Publications

30

Dec, 2016

Physiologically Based Modelling of Darunavir/Ritonavir Pharmacokinetics During Pregnancy

 

Authors: Colbers A, Best B, Schalkwijk S, et al. PANNA Network and the IMPAACT 1026 Study Team.

Published in: Clin Pharmacokinet. 2016;55(3):381-96

Abstract Pregnant women are usually excluded from clinical trials. Physiologically based pharmacokinetic (PBPK) modelling may provide a method to predict pharmacokinetics in pregnant women, without the need to perform extensive in vivo clinical trials. Here, we used mechanistic modelling to delineate the potential impact of drug transporters on darunavir pharmacokinetics and to identify current knowledge gaps that limit accurate PBPK modelling of darunavir/ritonavir (darunavir/r) exposure in pregnancy. Simcyp (version 13.2) was used for PBPK modelling, using physicochemical and in vitro pharmacokinetic parameters of darunavir and ritonavir from the literature. The Michaelis-Menten constant (K m) and the maximum rate of metabolite formation (V max) for cytochrome P450 3A4-mediated darunavir biotransformation and inhibition by ritonavir were determined experimentally, while the contributions of hepatocyte influx and efflux transporters were assessed by sensitivity analysis. The simulations were compared with previously published clinical pharmacokinetic data. We found that use of a well-stirred liver model overestimated darunavir exposure substantially. A permeability-limited liver model, including hepatic uptake and efflux transporters and an efficient enterohepatic circulation step, resulted in an acceptable description of darunavir/r exposure. For the 600/100 mg darunavir/r twice-daily dose and the 800/100 mg once-daily dose, the estimated pharmacokinetic parameters were within a 2-fold range of the reported data. The predicted decreases in the area under the concentration-time curve (AUC) values during pregnancy for the twice- and once-daily doses were 27 and 41%, respectively, which were in line with the observed decreases of 17-22 and 33%. In conclusion, our data support a clinically relevant role of hepatic transporters in darunavir pharmacokinetics. By including them in our model, we successfully approximated the increase in darunavir exposure mediated by ritonavir co-administration and the decrease in darunavir exposure observed during pregnancy.

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15

Dec, 2016

Pharmacodynamics of vancomycin for CoNS infection: experimental basis for optimal use of vancomycin in neonates

 

Authors: Ramos-Martin R , Johnson A, Livermore J, et al.

Published in: J Antimicrob Ther 2016;71(4):992-1002

Objectives CoNS are the most common cause of neonatal late-onset sepsis. Information on the vancomycin

pharmacokinetics/pharmacodynamics against CoNS is limited. The aim of this study was to characterize vancomycin

pharmacokinetic/pharmacodynamic relationships for CoNS and investigate neonatal optimal dosage

regimens.

Methods A hollow fibre and a novel rabbit model of neonatal central line-associated bloodstream CoNS

infections were developed. The results were then bridged to neonates by use of population pharmacokinetic

techniques and Monte Carlo simulations.

Results There was a dose-dependent reduction in the total bacterial population and C-reactive protein levels.

The AUC/MIC and Cmax/MIC ratios were strongly linked with total and mutant resistant cell kill. Maximal amplification of resistance was observed in vitro at an fAUC/MIC of 200 mg.h/L. Simulations predicted that neonates, 29 weeks post-menstrual age are underdosed with standard regimens with respect to older age groups.

Conclusions The AUC/MIC and Cmax/MIC ratios are the pharmacodynamic indices that best explain total and

resistant cell kill in CoNS infection. This suggests that less-fractionated regimens are appropriate for clinical

use and continuous infusions may be associated with increased risk of emergence of antimicrobial resistance.

This study has provided the pharmacodynamic evidence to inform an optimized neonatal dosage regimen to

take into a randomized controlled trial

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12

Dec, 2016

Prevalence of depressive symptoms in pregnant and postnatal HIV-positive women in Ukraine: a cross-sectional survey

 

Authors: Bailey H, Malyuta R, Townsend C, Cortina Borja M, Thorne C for the Ukraine European Collaborative Study in EuroCoord.

Published in: Reprod Health. 2016;22(3):13-27.

Background Perinatal depression among HIV-positive women has negative implications for HIV-related and other maternal and infant outcomes. The aim of this study was to investigate the burden and correlates of perinatal depression among HIV-positive women in Ukraine, a lower middle income country with one of the largest HIV-positive populations in Europe.

Methods Cross-sectional surveys nested within the Ukraine European Collaborative Study were conducted of HIV-positive women at delivery and between 1 and 12 months postpartum. Depressive symptoms in the previous month were assessed using a self-report screening tool. Other data collected included demographics, antiretroviral therapy (ART)-related self-efficacy, and perceptions of risks/benefits of interventions to prevent mother-to-child transmission (PMTCT). Characteristics of women with and without a positive depression screening test result were compared using Fisher’s exact test and χ2 test for categorical variables.

Results A quarter (27% (49/180) antenatally and 25% (57/228) postnatally) of participants screened positive for depressive symptoms. Antenatal risk factors were living alone (58% (7/12) vs. 25% (42/167) p = 0.02), being somewhat/terribly bothered by ART side effects (40% (17/43) vs. 23% (30/129) not /only slightly bothered, p = 0.05) and having lower ART-related self-efficacy (43% (12/28) vs. 23% (25/110) with higher self-efficacy, p = 0.05). Postnatally, single mothers were more likely to screen positive (44% (20/45) vs. 21% (18/84) of cohabiting and 19% (19/99) of married women, p < 0.01) as were those unsure of the effectiveness of neonatal prophylaxis (40% (20/45) vs. 18% (28/154) sure of effectiveness, p < 0.01), those worried that neonatal prophylaxis could harm the baby (30% (44/146) vs. 14% (10/73) not worried p < 0.01) and those not confident to ask for help with taking ART (48% (11/23) vs. 27% (10/37) fairly confident and 15 % (4/26) confident that they could do this). Of women who reported wanting help for their depressive symptoms, 82% (37/45) postnatally but only 31% (12/39) antenatally were already accessing peer counselling, treatment adherence programmes, support groups or social services.

Conclusions A quarter of women screened positive for depression. Results highlight the need for proactive strategies to identify depressive symptoms, and an unmet need for provision of mental health support in the perinatal period for HIV-positive women in Ukraine.

 

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10

Dec, 2016

Zika virus: what have we learned?

 

Authors: Safadi MA

Published in: Amer J Perinatol.2016; 33(11): 1029-1031

Abstract Zika virus (ZIKV) is an emerging arthropod-borne, enveloped RNA virus of the Flaviviridae family, which belongs to the genus Flavivirus, related to dengue, yellow fever, Japanese encephalitis, and West Nile viruses. Two major lineages, African and Asian, have been identified through phylogenetic analyses.

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3

Dec, 2016

Outcome of dengue in hospitalized jamaican children

 

Authors: Davidson T., Vickers I., Christie CD

Published in: West Indian Med J 2016;65(3);442-449

Background Dengue fever is hyper-endemic in Jamaica with exponential rates of infection in successive outbreaks. The absence of local data and the potential for massive outbreaks in a country where a third of the population are children formed the basis for this study.

Methods We evaluated the outcome of dengue in children hospitalized at the University Hospital of the West Indies (UHWI), Mona, Jamaica, during the island-wide dengue fever epidemic of 2012. This retrospective study reports all physician-diagnosed cases of dengue in hospitalized children aged less than 15 years.

Results A total of 134 hospitalized children with physician-diagnosed dengue were included. One hundred and eighteen (88%) had a confirmatory dengue laboratory test.  One hundred and twenty (90%) were uncomplicated and 14 (10%) had severe dengue. Severe disease was significantly associated with a longer duration between disease onset and hospital admission (p = 0.0076). Main co-morbidities were sickle cell disease (14%) and asthma (13%), however neither was associated with increased mortality. Duration of hospitalization was longer for patients with sickle cell disease. Children with short stature were significantly more likely to have severe dengue [Z-score height-for-age < 2.0; OR 6.46(1.61, 25.88), p = 0.016]. There were five deaths with a case fatality rate of 3.73%. Prior use of Non-steroidal Anti-inflammatory Drugs was documented in four deaths.

Conclusion Delayed presentation and short stature were significantly associated with severe dengue. Children with sickle cell disease had longer hospital stay. The case fatality rate was 3.73%. Use of safe and efficacious dengue vaccines should mitigate the effects of dengue-attributable childhood morbidity and mortality.

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3

Dec, 2016

Chikungunya in Jamaica – public health effects and clinical features in children

 

Authors: Christie CD, Melbourne-Chambers R, Ennevor J, et al.

Published in: West Indian Med J 2016;65(3);431-437

Background Chikungunya virus entered the Caribbean for the first time in 2013 and Jamaica experienced its maiden epidemic with Chikungunya Fever in 2014. We aimed to describe the public health effects and describe the clinical features in children and adolescents in Jamaica.

Methods This study reviewed the public health effects of the illness in Jamaica by reviewing available data sources and the clinical features in 210 children and adolescents meeting the case definition at two hospitals, Bustamante Hospital for Children and University Hospital of the West Indies between August 23 and October 31, 2014 by chart review. Descriptive analyses and comparisons between groups using the Mann-Whitney U test were performed with SPSS version 22.

Results The majority of households were affected by the illness which caused widespread absenteeism from school and work, loss of productivity and economic losses estimated at 60 billion dollars. The health sector was impacted by increased numbers seen in clinics and emergency departments, increased need for bed space and pharmaceuticals. Ninety-nine per cent of cases were febrile with a median maximal temperature of 102.4 F. Ninety-three per cent had household contacts of 0–20 persons. In addition to fever, maculopapular rash and joint pains, infants six months and younger presented with irritability and groaning (p = 0.00) and those between six months and six years presented with febrile seizures (p = 0.00). Neurologic involvement was noted in 24%. Apart from anaemia, few had other laboratory derangements. Few had severe organ dysfunction and there were no deaths.

Conclusion The Chikungunya Fever epidemic had significant public health and economic impact in Jamaica. In children, there were characteristic presentations in neonates and young infants and in children six months to six years. Neurologic involvement was common but other organ dysfunction was rare. These findings underscore the need to prevent further epidemics and the quest for a vaccine.

 

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3

Dec, 2016

Emergence of Zika virus epidemic and the national response in Jamaica

 

Authors: Webster-Kerr K, Christie CDC, Grant A, et al.

Published in: West Indian Med J. 2016;65(1):243-249

Background Jamaica, along with the Americas, experienced major epidemics of arboviral diseases transmitted by the Aedes aegypti mosquito in recent years. These include dengue fever in 2012, chikungunya fever in 2014 and Zika virus infection (ZIKV) in 2016. We present the emergence of the ZIKV epidemic in Jamaica and outline the national response.

Methods The Ministry of Health’s preparedness included: heightened surveillance, clinical management guidance, vector control and management, laboratory capacity strengthening, training and staffing, risk communication and public education, social mobilization, inter-sectoral collaboration, resource mobilization and international cooperation.

Results The first case of ZIKV was confirmed on 29 January 2016 with date of onset of 17 January 2016. From 3 January to 30 July 2016 (Epidemiological Week (EW) 1-30), 4648 cases of ZIKV were recorded (4576 suspected, 72 laboratory-confirmed). Leading symptoms were similar among suspected and confirmed cases: rash (71% and 88%), fever (65% and 53%) and joint pains (47% and 38%). There were 17 suspected cases of Guillain-Barre Syndrome. Three hundred and eighty-three were reported in pregnant women, with no reports of microcephaly to date. Zika and dengue viruses were circulating predominantly in 2016. At EW30, 1744 cases of dengue were recorded (1661 suspected and 83 confirmed). Dengue serotypes 3 and 4 circulating with 121 reports of dengue haemorrhagic fever.

 

 

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3

Dec, 2016

Prolonged shedding of Zika virus associated with congenital infection

 

Authors: Oliveira DB, Almeida FJ, Durigon EL, et al.

Published in: N Engl J Med. 2016. 22;375(12):1202-4

The presence of Zika virus (ZIKV) infection has been associated with microcephaly in multiple studies, although little is known about ZIKV shedding in congenitally infected infants. We report a case of a newborn who had continued viremia with ZIKV for at least 67 days after birth.

 

3

Dec, 2016

Unravelling the paediatric and perinatal Zika virus epidemic through population-based research

 

Authors: Christie CD, Giaquinto C

Published in: West Indian Med J.2016;65(1):239-242

Abstract Zika virus epidemic now involves 72 countries, worldwide. Transmission is multimodal through mosquito bites and blood and body fluids. Zika virus causes Guillain Barre Syndrome syndrome and pregnancy complications including perinatal microcephaly. Diagnosis is complicated by subclinical infection in 80%, co-circulation with dengue and chikungunya fevers with similar presentations and cross-reactivity in serological tests. There is no cure, or preventive vaccine. Large population-based studies will help to elucidate ZIKV epidemiology, vertical transmission, risks to the fetus of maternal ZIKV infection and natural history of congenital and non-congenital ZIKV infection as provided by the activities in the “ZIKAction” research consortium in Latin America, Europe and the Caribbean, which was recently funded by the European Commission.

 

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3

Dec, 2016

Zika virus infection in pregnant women in Barcelona, Spain

 

Authors: Bocanegra C, Sulleiro E, Soriano-Arandes A, et al.

Published in: Clin Microbiol Infect. 2016;22(7):648-50

This case series of two pregnant women infected with the Zika virus in Barcelona, Spain and provides an algorithm for diagnosing pregnant women with suspected ZIKV infection in non-endemic areas.

 

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