RESUMEN
BACKGROUND: Two thirds of children with tuberculosis have nonsevere disease, which may be treatable with a shorter regimen than the current 6-month regimen. METHODS: We conducted an open-label, treatment-shortening, noninferiority trial involving children with nonsevere, symptomatic, presumably drug-susceptible, smear-negative tuberculosis in Uganda, Zambia, South Africa, and India. Children younger than 16 years of age were randomly assigned to 4 months (16 weeks) or 6 months (24 weeks) of standard first-line antituberculosis treatment with pediatric fixed-dose combinations as recommended by the World Health Organization. The primary efficacy outcome was unfavorable status (composite of treatment failure [extension, change, or restart of treatment or tuberculosis recurrence], loss to follow-up during treatment, or death) by 72 weeks, with the exclusion of participants who did not complete 4 months of treatment (modified intention-to-treat population). A noninferiority margin of 6 percentage points was used. The primary safety outcome was an adverse event of grade 3 or higher during treatment and up to 30 days after treatment. RESULTS: From July 2016 through July 2018, a total of 1204 children underwent randomization (602 in each group). The median age of the participants was 3.5 years (range, 2 months to 15 years), 52% were male, 11% had human immunodeficiency virus infection, and 14% had bacteriologically confirmed tuberculosis. Retention by 72 weeks was 95%, and adherence to the assigned treatment was 94%. A total of 16 participants (3%) in the 4-month group had a primary-outcome event, as compared with 18 (3%) in the 6-month group (adjusted difference, -0.4 percentage points; 95% confidence interval, -2.2 to 1.5). The noninferiority of 4 months of treatment was consistent across the intention-to-treat, per-protocol, and key secondary analyses, including when the analysis was restricted to the 958 participants (80%) independently adjudicated to have tuberculosis at baseline. A total of 95 participants (8%) had an adverse event of grade 3 or higher, including 15 adverse drug reactions (11 hepatic events, all but 2 of which occurred within the first 8 weeks, when the treatments were the same in the two groups). CONCLUSIONS: Four months of antituberculosis treatment was noninferior to 6 months of treatment in children with drug-susceptible, nonsevere, smear-negative tuberculosis. (Funded by the U.K. Medical Research Council and others; SHINE ISRCTN number, ISRCTN63579542.).
Asunto(s)
Antituberculosos/administración & dosificación , Tuberculosis/tratamiento farmacológico , Adolescente , África , Niño , Preescolar , Esquema de Medicación , Quimioterapia Combinada , Femenino , Humanos , India , Lactante , Análisis de Intención de Tratar , Isoniazida/administración & dosificación , Masculino , Gravedad del Paciente , Pirazinamida/administración & dosificación , Rifampin/administración & dosificación , Resultado del TratamientoRESUMEN
BACKGROUND: We evaluated dolutegravir pharmacokinetics in infants with human immunodeficiency virus (HIV) receiving dolutegravir twice daily (BID) with rifampicin-based tuberculosis (TB) treatment compared with once daily (OD) without rifampicin. METHODS: Infants with HIV aged 1-12 months, weighing ≥3â kg, and receiving dolutegravir BID with rifampicin or OD without rifampicin were eligible. Six blood samples were taken over 12 (BID) or 24 hours (OD). Dolutegravir pharmacokinetic parameters, HIV viral load (VL) data, and adverse events (AEs) were reported. RESULTS: Twenty-seven of 30 enrolled infants had evaluable pharmacokinetic curves. The median (interquartile range) age was 7.1 months (6.1-9.9), weight was 6.3 kg (5.6-7.2), 21 (78%) received rifampicin, and 11 (41%) were female. Geometric mean ratios comparing dolutegravir BID with rifampicin versus OD without rifampicin were area under curve (AUC)0-24h 0.91 (95% confidence interval, .59-1.42), Ctrough 0.95 (0.57-1.59), Cmax 0.87 (0.57-1.33). One infant (5%) receiving rifampicin versus none without rifampicin had dolutegravir Ctrough <0.32â mg/L, and none had Ctrough <0.064â mg/L. The dolutegravir metabolic ratio (dolutegravir-glucuronide AUC/dolutegravir AUC) was 2.3-fold higher in combination with rifampicin versus without rifampicin. Five of 82 reported AEs were possibly related to rifampicin or dolutegravir and resolved without treatment discontinuation. Upon TB treatment completion, HIV viral load was <1000â copies/mL in 76% and 100% of infants and undetectable in 35% and 20% of infants with and without rifampicin, respectively. CONCLUSIONS: Dolutegravir BID in infants receiving rifampicin resulted in adequate dolutegravir exposure, supporting this treatment approach for infants with HIV-TB coinfection.
Asunto(s)
Infecciones por VIH , Compuestos Heterocíclicos con 3 Anillos , Rifampin , Femenino , Humanos , Lactante , Masculino , Compuestos Heterocíclicos con 3 Anillos/farmacocinética , VIH , Oxazinas , Piperazinas , Piridonas , Rifampin/uso terapéuticoRESUMEN
BACKGROUND: Children with human immunodeficiency virus (HIV, CWH) are at high risk of tuberculosis (TB) and face poor outcomes, despite antiretroviral therapy (ART). We evaluated outcomes in CWH and children not living with HIV treated for nonsevere TB in the SHINE trial. METHODS: SHINE was a randomized trial that enrolled children aged <16 years with smear-negative, nonsevere TB who were randomized to receive 4 versus 6 months of TB treatment and followed for 72 weeks. We assessed TB relapse/recurrence, mortality, hospitalizations, grade ≥3 adverse events by HIV status, and HIV virological suppression in CWH. RESULTS: Of 1204 children enrolled, 127 (11%) were CWH, of similar age (median, 3.6 years; interquartile range, 1.2, 10.3 versus 3.5 years; 1.5, 6.9; P = .07) but more underweight (weight-for-age z score, -2.3; (3.3, -0.8 versus -1.0; -1.8, -0.2; P < .01) and anemic (hemoglobin, 9.5 g/dL; 8.7, 10.9 versus 11.5 g/dL; 10.4, 12.3; P < .01) compared with children without HIV. A total of 68 (54%) CWH were ART-naive; baseline median CD4 count was 719 cells/mm3 (241-1134), and CD4% was 16% (10-26). CWH were more likely to be hospitalized (adjusted odds ratio, 2.4; 1.3-4.6) and to die (adjusted hazard ratio [aHR], 2.6; 95% confidence interval [CI], 1.2 to 5.8). HIV status, age <3 years (aHR, 6.3; 1.5, 27.3), malnutrition (aHR, 6.2; 2.4, 15.9), and hemoglobin <7 g/dL (aHR, 3.8; 1.3,11.5) independently predicted mortality. Among children with available viral load (VL), 45% and 61% CWH had VL <1000 copies/mL at weeks 24 and 48, respectively. There was no difference in the effect of randomized treatment duration (4 versus 6 months) on TB treatment outcomes by HIV status (P for interaction = 0.42). CONCLUSIONS: We found no evidence of a difference in TB outcomes between 4 and 6 months of treatment for CWH treated for nonsevere TB. Irrespective of TB treatment duration, CWH had higher rates of mortality and hospitalization than their counterparts without HIV. Clinical Trials Registration. ISRCTN63579542.
Asunto(s)
Antituberculosos , Infecciones por VIH , Tuberculosis , Humanos , Infecciones por VIH/tratamiento farmacológico , Infecciones por VIH/complicaciones , Masculino , Femenino , Preescolar , Niño , Lactante , Tuberculosis/tratamiento farmacológico , Tuberculosis/mortalidad , Resultado del Tratamiento , Antituberculosos/uso terapéutico , Hospitalización , Carga Viral/efectos de los fármacos , Recurrencia , Recuento de Linfocito CD4 , Adolescente , Fármacos Anti-VIH/uso terapéuticoRESUMEN
BACKGROUND: Dolutegravir (DTG), combined with a backbone of 2 nucleoside reverse transcriptase inhibitors, is currently the preferred first-line treatment for human immunodeficiency virus (HIV) in childhood. CHAPAS4 is an ongoing randomized controlled trial investigating second-line treatment options for children with HIV. We did a nested pharmacokinetic (PK) substudy within CHAPAS4 to evaluate the DTG exposure in children with HIV taking DTG with food as part of their second-line treatment. METHODS: Additional consent was required for children on DTG enrolled in the CHAPAS4 trial to participate in this PK substudy. Children weighing 14-19.9 kg took 25 mg DTG as dispersible tablets and children ≥20 kg took 50 mg film-coated tablets. Steady-state 24-hour DTG plasma concentration-time PK profiling was done at t = 0 and 1, 2, 4, 6, 8, 12, and 24 hours after observed DTG intake with food. Reference adult PK data and pediatric data from the ODYSSEY trial were used primarily for comparison. The individual target trough concentration (Ctrough) was defined as 0.32 mg/L. RESULTS: Thirty-nine children on DTG were included in this PK substudy. The geometric mean (GM) area under the concentration-time curve over the dosing interval (AUC0-24h) was 57.1 hours × mg/L (coefficient of variation [CV%], 38.4%), which was approximately 8% below the average AUC0-24h in children in the ODYSSEY trial with comparable dosages, but above the adult reference. The GM (CV%) Ctrough was 0.82 mg/L (63.8%), which was comparable to ODYSSEY and adult reference values. CONCLUSIONS: This nested PK substudy shows that the exposure of DTG taken with food in children on second-line treatment is comparable with that of children in the ODYSSEY trial and adult references. Clinical Trials Registration.ISRCTN22964075.
Asunto(s)
Fármacos Anti-VIH , Infecciones por VIH , Inhibidores de Integrasa VIH , Niño , Humanos , Fármacos Anti-VIH/uso terapéutico , Compuestos Heterocíclicos con 3 Anillos , VIH , Infecciones por VIH/tratamiento farmacológico , Oxazinas , ComprimidosRESUMEN
BACKGROUND: We evaluated the pharmacokinetics of tenofovir alafenamide fumarate (TAF) and tenofovir in a subset of African children enrolled in the CHAPAS-4 trial. METHODS: Children aged 3-15 years with human immunodeficiency virus infection failing first-line antiretroviral therapy were randomized to emtricitabine/TAF versus standard-of-care nucleoside reverse transcriptase inhibitor combination, plus dolutegravir, atazanavir/ritonavir, darunavir/ritonavir, or lopinavir/ritonavir. Daily emtricitabine/TAF was dosed according to World Health Organization (WHO)-recommended weight bands: 120/15 mg in children weighing 14 to <25 kg and 200/25 mg in those weighing ≥25 kg. At steady state, 8-9 blood samples were taken to construct pharmacokinetic curves. Geometric mean (GM) area under the concentration-time curve (AUC) and the maximum concentration (Cmax) were calculated for TAF and tenofovir and compared to reference exposures in adults. RESULTS: Pharmacokinetic results from 104 children taking TAF were analyzed. GM (coefficient of variation [CV%]) TAF AUClast when combined with dolutegravir (n = 18), darunavir/ritonavir (n = 34), or lopinavir/ritonavir (n = 20) were 284.5 (79), 232.0 (61), and 210.2 (98) ng*hour/mL, respectively, and were comparable to adult reference values. When combined with atazanavir/ritonavir (n = 32), TAF AUClast increased to 511.4 (68) ng*hour/mL. For each combination, tenofovir GM (CV%) AUCtau and Cmax remained below reference values in adults taking 25 mg TAF with a boosted protease inhibitors. CONCLUSIONS: In children, TAF combined with boosted PIs or dolutegravir and dosed according to WHO-recommended weight bands provides TAF and tenofovir concentrations previously demonstrated to be well tolerated and effective in adults. These data provide the first evidence for use of these combinations in African children. CLINICAL TRIALS REGISTRATION: ISRCTN22964075.
Asunto(s)
Fármacos Anti-VIH , Infecciones por VIH , Adulto , Niño , Humanos , Ritonavir/uso terapéutico , Sulfato de Atazanavir/uso terapéutico , Inhibidores de Proteasas/uso terapéutico , Lopinavir/uso terapéutico , Darunavir/uso terapéutico , Tenofovir/uso terapéutico , Emtricitabina/uso terapéutico , Infecciones por VIH/tratamiento farmacológico , Antivirales/uso terapéutico , Fumaratos/uso terapéutico , Fármacos Anti-VIH/uso terapéuticoRESUMEN
BACKGROUND: The current World Health Organization (WHO) pediatric tuberculosis dosing guidelines lead to suboptimal drug exposures. Identifying factors altering the exposure of these drugs in children is essential for dose optimization. Pediatric pharmacokinetic studies are usually small, leading to high variability and uncertainty in pharmacokinetic results between studies. We pooled data from large pharmacokinetic studies to identify key covariates influencing drug exposure to optimize tuberculosis dosing in children. METHODS AND FINDINGS: We used nonlinear mixed-effects modeling to characterize the pharmacokinetics of rifampicin, isoniazid, and pyrazinamide, and investigated the association of human immunodeficiency virus (HIV), antiretroviral therapy (ART), drug formulation, age, and body size with their pharmacokinetics. Data from 387 children from South Africa, Zambia, Malawi, and India were available for analysis; 47% were female and 39% living with HIV (95% on ART). Median (range) age was 2.2 (0.2 to 15.0) years and weight 10.9 (3.2 to 59.3) kg. Body size (allometry) was used to scale clearance and volume of distribution of all 3 drugs. Age affected the bioavailability of rifampicin and isoniazid; at birth, children had 48.9% (95% confidence interval (CI) [36.0%, 61.8%]; p < 0.001) and 64.5% (95% CI [52.1%, 78.9%]; p < 0.001) of adult rifampicin and isoniazid bioavailability, respectively, and reached full adult bioavailability after 2 years of age for both drugs. Age also affected the clearance of all drugs (maturation), children reached 50% adult drug clearing capacity at around 3 months after birth and neared full maturation around 3 years of age. While HIV per se did not affect the pharmacokinetics of first-line tuberculosis drugs, rifampicin clearance was 22% lower (95% CI [13%, 28%]; p < 0.001) and pyrazinamide clearance was 49% higher (95% CI [39%, 57%]; p < 0.001) in children on lopinavir/ritonavir; isoniazid bioavailability was reduced by 39% (95% CI [32%, 45%]; p < 0.001) when simultaneously coadministered with lopinavir/ritonavir and was 37% lower (95% CI [22%, 52%]; p < 0.001) in children on efavirenz. Simulations of 2010 WHO-recommended pediatric tuberculosis doses revealed that, compared to adult values, rifampicin exposures are lower in most children, except those younger than 3 months, who experience relatively higher exposure for all drugs, due to immature clearance. Increasing the rifampicin doses in children older than 3 months by 75 mg for children weighing <25 kg and 150 mg for children weighing >25 kg could improve rifampicin exposures. Our analysis was limited by the differences in availability of covariates among the pooled studies. CONCLUSIONS: Children older than 3 months have lower rifampicin exposures than adults and increasing their dose by 75 or 150 mg could improve therapy. Altered exposures in children with HIV is most likely caused by concomitant ART and not HIV per se. The importance of the drug-drug interactions with lopinavir/ritonavir and efavirenz should be evaluated further and considered in future dosing guidance. TRIAL REGISTRATION: ClinicalTrials.gov registration numbers; NCT02348177, NCT01637558, ISRCTN63579542.
Asunto(s)
Infecciones por VIH , Tuberculosis , Adulto , Recién Nacido , Niño , Humanos , Femenino , Lactante , Preescolar , Adolescente , Masculino , Ritonavir/farmacocinética , Ritonavir/uso terapéutico , Lopinavir/farmacocinética , Lopinavir/uso terapéutico , Rifampin , Isoniazida/uso terapéutico , Isoniazida/farmacocinética , Pirazinamida/farmacocinética , Antituberculosos , Tuberculosis/tratamiento farmacológico , Tuberculosis/epidemiología , Infecciones por VIH/tratamiento farmacológico , VIHRESUMEN
BACKGROUND: Suboptimal exposure to antituberculosis (anti-TB) drugs has been associated with unfavourable treatment outcomes. We aimed to investigate estimates and determinants of first-line anti-TB drug pharmacokinetics in children and adolescents at a global level. METHODS: We systematically searched MEDLINE, Embase and Web of Science (1990-2021) for pharmacokinetic studies of first-line anti-TB drugs in children and adolescents. Individual patient data were obtained from authors of eligible studies. Summary estimates of total/extrapolated area under the plasma concentration-time curve from 0 to 24â h post-dose (AUC0-24) and peak plasma concentration (C max) were assessed with random-effects models, normalised with current World Health Organization-recommended paediatric doses. Determinants of AUC0-24 and C max were assessed with linear mixed-effects models. RESULTS: Of 55 eligible studies, individual patient data were available for 39 (71%), including 1628 participants from 12 countries. Geometric means of steady-state AUC0-24 were summarised for isoniazid (18.7 (95% CI 15.5-22.6)â h·mg·L-1), rifampicin (34.4 (95% CI 29.4-40.3)â h·mg·L-1), pyrazinamide (375.0 (95% CI 339.9-413.7)â h·mg·L-1) and ethambutol (8.0 (95% CI 6.4-10.0)â h·mg·L-1). Our multivariate models indicated that younger age (especially <2â years) and HIV-positive status were associated with lower AUC0-24 for all first-line anti-TB drugs, while severe malnutrition was associated with lower AUC0-24 for isoniazid and pyrazinamide. N-acetyltransferase 2 rapid acetylators had lower isoniazid AUC0-24 and slow acetylators had higher isoniazid AUC0-24 than intermediate acetylators. Determinants of C max were generally similar to those for AUC0-24. CONCLUSIONS: This study provides the most comprehensive estimates of plasma exposures to first-line anti-TB drugs in children and adolescents. Key determinants of drug exposures were identified. These may be relevant for population-specific dose adjustment or individualised therapeutic drug monitoring.
Asunto(s)
Antituberculosos , Isoniazida , Niño , Adolescente , Humanos , Preescolar , Antituberculosos/uso terapéutico , Isoniazida/uso terapéutico , Pirazinamida/uso terapéutico , Etambutol/uso terapéutico , Rifampin/uso terapéuticoRESUMEN
BACKGROUND: Dispersible pediatric fixed-dose combination (FDC) tablets delivering higher doses of first-line antituberculosis drugs in World Health Organization-recommended weight bands were introduced in 2015. We report the first pharmacokinetic data for these FDC tablets in Zambian and South African children in the treatment-shortening SHINE trial. METHODS: Children weighing 4.0-7.9, 8.0-11.9, 12.0-15.9, or 16.0-24.9 kg received 1, 2, 3, or 4 tablets daily, respectively (rifampicin/isoniazid/pyrazinamide [75/50/150 mg], with or without 100 mg ethambutol, or rifampicin/isoniazid [75/50 mg]). Children 25.0-36.9 kg received doses recommended for adultsâ <37 kg (300, 150, 800, and 550 mg/d, respectively, for rifampicin, isoniazid, pyrazinamide, and ethambutol). Pharmacokinetics were evaluated after at least 2 weeks of treatment. RESULTS: In the 77 children evaluated, the median age (interquartile range) was 3.7 (1.4-6.6) years; 40 (52%) were male and 20 (26%) were human immunodeficiency virus positive. The median area under the concentration-time curve from 0 to 24 hours for rifampicin, isoniazid, pyrazinamide, and ethambutol was 32.5 (interquartile range, 20.1-45.1), 16.7 (9.2-25.9), 317 (263-399), and 9.5 (7.5-11.5) mgâ h/L, respectively, and lower in children than in adults for rifampicin in the 4.0-7.9-, 8-11.9-, andâ ≥25-kg weight bands, isoniazid in the 4.0-7.9-kg andâ ≥25-kg weight bands, and ethambutol in all 5 weight bands. Pyrazinamide exposures were similar to those in adults. CONCLUSIONS: Recommended weight band-based FDC doses result in lower drug exposures in children in lower weight bands and in those ≥25 kg (receiving adult doses). Further adjustments to current doses are needed to match current target exposures in adults. The use of ethambutol at the current World Health Organization-recommended doses requires further evaluation.
Asunto(s)
Pirazinamida , Tuberculosis , Adulto , Antituberculosos/uso terapéutico , Niño , Preescolar , Etambutol/uso terapéutico , Femenino , Humanos , Isoniazida/farmacocinética , Isoniazida/uso terapéutico , Masculino , Pirazinamida/farmacocinética , Rifampin/uso terapéutico , Tuberculosis/tratamiento farmacológico , Organización Mundial de la SaludRESUMEN
OBJECTIVES: Ethambutol protects against the development of resistance to co-administered drugs in the intensive phase of first-line anti-TB treatment in children. It is especially relevant in settings with a high prevalence of HIV or isoniazid resistance. We describe the population pharmacokinetics of ethambutol in children with TB to guide dosing in this population. METHODS: We pooled data from 188 intensively sampled children from the DATiC, DNDi and SHINE studies, who received 15-25â mg/kg ethambutol daily according to WHO guidelines. The median (range) age and weight of the cohort were 1.9 (0.3-12.6)â years and 9.6 (3.9-34.5)â kg, respectively. Children with HIV (HIV+; nâ=â103) received ART (lopinavir/ritonavir in 92%). RESULTS: Ethambutol pharmacokinetics were best described by a two-compartment model with first-order elimination and absorption transit compartments. Clearance was estimated to reach 50% of its mature value by 2â months after birth and 99% by 3â years. Typical steady-state apparent clearance in a 10â kg child was 15.9â L/h. In HIV+ children on lopinavir/ritonavir, bioavailability was reduced by 32% [median (IQR) steady-state Cmaxâ=â0.882 (0.669-1.28) versus 1.66 (1.21-2.15)â mg/L). In young children, bioavailability correlated with age. At birth, bioavailability was 73.1% of that in children 3.16â years or older. CONCLUSIONS: To obtain exposure within the 2-6â mg/L recommended range for Cmax, the current doses must be doubled (or tripled with HIV+ children on lopinavir/ritonavir) for paediatric patients. This raises concerns regarding the potential for ocular toxicity, which would require evaluation.
Asunto(s)
Fármacos Anti-VIH , Infecciones por VIH , Fármacos Anti-VIH/uso terapéutico , Antituberculosos/farmacocinética , Antituberculosos/uso terapéutico , Niño , Preescolar , Etambutol/farmacocinética , Etambutol/uso terapéutico , Infecciones por VIH/tratamiento farmacológico , Humanos , Recién Nacido , Lopinavir/farmacocinética , Lopinavir/uso terapéutico , RitonavirRESUMEN
BACKGROUND: In high tuberculosis (TB) burden settings, there is growing evidence that TB is common in children with pneumonia, the leading cause of death in children under 5 years worldwide. The current WHO standard of care (SOC) for young children with pneumonia considers a diagnosis of TB only if the child has a history of prolonged symptoms or fails to respond to antibiotic treatments. As a result, many children with TB-associated severe pneumonia are currently missed or diagnosed too late. We therefore propose a diagnostic trial to assess the impact on mortality of adding the systematic early detection of TB using Xpert MTB/RIF Ultra (Ultra) performed on nasopharyngeal aspirates (NPA) and stool samples to the WHO SOC for children with severe pneumonia, followed by immediate initiation of anti-TB treatment in children testing positive on any of the samples. METHODS: TB-Speed Pneumonia is a pragmatic stepped-wedge cluster randomized controlled trial conducted in six countries with high TB incidence rate (Côte d'Ivoire, Cameroon, Uganda, Mozambique, Zambia and Cambodia). We will enrol 3780 children under 5 years presenting with WHO-defined severe pneumonia across 15 hospitals over 18 months. All hospitals will start managing children using the WHO SOC for severe pneumonia; one hospital will be randomly selected to switch to the intervention every 5 weeks. The intervention consists of the WHO SOC plus rapid TB detection on the day of admission using Ultra performed on 1 nasopharyngeal aspirate and 1 stool sample. All children will be followed for 3 months, with systematic trial visits at day 3, discharge, 2 weeks post-discharge, and week 12. The primary endpoint is all-cause mortality 12 weeks after inclusion. Qualitative and health economic evaluations are embedded in the trial. DISCUSSION: In addition to testing the main hypothesis that molecular detection and early treatment will reduce TB mortality in children, the strength of such pragmatic research is that it provides some evidence regarding the feasibility of the intervention as part of routine care. Should this intervention be successful, safe and well tolerated, it could be systematically implemented at district hospital level where children with severe pneumonia are referred. TRIAL REGISTRATION: ClinicalTrials.gov, NCT03831906 . Registered 6 February 2019.
Asunto(s)
Mycobacterium tuberculosis , Neumonía , Tuberculosis , Cuidados Posteriores , Cambodia , Camerún , Niño , Preescolar , Humanos , Mozambique , Mycobacterium tuberculosis/genética , Alta del Paciente , Neumonía/diagnóstico , Sensibilidad y Especificidad , Tuberculosis/complicaciones , Tuberculosis/diagnóstico , Uganda , ZambiaRESUMEN
BACKGROUND: Zambia is currently experiencing an epidemiological transition, from communicable to non-communicable diseases. The annual rate of physician-diagnosed asthma is estimated at 3 %. However, the general public's knowledge of asthma symptoms and signs, and their perception of asthma remain unknown. A survey was conducted aiming to determine knowledge and perceptions of asthma among Zambians. METHODS: Adults and adolescents attending four clinics in the capital, Lusaka, were surveyed using a standardized questionnaire from July 2011 to March 2012. RESULTS: Data from 1,540 participants (mean age 30.7 years, 65% female) were collected. Most patients (74%) were living in low-cost housing. One hundred and sixteen (7.6%) participants reported either a medical diagnosis of asthma or currently taking asthma medications. The most frequent asthma symptoms reported were wheezing (88%), and waking up at night with either shortness of breath (85%), chest tightness (85%), or cough (67%). Medications used to treat asthma were mostly oral short-acting beta-agonists (SABA) (59%), inhaled SABA (30.2%) and antibiotics (29.8%). Inhaled steroids were only used by 16.4% while less than 1% were on long-acting beta-agonists (LABA). Many misconceptions were identified among the entire surveyed population with only 54.7% believing hospitalisations are not preventable, 54.7% believing asthma symptoms can be prevented with the right medications and 37% believing inhalers are addictive. Nearly 60% thought that people with asthma cannot exercise or play hard. Significantly more individuals with asthma compared to those without thought tablets are better than inhalers for the treatment of asthma (46% vs 30%). CONCLUSIONS: We conclude that knowledge on asthma is poor in Zambia, where there remains many misconceptions on asthma and its management.
Asunto(s)
Asma , Conocimientos, Actitudes y Práctica en Salud , Administración por Inhalación , Administración Oral , Adolescente , Corticoesteroides/uso terapéutico , Agonistas Adrenérgicos beta/uso terapéutico , Adulto , Anciano , Antibacterianos/uso terapéutico , Asma/tratamiento farmacológico , Asma/epidemiología , Niño , Estudios Transversales , Quimioterapia Combinada , Disnea , Ejercicio Físico , Femenino , Hospitalización , Humanos , Masculino , Persona de Mediana Edad , Ruidos Respiratorios , Encuestas y Cuestionarios , Adulto Joven , ZambiaRESUMEN
BACKGROUND: Betaherpesviruses are established causes of morbidity and mortality in immunosuppressed patient groups but have been little studied in sub-Saharan Africa, the epicenter of the human immunodeficiency virus (HIV) pandemic. In this region, primary infections with human cytomegalovirus (HCMV) and human herpesvirus type 6 (HHV-6) type 6 are endemic in infancy, but the clinical impact of these infections among pediatric inpatient groups is poorly characterized and assumptive, based largely on data from Western populations. METHODS: We used TaqMan polymerase chain reaction to screen sera from a group of 303 pediatric inpatients aged between 3 weeks and 2 years, at the University Teaching Hospital in Lusaka, Zambia. We report the prevalence of DNAemia and viral loads within this patient group, and evaluate possible clinical associations/risk factors for betaherpesvirus infections in these hospitalized children. RESULTS: We detected betaherpesvirus DNAemia in 59.1% (179/303) of children. HCMV was the most prevalent (41.3%), followed by HHV-6B (20.5%), HHV-7 (20.1%), and HHV-6A (0.3%). HIV infection (odds ratio [OR], 2.31; 95% confidence interval [CI], 1.37-3.90; P = .002), being underweight (OR, 1.82; 95% CI, 1.06-3.12; P = .03), and an admission diagnosis of suspected meningitis (OR, 5.72; 95% CI, 1.07-30.5; P = .041) were independently associated with an increased odds of HCMV DNAemia. Conversely, HHV-6B and HHV-7 DNAemia were not associated with HIV, underweight, or admission diagnosis. Median HCMV viral load was moderately but significantly higher in HIV-infected children. CONCLUSIONS: Highly prevalent HCMV DNAemia was independently associated with HIV infection and being underweight across all age groups, and was also associated with meningitis, with previously underappreciated implications for the health and development of African children.
Asunto(s)
Infecciones por Citomegalovirus/epidemiología , Citomegalovirus/aislamiento & purificación , Herpesvirus Humano 6/aislamiento & purificación , Herpesvirus Humano 7/aislamiento & purificación , Infecciones por Roseolovirus/epidemiología , Preescolar , Citomegalovirus/genética , Infecciones por Citomegalovirus/etiología , Infecciones por Citomegalovirus/virología , ADN Viral/sangre , Femenino , Infecciones por VIH/complicaciones , Herpesvirus Humano 6/genética , Herpesvirus Humano 7/genética , Hospitales de Enseñanza , Hospitales Universitarios , Humanos , Huésped Inmunocomprometido , Lactante , Recién Nacido , Masculino , Prevalencia , Derivación y Consulta , Factores de Riesgo , Infecciones por Roseolovirus/etiología , Infecciones por Roseolovirus/virología , Delgadez , Carga Viral , ZambiaRESUMEN
BACKGROUND: Congenital cytomegalovirus (CMV) infection is the major infectious cause of birth defects and hearing loss globally. There is a growing recognition of the potential clinical impact of congenital CMV infections in high-seroprevalence settings. METHODS: A cross-sectional study of neonatal admissions at a large referral center in sub-Saharan Africa to determine the prevalence of both symptomatic and asymptomatic congenital CMV infection was performed. Real-time polymerase chain reaction was used to screen DNA-extracted sera, urine, and saliva, and an enzyme-linked immunosorbent assay was used to screen serum samples for anti-CMV immunoglobulin M. Multivariate binary logistic regression was used to identify risk factors associated with increased odds of congenital CMV infection. RESULTS: Congenital CMV was detected in 3.8% (15/395) of neonates. Among these infants, 6 of 15 (40%) presented with jaundice, 1 of whom also had petechiae. Congenital CMV infection was detected in 9 of 79 (11.4%; 95% confidence interval [CI], 6.1%-20.3%) neonates born to human immunodeficiency virus (HIV)-infected mothers, and both maternal HIV (odds ratio [OR], 6.661 [95% CI, 2.126-20.876], P = .001) and jaundice (OR, 5.701 [95% CI, 1.776-18.306], P = .003) were independently linked with significantly increased odds of congenital CMV infection. CONCLUSIONS: Congenital and early infant CMV infections may have important consequences for child health in sub-Saharan Africa and other high HIV and CMV seroprevalence populations globally.
Asunto(s)
Infecciones por Citomegalovirus/congénito , Infecciones por Citomegalovirus/epidemiología , Infecciones por VIH/complicaciones , Hospitalización , Complicaciones Infecciosas del Embarazo/epidemiología , África del Sur del Sahara , Anticuerpos Antivirales/sangre , Estudios Transversales , ADN Viral/análisis , Ensayo de Inmunoadsorción Enzimática , Femenino , Hospitalización/estadística & datos numéricos , Humanos , Inmunoglobulina M/sangre , Recién Nacido , Masculino , Embarazo , Prevalencia , Reacción en Cadena en Tiempo Real de la Polimerasa , Factores de Riesgo , Saliva/virología , Suero/virología , Centros de Atención Terciaria , Orina/virologíaRESUMEN
Background: In children with severe acute malnutrition (SAM) tuberculosis is common, challenging to diagnose, and often fatal. We developed tuberculosis treatment decision algorithms (TDAs) for children under the age of 5 years with SAM. Methods: In this prospective diagnostic study, we enrolled and followed up children aged <60 months hospitalised with SAM at three tertiary hospitals in Zambia and Uganda from 4 November 2019 to 20 June 2022. We included children aged 2-59 months with SAM as defined by WHO and hospitalised following the WHO clinical criteria. We excluded children with current or history of antituberculosis treatment within the preceding 3 months. They underwent tuberculosis symptom screening, clinical assessment, chest X-ray, abdominal ultrasound, Xpert MTB/RIF Ultra (Ultra) and culture on respiratory and stool samples with 6 months follow-up. Tuberculosis was retrospectively defined using the 2015 standard case definition for childhood tuberculosis. We used logistic regression to develop diagnostic prediction models for a one-step diagnosis and a two-step screening and diagnostic approaches. We derived scores from models using WHO-recommended thresholds for sensitivity and proposed TDAs. This study is registered with ClinicalTrials.gov, NCT04240990. Findings: Of 1906 children hospitalised with SAM during the study period, 1230 were screened, 1152 were eligible and 603 were enrolled. Of the 603 children enrolled-median age 15 (inter-quartile range (IQR): 11-20) months and 65 (11.0%) living with HIV-114 (18.9%) were diagnosed with tuberculosis, including 51 (8.5%) with microbiological confirmation and 104 (17.2%) initiated treatment at a median of 6(IQR: 2-10) days after inclusion. 108 children were retrospectively classified as having tuberculosis resulting in a prevalence of 17.9% (95% confidence intervals (CI): 15.1; 21.2). 75 (69.4%) children with tuberculosis reported cough of any duration, 32 (29.6%) cough ≥2 weeks and 11 (10.2%) tuberculosis contact history. 535 children had complete data and were included in the diagnostic prediction model. The one-step diagnostic model had 15 predictors, including Ultra, clinical, radiographic, and abdominal features, an area under the receiving operating curve (AUROC) of 0.910, and derived TDA sensitivity of 86.14% (95% CI: 78.07-91.56) and specificity of 80.88% (95% CI: 76.91-84.30). The two-step model had AUROCs of 0.750 and 0.912 for screening and diagnosis, respectively, and derived combined TDA sensitivity of 79.21% (95% CI: 70.30-85.98) and a specificity of 83.64% (95% CI: 79.87-86.82). Interpretation: Tuberculosis prevalence was high among hospitalised children with SAM, with atypical clinical features. TDAs achieved satisfactory diagnostic accuracy and could be used to improve diagnosis in this vulnerable group. Funding: Unitaid.
RESUMEN
Infants born to mothers with tuberculosis disease are at increased risk of developing tuberculosis disease themselves. We reviewed published studies and guidelines on the management of these infants to inform the development of a consensus practice guideline. We searched MEDLINE, CINAHL, and Cochrane Library from database inception to Dec 1, 2022, for original studies reporting the management and outcome of infants born to mothers with tuberculosis. Of the 521 published papers identified, only three met inclusion criteria and no evidence-based conclusions could be drawn from these studies, given their narrow scope, variable aims, descriptive nature, inconsistent data collection, and high attrition rates. We also assessed a collection of national and international guidelines to inform a consensus practice guideline developed by an international panel of experts from different epidemiological contexts. The 16 guidelines reviewed had consistent features to inform the expert consultation process. Two management algorithms were developed-one for infants born to mothers considered potentially infectious at the time of delivery and another for mothers not considered infectious at the time of delivery-with different guidance for high and low tuberculosis incidence settings. This systematic review and consensus practice guideline should facilitate more consistent clinical management, support the collection of better data, and encourage the development of more studies to improve evidence-based care.
Asunto(s)
Transmisión Vertical de Enfermedad Infecciosa , Complicaciones Infecciosas del Embarazo , Tuberculosis , Humanos , Femenino , Embarazo , Recién Nacido , Transmisión Vertical de Enfermedad Infecciosa/prevención & control , Consenso , Guías de Práctica Clínica como Asunto , LactanteRESUMEN
BACKGROUND: Lopinavir/ritonavir plasma concentrations are profoundly reduced when co-administered with rifampicin. Super-boosting of lopinavir/ritonavir is limited by nonavailability of single-entity ritonavir, while double-dosing of co-formulated lopinavir/ritonavir given twice-daily produces suboptimal lopinavir concentrations in young children. We evaluated whether increased daily dosing with modified 8-hourly lopinavir/ritonavir 4:1 would maintain therapeutic plasma concentrations of lopinavir in children living with HIV receiving rifampicin-based antituberculosis treatment. METHODS: Children with HIV/tuberculosis coinfection weighing 3.0 to 19.9 kg, on rifampicin-based antituberculosis treatment were commenced or switched to 8-hourly liquid lopinavir/ritonavir 4:1 with increased daily dosing using weight-band dosing approach. A standard twice-daily dosing of lopinavir/ritonavir was resumed 2 weeks after completing antituberculosis treatment. Plasma sampling was conducted during and 4 weeks after completing antituberculosis treatment. RESULTS: Of 20 children enrolled; 15, 1-7 years old, had pharmacokinetics sampling available for analysis. Lopinavir concentrations (median [range]) on 8-hourly lopinavir/ritonavir co-administered with rifampicin (n = 15; area under the curve 0-24 55.32 mg/h/L [0.30-398.7 mg/h/L]; C max 3.04 mg/L [0.03-18.6 mg/L]; C 8hr 0.90 mg/L [0.01-13.7 mg/L]) were lower than on standard dosing without rifampicin (n = 12; area under the curve 24 121.63 mg/h/L [2.56-487.3 mg/h/L]; C max 9.45 mg/L [0.39-26.4 mg/L]; C 12hr 3.03 mg/L [0.01-17.7 mg/L]). During and after rifampicin cotreatment, only 7 of 15 (44.7%) and 8 of 12 (66.7%) children, respectively, achieved targeted pre-dose lopinavir concentrations ≥1mg/L. CONCLUSIONS: Modified 8-hourly dosing of lopinavir/ritonavir failed to achieve adequate lopinavir concentrations with concurrent antituberculosis treatment. The subtherapeutic lopinavir exposures on standard dosing after antituberculosis treatment are of concern and requires further evaluation.
Asunto(s)
Fármacos Anti-VIH , Infecciones por VIH , Tuberculosis , Niño , Humanos , Preescolar , Lactante , Rifampin/uso terapéutico , Lopinavir/farmacocinética , Ritonavir/farmacocinética , Fármacos Anti-VIH/uso terapéutico , Tuberculosis/complicaciones , Tuberculosis/tratamiento farmacológico , Infecciones por VIH/complicaciones , Infecciones por VIH/tratamiento farmacológico , Quimioterapia Combinada , Antituberculosos/uso terapéutico , Antituberculosos/farmacocinéticaRESUMEN
BACKGROUND: Although super-boosted lopinavir/ritonavir (LPV/r; ratio 4:4 instead of 4:1) is recommended for infants living with HIV and receiving concomitant rifampicin, in clinical practice, many different LPV/r dosing strategies are applied due to poor availability of pediatric separate ritonavir formulations needed to superboost. We evaluated LPV pharmacokinetics in infants with HIV receiving LPV/r dosed according to local guidelines in various sub-Saharan African countries with or without rifampicin-based tuberculosis (TB) treatment. METHODS: This was a 2-arm pharmacokinetic substudy nested within the EMPIRICAL trial (#NCT03915366). Infants aged 1-12 months recruited into the main study were administered LPV/r according to local guidelines and drug availability either with or without rifampicin-based TB treatment; during rifampicin cotreatment, they received double-dosed (ratio 8:2) or semisuperboosted LPV/r (adding a ritonavir 100 mg crushed tablet to the evening LPV/r dose). Six blood samples were taken over 12 hours after intake of LPV/r. RESULTS: In total, 14/16 included infants had evaluable pharmacokinetic curves; 9/14 had rifampicin cotreatment (5 received double-dosed and 4 semisuperboosted LPV/r). The median (IQR) age was 6.4 months (5.4-9.8), weight 6.0 kg (5.2-6.8), and 10/14 were male. Of those receiving rifampicin, 6/9 infants (67%) had LPV Ctrough <1.0 mg/L compared with 1/5 (20%) in the control arm. LPV apparent oral clearance was 3.3-fold higher for infants receiving rifampicin. CONCLUSION: Double-dosed or semisuperboosted LPV/r for infants aged 1-12 months receiving rifampicin resulted in substantial proportions of subtherapeutic LPV levels. There is an urgent need for data on alternative antiretroviral regimens in infants with HIV/TB coinfection, including twice-daily dolutegravir.
Asunto(s)
Fármacos Anti-VIH , Infecciones por VIH , Inhibidores de la Proteasa del VIH , Masculino , Lactante , Humanos , Niño , Femenino , Lopinavir/uso terapéutico , Ritonavir/uso terapéutico , Rifampin/uso terapéutico , Infecciones por VIH/tratamiento farmacológico , Fármacos Anti-VIH/uso terapéutico , Inhibidores de la Proteasa del VIH/uso terapéuticoRESUMEN
Optimal antituberculosis therapy is essential for favorable clinical outcomes. Peak plasma concentrations of first-line antituberculosis drugs in infants with living HIV receiving WHO-recommended dosing were low compared with reference values for adults, supporting studies on increased doses of first-line TB drugs in infants.
Asunto(s)
Infecciones por VIH , Neumonía , Adulto , Lactante , Humanos , Antituberculosos , Infecciones por VIH/complicaciones , Infecciones por VIH/tratamiento farmacológico , Neumonía/tratamiento farmacológico , Valores de ReferenciaRESUMEN
BACKGROUND: Tuberculosis diagnosis might be delayed or missed in children with severe pneumonia because this diagnosis is usually only considered in cases of prolonged symptoms or antibiotic failure. Systematic tuberculosis detection at hospital admission could increase case detection and reduce mortality. METHODS: We did a stepped-wedge cluster-randomised trial in 16 hospitals from six countries (Cambodia, Cameroon, Côte d'Ivoire, Mozambique, Uganda, and Zambia) with high incidence of tuberculosis. Children younger than 5 years with WHO-defined severe pneumonia received either the standard of care (control group) or standard of care plus Xpert MTB/RIF Ultra (Xpert Ultra; Cepheid, Sunnyvale, CA, USA) on nasopharyngeal aspirate and stool samples (intervention group). Clusters (hospitals) were progressively switched from control to intervention at 5-week intervals, using a computer-generated random sequence, stratified on incidence rate of tuberculosis at country level, and masked to teams until 5 weeks before switch. We assessed the effect of the intervention on primary (12-week all-cause mortality) and secondary (including tuberculosis diagnosis) outcomes, using generalised linear mixed models. The primary analysis was by intention to treat. We described outcomes in children with severe acute malnutrition in a post hoc analysis. This study is registered with ClinicalTrials.gov (NCT03831906) and the Pan African Clinical Trial Registry (PACTR202101615120643). FINDINGS: From March 21, 2019, to March 30, 2021, we enrolled 1401 children in the control group and 1169 children in the intervention group. In the intervention group, 1140 (97·5%) children had nasopharyngeal aspirates and 942 (80·6%) had their stool collected; 24 (2·1%) had positive Xpert Ultra. At 12 weeks, 110 (7·9%) children in the control group and 91 (7·8%) children in the intervention group had died (adjusted odds ratio [OR] 0·986, 95% CI 0·597-1·630, p=0·957), and 74 (5·3%) children in the control group and 88 (7·5%) children in the intervention group had tuberculosis diagnosed (adjusted OR 1·238, 95% CI 0·696-2·202, p=0·467). In children with severe acute malnutrition, 57 (23·8%) of 240 children in the control group and 53 (17·8%) of 297 children in the intervention group died, and 36 (15·0%) of 240 children in the control group and 56 (18·9%) of 297 children in the intervention group were diagnosed with tuberculosis. The main adverse events associated with nasopharyngeal aspirates were samples with blood in 312 (27·3%) of 1147 children with nasopharyngeal aspirates attempted, dyspnoea or SpO2 less than 95% in 134 (11·4%) of children, and transient respiratory distress or SpO2 less than 90% in 59 (5·2%) children. There was no serious adverse event related to nasopharyngeal aspirates reported during the trial. INTERPRETATION: Systematic molecular tuberculosis detection at hospital admission did not reduce mortality in children with severe pneumonia. High treatment and microbiological confirmation rates support more systematic use of Xpert Ultra in this group, notably in children with severe acute malnutrition. FUNDING: Unitaid and L'Initiative. TRANSLATION: For the French translation of the abstract see Supplementary Materials section.
Asunto(s)
Mycobacterium tuberculosis , Tuberculosis , Humanos , Niño , Preescolar , Incidencia , Sensibilidad y Especificidad , Esputo/microbiología , Tuberculosis/diagnósticoRESUMEN
INTRODUCTION: With growing attention globally to the childhood tuberculosis epidemic after decades of neglect, and with the burden of severe acute malnutrition (SAM) remaining unacceptably high worldwide, the collision of these two diseases is an important focus for improving child health. AREAS COVERED: This review describes the clinical and public health implications of the interplay between tuberculosis and SAM, particularly for children under the age of five, and identifies priority areas for improved programmatic implementation and future research. We reviewed the literature on PubMed and other evidence known to the authors published until August 2021 relevant to this topic. EXPERT OPINION: To achieve the World Health Organization's goal of eliminating deaths from childhood tuberculosis and to improve the abysmal outcomes for children with SAM, further research is needed to 1) better understand the epidemiologic connections between child tuberculosis and SAM, 2) improve case finding of tuberculosis in children with SAM, 3) assess unique treatment considerations for tuberculosis when children also have SAM, and 4) ensure tuberculosis and SAM are strongly addressed in decentralized, integrated models of providing primary healthcare to children.