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Pakistan-US Science and Technology Cooperation Program                                                            
Phase 4 (2009 Deadline)

Hepatitis B Virus-Associated Hepatocellular Carcinoma in Pakistan

Aleem Siddiqui, University of California, San Diego
Hajra Sadia (beginning January 2012) (previous PI Ishtiaq Qadri, until October 2011), National University of Sciences and Technology
Pakistani Funding (Department of State): $358,906
US Funding (Department of State): $311,990
Project Dates on US Side: November 15, 2010 - November 14, 2013 (Completed)

Project Overview
Human hepatitis B virus (HBV) infection is one of the leading causes of chronic hepatitis, which increases the risk for the development of hepatocellular carcinoma (HCC). There are an estimated 350 million chronic carriers of hepatitis B worldwide, and in Pakistan the incidence of HBV infection is alarmingly high. HBV is classified into eight genotypes, each with a distinct geographical distribution, which can be used in tracing the evolution and transmission of the virus. Differences between genotypes affect the disease severity, course and likelihood of complications, and response to treatment. The researchers in this collaborative project will characterize the HBV genotypes in Pakistan and determine the prevalence of specific genetic mutations that place hepatitis B chronic patients at high risk of liver failure and HCC. Early diagnosis for HCC has significant advantages for preventing the incidence of full-blown HCC. This epidemiological study should benefit the future prognosis of patients suffering from HCC and will also provide valuable training opportunities for Pakistani students, research fellows, and clinicians in molecular studies of infectious diseases.
Quarterly Update
The project is aimed at establishing the associations between HBV genotype(s), genetic mutations and the risk of HCC in chronic hepatitis B patients. The work done so far led to the isolation of about 90 serum samples from different regions of Pakistan and molecular characterization by serology, PCR amplification methods, genotyping, molecular cloning etc. The results showed that HBV genotype D is the most common in Pakistan. Mutations were identified within HBV genome as noted for liver cancer patients. Overall, these results suggest that HBV mutations may be one of the principal characteristics in the pathogenesis of HCC, as has been predicted. More work is however needed to establish firmly the underlying mechanism(s) by which mutations and the genotype play in the genesis of liver cancer associated with HBV infection.

The Pakistani side is in process of purchasing the Gradient PCR (Polymerase Chain Reaction) and High Speed Ultracentrifuge. The Ultracentrifuge will not only be used for isolation of HBV particles for this particular project, but also for isolation of other viruses by other researchers and students in the school. Four undergraduate students have completed their designated projects. Five Graduate students are currently working on different projects, four of which have completed their M.Phil and now continuing into PhD. A number of consultant gastroenterologist and hepatologist from various institutions across Pakistan are collaborating in this project (Aga Khan University (Karachi), Dow University of Health Sciences (Karachi), Shifa School of Medicine (Islamabad), Pakistan Institute of Medical Sciences (Islamabad), Poly Clinic Hospital (Islamabad), Holy Family Hospital (Rawalpindi), Nuclear Medicine Oncology and Radiation Institute (Islamabad). On the US side, four postdoctoral fellows carried out the project on HBV X protein’s role in mitochondrial metabolism. They have not been able to clone the HBx gene from Pakistani patients’ sera to continue to explore its functional relevance to HCC, mainly due to the departure of the original collaborator Dr. Qadri. 
Progress Reports

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2012 Show summary || Hide summary  || Download full report

2013 Show summary || Hide summary || Download full report