had transient transaminase elevation. Of 650 patients who received INH (10 mg/kg) and RMP (10 mg/kg) for 3–4 months, 1.2% had transient increase in liver enzymes, 0.7% experienced nausea/epigastric pain, 1.3% had transient macular/papular rash and 0.7% had photosensitivity. The same combination regimen was used for 3–9 months in two studies including a total of 605 children and was well tolerated (Ormerod 1987, 1998).Discontinuation or modification of treatment was not required in any patient enrolled in these studies.

Rifampicin

Rifampicin (RMP) given in currently recommended doses is well tolerated. The most serious adverse events are allergic or hepatotoxic. Allergic reactions include fever, rash, flu-like syndrome, eosinophilia and much less often haemolytic anaemia, haemoglobinuria and kidney damage with acute renal insufficiency. They are largely described in adults, and are more commonly observed with intermittent, high-dose administration and with increasing age (Reed & Blumer 1983; Brasil et al. 1996).

There are limited data on rates of hepatotoxicity in children using RMP alone. No adverse events were reported in a study of 25 German children that received RMP alone as chemoprophylaxis (Magdorf et al. 1994). RMP (10 mg/kg) was used alone as chemoprophylaxis in 157 adolescents in USA who had been in contact with a case of isoniazid-resistant TB (Villarino et al. 1997). All remained asymptomatic although RMP was discontinued in one adolescent because of a rise in transaminase levels.

As chemoprophylaxis, RMP is mainly used in combination with INH as reported in the previous section on INH (Ormerod 1987, 1998; Spyridis et al. 2007).

Most reports of RMP is when used with other drugs for TB disease. A retrospective review of rates of hepatotoxicity in children in the USA reported that 14 (3.3%) of 430 children receiving INH and RMP as TB treatment had a hepatotoxic reaction (O’Brien et al. 1983). Large, prospective studies of children receiving INH, RMP and PZA for at least 2 months in the intensive phase report a very low incidence of any adverse events including hepatotoxicity (Kopanoff et al. 1978; Biddulph 1990; Hussein 1990; Tsakalidis et al. 1992; Padmini et al. 1993; Te Water Naude et al. 2000; Al-Dossary et al. 2002; Swaminathan et al. 2005). These studies represent a variety of settings including high TB-endemic, resource-limited settings and are reported in more detail in the following section on treatment trials.

Pyrazinamide

Pyrazinamide (PZA) is most commonly used in combination with other agents in the first two months of therapy for active TB disease. The most clinically significant adverse events associated with PZA are hepatotoxicity, gastrointestinal intolerance, non-gouty polyarthralgia and gouty arthritis. However, these reflect findings from studies in adults. The incidence of toxicity in British Medical Research Council trials was low: 3 (0.2%) of 1 845 patients in East and Central Africa, 13 (0.6%) of 2 219 patients in Hong Kong and 11 (2.8%) of 397 patients in Singapore (Girling 1984). Hepatotoxicity in adults is related to dosage and duration of treatment (Tostmann et al. 2008). There are few data on tolerance and adverse effects of PZA alone in children.

Use of PZA in 86 children as part of combination chemoprophylaxis with RMP for 2 months was well tolerated with no hepatotoxicity reported (Magdorf et al. 1994; Tortajada et al. 2005). Hepatic enzyme abnormalities were infrequent and transient in the first month in children receiving PZA as part of TB treatment (le Bourgeois et al. 1989; Sanchez-Albisua et al. 1997; Corrigan & Paton 1999). A slight increase in serum concentration of uric acid has been reported in a number of studies (le Bourgeois et al. 1989; Tsakalidis et al. 1992; Sanchez-Albisua et al. 1997). This may be accompanied by clinical manifestations of gouty arthritis in adults but this has not been reported in children.

Ethambutol

Usage of EMB in young children increased in TB endemic countries when EMB was introduced to replace thiacetazone, which commonly caused severe, often fatal Stevens–Johnson reactions in HIV-infected adults and children (Nunn et al. 1991; Chintu et al. 1993). At the time, this caused concern about using EMB in children too young to report early symptoms of optic neuritis and resulted in a number of literature reviews of efficacy and toxicity of EMB (Trebucq 1997; Graham et al. 1998). WHO now supports the use of EMB in infants and young children and recently revised the recommended dosages following careful review (World Health Organization 2006c).

The most serious toxic effect of EMB is retrobulbar neuritis, which is reversible if detected early. Because the neuritis is retrobulbar, the fundus appears normal on opthalmoloscopic examination. Signs of toxicity include loss of visual acuity and colour vision or reduction in visual fields. Detection of these symptoms may be delayed in young children (Trebucq 1997). The occurrence of ocular toxicity is related to dose and duration of therapy (Graham et al. 1998; Donald et al. 2006; World Health Organization 2006c). More than 40% of adults developed toxicity at doses of greater than 50 mg/kg compared to 0–3% at a dose of 15 mg/kg daily. In only two of 3 811 children (0.05%) receiving EMB doses of 15–30 mg/kg was EMB stopped due to possible ocular toxicity (Graham et al. 1998; Donald et al. 2006). Reports of EMB toxicity incidence in children represent a variety of TB endemic settings including Europe, Asia and Latin America. The current recommended daily dose is 20 mg/kg and it is mainly used only in the intensive phase for a limited duration of 2 months (Table 2).

Streptomycin

The potential toxic effects of Streptomycin (SM) are dose-related and inherent to aminoglycoside antibiotics in general: otovestibular toxicity, which can result in permanent deafness, and nephrotoxicity which has been rarely reported in children (Reed & Blumer 1983). If SM is not discontinued with onset of symptoms of toxicity, then damage may be permanent. Difficulties associated with prolonged parenteral therapy and potential toxicity means its recommended use in children is now limited. SM usage in pregnant women with TB has been associated with deafness in their newborns (Robinson & Cambon 1964). SM should also be avoided in patients with renal impairment.

Treatment trials and adverse events

The frequency of adverse events may be affected by the presence of TB disease compared to reports of chemoprophylaxis where the patient presumably had TB infection but not disease. Treatment trials report adverse events in children with mainly pulmonary TB from a variety of settings where patients have been carefully monitored throughout the treatment regimen.

No significant side effects were noted in a prospective randomized controlled trial of 206 South African children comparing 6 months daily regimen (RMP 10 mg/kg, INH 10 mg/kg, PZA 25 mg/kg) to a higher dose twice-weekly regimen (RMP 15 mg/kg, 15 mg/kg, PZA 55 mg/kg) (Te Water Naude et al. 2000). There have been a number of similar studies from India. A study of 76 Indian children compared intermittent (twice weekly INH 20–30 mg/kg, RIF 10–15 mg/kg and PZA 50–60 mg/kg) to daily (INH 10–15 mg/kg, RMP 10–15 mg/kg, PZA 20–30 mg/kg) in the intensive phase (Kumar et al. 1990). Monitoring included monthly liver function tests and no adverse effects requiring modification of treatment occurred. Six patients complained of vomiting initially and two had mild joint pains. Another compared daily regimen (INH 6 mg/kg and RMP 12 mg/kg) of 9 months duration to an intermittent regimen (INH 15 mg/kg, RMP 12 mg/kg and PZA 45 mg/kg) of 6 months duration (Swaminathan et al. 2005). Patients were followed closely but liver function tests were not monitored. Tolerance was reported as excellent with no adverse events reported. A prospective trial in 83 children using a variety of regimens, all including INH at 15 mg/kg and RMP at 10–15 mg/kg, reported side-effects to be uncommon and mild: transient hepatitis (four), vomiting (one) and skin rash (one) (Padmini et al. 1993).

A prospective study of 36 Greek children treated with RMP (10–12 mg/kg), INH (10–12 mg/kg) and PZA (30–35 mg/kg) resulted in no serious problems with drug tolerance or toxicity. Temporary asymptomatic hyperuricaemia and transient elevation in serum transaminases were observed in 11 patients but no drug modification was required (Tsakalidis et al. 1992). An observational study of 175 children in USA reported experience with a 6-month directly observed regimen including INH (20–40 mg/kg), RMP (10–20 mg/kg) and PZA (50–70 mg/kg) twice weekly from week 3. Only two (1%) had significant adverse events of vomiting and skin rash, which interrupted drug treatment for 1–2 months (Al-Dossary et al. 2002). An additional nine patients had episodes of gastrointestinal disturbance (vomiting or abdominal pain) that did not require discontinuation of therapy or change in drug doses. These occurred in young children during the first month of therapy and were thought to be caused by the large volume of medications. No patient developed hepatitis, peripheral neuritis or joint pain.

In an uncontrolled prospective study, children in Papua New Guinea were treated with RMP (10–15 mg/kg), INH (10–15 mg/kg), PZA (25–35 mg/kg) and SM daily for 2 months and then twice weekly with RMP (10–15 mg/kg) and INH (15–20 mg/kg) for 4 months (Biddulph 1990). Of the 639 children, 15 (2%) developed side effects. Twelve developed rash during the initial 2 months daily treatment and it was attributed to SM in eight cases, PZA in three cases and INH in one case and two developed jaundice. One child who had received SM and INH for several months in an earlier incomplete treatment course complained of deafness. Four children were considered to be allergic to either PZA or INH and were desensitized with increasing dosages and had no further problems. This study included children with various forms of TB including 43 with tuberculous meningitis (TBM) and 16 with miliary TB.

The frequency of adverse events may be affected by the severity of TB disease. A study of Indian children reported hepatotoxicity in 2% of 323 children receiving daily INH, RMP, PZA and EMB in intensive phase for more severe forms of disease compared to 1% of 120 children who received INH, RMP and PZA for less severe forms (Kabra et al. 2004). Dosages of 15–20 mg/kg of INH in children in TB-endemic countries are more commonly associated with hepatotoxicity and clinical jaundice but these higher dosages are used in children with TBM (Ramachandran 1980; Tsagaropoulou-Stinga et al. 1985; Parthasarathy et al. 1986; Donald et al. 1987). In one study of TBM, the risk of jaundice was higher (39%vs. 12%) in those receiving 20 mg/kg than in those receiving 12 mg/kg INH daily (Parthasarathy et al. 1986).

Discussion

  1. Top of page
  2. Summary
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. References

Treatment trials in children using combination therapy in a variety of regimens show that anti-TB drugs at currently recommended dosages are well tolerated. Serious adverse reactions are rare and even mild, reversible side effects are uncommon. Poor treatment completion rates are reported in children in resource-limited settings but it is unlikely that adverse reactions are a major factor for this. INH is the most extensively studied as a single agent because of its use as prophylaxis. Hepatotoxicity is the major adverse event of concern and there are case reports in the literature of INH-induced hepatic failure when recommended dosages are used.

Review of the literature shows that children tolerate anti-TB drugs better than adults. This consistent observation has been related to alcohol use and a higher prevalence of underlying disease such as chronic hepatitis with age (Kopanoff et al. 1978; Reed & Blumer 1983). Another important factor may be that young children eliminate drugs faster than older children and adults, requiring a higher dosage to achieve similar levels (McIlleron et al. 2009).Children have lower serum concentrations for anti-TB drugs than adults when receiving equivalent milligram per kilogram doses as recommended (Zhu et al. 2002; Schaaf et al. 2005; Graham et al. 2006).

In the past, this has not been considered a problem as clinical response and outcomes have generally been very favourable in children with TB using these recommended dosages. The poorer outcomes noted in children with TB/HIV co-infection (Marais et al. 2007; Schaaf et al. 2007) have called attention to the need for appropriate dosages in children to achieve optimal serum levels and the need for more careful surveillance in such settings. Recommended doses for first-line drugs such as RMP and INH may be increased in the near future. It will be important to monitor for the possibility of an increasing incidence of side effects. There are some toxicity data from children using higher daily dosages but this has mainly been in the context of treatment of severe, disseminated disease such as TBM when there are other potential co-factors for toxicity such as disease involving the liver, the use of other anti-TB drugs and anticonvulsants.

Some studies in adults have found that HIV infection is associated with an increased risk of hepatotoxicity to anti-TB drugs (Tostmann et al. 2008). There are no published data for children. EMB and PZA levels were not significantly different between HIV-infected and HIV-uninfected Malawian children (Graham et al. 2006). However, these are the only published data that try to examine the impact of age, HIV and malnutrition on TB drug levels in children. The potential for toxicity also relates to drug-drug interactions and a greater likelihood of underlying liver disease in HIV-infected children. Anti-TB drugs, mainly RMP, have important interactions with antiretroviral therapy (ART) and have many similar side effects. RMP reduces the serum levels of almost all protease inhibitors except ritonavir by more than 75% (Burman & Jones 2001) and levels also fall for non-nucleoside reverse transcriptase inhibitors such as efavirenz and nevirapine (Centers for Disease Control and Prevention 2007).

It is also recommended that all HIV/TB co-infected children should receive cotrimoxazole preventive therapy as well as pyridoxine while on anti-TB treatment (World Health Organization 2006b). Hepatotoxicity, skin rash, gastrointestinal upset, leucopaenia, anaemia and peripheral neuropathy are all side effects that could be caused by either anti-TB drugs or ART. It is therefore difficult to distinguish which drug is responsible for these side effects when treatment for both diseases is combined (Donald & Schaaf 2007). As HIV and TB are frequent co-morbidities in children in developing countries, and with the increasing use of ART in HIV infected children, it will be important to monitor for adverse effects in these populations.

In conclusion, anti-TB drugs at current recommended doses are well tolerated in children. Although occasional fatal hepatotoxic events are described in children, the incidence of serious toxicity is very low. Monitoring for adverse effects will need to be improved if increased doses are to be used in children especially in regions where co- morbidities are common. There is a need for more clinical outcome and pharmacokinetic data from children in resource-limited settings including those with HIV and malnutrition.

Acknowledgements

  1. Top of page
  2. Summary
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. References

We thank Dr Julian Kelly and Prof. Peter Donald for suggestions and support. This review is part of the International Child Health Review Collaboration: http://www.ichrc.org.

References

  1. Top of page
  2. Summary
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. References
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