Deadline for full application: December 15th, 2013
Interviews: March, 2014
Start of the Ph.D.: October 1st, 2014
Department: Infection and epidemiology
Title of the PhD project: Genotype 4 hepatitis C treatment in Egypt
Name of the lab: Emerging Diseases Epidemiology Unit (EDEU)
Head of the lab: Arnaud Fontanet
PhD advisor: Arnaud Fontanet
Email address: firstname.lastname@example.org
Doctoral school affiliation and University: ED393 Université Pierre et Marie Curie
Presentation of the laboratory and its research topics:
The main focus of the Emerging Diseases Epidemiology Unit (EDEU) is the epidemiology of infectious and tropical diseases in resources-limited countries. Viral hepatitis, meningitis and encephalitis, Buruli ulcer, and emerging viruses (e.g., coronaviruses) are among the main topics. Our projects involve various epidemiological designs, including surveillance systems, cohort studies and clinical trials.
Our laboratory has been working in Egypt for the past ten years. Arnaud Fontanet is the North Coordinator of the ANRS research site on viral hepatitis in Egypt. The research programs deals with the epidemiology of HCV transmission, the evaluation of new treatments for chronic hepatitis C, and studies on the determinants of early clearance of HCV infection during the acute symptomatic phase (collaboration with Matthew Albert; EC FP7 Sphinx project). As part of our activities within the Egypt National Committee against Viral Hepatitis, we have been closely involved in the drafting of the two national strategies against viral hepatitis (2008-2012 and 2013-2017). One main outcome of the national strategy has been the opening of 23 national treatment centers where subsidized treatment is offered to eligible patients with chronic hepatitis C. Since 2008, more than 200 000 patients have been treated under this initiative. More details can be found on the website of the project: www.hepnile.org
Description of the project:
The PhD student will analyse the data of a funded ANRS-sponsored clinical trial (ANRS 12226) evaluating the efficacy of vitamin D in addition to the standard combined therapy in the treatment of chronic hepatitis C in Egypt. Indeed, while it is expected that new drugs with high efficacy will be available in industrialised countries in the next 3-5 years (e.g., sofosbuvir from Gilead©), it may take longer time for these drugs to reach Egypt. Their estimated sales cost of sofosbuvir-including regimen is 80000 euros per treatment for Europe, and if ever used at reduced price in Egypt, they will be kept for the most difficult-to-treat patients. Meanwhile, it is important to identify drug regimens at lower cost that may be used for the majority of patients. The current standard therapy in Egypt is pegylated interferon (PEG-IFN) and ribavirin (RBV), sold locally at 1500 euros for a 48-week treatment, with a cure rate (sustained virological response) of 60%. The main hypothesis of this clinical trial is that adding vitamin D (a safe and very cheap drug already available locally) to this standard regimen will increase the cure rate to 72%.
The design will be an open-label randomised controlled trial with two arms. The objective will be to show the superiority of a 4 weeks lead-in phase of Vitamin D followed by a 48 weeks combination of Vitamin D with PEG-IFN plus RBV in comparison with standard PEG-IFN + RBV in untreated Egyptian patients with chronic hepatitis C. The main outcome will be the sustained virological response (SVR) at 6 months after end of treatment (week 72). Superiority of the vitamin D arm will be tested against the standard PEG IFN + RBV combination (expected difference=12%: SVR from 60 to 72%; power = 80%; alpha=0.05). The primary efficacy analysis will be an Intention-to-treat analysis comparing the SVR rate of of the combination therapy against standard therapy alone. The sample size will be 260 patients per arm.
The trial is expected to start in January 2014. It will be carried at the NHTMRI, the main national treatment center of Egypt. Gamal Esmat and Arnaud Fontanet are the principal investigators. Several team members of the EDEU will play key roles in the realisation of the study, in close collaboration with the local hepatology team and a local Clinical Research Organisation (CRO): Muriel Vray, specialist of clinical trials, will be the trial coordinator; Mohand-Ait-Ahmed will be the project manager; and Loïc Chartier the Data Manager. Enrolment is expected to last 12 months, and follow-up 18 months. All results should be available for analysis on 30 June 2016.
The PhD student will write a first paper on the enrolment characteristics of the patients (results available in January 2015). Other potential papers deal with the trial results, the evaluation of a point-of-care test for viral load and HCV genotyping, and the determinants of response to treatment.
References (team publications in the field):
Munier A, Marzouk D, Abravanel F, El-Daly M, Taylor S, Mamdouh R, Eldin WS, El-Arab HE, Sos DG, Momen M, Okasha O, Le Fouler L, El-Hosini M, Izopet J, Rafik M, Albert M, Abdel-Hamid M, Mohamed MK, Delarocque-Astagneau E, Fontanet A. Frequent transient hepatitis C viremia without seroconversion among healthcare workers in Cairo, Egypt. PLoS One. 2013;8(2):e57835.
Breban R, Doss W, Esmat G, Elsayed M, Hellard M, Ayscue P, Albert M, Fontanet A, Mohamed MK. Towards realistic estimates of HCV incidence in Egypt. J Viral Hepat. 2013 Apr;20(4):294-6.
Guerra J, Garenne M, Mohamed MK, Fontanet A. HCV burden of infection in Egypt: results from a nationwide survey. J Viral Hepat. 2012;19:560-7.
Vignier N, Esmat G, Sharkawy AE, Hassany M, Bonnard P, Delarocque-Astagneau E, Said M, Raafat R, El-Hoseiny M, Fontanet A, Mohamed MK, Vray M. Reproducibility of liver stiffness measurements in hepatitis C virus (HCV)-infected patients in Egypt. J Viral Hepat 2011;18: e358-e365.
Albert ML, Casrouge A, Chevaliez S, Hézode C, Rosa I, Renard P, Mallet V, Fontanet A, Pawlotsky JM, Pol S. Interferon induced protein 10 remains a useful biomarker of treatment failure in patients stratified for the interleukin-28B rs12979860 haplotype. Hepatology. 2011;53:1410-1.
Casrouge A, Decalf J, Ahloulay M, Lababidi C, Mansour H, Vallet-Pichard A, Mallet V, Mottez E, Mapes J, Fontanet A, Pol S, Albert ML. Evidence for an antagonist form of the chemokine CXCL10 in patients chronically infected with HCV. J Clin Invest 2011;121:308-17.
Mansour H, Laird ME, Saleh R, Casrouge A, Eldin NS, El Kafrawy S, Hamdy M, Decalf J, Rosenberg BR, Fontanet A, Abdel-Hamid M, Mohamed MK, Albert ML, Rafik M. Circulating plasmacytoid dendritic cells in acutely infected patients with hepatitis C virus genotype 4 are normal in number and phenotype. J Infect Dis. 2010;202:1671-5.
Paez Jimenez A, Sharaf Eldin N, Rimlinger F, El-Daly M, El-Hariri H, El-Hoseiny M, Mohsen A, Mostafa A, Delarocque-Astagneau E, Abdel-Hamid M, Fontanet A (corresponding author), Mohamed MK, Thiers V. HCV iatrogenic and intrafamilial transmission in Greater Cairo, Egypt. Gut. 2010;59:1554-60.
El Makhzangy H, Esmat G, Said M, Elraziky M, Shouman S, Refai R, Rekacewicz C, Gad RR, Vignier N, Abdel-Hamid M, Zalata K, Bedossa P, Pol S, Fontanet A, Mohamed MK. Response to pegylated interferon alfa-2a and ribavirin in chronic hepatitis C genotype 4. J Med Virol. 2009;81:1576-83.
Plancoulaine S, Mohamed MK, Arafa N, Bakr I, Rekacewicz C, Trégouët DA, Obach D, El Daly M, Thiers V, Féray C, Abdel-Hamid M, Abel L, Fontanet A. Dissection of familial correlations in hepatitis C virus (HCV) seroprevalence suggests intrafamilial viral transmission and genetic predisposition to infection. Gut. 2008;57:1268-74.
Hepatitis C; epidemiology; clinical trial; Egypt
Expected profile of the candidate (optional):
The candidate should have an MSc in epidemiology/public health, preferably on infectious diseases, with working experience in resource-limited countries. Having previously worked on clinical trial is a plus, but not a requirement. Knowledge of survival analysis and multivariate analysis techniques will be required for data analysis, but may be acquired during the course of the PhD. Working with Stata is a plus. Fluency in English is required, knowledge of Arabic and/or French is a plus.
Tel : 33 1 4061 3763