BEIJING, Oct. 5 (Xinhua) — The 2020 Nobel Prize in Physiology or Medicine has been announced: American scientist Harvey J. Alter, British scientist Michael Houghton and American scientist Charles M. Rice three people won the award, the reason for the award: the discovery of hepatitis C virus. The story from the discovery of the hepatitis C virus to the cure of hepatitis C is very much like the plot of a classic suspense novel.
First the inexplicable crime, then the long pursuit of the suspect, and finally the severe attack on the guilty. Although the story is not yet complete, the battle against hepatitis C has evolved into one of the greatest success stories in modern scientific research.
Hepatitis, the inflammation of the liver, has long been associated with human history. Unfortunately, the symptoms of hepatitis are familiar to many people, including abdominal pain, fatigue, jaundice (yellowing of the skin and eyes) and, in many serious cases, liver failure and death. It wasn’t until the 20th century that scientists discovered that most cases of hepatitis were caused by viruses that infected liver cells. Later, the researchers divided them into two different diseases based on the characteristics of viral hepatitis cases; Hepatitis A is transmitted through human contact or through contaminated food or water, with a short incubation period that can lead to acute diseases. Hepatitis B is transmitted through blood and other body fluids and has a long incubation period, which can lead to chronic (long-term) infection. Since many cases of hepatitis appear to be caused by blood transfusions, the identification of the virus, especially the blood-induced pathogens that cause hepatitis B, becomes critical. If a virus is known to exist, blood supplies can be screened to prevent the spread of the disease.
In 1963, scientists at the National Institutes of Health’s Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), then known as the National Institute of Arthritis and Metabolic Diseases, discovered a major protein in the hepatitis B virus that eventually allowed blood supplies to be tested. However, screening and excluding infectious blood donors only reduced hepatitis cases after blood transfusions by 25 to 50 per cent. It is speculated that the remaining cases are either caused by the hepatitis A virus or by the hepatitis B virus, which may have been missed during the screening process. By the mid-1970s, however, the Harvey James Alter team at the National Institutes of Health’s Institute of Allergy and Infectious Diseases (NIAID) Infectious Diseases Laboratory identified the hepatitis A virus and, in collaboration with the NIH Clinical Blood Transfusion Medical Center, found that other cases of hepatitis were neither hepatitis A nor hepatitis B. Inside the liver, there are other viruses that are destroying, and all the signs point to a third virus. Like hepatitis B, this newly discovered disease can be transmitted through infected blood and can lead to chronic infections and cirrhosis (scarring). However, the risk of developing the chronic disease in adults is much higher than in adults, and acute symptoms are rare in patients, which may mean that the disease may fall into a chronic state before there are clear signs of infection. For the next 15 years, the culprits behind the disease remained unknown, so the disease was simply referred to as non-A-non-hepatitis B.
Prevent non-A and non-hepatitis B.
Scientists are looking for the mysterious factors behind non-A-non-B hepatitis, while also focusing on treatment. As the virus is still unknown, the first trials were of drugs that had been shown to be effective against the vast majority of the virus. Patients with hepatitis B react to a chemical called alpha interferon. Alpha interferon is a naturally occurring substance that immune cells respond to viral infections or other environmental pressures. Interferons are usually injected into the lesions, allowing cells to enter an antiviral state, known as “disturbing” virus replication, thus protecting cells from infection. Since interferon is a general defense against multiple viruses, it is logical to try to use it against unrecognized viruses that cause non-A-non-hepatitis B.
In 1984, scientists from the NIDDK in-house research project conducted a preliminary study of interferon in 10 patients at the NIH Clinical Center in Bethesda, Maryland. For 16 weeks, these patients took medication every day and monitored their liver health by detecting signs of liver damage in their blood. The researchers quickly came up with the results, and dramatically, that most patients’ livers looked healthier after a month of treatment. After 4 months, interferon therapy is stopped and the patient relapses; however, once the treatment is resumed, their liver health improves again, even after the dose is gradually reduced and the treatment is discontinued after one year. Some patients had minimal responses to interferon therapy, while others responded but then relapsed; They were the first to cure the disease, eventually known as hepatitis C.
Despite these preliminary results, larger clinical trials have lowered expectations for interferon. The results of these studies vary from patient to patient, but the success rate of interferon therapy alone , measured in terms of continuous virological response rate (SVR), is low. Patients who achieve SVR do not detect the virus for at least 24 weeks after stopping treatment, meaning that treatment is successful and patients are highly likely not to relapse. SVR treated with interferon alone is usually less than 20%. However, the combination of interferons with other antiviral drugs gives researchers hope. One of these drugs, ribavirin, has been first trialed by NIDDK researchers as an independent therapy, but it has had only a low and temporary effect on viral levels. Subsequent studies have shown that the combined use of interferon and libavelin is better than the use of interferon alone, showing that SVR is 30 to 40 percent. Another development is that scientists chemically modify interferons to keep them in the body longer. This “peginterferon” approach, combined with libavelin, has reached a 55% SVR rate and has become the standard treatment for hepatitis C patients.
The results of these studies suggest that scientists have much more to do. Although interferon-based treatment is often successful in more than half of patients, it is often accompanied by side effects such as fever, fatigue, muscle pain, and depression, which often limit the dose and duration of treatment. Nevertheless, these preliminary trials provide important information on how viruses respond (or resist) to treatment, as well as important clues about the biological characteristics and resilience of viruses. These will be useful when designing treatments based on more effective means, and significant advances to come will make them at your reach.
The discovery of the hepatitis C virus.
In 1989, Michael Houghton, a biochemist at Chiron, a California-based biotech company, teamed up with researchers at the U.S. Centers for Disease Control and Prevention (CDC) to discover the non-hepatitis A virus. The study confirmed that this is a new virus, now officially known as hepatitis C virus (HCV). This is a landmark medical advance that allows scientists to develop detection methods for hepatitis C virus and rapidly apply it to blood donation screening. Over the next few years, as testing techniques improved, HCV was effectively eliminated from the blood transfusion supply. The identification of HCV has also led to a series of follow-up studies to determine the molecular structure of the virus. This is essential for the design of drugs that specifically interact with viral components and inhibit their replication. The identification of the virus also allows researchers to diagnose hepatitis C more accurately and understand its prevalence; in fact, the final results show that hepatitis C is the most common cause of chronic hepatitis, cirrhosis and liver cancer in the Western world.
The discovery of the hepatitis C virus is decisive, but another key part of the puzzle remains unanswered: Can the virus alone cause hepatitis? To answer this question, scientists must study whether cloned viruses can replicate and cause disease. Charles E. Smith, a researcher at the University of Washington in St. Louis, said that the university’s M. Rice (Charles M. Rice) and other teams studying RNA viruses have noted that there is a previously unrecognized region at the end of the hepatitis C virus genome, which they suspect may be important for virus replication. Rice also observed genetic variations in isolated virus samples, and speculated that some of them might hinder virus replication. Through genetic engineering, Rice obtained RNA variants of the hepatitis C virus, including a newly defined viral genomic region, without inflamed gene variants. When the RNA was injected into chimpanzees’ livers, the virus was detected in their blood and pathological changes similar to those observed in humans with the chronic disease. This is the final evidence that the hepatitis C virus alone can lead to unexplained cases of blood transfusion-mediated hepatitis.
The detection of HCV using new direct detection techniques showed that interferon therapy reduced the level of the virus in the blood; Detection of HCV RNA (the genetic material of the virus) in the blood is key to future treatment. Studies have shown that no HCV RNA can be found as a reliable treatment endpoint for 12 weeks after discontinuation of treatment. The SVR value became the benchmark for clinical trials of new therapies, and the standard for approving a new treatment was that it produced a higher SVR than the libavelin combination polyglycol interferon therapy.
Studies of the genetic composition of the HCV virus have shown that the virus has several genotypes (or variants) that determine the effectiveness of the virus’s response to treatment. Genotype 1, for example, is the most common genotype worldwide, but clinical trials have found that it is more resistant to interferon therapy than other genotypes. Identification of different genotypes allows researchers to better predict and customize treatments, which explains why some clinical trial participants have better results using polyethyl glycol interferon than others. Another important result of the identification of the hepatitis C virus is that researchers are now able to analyze the molecular composition of the virus and determine which ones can be the ideal drug target. These potential targets include a polymerase that is essential for the replication of viral genetic material; a protease that the virus uses to process its components before assembly; and a protein called NS5A, which plays a variety of important roles in viral replication, including regulating cell responses to interferons.
As scientists try to study the characteristics of the HCV virus, they have also made progress in treating HCV. In 2005, three groups of researchers each developed the virus in cells in the lab, a huge step forward in drug design. This makes it possible to study the life cycle of HCV and identify key viral components. These studies promote the development of treatments that specifically block HCV replication, directly targeting viral targets. Although a wide range of antiviral therapies, such as interferon and libavirin, have some effect, the side effects are unbearable. If a drug specifically designed specifically for HCV can be designed, the effect may be more limited to infected cells, thereby greatly limiting the damage to other parts of the body caused by “friendly fire”.
Focus on the hepatitis C virus.
The era of direct antiviral drugs (DAAs) specifically for HCV began in 2011 when the U.S. Food and Drug Administration (FDA) approved the first protease inhibitors. These drugs, including telaprevir and boceprevir, as well as several similar drugs that were later approved, target HCV proteases, which are key to viral replication. When protease inhibitors are used in the same time as polyglycol interferon and libavirin, SVR is up to 75%. However, this triple therapy has additional side effects compared to patients who have already used polyglycol interferon and libavirin. Nevertheless, the success of hepatitis C virus-specific protease inhibitors has shown that the virus has weaknesses that can be exploited through well-designed and appropriately used drugs.
Over the next few years, researchers developed and tested more new anti-HCV drugs. These new drugs include sofosbuvir and dasabuvir, both of which interfere with the activity of HCV polymerases. Members of the second class of drugs, Ledipasvir and daclatasvir, target the NS5A region of the virus, a structural protein critical to virus replication. Many of these drugs were first tested in a joint trial with polyglycol interferon and libavirin, or with protease inhibitors. In general, the SVR is at least 80%.
With the success of direct antiviral therapies, it became clearer that interferon was no longer necessary when several of these therapies were used in combination. This is a crucial step in the progress of hepatitis C treatment, as reliance on polyethyl glycol interferon is eliminated, avoiding many painful side effects associated with interferon therapy. These full oral solutions also offer the possibility of treatment for patients who are unable to use polyethyl glycol interferon safely. Perhaps the most successful DAA combinations are Sofabwe and Redipawe, both of which have soared to 99 to 100 percent. In addition, the combination was successful with only 8 to 12 weeks of treatment. After years of painstaking research, there is finally a real cure for hepatitis C, and it works for almost everyone.
The future of hepatitis C treatment.
The current treatment has such a high success rate that it seems that the story of hepatitis C has reached its final chapter, but it is not over yet. A vaccine against hepatitis C would dramatically reduce the prevalence of the disease, but efforts to develop the vaccine are ongoing and have not yet been successful. Although both hepatitis A and B have vaccines, the hepatitis C virus is more mutated than the two viruses, and other factors make vaccine development more complex. In addition, while current drugs are showing good results, the high cost of FDA-approved, more successful direct antiviral therapies poses a major obstacle for many patients.
In any case, hepatitis C research has come a long way. From an early search for a mysterious new virus, to the identification of the culprits, to the development of effective treatments, the story of humanity’s victory over hepatitis C is a classic suspense film.