Screening and Preventive Therapy for Tuberculosis

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Screening andPreventiveTherapyforTuberculosisBenJ. Marais, MMed Paed, FCPaed(SA), PhDa,*,Helen Ayles, MD, PhDb,c, StephenM. Graham, MD, PhDd,e,Peter Godfrey-Faussett, MD, PhDb,c

The tuberculosis (TB) epidemic is well controlled inmost developed countries and the focus in theseareas has shifted to TB eradication. Transmissionwithin nonendemic areas is limited and most casesof TB result from reactivation of distant (latent)infection. With adequate resources, wide-scaleuse of preventive therapy can assist to eliminatethe pool of latent infection that is required for TBeradication. In contrast, TB control remains poorin many developing countries, especially thoseworst affected by poverty and the human immuno-deficiency virus (HIV) epidemic.

This dichotomy demonstrates the need forrational approaches tailored to the situation inTB-endemic areas where epidemic control andmorbidity/mortality reduction are the primaryaims. Differences in transmission dynamics andthe availability of resources imply careful consider-ation of feasibility and prioritization of interven-tions. High rates of ongoing transmission persistin TB-endemic areas making it impossible to elim-inate the pool of latent infection. Poor epidemiccontrol and limited resources require TB-endemicareas to focus preventive therapy strategies onthose individuals who are at greatest risk of pro-gressing to active disease.

In this review the authors critically assess theapproach to TB preventive therapy in childrenand adults, focus on the underlying treatmentrationale, discuss available data, and identifyissues of concern. There is strong evidence of effi-cacy and tolerance of preventive therapy in thesepopulations. Preventive therapy for all high-riskindividuals following documented exposure to TBshould be regarded as the standard of care.However, there is limited evidence of effectivenessbecause implementation and adherence are oftenpoor. In resource-limited settings, excluding activedisease in HIV-infected individuals and the addi-tional burden on health care services are particularchallenges. There is a need to implement and eval-uate preventive therapy strategies in varioussettings to better inform policy and practice.

BACKGROUND

It is difficult to grasp the full scale of the global TBepidemic. An estimated 10.4 million cases (newand recurrent) and 1.8 million deaths were attrib-uted to TB in 2007.1 Great strides have beenmade in the last 15 years to scale up diagnosticand treatment services, but the effect on the

Conflicts of interest: None to declare.a Department of Paediatrics and Child Health, Faculty of Health Sciences, Stellenbosch University, PO Box19063, Tygerberg 7505, South Africab Clinical Research Unit, Department of Infectious and Tropical Disease, London School of Hygiene andTropical Medicine (LSHTM), London, UKc ZAMBART Project, University of Zambia, Lusaka, Zambiad Department of Paediatrics, Centre for International Child Health, Murdoch Children’s Research Institute,Royal Children’s Hospital, University of Melbourne, Victoria, Australiae International Union Against Tuberculosis and Lung Disease, Paris, France* Corresponding author.E-mail address: [email protected] (B.J. Marais).

KEYWORDS� Tuberculosis � Screening � Preventive therapy� Prophylaxis � Latent infection

Clin Chest Med 30 (2009) 827–846doi:10.1016/j.ccm.2009.08.0120272-5231/09/$ – see front matter ª 2009 Published by Elsevier Inc. ch

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epidemic remains limited in poor countries whereTB is most prevalent. Although incidence ratesper capita are starting to decrease, the absolutenumber of cases continues to increase becauseof increases in population size.1 Incidence ratesin HIV-endemic countries are also showinga slow decline, but rates remain at very highlevels.1,2 The dichotomy that exists betweenhigh-income countries where incidence rates areless than 10/100,000 and low-income TB-endemiccountries where incidence rates exceed 100/100,000 justifies critical assessment of currentapproaches and the identification of optimal strat-egies tailored to specific situations. Strategiesneed to consider feasibility issues and howdifferent levels of epidemic control influence therationale that guides the implementation of effec-tive screening and preventive therapy programs.

Nonendemic Areas

Transmission within these areas is limited andmost cases of TB disease occur among immigrantpopulations, the socially destitute, and theelderly.3 Immune-compromised individuals are atincreased risk for TB but their risk of TB exposureis low. Therefore, most cases of TB disease resultfrom reactivation of distant (latent) infection. Withadequate resources, preventive therapy can assistto eliminate the pool of latent infection. Compre-hensive screening of all contacts of active TBcases is often feasible. Methods to identify thoseinfected by the index case, such as the tuberculinskin test (TST), are more specific as an indicator ofrecent infection in nonendemic settings where TBtransmission is uncommon and bacillus Calm-ette-Guerin (BCG) vaccination often not used.Low rates of transmission imply limited risk offuture reinfection. These factors provide a strongrationale for the treatment of all cases with latentinfection. To reduce the risk of transmission fromimported TB cases, new immigrant controlmeasures require screening and treatment of TBdisease in the country of origin.

Endemic Areas

High rates of transmission persist in TB-endemicareas. Directly observed therapy, short-course(DOTS)-based programs failed to report an esti-mated 3.7 million cases of TB in 2007, including1.5 million with sputum smears positive for TB rep-resenting 40% of incident cases.1 Although someof these estimated cases may have receivedundocumented care, ongoing transmission in TB-endemic areas is sustained by a high prevalenceof undiagnosed TB and prolonged diagnosticdelay. The level of ongoing transmission equates

to the infection pressure that exists withincommunities.

The TST has traditionally been used insurveys on TB infection to provide an estimationof the annual risk of TB infection (ARTI) in a pop-ulation. ARTI studies provide a good assess-ment of accumulated primary (first time) TBinfection rates and infection pressure amongchildren despite sensitivity and specificityconstraints using the TST. However, a majorlimitation of ARTI studies is that they typicallyenroll primary school children. This age restric-tion introduces selection bias and ARTI surveysprobably represent a significant underestimateof the infection pressure experienced by adoles-cents and adults within the same community,especially among those with high-risk socialbehavior. The selection of primary school chil-dren is necessitated by the inability of the TSTto register a reinfection event. Because manyadolescents and adults in TB-endemic areasare already infected with Mycobacterium tuber-culosis, it is impossible to determine their riskof reinfection or quantify the infection pressurethat they are exposed to. Confirmation of thehigh infection pressure that exists in endemicareas is provided by molecular epidemiologystudies, which demonstrated that exogenousreinfection is the most common cause of recur-rent TB in some settings.4,5 The risk of reinfec-tion has relevance because it determines theability to eliminate the pool of latent infectionand the duration of benefit derived from thetreatment of latent infection.

Contrary to most diseases preventable byvaccine, previous TB infection or disease offersno protection against future infection or disease.In fact, TB patients are at increased risk ofrecurrent TB compared with those who neverhad TB before,6 which may reflect increasedvulnerability and/or increased likelihood ofrepeat exposure. Comstock7 demonstrated thatit is possible to break the reinfection cyclewith a successful TB eradication programamong the Inuit population in northern Canada.The intervention was able to eliminate the poolof latent infection (by provision of preventivetherapy) and terminate ongoing transmission(by treating all TB cases) at the same time,which explains its long-lasting impact. However,although this public health intervention providesproof of principle, it is important to emphasizethat it was achieved in a geographically remotearea where the entire population was screenedin a short period of time and provided with eitherTB treatment or preventive therapy. It seemsimpossible to replicate these findings in less

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isolated TB-endemic areas where continuouspopulation mixing would facilitate reinfectioneven if the pool of latent infection were success-fully eradicated in 1 part of the population.

These differences between and within settingsof varying TB endemicity explain why achievableaims should be carefully formulated. The provisionof preventive therapy to all infected individualsmay be warranted in nonendemic areas, butlimited resources and ongoing transmissionrequire endemic areas to focus on populations atgreatest risk of progression to disease. This reviewprovides a comprehensive overview of preventivetherapy strategies in children and adults, and thedifferent variables to consider in endemic versusnonendemic areas.

Clarification of Terminology

Terms such as ‘‘treatment of latent infection,’’‘‘chemoprophylaxis,’’ and ‘‘preventive therapy’’are often used interchangeably, which obscuressome important differences. Controlled trialshave largely focused on preventing progressionto active disease in those already infected, anapproach referred to as ‘‘treatment of latent infec-tion.’’ The exact meaning of ‘‘latent infection’’remains a topic of discussion and debate.8,9 Thetreatment rationale is to provide a limited course(either in duration or number of drugs) of chemo-therapy with the main aim of sterilizing existingsubclinical lesions and preventing future progres-sion to disease. ‘‘Chemoprophylaxis’’ (genuineprimary prevention) aims to prevent new infectionsfrom becoming established and only providesprotection during the period of exposure. Recur-rent TB may be prevented by ‘‘secondary prophy-laxis,’’ which is provided after successfulcompletion of TB treatment and may servea dual function. First, secondary prophylaxis mayreduce relapse disease as a result of improvedsterilization achieved with prolonged duration oftherapy. Second, it may reduce reinfectiondisease by preventing reinfection events frombecoming established (analogous to primarychemoprophylaxis) during the period of secondaryprophylaxis. ‘‘Preventive therapy’’ is a blanketterm that incorporates chemoprophylaxis, treat-ment of latent infection, and secondaryprophylaxis.

PEDIATRIC PERSPECTIVE

In TB control, the treatment of children is notconsidered a priority in endemic areas, as theyrarely transmit disease and contribute little tothe maintenance of the TB epidemic. Given thediagnostic difficulties and poor reporting systems

in endemic areas, accurate quantification of theglobal pediatric TB disease burden is impossible.10

In a community-based survey from South Africa,children (<13 years of age) contributed 13.7% ofthe total disease burden with a calculated inci-dence of TB of 408/100,000/y (about 50% of thetotal adult incidence of TB of 840/100,000/y).11

Childhood TB is generally a mild disease if diag-nosed early. However, autopsy results fromZambia demonstrated that advanced TB rivalsbacterial pneumonia as a major cause of deathfrom respiratory disease in children; these findingsprobably reflect the reality in most TB-endemicareas.12 A major part of this disease burden ispreventable if feasible and effective preventivetherapy strategies can be implemented. Childrenin HIV-affected areas are experiencing increasedexposure at a young and vulnerable age as a resultof changing TB epidemiology. HIV infection intro-duced a pronounced age and gender shift withmore young adults and especially women ofchild-bearing age developing TB, which increasesthe risk of exposure in young children.13–15

Risk of Infection

M tuberculosis is usually acquired by inhalation,following exposure to an index case with infectiousTB. The risk of infection (TST positivity) amongchild contacts is associated with the proximityand duration of contact, and the degree of lunginvolvement and/or sputum smear positivity ofthe index case.16–19 Cases with positive sputumsmears pose the greatest transmission risk,although patients with pulmonary TB with negativesputum smears can also transmit disease, albeit ata reduced rate. Higher infection rates have beenreported in child contacts of primary caregiverswith TB, such as mothers or grandmothers.18,20

This may have particular relevance in HIV-affectedcommunities, where the transmission risk posedby a primary caregiver with a negative sputumsmear should be taken into consideration.15,21

Other studies demonstrated a relationship withcrowding and sleeping arrangements.19 The levelof transmission within a community determinesthe rate at which TST positivity increases withage, and the potential value of the TST asa measure of recent infection. TB-endemic coun-tries such as India, Indonesia, and Malawi reportARTIs of around 1% to 2%,22–24 and ARTIs inexcess of 4% have been reported in somehyper-endemic South African communities.25,26

In endemic areas transmission frequently occursoutside of the household, especially in olderchildren.27–29 This is different from nonendemicareas where TB infection usually occurs in an

Screening and Preventive Therapy for Tuberculosis 829


identifiable setting such as the home or school.17,30

Irrespective of the setting, TB infection and/ordisease in young children is associated with anidentifiable adult index case in most instances,because social contact is restricted during the firstyears of life. The risk of TB infection in children fromfamilies affected by HIV/AIDS is likely to besubstantially increased, because TB is the mostcommon opportunistic infection in TB-endemicareas and most cases of TB/HIV coinfection occurin young adults (20–40 years of age) who are oftenparents themselves.14 This is confirmed by theexceptionally high rates of TB exposure recordedamong South African infants born to HIV-infectedmothers.15 Other modes of transmission includein utero transplacental infection, which presentsas congenital TB in the newborn.31 TB during andshortly after pregnancy is increasingly beingdescribed in HIV-infected mothers, which posesa risk of pre- and postpartum infection to thebaby14,31; the risk also extends to other mothersand newborns cared for in the same facility.32

Risk of Disease

Once infected, the risk of a child developing TB isrelated to the maturation and competence of theimmune system, especially of cell-mediatedimmunity. Natural history data indicate that youngage is a major risk factor for the development of TBdisease following primary infection. The risk fordisease following documented infection was40% to 50% during infancy, 25% if infected inthe second year of life, less than 10% for the 2-to 5-year age group, and only 2% for those 5 to10 years of age.33 The routine use of neonatalBCG vaccination has reduced the risk of severedisseminated disease, such as TB meningitis andmiliary TB, but the risk in endemic areas remainshigh and BCG has failed to reduce the prevalenceof adult-type TB, which sustains the TBepidemic.34 Most children who are infected withTB remain asymptomatic and never progress todisease. Of those who do develop disease, thevast majority (>95%) do so in the first year afterinfection and develop progressive symptomssuggestive of disease.33 However, HIV infectionis an important risk factor for TB disease in allage groups that was not reflected in the early pre-chemotherapy studies. Immune-compromisedHIV-infected children are at the same high risk asvery young children, and are vulnerable to devel-oping disease following primary infection, reinfec-tion, or reactivation of distant latent infection.14,35

Prospective data from South Africa indicate thatthe risk of culture-confirmed and disseminated TBis around 20 times higher among HIV-infected

compared with uninfected infants36; a similarmagnitude of risk was calculated in a previousretrospective study.37 Clinical data from settingsendemic for TB/HIV indicate that HIV infection iscommon in children with culture-confirmed TB.However, the ratio of HIV-infected children isgenerally lower than in adults because relativelyfewer children are infected with HIV and youngchildren are highly vulnerable to develop TB irre-spective of their HIV status.14,35 The relationshipbetween malnutrition and TB is difficult to quantifybecause of overlapping epidemiologic associa-tions, cause-effect confounding, and frequentinability to confirm TB in settings where these co-morbidities occur.

Rationale for Preventive Therapy

The most effective means to prevent TB infectionin children is to improve epidemic control. Earlydetection and cure of infectious cases reducestransmission, which should reduce the high repro-ductive rate that sustains the epidemic. Thisexplains why a well-functioning National TBControl Programme (NTP) with a strong focus onearly diagnosis and effective management of themost infectious cases is critical to protect chil-dren.21,22 However, with poor epidemic controland ongoing transmission TB will remain an impor-tant preventable cause of childhood morbidity andmortality.35,38 Therefore, opportunities to preventTB disease in susceptible children should forman important part of efforts to reduce mortality inchildren less than 5 years of age in TB-endemicareas. The high risk of infection and disease in chil-dren exposed to TB provides the rationale forrecommendations from the World Health Organi-zation (WHO), the International Union Against TBand Lung Disease (IUATLD) and the Centers forDisease Control and Prevention (CDC) to makepreventive therapy available to all high-risk closecontacts.39–41

Screening for Disease

Contact screening represents an important oppor-tunity to identify new cases of TB and educatepeople about the disease. All close contacts, irre-spective of age, should be informed of their expo-sure and encouraged to return for formalevaluation should they develop symptoms suspi-cious of TB in the coming months and years. Thelong delay between TB exposure and subsequentdevelopment of disease often obscures exposure-disease relationships and may induce a falsesense of security among contacts in whom activedisease has been ruled out. Screening is rarelyperformed in endemic areas, because of limited

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awareness of its benefits and inability to performprerequisite screening tests.42 The natural historyof TB in children demonstrates that transient hilaradenopathy is a common finding following recentprimary infection, with only a small percentage ofthese children developing progressive disease.This suggests that asymptomatic hilar adenopathyis a natural component of the primary (Ghon)complex, reflecting recent M tuberculosis infectionrather than TB disease.33,43 By convention,asymptomatic hilar adenopathy is currentlytreated as TB disease in most countries, but expe-rience during public health trials in the UnitedStates in the 1950s demonstrated that isoniazid(INH) monotherapy should be sufficient.44

Lack of capacity to perform TST and chestradiograph-based screening is a barrier to theprovision of preventive therapy. Symptom-basedscreening (Fig. 1) may offer a feasible alternativeand has been promoted by the WHO for initialscreening in resource-limited settings.39 In a recentsurvey in South Africa, about 70% of child TBcontacts were completely asymptomatic at the

time of screening.45 The TST result did not influ-ence patient management and none of the asymp-tomatic children had signs of complicated orprogressive disease on chest radiography, indi-cating likely adequacy of preventive therapy in allasymptomatic children. This suggests that asymp-tomatic high-risk contacts should be offeredimmediate access to preventive therapy even ifadditional screening tests are unavailable. Addi-tional investigations could be reserved for theminority with symptoms suggestive of TB andthose who may develop these symptoms whilereceiving preventive therapy. The current algo-rithm does not indicate the need for and timingof an HIV test, although in settings endemic forTB/HIV all children with symptoms suggestive ofHIV infection and/or TB disease should be testedfor HIV. Children of a parent known to be infectedwith HIV should also be tested. HIV testing shouldbe done at the initial screening, because it influ-ences the management of the child. If TB diseaseis excluded in an HIV-infected child, both TB andcotrimoxazole preventive therapy should be

&Also consider if the mother or primary caregiver has sputum smear-negative pulmonary TB

*Symptomatic: If TB is suspected, refer to local guidelines on diagnosis of childhood TB# Isoniazid 10/mg/kg daily for 6 months $ Unless the child is HIV-infected (in which case isoniazid 10/mg/kg daily for 6

months is indicated)

Child in close contact with a case of sputum smear-positive TB &

Less than 5 years 5 Years and Over

Well$

Symptomatic*Well Symptomatic*

No Treatment

If becomes Symptomatic*

Preventive Therapy#

If becomes Symptomatic*

Evaluate for TB disease

Fig.1. Suggested approach to contact management when chest radiography and tuberculin skin testing are notreadily available. (Adapted from World Health Organization. Guidance for national tuberculosis programmes onthe management of tuberculosis in children. World Health Organization 2006; with permission. Available at:http://whqlibdoc.who.int/hq/2006/WHO_HTM_TB_2006.371_eng.pdf.)



provided and the child assessed for initiation ofantiretroviral therapy. TB disease should be ruledout if the child develops symptoms suggestive ofTB at any time.

A positive TST simply indicates TB infection andcontributes no additional information other thana history of close contact with a case of infectiousTB. The limitations of a negative TST test are wellknown especially in malnourished, HIV-infected, orsick children with possible disseminated disease.As a result of suboptimal sensitivity and becauseTST conversion can be delayed for 2 to 3 months,preventive therapy is indicated in all high-riskcontacts irrespective of the initial TST result.Repeat TST may help to rule out the possibility ofTB infection in an immune-competent childguiding early termination of preventive therapy,but this is rarely feasible in resource-limitedsettings. Interferon-gamma release assays(IGRAs) are an alternative to the TST. T cells arestimulated with M tuberculosis–specific antigensincluding early secreted antigenic target 6 (ESAT-6) and culture filtrate protein 10 (CFP-10), whichare not found in M bovis BCG and most environ-mental mycobacteria. Two assays are currentlyavailable as commercial kits: the T-SPOT.TB test(Oxford Immunotec, Oxford, UK), and theQUANTIferon-TB Gold In-tube assay (CellestisLtd, Carnegie, Australia). As with the TST, IGRAsfail to differentiate latent infection from activedisease and do not offer a reliable measure of rein-fection. Although IGRAs are supposedly morespecific than the TST, specificity and sensitivityassessments are difficult to perform in theabsence of a gold standard test and in the pres-ence of highly discordant results.46–48 In nonen-demic areas with sufficient resources IGRAs arecurrently recommended for immigrant screening,mainly because of the improved specificity.However, high cost and limited expected benefitprecludes its use in TB-endemic areas.

Preventive Chemotherapy Options

INH monotherapyA meta-analysis of randomized controlled trialsthat included 73,375 HIV-uninfected adults andchildren found that INH preventive therapyreduced the risk of disease by 60% (relative risk[RR] 0.40, 95% confidence interval [CI] 0.31–0.52) compared with placebo, and that there wasno significant difference between 6- and 12-monthcourses.49 A large prospective study over 30 yearsobserved 1882 TB-infected children in the UnitedStates who received INH for 9 to 18 months andwere followed up for a mean of 6.1 years.50,51

Only 8 children developed overt disease,

a morbidity rate of 4.2/1000 persons; 7 of 8 wereadolescents with pulmonary TB in whom re-infec-tion could not be ruled out and one had docu-mented INH resistance. None of the childreninfected before the age of 4 years developeddisease, demonstrating high levels of protectioncompared with natural history data.33 Availableefficacy data support current recommendationsfor 6 to 9 months of INH. However, effective imple-mentation requires strategies that will ensureoptimal adherence. Most NTP manuals recom-mend screening of child contacts and provisionof INH to at-risk children, but implementation isoften nonexistent or very poor.52 Even in nonen-demic areas with adequate resources such asthe United States, contact management does notalways reach recommended targets ofcoverage.53

The efficacy of INH preventive therapy in adultswith TB/HIV coinfection is discussed in detail in thenext section. One study investigated the effect ofuniversal INH given to all HIV-infected infants, irre-spective of documented TB exposure.54 Theplacebo arm was discontinued after recruitmentof just 263 children (median follow-up of 5.7months) because a significant reduction inmortality was observed in those receiving INH(8% vs 16%, hazard ratio (HR) 0.46, 95% CI0.22–0.95). TB incidence was also significantlylower in the group receiving INH and all cases ofTB confirmed by culture occurred in the placebogroup. However, the reduction in mortalityobserved was not related to less TB disease. Afollow-on study conducted in the same settingfailed to demonstrate benefit from universal INH,when conducted against a background of meticu-lous exposure screening at enrollment and provi-sion of INH to all children with documented TBexposure (M. Cotton, personal communication,2009).

Combination therapyRifampicin (RMP) has strong sterilizing activity andwhen combined with INH the duration of preven-tive therapy required may be shortened.55,56 Spyr-idis and colleagues57 randomized 926 childrenwith latent TB infection to receive 9 months INHversus 4 or 3 months INH/RMP dual therapy andfollowed them for at least 3 years. No child inany group developed TB disease or adverse reac-tions to therapy, but adherence was better with theshorter regimens. There are no similar data on HIV-infected children but data from adult studiesincluding a large number of HIV-infected adults re-ported equivalence between 3 months INH/RMPand INH alone for 6 to 12 months.58 Pyrazinamide(PZA) is another important sterilizing drug that is

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active against semi-dormant mycobacteria.55,56 Acombination of RMP/PZA for 2 to 3 months seemsas efficacious as INH for 6 to 12 months in HIV-in-fected and uninfected adults,59 but there are nosimilar data comparing efficacy in children.

Implementation of Contact Management

Despite the sound scientific basis underlyingcurrent recommendations and their enormouspotential to reduce the burden of TB disease inchildren, contact screening and managementrarely happen in resource-poor countries. Tworecent studies from Malawi demonstrated thatless than 10% of child TB contacts were screenedor offered preventive therapy.42,52 In thosesuccessfully screened, the prevalence of infectionand suspected TB disease was high.20 Opportuni-ties for early TB diagnosis in symptomatic childrenand the provision of preventive therapy to asymp-tomatic contacts are frequently missed. Healthcare services are severely overburdened inresource-limited settings, especially those copingwith concurrent TB and HIV epidemics, whichemphasizes the need to identify pragmatic andfeasible strategies for screening and the provisionof preventive therapy. The screening process hasoften been a major hurdle because recommenda-tions were often impossible to apply, making itlocally irrelevant. As discussed, the screeningprocess can be simplified to use clinical assess-ment alone. With this approach, screening cantake place even in settings where access to TSTand chest radiography is problematic; initialscreening will require only 1 visit to the healthservice or a visit by a health care worker to thehousehold, and the process can be decentralizedto peripheral health centers where DOTS isapplied.

To facilitate implementation and monitor theprovision of preventive therapy to high-risk

contacts, it may be sensible to add a box (Fig. 2)to the TB treatment card of all cases with positivesputum smears.39 Achievable goals for practicecould then be set and monitored by the NTP. Insettings where health services are severelystrained, the provision of preventive therapy couldbe restricted to the highest-risk groups. Data fromthe prechemotherapy era indicate that children in-fected before 2 years of age experience the great-est risk and that more than 95% of children whodevelop disease do so within 1 year of infection;therefore, it seems prudent to classify all childrenless than 3 years old as high-risk.35 Those incontact with a index case with a positive sputumsmear (or a primary caregiver with a negativesputum smear and pulmonary TB) would requirepreventive therapy. This restricted focus,compared with all children less than 5 years ofage, should substantially reduce the workloadand make the provision of preventive therapy tothose at highest risk more feasible. Presently, allchildren with concomitant HIV infection are classi-fied as high-risk and require a course of INH aftereach documented exposure to TB. Following initi-ation of antiretroviral therapy, those with undetect-able viral loads and normal CD4 counts are lessvulnerable, but immune recovery is nevercomplete and heightened vigilance remainswarranted.

The Millennium Development Goals aim toreduce mortality in children less than 5 years ofage, and the prevalence of and deaths causedby TB by 2015. These targets deal with the overallburden of TB and its contribution to disease anddeath in young children. Treating child contactsshould have an increasingly important place onthe NTP agenda. At an international level, the polit-ical commitment to reduce the prevalence andseverity of pediatric TB in endemic areas isgrowing, but at a national and regional levelmany obstacles remain. Although more resources

Name ofcontact

Age(years)

TBsymptoms

(Y/N)

Preventivetherapy(Y/N)

TBtreatment

(Y/N)

TBregistration

number

Treatment outcome

HIVatusst/ - / (+

NT)

Fig. 2. Proposed contact screening register to be added to the treatment card of all patients with a sputumsmear-positive for TB. NT, not tested.



will be needed for implementation, many practicaland logistical barriers can be overcome by usinga simple decentralized screening process. Crea-tive efforts are required to improve the visibility ofpediatric TB as a public health concern and toraise awareness about the value of preventivetherapy among caregivers, health care workersand policy makers.

ADULT PERSPECTIVE

As discussed earlier, complementary strategiesmust be considered to reduce the individualmorbidity and mortality associated with TB inendemic areas and to limit the spread of theepidemic. Preventive therapy offers an attractiveaddition to the treatment of active disease. Thissection defines the groups most at risk, presentsthe evidence for treatment of latent infection andthe more limited data on secondary prophylaxis,describes options for different drug regimens,and considers the 2 major challenges of adher-ence and exclusion of active TB. Managingcontacts of patients with multidrug-resistant TBand the effect of antiretroviral therapy on TBprevention strategies are also discussed briefly.

Who Should Receive Preventive Therapy?

TB preventive therapy is recommended for high-risk groups including people living with HIV,60

those on immune suppressive therapy,61 renaldialysis and transplant patients,62 and individualsin close contact with TB patients, including pris-oners,63 household contacts,64 and health carestaff.65 In addition, individuals who migrate fromendemic to nonendemic countries are usuallyscreened and offered preventive therapy if latentlyinfected with the aim of eradicating the pool oflatent infection from which future disease mayarise.66

HIV-infected individualsMost of the recent work on screening and provi-sion of preventive therapy has been conductedamong people living with HIV. The incidence rateratio (IRR) used by the WHO to reflect the relativerisk of developing TB in HIV-infected individualscompared with HIV-uninfected people hasrecently been revised upwards.1 In countries witha generalized HIV epidemic (ie, countries wherethe prevalence of HIV is more than 1% in thegeneral population), the IRR is estimated to be20.6 (95% CI 15.4–27.5) and this increases to36.7 (95% CI 11.6–116) in countries where theprevalence of HIV in the general population isless than 0.1%.1 People living with HIV are at riskof reactivating distant (latent) TB infection or

progressing to active TB after recent infection, atall levels of immunosuppression. In a retrospectivecohort study in the South African gold mines, therelative risk of incident TB in HIV-infected individ-uals was 3 times that of HIV-uninfected individualsduring the first 2 years after seroconversion,increasing to almost 10 after 10 years of HIV infec-tion.67 It was hoped that widespread use of antire-troviral therapy would reduce the risk of TB forthose taking it, and although this is true theresidual risk remains high with incident rate ratios3 to 5 times that of the HIV-uninfected popula-tion.68,69 Current CD4 cell count is the mainpredictor of TB risk and highly active antiretroviraltherapy (HAART) strategies that minimize the timepatients spend with CD4 cell counts less thana threshold of 500 cells/mL would seem to offerthe best preventive strategy.70

HIV-uninfected individualsThe increased risk of TB in HIV-uninfected indi-viduals with immunosuppression is highly vari-able. A review of the incidence of TB amongpatients with long-term steroid use found anincreased risk of between 5 and 60 times thatof the general population, although some studieshad few cases.71 Individuals exposed to multiplecases of TB, such as health care workers andpeople in institutional settings, have a higherrisk of infection. A review of studies that evalu-ated the risk of TB infection and disease in healthcare workers in endemic countries reported IRRsranging between 0.7 and 13.6 with annual noso-comial transmission risks of up to 11.3%.72

Similar findings with lower overall risks havebeen reported in nonendemic countries.73 Duringperiods of high intensity exposure, such individ-uals might benefit from primary prophylaxis ortreatment of latent infection if TST conversionoccurs, although no randomized studies havebeen conducted. Among nurse trainees, thosewith an initial negative TST (previously uninfected)are at higher risk of disease developmentfollowing TB exposure than those with pre-existing latent infection (TST positive), whichmay indicate that primary infection posesa greater risk than reinfection in young adults.74

Options for Preventive Therapy

Several drug regimens have been used as preven-tive therapy in adults including INH or RMPmonotherapy and combination therapy with INH,RMP or PZA. Different durations have also beenused ranging from 2 months for regimens contain-ing RMP to more than 12 months with INHmonotherapy.

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HIV-infected individualsA meta-analysis of 11 studies in HIV-infected indi-viduals, including studies from TB-endemic andnonendemic countries, reported a 36% reductionin active TB (relative risk (RR) 0.64, 95% CI0.51–0.81) for any drug combination, includingall individuals regardless of TST result.75 Thismeta-analysis found an overall reduction in theincidence of TB, but not in all-cause mortality.Benefit was greatest in those who were TST posi-tive (RR 0.38, 95% CI 0.25–0.57); in those whowere TST negative there was no statistically signif-icant effect (RR 0.83, 95% CI 0.58–1.18). Thestudies varied in the drugs (INH, INH plus RMP,RMP plus PZA, or INH plus RMP plus PZA), thedosage (INH 300 mg/600 mg daily, INH 600/900 mg twice weekly, RMP 450/600 mg), thedosing interval (daily, twice weekly) and the dura-tion (2–3 months for combination and 6–12 monthsfor INH alone) of treatment provided. Table 1presents a summary of randomized trials thatevaluated the value of TB preventive therapy inHIV-infected adults.76–85 Studies of TST-negativeand anergic individuals failed to show any benefit;head-to-head comparisons of different regimensshowed no statistically significant differences inoutcome.59

Observational studies from Haiti suggesteda limited postpreventive therapy effect, dependenton the duration of INH monotherapy provided.86 Instudies from Zambia and Uganda, the duration ofeffect was approximately 3 years. In the Zambianstudy there was no difference between the INHor RMP/PZA regimens,87 whereas in Uganda theRMP/INH/PZA regimen was found to have a longerduration of effect.88 Both studies were added tothe original trials and suffered excessive loss tofollow-up. However, the limited duration of effectis not surprising because transmission in endemicareas is ongoing and preventive therapy offers noprotection against new infections following cessa-tion of therapy. The only way to protect vulnerableindividuals against reinfection would be toconsider prolonged or repeated courses ofpreventive therapy. A study in South Africaincluded continuous INH as 1 arm in a 4-armrandomized controlled trial, but failed to showthat it was significantly more efficacious thana 6-month course of INH.89 A larger study lookingat the efficacy, safety, and tolerability of prolongedpreventive regimens is still underway.

HIV-uninfected individualsA Cochrane meta-analysis of 11 studies onpreventive therapy in HIV-uninfected individualsincluded diverse risk groups.49 Most of thesestudies used INH 300 mg daily for adults and the

combined efficacy was a reduction in active TBof 60% (RR 0.4, 95% CI 0.31–0.52) comparedwith the placebo group. A review of 4 nonrandom-ized trials examining the efficacy of INH in patientstreated with glucocorticosteroids reported mixedresults.71 Studies from India90 and Mexico91 re-ported benefit with INH preventive therapy,whereas studies from Hong Kong92 and Japan93

showed no benefit. Interpretation of these resultsis difficult because of the nonrandomized natureof the studies, different TB prevalence rates, andthe low number of participants. In 1 randomizedstudy of INH taken by renal transplant recipientsfor 12 months in Pakistan, a significantlydecreased risk of TB was found in the first 2 yearspost-transplantation with no discontinuationsbecause of drug toxicity.94

An International Union against TB trial con-ducted in Eastern Europe compared 3, 6 and12 months of INH preventive therapy in individ-uals with fibrotic changes on chest radiog-raphy.95 Only the 6- and 12-month regimensreduced the number of TB cases comparedwith placebo, with no difference between the2 regimens. Subgroup analysis of adherentindividuals showed increased benefit with thelonger regimen, but adverse effects were morefrequent. Evidence from large communitylevel7,96 and household contact studies97 con-ducted in North America also suggested benefitfrom longer duration INH therapy, but there wasno added benefit beyond 12 months. The largecommunity trial conducted among the Inuit pop-ulation in Alaska suggests that the protectiveeffect of INH may persists for more than 10years.7,96 However, with this mass population–based intervention study, preventive therapywas implemented along with active case-findingand treatment of all diseased individuals, whicheliminated the pool of latent infection andongoing transmission at the same time.

Screening

TB screening is indicated to assess the risk ofdeveloping TB in the future and to exclude currentactive TB. Confidently excluding active TB beforeadministration of preventive therapy is problem-atic, especially in individuals infected with HIVwho are more likely to develop TB with negativesputum smear. Current recommendations arethat a symptom screen and chest radiograph, ifpossible, should be used to exclude active TB inhigh-risk adults. The symptoms generally usedinclude prolonged cough (prolonged or for 2–3weeks), night sweats, fever, unintentional weightloss and chest pain or shortness of breath.



Table1Summary of randomized trials evaluating the benefit of differentTB preventive therapy regimens in HIV-infected individuals

Study Location,Year Doneref

Number ofParticipants

% TSTPositive

TreatmentProvided

DurationinMonths

TB rate/100Person-Years RR (95% CI)

Haiti, 199359 58 66 INH/B6a 12 2.2 0.29 (0.09–0.91)

60 42 B6 (12) 12 7.5 1

Kenya, 199786 342 22 INH 6 4.29 0.92 (0.49–1.71)342 23.5 Placebo 6 3.86 1

Uganda, 199787,d 536 100 INH 6 1.1 0.33 (0.14–0.77)556 100 INH/RMP 3 1.3 0.40 (0.18–0.86)463 100 INH/RMP/PZA 3 1.7 0.51 (0.24–1.08)464 100 Placebo 6 3.4 1395 Anergice INH 6 2.53 0.83 (0.34–2.04323 Anergice Placebo 6 3.06 1

USA, 199788 260 Anergice INH/B6 6 0.4 0.48 (0.12–1.91)257 Anergice Placebo/B6 6 0.9 1

Zambia, 199889 350 23 INH 6b 2.74 0.56 (0.3–1.05)351 22 RIF/PZA 3b 3.16 0.65 (0.35–1.19)352 27 Placebo 6b 4.94 1

Haiti, 199890 370 100 INH 6 1.7 N/Ac

370 100 RMP/PZA 2 1.8 N/Ac

Haiti, Brazil, Mexico,USA 200091

792 100 INH 12 1.1 1791 100 RMP/PZA 2 0.8 0.72 (0.40–1.31)

Haiti, 200192 111 0 Placebo/B6 6 1.5 1126 0 INH/B6 6 1.9 1.26 (0.36–4.37)

Spain, 200393 77 Anergice None 3.1 183 Anergice INH 6 3.4 1.07 (0.24–4.80)82 Anergice RMP/INH 3 3.1 0.98 (0.22–4.40)77 Anergice RMP/PZA 2 1.2 0.39 (0.04–3.48)

South Africa, 200794 50 Anergice Placebo 12b 11.6 (4.2–25.2) 148 Anergice INH 12b 18 (8.2–34.1) 1.59 (0.57–4.49)

a Pyridoxine (vitamin B6).b Twice weekly regimens.c Not calculated in paper.d Counted as 2 studies in meta-analysis: 1 for TST positives and 1 for anergic.e Anergy was defined as being TST negative and also anergic to other common antigens on skin testing, eg, mumps, candida, tetanus and so forth.

Mara

iset

al

836


However, the predictive values of this screeningapproach are variable and would be highly depen-dent on the symptom definitions used, the rigorwith which it is performed, and the presence ofsevere immune compromise. Symptom-basedscreening will miss some cases of TB,98 but chestradiographs are often unavailable in endemicareas and insistence on their use may limit accessto preventive therapy. Routine chest radiographsincreased the sensitivity in an extremely high-riskgroup of gold miners,99,100 but its value has notbeen confirmed in a more generalized populationwith a lower prevalence of TB.101 An importantmeasure from a safety perspective is the negativepredictive value of the screening test, which variesdepending on the prevalence of TB in the popula-tion.102 Reliably ruling out active TB remainsa contentious area that requires ongoing surveil-lance and research to identify more accuratemarkers of disease. In HIV-infected individualsthe benefit of preventive therapy has only beenshown in those with a positive TST. IGRAs have re-placed the TST in some high-income countries asa result of increased specificity,103 but neither testis widely available in TB-endemic countries; insituations where they have been implemented,their use presented a significant barrier totherapy.104

OVERLAPPING ISSUESAdherence

Adherence to preventive therapy is a major chal-lenge in all populations studied. Preventivetherapy does not provide immediate benefit tothe patient, but may be associated with adverseeffects that are unpleasant and immediatelyapparent. Highly variable adherence rates (20%–80%) have been reported, being higher in closelycontrolled trial settings than in real world situa-tions.104–107 Risk factors for nonadherence inadults include homelessness, male gender, age,and health beliefs.108–110 Groups at highest riskof developing TB also have the greatest adherencechallenges as a result of poverty, concomitantillness, or the need for additional chronic medica-tion. In general, shorter duration regimens arestrongly associated with increased adherence inadults,81,111 although completion rates of shortercourse combination therapy were not improvedcompared with 6 months of INH monotherapy ina retrospective study among migrants and refu-gees in Australia.112 Measuring adherence is diffi-cult. Most programs use pill collection and/orpatient self-reporting. Urine testing for INH metab-olites can be done using the Arkansas method orstrip tests,113 but added value may be limited if

only performed during scheduled visits. Cashand nutritional incentives have been shown toimprove adherence.107,114 Careful considerationshould be given to optimal implementationstrategies.

With children it is difficult to convince families ofthe need for 6 months or more of medication plusregular follow-up visits when the child is andremains well. Health workers are also not alwaysconvinced of the need for preventive therapy. Ina recent survey of medical staff in 2 hospitals inNew York, those trained in TB-endemic countrieswere less likely to treat latent TB infection thanUS-trained graduates despite both groups havingsimilar knowledge of the recommendations.115 Aprospective study of South African children re-ported that of household TB contacts screenedand advised to receive INH for 6 months, only20% completed more than 4 months of unsuper-vised therapy.116 In a separate retrospectivestudy, adherence to INH/RMP for 3 months wassignificantly better than adherence to INH for 6months (69.6% vs 27.6%, OR 4.97, 95% CI2.40–10.36).117 Experience from the United Statesand Greece also showed superior treatmentcompletion rates among patients taking shortercourses of therapy compared with those takingINH for 9 months.57,118 Because effectiveness isdetermined by efficacy and adherence, short-course combination regimens that are equivalentin efficacy to 6 to 9 months of INH under trialconditions may improve real life effectiveness.Alternative strategies to improve adherence,such as intermittent supervised therapy, alsorequire further evaluation.

Adverse Events

It is important that preventive therapy is well toler-ated. Adverse events reported with the use ofpreventive therapy are generally mild with fewepisodes of hepatotoxicity. A meta-analysis thatcompared INH with RMP/PZA in HIV-infected indi-viduals found no difference in the number ofadverse events or death.59 However, there seemsto be a major difference between the HIV-infectedand uninfected groups in the incidence of adverseevents with the RMP/PZA regimen. Combiningtrials performed among HIV-uninfected individualsshowed that 8.2% of participants receiving RMP/PZA discontinued drugs because of severe hepa-totoxicity compared with 1.7% of those receivingINH alone.59 No mortality as a result of hepatotox-icity was reported, although cohort data collectedin the United States did find an increased risk ofhepatotoxicity and death following RMP/PZA



preventive therapy and its use is no longerrecommended.119,120

The major adverse events associated with first-line TB drugs in children were recently reviewed; ingeneral, children tolerate TB drugs better thanadults.121 This may reflect differences in preva-lence of other risk factors such as alcohol use orunderlying hepatic disease, and/or differences inpharmacokinetics as serum levels are lower in chil-dren than in adults using the same mg/kgdosages.122–124 Most reports of adverse eventsare with the use of INH alone, reflecting its long-standing and widespread use as preventivetherapy. The major concern is hepatotoxicity andthere are occasional case reports of severe INH-induced hepatitis and even hepatic failure.118,125

However, prospective studies including largenumbers of children using INH at daily dosagesof 5 to 15 mg/kg for 6 to 12 months show thatclinical hepatotoxicity is very rare. Jaundice wasreported in 1 of more than 3500 childrenfrom studies using INH prophylaxis at 10 to20 mg/kg.51,57,126–131 Subclinical transient trans-aminase elevation is observed in 5% to 10% ofchildren receiving INH,130,131 the highest ratesbeing reported in adolescents,132 but routinemonitoring is not recommended. An 11-yearprospective trial conducted in Greece detectedno serious drug-related adverse events with 9months of INH or 3 to 4 months of RMP/INH.57

RMP/INH dual therapy was also well tolerated inlarge observational studies from the UnitedKingdom.133,134 Hepatotoxicity caused by RMP/PZA seems related to HIV infection status andage. Data in children are limited but standardfirst-line therapy that includes RMP and PZA iswell tolerated and no hepatotoxicity was reportedin 86 HIV-uninfected children who received 2months of RMP/PZA preventive therapy.135,136

Creating Drug Resistance

The reason why accurate exclusion of TB diseaseis crucially important is that inadvertent treatmentof active disease with 1 or 2 drugs could selectfor drug resistance. A systematic review of INHresistance amongst individuals who had receivedINH preventive therapy showed a relative risk of1.45 (95% CI 0.85–2.47).137 Although this is nota statistically significant finding, it representsa trend towards increased INH resistance,possibly as a result of secondary selection ofINH resistant strains or a shift towards diseasecaused by primary resistant strains not respondingto INH preventive therapy. Fear of inducing drug-resistant TB is the most frequently cited reasonwhy countries are reluctant to implement INH

preventive therapy strategies.100 This fear is notunfounded, because the exclusion of activedisease can be extremely challenging in HIV-in-fected patients and effects that are nonsignificantin small scale trials may be amplified on a publichealth scale. INH is the most potent TB drug avail-able and is crucial to rapidly reduce the organismload, which terminates transmission and protectscompanion drugs against resistance. Currentevidence suggests that the standard 4-drugregimen used in adults should still be sufficient toeffect cure in most patients with INH monoresist-ant disease,138 although the theoretic risk ofacquiring multidrug-resistant (MDR)-TB isincreased. Good data collection from countriesthat have implemented universal INH preventivetherapy in HIV-infected adults, such as Botswana,is vital to guide international policy.

The situation in young children is completelydifferent. Children tend to develop pauci-bacillarydisease, which implies a greatly reduced risk ofacquiring drug resistance because the microbialload is low and drug penetration is good. In addi-tion, young children rarely infect those aroundthem and therefore the risk of transmitting drug-resistant disease within the community, should itdevelop, is minimal. Therefore concerns regardingthe creation of drug resistance should not preventthe provision of preventive therapy to children.

Contact with Drug-resistant TB

Preventive therapy for close contacts of individ-uals with drug-resistant TB is more complex. Arecent systematic review found no randomizedtrials and only 2 observational studies on closecontacts of cases of drug-resistant TB.139 Onesmall retrospective study from Brazil used INH400 mg daily for 6 months and found that fewerTST positive contacts developed TB in the treatedgroup compared with the untreated group (OR0.46, 95% CI 0.07–2.32).140 The cases of TB thatdeveloped in the treated group had the samedrug-resistance patterns as their presumedsource cases, which is also true for children withdrug-resistant TB, and demonstrates the need totake cognizance of drug resistance among likelysource cases.141 Drug-resistance patterns amongchildren with TB provide an accurate measure oftransmitted drug-resistant disease within commu-nities.142 Prospective surveillance data from CapeTown, South Africa, suggests an upward trend ofdrug-resistant TB among children,143 with an over-representation of certain genotypes such as Bei-jing and Haarlem,144 indicating successfultransmission of these drug-resistant strains. Theclinical presentation and basic principles guiding

Marais et al838


the management of drug-resistant disease aresimilar to those of drug-susceptible TB.

MonoresistanceResistance to INH is usually the first step in thedevelopment of MDR; therefore, it is importantfrom a public health perspective to monitor theprevalence of INH monoresistance. For the provi-sion of preventive therapy to high-risk contactsof an infectious INH monoresistant index case,RMP alone for 4 months should suffice. Monore-sistance to RMP is uncommon, although it seemsmore common among patients infected with HIV.INH preventive therapy should be sufficient forhigh-risk contacts of true RMP monoresistantcases. However, RMP resistance is frequently re-garded as a marker for MDR and cases are usuallymanaged as MDR-TB.

MDRThe term MDR-TB implies resistance to the mostpotent drugs in the first-line regimen, INH andRMP, with or without resistance to other TB drugs.The evidence base for the provision of preventivetherapy to close contacts of MDR-TB cases islimited. Because second-line drugs are generallymore toxic, a rational guide for preventive therapywould be to restrict this to high-risk contacts (chil-dren <3 years of age and those with severe immunecompromise) and to use at least 2 drugs to whichthe organism is susceptible (or the presumedsource case naive) for a duration of at least 6months.145 A single, prospective, cohort study inchildren reported a significant reduction in activedisease among those receiving preventive therapycompared with those who did not (OR 0.2, 95% CI0.04–0.94) using the strategy outlined earlier.146

Extensive drug-resistant (XDR)-TB implies resis-tance to INH, RMP, the fluoroquinolones, anda second-line injectable agent such as kanamycin,amikacin, or capreomycin. Treatment options forthese patients are extremely limited. Currentlypreventive therapy for XDR contacts is not advised,but in the light of possible low- or intermediate-levelINH resistance, high-dose INH (15 mg/kg) mayprovide some protection to high-risk contacts.

Cost Effectiveness

Studies of TB preventive therapy in high- and low-income settings have found it to be cost effectiveand feasible, but clear program aims, adherenceto guidelines, and high rates of preventive therapyare essential to achieve cost-effectiveness.147–149

However, fears about drug resistance, feasibilityconcerns, and competing priorities have pre-vented most endemic countries from implement-ing wide-scale TB preventive therapy programs.

Screening for active TB in high-risk groups, espe-cially HIV-infected populations, is not only an entrypoint for TB preventive therapy but also identifiesTB cases who can be treated promptly therebyimproving treatment outcomes and reducingtransmission. In children, the identification offeasible strategies for the provision of preventivetherapy to high-risk contacts provides an opportu-nity to reduce the massive pediatric diseaseburden in TB-endemic areas, although cost-effectiveness has not been formally assessed.

Options for HIV-infected Patients

Apart from treatment of latent infection, there isgrowing evidence that secondary preventivetherapy, that is, prevention after a first episode ofTB, can reduce the risk of recurrent TB amongindividuals infected with HIV in endemicareas.100,150,151 Recurrent TB may occur asa result of relapse or reinfection and is commonamong children and adults infected with HIV inTB-endemic areas.152,153 In a study from theSouth African mines, the incidence of recurrentTB was reduced by 55% among those whoreceived INH (incidence rates 8.6 vs 19.1/100person-years, IRR 0.45, 95% CI 0.26–0.78).151

The efficacy of preventive therapy was unchangedafter controlling for CD4 cell count, although thegreatest benefit was derived among the moreseverely immune compromised. The number ofperson-years of INH preventive therapy requiredto prevent 1 case of recurrent TB among individ-uals with a CD4 cell count less than 200 cells/mLwas 5; 19 for those with counts greater than 200cells/mL. No similar study has been conducted inchildren infected with HIV.

Antiretroviral therapy reduces the incidence ofTB in individuals infected with HIV especially thosewith the lowest CD4 counts.154,155 However, therisk of developing TB while taking antiretroviraltherapy remains higher than the risk for HIV-unin-fected individuals. Randomized trials to establishthe additional benefit of INH preventive therapyconfirm that the combination has additive protec-tive effect and that it is safe,156,157 although dataon TST-negative individuals and pregnant womenare lacking. In children, early initiation of antiretro-viral therapy provides clear survival benefit andreduces the likelihood of developing TB.158,159

However, assessment of potential TB exposureshould be routine at every follow-up visit, andwith documented TB exposure, even if this occursmultiple times, INH preventive therapy is indicatedin young or immune-suppressed children.



SUMMARY

Contact screening has an important role in identi-fying close contacts with TB who require treatmentand those at risk for future disease who requirepreventive therapy. With limited resources andhigh rates of TB transmission, endemic countriesneed to focus on specific at-risk groups, whereasnonendemic countries may elect to providepreventive therapy to all individuals with docu-mented TB infection and/or exposure. The majorat-risk groups are young children and individualsinfected with HIV. There is good evidence of effi-cacy and tolerance of preventive therapy in thesepopulations, but adherence is a common problemand effective implementation is a major challenge.

Reliably excluding TB disease in individuals in-fected with HIV and the additional burden placedon already strained health care services requirecareful consideration. Where feasible strategiesare implemented, the short- and long-term effectsshould be closely monitored. However, there arefew complicating factors to consider in child TBcontacts and the provision of preventive therapyto all high-risk children should be regarded asthe standard of care, irrespective of the resourcesavailable.

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