Adherence to anti-tuberculosis chemoprophylaxis and treatment in ...

INT J TUBERC LUNG DIS 10(1):13–18 © 2006 The Union

Adherence to anti-tuberculosis chemoprophylaxis and treatment in children S. van Zyl,* B. J. Marais,*† A. C. Hesseling,* R. P. Gie,*† N. Beyers,*† H. S. Schaaf*† * Desmond Tutu TB Centre and † Department of Paediatrics and Child Health, Faculty of Health Sciences, Stellenbosch University, Cape Town, South Africa SUMMARY S E T T I N G : Limited data exist on adherence to anti-tuberculosis treatment and chemoprophylaxis in children in high-burden settings. O B J E C T I V E : To determine the adherence to anti-tuberculosis chemoprophylaxis and treatment in children evaluated as household contacts of adult pulmonary tuberculosis (PTB) cases. M E T H O D S : A retrospective study, conducted from January 1996 to September 2003, in suburban Cape Town, South Africa, with a high TB incidence. A folder search was done on all children 5 years of age identified as household contacts of adult PTB cases between 1996 and 2003. Data on screening for TB and adherence to prescribed therapy in child contacts were analysed. R E S U L T S : Three hundred and sixty-one contact episodes with 243 adult PTB cases were identified in 335

children. The median age was 25 months. Adherence to anti-tuberculosis treatment was significantly better than adherence to chemoprophylaxis (82.6% vs. 44.2%; OR 6.83; 95%CI 3.6–12.96). Adherence to a 3-month chemoprophylaxis regimen of isoniazid and rifampicin (3HR) was significantly better than adherence to a 6-month chemoprophylaxis regimen of isoniazid only (69.6% vs. 27.6%; OR 4.97; 95%CI 2.40–10.36). C O N C L U S I O N S : Although adherence to treatment was good, adherence to unsupervised chemoprophylaxis was poor. We recommend that shorter chemoprophylaxis regimens such as 3HR should be considered to improve adherence, but further studies are required. K E Y W O R D S : adherence; chemoprophylaxis; treatment; children

IN RECENT STUDIES from areas with a high tuberculosis (TB) incidence, 48–64% of young children in household contact with adult pulmonary TB (PTB) cases were infected or developed disease.1,2 The risk of developing disease after infection is 20–50% in children infected before 2 years of age, and decreases to approximately 5–10% for children infected between 3 and 5 years of age.3 Active tracing of children 5 years of age who are in household contact with sputum smear-positive PTB cases is therefore currently recommended by the World Health Organization (WHO) and the International Union Against Tuberculosis and Lung Disease.4.5 The WHO recommends chemoprophylaxis for child contacts aged 5 years who are clinically well, and clinical follow-up in those 5 years who are well.4 Symptomatic child contacts and those diagnosed with TB should be treated.4,5 Children may also be infected by sputum smearnegative TB cases, but this is less common (30–40%

of contacts infected),6,7 and routine contact tracing is not currently recommended for these children.4 Chemoprophylaxis with isoniazid (H, INH) is recommended for at least 6 months.4,5 With good adherence, INH chemoprophylaxis is effective, preventing progression to disease in 69–93% of infected children.8 The only alternative paediatric chemoprophylactic regimen that has been evaluated (retrospectively) is a 3-month combination regimen of INH and rifampicin (R, RMP), which appeared to be as efficacious as the identical regimen for up to 12 months.9 One of the main components of the DOTS strategy is direct observation of treatment regimens containing RMP. Although an increasing number of National Tuberculosis Programmes (NTPs) endorse this strategy, practical implementation of directly observed treatment (DOT) remains a problem in high-burden areas. Furthermore, child contacts of infectious TB cases are seldom actively traced, and unsupervised chemoprophylaxis is usually prescribed.10

Correspondence to: Prof H Simon Schaaf, Department of Paediatrics and Child Health, Faculty of Health Sciences, Stellenbosch University, P O Box 19063, 7505 Tygerberg, South Africa. Tel: (27) 21.9389112. Fax: (27) 21.9389138. e-mail: [email protected] Article submitted 18 May 2005. Final version accepted 5 July 2005.

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The International Journal of Tuberculosis and Lung Disease

Limited data exist on adherence to anti-tuberculosis treatment and chemoprophylaxis in children in high-burden settings. The aim of this study was to describe rates of infection and disease by source case sputum result and to determine the adherence to chemoprophylaxis and treatment for TB disease in children evaluated as household contacts of adult index cases.

METHODS Setting and patients This retrospective study, conducted from January 1996 to September 2003, was done in a suburb of Cape Town, South Africa, with an estimated population of 11 850 (census data 2001) and a high incidence of bacteriologically confirmed TB (average yearly incidence of new smear-positive cases 320 per 100 000 population between 1993 and 1998).11 The community is served by a community health clinic and a referral hospital. The TB register kept at clinic level was used to identify all adult (aged 15 years) PTB cases started on treatment during the study period. A folder search was done of all children aged 5 years who were identified as contacts of these adults. Child contacts were defined as children aged 5 years living at the same residential address as the adult index case. At the time, the policy was to ask parents or care givers to bring these children to the clinic to be screened for TB. Awareness of TB in the community was high, and participation of the parents in bringing their children for evaluation was good, because of active ongoing TB research during this period. Children who were not brought to the clinic by their care givers were not actively traced. Evaluation Evaluation of child contacts included a history of symptoms associated with TB, clinical examination, a tuberculin skin test (TST) (Mantoux 2 TU PPD RT23 intradermally) and chest radiograph ([CXR] anteroposterior and lateral). Cultures for Mycobacterium tuberculosis were only done if children were referred to hospital. The Mantoux TST was interpreted as positive if induration was 15 mm, as more than 95% of children received BCG vaccination at birth.12 Human immunodeficiency virus (HIV) tests were only done if the mother was known to be HIV-infected or if there was a clinical indication. CXRs were read in a standardised way by an experienced paediatrician.13 Children were classified as TB disease (clinical disease compatible with TB and/or CXR changes of TB with or without a positive TST or positive culture for M. tuberculosis), TB infection (positive TST without clinical findings or CXR changes of TB) or TB exposed (clinically well, normal CXR and a non-reactive TST).

Treatment Treatment for disease consisted of three anti-tuberculosis drugs (INH, RMP and pyrazinamide) for 2 months, followed by two drugs (INH and RMP) for 2–4 months, according to the South African NTP guidelines at the time. DOT, either by clinic nursing staff or by a community treatment supporter, was given to some children, but in others, the care giver was asked to fetch the anti-tuberculosis drugs from the clinic, to be given by the care giver at home on a daily basis. Two regimens were used for routine chemoprophylaxis: INH only for 6 months, or INH and RMP for 3 months. The 3-month combination regimen of INH and RMP was mainly used in children 2 years, and was discontinued due to a NTP policy change in 2000. Completion of treatment or chemoprophylaxis was defined as completing 80% of treatment without interruption of more than 2 months. Statistical analysis Data were entered into an Access 2000 database and descriptive analysis was done using SPSS (version 11.5, SPSS Inc, Chicago, IL, USA). Categorical variables were analysed using the 2 test and continuous variables using the Student’s t-test. A 2-tailed P value of 0.05 was considered statistically significant. Ethics approval was obtained from the City of Cape Town Health Department, the local health committee and the institutional review board, Stellenbosch University.

RESULTS From January 1996 to September 2003, 335 children 5 years of age were identified as household contacts of 243 adult PTB cases. During this period, 622 adults with sputum smear- or culture-positive TB were diagnosed. Of the 335 child contacts, 26 (7.8%) were evaluated twice during the study period, giving a total of 361 contact episodes. Of those evaluated twice, 13/26 (50.0%) children had a new index case in the household, in 10 (38.5%) the index case had a second episode of PTB, and three (11.5%) children were re-evaluated after non-adherence to chemoprophylaxis. The median age at evaluation was 25 months (range 2 days to 60 months), and in 157 (43.5%) episodes the child contacts were boys. The mother was the index case in 85 (23.5%), the father in 73 (20.2%), an uncle or aunt in 34 (9.4%), an older sibling in five (1.4%) and other household members in the remaining 164 (45.4%). Only seven (2.1%) children were tested for HIV, of whom two were HIV-infected. The median age of the index cases was 34 years (range 14–79 years); 112 (46.1%) were male. The index case was sputum smear-positive for acid-fast bacilli (AFB) in 256 (70.9%) of 361 episodes. Of the 105 index cases with smear-negative (81; 22.4%) or

Adherence to chemoprophylaxis and treatment

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Table 1 TB disease and infection in child contacts based on sputum smear and culture results of index cases

Sputum smear and culture results Smear-positive (n 256)† Smear-negative, culture-positive (n 70)† Smear- and culture-negative/smear not done and culture-negative/smear and culture not known (n 35)

TB exposed n (%)

TB infected* n (%)

TB disease* n (%)

87 (34.0) 38 (54.3)

74 (28.9) 11 (15.7)

76 (29.7) 15 (21.4)

10 (28.5)

8 (22.9)

8 (22.9)

Incomplete evaluation n (%) 19 (7.4) 6 (8.6) 9 (25.7)

* Comparing contacts of smear-positive source cases with contacts of smear-negative cases, there is a significant difference between those classified as TB exposed and the combined group of those classified as TB infected and TB disease. † P 0.002; OR 2.52; 95%CI 1.38–4.61. TB tuberculosis; OR odds ratio; CI confidence interval.

unknown (24; 6.6%) smear results, 70/105 (66.7%) were sputum culture-positive for M. tuberculosis, 18 (17.1%) were culture-negative and in 17 (16.2%) cases no culture results were available. Table 1 reflects the number of children who developed infection or disease, according to the sputum results of the index cases. The prevalence of infection and disease was significantly higher in children in contact with smearpositive compared with smear-negative culture-positive index cases (150/255 vs. 26/70; odds ratio [OR] 2.42; 95% confidence interval [CI] 1.36–4.33; P 0.002). Children were diagnosed as TB disease in 99 (27.4%) episodes, as TB infection in 93 episodes (25.8%) and as TB exposed in 134 (37.1%) episodes. In 35 (9.7%) episodes evaluation was incomplete, which included four neonates in whom no TST was done. The TST was positive in 74 (74.8%) children diagnosed with TB disease. Drug susceptibility test (DST) results of the index case were known for 172 (47.6%) contact episodes; 55 (32.0%) children had contact with a multidrugresistant (MDR; resistant to at least INH and RMP) index case, and seven (4.1%) had contact with an INH-monoresistant index case. The high rate of drug resistance is mainly due to selection bias, as DST was only done in patients not responding to treatment or retreatment cases. Of the children in contact with known drug-susceptible compared with MDR cases, respectively 32/110 (29.1%) vs. 16/55 (29.1%) had

disease, 31 (28.2%) vs. 14 (25.5%) were infected, 41 (37.3%) vs. 23 (41.8%) were exposed only, and 6 (5.5%) vs. 2 (3.6%) children were incompletely evaluated (P 0.05). Management of child contacts Child contacts were assigned full TB treatment in 109 (30.2%) episodes (95 TB disease, 10 infected only, 2 exposed and 2 incompletely evaluated) and chemoprophylaxis in 181 (50.1%) (2 TB disease, 72 infected only, 105 exposed and 2 incompletely evaluated). No treatment or chemoprophylaxis was prescribed in 71 (19.7%) episodes. Of the 71 children for whom no treatment was prescribed, 30 (42.3%) were not completely evaluated, 28 (39.4%) were exposed only, 11 (15.5%) were infected, of whom 5 had previously received full anti-tuberculosis treatment, and 2 (2.8%) had TB. Chemoprophylaxis was prescribed as INH only for 6 months (6H) in 105 (58.0%) of 181 children, INH and RMP for 3 months (3HR) in 72 (39.8%) cases and chemoprophylaxis for MDR contact in four (2.2%) children. Adherence to treatment and chemoprophylaxis Treatment adherence is summarised in Table 2. Adherence to anti-tuberculosis treatment for disease was 82.6%, which was significantly better than the 44.2% adherence to chemoprophylaxis (P 0.001; OR 6.83;

Table 2 Adherence to anti-tuberculosis treatment and chemoprophylaxis (n 290);* comparison between treatment and all chemoprophylaxis, and between two chemoprophylaxis regimens

Treatment or chemoprophylaxis prescribed TB treatment (n 109) Chemoprophylaxis (all) (n 181)‡ Chemoprophylaxis 6H (n 105) Chemoprophylaxis 3HR (n 72)

Treatment or chemoprophylaxis Unknown not started adherence n (%) n (%) 3 (2.8) 9 (5.0) 7 (6.7) 2 (2.8)

2 (1.8) 7 (3.8) 6 (5.7) 1 (1.4)

Not completed n (%)

Completed n (%)

14 (12.8) 85 (47.0) 63 (60.0) 21 (29.2)

90 (82.6) 80 (44.2) 29 (27.6) 48 (66.6)

P value† 0.001 0.001

OR† (95%CI) 6.83 (3.60–12.96) 4.97 (2.40–10.36)

* Children in whom no treatment was prescribed were excluded; n 71. † P value and OR refers to comparison between columns not completed and completed only; two-sided P value. ‡ Includes 6H, 3HR and MDR chemoprophylaxis. OR odds ratio; CI confidence interval; TB tuberculosis; 6H isoniazid for 6 months; 3HR isoniazid and rifampicin for 3 months; MDR multidrug resistance.

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Table 3 Completion of treatment and chemoprophylaxis in children 5 years of age with different levels of supervision

Treatment supervision Supervised* Observed by HCW at clinic Observed by community supporter Unsupervised* Observed by parent or care giver Observation method unknown

TB treatment (n 104) n

Completed n (%)

Chemoprophylaxis (n 165) Completed n n (%)

40 30

34 (85.0) 26 (86.7)

18 14

14 (77.8) 9 (64.3)

17 17

17 (100) 13 (76.5)

41 92

15 (36.6) 42 (45.7)

* Comparison of supervised (HCW and community supporter) vs. unsupervised (parent or care giver) chemoprophylaxis: P 0.006; OR 4.43: 95%CI 1.47–13.72. TB tuberculosis; HCW health care worker; OR odds ratio; CI confidence interval.

95%CI 3.60–12.96). Adherence to 3HR (69.6%) was significantly better than adherence to 6H (27.6%) (P 0.001; OR 4.97; 95%CI 2.40–10.36). Sixty-six of the 72 (91.7%) children prescribed the 3HR regimen were 2 years of age. In these children, adherence to 6H vs. 3HR was 2/19 (10.5%) compared with 43/66 (65.2%) episodes (P 0.001; OR 0.06; 95%CI 0.01–0.32). There was no temporal trend or improved adherence according to the child’s age. Table 3 summarises the data of supervised (by health care worker [HCW] or community DOTS supporter) and unsupervised (by parent or care giver) treatment and chemoprophylaxis. There was no difference in adherence to anti-tuberculosis treatment between children who received supervised or unsupervised treatment, but adherence to chemoprophylaxis was significantly better in the supervised group (P 0.006). There was insufficient data to compare supervised and unsupervised 3HR to 6H chemoprophylaxis.

DISCUSSION Available data on adherence to treatment and chemoprophylaxis in children are limited. Despite several limitations, such as the retrospective nature of the study, the fact that not all children from all source cases were evaluated and more symptomatic children may have been evaluated, and incomplete information on the choice of administration method (HCW/ DOT supporter vs. parent/care giver), this study contributes to current limited knowledge. One study in children reported adherence of 85% to anti-tuberculosis treatment when community-based DOT was used,14 similar to the adherence of 82.6% found in our study. Our study showed good adherence to both supervised (HCW or community DOT supporter) and unsupervised (parent or care giver) treatment of disease. Adherence to treatment among adult cases in the same community was 72% during the study period. Reports on adherence to chemoprophylaxis in children and adults vary greatly. In a report from Uganda, 78% of 209 children who were started on a 6H regi-

men adhered to treatment under study circumstances, compared with 54% of 78 children in whom adherence could be confirmed in an Australian study.15,16 Adherence to chemoprophylaxis amongst adults and children was 203/398 (51%) and 84/310 (27%) in two studies from the United States.17,18 In our study, overall adherence to chemoprophylaxis was also low, at 44%, but adherence to the shorter duration combination regimen of 3HR (67%) was significantly better than adherence to 6H only (27%). Although only the 6-month or more INH regimen has been prospectively evaluated in children through randomised clinical trials, retrospective observational cohort studies show equal benefit in prevention of disease in infected children using a 3HR regimen compared with longer duration chemoprophylaxis using the same combination.9 A meta-analysis of daily chemoprophylaxis with 3HR and standard chemoprophylaxis with INH for 6–12 months in adults showed that these regimens were equivalent in terms of efficacy, severe side effects and mortality.19 Prospective studies of 3HR compared with 6–9H are needed to determine the effectiveness, cost implications and side effects in children, especially in the face of an increasing burden of HIV infection and the potential interaction of RMP with antiretroviral treatment, before shorter combination regimens can be recommended. According to the 1996 South African NTP guidelines, child contacts under 2 years of age were to receive the 3HR regimen and those aged 2–5 years the 6H chemoprophylactic regimen.20 This was changed to a 6H regimen for all children under 5 years of age in the NTP 2000 guidelines, with the 3HR regimen not recommended as an alternative.21 The reasons for this change in policy are not known, but we are not aware of any studies comparing adherence to these regimens, especially in field conditions. Possible considerations may have been the prevention of the development of RMP resistance, as chemoprophylaxis is usually unsupervised. However, only a fixed-dose combination of INH and RMP is currently used, which will, together with the paucibacillary nature of TB infection and disease in children, minimise the risk

Adherence to chemoprophylaxis and treatment

of development of resistance. In high burden areas with limited resources, supervised short-course chemoprophylaxis such as 3HR could be considered in child contacts at highest risk of developing progressive disease. These are children infected before 2 years of age (therefore children 3 years of age, as risk of developing disease is the highest in the first year after infection) and immunocompromised children.6 Of concern in our study is the large number of children who had contact with MDR-TB index cases. Although many of those who developed disease were treated as MDR-TB cases (data not shown), only four of the contacts received chemoprophylaxis according to the DST results of the index cases. This was mainly because NTP guidelines do not differentiate between chemoprophylaxis for drug-susceptible or drug-resistant cases, and because DST results of the index case were often not considered when starting chemoprophylaxis in the child contact. It has subsequently been shown that children may benefit from tailored chemoprophylactic regimens based on the index case’s DST.22 Sputum smear-positive TB patients infect more of their child contacts than do smear-negative patients, with numbers varying between studies.4 This was confirmed in our study, where contacts of smearpositive index cases had a significantly higher risk of infection and disease than contacts of smear-negative cases (59% vs. 37%). However, disease following smear-negative culture-positive contact was still high, at 21%. Strategies to control TB in high-burden countries are mainly aimed at adult smear-positive cases, but earlier treatment, when cases are culturepositive only, may substantially reduce transmission and prevent infection in children.23 After case finding and treatment of active cases, contact tracing should be the priority of NTPs.24 Although our study is limited by its retrospective nature and may not reflect an unbiased sample of all child contacts in this community, our findings confirm the importance of contact investigation in identifying new TB cases and providing chemoprophylaxis in young children based on the high risk of infection and disease. In conclusion, case finding and treatment of all bacteriologically positive adults remain the highest priority for disease prevention. Where case finding and case holding reach acceptable levels and where resources permit, contact tracing should be a second priority. Where resources are limited, greater emphasis should be placed on identifying children at highest risk for development of TB disease and its complications. Shorter regimens such as 3HR should be considered to improve adherence to chemoprophylaxis, but to further this goal, prospective studies comparing adherence, cost and outcomes with a 6–9H vs. 3HR chemoprophylaxis regimen for young child contacts of infectious adult index cases should be conducted.

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Acknowledgements We thank the primary health care clinics involved and Dr Ivan Toms (City of Cape Town Health Department).

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RÉSUMÉ

Il n’existe que peu de données sur l’adhésion au traitement antituberculeux et à la chimioprophylaxie chez les enfants dans des contextes à haute prévalence. O B J E C T I F : Déterminer l’adhésion à la chimioprophylaxie antituberculeuse et au traitement chez les enfants examinés comme contacts au domicile de cas de tuberculose pulmonaire (TBP) de l’adulte. M É T H O D E S : Etude rétrospective conduite entre janvier 1996 et septembre 2003 dans le Cape Town suburbain en Afrique du Sud où l’incidence de la TB est élevée. Une recherche de registres a été faite chez tous les enfants âgés de moins de 5 ans identifiés comme contacts au domicile de cas de TBP de l’adulte entre 1996 et 2003. On a analysé les données sur le dépistage de la TB et l’adhésion au traitement prescrit chez les enfants-contact. R É S U L T A T S : On a identifié chez 335 enfants 361 épiCONTEXTE :

sodes de contact avec 243 cas de TBP chez l’adulte. L’âge médian est de 25 mois. L’adhésion au traitement antituberculeux est significativement meilleure que l’adhésion à la chimioprophylaxie (82,6% vs. 44,2% ; OR 6,83 ; IC95% 3,6–12,96). L’adhésion à un régime de chimioprophylaxie de 3 mois à base d’isoniazide et de rifampicine (3HR) est significativement meilleure que l’adhésion à un régime de chimioprophylaxie de 6 mois à base d’isoniazide seule (69,6% vs. 27,6% ; OR 4,97 ; IC95% 2,40–10,36). C O N C L U S I O N S : Bien que l’adhésion au traitement ait été bonne, l’adhésion à une chimioprophylaxie non supervisée a été faible. Nous recommandons que l’on envisage des régimes de chimioprophylaxie courts, tels que 6HR, pour améliorer l’adhésion. Des études complémentaires s’imposent. RESUMEN

Los datos existentes sobre el cumplimiento del tratamiento antituberculoso y de la quimioprofilaxis en niños provenientes de medios con alta carga de morbilidad por tuberculosis (TB) son escasos. O B J E T I V O : Determinar el cumplimiento con el tratamiento antituberculoso y con la quimioprofilaxis de los niños examinados en el marco del estudio de contactos domiciliarios de pacientes adultos con TB pulmonar (TBP). M É T O D O S : Fue este un estudio retrospectivo realizado entre enero de 1996 y septiembre de 2003 en un suburbio con alta incidencia de TB en Ciudad del Cabo, Sudáfrica. Se estudiaron los archivos de todos los niños 5 años identificados como contactos domiciliarios de pacientes adultos con TBP entre 1996 y 2003. Se analizaron los datos sobre la detección de la TB y sobre el cumplimiento del tratamiento recetado a los contactos pediátricos. R E S U L T A D O S : Se demostraron en 335 niños 361 episoMARCO DE REFERENCIA :

dios de contacto con 243 adultos con TBP. La mediana de la edad fue 25 meses. El cumplimiento del tratamiento antituberculoso fue significativamente superior al cumplimiento de la quimioprofilaxis (82,6% y 44,2% respectivamente ; OR 6,83 ; IC95% 3,6–12,96). La observancia terapéutica de la quimioprofilaxis de 3 meses con isoniacida y rifampicina (3 HR) fue significativamente mayor que la observancia de la pauta de 6 meses con isoniacida (69,6% y 27,6% respectivamente ; OR 4,97 ; IC95% 2,40–10,36). C O N C L U S I O N E S : El cumplimiento con el tratamiento antituberculoso fue adecuado, pero la observancia de la quimioprofilaxis no supervisada fue muy baja. Los autores recomiendan que se consideren pautas de quimioprofilaxis más cortas, como 3 HR, con el fin de mejorar la observancia terapéutica ; se precisan, no obstante, estudios complementarios.