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

[摘要] ENGLISH ABSTRACT : Infants (<12 months) born to women with tuberculosis are at high risk ofMycobacterium tuberculosis (M. tuberculosis) exposure, infection and disease early inlife. In settings with high prevalence of human immunodeficiency virus (HIV) andtuberculosis, tuberculosis disproportionately affects women of childbearing age. Theaim of this dissertation was to comprehensively investigate prevention and treatmentstrategies for perinatal and infant tuberculosis in a high HIV-prevalence setting.Research objectives included: 1) defining clinical and epidemiological aspects ofmaternal-infant tuberculosis at a large referral hospital; 2) identifying barriers andsolutions to isoniazid preventive therapy (IPT) delivery in tuberculosis-exposednewborns; and 3) obtaining rigorous pharmacokinetic data to guide the dosing of firstlineantituberculosis drugs in newborns and infants for the prevention and treatmentof tuberculosis.In the first retrospective study, 70 newborns (42 HIV-exposed) were investigated fortuberculosis 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 ofmaternal tuberculosis infectious risk and exposure of infants. Few of the newbornswho received IPT were traceable at one-year, and of those traced, less than halfcompleted IPT.To generate more rigorous clinical and epidemiological data on maternal-infanttuberculosis, a prospective cohort study was conducted in pregnant and postpartumwomen receiving tuberculosis treatment at Tygerberg Hospital. Over a one-yearperiod, 74 pregnant and postpartum women, 53 (72%) HIV-infected, wereconsecutively enrolled. Nearly half of the women, 35 (47%) were diagnosed withtuberculosis only at delivery or postpartum, and a third of women with tuberculosisreported prior tuberculosis treatment. Tuberculosis-exposed newborns were oftenpremature and of low birth weight (LBW; <2500 grams). All deaths occurred in HIVinfectedwomen (n=5) and all stillbirths (n=4) and newborn deaths (n=6) were fromHIV-infected women. Favourable maternal tuberculosis treatment outcomes (cure andtuberculosis treatment completion) were documented only in 41/74 (55%) women, while 33 (45%) had unfavourable treatment outcomes (death, treatment failure andloss to follow-up). These poor observed outcomes highlight the need for earlierdiagnosis and treatment of tuberculosis during pregnancy, and close follow-up toensure maternal tuberculosis treatment completion. Improved care for pregnantwomen with tuberculosis, with and without HIV infection, will likely reducemorbidity and mortality in mothers and tuberculosis-exposed newborns. Delayedmaternal tuberculosis diagnosis led to IPT initiation in a large number of newborns.Forty-four newborns on IPT were followed to 6 months. A hospital-basedtuberculosis linkage to care intervention, led to 29/44 (66%) newborns completingIPT without a study team intervention. A further 8 infants completed IPT after studyteamintervention. Appropriate tuberculosis referral and linkage to care from hospitalto local tuberculosis clinic substantially improved IPT completion amongtuberculosis-exposed newborns.More pharmacokinetic data regarding the appropriate use of antituberculosis drugs arerequired in neonates and infants, who undergo considerable physiological changes inthe first year of life. An intensive isoniazid (INH) pharmacokinetic study wastherefore designed and implemented in premature and LBW infants (n=20).Relatively high median INH peak concentrations of 5.63 μg/ml were achieved inLBW infants (at an INH dose of 10 mg/kg), compared to the adult proposed targetvalue of > 3 μg/ml. INH exposures were higher with longer half-lives in smallerinfants, and among genotypically determined N-acetyltransferase-2 (NAT2) slowacetylators, suggesting reduced clearance of INH. This first study of isoniazid use inLBW and premature neonates showed that the INH dose in premature and LBWinfants 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 infantsenrolled achieved the minimum proposed adult target peak concentrations of > 3μg/ml for INH at a mean dose of 12.8 mg/kg (10.3 - 15.4 mg/kg), and the minimumadult target of > 20 μg/ml for PZA at a mean dose of 33.3 mg/kg (28.5 – 38.5mg/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 thestudy. None of the infants achieved the minimum proposed adult RMP targetconcentration of > 8 μg/ml. Given the findings of this study, higher doses of RMP ininfants should be considered especially given emerging data from adult RMP doseescalationstudies showing better efficacy at higher doses with limited toxicity forshort-term use. For EMB, only 1 of 16 infants achieved the recommended adult targetconcentration of > 2 μg/ml when given at a mean dose of 20.2 mg/kg (15.4-24.1mg/kg). EMB dose-dependent ocular toxicity however poses a concern regarding therecommendation of higher EMB doses in infants where vision testing is challenging.This is the largest pharmacokinetic study of first-line antituberculosis drugsperformed in infants to date, which has generated valuable pharmacokinetic data toinform 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 theirinfants face a considerable burden of tuberculosis disease in HIV-endemic settings.Maternal-infant tuberculosis care can be improved by health systems strengtheninginterventions. Data generated from pharmacokinetic studies of antituberculosis drugsin tuberculosis-exposed infants will inform much needed dosing guidelines of firstlineantituberculosis drugs for newborns and infants, who have a high risk oftuberculosis and are prone to develop severe forms of tuberculosis.

[发布机构] Stellenbosch University