Hepatitis Viruses Explained
Curing disease is serious business. Lou Reed, the infamous leader of the rock band Velvet Underground, died in 2013 of complications from hepatitis C and liver disease. Death is the most profound fear for people living with hepatitis C, but thanks to powerful new combination treatments such as Gilead’s (Foster City, CA) Harvoni and AbbVie’s (North Chicago, IL) Viekira Pak, today most patients can beat this disease.
The word “hepatitis” means liver inflammation and while the most common culprit is the hepatitis virus, liver inflammation can also be attributed to other causes—think excess alcohol, autoimmune disorders, and non-alcoholic fatty liver disease. In honor of World Hepatitis Day coming up on July 28, this WEEKLY takes a closer look at the story behind the different hepatitis viruses and the drugs vying their way to a cure.
THE ABCS—AND D & E
All hepatitis viruses infect liver cells and cause inflammation, but there are important distinctions in how they are spread and the type of illness that they cause:
- Hepatitis A (HAV) is usually transmitted by ingestion of contaminated food or water. HAV is almost always acute, meaning people may get very sick for a few weeks, but then they clear the virus and do not suffer long-term liver inflammation.
- Hepatitis B (HBV) requires direct exposure to body fluids, such as blood or semen. HBV can be either acute or chronic. 90% of cases that occur before the age of five become chronic, while the majority of those that occur after age five are acute. Since 1972, all donated blood has been screened for HBV.
- Hepatitis C (HCV) requires direct exposure to blood and is typically spread by using contaminated needles or syringes. Although some people clear the virus within six weeks of infection, the majority—approximately 80%—develop chronic infections. Chronic infections may initially be asymptomatic, but if left untreated, can lead to serious problems such as cirrhosis (scarring) of the liver or liver cancer. Since 1992, all donated blood has been screened for HCV. An estimated 3.2 million people in the U.S. have chronic hepatitis C according to the Centers for Disease Control, and liver disease due to HCV infection is the leading indication for liver transplants in the U.S.
- Hepatitis D (HDV) is transmitted through the blood and only occurs if HBV is also present.
- Hepatitis E (HEV) is transmitted by ingestion of contaminated food or water and is seen almost exclusively in parts of the world without clean water supplies. HEV is usually an acute infection, although it may become chronic in cases where the immune system is compromised.
MANAGING CHRONIC HEPATITIS B
Chronic cases of HBV pose a risk of cirrhosis or liver cancer. There is no cure for HBV, but there are a variety of treatments that inhibit the enzyme the virus uses to replicate itself, including Epivir (ViiV Healthcare; Brentford, U.K.), Hepsera (Gilead), Tyzeka (Novartis; Basel, Switzerland) and Baraclude (Bristol-Myers Squibb; New York, New York). These drugs slow down the progression and make the disease manageable, but do not get rid of the virus.
A number of companies are working on a cure for HBV, in some cases by applying cutting-edge gene silencing technology that targets the HBV genome. Disrupting viral genes means disrupting viral protein production—which means no virus. Companies taking this approach include Arrowhead Pharmaceuticals (Pasadena, CA), Arbutus Biopharma (Warminster, PA), Alnylam Pharmaceuticals (Cambridge, MA), and Ionis Pharmaceuticals (Carlsbad, CA).
BEATING HEPATITIS C
The landscape for HCV changed dramatically with the FDA approval of Gilead’s Solvadi. As a “nucleotide analog polymerase inhibitor,” Solvadi inhibits the viral polymerase—the enzyme used by HCV to replicate its genetic material (RNA). To make copies of the viral RNA, the polymerase simply connects new building blocks—nucleotides—together in the same order as the existing viral RNA. Solvadi is structurally very similar to nucleotides found in nature, so the polymerase will incorporate the drug into a growing RNA strand. However, Solvadi has been chemically modified so that once incorporated, the polymerase is unable to add any additional nucleotides, thereby halting viral replication.
Gilead gained FDA approval for a second drug, Ledipasvir, which inhibits the HCV protein NS5A. The exact function of NS5A in the viral life cycle is not known—it is thought to play a role in viral replication, assembly, and secretion. Sovaldi and Ledipasvir are now marketed together as Harvoni, and the combo clears HCV from infected livers.
AbbVie’s Viekira Pak brought another HCV breakthrough therapy to market. Viekira Pak knocks out HCV with a three-part punch:
- Dasabuvir: changes the shape of the viral polymerase. Without its proper shape, the enzyme is ineffective and viral replication is inhibited.
- Paritaprevir: inhibits the HCV protein, NS34A. NS34A job is to cut large proteins into smaller ones; these smaller proteins are critically important in the HCV lifecycle. No small viral proteins, no HCV.
- Ombitsavir: shuts down the HCV protein, NS5A. The exact mechanism of action of Ombitsavir is not known, but it is thought to bind the NS5A protein and inhibit its role in the HCV lifecycle.
VACCINES FOR A & B, SO WHY NOT C?
There are several reasons why there are safe and effective vaccines for HAV and HBV, but not for HCV:
- HCV virus is more genetically variable than the viruses that cause HAV and HBV. This means it is more difficult to generate an immune response that will be effective against different strains of the virus.
- Vaccines must be tested in animals before they can be tested in humans. It is difficult to find an animal model that can host the HCV virus other than chimpanzees—testing is limited due to ethical and cost concerns. Recently developed mice with grafted human liver cells are proving to be valuable models for the disease.
- It is difficult to find people to enroll in HCV vaccine trials. A new vaccine requires researchers to vaccinate people who are at high risk of infection. In developed countries, those at highest risk are those who inject street drugs and this particular population tends to avoid health care, and can be difficult to track for follow-up studies. There is a much larger at-risk population in developing countries where the infection tends to spread through contaminated hospital equipment. However, the conditions that put these patients at risk also makes developing country hospitals a poor environment to run clinical trials.
Hepatitis remains a serious disease, but fortunately biopharma research has led to remarkable cures for HCV. We expect to see similar success within the next few years as multiple companies pitch a fight against HBV.