Today, I am thankful for the knowledge that we can overcome even the most recalcitrant of viruses.
Clearly, the recent coronavirus pandemic, caused by the SARS-CoV-2 virus, has left the world on edge. Many have questioned if the spread is a harbinger of Armageddon over a future viral infection we cannot stem. Today, I’d like to share the story as to how we tackled another virus, some might say of much higher complexity because of its propensity to cause a chronic infection.
Today is World Hepatitis Day, an event observed on July 28 every year. This commemorative event aims to enhance global awareness against the 5 viruses that cause hepatitis (Hepatitis A, B, C, D, and E). As one of the 8 official global public health campaigns of the World Health Organization (WHO), World Hepatitis Day is designed to encourage the diagnosis, treatment, and prevention of these various, debilitating liver infections. Viral hepatitis affects hundreds of millions of people worldwide, causing acute and chronic disease and killing close to 1.34 million people every year. Nearly 300 million people are living with hepatic viral infections, and, sadly, 2 of every 3 deaths related to liver cancer are attributed to these viruses. Over the last 4 decades, scientists across the globe have played an instrumental role in the prevention and/or treatment of many of the most prominent viral hepatitis infections, including Hepatitis A, B, and C. Today, I’d like to focus on all we have done over the last 3 decades to address chronic Hepatitis C virus (HCV) infection – a disease that has long been identified as the leading cause of liver cancer and, until recently, the most common reason for a liver transplantation.
This year (2020) commemorates the 31-year anniversary of the discovery of the RNA virus that causes HCV. Prior to its identification in 1989 and the availability of a screening test in 1992, HCV was commonly spread from one individual to another either via blood transfusions or organ transplantation. For every 100 individuals infected with HCV, as many as 85 would normally develop a chronic infection. Over time, this chronic infection in the liver progresses from inflammation to liver tissue hardening (known as fibrosis) and eventually to irreversible, permanent scarring (or cirrhosis). In fact, up to 70 of every 100 infected individuals develop chronic liver disease with some level of scarring, and close to 10-20 will develop frank cirrhosis. Ultimately, 1 to 5 of these 100 infected folks succumbs to this infection. In addition, the healthcare costs associated with chronic HCV infection are enormous; it is estimated that the average annual cost for a patient infected with HCV is ~$24K.
Scientists in academic, governmental, and corporate institutions played instrumental roles in developing therapies that have successfully pushed our limits from having an incurable condition (prior to 1991) to an effective cure in over 95% of individuals with just 8 to 12 weeks of daily treatment (starting in 2014). It all started with a medicine called interferon alpha 2b, which was originally approved in 1986 to treat hairy cell leukemia, a rare blood cancer. In July 2000, a publication within the New England Journal of Medicine highlighted that this medicine was also useful to treat chronic HCV, but the cure rate (i.e., those who maintained a sustained viral response [SVR] associated with its use) was rather low – only 6%. Moreover, it was not an easy medicine to take on a daily basis, as it required a subcutaneous administration by needle and was routinely associated with very debilitating side effects (fever, chills, malaise, and so on). But, scientists kept at it, and, in 1998, a new agent, ribavirin, was developed, which, when given in combination with interferon, increased the SVR rate to 29%. But, the work did not stop there. In 2001, scientists helped usher in a new form of interferon, known as pegylated interferon, which persisted longer in the body and allowed for once-weekly dosing. Combined with ribavirin, peg-interferon improved the safety profile to some extent and boosted SVR rates to 41%. But, when your cure rate is still less than 50%, it’s hard to rest on your laurels. Hence, scientists continued to scour for new tools to combat HCV.
Fortunately, the world had made notable advances in the field of HIV research during this same time. Recognizing that the HCV virus also contains a protease enzyme analogous to that seen in HIV, scientists set on the task to develop an HCV-specific protease inhibitor. The road to success was not easy, as chronicled by the over 75 different investigational medications that failed in clinical trials between 1998 and 2014. But, research into HCV protease inhibitors continued, and a big break came with the development of boceprevir and telaprevir, both of which showed promise in clinical trials when combined with pegylated interferon and ribavirin for either a 24-week or 48-week regimen. Studies of these combinations demonstrated SVR rates of ~70%.
Over time, newer mechanisms of action targeting the non-structural proteins of HCV, including NS5A (interferon resisting protein) and NS5B (RNA polymerase), showed incredible promise. The approval of Gilead’s HARVONI, which contained a combination of these 2 classes helped transform the field even further, resulting in SVR rates of >90% with treatment regimens as short as 8-12 weeks. Today, individuals infected with HCV can be effectively cured with medicines such as HARVONI, EPCLUSA, ZEPATIER, and MAVYRET because of the incredible work that scientists and pharmaceutical companies have done to advance the field. In fact, the 25-year, HCV research is heralded as the quickest time in medical history wherein scientists have ever gone from identifying the cause of a chronic infection to successfully developing an effective cure.
So, as you enjoy Your cup of coffee this morning wondering whether COVID-19 will ever go away, take a moment to pay tribute to those who toiled diligently to advance our scientific comprehension of the HCV realm. The nearly 170 million people around the world, including 3.2 million Americans, infected with this horrible chronic infection are grateful for what you have done to change the world.
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