The impact of HIV and antiretroviral therapy on TB risk in children: a systematic review and meta-analysis.

BACKGROUND: Children (<15 years) are vulnerable to TB disease following infection, but no systematic review or meta-analysis has quantified the effects of HIV-related immunosuppression or antiretroviral therapy (ART) on their TB incidence. OBJECTIVES: Determine the impact of HIV infection and ART on risk of incident TB disease in children. METHODS: We searched MEDLINE and Embase for studies measuring HIV prevalence in paediatric TB cases ('TB cohorts') and paediatric HIV cohorts reporting TB incidence ('HIV cohorts'). Study quality was assessed using the Newcastle-Ottawa tool. TB cohorts with controls were meta-analysed to determine the incidence rate ratio (IRR) for TB given HIV. HIV cohort data were meta-analysed to estimate the trend in log-IRR versus CD4%, relative incidence by immunological stage and ART-associated protection from TB. RESULTS: 42 TB cohorts and 22 HIV cohorts were included. In the eight TB cohorts with controls, the IRR for TB was 7.9 (95% CI 4.5 to 13.7). HIV-infected children exhibited a reduction in IRR of 0.94 (95% credible interval: 0.83-1.07) per percentage point increase in CD4%. TB incidence was 5.0 (95% CI 4.0 to 6.0) times higher in children with severe compared with non-significant immunosuppression. TB incidence was lower in HIV-infected children on ART (HR: 0.30; 95% CI 0.21 to 0.39). Following initiation of ART, TB incidence declined rapidly over 12 months towards a HR of 0.10 (95% CI 0.04 to 0.25). CONCLUSIONS: HIV is a potent risk factor for paediatric TB, and ART is strongly protective. In HIV-infected children, early diagnosis and ART initiation reduces TB risk. TRIAL REGISTRATION NUMBER: CRD42014014276

Recommendations for the diagnosis of pediatric tuberculosis

Tuberculosis (TB) is still the world's second most frequent cause of death due to infectious diseases after HIV infection, and this has aroused greater interest in identifying and managing exposed subjects, whether they are simply infected or have developed one of the clinical variants of the disease. Unfortunately, not even the latest laboratory techniques are always successful in identifying affected children because they are more likely to have negative cultures and tuberculin skin test results, equivocal chest X-ray findings, and atypical clinical manifestations than adults. Furthermore, they are at greater risk of progressing from infection to active disease, particularly if they are very young. Consequently, pediatricians have to use different diagnostic strategies that specifically address the needs of children. This document describes the recommendations of a group of scientific societies concerning the signs and symptoms suggesting pediatric TB, and the diagnostic approach towards children with suspected disease

Tuberculosis and HIV interaction in Ethiopian children : Aspects on epidemilogy, diagnosis and clinical management

This thesis investigates the influence of HIV on childhood tuberculosis (TB) in a high TB and HIV endemic setting. It is based on four studies involving the same study population of 522 tuberculous children and their 25 3 non-tuberculous controls, consecutively enrolled as out- and inpatients at the major paediatric hospital in Addis Ababa, Ethiopia. The first study identifies HIV as a major risk factor for TB. HIV prevalence among tuberculous children in Addis Ababa was 12.5%, compared with 1.6% among the controls (AOR 12.7; 95% Cl 2.9,55). The second study explores possible background features associated with dual infection. These were young age, high educational level of mothers, having lost one or both parents and being BCG vaccinated. The findings have implications for the National Tuberculosis Control Programme, suggesting higher demands on hospital beds for the youngest, active case- finding in connection to adult smear positive cases, and preventive strategies beyond BCG vaccination, since the protective effect against TB is lost among HIV-positive children. Childhood TB is caused by recent transmission. Drug susceptibility testing and molecular typing of M. tuberculosis isolates from paediatric patients may thus add to the surveillance of adult strains of M. tuberculosis, since the latter tend to reflect a combination of newly acquired and older reactivated TB. In the third study, a positive culture of Mycobacterium tuberculosis was isolated from 191 out of 362 (53%) children with pulmonary manifestations. HIV infection was negatively associated with a positive culture (OR 0.3; 95% Cl 0.2, 0.6). Drug sensitivity testing was done in 167 and molecular strain typing, using the IS6110 (RFLP) and direct repeat (spoligotyping) genetic markers, in 163 of the isolates of Mycobacterium tuberculosis. Resistance to any of the standard anti-TB drugs was found in 13% of the isolates, isoniazid resistance (11 %) being the most important. No resistance to rifampicin was found. Two clusters included 29% of the bacterial isolates by RFLP. Spoligotyping reduced this figure to 26%. HIV was associated neither with drug resistance nor with any specific cluster within this sample frame. The fourth study presents results from the diagnosis and follow-up of the same 517 tuberculous children included in the second study. HIV-positive patients were more symptomatic and the very young severely underweight compared with the HIV-negative TB patients. The tuberculin test was less sensitive and chest radiography less specific in dually infected children. The diagnostic delay, counted as number of visits to a health institution before the diagnosis of TB, was also higher in this group (OR 2.1; Cl 1.2, 3.7). The children were followed until 6 months after treatment completion. Adherence to treatment was high (96%), only few side effects of TB drugs were noted and the cure rate was 58% for HIV-positive and 89% for HIV-negative patients. A fatal outcome was found in 40% of the HIVpositive compared to 7% in the HIV-negative TB patients (AOR 6.0; 95% Cl 3.0, 11.4) and HIV was the only identified predictor for death. Within the HIV-positive group, a low weight-for- age could be used to identify children at highest risk of a fatal outcome. The need for routine HIV screening, including counselling, of all TB patients is essential in order to diminish the risk of over- as well as under-diagnosis of dually infected children and to secure an adequate, safe treatment of TB as well as of other opportunistic infections. Possibly, such measures might reduce the high mortality among HIV-positive tuberculous children encountered in this study

Enantioselective pharmacokinetics of mefloquine during long-term intake of the prophylactic dose

Aims To investigate the kinetics of the (+)RS- and (−)SR-enantiomers and the carboxylic acid metabolite (MMQ) of the antimalarial drug mefloquine (MQ) in healthy volunteers

Molecular Epidemiology and Drug Resistance of Mycobacterium tuberculosis Isolates from Ethiopian Pulmonary Tuberculosis Patients with and without Human Immunodeficiency Virus Infection

We have analyzed the molecular epidemiology and drug resistance of 121 Mycobacterium tuberculosis isolates from consecutive patients with culture-positive pulmonary tuberculosis attending a university hospital outpatient department in Addis Ababa, Ethiopia. Restriction fragment length polymorphism analysis and spoligotyping were used to analyze the DNA fingerprinting patterns. Fifty-one (41.2%) of the isolates were found in 13 clusters with two or more identical DNA patterns. Two such clusters contained 49.0% of all clustered isolates. In a multivariate logistic regression model, human immunodeficiency virus (HIV)-positive serostatus was significantly associated with clustering of isolates for patients of both sexes (odds ratio [OR], 2.55; 95% confidence interval [CI], 1.17 to 5.80). There was a trend toward increased clustering of isolates from tuberculous women residing in Addis Ababa (OR, 2.10; 95% CI, 0.85 to 5.25). In total, 17 of 121 isolates (14.0%) were resistant to one or more of the antituberculosis drugs isoniazid (8.3%), streptomycin (7.4%), rifampin (2.5%), and ethambutol (1.7%). The high rate of drug-resistant isolates (29.6%) coincided with the peak prevalence of HIV infection (77.8%) in patients 35 to 44 years old. The majority (62.5%) of resistant isolates in this group were found within clusters. The simultaneous accumulation of certain bacterial clones in a patient population likely reflects recent transmission. Hence, we conclude that tuberculosis is commonly caused by recent infection with M. tuberculosis in HIV-positive Ethiopian patients. Furthermore, with the rapidly increasing prevalence of HIV infection in Ethiopia, the burden of tuberculosis, including drug-resistant tuberculosis, is likely to increase. Strengthening of classical tuberculosis control measures by promoting active case finding among HIV-positive adults with tuberculosis is warranted to reduce rates of transmission