Prevention and treatment of perinatal and infant tuberculosis in the HIV era

Abstract

ENGLISH ABSTRACT : Infants (<12 months) born to women with tuberculosis are at high risk of Mycobacterium tuberculosis (M. tuberculosis) exposure, infection and disease early in life. In settings with high prevalence of human immunodeficiency virus (HIV) and tuberculosis, tuberculosis disproportionately affects women of childbearing age. The aim of this dissertation was to comprehensively investigate prevention and treatment strategies for perinatal and infant tuberculosis in a high HIV-prevalence setting. Research objectives included: 1) defining clinical and epidemiological aspects of maternal-infant tuberculosis at a large referral hospital; 2) identifying barriers and solutions to isoniazid preventive therapy (IPT) delivery in tuberculosis-exposed newborns; and 3) obtaining rigorous pharmacokinetic data to guide the dosing of firstline antituberculosis drugs in newborns and infants for the prevention and treatment of tuberculosis. In the first retrospective study, 70 newborns (42 HIV-exposed) were investigated for tuberculosis at Tygerberg Hospital, a large provincial referral hospital in Cape Town. Newborns were mainly screened for tuberculosis because of maternal tuberculosis. Isoniazid preventive therapy (IPT) was initiated in 36/50 (72%) newborns, because of maternal tuberculosis infectious risk and exposure of infants. Few of the newborns who received IPT were traceable at one-year, and of those traced, less than half completed IPT. To generate more rigorous clinical and epidemiological data on maternal-infant tuberculosis, a prospective cohort study was conducted in pregnant and postpartum women receiving tuberculosis treatment at Tygerberg Hospital. Over a one-year period, 74 pregnant and postpartum women, 53 (72%) HIV-infected, were consecutively enrolled. Nearly half of the women, 35 (47%) were diagnosed with tuberculosis only at delivery or postpartum, and a third of women with tuberculosis reported prior tuberculosis treatment. Tuberculosis-exposed newborns were often premature and of low birth weight (LBW; <2500 grams). All deaths occurred in HIVinfected women (n=5) and all stillbirths (n=4) and newborn deaths (n=6) were from HIV-infected women. Favourable maternal tuberculosis treatment outcomes (cure and tuberculosis treatment completion) were documented only in 41/74 (55%) women, while 33 (45%) had unfavourable treatment outcomes (death, treatment failure and loss to follow-up). These poor observed outcomes highlight the need for earlier diagnosis and treatment of tuberculosis during pregnancy, and close follow-up to ensure maternal tuberculosis treatment completion. Improved care for pregnant women with tuberculosis, with and without HIV infection, will likely reduce morbidity and mortality in mothers and tuberculosis-exposed newborns. Delayed maternal tuberculosis diagnosis led to IPT initiation in a large number of newborns. Forty-four newborns on IPT were followed to 6 months. A hospital-based tuberculosis linkage to care intervention, led to 29/44 (66%) newborns completing IPT without a study team intervention. A further 8 infants completed IPT after studyteam intervention. Appropriate tuberculosis referral and linkage to care from hospital to local tuberculosis clinic substantially improved IPT completion among tuberculosis-exposed newborns. More pharmacokinetic data regarding the appropriate use of antituberculosis drugs are required in neonates and infants, who undergo considerable physiological changes in the first year of life. An intensive isoniazid (INH) pharmacokinetic study was therefore designed and implemented in premature and LBW infants (n=20). Relatively high median INH peak concentrations of 5.63 μg/ml were achieved in LBW infants (at an INH dose of 10 mg/kg), compared to the adult proposed target value of > 3 μg/ml. INH exposures were higher with longer half-lives in smaller infants, and among genotypically determined N-acetyltransferase-2 (NAT2) slow acetylators, suggesting reduced clearance of INH. This first study of isoniazid use in LBW and premature neonates showed that the INH dose in premature and LBW infants should probably not exceed 10 mg/kg/day. The final study evaluated whether the revised higher 2009 World Health Organization (WHO)-recommended paediatric doses for rifampicin (RMP), INH, pyrazinamide (PZA) and ethambutol (EMB) achieved adequate drug concentrations in infants, compared to current adult pharmacokinetic target concentrations. All 39 infants enrolled achieved the minimum proposed adult target peak concentrations of > 3 μg/ml for INH at a mean dose of 12.8 mg/kg (10.3 - 15.4 mg/kg), and the minimum adult target of > 20 μg/ml for PZA at a mean dose of 33.3 mg/kg (28.5 – 38.5 mg/kg). RMP administered at mean dose of 15.4 mg/kg (10.1 - 20.5 mg/kg) resulted in very low RMP peak concentrations for both RMP formulations used during the study. None of the infants achieved the minimum proposed adult RMP target concentration of > 8 μg/ml. Given the findings of this study, higher doses of RMP in infants should be considered especially given emerging data from adult RMP doseescalation studies showing better efficacy at higher doses with limited toxicity for short-term use. For EMB, only 1 of 16 infants achieved the recommended adult target concentration of > 2 μg/ml when given at a mean dose of 20.2 mg/kg (15.4-24.1 mg/kg). EMB dose-dependent ocular toxicity however poses a concern regarding the recommendation of higher EMB doses in infants where vision testing is challenging. This is the largest pharmacokinetic study of first-line antituberculosis drugs performed in infants to date, which has generated valuable pharmacokinetic data to inform the effective and safe dosing of first-line antituberculosis drugs in infants. Pregnant women in settings with a high burden of tuberculosis and HIV and their infants face a considerable burden of tuberculosis disease in HIV-endemic settings. Maternal-infant tuberculosis care can be improved by health systems strengthening interventions. Data generated from pharmacokinetic studies of antituberculosis drugs in tuberculosis-exposed infants will inform much needed dosing guidelines of firstline antituberculosis drugs for newborns and infants, who have a high risk of tuberculosis and are prone to develop severe forms of tuberculosis.

AFRIKAANSE OPSOMMING : Babas (<12 maande) van vroue met tuberkulose het ’n hoë risiko vir Mikobacterium tuberculosis (M. tuberculosis) blootstelling na geboorte, wat kan lei tot infeksie en die ontwikkeling van tuberkulose siekte. In gebiede met ’n hoë voorkoms van menslike immuungebrek virus (MIV) word vroue van kinderdraende ouderdom tot ’n groot mate aangetas deur tuberkulose. Die doel van hierdie verhandeling was om die voorkoming en behandelingstrategieë vir tuberkulose in die perinatale en baba tydperk omvattend te ondersoek binne die konteks van ‘n omgewing met ‘n hoë voorkoms van MIV. Navorsingsdoelwitte het die volgende ingesluit: 1) die definïering van kliniese en epidemiologiese aspekte van tuberkulose in moeders en babas by ’n groot verwysingshospitaal, 2) die identifisering van struikelblokke en oplossings vir die gebruik van isoniasied voorkomende behandeling in babas met blootstelling aan M. tuberculosis; en 3) die verkryging van betroubare farmakokinetiese data wat doseringsriglyne kan verskaf vir eerste-linie antituberkulose middels vir die voorkoming en behandeling van tuberkulose in pasgeborenes en babas. In die eerste studie is 70 pasgeborenes (waarvan 42 blootgestel was aan MIV) retrospektiewelik ondersoek vir tuberkulose by Tygerberg Hospitaal. Tygerberg Hospitaal is ‘n groot provinsiale verwysingshospitaal in Kaapstad. Pasgeborenes was hoofsaaklik vir tuberkulose ondersoek as gevolg van moederlike tuberkulose. Vanweë potensiële tuberkulose blootstelling aan pasgeborenes en die risiko dat tuberkulose moeders nog aansteeklik was, is isoniasied voorkomende behandeling gegee in 36/50 (72%) pasgeborenes. Min van die pasgeborenes wat isoniasied voorkomende behandeling ontvang het kon opgespoor word na een jaar, en minder as die helfte van die babas wat opgespoor is, het isoniasied voorkomende behandeling voltooi. ’n Prospektiewe kohortstudie is onderneem in swanger en postpartum vroue op behandeling vir tuberkulose by Tygerberg Hospitaal. Die doel van hierdie studie was om meer omvattende kliniese en epidemiologiese inligting te versamel in moeders met tuberkulose en hulle babas. Gedurende die verloop van een jaar is 74 swanger en postpartum vroue, 53 (72%) met MIV-infeksie, ingesluit in die studie. Ongeveer die helfte van die vroue, 35 (47%) was eers gediagnoseer met tuberkulose tydens verlossing of in die postpartum periode. ’n Derde van vroue met tuberkulose het ’n geskiedenis gehad van vorige tuberkulose behandeling. Tuberkulose-blootgestelde pasgeborenes was dikwels prematuur en/of gebore met ’n lae geboorte gewig (LGG; <2500 gram). Alle moederlike sterftegevalle het voorgekom in moeders met MIVinfeksie (n=5) en alle stilgeboortes (n=4) en babasterftes (n=6) was in babas van moeders met MIV-infeksie. Gunstige uitkomste van moederlike tuberkulose behandeling (genesing en voltooiïng van TB behandeling) was gedokumenteer in slegs 41/74 (55%) vroue, terwyl 33 (45%) ongunstige behandelingsuitkomste gehad het (sterfte, onsuksesvolle behandeling en verlore tydens opvolg). Hierdie ongunstige uitkomste beklemtoon die behoefte aan ‘n vroeër diagnose en behandeling van tuberkulose tydens swangerskap, asook noukeurige opvolg gedurende tuberkulose behandeling ten einde voltooiïng te verseker. Verbeterde sorg vir swanger vroue met tuberkulose, ongeag van MIV-infeksie, behoort die morbiditeit en mortaliteit in moeders en hulle tuberkulose-blootgestelde pasgeborenes te verminder. Die laat diagnose van moederlike tuberkulose tydens swangerskap het daartoe aanleiding gegee dat ‘n groot aantal pasgeborenes isoniasied voorkomende behandeling benodig het. Vier-en-veertig pasgeborens wat isoniasied voorkomende behandeling ontvang het, is vir ‘n tydperk van 6 maande opgevolg. ’n Hospitaal-gebaseerde strategie wat die koppeling van hospitaal na plaaslike TB klinieke ingesluit het, het aanleiding gegee tot die voltooiïng van isoniasied voorkomende behandeling in 29/44 (66%) pasgeborenes. Hierdie voltooiïng van isoniasied voorkomende behandeling is bewerkstellig sonder die ingryping van die studiespan. Na ingryping deur die studiespan het ‘n verdere 8 pasgeborenes isoniasied voorkomende behandeling voltooi. Toepaslike tuberkulose verwysing, wat die koppeling vanaf hospitaal na plaaslike TB klinieke verbeter het, het ‘n beduidende bydrae gelewer tot die voltooiïng van isoniasied voorkomende behandeling in pasgeborenes blootgestel aan M. tuberculosis. Verdere farmakokinetiese inligting word benodig vir effektiewe antituberkulose behandeling in pasgeborenes en babas wat aansienlike fisiologiese veranderinge in die eerste lewensjaar ondergaan. ’n Intensiewe isoniasied (INH) farmakokinetiese studie is beplan en uitgevoer in premature en LGG babas (n=20). LGG babas wat ‘n dosis van 10 mg/kg INH ontvang het, het relatiewe hoë mediane INH piek konsentrasies van 5.63 μg/ml bereik, in vergelyking met die die voorgestelde teiken waarde vir volwassenes van > 3 μg/ml. INH konsentrasies was hoër met ‘n langer half-leeftyd in kleiner babas, asook in genotipies-vasgestelde N-asetieltransferase-2 (NAT-2) stadige asetileerders, wat daarop aandui dat daar verminderde INH opruiming was. Hierdie eerste studie van isoniasied in LGG en premature pasgeborenes het aangedui dat die dosering van INH na alle waarskynlikheid nie 10 mg/kg/dag behoort te oorskry nie. Die finale studie het die gewysigde hoër 2009 Wêreld Gesondheidsheidsorganisasie (WGO)-aanbevole pediatriese doserings vir rifampisien (RMP), INH, pirasinamied (PZA) en etambutol (EMB) ondersoek, om te bevestig of voldoende geneesmiddelkonsentrasies in babas bereik word, in vergelyking met die huidige teikenkonsentrasies in volwassenes. Al 39 babas op die studie het die minimum voorgestelde volwasse teikenkonsentrasies van > 3 μg/ml vir INH bereik met die toediening van ‘n gemiddelde dosering van 12.8 mg/kg (10.3 - 15.4 mg/kg), en die minimum volwasse teikenkonsentrasie van > 20 μg/ml vir PZA met die toediening van ‘n gemidddelde dosering van 33.3 mg/kg (28.5 - 38.5 mg/kg). Rifampisien was toegedien teen ’n gemiddelde dosering van 15.4 mg/kg (10.1 - 20.5 mg/kg) en het baie lae RMP-konsentrasies tot gevolg gehad vir beide RMP formulerings wat in die studie gebruik is. Die voorgestelde volwasse RMP teikenkonsentrasie van > 8μg/ml is nie waargeneem in enige van die babas nie. Gegewe die bevindinge van hierdie studie behoort hoër doserings van RMP in babas oorweeg te word. Hoër RMP doserings is veral noodsaaklik in die lig van onlangse studies in volwassenes waar dit meer doeltreffend blyk te wees, en ook ‘n beperkte toksisiteit getoon het met korttermyn toediening. Vir EMB het slegs 1 uit 16 babas die vereiste aanbeveelde volwasse teiken konsentrasie van > 2 μg/ml bereik, met ‘n gemiddelde EMB toediening van 20.2 mg/kg (15.4 - 24.1 mg/kg). ‘n Dosis-afhanklike risiko vir oog-toksisiteit met EMB is rede tot kommer ingevolge die gebruik van hoër EMB dosisse in babas, aangesien die bepaling van sig moeilik is in babas. Hierdie is die grootste farmakokinetiese studie van eerste-linie antituberkulose geneesmiddels wat al in babas uitgevoer is en het waardevolle farmakokinetiese inligting verskaf wat bydra tot die effektiewe en veilige doserings van hierdie geneesmiddels in babas. Swanger vrouens, asook hulle babas, is baie vatbaar vir blootstelling aan M. tuberculosis infeksie en die ontwikkeling van tuberkulose in gebiede met ‘n hoë voorkoms van tuberkulose en HIV. Die sorg van moeders en babas met tuberkulose kan verbeter word deur die versterking van bestaande gesondheidssisteem strukture. Inligting verskaf van farmakokinetika studies in eerste-linie antituberkulose geneesmiddels wat in pasgeborenes en babas met tuberkulose gedoen word, sal help om die nodige doseringsriglyne te verskaf vir babas, wat n hoë risiko het vir die ontwikkeling van tuberkulose, insluitende ernstige vorms van tuberkulose.