Publications by authors named "Manal H El-Sayed"

41 Publications

Vaccination at the forefront of the fight against hepatitis B and C.

Nat Rev Gastroenterol Hepatol 2021 Dec 21. Epub 2021 Dec 21.

Toronto Centre for Liver Disease, Toronto General Hospital, University of Toronto, Toronto, Ontario, Canada.

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http://dx.doi.org/10.1038/s41575-021-00570-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8690566PMC
December 2021

Effective and Safe Daclatasvir Drug Exposures Predicted in Children Using Adult Formulations.

Pediatr Infect Dis J 2021 Dec;40(12):1081-1086

Pediatric Department, Ain Shams University.

Background: Sofosbuvir (SOF)/daclatasvir (DCV) is the direct-acting antiviral regimen of choice in many low- and middle-income countries for curative treatment of chronic hepatitis C virus (HCV) infection in adults, but data on the use of DCV in children are lacking. We performed a population pharmacokinetic (PK) analysis to predict DCV exposure in children treated with available adult formulations.

Methods: DCV concentration data from HCV-infected adolescents receiving SOF/DCV [400/60 mg, once daily (OD)] who participated in a PK study in Egypt were used for model development. PK parameters were estimated using a population approach. Monte Carlo simulations were run for virtual children weighing 10 to <35 kg receiving 60 or 30 mg OD, and DCV exposures were compared with adults ranges.

Results: Seventeen HCV-infected adolescents (13 males) provided 151 DCV concentrations. Median (range) age was 14 (11-18) years and weight 50 (32-63) kg. In these adolescents receiving 60 mg DCV, median (interquartile range) DCV area under the concentration time curve 0 to 24 hours, maximum concentrations, and minimum concentrations were 11,130 (8140-14,690) ng·h/mL, 1030 (790-1220) ng/mL and 130 (110-220) ng/mL, respectively, compared with 10,343 (7661-14,095) ng·h/mL, 1132 (876-1518) ng/mL and 110 (55.7-192) ng/mL predicted in children 10 to <35 kg receiving 30 mg. The proportion of children with DCV exposures above the adult range rapidly increased for children <30 kg using 60 mg OD, similarly for children 10-14 kg using 30 mg.

Conclusions: DCV 30 mg OD was predicted to achieve effective and safe exposures in children 14 to <35 kg, perhaps down to 10 kg. These results should be validated clinically. Low-cost available adult DCV formulations together with approved pediatric doses of SOF would expand global access to HCV treatment for children.
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http://dx.doi.org/10.1097/INF.0000000000003282DOI Listing
December 2021

Beta-thalassemia major alters sofosbuvir/ledipasvir exposure in Hepatitis C virus infected adolescent patients.

Clin Res Hepatol Gastroenterol 2021 09 26;45(5):101747. Epub 2021 Jun 26.

Department of Paediatrics and Paediatric Haematology/Oncology unit, Faculty of Medicine, Ain Shams University, Cairo, Egypt; Faculty of Medicine, Ain-Shams University Research Institute-Clinical Research Centre (MASRI-CRC), Egypt.

Background: Hepatitis C virus (HCV) infected adolescents with beta-thalassemia major (BTM) are considered a potential population for HCV micro-elimination model development where BTM may negatively impact the pharmacokinetic exposure parameters of sofosbuvir/ledipasvir (SOF/LED).

Objectives: The study aimed at studying the effect of BTM on SOF/LED and SOF metabolite (GS-331007) pharmacokinetics.

Methods: A prospective, controlled study recruiting BTM and control HCV infected adolescents (Clinicaltrials.gov identifier-NCT04353986). Pharmacokinetic exposure to GS-331007 and LED was the primary pharmacokinetic outcome. No-effect boundaries were set to 90% confidence interval (CI) of exposure geometric mean ratio (GMR) within 70-143%. Dose suitability was based on the 90% CI of exposure GMR within 50-200% compared to adults. The percentage of patients achieving sustained virologic response 12 weeks post-treatment (SVR12) was the primary efficacy endpoint.

Results: Thirteen patients were enrolled per study group. All patients were included in the pharmacokinetic analysis (n=26). BTM patients showed lower GS-331007 and LED exposure that could, respectively, be as low as 45.4% and 36.1% compared to their control group. GS-331007 exposure in BTM patients was nearly half (56.8%, 90% CI 45.3-71.2%) that observed in adults. Despite that low drug exposure in 46.2% of BTM patients may alert dose unsuitability, they achieved SVR12. Moreover, patients with total bilirubin ≥1.93 mg/dL were predicted to have low GS-331007 exposure (0.913 receiver operating characteristic area under the curve with sensitivity and specificity >80%).

Conclusion And Relevance: The identified systematically lower drug exposure in BTM patients might partially explain relapses or treatment failures among BTM patients reported in other studies. BTM may be a hurdle towards implementing HCV micro-elimination model that may necessitate dose-adjustment.
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http://dx.doi.org/10.1016/j.clinre.2021.101747DOI Listing
September 2021

SARS-Co-V2 infection in never, former, and current tobacco/nicotine users: a cohort study of 4040 Egyptian healthcare workers.

BMC Public Health 2021 06 28;21(1):1243. Epub 2021 Jun 28.

Department of Community, Environmental, and Occupational Medicine, Faculty of Medicine, Ain Shams University, 38 Ramses st., Abbassia square, PO-box 11566, Cairo, Egypt.

Background: Smoking negatively impacts COVID-19 severity and adverse outcomes. Evidence on whether smoking is associated with SARS-Co-V2 infection and having a positive test is scarce, particularly from low-and middle-income countries, where most of the world's billion smokers live. The inconsistency in relevant findings calls for study designs and analyses to account for possible confounders including background characteristics and pre-existing co-morbidities, to disentangle the specific effect of smoking. In healthcare workers (HCWs) the frequency of exposure to COVID-19 cases adds another layer of risk that was not factored in previous studies. We examined the association of HCWs' tobacco/nicotine use (never, former, and current use) with having a positive SARS-Co-V2 test result and symptoms suggestive of infection, accounting for demographics, exposures, and co-morbidities.

Methods: A prospective cohort study of 4040 healthcare workers with baseline and follow-up screening took place during April-June 2020 in 12 healthcare facilities in Cairo, Egypt. Data on demographics, tobacco/nicotine use (manufactured or roll-your-own cigarettes, waterpipe tobacco, and electronic devices), co-morbidities, symptoms, exposures, and SARS-Co-V2 investigations were analyzed. Multinomial and multivariable logistic regression analyses were performed.

Results: Overall, 270/4040 (6.7, 95%CI: 5.9-7.5) had positive SARS-CoV-2 tests, 479 (11.9%) were current and 79 (2.0%) were former tobacco/nicotine users. The proportion of positive tests was 7.0% (243/3482, 95%CI: 6.1-7.8) among never, 5.1% (4/79, 95%CI: 0.1-10.0) among former, and 4.8% (23/479, 95%CI: 2.9-6.7) among current users. HCWs' SARS-CoV-2 test results did not vary significantly by single/multiple or daily/non-daily tobacco/nicotine use. Compared to never users, former users were more likely to self-report a pre-existing medical condition (OR1.87, 95%CI: 1.05-3.33, p = 0.033), and to experience symptoms suggestive of COVID-19 (OR1.76, 95%CI: 1.07-2.90, p = 0.027). After adjustment, former (OR0.45, 95%CI: 0.11-1.89, p = 0.273) and current (OR0.65, 95%CI: 0.38-1.09, p = 0.101) tobacco/nicotine use was not associated with HCWs' SARS-CoV-2 positive test results.

Conclusions: This is the first report on this association from low- and middle-income countries with high tobacco/nicotine use prevalence. In this HCW cohort, having a positive SARS-CoV-2 test was not associated with tobacco/nicotine use after accounting for demographics, exposures, and co-morbidities. Additional population-based studies could use such preliminary evidence to investigate this controversial association.
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http://dx.doi.org/10.1186/s12889-021-11290-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8238378PMC
June 2021

Pregnancy outcome of anti-HCV direct-acting antivirals: Real-life data from an Egyptian cohort.

Liver Int 2021 07 11;41(7):1494-1497. Epub 2021 May 11.

Department of Pediatrics and Clinical Research Center, Faculty of Medicine, Ain Shams University, Cairo, Egypt.

We aimed to assess the pregnancy outcome in women with chronic HCV who had negative pregnancy test prior to the anti-HCV course and had unintended pregnancy while on HCV treatment. Hundred patients with a mean age of 30 ± 6.7 y were included and advised to withhold antivirals and continue follow-up in viral hepatitis and obstetrics centres till delivery. All patients received a 12-weeks regimen of anti-HCV [sofosbuvir plus daclatasvir (SOF/DCV): n = 95, SOF/DCV plus ribavirin: n = 3, and paritaprevir/ritonavir/ombitasvir plus ribavirin: n = 2]. Only nine patients completed the full antiviral course against medical advice, and 91 stopped between on-treatment weeks 4 and 8. Eighty-eight patients delivered full-term babies, eight had preterm babies and two had abortions. Of the nine patients who completed the full course of DAAs, seven (77.8%) delivered normal babies, attended their post-treatment week 12 visit, and all (100%) achieved sustained virological response. No major antiviral-related adverse events were reported.
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http://dx.doi.org/10.1111/liv.14913DOI Listing
July 2021

Safety and efficacy of favipiravir versus hydroxychloroquine in management of COVID-19: A randomised controlled trial.

Sci Rep 2021 03 31;11(1):7282. Epub 2021 Mar 31.

Chest Department, Ain Shams University, Cairo, Egypt.

Favipiravir is considered a potential treatment for COVID-19 due its efficacy against different viral infections. We aimed to explore the safety and efficacy of favipiravir in treatment of COVID-19 mild and moderate cases. It was randomized-controlled open-label interventional phase 3 clinical trial [NCT04349241]. 100 patients were recruited from 18th April till 18th May. 50 patients received favipiravir 3200 mg at day 1 followed by 600 mg twice (day 2-day 10). 50 patients received hydroxychloroquine 800 mg at day 1 followed by 200 mg twice (day 2-10) and oral oseltamivir 75 mg/12 h/day for 10 days. Patients were enrolled from Ain Shams University Hospital and Assiut University Hospital. Both arms were comparable as regards demographic characteristics and comorbidities. The average onset of SARS-CoV-2 PCR negativity was 8.1 and 8.3 days in HCQ-arm and favipiravir-arm respectively. 55.1% of those on HCQ-arm turned PCR negative at/or before 7th day from diagnosis compared to 48% in favipiravir-arm (p = 0.7). 4 patients in FVP arm developed transient transaminitis on the other hand heartburn and nausea were reported in about 20 patients in HCQ-arm. Only one patient in HCQ-arm died after developing acute myocarditis resulted in acute heart failure. Favipiravir is a safe effective alternative for hydroxychloroquine in mild or moderate COVID-19 infected patients.
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http://dx.doi.org/10.1038/s41598-021-85227-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8012649PMC
March 2021

Accelerating Hepatitis C virus elimination in Egypt by 2030: A national survey of communication for behavioral development as a modelling study.

PLoS One 2021 23;16(2):e0242257. Epub 2021 Feb 23.

Department of Pediatrics and Clinical Research Center, Faculty of Medicine, Ain Shams University, Cairo, Egypt.

Aim Of The Work: This study aimed at assessing the dominance of risk practices associated with HCV endemicity in Egypt and detecting the behavioral development level concerning different aspects of HCV risk behaviors with respect to age and gender. The survey highlights the most cost-effective strategies that could accelerate HCV elimination in Egypt.

Subjects And Methods: A national household survey targeted 3780 individuals (age range: 10-85 years). The sample was a systematic probability proportionate to size from 6 governorates representing the six major subdivisions of Egypt. The indicators used for assessing the behavioral development level towards HCV included six domains: awareness (7 indicators), perceived risk (5 indicators), motivation with the intention to change (4 and 5 indicators for males and females respectively), trial, rejection or adoption (6 and 5 indicators for males and females respectively).

Results: The study revealed that along the continuum of behavior development, the percentage of the participants who acquired half of the scores was as follows: 73.1% aware, 69.8% developed perceived risk, 80.6% motivated with only 28.9% adopting the recommended behaviors, 32% rejected them, 2.3% were in the trial stage versus 35.8% who did not try any. Adolescents had significantly lower levels of development for almost all domains when compared to adults. Statistical higher significance was detected in favor of adults, employees, married, Lower Egypt governorates, and university-educated participants (p<0.001) regarding awareness, perceived risk, and motivation scores. More than half of the participants incorrectly believed that contaminated food, sharing food utilities, contaminated water, mosquitoes, and schistosomiasis would lead to HCV transmission.

Conclusion: Egypt would be closer to HCV elimination when cost-effective strategies are directed not towards creating awareness, perceived risk or motivation to change- (at an acceptable level)- but towards motivating adopting risk-reduction behaviors for HCV, tackling misconceptions and reinforcement of social support.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0242257PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7901784PMC
July 2021

The potential hepatoprotective effect of metformin in hepatitis C virus-infected adolescent patients with beta thalassemia major: Randomised clinical trial.

Int J Clin Pract 2021 Jun 17;75(6):e14104. Epub 2021 Mar 17.

Department of Pediatrics and Pediatric Hematology/Oncology Unit, Faculty of Medicine, Ain Shams University, Cairo, Egypt.

Background: Iron overload-induced oxidative stress and transfusion-acquired hepatitis C virus (HCV) infection are the main reasons of liver damage in beta thalassemia major (β-TM).

Objectives: Based on metformin's hepatic benefits in nondiabetic populations, the study aims to investigate the safety and the potential hepatoprotective effect of metformin in HCV-infected β-TM adolescent patients.

Methods: This was a prospective, randomised, parallel, controlled, open-label study in which 60 HCV-infected β-TM adolescent patients aged 11 to 18 years and receiving no antiviral therapy were selected and randomly assigned to treatment or control group in 1:1 allocation. Both groups were receiving β-TM standard-of-care regimen, whereas metformin (500 mg, twice daily) was added to the treatment group's regimen only. Patients were prospectively followed up for 6 months with assessment of liver biochemical profile, oxidative stress markers, liver fibrosis, clinical symptom improvement and metformin's adverse effects.

Results: Aspartate aminotransferase serum level decreased significantly over time in the treatment group only (P = .013). However, improvement was not clinically significant and did not attain normality. Change in total antioxidant capacity and malondialdehyde serum levels indicated significantly improved oxidative stress status in the treatment group versus significant deterioration in the control group (P < .001). Fibrosis grade improvement was observed in 14 patients in the treatment group versus one improved case in the control group.

Conclusion: The use of metformin in HCV-infected β-TM adolescent patients as an adjuvant antioxidant hepatoprotective agent is promising and can improve liver damage.
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http://dx.doi.org/10.1111/ijcp.14104DOI Listing
June 2021

Efficacy of favipiravir in COVID-19 treatment: a multi-center randomized study.

Arch Virol 2021 Mar 25;166(3):949-954. Epub 2021 Jan 25.

Department of Chest Diseases, Faculty of Medicine, Ain Shams University, Cairo, Egypt.

No specific antiviral drugs have been approved for the treatment of COVID-19. This study aimed to evaluate the efficacy of favipiravir in treatment of COVID-19. This was a multicenter randomized controlled study including 96 patients with COVID- 19 who were randomly assigned into a chloroquine (CQ) group and a favipiravir group. None of the patients in the favipiravir group needed mechanical ventilation (p = 0.129). One patient (2.3%) in the favipiravir group and two patients (4.2%) in the CQ group died (p = 1.00). Favipiravir is a promising drug for COVID-19 that decreases the hospital stay and the need for mechanical ventilation.ClinicalTrials.gov Identifier NCT04351295.
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http://dx.doi.org/10.1007/s00705-021-04956-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7829645PMC
March 2021

SARS-CoV-2 seroconversion among 4040 Egyptian healthcare workers in 12 resource-limited healthcare facilities: A prospective cohort study.

Int J Infect Dis 2021 Mar 20;104:534-542. Epub 2021 Jan 20.

Department of Hepatobiliary Surgery & Liver Transplantation, Ain Shams Center for Organ Transplantation (ASCOT), Faculty of Medicine, Ain Shams University, Cairo, Egypt.

Background: We examined Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) seroconversion incidence and risk factors 21 days after baseline screening among healthcare workers (HCWs) in a resource-limited setting.

Methods: A prospective cohort study of 4040 HCWs took place at 12 university healthcare facilities in Cairo, Egypt; April-June 2020. Follow-up exposure and clinical data were collected through online survey. SARS-CoV-2 testing was done using rapid IgM and IgG serological tests and reverse transcriptase-polymerase chain reaction (RT-PCR) for those with positive serology. Cox proportional hazards modelling was used to estimate adjusted hazard ratios (HR) of seroconversion.

Results: 3870/4040 (95.8%) HCWs tested negative for IgM, IgG and PCR at baseline; 2282 (59.0%) returned for 21-day follow-up. Seroconversion incidence (positive IgM and/or IgG) was 100/2282 (4.4%, 95% CI:3.6-5.3), majority asymptomatic (64.0%); daily hazard of 0.21% (95% CI:0.17-0.25)/48 746 person-days of follow-up. Seroconversion was: 4.0% (64/1596; 95% CI:3.1-5.1) among asymptomatic; 5.3% (36/686; 95% CI:3.7-7.2) among symptomatic HCWs. Seroconversion was independently associated with older age; lower education; contact with a confirmed case >15 min; chronic kidney disease; pregnancy; change/loss of smell; and negatively associated with workplace contact.

Conclusions: Most seroconversions were asymptomatic, emphasizing need for regular universal testing. Seropositivity was three-fold that observed at baseline. Cumulative infections increased nationally by a similar rate, suggesting HCW infections reflect community not nosocomial transmission.
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http://dx.doi.org/10.1016/j.ijid.2021.01.037DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7817419PMC
March 2021

COVID-19 in Children With Cancer: A Single Low-Middle Income Center Experience.

J Pediatr Hematol Oncol 2021 11;43(8):e1077-e1081

Pediatric Hematology Oncology Department.

Background: Coronavirus disease-2019 (COVID-19) could be associated with morbidity and mortality in immunocompromised children.

Objective: The objective of this study was to measure the frequency of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection among hospitalized children with cancer and to detect the associated clinical manifestations and outcomes.

Methodology: A prospective noninterventional study including all hospitalized children with cancer conducted between mid-April and mid-June 2020 in Ain Shams University Hospital, Egypt. Clinical, laboratory, and radiologic data were collected. SARS-CoV-2 infection was diagnosed by reverse transcription polymerase chain reaction tests in nasopharyngeal swabs.

Results: Fifteen of 61 hospitalized children with cancer were diagnosed with SARS-CoV-2. Their mean age was 8.3±3.5 years. Initially, 10 (66.7%) were asymptomatic and 5 (33.3%) were symptomatic with fever and/or cough. Baseline laboratory tests other than SARS-CoV-2 reverse transcription polymerase chain reaction were not diagnostic; the mean absolute lymphocyte count was 8.7±2.4×109/L. C-reactive protein was mildly elevated in most of the patients. Imaging was performed in 10 (66.7%) patients with significant radiologic findings detected in 4 (40%) patients. Treatment was mainly supportive with antibiotics as per the febrile neutropenia protocol and local Children Hospital guidance for management of COVID-19 in children.

Conclusions: Pediatric cancer patients with COVID-19 were mainly asymptomatic or with mild symptoms. A high index of suspicion and regular screening with nasopharyngeal swab in asymptomatic hospitalized cancer patients is recommended.
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http://dx.doi.org/10.1097/MPH.0000000000002025DOI Listing
November 2021

Universal COVID-19 screening of 4040 health care workers in a resource-limited setting: an Egyptian pilot model in a university with 12 public hospitals and medical centers.

Int J Epidemiol 2021 03;50(1):50-61

Department of Hepatobiliary Surgery and Liver Transplantation, Ain Shams Center for Organ Transplantation (ASCOT), Faculty of Medicine, Ain Shams University, Cairo, Egypt.

Background: The scale of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection among health care workers (HCWs), particularly in resource-limited settings, remains unclear. To address this concern, universal (non-symptom-based) screening of HCWs was piloted to determine the proportion of SARS-CoV-2 infection and the associated epidemiological and clinical risk factors at a large public health care facility in Egypt.

Methods: Baseline voluntary screening of 4040 HCWs took place between 22 April and 14 May 2020 at 12 hospitals and medical centres in Cairo. Epidemiological and clinical data were collected using an online survey. All participants were tested for SARS-CoV-2 using reverse transcription polymerase chain reaction (RT-PCR) and rapid IgM and IgG serological tests.

Results: Of the 4040 HCWs screened, 170 [4.2%; 95% confidence interval (CI): 3.6-4.9] tested positive for SARS-CoV-2 by either of the three tests (i.e. infected); 125/170 (73.5%) tested PCR-positive. Most infected HCWs were nurses (97/170, 57.5%). Median age of infected HCWs was 31.5 [interquartile range (IQR): 27.0-41.3] years. Of infected HCWs, 78 (45.9%) reported contact with a suspected case and 47 (27.6%) reported face-to-face contact within 2 m with a confirmed case. The proportion of infection among symptomatic HCWs (n = 54/616) was 8.8% (95% CI: 6.7-11.3); 6/54 (11.1%) had fever ≥38°C and 7/54 (13.0%) reported severe symptoms. Most infected HCWs were asymptomatic (116/170, 68.2%). The proportion of infection among asymptomatic HCWs (n = 116/3424) was 3.4% (95% CI: 2.8-4.0).

Conclusions: The high rate of asymptomatic infections among HCWs reinforces the need for expanding universal regular testing. The infection rate among symptomatic HCWs in this study is comparable with the national rate detected through symptom-based testing. This suggests that infections among HCWs may reflect community rather than nosocomial transmission during the early phase of the COVID-19 epidemic in Egypt.
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http://dx.doi.org/10.1093/ije/dyaa173DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7665557PMC
March 2021

Liver disease in children and adolescents with type 1 diabetes mellitus: A link between glycemic control and hepatopathy.

Diabetes Res Clin Pract 2020 Dec 23;170:108458. Epub 2020 Sep 23.

Faculty of Medicine, Ain Shams University, Egypt. Electronic address:

Aim: The aim of this study was to assess the prevalence of liver disease in children and adolescents with type-1 diabetes mellitus (T1DM) by detection of elevated liver transaminases, confirmed by fibroscan and ultrasound. The secondary objective was to assess the effect of glycemic control on improvement of liver functions.

Methods: One hundred and seven children and adolescents with T1DM were investigated by liver transaminases, mean HbA1c and pelviabdominal ultrasound while fibroscan was done for those with elevated liver transaminases only. Patients with elevated liver enzymes were reassessed after one year.

Results: Only nine (8.4%) of the studied patients have exhibited liver dysfunction in the form of elevated liver transaminases with median ALT 140 U/L and AST 191 U/L and hepatomegaly by ultrasound; The HbA1c (median = 10.8%) and fibroscan abnormalities (median fibrosis score 1) were significantly higher in patients with elevated liver transaminases (p < 0.001). Adequate glycemic control resulted in a significant decrease in liver transaminases (median ALT = 25 U/L and AST = 29 U/L), fibroscan fibrosis score (median = 0) and HbA1c (median = 9%) (p = 0.003), (p = 0.01) and (p = 0.003) respectively.

Conclusion: Adequate glycemic control was associated with improvement of liver disease in children and adolescents with diabetes.
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http://dx.doi.org/10.1016/j.diabres.2020.108458DOI Listing
December 2020

High Risk of HBV Infection Among Vaccinated Polytransfused Children With Malignancy.

J Pediatr Hematol Oncol 2021 01;43(1):e45-e50

Department of Community Medicine, National Research Center, Cairo, Egypt.

Aim Of The Study: The national Egyptian hepatitis B virus (HBV) vaccination program coverage of all infants started in 1992. The study aimed to assess immunity against HBV and occurrence of HBV breakthrough infections in vaccinated polytransfused children with malignancies.

Patients And Methods: Eighty-nine polytransfused children with malignancies were recruited; 37 were on chemotherapy (male:female 20:17; mean age 7.7±4.0 y), and there were 52 naive patients (male:female 31:21; mean age 7.6±3.2 y). In addition, 162 age-matched and sex-matched healthy controls were recruited. Patients' sera were tested for quantitative anti-hepatitis B surface (HBs) (enzyme-linked immunoassays technique), hepatitis B surface antigen (HBsAg), total anti-hepatitis B core, and HBV-DNA (nested polymerase chain reaction for surface, core, and x-regions).

Results: There was a significant lower percentage of having protective anti-HBs (10 to 100 IU/L) level among those receiving chemotherapy (13.5%) than those without (44.2%) and controls (32.1%). Twenty-one (67.7%) of those on chemotherapy were HBsAg positive compared with 10 (32.2%) of those without. Overall, 46 patients were HBV-DNA positive; 38 were c-region positive, 5 were s-region positive, 2 positive for the c-region and the s-region, and 1 tested positive for the c-region and the x-region. Of 46 patients, 20 were also positive for HBsAg (overt infection), while 26 had occult HBV infection (HBsAg-negative). Anti-HBs ≥10 IU/L co-existed among 45% of patients with overt infection and in 50% of those with occult infection. There was nonsignificant impact of receiving chemotherapy on the level of HBV-DNA.

Conclusions: Vaccinated children with malignancies, especially those under chemotherapy, are at a significant risk of HBV infection. The co-existence of anti-HBs with HBsAg and/or HBV-DNA may represent a possible residual transfusion-transmission risk with mutant HBV strains.
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http://dx.doi.org/10.1097/MPH.0000000000001887DOI Listing
January 2021

Progress towards elimination goals for viral hepatitis.

Nat Rev Gastroenterol Hepatol 2020 09 23;17(9):533-542. Epub 2020 Jul 23.

Medical School, Lyon University, Lyon, France.

The global burden of viral hepatitis is substantial; in terms of mortality, hepatitis B virus and hepatitis C virus infections are on a par with HIV, malaria and tuberculosis, among the top four global infectious diseases. In 2016, the 194 Member States of the World Health Organization committed to eliminating viral hepatitis as a public health threat by 2030, with a particular focus on hepatitis B virus and hepatitis C virus infection. With only 10 years to go until the 2030 deadline is reached, and although much progress has been made towards elimination, there are still some important gaps in terms of policy and progress. In this Viewpoint, we asked a selection of scientists and clinicians working in the viral hepatitis field for their opinions on whether elimination of viral hepatitis by 2030 is feasible, what the key areas of progress are and what the focus for the next 10 years and beyond should be for viral hepatitis elimination.
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http://dx.doi.org/10.1038/s41575-020-0332-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7376316PMC
September 2020

Hepatitis C Virus Treatment in Children: A Challenge for Hepatitis C Virus Elimination.

Semin Liver Dis 2020 Aug 11;40(3):213-224. Epub 2020 Jun 11.

Pediatric and Liver Unit, Meyer Children's University Hospital and Department NEUROFARBA, University of Florence, Florence, Italy.

Hepatitis C is a global public health threat. The introduction of direct-acting antivirals (DAAs) brings the prospect of curing the 71 million people living with the disease, dramatically changing the landscape of hepatitis C. The World Health Organization developed a roadmap for the elimination and cure of hepatitis C by 2030 with a clear goal with measurable targets. However, there is a lack of a well-defined strategy to tackle the hepatitis C virus (HCV) problem in children and adolescents vis-à-vis the adult population. Hepatitis C in children and adolescents can be addressed as part of a national policy for elimination in the whole population, namely macroelimination, or could be fragmented into a microelimination approach targeting the high-risk population groups. Children born to HCV-infected mothers, adolescents who are injecting drugs, migrants, and those suffering from inherited blood diseases are important target populations. After the U.S. Food and Drug Administration approval for the use of DAAs in children aged 3 years and above, evidence from clinical trials and real-world experience was accumulated using brand and generic medicines, with sustained virological response rates exceeding 95%. The evidence created should guide policies on the management of hepatitis C in children and adolescents. There are many challenges in managing HCV in this left-behind marginalized population. The lack of awareness and epidemiological data, consent age, prohibitive prices of medicines, and absence of policies on access to diagnostics, treatment, and linkage to care are among the many barriers to service delivery that should be addressed to achieve the elimination goal by 2030.
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http://dx.doi.org/10.1055/s-0040-1708812DOI Listing
August 2020

Pharmacokinetics of daclatasvir in Egyptian adolescents with genotype-4 HCV infection.

Antivir Ther 2020 ;25(2):101-110

Clinical Pharmacy Department, Faculty of Pharmacy, Cairo University, Cairo, Egypt.

Background: Daclatasvir has potent antiviral activity against HCV infection when used in combination with sofosbuvir, however, its pharmacokinetics have not been described in adolescents. The aim is to determine the pharmacokinetic parameters of daclatasvir in adolescents, and to develop a population pharmacokinetic (PopPK) model.

Methods: Seventeen adolescent patients with genotype-4 chronic HCV infection received once daily oral daclatasvir 60 mg in combination with 400 mg sofosbuvir for 12 weeks. Steady state concentrations were determined. Non-compartmental and population PK were determined.

Results: The average PK parameters calculated by non-compartmental analysis (NCA): maximum plasma concentration (C), area under the curve (AUC), apparent oral volume of distribution (V/F), apparent oral clearance (CL/F) and half-life (T) were 1,092 ng/ml, 11,178 ng/ml•h, 55 l, 4.5 l/h and 8.5 h, respectively. Daclatasvir was best described by one compartment structural PK model with zero order absorption and first-order elimination. The absorption rate constant (K), V/F, and CL/F of the final PopPK model of daclatasvir were 1.5/h, 52 l and 4.7 l/h, respectively. Body weight and serum albumin had significant effect on the V/F parameter.

Conclusions: Body weight and serum albumin were the major determinants of daclatasvir V/F in this population. PK parameters were comparable to those reported in adult HCV patients, demonstrating that 60 mg daclatasvir is an appropriate dose for adolescents. ClinicalTrials.gov NCT03540212.
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http://dx.doi.org/10.3851/IMP3357DOI Listing
October 2021

Micro-elimination of hepatitis C through testing of Egyptian pregnant women presenting at delivery: implications for screening policies.

Trop Med Int Health 2020 07 29;25(7):850-860. Epub 2020 May 29.

Department of Pediatrics, Faculty of Medicine, Ain Shams University, Cairo, Egypt.

Objectives: Despite the high burden of hepatitis C virus (HCV) infection in Egypt, screening of pregnant women is not yet universal, making national and global elimination unlikely. This study assessed the proportion of pregnant women who were screened for HCV infection at delivery, the prevalence and risk factors for HCV infection, the associated adverse neonatal outcomes, and the real-life linkage to care of infected women and follow-up of their infants' HCV status and timing of testing.

Methods: Data were collected from medical records of a retrospective cohort of all pregnant women who were admitted to a university hospital in Cairo for delivery between January and June 2018 (n = 6734). HCV antibody- and RNA-positive women and their infants were prospectively followed-up by phone interviews till September 2019.

Results: 2177 (32.3%) pregnant women were screened for HCV infection. 19 (0.9%) tested HCV antibody- and RNA-positive. Being ≥ 30 years old (ORa 3.6, 95% CI: 1.4-9.2; P = 0.009), history of abortion (ORa 3.5, 95% CI: 1.2-10.3; P = 0.022) and blood transfusion (ORa 29.1, 95% CI: 9.6-88.4; P < 0.001) were independent risk factors for infection. Adverse neonatal outcomes did not vary significantly among HCV antibody-positive and antibody-negative women. Only 13 (68.4%) HCV antibody- and RNA-positive women started treatment with direct-acting antivirals (DAAs) post-breastfeeding (two completed the treatment course and were cured). Four (21.1%) did not start treatment, and two (10.5%) were lost to follow-up. All infants of the 13 HCV antibody- and RNA-positive women who started DAA therapy tested HCV RNA-negative within their first year of life.

Conclusion: Extending screening services to all pregnant women and better linkage to care are essential for the national elimination of HCV infection.
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http://dx.doi.org/10.1111/tmi.13404DOI Listing
July 2020

Screening and Treatment Program to Eliminate Hepatitis C in Egypt.

N Engl J Med 2020 03;382(12):1166-1174

From the Hepatology Department, National Liver Institute, Menoufia University, Shebeen El Kom (I.W., W.A.-R.), and the Endemic Medicine Department, Faculty of Medicine, Cairo University (G. Esmat, A.E., M.E.-S., A.C., W.E.A., W.D.), the Ministry of Health and Population (R.G., G. Elshishiney, A.S., S.A.M., M.A.S., K.A.H., S.A.G., N.E.N., A.E.S., S.E.S., H.E.T., E.E., H.G., A. Hashem, N.H., A.N.H., A.K., K.L., F.M., S. Mamoun, T.M., S. Mekky, A.M., A.O., O.R., E.R., A.R., T.S., R.S., M. Sharshar, H. Shawky, M. Shawky, W.S., H. Soror, M. Taha, M. Talha, A.T., M.Z., H.Z.), the National Committee for Control of Viral Hepatitis (K.K.), the Pediatrics Department (M.H.E.-S.), the Hepatology and Tropical Medicine Department (H.D.), and the Department of Medicine (Y.E.S., Y.O.), Ain Shams University, the Hepatology Department, National Hepatology and Tropical Medicine Research Institute (M.H.), the Communicable Diseases Control Cluster, World Health Organization (A. Hashish), the Medical Research Division, National Research Center (E.K., M.A.), and the Tropical Medicine Department, Al-Azhar University (I.A.), Cairo - all in Egypt.

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http://dx.doi.org/10.1056/NEJMsr1912628DOI Listing
March 2020

Sofosbuvir-containing regimens are safe and effective in the treatment of HCV patients with moderate to severe renal impairment.

Liver Int 2020 04 20;40(4):797-805. Epub 2019 Dec 20.

Endemic Medicine and Hepato-Gastroentrology Department, Faculty of Medicine, Cairo University, Cairo, Egypt.

Background And Aims: This study aimed to assess the safety and efficacy of sofosbuvir (SOF)-based regimens in patients with moderate to severe renal impairment; a subject which has been questioned by many investigators with conflicting results.

Methods: This is a real-life multicentre retrospective cohort study on 4944 chronic Hepatitis C virus (HCV) patients with chronic kidney disease (CKD) (eGFR <60 mL/min/1.73 m ) who received SOF-based therapy in specialized treatment centres affiliated to the National Committee for the Control of Viral Hepatitis in Egypt. The efficacy and safety of SOF-based regimens was assessed.

Results: Week 12 virological response rates were 97.5%, 96.7%, 85.7% and 80% in the total cohort, patients with eGFR <30 mL/min/1.73 m , patients with associated hepatic decompensation and patients on dialysis respectively. Various treatment regimens did not statistically affect the response rates. Treatment experience, cirrhosis and diabetes were predictors of treatment failure on multivariate analysis. Serious adverse events occurred in 0.1% of cases. Forty patients (0.8%) discontinued treatment.

Conclusion: Sofosbuvir-based regimens are effective and safe for treating patients with chronic HCV and moderate to severe CKD, and in those with associated hepatic decompensation.
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http://dx.doi.org/10.1111/liv.14299DOI Listing
April 2020

Safety-Engineered Syringes: An Intervention to Decrease Hepatitis C Burden in Developing Countries-A Cost-Effectiveness Analysis From Egypt.

Value Health Reg Issues 2019 Sep 16;19:51-58. Epub 2019 Apr 16.

HTA Office, L.L.C., Cairo, Egypt; Pharmacy Practice Department, Heliopolis University, Cairo, Egypt. Electronic address:

Introduction: To assess the cost-effectiveness of introducing the safety-engineered syringe (SES) to decrease hepatitis C burden resultant from unsafe injection practices in healthcare settings.

Methods: A Markov process model for a hypothetical study cohort was developed over a 30-year time horizon to compare the adoption of SES use with the current strategy, conventional syringes (CS), in the Egyptian healthcare settings. The national treatment program was applied in both groups. Health benefits and total direct medical costs were estimated in both strategies.

Results: The SES use demonstrated a reduction in the burden of injection-associated HCV infection because of unsafe practices in the Egyptian healthcare settings. The probability of HCV infection was 1.4% in the SES group and 40% in the CS group. Adoption of the SES use averted 177 hepatitis C cases and 157 hepatitis C-related deaths per 10 000 individuals. Introducing SES as a preventive strategy resulted in better quality-adjusted life-years (QALYs) (difference; 0.95 QALYs) and lower costs (difference; $-1712).

Conclusions: Adoption of SES in the Egyptian healthcare settings is a more effective and cost-saving strategy. Our results are consistent with the WHO Injection Safety Program and Safe Injection Global Network initiatives, which call for adoption of smart syringes. The introduction of SES as one of the most urgently needed interventions is mostly encouraged to decrease hepatitis C burden in similar resource-limited settings. The use of SES as a prevention strategy may bring substantial population-level health gains and governmental cost savings in developing countries.
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http://dx.doi.org/10.1016/j.vhri.2018.11.009DOI Listing
September 2019

Hepatitis B virus infection in children and adolescents.

Lancet Gastroenterol Hepatol 2019 06 11;4(6):466-476. Epub 2019 Apr 11.

Global Hepatitis Programme and HIV Department, World Health Organization, Geneva, Switzerland.

Hepatitis B virus (HBV) infection is a major cause of acute and chronic liver disease and associated morbidity and mortality worldwide. Vertical (mother-to-child) and horizontal early childhood transmission are the main routes of HBV transmission and are responsible for most chronic infections, including among adults who bear the greatest burden of morbidity and mortality. Universal hepatitis B immunisation at birth and in infancy is the key strategy for global elimination of HBV infection, and has been highly effective in reducing new vertical infections. However, global progress in scale-up of HBV testing and treatment has been slow in adults and children. In this Series paper, we summarise knowledge on the epidemiology, natural history, and treatment of chronic HBV infection in adolescents and children, and we highlight key differences from HBV infection in adults. The estimated global prevalence of HBV infection in children aged 5 years or younger is 1·3%. Most children are in the high-replication, low-inflammation phase of infection, with normal or only slightly raised aminotransferases; cirrhosis and hepatocellular carcinoma are rare. Although entecavir is approved and recommended for children aged 2-17 years, and tenofovir for those aged 12-18 years, a conservative approach to treatment initiation in children is recommended. Key actions to address current policy gaps include: validation of non-invasive tests for liver disease staging; additional immunopathogenesis studies in children with HBV infection; long-term follow-up of children on nucleoside or nucleotide analogue regimens to inform guidance on when to start treatment; evaluation of different treatment strategies for children with high rates of HBV replication; and establishment of paediatric treatment registries and international consortia to promote collaborative research.
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http://dx.doi.org/10.1016/S2468-1253(19)30042-1DOI Listing
June 2019

Hepatitis C virus infection in children and adolescents.

Lancet Gastroenterol Hepatol 2019 06 11;4(6):477-487. Epub 2019 Apr 11.

Global Hepatitis Programme and HIV Department, World Health Organization, Geneva, Switzerland.

Hepatitis C virus (HCV) infection is a major cause of chronic liver disease and associated morbidity and mortality worldwide. Short-course, oral, curative, direct-acting antiviral regimens have transformed treatment for HCV infection. Since the 2016 launch of the first global strategy towards elimination of viral hepatitis as a public health threat by 2030, the predominant focus of the global response has been on the treatment of adults, who bear the greatest burden of morbidity and mortality of HCV-related chronic liver disease. Compared with adults, there has been little attention paid to addressing the response to HCV in children and adolescents, in part because of the scarcity of data to inform specific paediatric management practices and policy. In this Series paper, we summarise knowledge on the epidemiology, natural history, and treatment of chronic HCV infection in adolescents and children, and we highlight key differences from infection acquired in adulthood. The estimated global prevalence and burden of HCV infection in children aged 1-19 years is 0·15%, corresponding to 3·5 million people (95% CI 3·1-3·9 million). HCV infection is usually asymptomatic during childhood, and cirrhosis and hepatocellular carcinoma are rare. Sofosbuvir with ledipasvir and sofosbuvir with ribavirin have received regulatory approval and guidelines recommend their use in adolescents aged 12 years and older with HCV infection. In April, 2019, glecaprevir with pibrentasvir also received regulatory approval for adolescents aged 12-17 years. Key actions to address the current policy gaps and achieve treatment scale-up that is comparable to that in adults include: establishment of a campaign on access to testing and treatment that is targeted at children and adolescents; fast-track evaluation of pan-genotypic regimens; and accelerated approval of paediatric formulations. Research gaps that need to be addressed include: age-specific prevalence studies of HCV viraemia in priority countries; further validation of non-invasive tests for staging of liver disease in children; and establishment of paediatric treatment registries and international consortia to promote collaborative research agendas.
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http://dx.doi.org/10.1016/S2468-1253(19)30046-9DOI Listing
June 2019

The Micro-Elimination Approach to Eliminating Hepatitis C: Strategic and Operational Considerations.

Semin Liver Dis 2018 08 9;38(3):181-192. Epub 2018 Jul 9.

Department of Medicine, Clinical and Research Center, Humanitas Hospital, Rozzano, Italy.

The introduction of efficacious new hepatitis C virus (HCV) treatments galvanized the World Health Organization to define ambitious targets for eliminating HCV as a public health threat by 2030. Formidable obstacles to reaching this goal can best be overcome through a micro-elimination approach, which entails pursuing elimination goals in discrete populations through multi-stakeholder initiatives that tailor interventions to the needs of these populations. Micro-elimination is less daunting, less complex, and less costly than full-scale, country-level initiatives to eliminate HCV, and it can build momentum by producing small victories that inspire more ambitious efforts. The micro-elimination approach encourages stakeholders who are most knowledgeable about specific populations to engage with each other and also promotes the uptake of new models of care. Examples of micro-elimination target populations include medical patients, people who inject drugs, migrants, and prisoners, although candidate populations can be expected to vary greatly in different countries and subnational areas.
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http://dx.doi.org/10.1055/s-0038-1666841DOI Listing
August 2018

Early and long term anamnestic response to HBV booster dose among fully vaccinated Egyptian children during infancy.

Vaccine 2018 04 9;36(15):2005-2011. Epub 2018 Mar 9.

Pediatrics Department, Faculty of Medicine, Ain-Shams University, Cairo, Egypt.

Objective: To evaluate early and long term anamnestic response to a booster dose of HBV vaccine among non-seroprotected children.

Subjects And Method: A national community based project was carried out on 3600 children aged 9 months to 16 years, fully vaccinated during infancy. They were recruited from 6 governorates representing Egypt. It revealed that 1535 children (42.8%) had non sero-protective anti-HBs (<10 IU/L) and were HBsAg or anti-HBc negative. A challenging dose of 10 μg of mono-valent Euvax HBV vaccine was given to 1121/1535 children. Quantitative assessment of anti-HBs was performed to detect early (2-4 weeks) and long term (one year) anamnestic responses.

Results: Early anamnestic response developed among 967/1070 children (90.3%).Children having detectable anti-HBs (1-9 IU/L) significantly developed early anamnestic response (90%) compared to 85% with undetectable anti-HBs (<1 IU/L), P < 0.001. Multiple logistic analysis revealed that undetectable anti-HBs, living in rural residence and children aged 15-16 years were the most significant predicting risk factors for the absence of early anamnestic response (<10 IU/L), with AOR 2.7, 2.7 & 4.7 respectively. After one year, long term anamnestic response was absent among 15% of children who previously showed early response. Poor early anamnestic response and undetectable pre-booster anti-HBs were the significant predicting risk factors for absent long term anamnestic response, with AOR 18.7 & 2.7 respectively.

Conclusion: Immunological memory for HBV vaccine outlasts the presence of anti- HBs and HBV vaccination program provides effective long term protection even in children showing waning or undetectable concentrations of anti-HBs. This signifies no need for a booster dose especially to healthy children.
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http://dx.doi.org/10.1016/j.vaccine.2018.02.103DOI Listing
April 2018

The Challenge of Treating Children With Hepatitis C Virus Infection.

J Pediatr Gastroenterol Nutr 2017 06;64(6):851-854

*Pediatric and Liver Unit, Meyer Children's University Hospital of Florence, Italy †UCL Institute of Child Health, University College London, UK ‡Department of Pediatrics, Faculty of Medicine, Ain Shams University, Cairo, Egypt §Department of Women and Child Health, University of Padua ||PENTA Foundation, Padua, Italy ¶Division of Gastroenterology, Hepatology and Nutrition, Department of Paediatrics, University of Florida College of Medicine, Gainesville, FL.

The development of oral hepatitis C virus (HCV) direct-acting antivirals (DAAs) has revolutionized the therapeutic field. Nowadays, multiple safe and highly effective antiviral regimens are commercially available to treat adults with hepatitis C infection. These new regimens for the first time genuinely raise the prospects of eradicating HCV. Many challenges, however, remain from identifying infected individuals to optimizing treatment and ensuring global access to antiviral therapy to all population groups, including children. Recently, in April 2017, the association of sofosbuvir with ribavirin and the fixed-dose combination sofosbuvir/ledipasvir have been approved by the Food and Drug Administration for treatment of children with chronic HCV infection 12 years of age and older. The only drugs currently approved for children younger than 12 years are pegylated interferon and ribavirin. There are 6 registered ongoing pediatric trials assessing safety and efficacy of DAAs, but their current completion timelines are years away. Herein, we summarize the state of the art of DAAs' development for adult and children and highlight the crucial importance of overcoming barriers to treating children with HCV.
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http://dx.doi.org/10.1097/MPG.0000000000001589DOI Listing
June 2017

Development and validation of LC-MS/MS assay for the simultaneous determination of methotrexate, 6-mercaptopurine and its active metabolite 6-thioguanine in plasma of children with acute lymphoblastic leukemia: Correlation with genetic polymorphism.

J Chromatogr B Analyt Technol Biomed Life Sci 2016 Dec 28;1038:88-94. Epub 2016 Oct 28.

Department of Pediatrics, Hematology-Oncology Division, Faculty of Medicine, Ain-Shams University, Cairo, Egypt.

Individualized therapy is a recent approach aiming to specify dosage regimen for each patient according to its genetic state. Cancer chemotherapy requires continuous monitoring of the plasma concentration levels of active forms of cytotoxic drugs and subsequent dose adjustment. In order to attain optimum therapeutic efficacy, correlation to pharmacogenetics data is crucial. In this study, a specific, accurate and sensitive liquid chromatography tandem mass spectrometry (LC-MS/MS) has been developed for determination of methotrexate (MTX), 6-mercaptopurine (MP) and its metabolite 6-thioguanine nucleotide (TG) in human plasma. Based on the basic character of the studied compounds, solid phase extraction using a strong cation exchanger was found the optimum approach to achieve good extraction recovery. Chromatographic separation was carried out using RP-HPLC and isocratic elution by acetonitrile: 0.1% aqueous formic acid (85:15v/v) with a flow rate of 0.8mL/min at 40°C. The detection was performed by tandem mass spectrometry in MRM mode via electrospray ionization source in positive ionization mode. Analysis was carried out within 1.0min over a concentration range of 6.25-200.00ng/mL for the studied analytes. Validation was carried out according to FDA guidelines for bioanalytical method validation and satisfactory results were obtained. The applicability of the assay for the monitoring of the MTX, MP and TG and subsequent application to personalized therapy was demonstrated in a clinical study on children with acute lymphoblastic leukemia (ALL). Results confirmed the need for implementation of reliable analysis tools for therapeutic dose adjustment.
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http://dx.doi.org/10.1016/j.jchromb.2016.10.035DOI Listing
December 2016

Association Between Combined Presence of Hepatitis C Virus and Polymorphisms in Different Genes With Toxicities of Methotrexate and 6-Mercaptopurine in Children With Acute Lymphoblastic Leukemia.

Pediatr Blood Cancer 2016 09 10;63(9):1539-45. Epub 2016 May 10.

Department of Pediatrics, Hematology-Oncology Division, Faculty of Medicine, Ain-Shams University, Cairo, Egypt.

Background: The aim of the present study is to determine the correlation of hepatitis C virus (HCV) infection and polymorphisms in different genes with toxicity of either methotrexate (MTX) or 6-mercaptopurine (6-MP) administered to children with acute lymphoblastic leukemia (ALL).

Procedure: One hundred children with low-risk ALL, who were treated according to the St. Jude Total therapy XV, were recruited. The recruited children were receiving MTX and 6-MP during maintenance phase. Patients were excluded from the study if they had other types of leukemia. Genotyping analyses for the thiopurine methyltransferase (TPMT), methylenetetrahydrofolate reductase (MTHFR), and glutathione S-transferase (GST) genes were performed using a combination of polymerase chain reaction (PCR) and PCR-RFLP (where RFLP is restriction fragment length polymorphism) protocols. Relevant clinical data on adverse drug reactions were collected objectively (blinded to genotypes) from the patient medical records.

Results: There was a significant correlation between the combined presence of HCV and TPMT*3B G460A gene polymorphisms and grades 2-4 hepatotoxicity as aspartate aminotransferase (AST) elevation (P < 0.04). The same observation was seen when comparing either the presence of HCV alone or the presence of the gene polymorphism alone. A significant association between the combined presence of HCV and MTHFR C677T polymorphism and grades 2-4 hepatotoxicity as alanine aminotransferase (ALT), AST, and alkaline phosphatase (ALP) elevation was observed (P values <0.001, 0.02, and 0.001, respectively). The presence of HCV infection had a significant negative effect on hepatic transaminases.

Conclusions: The present data support a role for combining analysis of genetic variation in drug-metabolizing enzymes and the presence of HCV in the assessment of specific drugs toxicities in multiagent chemotherapeutic treatment regimens.
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http://dx.doi.org/10.1002/pbc.26045DOI Listing
September 2016
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