Hepatitis C virus cell-cell transmission and resistance to direct-acting antiviral agents

Hepatitis C virus (HCV) is transmitted between hepatocytes via classical cell entry but also uses direct cell-cell transfer to infect neighboring hepatocytes. Viral cell-cell transmission has been shown to play an important role in viral persistence allowing evasion from neutralizing antibodies. In contrast, the role of HCV cell-cell transmission for antiviral resistance is unknown. Aiming to address this question we investigated the phenotype of HCV strains exhibiting resistance to direct-acting antivirals (DAAs) in state-of-the-art model systems for cell-cell transmission and spread. Using HCV genotype 2 as a model virus, we show that cell-cell transmission is the main route of viral spread of DAA-resistant HCV. Cell-cell transmission of DAA-resistant viruses results in viral persistence and thus hampers viral eradication. We also show that blocking cell-cell transmission using host-targeting entry inhibitors (HTEIs) was highly effective in inhibiting viral dissemination of resistant genotype 2 viruses. Combining HTEIs with DAAs prevented antiviral resistance and led to rapid elimination of the virus in cell culture model. In conclusion, our work provides evidence that cell-cell transmission plays an important role in dissemination and maintenance of resistant variants in cell culture models. Blocking virus cell-cell transmission prevents emergence of drug resistance in persistent viral infection including resistance to HCV DAAs

The effect of dose on the antimalarial efficacy of artemether-lumefantrine: a systematic review and pooled analysis of individual patient data

Background: Artemether-lumefantrine is the most widely used artemisinin-based combination therapy for malaria, although treatment failures occur in some regions. We investigated the effect of dosing strategy on efficacy in a pooled analysis from trials done in a wide range of malaria-endemic settings. Methods: We searched PubMed for clinical trials that enrolled and treated patients with artemether-lumefantrine and were published from 1960 to December, 2012. We merged individual patient data from these trials by use of standardised methods. The primary endpoint was the PCR-adjusted risk of Plasmodium falciparum recrudescence by day 28. Secondary endpoints consisted of the PCR-adjusted risk of P falciparum recurrence by day 42, PCR-unadjusted risk of P falciparum recurrence by day 42, early parasite clearance, and gametocyte carriage. Risk factors for PCR-adjusted recrudescence were identified using Cox's regression model with frailty shared across the study sites. Findings: We included 61 studies done between January, 1998, and December, 2012, and included 14 327 patients in our analyses. The PCR-adjusted therapeutic efficacy was 97·6% (95% CI 97·4-97·9) at day 28 and 96·0% (95·6-96·5) at day 42. After controlling for age and parasitaemia, patients prescribed a higher dose of artemether had a lower risk of having parasitaemia on day 1 (adjusted odds ratio [OR] 0·92, 95% CI 0·86-0·99 for every 1 mg/kg increase in daily artemether dose; p=0·024), but not on day 2 (p=0·69) or day 3 (0·087). In Asia, children weighing 10-15 kg who received a total lumefantrine dose less than 60 mg/kg had the lowest PCR-adjusted efficacy (91·7%, 95% CI 86·5-96·9). In Africa, the risk of treatment failure was greatest in malnourished children aged 1-3 years (PCR-adjusted efficacy 94·3%, 95% CI 92·3-96·3). A higher artemether dose was associated with a lower gametocyte presence within 14 days of treatment (adjusted OR 0·92, 95% CI 0·85-0·99; p=0·037 for every 1 mg/kg increase in total artemether dose). Interpretation: The recommended dose of artemether-lumefantrine provides reliable efficacy in most patients with uncomplicated malaria. However, therapeutic efficacy was lowest in young children from Asia and young underweight children from Africa; a higher dose regimen should be assessed in these groups. Funding: Bill and Melinda Gates Foundation

Cholécystite aigue lithiasique: à propos de 73 cas opérés à l’Hôpital National Ignace Deen de Conakry.

Les données récentes de la littérature indiquent une hausse de la prévalence de la cholécystite aigue en Afrique. Le but de cette étude était de rapporter l’expérience de cette affection dans notre service. Nous avons effectué une étude rétrospective allant du 1er janvier 2001 au 31 décembre 2006 et portant sur tous les cas de cholécystite aigue lithiasique admis et opérés au CHU de Conakry. Soixante treize cas de cholécystite aigue lithiasique ont été colligés, représentant 1,61% des urgences chirurgicales abdominales et 48,03% des affections des voies biliaires. L’âge moyen des patients était de 43 ans avec des extrêmes de 19 et 70 ans. La tranche d’âge comprise entre 31 et 40 ans était la plus concernée avec 32,43%. Une prédominance féminine a été notée avec 59 cas sur 73, soit 80.82%. Les ménagères (58,90%) étaient les plus concernées. L’obésité (27,02%), les maladies hémolytiques (26,79%) et la multiparité (24,32%) ont été les facteurs prédisposant les plus observés. La douleur spontanée à l’hypochondre droit, la fièvre et le signe de Murphy étaient présents chez tous nos patients. L’échographie réalisée chez tous les malades a aidé au diagnostic. La cholécystectomie rétrograde a été pratiquée dans 62 cas, soit 84.93%. Les calculs étaient multiples dans 31 cas, soit 42,46% et de couleur noire dans 38 cas soit 52,05%. L’aspect de la vésicule était de type cholécystite congestive dans 41 cas, soit 56,16% des cas et chronique dans 39.73% des cas. Les suites opératoires ont été simples avec une mortalité nulle. Mots clés : Cholécystite aigue lithiasique, Cholécystectomie, Conakr

Determinants of transmission risk during the late stage of the West African Ebola epidemic

Understanding risk factors for Ebola transmission is key for effective prediction and design of interventions. We used data on 860 cases in 129 chains of transmission from the latter half of the 2013-16 Ebola outbreak in Guinea. Using negative binomial regression, we determined characteristics associated with the number of secondary cases resulting from each infected individual. We found that attending an Ebola Treatment Unit was associated with a 38% decrease in secondary cases (Incident rate ratio (IRR) 0.62, 95%CI: 0.38, 0.99) in individuals that did not survive. Unsafe burial was associated with a higher number of secondary cases (IRR 1.82, 95%CI: 1.10, 3.02). The average number of secondary cases was higher for the first generation of a transmission chain (mean = 1.77), compared with subsequent generations (mean = 0.70). Children were least likely to transmit (IRR 0.35 (95%CI: 0.21, 0.57) compared with adults, whereas older adults were associated with higher numbers of secondary cases. Men were less likely to transmit than women (IRR 0.71 (95%CI: 0.55, 0.93)). This detailed surveillance dataset provided an invaluable insight into transmission routes and risks. Our analysis highlights the key role that age, receiving treatment, and safe burial played in the spread of EVD