In this issue, we speak to Dr Jerika Lam of the School of Pharmacy at Chapman University, about her work applying pharmacogenomics to antiviral treatments.
“A lot has happened in the field of hepatitis C virus (HCV) infection, especially with better antiviral treatments for individuals who are mono- or coinfected with HCV and HCV/HIV, respectively. Prior to the development of the second generation direct acting antivirals (DAAs) in 2013, cure rates were dismally low, ranging between 50-70%.
“Furthermore, 20% of HCV-infected individuals would develop life-threatening complications, including cirrhosis and hepatocellular carcinoma. Liver failure from cirrhosis is the leading cause of liver transplantation in the US, resulting in an increased cost burden to our healthcare system.
“Currently, individuals who are HCV-infected can receive highly effective oral DAAs and be successfully cured of the infection after 2 or 3 months of treatment. Therapy with DAAs is associated with cure rates of 95% or higher regardless of the HCV genotype.
“There are few challenges that still exist today. Firstly, in 2012, the Centers for Disease Control and Prevention (CDC) and, more recently, U.S. Preventive Services Task Force recommended all persons born between 1945 and 1965 should receive routine serologic testing for HCV.
“If these “baby boomer” individuals are found to have HCV infection, then they could receive DAA therapy, be cured of the infection, and reduce the risk of developing end-stage liver disease and death.
“Secondly, with the opioid epidemic, there is an increase in HCV-infection among individuals who use or share injection drug use since HCV is easily transmissible through blood-to-blood contact.
“Thirdly, there is a high percentage of individuals who continue to develop non-alcoholic fatty liver disease (NAFLD), approximately 50% based on one US study, even after being cured of HCV infection. NAFLD is characterised by increased fat deposits in the liver that could increase the individual’s risk of liver cirrhosis and hepatocellular carcinoma.
“Remarkable progress has been made in developing effective and well-tolerated oral treatments for HCV infection, which have led to a significant cure rate of the infection. However, despite the therapeutic advances developed in this field, there is a proportion of those individuals who have achieved cure and still demonstrate evidence of NAFLD.
“There are molecular mechanisms and genetic factors associated with the development of NAFLD, such as fatty acid synthase, acetyl-CoA carboxylase 1, peroxisome proliferator-activated receptor, and the patatin-like phospholipase domain containing 3 (PNPLA3) gene. Many studies have reported genetic polymorphisms and their association with lipid metabolism, particularly the PNPLA3 genotypes within certain ethnic groups.
“The PNPLA3 gene is associated with mediating lipid deposition in hepatocytes and adipocytes. Pharmacogenomics, or the study about the effect of genes on an individual’s response to medications, could help predict the specific genotypes that predispose an individual to risks of developing NAFLD and/or NAFLD fibrosis progression even after successfully responding to DAA therapy.
“My research interests include applying translational clinical research (pharmacogenomics) in practice, determining mechanisms of viral resistance, promoting awareness of naloxone use and opioid misuse, and reducing the stigma associated with HIV and hepatitis infections.
“Our research study aims to explain the underlying molecular mechanisms of hepatitis steatosis, or fatty liver and its correlation with the PNPLA3 genotypes. At the present, my research lab and I are exploring the impact of commonly used DAAs on the expression of the PNPLA3 gene polymorphism, rs738409 I148M, in a concentration- and time-dependent manner. We use a hepatic cell model and transfect it with a HCV genotype 2a isolate, the JFH1 plasmid.
“After confirming infection of the hepatic cell model, we then treat the infected hepatic cells with DAA mono- and combination therapies at various concentrations and times to determine if there is any impact on the expression of the polymorphism. Our goal is to determine if there is a correlation of the PNPLA3 genetic polymorphism expression with specific DAA treatments over time.
“By performing this translational research, we hope to explain the possible mechanisms behind the development of NAFLD in certain patient populations that are cured of HCV infection. More importantly, we hope that our research findings will promote screening HCV-infected individuals for the polymorphism prior to receiving treatment and predict their likelihood of improvement after successful DAA therapy.
“The fact that there are several case reports of HCV-infected individuals who continue to have hepatic-related complications and development of NAFLD after being cured of the infection fascinates and challenges me to find an explanation. There are some scientific publications reporting the potential association between various molecular and genetic mechanisms and NAFLD.
“For patients who are cured of the HCV infection, there is a proportion of patients who continue to develop hepatic steatosis and may require liver transplantation in the future. By determining the underlying molecular mechanisms that could explain and confirm the correlation of the PNPLA3 gene polymorphisms, we could then use precision medicine to identify individuals who could benefit most from DAA therapy either at the early or late stage of their liver disease.
Perhaps the most difficult aspects of translational clinical research are to validate the same underlying polymorphisms in human studies. As of present, we have very interesting in vitro data to show that certain DAAs do affect the PNPLA3 gene polymorphism expression at higher concentrations and longer time intervals. With immunofluorescence assay, we also detected the translocation of the PNPLA3 gene from the nucleus to the cell membrane. We plan to publish our in vitro findings.
“Our research study aims to address the underlying molecular mechanisms of PNPLA3 gene polymorphisms and their impact on fatty liver development. The challenge that we may face includes sampling the HCV-infected patients’ blood to determine if we are actually testing the gene or protein of PNPLA3.
“The impact of our work is potentially significant. Knowing that the PNPLA3 gene is associated with NAFLD and alcoholic liver disease, screening for the PNPLA3 genotypes will allow us to identify the individuals who are less likely to recover after achieving cure of their HCV infection. Subsequently, these individuals would be closely monitored for potentially developing steatosis and educated to avoid certain foods and medications to reduce further injury to the liver.
“Currently, I’m also working on the antimicrobial effects of fatty acids on various bacteria. I plan to expand this research into the fatty acids’ antiviral activity against HIV and the human papilloma virus. We are exploring natural treatments to combat antimicrobial and antiviral resistance that would be safer for patients.
“I am also collaborating with faculty colleagues to evaluate the prevalence of naloxone furnishing and awareness among California pharmacists. Naloxone is an opioid antagonist and could save lives for those individuals experiencing an accidental overdose from taking too much synthetic and illicit opioids.
“My personal interest in this public health type of research stems from the increased use of illicit substances and opioids that usually occur via injectable paraphernalia. As a result, the increased use of injectable substances and opioids have led to increasing HIV and HCV infection rates within our communities.
“My inspiration as a research scientist stems from the fact that there are still many unanswered questions in science and research is essential toward improving clinical knowledge and science. The possibility to find the hidden truth for the current health challenges and the opportunity to add to the body of science and knowledge further inspire me to continue my research studies.
“My early academic career was focused on exploring the mechanisms of antiretroviral-associated toxicities in individuals living with HIV and applying pharmacogenomics in HCV-infected individuals receiving pegylated interferon and ribavirin dual therapy.
“With respect to pharmacogenomics, I was investigating serotonin transporter polymorphisms and their correlation to an individual’s predisposition to depression during pegylated interferon therapy for HCV infection.
“If the individual is screened to be at increased risk of having depression based on the genetic polymorphism, then he/she will receive an antidepressant as prophylaxis at least two weeks prior to starting pegylated interferon and ribavirin therapy.
“My earlier research interests focused on nephrotoxicity associated with certain antiretroviral agents that were part of the preferred treatment regimen for patients living with HIV infection. The defining moment in my work as a researcher began when I was able to validate the study results with scientific experiments. I was excited by the fact that I could explain the nephrotoxicity observed in my patients with the in vitro findings conducted in the laboratory.
“Obtaining intramural grant funding from my University to conduct studies exploring the impact of DAAs on PNPLA3 polymorphism expression was a huge step for me. Funding has led to my discovery of the molecular mechanism that may explain the influence of DAAs on PNPLA3 polymorphism expression in hepatic cells.
“What keeps me motivated each day is the hope that there will, someday, be a cure for HIV and better antimicrobial treatments for multi-drug resistant virulent pathogens. I hope that we will be able to use precision medicine, or pharmacogenomics to individualize therapies and ensure successful health outcomes.”
