Hepatitis C‘s journey from discovery to cure is remarkably similar to the plot of a good mystery book. It starts with a perplexing whodunit, is followed by a protracted search for the suspect, and ends with determined efforts to capture the offender. Although the story is far from over, the fight against hepatitis C is turning into one of the biggest modern success stories in scientific research. Many of these initiatives were led by the NIDDK.
A Cure For hepatitis C
Hepatitis, or liver inflammation, has existed in humans for a very long time. Unfortunately, many people are familiar with the symptoms: nausea, vomiting, fatigue, jaundice (a yellowing of the skin and eyes), and, in many severe cases, liver failure and death. It wasn’t until the 20th century that researchers realized that viruses that infect liver cells are the primary cause of the majority of cases of hepatitis.
In the end, researchers separated viral hepatitis cases into two distinct illnesses based on their traits; both illnesses had the potential to be serious, but they were different in how they affected people and propagated. “Hepatitis A” had a brief incubation time, was transferred from person to person or by tainted food or water, and led to an acute (temporary but serious) sickness.
“Hepatitis B” had a prolonged incubation time, was transmitted through blood and other bodily fluids, and had the potential to become a chronic (persistent) illness. It became crucial to identify the viruses, especially the blood-borne agent that causes hepatitis B, because many cases of hepatitis appeared to be related to blood transfusions. In order to stop the sickness from spreading, the blood supply might be tested if the virus was known.
Researchers at the NIDDK (then known as the National Institute of Arthritis and Metabolic Diseases) made a significant protein from the hepatitis B virus discovery in 1963, which subsequently allowed for blood supply testing. However, post-transfusion hepatitis cases were reduced by only 25 to 50% as a result of testing for the hepatitis B virus and excluding infected donors. It was assumed that the hepatitis A virus or a possible hepatitis B virus that evaded detection was to blame for the remaining cases.
The hepatitis A virus was discovered by NIH researchers in the Laboratory of Infectious Diseases’ Hepatitis Branch by the middle of the 1970s, and they demonstrated that the remaining hepatitis cases were neither hepatitis A nor hepatitis B in cooperation with the NIH Clinical Center’s Division of Transfusion Medicine. The liver was being harmed by something else, and a third virus was suspected based on the symptoms. Similar to hepatitis B, this newly discovered illness could be acquired through contaminated blood and cause persistent infection and liver cirrhosis (scarring).
However, compared to hepatitis B, the risk of chronic illness in adults was significantly higher. Additionally, unlike hepatitis B, this illness rarely causes acute symptoms, which may indicate that it can progress to a chronic stage before an individual shows any overt symptoms of infection. Non-A, non-B hepatitis was the disease’s common name for the subsequent 15 years while the actual cause of it remained a mystery.
Affecting non-A, non-b hepatitis
In addition to searching for the enigmatic cause of non-A, non-B hepatitis, researchers focused on finding a cure. The initial medications to be tested were ones that had been proved to be effective against a wide variety of viruses because the virus was still unknown. Interferon alpha (interferon), a naturally occurring molecule produced by immune cells in reaction to viral infections or other environmental stimuli, was showing some promise in treating hepatitis B patients.
Interferon, which is often provided by injection, induces an antiviral state within cells that prevents virus replication—hence its name—and shields the cells against infection. It was natural to attempt employing interferon as a tool against the unknown virus that caused non-A, non-B hepatitis since it functions as a general defense mechanism against a number of infections.
At the NIH Clinical Center in Bethesda, Maryland, ten patients participated in a pilot study of interferon conducted in 1984 by researchers with the NIDDK Intramural Research Program. For 16 weeks, the patients received daily doses, and blood tests were performed to check for a sign of liver damage. The trial’s outcomes were quick and striking: after a month of treatment, the majority of patients had signs of a healthier liver.
When the interferon therapy was halted after four months, the patients experienced relapses; however, after the therapy was resumed, their liver health once more improved and remained normal even after the dose was gradually reduced and then ceased after a full year. When follow-ups were eventually prolonged for 10 to 25 years, half of the trial participants exhibited no evidence of liver infection, while some patients had only minor responses to interferon therapy and others responded but relapsed. These patients were the first to be cured of the condition that would subsequently be called hepatitis C.
Larger clinical trials dampened expectations with interferon despite these preliminary findings. However, treatment with interferon alone often had a low success rate, as evaluated by the rate of persistent virologic response, even if the results of the studies varied greatly from patient to patient (SVR). Patients who achieve SVR have no detectable virus for at least 24 weeks after stopping treatment, indicating a strong likelihood that the treatment was effective and the patient won’t relapse. SVR rates of less than 20% were commonly obtained while using interferon alone as a treatment. However, combining interferon with additional antiviral medications showed promise.
One of these medications, ribavirin, had only a slight and transient impact on viral levels when it was studied at first by NIDDK intramural researchers as a stand-alone therapy. Later research, however, demonstrated that interferon with ribavirin was superior to interferon alone, with SVR rates of 30 to 40%. Another development was the chemical modification of interferon to extend its biological half-life. This “pegylated” interferon (peginterferon), in combination with ribavirin, established the gold standard of therapy for hepatitis C patients with SVR rates of 55%.
These studies’ findings also demonstrated the necessity of further investigation. Despite the fact that interferon-based therapy was usually beneficial for more than half of patients, it was frequently accompanied with adverse effects such fever, exhaustion, muscle aches, and melancholy that frequently restricted the dosage and length of the treatments. Nevertheless, these early studies offered crucial information about how the virus reacts to (or rejects) treatment and gave crucial hints about the biology and persistence of the virus. This knowledge would be helpful in developing cures based on more efficient treatments, and a significant advancement was just around the corner that would make those treatments feasible.
The Hepatitis C Virus’s Discovery
Scientists at Chiron, a biotechnology company based in California, worked with researchers at the Centers for Disease Control and Prevention to discover the non-A, non-B hepatitis virus in 1989. (CDC). The study established that this was a novel virus, which is now known as the hepatitis C virus, or HCV. It was a significant advancement in medicine that made it possible to create HCV detection tests, which were quickly used to check blood donors. As testing methods improved over the ensuing years, HCV was essentially removed from the supply of blood used for transfusions.
The discovery of HCV prompted other research projects, carried out by scientists with funding from NIAID and NIDDK as well as others, to ascertain its molecular structure. This was important for the development of medications that would precisely interact with virus components and prevent virus multiplication. In fact, it was ultimately discovered that HCV was the most prevalent cause of chronic hepatitis, cirrhosis, and liver cancer in the Western world. The discovery of the virus also allowed for a more precise diagnosis and a better understanding of its prevalence.
In addition, individuals who had a clinical response to treatment and did not relapse also became HCV negative and were cured of their chronic viral infection. This was demonstrated by the use of novel direct tests for the presence of HCV. Future advancements in therapy were made possible by blood tests for HCV RNA, which is the genetic material of the virus. These tests showed that a prolonged reduction of HCV RNA—for 12 weeks after treatment was stopped—was a valid indicator of treatment success. A new drug was only approved if it produced a higher SVR rate than peginterferon with ribavirin. SVR achievement became the standard end point for clinical studies of novel medicines.
The effectiveness of HCV therapy depends on the genotypes, or genetic variants, of the virus, which have been discovered through genetic analysis of the disease. For instance, while being the most prevalent genotype globally, genotype 1 was found in clinical trials to be more resistant to interferon-based therapy than other genotypes. One explanation for why some clinical trial participants responded better to peginterferon than others was that various genotypes allowed researchers to more accurately predict and adapt treatments.
The discovery of HCV had the additional benefit of enabling researchers to examine the molecular elements of the virus and identify those that would make good therapeutic targets. These potential targets included the HCV protein NS5A, which appears to play a number of key roles in virus replication, including regulating the cell’s response to interferon. Other potential targets included the HCV enzyme polymerase, which is essential for the replication of the virus’ genetic material.
While attempting to define HCV, researchers were simultaneously making progress in treating it. When three independent teams of researchers, including NIDDK intramural researchers, were able to grow the virus in cells in the lab in 2005, it marked a significant advancement in the field of medication creation. This made it possible to analyze the HCV life cycle and identify crucial viral components. Following the completion of these trials, the fi treatments were created with the express purpose of preventing HCV reproduction by concentrating on certain virus regions.
Interferon and ribavirin are two examples of widely antiviral medications that, despite having some effectiveness, were difficult to tolerate because to their adverse effects. The effects might be more restricted to the cells that were infected with the virus, considerably reducing “friendly fire” harm to other regions of the body, if a medication could be developed to target HCV precisely.
Spotlighting the Hepatitis C Virus
With the 2011 approval of the first protease inhibitors by the U.S. Food and Drug Administration (FDA), the age of direct-acting antivirals (DAAs) that precisely target HCV began. Telaprevir and boceprevir, as well as numerous other comparable medications licensed subsequently, targeted the HCV protease, which is essential for virus replication. Protease inhibitors produced SVR rates of up to 75% when used with peginterferon and ribavirin. However, in addition to the negative effects that peginterferon and ribavirin already had, this triple therapy also had them. However, the success of HCV-specific protease inhibitors demonstrated that the virus had weaknesses that could be attacked by a carefully formulated and effectively delivered medication.
Over the following few years, other brand-new anti-HCV medications were created and evaluated. These new medications included sofosbuvir and dasabuvir, which hindered the HCV polymerase’s activity and prevented the viral replication. The NS5A section of the virus, which produces a structural protein essential for viral replication, was the target of members of a second class of medications, ledipasvir and daclatasvir. Numerous of these medications were initially examined in combination with peginterferon, ribavirin, or a protease inhibitor. SVR rates of at least 80% were the norm for the outcomes.
Hepatitis C Treatment in the Future
Although it may appear that the hepatitis C story is nearing its conclusion given the high success rates of current medications, this is not the case. Hepatitis C would become far less common if there was a vaccine to prevent it, but efforts to create one are currently ongoing and have not yet proven successful. Although there are vaccinations for hepatitis A and B, the hepatitis C virus is more varied than either of these viruses, which coupled with other reasons makes the process of developing a vaccine more challenging. Additionally, the FDA-approved DAA medications are quite expensive yet offer better results than the currently available drugs, which is a big barrier for many people with the disease.
But research has advanced considerably. The history of hepatitis C is unquestionably a drama, from the early research into a puzzling new virus through the detection of the culprit and the relentless work to establish an effective therapy.
When was the cure for hep C discovered?
Since so little was known about the virus before it was discovered to be HCV in 1989, it was simply referred to as non-A, non-B hepatitis. Effective treatments have been created quite quickly after identification. Drugs today have more than a 95% success rate across brief treatment sessions, which is far higher than the first HCV medication ever licensed in 1991, when a patient faced cure rates of only about 6%. As a result, HCV was the viral disease that was discovered and treated the quickest. It continues to be the only persistent viral disease that is entirely curable, enabling millions of individuals to regain their health and lead healthy, active lives.
How did hep C get cured?
Patients with hepatitis C had limited therapeutic options just three years ago. The primary medication used to treat this viral illness was solely injected. Additionally, it had harmful side effects and wasn’t even useful for a large number of individuals. Then, a revolutionary new drug named sofosbuvir entered the market.
The medication, better known as Sovaldi, transformed hepatitis C from a difficult-to-treat condition into one that can be cured in a matter of months. It also had less adverse effects and a considerably better success rate when combined with other medications than any other hepatitis C treatment and worked much more quickly.