TB preventive therapy in children. Introduction

Transcription

1 TB preventive therapy in children H S Schaaf Department of Paediatrics and Child Health, and Desmond Tutu TB Centre Stellenbosch University, and Tygerberg Children s Hospital Introduction Children are mainly infected with M. tuberculosis by infectious adult pulmonary TB cases Although AFB sputum smear-positive cases are more infectious than smear-negative/culturepositive cases, the latter is also infectious BCG does NOT provide good protection against infection and disease in children, although it does reduce the risk of TBM and miliary TB Starting ti adult source cases on TB Rx or separating the child from the source case could prevent ongoing transmission BUT does not mean the child does not need preventive Rx 1

2 Introduction The risk for developing TB disease after infection is highest in young children (<3 yrs of age) and HIV-infected individuals Immune compromised % <1 1to2 2to5 5to10 10to15 Age in Years PTB Disseminated Courtesy of Ben Marais Time-related risk I II III Immune compromised IV Infection Months Years Phase of disease I II III IV Timeline Hypersensitivity including tuberculin skin test! Miliary TB and TBM Lymph node disease / Pleural effusion Adult-type disease HIV-infected - PERSISTENT RISK OF REACTIVATION DISEASE 2

3 Rationale for preventive treatment Prophylactic treatment is given after exposure to prevent TB infection, and treatment given after TB infection is intended to prevent progression to TB disease. Preventive treatment includes both these situations To provide preventive treatment - contact with a source case and risk of infection needs to be established and - TB disease should have been excluded The individual risk assessment should take into consideration the following: TB contact s (child s) risk for progression to TB disease (age, immune status) t Infectiousness of the source case AND the closeness and duration of contact with the source case Whether there is one or more source cases The DST pattern(s) of the source case(s) The risk for adverse events upon initiating preventive therapy 3

4 Contact management algorithm Child close contact of infectious PTB case 0-59 months or HIV+ >60 months & HIV- Well Symptomatic Symptomatic Well 6H Consider TB* No treatment If becomes symptomatic If becomes symptomatic *Follow guidelines for diagnosis WHO Guidance for NTPs on the management of tuberculosis in children How to investigate contacts Clinical assessment: History (Symptoms not only chronic symptoms; closeness and duration of contact; DST of source case s isolate) Clinical examination (PTB/EPTB) Clinical assessment alone is sufficient to decide whether contact is well or symptomatic If available: TST (exposure preventive Rx even if TST negative) TST (exposure preventive Rx even if TST negative) CXR (for diagnosis of disease) If DR-TB suspected and contact is symptomatic or has abnormal CXR specimens culture/dst 4

5 Current SA TB Guidelines (new EML) Post-exposure isoniazid preventive therapy (IPT) 10 mg/kg daily for 6 months is recommended in the following children after exclusion of TB disease: - HIV-uninfected children less than 5 years of age - HIV-infected children irrespective of age or ART status Post-exposure means close contact with an infectious PTB case (defined as a sputum microscopy smearpositive or culture-positive or Genexpert-positive case) In HIV-infected children, ART should start as early as possible in infancy. Early ART has an important protective effect against the development of TB following infection with M. tuberculosis. Schaaf et al. SAMJ 2013 Current SA TB Guidelines IPT should be repeated with each significant new exposure in children who qualify (<5 yrs; all HIVinfected) as isoniazid has no long-term protective effect In this regard, all HCWs should enquire about any new TB contact at every follow-up visit, as well as asking caregivers about their own health, to screen for possible TB symptoms Pre-exposure IPT is not recommended in any HIV- infected or -uninfected child (evidence not convincing) Post-TB disease IPT is not recommended. Ensure when treating TB in children that cure is complete which may mean longer treatment than 6 months in some children 5

6 Current SA TB Guidelines True rifampicin (RIF) monoresistant contacts (confirmed by culture-based drug susceptibility test results and not Xpert MTB/RIF resistance): INH 10 mg/kg daily for 6 months should be provided INH monoresistant contacts: RIF mg/kg for 4 months as single drug (or in RIF/isoniazid if single drug RIF not available at the same RIF dose) What about contacts of MDR/XDR-TB? Strain concordance of household members with DR-TB is high: - in adults 50-67% strain concordance - in child contacts <5 years 75-88% concordance Although many RCTs have confirmed IPT as effective, no RCTs have been done to evaluate preventive therapy for MDR-TB contacts However, a number of prospective observational studies have shown the potential of preventive treatment in preventing MDR-TB Despite this, the debate on the management of MDR-TB contacts is ongoing 6

7 WHO 2008 Guidelines for Drug-Resistant TB Management - Update Key recommendations: DR-TB contact investigation should be given high priority, and NTPs should consider contact investigation of XDR-TB as an emergency situation Close contacts of MDR-TB patients should receive careful clinical follow-up for at least two years If active disease is present or develops, prompt initiation of MDR-TB treatment is recommended (empiric MDR-TB regimen, even in adults, if DST and culture not available) WHO does not recommend the universal use of secondline drugs for preventive therapy in MDR-TB contacts 7

8 Decision algorithm for assessing child contacts of MDR-TB EXPOSED TO MDR-TB? EXCLUDE TB DISEASE Disease - Rx Management of children exposed to multidrug-resistant Mycobacterium tuberculosis. Seddon JA et al. Lancet Infect Dis 2012 RISK OF INFECTION? RISK OF DISEASE PROGRESSION? MDR-TB STRAIN OR OTHER? High risk MDR-TB Preventive Rx & follow-up DS-TB risk? IPT 8

9 ECDC guidance March 2012: Summary Expresses support for two different options: - preventive therapy and/or - careful clinical observation The central principle is that a comprehensive risk assessment should be part of the evaluation of any MDR- TB or XDR-TB contact. In case of XDR-TB, available drug regimens are limited and without proven efficacy, thus close observation is likely the only option. Urgent need for further research, specifically in two areas: - studies evaluating the benefit of preventive therapy in MDR-TB and XDR-TB contacts - cost-benefit analyses of implementing preventive Rx Recent prospective study WC 186 child contacts of MDR-TB, median age of 34 months (IQR mo) of which 5% were HIV-infected Started 3-drug regimen: hdh,oflox,emb well tolerated Adherence was good in 141 (75.8%) children. 7 (3.7%) children developed grade 3 adverse events One child (0.5%) died and 6 (3.2%) developed incident TB during 219 patient-years of observation time Factors associated with poor outcome were: - age <1year (RR( 10.1; 95% CI ; P =.009)) - HIV infection (RR 10.6; 95%CI, ; P =.049) - exposure >source case (RR 6.75; 95%CI ; P=.036) - poor adherence (RR 7.50; 95% CI ; P =.026) Seddon et al CID

10 Recent preventive Rx study WC Few children prescribed this standardized preventive therapy regimen developed TB or died if adherent to therapy Consideration should be given to providing preventive therapy to young children and HIVinfected children irrespective of age following exposure to MDR-TB Infants and HIV-infected children are at particular high risk of poor outcomes (death/tb) Our current practice NTP 2011 MDR-TB guidelines: INH 15 mg/kg/d x 6 months At our clinic we do the following: Exclude TB disease (culture/dst if suspected) ( p ) Long-term (12-24 months) follow-up (clinical, CXR and cultures when indicated); >90% children develop TB within 1 year of exposure/infection Preventive Rx: <5 year olds and HIV-infected children Preventive Rx (for 6 months): INH t hi h d (15 20 /k /d) INH at high-dose (15-20mg/kg/d) A fluoroquinolone OFX/LFX Ethambutol DST result adult case (not available!) Older children Evaluate and symptomatic follow-up only 10

11 Conclusions MDR preventive Rx could be effective in preventing MDR-TB in children There is an urgent need to address this issue in a randomised controlled trial(s) Single drug preventive Rx with a fluoroquinolone (e.g. levofloxacin) is considered What about XDR-TB contact? Careful follow-up and possibly high-dose INH treat as XDR-TB if TB develops In both MDR and XDR-TB regular clinical followup is indicated, but pendulum swinging towards preventive treatment. Financial Support: SA National Research Foundation, SA MRC, USAID Treat-TB 11