Papers by Veronica Mulenga
Journal of Antimicrobial Chemotherapy, Oct 5, 2016
Objectives: To characterize the effects of CYP2B6 polymorphisms, diurnal variation and demographi... more Objectives: To characterize the effects of CYP2B6 polymorphisms, diurnal variation and demographic factors on nevirapine pharmacokinetics in African children. Methods: Non-linear mixed-effects modelling conducted in NONMEM 7.3 described nevirapine plasma concentration-time data from 414 children aged 0.3-15 years. Results: Nevirapine pharmacokinetics was best described using a one-compartment disposition model with elimination through a well-stirred liver model accounting for a first-pass effect and transit-compartment absorption. Intrinsic clearance was affected by diurnal variation (characterized using a cosine function with peak amplitude 29% at 12 noon) and CYP2B6 metabolizer status [extensive metabolizer (EM) 516GG|983TT, reference; intermediate metabolizer (IM) 516GT|983TT or 516GG|983TC, 17% lower; slow metabolizer (SM) 516TT|983TT or 516GT|983TC, 50% lower; ultra-slow metabolizer (USM) 516GG|983CC, 68% lower]. Age was found to affect pre-hepatic bioavailability: 31.7% lower at birth and increasing exponentially. Median (90% CI) evening C min values in the different metabolizer groups were 5.01 (3.01-7.47), 6.55 (3.65-13.32), 11.59 (5.44-22.71) and 12.32 (12.32-27.25) mg/L, respectively. Evening C min values were ,3 mg/L in 43% of EM weighing ,6 kg and 26% of IM weighing ,6 kg, while 73% of SM and 88% of USM in all weight-bands had evening C min values .8 mg/L. C min was not markedly affected by administration time, but was altered by unequal splitting of the daily dose. Conclusions: Diurnal variation does not greatly affect nevirapine exposure. However, when daily doses cannot be split equally, the larger dose should be given in the morning. To achieve homogeneous exposures, nevirapine doses for SM and USM should be reduced by 50%, and children weighing ,6 kg with EM or IM metabolizer status should receive the same dose as children weighing 6-10 kg.
British Journal of Clinical Pharmacology, Apr 25, 2016
Using a model-based approach, the efavirenz steady-state pharmacokinetics in African children is ... more Using a model-based approach, the efavirenz steady-state pharmacokinetics in African children is characterized, quantifying demographic and genotypic effects on the drug's disposition. Simulations are also conducted allowing prediction of optimized doses of efavirenz in this population. METHODS We modelled the steady-state population pharmacokinetics of efavirenz in Ugandan and Zambian children using nonlinear mixed-effects modelling. Individual mid-dose efavirenz concentrations were derived and simulations explored genotype-based dose optimization strategies. RESULTS A two-compartment model with absorption through transit compartments well described 2086 concentration-time points in 169 children. The combined effect of single nucleotide polymorphisms (SNPs) 516G>T and 983T>C explained 44.5% and 14.7% of the variability in efavirenz clearance and bioavailability, respectively. The detected frequencies of composite CYP2B6 genotype were 0.33 for 516GG|983TT, 0.35 for 516GT|983TT, 0.06 for 516GG|983TC, 0.18 for 516TT|983TT, 0.07 516GT|983TC and 0.01 for 516GG|983CC.
AIDS, Apr 24, 2017
Background: Nevirapine is the only nonnucleoside reverse transcriptase inhibitor currently availa... more Background: Nevirapine is the only nonnucleoside reverse transcriptase inhibitor currently available as a paediatric fixed-dose-combination tablet and is widely used in African children. Nonetheless, the number of investigations into pharmacokinetic determinants of virological suppression in African children is limited, and the predictive power of the current therapeutic range was never evaluated in this population, thereby limiting treatment optimization. Methods: We analysed data from 322 African children (aged 0.3-13 years) treated with nevirapine, lamivudine, and either abacavir, stavudine, or zidovudine, and followed up to 144 weeks. Nevirapine trough concentration (C min) and other factors were tested for associations with viral load more than 100 copies/ml and transaminase increases more than grade 1 using proportional hazard and logistic models in 219 initially antiretroviral treatment (ART)-naive children. Results: Pre-ART viral load, adherence, and nevirapine C min were associated with viral load nonsuppression [hazard ratio ¼ 2.08 (95% confidence interval (CI): 1.50-2.90, P < 0.001) for 10-fold higher pre-ART viral load, hazard ratio ¼ 0.78 (95% CI: 0.68-0.90, P < 0.001) for 10% improvement in adherence, and hazard ratio ¼ 0.94 (95% CI: 0.90-0.99, P ¼ 0.014) for a 1 mg/l increase in nevirapine C min ]. There were additional effects of pre-ART CD4 þ cell percentage and clinical site. The risk of virological nonsuppression decreased with increasing nevirapine C min , and there was no clear C min threshold predictive of virological nonsuppression. Transient transaminase elevations more than grade 1 were associated with high C min (>12.4 mg/l), hazard ratio ¼ 5.18 (95% CI 1.95-13.80, P < 0.001). Conclusion: Treatment initiation at lower pre-ART viral load and higher pre-ART CD4 þ cell percentage, increased adherence, and maintaining average C min higher than current target could improve virological suppression of African children treated with nevirapine without increasing toxicity.
Journal of Acquired Immune Deficiency Syndromes, Oct 1, 2016
Background: Owing to insufficient evidence in children, target plasma concentrations of efavirenz... more Background: Owing to insufficient evidence in children, target plasma concentrations of efavirenz are based on studies in adults. Our analysis aimed to evaluate the pediatric therapeutic thresholds and characterize the determinants of virological suppression in African children. Methods: We analyzed data from 128 African children (aged 1.7-13.5 years) treated with efavirenz, lamivudine, and one among abacavir, stavudine, or zidovudine, and followed up to 36 months. Individual pharmacokinetic (PK) measures [plasma concentration 12 hours after dose (C12h), plasma concentration 24 hours after dose (C24h), and area under the curve (AUC 0-24)] were estimated using population PK modeling. Cox multiple failure regression and multivariable fractional polynomials were used to investigate the risks of unsuppressed viral load associated with efavirenz exposure and other factors among 106 initially treatment-naive children, and likelihood profiling was used to identify the most predictive PK thresholds. Results: The risk of viral load .100 copies per milliliter decreased by 42% for every 2-fold increase in efavirenz mid-dose concentration [95% confidence interval (CI): 23% to 57%; P , 0.001]. The most predictive PK thresholds for increased risk of unsuppressed viral load were C12h 1.12 mg/L [hazard ratio (HR): 6.14; 95% CI: 2.64 to 14.27], C24h 0.65 mg/L (HR: 6.57; 95% CI: 2.86 to 15.10), and AUC 0-24 28 mg$h/L (HR: 5.77; 95% CI: 2.28 to 14.58). Children older than 8 years had a more than 10-fold increased risk of virological nonsuppression (P = 0.005); among children younger than 8 years, boys had a 5.31 times higher risk than girls (P = 0.007). Central nervous system adverse events were infrequently reported. Conclusions: Our analysis suggests that the minimum target C24h and AUC 0-24 could be lowered in children. Our findings should be confirmed in a prospective pediatric trial.
The Lancet Infectious Diseases
Despite efforts to scale up prevention of mother-to-child transmission (PMTCT) of HIV, over 1,000... more Despite efforts to scale up prevention of mother-to-child transmission (PMTCT) of HIV, over 1,000 infants continue to be infected daily, particularly in sub-Saharan Africa [1]. Disease progression in infants is much more rapid than in older children and adults, with mortality exceeding 50% by 2 years of age in the absence of antiretroviral therapy (ART) [2]. Although combination ART has been available since 1997, diagnosis and treatment of infants is much more challenging com-pared to older children and adults (Box 1). Furthermore, until recently there was little evidence to guide treatment approaches in infants and young children, with interna-tional policymakers relying on data from cohort studies and expert opinion to inform guidelines. In the past 5 years, results have emerged from several ran-domized clinical trials of children with HIV under 2 years of age (Table 1) [3–8]; a systematic review of these trials has just been published [9]. Here, we consider the implications of re...
AIDS and Behavior, 2016
A high level of adherence to antiretroviral treatment is essential for optimal clinical outcomes ... more A high level of adherence to antiretroviral treatment is essential for optimal clinical outcomes in HIV infection, but measuring adherence is difficult. We investigated whether responses to a questionnaire eliciting caregiver beliefs in medicines were associated with adherence of their child (median age 2.8 years), and whether this in turn was associated with viral suppression. We used the validated beliefs in medicine questionnaire (BMQ) to measure caregiver beliefs, and medication event monitoring system caps to measure adherence. We found significant associations between BMQ scores and adherence, and between adherence and viral suppression. Among children initiating Antiretroviral therapy (ART), we also found significant associations between BMQ 'necessity' scores, and BMQ 'necessity-concerns' scores, and later viral suppression. This suggests that the BMQ may be a valuable tool when used alongside other adherence measures, and that it remains important to keep caregivers well informed about the long-term necessity of their child's ART. Keywords Adherence Á Children Á Beliefs in medicine Á Sub-Saharan Africa Á Antiretroviral therapy On behalf of CHAPAS-3 trial Team.
AIDS, 2007
Cotrimoxazole prophylaxis reduces morbidity and mortality in HIV-1-infected children, but mechani... more Cotrimoxazole prophylaxis reduces morbidity and mortality in HIV-1-infected children, but mechanisms for these benefits are unclear. CHAP was a randomized trial comparing cotrimoxazole prophylaxis with placebo in HIV-infected children in Zambia where background bacterial resistance to cotrimoxazole is high. We compared causes of mortality and hospital admissions, and antibiotic use between randomized groups. Of 534 children (median age, 4.4 years; 32% 1-2 years), 186 died and 166 had one or more hospital admissions not ending in death. Cotrimoxazole prophylaxis was associated with lower mortality, both outside hospital (P = 0.01) and following hospital admission (P = 0.005). The largest excess of hospital deaths in the placebo group was from respiratory infections [22/56 (39%) placebo versus 10/35 (29%) cotrimoxazole]. By 2 years, the cumulative probability of dying in hospital from a serious bacterial infection (predominantly pneumonia) was 7% on cotrimoxazole and 12% on placebo (P = 0.08). There was a trend towards lower admission rates for serious bacterial infections in the cotrimoxazole group (19.1 per 100 child-years at risk versus 28.5 in the placebo group, P = 0.09). Despite less total follow-up due to higher mortality, more antibiotics (particularly penicillin) were prescribed in the placebo group in year one [6083 compared to 4972 days in the cotrimoxazole group (P = 0.05)]. Cotrimoxazole prophylaxis appears to mainly reduce death and hospital admissions from respiratory infections, supported further by lower rates of antibiotic prescribing. As such infections occur at high CD4 cell counts and are common in Africa, the role of continuing cotrimoxazole prophylaxis after starting antiretroviral therapy requires investigation.
Antiviral Therapy
Objective To investigate nevirapine concentrations in African HIV-infected children receiving div... more Objective To investigate nevirapine concentrations in African HIV-infected children receiving divided Triomune tablets (stavudine+lamivudine+nevirapine). Design Cross-sectional study. Methods Steady-state plasma nevirapine concentrations were determined in Malawian and Zambian children aged 8 months to 18 years receiving Triomune in routine outpatient settings. Predictors from height-for-age, body mass index (BMI)-for-age, age, sex, post-dose sampling time and dose/m2/day were investigated using centre-stratified regression with backwards elimination ( P<0.1). Results Of the 71 Malawian and 56 Zambian children (median age 8.4 vs 8.5 years, height-for-age -3.15 vs -1.84, respectively), only 1 (3%) of those prescribed ≥300 mg/m2/day nevirapine had subtherapeutic concentrations (<3mg/l) compared with 22 (23%) of those prescribed <300 mg/m2/day; most children with subtherapeutic nevirapine concentrations were taking half or quarter Triomune tablets. Lower nevirapine concentrati...
BMC Pediatrics, 2021
Background In high tuberculosis (TB) burden settings, there is growing evidence that TB is common... more 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 h...
New England Journal of Medicine, 2022
BACKGROUND Two thirds of children with tuberculosis have nonsevere disease, which may be treatabl... more 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.
BMC Medical Research Methodology, 2022
Background Clinical trial investigators may need to evaluate treatment effects in a specific subg... more Background Clinical trial investigators may need to evaluate treatment effects in a specific subgroup (or subgroups) of participants in addition to reporting results of the entire study population. Such subgroups lack power to detect a treatment effect, but there may be strong justification for borrowing information from a larger patient group within the same trial, while allowing for differences between populations. Our aim was to develop methods for eliciting expert opinions about differences in treatment effect between patient populations, and to incorporate these opinions into a Bayesian analysis. Methods We used an interaction parameter to model the relationship between underlying treatment effects in two subgroups. Elicitation was used to obtain clinical opinions on the likely values of the interaction parameter, since this parameter is poorly informed by the data. Feedback was provided to experts to communicate how uncertainty about the interaction parameter corresponds with ...
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Papers by Veronica Mulenga