Story of Discovery: Hepatitis C: from non-A, non-B hepatitis to a cure
The story of hepatitis C from discovery to cure is very much like the plot of a good mystery novel. It begins with a puzzling who-done-it, followed by a lengthy hunt for the suspect, and, finally, rigorous efforts to subdue the perpetrator. Many of these efforts were spearheaded by the NIDDK, and, although the narrative is not quite finished, the battle against hepatitis C is evolving into one of the biggest modern success stories in scientific research.
An Unknown Culprit
Hepatitis, or inflammation of the liver, has long been a part of human history. The symptoms are unfortunately familiar to many: abdominal pain, tiredness, jaundice (the yellowing of skin and eyes), and, in many serious cases, liver failure and death. It wasn’t until the twentieth century that scientists discovered that most cases of hepatitis were caused by viruses that infect cells in the liver. Eventually, researchers divided viral hepatitis cases into two distinct diseases based on their characteristics; both diseases were potentially serious, but they differed in how they spread and made people sick. “Hepatitis A” was spread by person-to-person contact or through contaminated food or water, had a short incubation period, and resulted in an acute (temporary yet serious) illness. “Hepatitis B” was spread through blood and other bodily fluids, had a longer incubation period, and could lead to a chronic (long-lasting) infection. Because many cases of hepatitis seemed to be coming from blood transfusions, the identification of the viruses, particularly the blood-borne agent that causes hepatitis B, became imperative. If the virus was known, the blood supply could be screened to prevent spread of the disease.
A major protein from the hepatitis B virus was discovered in 1963 by scientists at the NIDDK (then called the National Institute of Arthritis and Metabolic Diseases), which eventually allowed for testing of the blood supply. However, screening for the hepatitis B virus and exclusion of infectious donors resulted in a decrease of only 25 to 50 percent in post-transfusion hepatitis cases. It was assumed that the remaining cases were either caused by the hepatitis A virus, or by the hepatitis B virus that may have slipped through the screening process. By the mid-1970s, however, investigators at the NIH in the Hepatitis Branch of the Laboratory of Infectious Diseases of the National Institute of Allergy and Infectious Diseases (NIAID) had identified the hepatitis A virus, and, in collaboration with the NIH Clinical Center’s Division of Transfusion Medicine, they showed that the remaining hepatitis cases were neither hepatitis A nor hepatitis B. Something else was damaging the liver, and the signs were pointing to a third virus. Like hepatitis B, this newly Identified disease could be contracted via infected blood and could result in a chronic infection and liver cirrhosis (scarring). However, the chance of chronic disease in adults was much higher than with hepatitis B. Also, unlike hepatitis B, people with this disease rarely experienced acute symptoms, which could mean that the disease could slip into a chronic state before an individual had any obvious signs that he or she was even infected. For the next 15 years, the stealthy culprit behind this disease was unknown, and thus the disease was simply called non-A, non-B hepatitis.
Interfering with Non-A, Non-B Hepatitis
While scientists hunted for the mysterious agent behind non-A, non-B hepatitis, they also concentrated efforts on its treatment. Because the virus was still unknown, the first drugs to be tested were those that had been shown to be effective against a broad range of viruses. Hepatitis B patients were responding with some success to a chemical called interferon alpha (interferon), a naturally occurring substance produced by immune cells in response to viral infections or other environmental stresses. Usually administered via injection, interferon produces an antiviral state inside cells that “interferes” with virus replication—hence its name—and protects the cells against infection. Because interferon acts as a general defense mechanism against a variety of viruses, it was logical to try using it as a tool against the unidentified virus that caused non-A, non-B hepatitis.
In 1984, scientists in the NIDDK Intramural Research Program led a pilot study of interferon in 10 patients at the NIH Clinical Center in Bethesda, Maryland. The patients were given daily doses for 16 weeks, and their liver health was monitored by testing their blood for a marker of liver damage. The results of the trial were immediate and dramatic: most of the patients showed evidence of a healthier liver after a month of treatment. The patients relapsed when the interferon treatment was stopped after 4 months; however, once the treatment was restarted, their liver health again improved and stayed normal even after the dose was gradually lowered and then stopped after a full year. Some of the patients had only minimal responses to interferon therapy, and others responded but then relapsed, but, in the end, half the patients in the trial showed no signs of liver infection in follow-ups that were eventually extended for 10 to 25 years. These were the first patients to be cured from the disease that would eventually be known as hepatitis C.
Despite these initial results, larger clinical trials tempered expectations with interferon. The outcomes of the studies varied greatly from patient to patient, but treatment with interferon alone generally had a low success rate, measured as the rate of sustained virologic response (SVR). Patients achieving SVR have no detectable virus for at least 24 weeks after discontinuing the treatment—which means there is a very high probability that the treatment was successful and the patient will not relapse. Treating with interferon alone typically yielded SVR rates of less than 20 percent. Combining interferon with other antiviral drugs showed promise, however. One of these drugs, ribavirin, had first been tested by NIDDK intramural researchers as a stand-alone therapy, but it had only a modest and temporary effect on virus levels. However, later studies showed that a combination of interferon and ribavirin was superior to interferon alone, showing SVR rates of 30 to 40 percent. Another improvement came when scientists chemically modified interferon to make it last longer in the body. With SVR rates of 55 percent, this “pegylated” interferon (peginterferon), combined with ribavirin, became the standard of care for hepatitis C patients.
The results of these studies also made it clear that more research was needed. While interferon-based therapy was typically successful for over half of patients, it was usually accompanied by side effects such as fever, fatigue, muscle aches, and depression that often limited the dose and duration of the treatments. Nevertheless, these initial trials delivered important insights into how the virus responds to (or resists) therapy and provided important clues about the virus’ biology and resilience. This information would prove to be useful when designing therapies based on more effective treatments, and there was a huge development right around the corner that would bring those treatments within reach.
The Discovery of the Hepatitis C Virus
The non-A, non-B hepatitis virus was identified in 1989 by scientists at a California biotechnology company called Chiron who were collaborating with investigators at the Centers for Disease Control and Prevention (CDC). The research confirmed that this was a new virus—now officially called the hepatitis C virus, or HCV. This was a landmark advance in medicine that allowed for development of tests to detect HCV, which were rapidly applied to screen blood donations. Over the next few years, as the testing improved, HCV was effectively eliminated from the blood transfusion supply. The identification of HCV also led to further studies, undertaken by NIAID- and NIDDK-funded researchers and others, to determine its molecular structure. This was crucial for the design of drugs that would specifically interact with components of the virus and inhibit its replication. The identification of the virus also allowed for a more accurate diagnosis and a better sense of its prevalence; in fact, it was eventually determined that HCV was the most common cause of chronic hepatitis, cirrhosis, and liver cancer in the Western world.
Applying new direct tests for the presence of HCV showed that interferon therapy lowered the level of virus in the blood; importantly, patients who had a clinical response to treatment and did not relapse also became HCV negative and were cured of their chronic viral infection. Tests for HCV RNA (the virus’ genetic material) in blood were key to future progress in treatment, because they demonstrated that a sustained loss of the HCV RNA—for 12 weeks after stopping treatment—was a reliable end point for treatment. Achievement of SVR became the benchmark end point for clinical trials of new treatments, and the criteria for approval of a new therapy was that it yielded a better SVR rate than peginterferon with ribavirin.
Studying HCV’s genetic makeup revealed that the virus has several genotypes, or genetic varieties, and these determine how effectively the virus responds to therapy. For example, genotype 1 is the most common genotype worldwide, but clinical trials found that it was more resistant to interferon-based therapy than other genotypes. The identification of different genotypes meant researchers were able to better predict and tailor therapies, and it provided one explanation for why some clinical trial participants had better outcomes with peginterferon than others. Another important consequence of identifying HCV was that researchers were now able to analyze the molecular components of the virus and determine which ones could be ideal targets for drugs. These potential targets included an HCV enzyme called a polymerase that is crucial for the replication of the virus’ genetic material; an enzyme called a protease that the virus uses to process its components before assembly; and a protein called NS5A, which appears to have several important roles in virus replication, including regulating the cell’s response to interferon.
While scientists were working towards characterizing HCV, they were also making strides in its treatment. A huge step toward drug design occurred in 2005, when three different groups of investigators, including NIDDK intramural researchers, were able to grow the virus in cells in the laboratory. This allowed for the study of the HCV life cycle and the identification of essential viral components. These studies then led to the development of the fi therapies that were specifically designed to block HCV replication by directly targeting parts of the virus. While broadly antiviral therapies like interferon and ribavirin were somewhat effective, the side effects made the treatments difficult to tolerate. If a drug could be designed to target HCV specifically, the effects might be more limited to the cells that were infected with the virus, greatly limiting “friendly fire” damage to other parts of the body.
Zeroing in on the Hepatitis C Virus
The era of direct-acting antivirals (DAAs) that specifically target HCV began in 2011 with the U.S. Food and Drug Administration (FDA) approval of the first protease inhibitors. These drugs—telaprevir and boceprevir, along with several similar drugs approved later—targeted the HCV protease that is critical for viral replication. When used in conjunction with peginterferon and ribavirin, protease inhibitors yielded SVR rates of up to 75 percent. However, this triple therapy was accompanied by additional side effects to those already present with peginterferon and ribavirin. Nevertheless, the success of HCV-specific protease inhibitors showed that the virus had vulnerabilities that could be exploited by a well-designed and properly administered drug.
More new anti-HCV drugs were developed and tested over the next several years. These new drugs included sofosbuvir and dasabuvir, which interfered with the activity of the HCV polymerase, an enzyme that is responsible for the viral replication. Members of a second class of drugs, ledipasvir and daclatasvir, targeted the NS5A region of the virus, which makes a structural protein critical for viral replication. Many of these drugs were initially tested in conjunction with peginterferon and ribavirin, or in combination with a protease inhibitor. Generally, the results were SVR rates of at least 80 percent.
With the success of DAA therapies, it soon became apparent that when several of them were used in combination, interferon was no longer necessary. This was a crucial step in the progress of hepatitis C therapy, because eliminating the need for peginterferon avoided the many distressing side effects that accompanied interferon-based therapy. These all-oral regimens also opened up the possibility of treatment in individuals in whom peginterferon could not be safely administered. Perhaps the most successful DAA combination was that of sofosbuvir and ledipasvir; with these two drugs, the SVR rates soared to 99 to 100 percent. Furthermore, this combination was successful with just 8 to 12 weeks of treatment. After years of painstaking research, there was a bona fide cure for hepatitis C that worked for nearly everyone.
The Future of Hepatitis C Therapy
With such high rates of success with current treatments, it may seem like the hepatitis C story is in its final chapters, but it is not over yet. A vaccine against hepatitis C would cause the prevalence of the disease to plummet, but efforts to produce a vaccine, while still under way, have not yet been successful. While hepatitis A and B have vaccines, the hepatitis C virus is more variable than either of these viruses, which, along with other factors, complicates vaccine development efforts. Additionally, the current drugs show great promise, but the costs of the more successful FDA-approved DAA treatments are extremely high, which present a significant obstacle to many with the disease. But the research has come a long way. From the early investigations into a mysterious new virus, to the identification of the culprit, and the rigorous work to develop an effective treatment—the story of hepatitis C is definitely a thriller.