Current Treatment and Modern Trends in the Treatment of Hepatitis C - Essay Example

14 November 2007 Hepatitis C: The Virus, Current Treatments and Future Treatment Options Hepatitis C is the inflammation of the liver caused by a hepatotropic virus called Hepatitis C virus (HCV) through blood-borne or percutaneous infection. About 170 million individuals (3 % of the world population) are chronically infected with the HCV and 3 to 4 million individuals are newly infected each year (WHOa 1). HCV is the leading cause of acute and chronic hepatitis, liver cirrhosis, and hepatocellular carcinoma and is also the leading cause of liver transplants in the world (WHO 1). Although there are a few treatment options available currently, they are limited in that they do not provide a cure for the disease. However, several research studies are being conducted to combat the disease. In this review, I have tried to depict the elusive nature of the Hepatitis C virus and provide a comprehensive list of ongoing research that aim to provide improved therapies to individuals suffering from Hepatitis C. Description of the Hepatitis C virus There is a great interest in learning about the structure of HCV, its genetic variants and its reproductive method because scientists are eager to find a good treatment solution to combat this dreaded disease. However, there has been some progress in this area: HCV has been classified as the only member of the genus Hepacivirus in the family Flaviviridae (Moradpour and Blum 519). The virus is approximately 50 nm in diameter and has a 9.6 kb-long, single-stranded, positive sense RNA as its genetic material (WHOb 3). Although the morphological structure of the HCV is still unknown, based on 3-D structures of related viruses, it is hypothesized that the single positive strand of RNA is surrounded by a protective shell of protein called nucleocapsid, which is icosahedral in shape (See figure. 1). This shell is further encased in an icosahedral lipid membrane which contains two envelope glycoproteins 1 and 2 which form heterodimers at the surface of the virion (Penin et al 10). Since the genetic information of the Hepatitis C virus is stored in a single strand of RNA, it gives the virus its dangerous ability to mutate frequently and thereby develop new genetic variations of itself. These mutated versions are mostly different from their predecessors such that the immune system of the host fails to recognize them (The Hepatitis C Virus 1). Therefore, if the immune system begins to succeed against one variation, the mutant strains quickly multiply and become the new, predominant strains. Hence, the development of antibodies against HCV does not produce immunity against the disease like it does with most other viruses. In addition to this complexity, scientists have identified genetic differences between HCV isolates based on which the hepatitis C virus species have been classified into six genotypes (1-6) with several subtypes within each genotype. These viral genetic variants are termed quasispecies (Moradpour et al 232). The prevalence and distribution of the HCV genotypes vary globally. For example, in North America, genotype 1a predominates followed by 1b, 2a, 2b, and 3a. In Europe, genotype 1b is predominant followed by 2a, 2b, 2c, and 3a. Genotypes 4 and 5 are found almost exclusively in Africa (Hepatitis C Virus 2). These genotypes have been found to be clinically important in determining potential response to anti-viral treatment and the required duration of such therapy (Bowden and Berzsenyi 105). For example, Genotypes 1 and 4 are less responsive to interferon-based treatment than genotypes 2, 3, 5 and 6, although the reason for this is unknown. Again, the duration of standard interferon-based therapy for genotypes 1 and 4 is 48 weeks, whereas treatment for genotypes 2 and 3 is completed in 24 weeks. The reproductive method of the Hepatitis C virus has also been found to give the virus an added advantage. The single stranded viral RNA can co-opt with the ribosomes of the host liver cell and trigger the production of materials necessary for viral reproduction. Since Hepatitis C stores its information in a “sense” strand of RNA, the viral RNA can be read directly by the host liver cell’s ribosomes, thereby functioning like the normal mRNA of the cell (Life cycle of Hepatitis C 1). Once an adequate level of RNA transcriptase is produced, the viral RNA creates an “antisense” version (the paired opposite) of itself as a template for the creation of new viral RNA. This process helps to make hundreds or thousands of copies of viral RNA for the new viruses (See figure 2). Since Hepatitis C requires only a small amount of RNA to encode its core information, it has a lot of room for genetic variation within the non-essential portions of its RNA. This gives it fewer common characteristics that can be readily identified by the immune system - or, for that matter, exploited by scientists working to create a treatment. It is this ability of the virus to mutate and multiply quickly that helps it to evade most treatment options. Consequences of Hepatitis C infection A crucial aspect of Hepatitis C infection is the fact that most individuals infected with the HCV are asymptomatic and unaware that they are infected. About 70% to 80% of infected individuals do not have jaundice, which is a widely recognized symptom of hepatitis (Dougherty & Dreher 2). In some cases, the consequences of chronic liver disease from hepatitis C do not become apparent until 10 to 20 years after infection. Therefore, diagnosis of hepatitis C is often made after elevated liver enzymes are discovered during a routine examination or diagnostic workup for an unrelated condition. The aminotransferases, aspartate aminotransferase (AST, SGOT [serum glutamic oxaloacetic transaminase]), and alanine aminotransferase (ALT, SGPT [serum glutamic pyruvic transaminase]), are intracellular proteins released into the bloodstream from injured liver cells. The normal range of these enzymes is presented in Table 1. Elevation of these enzymes is often the first abnormality detected in patients with the disorder (Dougherty & Dreher 2). The next step toward a definitive diagnosis of hepatitis C involves testing for the presence of antibodies to HCV antigens (anti-HCV) and a liver biopsy. Table 1: Normal Values for Liver Enzymes Enzyme Normal Values SGOT 8-20 u/l SGPT 10-32 u/l (Men) 9-24 u/l (Women) Of the individuals who are exposed to the Hepatitis C virus, only about 20% develop symptoms which include jaundice (yellowing of the skin and whites of the eyes), fatigue, dark-colored urine, stomach pain, loss of appetite and nausea. Once infected, individuals with acute HCV infection have been found to exhibit one of the following three patterns of viremia (Shoukry et al 401): 1. Nearly 15% of the people infected with acute HCV, show a precipitous drop in viral load just after peak. This results in successful control of the infection. 2. A staggering 85 % of individuals infected with HCV become chronically infected (lifelong infection). Some of them show a temporary drop in viral load after peak followed by rebound in viremia 3. The remaining individuals exhibit no drop in the viral load in their plasma. Individuals infected with HCV not only acquire varying rates of chronic infection, but they also have a greater propensity for progression to cirrhosis, hepatocellular carcinoma, and death. Of people with chronic HCV infection, 30% develop chronic liver disease. 1-5% of these individuals die from liver cancer or cirrhosis (Moradpour et al 232). However, not all patients diagnosed with chronic hepatitis C are good candidates for treatment with the current available drugs. Outline the limitations of current treatment options The current treatment options for individuals diagnosed with chronic hepatitis include interferon monotherapy and combination therapy with pegylated alpha-interferon and ribavirin (a nucleoside analog). The mechanism of these drugs is poorly understood, but they have been implicated in viral protein synthesis suppression and degradation of plus strand RNA (Guo et al 80). The combination therapy has been found to be only 50% effective for genotype 1 and 80% effective for genotypes 2 and 3 (Guo et al 80; CDC). Again, there are substantial limitations to the current treatment options: Individuals undergoing treatment for Hepatitis C exhibit significant side effects which include flu-like syndrome, characterized by fever, tiredness, body aches, and malaise, which usually resolves with continued treatment. Other side effects include thrombocyopenia and leukopenia. This can be especially frightening in patients co-infected with HIV, because the disease itself causes thrombocytopenia (Dougherty & Dreher 5). Patients who do not respond to interferon monotherapy are put on a combination therapy with ribavirin. The primary side effect of this treatment is hemolysis which can result in a significant drop in hemoglobin. A far less common but life-threatening side effect of interferon is depression with suicidal ideation. Therefore, nearly 20% of individuals tend to discontinue therapy due to these side effects (Hepatitis C 1). The current research studies testing the various treatment options for Hepatitis C have focused primarily on specific population groups and/or have used small sample sizes due to which the results cannot be generalized. Populations like the African Americans and at-risk individuals who are incarcerated/ homeless have not been studied thus far. Again, co morbidity with substance abuse or psychiatric illnesses or those with advanced disease or HIV co-infection have also not been studied (Everson 2). Ongoing efforts to provide improved therapies There have been wide strides made in the area of exploring for new treatment options to fight against Hepatitis C. Some of the more promising classes of HCV treatments which are currently in development are discussed below: 1. BILN 2061, a serine protease inhibitor discovered by Boehringer Ingelheim has shown potent activity against HCV replicons in tissue culture and is currently under clinical investigation for the treatment of HCV infection. This novel drug structurally mimics the HCV peptide and competes with it to bind with the protease, thereby inactivating it (Lamarre et al 186). In a two day trial, BILN 2061 was found to work more rapidly and cause significant viral decline compared to its interferon counterpart. 2. Transforming Growth Factor-β (TGF-β), a naturally occurring cytokine induced by the HCV core protein has been found to be correlated with decreased viral load. However, TGF-β has also been found to cause increased development of fibrosis and cirrhosis. Therefore, therapy with this drug may not be possible for those with advanced liver disease (Murata et al 407). 3. Cyclosporin, a widely used immunosuppressant has been found to curb HCV replication via a mechanism that involves more than simply suppressing the immune system. Although its mechanism against HCV replication is unknown, cyclosporine has been known to inhibit stimulation of genes essential for T cell activation by binding to cyclophilins and blocking calcineurin. In combination with interferon, it produces a synergistic effect against HCV replication in vitro. (Nakagawa et al 42). 4. Non-nucleoside inhibitors (NNIs) have been found to target and bind directly to the RNA dependent RNA polymerase and demonstrate allosteric inhibition of the HCV RNA polymerase. The HCV NNIs have been found to be structurally distinct and have distinct binding sites which could allow for more effective combination therapy and combat cross-resistance (Sarisky 14). 5. Although arsenic can be toxic, it inhibits HCV replication at concentrations that are low enough to demonstrate no cellular toxicity (Hwang et al 2876). The U.S. Food and Drug Administration approved arsenic trioxide for use in the treatment of acute promyelocytic leukemia. In combination with interferon, it produces a synergistic effect against HCV replication in vitro. 6. Three drugs, designed specifically to inhibit functions of the hepatitis C virus, are currently being tested (Worman 2). The first drug is a ribozyme (Hepatazyme, Ribozyme Pharmaceuticals) which has been designed to cleave the hepatitis C virus RNA genome in a region that the virus needs to survive. The efficacy of this drug has already been established in the test tube and the drug is now in early clinical trials. The second drug, ISIS-14803 (Isis Pharmaceuticals) is an antisense inhibitor complementary to a conserved sequence of the hepatitis C virus RNA. This molecule binds to the viral RNA and inhibits the expression of proteins required for replication. This drug is also currently in early stage clinical trials. The third drug VP-50406 (ViroPharma) has also been demonstrated to inhibit hepatitis C virus RNA in the laboratory and is in early stage clinical development. Conclusion Owing to its contagious nature and genetic variations of the HCV caused by frequent mutations, Hepatitis C has become a major health concern globally. Although our knowledge about Hepatitis C and the HCV has continued to grow in the last decade, the current drug therapy is definitely inadequate and insufficient. However, the ongoing efforts towards novel therapies do offer interferon -resistant individuals and those with serious side effects a hope of eliminating the Hepatitis C infection. Works Cited Bowden, D.S., Berzsenyi, D.M. Chronic hepatitis C virus infection: genotyping and its clinical role. Future Microbiology 1.1 (2006): 103-112. CDC. 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Non-nucleoside inhibitors of the HCV polymerase. Journal of Antimicrobial Chemotherapy 54 (2004): 14-16. Shoukry, N.H., Cawthon, A.G. and Walker, C.M. Cell-mediated immunity and the outcome of hepatitis C virus infection. Annual Reviews in Microbiology. 58 (2004): 391-424. The Hepatitis C Virus. The C Everett Koop Institute: Dartmouth Medical School, 2007. The Life Cycle of Hepatitis C. The C Everett Koop Institute: Dartmouth Medical School, 2007. World Health Organization a. October 2000. Hepatitis C. 10 November 2007 < http://www.who.int/mediacentre/factsheets/fs164/en/>. World Health Organization b. October 2000. Viral Cancers. 10 November 2007 < http://www.who.int/vaccine_research/diseases/viral_cancers/en/index.html>. Worman, H.J. New and Future Treatments for Chronic Hepatitis C. American Liver Foundation: View Points newsletter, Spring/Summer 2001. Read More