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Abstract Background Use of anti-malarial medication in children is hampered by a paucity of dosage, pharmacokinetic and tolerability data. Methods Data on the use of mefloquine in children, particularly in young children weighing less than 20 kg, were reviewed using PubMed literature and reports on file. Results Chemoprophylaxis data: Two studies with a total of 170 children were found. A simulated mefloquine plasma profile showed that doses to achieve protective chemoprophylaxis blood concentration of mefloquine of approximately 620 ng/mL (or 1.67 μmol/L) in children should be at least 5 mg/kg. This simulated plasma profile in children corresponds to that seen in adult travellers using a weekly prophylaxis dose of 250 mg. This reinforces current practice of using weight-based dosage for children. Clearance per body weight is higher in older children. For children who travel to malaria risk areas tablets can be broken and crushed as required. It is necessary to disguise the bitter taste of the drug. Treatment data: Mefloquine treatment (alone or in combination) data are available for more than 6000 children of all age and weight categories. The stereoselectivity and pharmacokinetic profile of mefloquine in children is similar to that observed in adults. There is higher clearance in older children (aged 5-12 years) compared to younger children (aged 6-24 months). Mefloquine treatment is well tolerated in infants (5-12 kg) but vomiting is a problem at high doses. This led to the use of a "split dose" regimen with 15 mg/kg initially, followed 12 hours later by 10 mg/kg. Mefloquine 125 mg has been used as intermittent preventive treatment (IPT) and was found to be efficacious in reducing episodes of malaria in a moderate-transmission setting but vomiting was a problem in 8% of children aged 2-11 months. Mefloquine is also used as a component of artemisinin combination therapy (ACT) in small children. The combination artesunate plus mefloquine is a WHO approved first-line treatment for uncomplicated malaria in Africa. Conclusion Currently available data provide a scientific basis for the use of mefloquine in small children in the chemoprophylaxis setting and as a part of treatment regimens for children living in endemic areas.

Abstract Background Malaria chemoprophylaxis prevents the occurrence of the symptoms of malaria. Travellers to high-risk Plasmodium falciparum endemic areas need an effective chemoprophylaxis. Methods A literature search to update the status of mefloquine as a malaria chemoprophylaxis. Results Except for clearly defined regions with multi-drug resistance, mefloquine is effective against the blood stages of all human malaria species, including the recently recognized fifth species, Plasmodium knowlesi. New data were found in the literature on the tolerability of mefloquine and the use of this medication by groups at high risk of malaria. Discussion Use of mefloquine for pregnant women in the second and third trimester is sanctioned by the WHO and some authorities (CDC) allow the use of mefloquine even in the first trimester. Inadvertent pregnancy while using mefloquine is not considered grounds for pregnancy termination. Mefloquine chemoprophylaxis is allowed during breast-feeding. Studies show that mefloquine is a good option for other high-risk groups, such as long-term travellers, VFR travellers and families with small children. Despite a negative media perception, large pharmaco-epidemiological studies have shown that serious adverse events are rare. A recent US evaluation of serious events (hospitalization data) found no association between mefloquine prescriptions and serious adverse events across a wide range of outcomes including mental disorders and diseases of the nervous system. As part of an in-depth analysis of mefloquine tolerability, a potential trend for increased propensity for neuropsychiatric adverse events in women was identified in a number of published clinical studies. This trend is corroborated by several cohort studies that identified female sex and low body weight as risk factors. Conclusion The choice of anti-malarial drug should be an evidence-based decision that considers the profile of the individual traveller and the risk of malaria. Mefloquine is an important, first-line anti-malarial drug but it is crucial for prescribers to screen medical histories and inform mefloquine users of potential adverse events. Careful prescribing and observance of contraindications are essential. For some indications, there is currently no replacement for mefloquine available or in the pipeline.

Background and Aims: Sustained off-treatment immune control is achievable in a proportion of patients with chronic hepatitis B treated with peginterferon alfa-2a. We evaluated on-treatment predictors of hepatitis B surface antigen (HBsAg) clearance 3 years after peginterferon alfa-2a treatment and determined the incidence of hepatocellular carcinoma., Methods: A prospective, international, multicenter, observational study in patients with chronic hepatitis B who have been prescribed peginterferon alfa-2a (40KD) in a real-world setting. The primary endpoint was HBsAg clearance after 3 years' follow-up., Results: The modified intention-to-treat population comprised 844 hepatitis B e antigen (HBeAg)-positive patients (540 [64%] completed 3 years' follow-up), and 872 HBeAg-negative patients (614 [70%] completed 3 years' follow-up). At 3 years' follow-up, HBsAg clearance rates in HBeAg-positive and HBeAg-negative populations, respectively, were 2% (16/844) and 5% (41/872) in the modified intention-to-treat population and 5% [16/328] and 10% [41/394] in those with available data. In HBeAg-positive patients with data, Week 12 HBsAg levels <1500, 1500-20,000, and >20,000 IU/mL were associated with HBsAg clearance rates at 3 years' follow-up of 11%, 1%, and 5%, respectively (Week 24 predictability was similar). In HBeAg-negative patients with available data, a ≥10% decline vs a <10% decline in HBsAg at Week 12 was associated with HBsAg clearance rates of 16% vs 4%. Hepatocellular carcinoma incidence was lower than REACH-B (Risk Estimation for Hepatocellular Carcinoma in Chronic Hepatitis B) model predictions., Conclusions: Sustained off-treatment immune control is achieved with peginterferon alfa-2a in a real-world setting. HBsAg clearance 3 years after completion of peginterferon alfa-2a can be predicted on the basis of on-treatment HBsAg kinetics., Competing Interests: This study was funded by F Hoffmann-La Roche Ltd. The following authors have competing interests to declare. Patrick Marcellin: Grant: Abbvie, Assembly Biosciences, Eiger, Genfit; Gilead, Intercept, MSD, Investigator: Eiger, Gilead; Speaker/expert: Gilead, Hebabiz, MSD, Mylan. Qing Xie: Speaker/advisor: AbbVie, BMS, Gilead, Janssen, MSD, Novartis, Roche. Seung Woon Paik: Research support: BMS, Gilead, GSK, Roche. Robert Flisiak: Speaker/advisor: AbbVie, BMS, Gilead, Janssen, MSD, Novartis, Roche. Teerha Piratvisuth: Grant: Roche, MSD, Bayer; Sponsored Lectures: BMS, Roche, MSD, Novartis, GSK; Advisory Board: Roche, MSD, BMS. Jörg Petersen: Grant/Research: BMS, Novartis, Roche; Consultant/Advisor: Abbott, AbbVie, BMS, Boehringer Ingelheim, Gilead, GSK, Kedrion, Janssen, MSD, Novartis, Roche; Speaker: Abbott, BMS, Boehringer Ingelheim, Gilead, Kedrion, Janssen, Merck, MSD, Novartis, Roche. Tarik Asselah: Consultant and Clinical Investigator/Speaker: Roche, AbbVie, BMS, Gilead, Janssen, MSD Markus Cornberg: Advisory Committees/Review Panels: AbbVie, Biogen, BMS, Gilead, Janssen-Cilag, MSD, Roche, Spring Bank; Speaking/Teaching: AbbVie, BMS, Falk, Gilead, Janssen-Cilag, MSD, Roche. Data Safety Management Board: Janssen-Cilag. Grant/Research Support: Roche. Denis Ouzan: Grant and speaker/expert: AbbVie, Gilead, MSD. Graham R. Foster: Speaker/consultancy: AbbVie, BMS, Merck, Gilead, Janssen, Tekmira, Alnylam, Roche. Georgios Papatheodoridis: Advisory Committees/Review Panels: AbbVie, Boehringer Ingelheim, BMS, Gilead, GSK, Ipsen, Janssen, MSD, Novartis, Roche, Spring Bank; Grant/Research Support: AbbVie, BMS, Gilead, Janssen, Roche; Speaking and Teaching: AbbVie, BMS, Gilead, GSK, Janssen, MSD, Novartis, Roche; Data Safety Management Board: Gilead. Diethelm Messinger: Employment: Prometris GmbH (provide statistical support for Roche). Georgios Bakalos, Loredana Regep, Ulrich Alshuth: Employment: F Hoffmann-La Roche Ltd (Roche s.r.o, Roche Pharma AG). Pietro Lampertico: Advisory board/speaker bureau: AbbVie, Alnylam, Arrowhead, BMS, Gilead, GSK, Janssen, Merck Sharp & Dohme, Roche. Heiner Wedemeyer: Grant: Abbott, AbbVie, BMS, Gilead, Merck, Novartis, Roche, Roche Diagnostics, Siemens; Consultant: Abbott, AbbVie, BMS, Boehringer Ingelheim, Gilead, JJ/Janssen-Cilag, Merck/Schering-Plough, Novartis, Roche, Roche Diagnostics, Siemens, Transgene, ViiV; Speaker: Abbott, AbbVie, BMS, Boehringer Ingelheim, Gilead, JJ/Janssen- Cilag, Merck/Schering-Plough, Novartis, Roche, Roche Diagnostics, Siemens, Transgene, ViiV. All authors disclose medical writing support from F. Hoffmann-La Roche Ltd. This does not alter our adherence to PLOS ONE policies on sharing data and materials.

Aims: This study was aimed at determining the seroprevalence of hepatitis C virus (HCV) infection in Romania and the possible risk factors and modality of HCV transmission., Methods: A nationwide cross-sectional survey among the adult population was conducted between 2006-2008 in Romania through a population multicenter stratified random cluster sampling. Serum samples from 13,460 subjects were tested with a 3rd generation ELISA and a standardized questionnaire concerning the socio-demographic characteristics and potential risk factors was used., Results: The prevalence rate of HCV infection in Romanian adult population was 3.23% with significant differences between the main geographical regions (Moldavia 4.25%, Wallachia & Dobrogea 3.35% and Transylvania & Banat 2.63%), as well as between different counties (maximum 7.19%, minimum 0.56%). Overall participation rate to the survey of the selected subjects was 74.69%. Risk factors for HCV infection were: blood/blood products transfusions (p=0.0001), previous surgery (elective and emergency, p=0.0001 and p=0.043, respectively), frequent hospitalizations (p=0.0001), injections at home (p=0.0001), accidents/trauma (p=0.0001), occupational hazard related to blood exposure (p=0.025), intravenous drug administration (p=0.002), a partner chronically infected with HCV/hepatitis B virus (HBV) (p=0.046), first sexual intercourse <18 years (p=0.019), familial exposure to HCV/HBV infection (p=0.001) or to chronic HBV/HCV liver disease (p=0.001), personal history of chronic HBV infection (p=0.001). HCV RNA positivity was detected in 91% of the anti HCV positive subjects., Conclusions: Overall HCV prevalence in Romania is 3.23%. Both nosocomial and non-nosocomial routes are implicated as risk factors for HCV infection.