a study of hepatitis C

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Introduction

History of HCV

It is impossible to know the origin of Hepatitis C since there are no blood samples available that are over 50 years old. However, taking into consideration the evolution of all the viruses, it has probably existed for hundreds of thousands of years before evolving into its current strain. Experts speculate that the beginning of HCV may be traced back to 35 million years ago. On firmer grounds stands the speculation that different subtypes of HCV originated about 200 years ago and that the six main genotypes of HCV had a common ancestor. Despite these claims, one may argue that it is difficult to limit the origin of HCV to such a short period in human history because the virus is found all over the world. Another aspect that supports the argument is the main transmission route of the virus - blood. Therefore it is difficult for the virus to spread and evolve rapidly around the world since the practice of blood transfusion and the use of needles has been in existence for a short period of time.

During and after World War II, post-transfusion hepatitis (PTH) was appreciated as a result of increasing number of hepatitis cases in the US. In the 1940's research groups in the United Kingdom and the US identified two immunologically distinct types of Hepatitis - type A (infectious) and type B (Serum). Scientists developed tests to identify Hepatitis B (1963) and Hepatitis A (1973) but were faced with another challenge. Many of the blood samples taken for post-transfusion illness tested negative for both Hepatitis A and B. Keeping into consideration the mode of transmission - blood - scientists classified these cases as non-A, non-B hepatitis. It is now believed that approximately 90-95% of these non-A, non-B hepatitis cases were actually Hepatitis C.

Summary of main viral hepatitis characteristics

Hepatitis

Genome

Transmission

Chronic hepatitis

Fulminant hepatitis

Treatment

Vaccine

A

RNA

Oral

No

Yes

No

Yes

B

DNA

Mother to infant, blood, sexual

10%

Yes

Interferon, lamivudine, adefovir

Yes

C

RNA

Blood, rarely mother to infant/sexual

70%

Very rare

Interferon, ribavirin

No

D

DNA

Blood, sexual

50%

Yes

Interferon

Yes

E

RNA

Oral

No

Yes

No

No

G

RNA

Blood

No

No

No

No

Hepatitis C was identified in the 1980's investigators from the Centers for Disease Control and Chiron. In the 1990's blood banks began screening donors for HCV. But it was only in 1992 that a blood test for HCV was perfected and this lead to the elimination of HCV from the blood transfusion supply. Today, the risk of contracting HCV through blood transfusion is about 0.01%. Despite these developments, according to the World Health Organization, up to 4 million people are newly infected each year around the world.

What is Hepatitis C?

Hepatitis C is an infectious disease infecting the liver caused by hepatitis C virus (HCV). The hepatitis C virus is the only known member of the hepacivirus genus in the Flaviviridae family. HCV is an enveloped, single-stranded RNA virus of positive polarity, about 50nm in size. HCV replicates in the cytoplasm of hepatocytes and persistent infection depends upon rapid production and spreading of the virus from cell-to-cell. Replication of HCV in the infected host is thought to occur primarily in hepatocytes.

The replication of HCV is very rapid and the RNA polymerase lacks error proofreading. Therefore, the viral DNA mutates frequently, thus adding to the challenge for the search of an effective vaccine. HCV has eleven known genotypes (1-11), many subtypes, and over 100 different strains.

Chronic hepatitis C is the most common cause of cirrhosis which in turn often leads to death. Chronic hepatitis C is also the most common indication of liver transplant in developed countries like the United Kingdom and the US. Once a person gets infected by HCV, the virus leads to inflammation followed by liver fibrosis (scarring of liver tissue). People infected with HIV or alcohol consumers show a faster development of liver damage. In some people this damage progresses to liver cirrhosis (severe scarring of the liver) over a period of 20-30 years. With the onset of liver cirrhosis comes the increased risk of liver cancer or liver failure. Although treatment with interferon and ribavirin clears the infection in about 50% of the people infected, there is no full-proof method that can guarantee the elimination of the virus.

Epidemiology of HCV

The incidence of HCV on a global scale is not well known since acute infection in most cases has been found to be asymptomatic. The World Health Organization estimates about 200 million people that make up about 3% of the world's population are affected with the disease. The prevalence of HCV varies around different regions of the world (Figure 1).

Figure . Worldwide prevalence of Hepatitis C

(WHO Weekly Epidemiol Record 2000)

As many as 2 to 4 million people may be chronically infected in the US, 5 to 10 million in Europe, and about 12 million in India. Estimates suggest that over 250,000 people in the United Kingdom are affected by the disease. About 150,000 new cases occur annually in the US and Western Europe and about 350,000 in Japan. Of these about 25% patients are symptomatic, but 60 to 80% progress to chronic hepatitis C, and about 20 to 30% of these develop cirrhosis. About 5 to 7% of the patients ultimately die as a consequence of the infection. Worryingly, 8 out of every 10 affected people do not know they are infected and about 75% of them go on to develop chronic hepatitis.

The six major HCV genotypes (1 to 6) show about 30% divergence. Despite the common basic virology, the genotypes differ in their geographical distribution and prevalence. Genotypes 1, 2 and 3 although distributed worldwide, are prevalent in Western Europe, US and Canada, while genotypes 4, 5 and 6 are found in more distinct geographical areas (Figure 2).

Figure 2. Distribution of Hepatitis C Genotypes

(Fang et al. Clin Liver Dis. 1997)

Although the outcome of HCV is generally determined within six months of infection with the virus, it seems to be partly associated with the genotype of the virus. Individuals that are affected with HCV genotype 1 are more susceptible to developing chronic hepatitis C and hepatocellular carcinoma. Steatosis (an abnormal accumulation of lipids) is more frequently observed in the case a genotype 3 infection and is possibly associated with fibrosis. Also, HCV genotype 1 is known to show greater treatment resistance than genotypes 2 and 3, with only 40-50% of individuals infected by genotype 1 responding to combination therapy as compared to 70-80% of those infected by genotype 2 and 3.

The Disease

Mechanism of HCV entry into the host cell

Infection of the host cell is initiated when the virion binds to the cell surface receptors and undergoes endocytosis. Fusion of viral and cellular membrane, which is induced by low pH, brings the nucleocapsid in contact with the cytosol (Figure 3). HCV entry into the host takes place as follows:

Virion interacts with the host lipoproteins in the plasma

Entry into the host cell is initiated through interactions with receptors and co-receptors on the cell surface

Clathrin-mediated endocytosis takes place

Rab5-dependent transport to endosome where acidification occurs

This acidification triggers the fusion between endosomal membrane and viral envelope and the viral RNA genome is released into the cytosol

Once the viral genome has established itself inside the host cell, it follows its normal lifecycle where translation, replication, assembly of virion progeny, and their release in and around surrounding cells takes place. Thus, the infection establishes itself inside the host.

Figure 3. HCV entry into the Host cell

(Hahn, Thomas von and Rice, Charles M. 2007)

Acute Hepatitis C

Acute hepatitis C can be referred to as the first 6 months after infection with HCV. Diagnosis of acute hepatitis C infection is infrequent since majority of the infected people (~80%) are asymptomatic. About 20-30% of the individuals with acute HCV infection develop clinical symptoms such as illness, fatigue, flu-like-symptoms, anorexia, vague abdominal discomfort and jaundice. Hepatocyte necrosis begins to increase 2-8 weeks after exposure, leading to an increase in serum alanine aminotransferase (ALT) levels of over 10 times the upper limit that is considered normal. HCV RNA levels shoe a rapid increase during the first few weeks of infection and peak between 105-107 IU, shortly before the onset of symptoms. It is possible to detect the HCV RNA in the serum within 1-2 weeks of infection. In the case of self-limited acute hepatitis C, symptoms may last up to several weeks and decline with declining levels of HCV RNA and ALT.

Enzyme immunoassay has detected that the antibody to HCV becomes positive approximately 1-3 months after exposure, very near to the onset of symptoms. However, about 30% of the patients test negative for anti-HCV testing at the onset of symptoms, testing positive only after another 2-8 weeks. This makes anti-HCV testing unreliable for the diagnosis of anti-HCV. Although most patients develop the antibody to HCV, those that are immunodeficient may have undetectable levels. Therefore the best current approach is to repeat anti-HCV testing a month after the onset of symptoms.

Chronic Hepatitis C

Chronic hepatitis C is diagnosed as a result of persistent HCV RNA in the blood for over 6 months after the onset of acute hepatitis C. Chronic hepatitis is not a single disease, but a complex clinic-pathological syndrome with multiple causes, varying stages of necro-inflammatory and sclerosing liver damage, different prognoses and responses to treatment (WHO, 2002). HCV has been found to be self-limiting in only 15-25% of patients where ALT levels return to normal and HCV RNA in the serum becomes undetectable. However, 75-85% of the infected individuals fail to clear the virus which develops into chronic hepatitis C. The natural course of chronic hepatitis C varies considerably from person to person depending on factors such as age, time of infection, ethnicity, and development of jaundice during acute infection (Table 1).

Table 1. Risk factors involved with development of Chronic HCV infection

(Chen, Stephen L. and Morgan, Timothy R. 2006)

Although nearly all patients infected with HCV show liver inflammation on conducting liver biopsy, the rate of progression of liver fibrosis is significantly variable from person to person thereby making it is difficult to get an accurate estimate of the risk over time for individuals. Chronic HCV infection has been found to be associated with hepatocellular carcinoma (HCC) in 1-5% of individuals suffering from chronic hepatitis but is rare in individuals with chronic hepatitis who do not have cirrhosis.

Chronic infection is often asymptomatic until there is clinical evidence of liver failure. However, the rate of progression of infection by HCV to cirrhosis of the liver is slow and generally takes about 20 or more years for development of serious complications. Individuals with chronic hepatitis C are at a greater risk from fulminant hepatitis A. Most of the serious liver disease that is associated with HCV is mainly due to the chronic, persistent nature of the disease. An overall decrease in the quality of life and general wellbeing has been reported even in the case of asymptomatic carriers.

Progression of liver fibrosis in chronic hepatitis C patients

It is estimated that anywhere between 10-25% patients suffering from chronic hepatitis C develop cirrhosis, a process that takes 20-30 years. Liver fibrosis is the accumulation of tough, fibrous scar tissue in the liver. Although formation of scar tissue is a normal body response to injury, it goes wrong in the case of fibrosis. When hepatocytes are damaged due to a virus, heavy alcohol consumption, or other factors, the immune system kicks in to control the damage. Damage or necrosis of hepatocytes stimulates inflammatory immune cells to secrete cytokines and other chemicals. These chemicals activate hepatic stellate cells which in turn produce collagen, proteoglycans, glycoproteins, and other substances that are deposited in the liver resulting in the build-up of extracellular matrix. At the same time, the degradation of collagen is impaired. Thus, there is no balance between fibrogenesis and fibrolysis which leads to excessive scar tissue formation.

The rate of progression of liver fibrosis in patients with persistent HCV varies widely. Extensive studies have been carried out that focus on the course of progression from chronic hepatitis C to cirrhosis, hepatocellular carcinoma (HCC), and death. Liver biopsy has been determined as the best method for determining the damage that has been caused by chronic hepatitis C. The extent of fibrosis is estimated by determining the number of mononuclear inflammatory cells present in and around portal areas along with the number of dead and dying hepatocytes.

Several external and host factors may play a role in the progression of fibrosis (Table 2). Several studies have indicated alcohol consumption in chronic patients is a major risk factor that often leads to the advancement of chronic hepatitis C to cirrhosis, HCC, and eventually death. Host risk factors include degree of inflammation and fibrosis indicated in the biopsy, old age, co-infection with HIV, and male gender.

Table 2. Risk factors for progression of Liver Fibrosis

(Chen, Stephen L. and Morgan, Timothy R. 2006)

The possibility of developing HCC has been found to be 17-fold higher in HCV infected persons as compared to HCV-negative persons. The results of several trials have shown a moderate decrease in risk of developing HCC among HCV infected patients that have been treated with interferon. This benefit appears to be higher in patients that have shown a sustained viral response as compared to those who did not respond to interferon treatment. It is very important to know the stage of fibrosis and the condition of the liver in order to make appropriate decisions to manage hepatitis C. It was once thought that fibrosis was irreversible but research has proven that treatment can not only slow down the progression of the disease but can also reverse liver fibrosis. There are several steps that can slow down the progression of hepatitis C:

Undergo medical treatment that slows down disease progression and can possibly reverse fibrosis

Exercise regularly and get good rest

Consume a well-balanced and healthy diet that is low in fat and salt content, high in protein and complex carbohydrates

Strictly avoid consumption of alcohol

Abstain from the use of any sort of recreational drug

Learn as much as possible about hepatitis C

Transmission, Diagnosis and Prevention of Hepatitis C

Transmission

Transmission of hepatitis C occurs primarily due to exposure to blood despite the fact that HCV RNA has been found in several body fluids and tissues such as tears, saliva, and breast-milk (Figure 4). There is no specific threshold of viral load that can determine chances of transmission of HCV from the blood of an infected person to a HCV-negative person. Approximately 85% of the transmission occurs through chronically infected HCV patients. The risk of transmission of HCV as a result of a single percutaneous exposure to the virus is about 2.7-6%.

(www.epidemic.org 2010)

Transmission through unsafe injections in developing countries

Millions of injections are administered to patients each year in various developing countries. However, many of these injections are unsafe and pose a major problem to public health as they result in several blood-related, deadly diseases such as HIV and Hepatitis C. According to The World Health Organisation, a safe injection is one that does not harm the recipient, the health care worker or the community. It is caused due to the reuse of syringes, and needles in some cases, without proper sterilization. According to estimates, about 8-12 billion injections are administered each year around the world. That roughly comes up to 1.5-2 injections per person every year. WHO estimates that the lowest levels of safety were observed in sub-Saharan Africa and Asia where at least 50% of the injections were considered unsafe. It also estimates that over 80% of the injections administered in Pakistan are unsafe due to the poor health services. Studies have estimated that 2.3-4.7 million HCV infections occur annually due to unsafe injections.

Transmission amongst injection drug users

There is high prevalence of transmission of HCV amongst injecting drug user (IDU) populations. One of the countries that is most affected by this mode of transmission is Canada. In Vancouver and Montreal, the prevalence of HCV amongst IDU groups is estimated to be 87% and 70% respectively, and the annual incidence is estimated to be 26% and 27% respectively (Patrick, David M. Jane, Buxton A. Bigham, Mark Mathias, Richard G. 2000). A study conducted in the US by ALIVE indicated that there was a dramatic increase in the incidence of HCV within the first two years of drug use. With an alarming increase in the number of HCV cases amongst IDU's, it is important that prevention measures targeting new IDU's should be implemented globally.

Transmission through blood transfusion

The possibility of transmission of HCV as a result of blood transfusion is about 0.01% due to various third-generation testing and screening procedures that blood from a donor is subjected to. However, this mode of transmission was a major cause of concern about 20 years ago when HCV had not been identified and therefore there existed no tests for screening of the disease. As of today, almost all corners of the world use some sort of testing procedures to check for the presence of HCV in blood that is used for transfusion.

Tattoo and piercing

The dyes, ink pots, needles and other instruments used for tattooing and piercing can transmit HCV if proper sterilization procedures are not followed. Such cases have decreased with the passage of time since it is common now-a-days for tattoo and piercing enthusiasts to use the services of reputed professionals that follow proper sterilization procedures.

Transmission of HCV in healthcare settings

Transmission of HCV from patients to healthcare professionals is mainly caused by percutaneous exposure which is generally due to unintentional injury with needles. Although the prevalence of HCV amongst healthcare workers is almost the same as the public in general (2-3%), cases of transmission of HCV from patients is relatively low amongst these individuals. The only way to prevent this is by practising universal methods and avoiding contact with the patient's body fluids.

3.1.6 Sexual Transmission

The risk of transmission of HCV as a result of sexual contact is relatively low, unless there are other complicating factors associated with intercourse such as presence of blood from menstruation or anal sex, the presence of sores or ulcers on the genitalia, or co-infection with HIV. Studies performed on a group of heterosexual monogamous couples indicated that sexual transmission of HCV is relatively low or even null (Carmen Vandelli, 2004).

Vertical Transmission (Mother-to-child)

The risk of vertical transmission of HCV is estimated at ~5% in HCV-infected, HIV-negative mothers. However, in the case of co-infection, the risk of transmission increases three-fold. Although there is some evidence suggesting that mothers with low viral loads of below 105-106 copies of HCV RNA/ml are at a very low rate of transmitting. There is no significance evidence of transmission as a result of breastfeeding, but there is risk involved in breastfeeding when nipples are bleeding.

Diagnosis

Diagnosis of hepatitis C is seldom made during the acute phase of the disease since most individuals remain asymptomatic. However, there are certain diagnostic tests available for detection of the virus. Serological assays for the detection of antibodies and molecular tests to identify viral particles are effective testing methods. Large scale screening to detect serum anti-HCV antibodies is effective and has led to a significant reduction in transmission of HCV through blood transfusion. Detection of anti-HCV is carried out using highly sensitive and specific third-generation enzymes which can detect their presence within 4-10 weeks of exposure.

Molecular detection of HCV RNA is also an effective method and is based on the PCR technique. This is the most specific test for detection since the test has a lower limit of detection of about 50IU/ml. This technique is very useful in immunosuppressed patients and also during acute hepatitis C where anti-HCV antibodies have not yet developed. A less expensive method based on ELISA has also been developed which is based on measuring the quantity of HCV core antigen.

An undetectable infection with HCV has been suspected in several patients that have shown abnormal levels of transaminases along with negative PCR HCV in serum. Along with these results, these patients have also tested positive for HCV PCR in the liver. These findings have put researchers in a dilemma because this may extend the risk and prevalence of HCV.

3.2.1 HCV antibody Tests

Post-infection, the immune system kicks into activity and antibodies against the virus are produced. Within a few weeks there are generally enough antibodies that can be detected using antibody tests. Performing an antibody test requires the blood sample of the patient. The two common antibody tests used to detect HCV antibodies are HCV EIA and HCV RIBA. The latter is generally used only to re-confirm a positive result from HCV ELISA in persons with no risk factors. It is important to note that people infected with the HCV retain HCV antibodies throughout their life and these in no way protect them from re-infection.

3.2.2 HCV RNA Tests (Viral Load tests)

Viral load tests measure the amount of HCV RNA present in the blood. Therefore, blood from the patient is required to perform this test. This test is important as it can aid determining whether or not treatment is likely to be effective. This test is also performed at different stages of the treatment in order to check if the treatment is working effectively. Viral test can either be qualitative or quantitative. Research however has proven that there is no real co-relation between viral load and the rate of progression of the disease. Today, viral load tests are reported in standard international units where results are expressed as low (under 800,000 IU/ml) or high (over 800,000 IU/ml).

3.2.3 Genotype Test

As indicated earlier, HBV exists in the form of several strains. These strains, although very similar to one another, have certain genetic differences. Based on the differences they have been classified into 6 major types (1-6). Genotype one is the most common type of HCV and accounts for about 60-70% of all the HCV cases around the world. Genotype test using blood sample of the patient is considered important as it can help predict the chances of responding to treatment with pegylated interferon along with ribavirin. The treatment is effective for ~50% of HCV genotype 1 cases whereas it has a significantly higher success rate for those suffering from HCV genotype 2 or 3 infection. This test is performed for patients who are considering treatment.

3.2.4 Liver Biopsy

A liver biopsy is used to measure the degree of inflammation and the extent of fibrosis in the liver. Percutaneous biopsy is the most common type of biopsy that is practised. Before this is performed, an ultrasound is performed in order to locate the area where the needle is to be inserted. An anesthetic is used to numb the skin and muscle in the surrounding area so as to reduce pain and discomfort. The needle is used to draw out a tiny piece of the liver. After the liver piece has been extracted, the patients are observed for a few hours. Approximately 30% patients complain of moderate pain, although complications are a rarity.

Liver biopsy can be performed on a patient once every 3-5 years in order to measure the degree of damage caused by the disease. Although liver biopsy continues to be the best diagnostic test for determining the health of the liver, research is being carried out in order to obtain a simpler and less invasive test.

Prevention

3.3.1 Harm reduction measures

The strategy of harm reduction is an effective way of reducing several parenteral diseases. The only way of implementing this strategy is to raise public awareness and to educate people about basics such as syringe cleaning, lower risk injection practices and the need for needle exchange. However, it has been noted that the majority of IDU's continue to get infected despite these measures being in place.

Prevention of sexual transmission can be successfully achieved by limiting the number of sexual partners and by using male and female condoms during intercourse, especially if it is anal. This not only eliminates sexual transmission of HCV, but also protects individuals from other deadly diseases such as HIV.

3.3.2 Hepatitis A prevention in HCV-positive patients

It has been found that patients with chronic hepatitis C are at high risk of fulminant hepatitis and death if they happen to get infected by hepatitis A virus. It is therefore important for all healthcare systems to provide hepatitis A vaccines, possibly free of cost, to HCV-positive patients. Also, programs targeted specifically to reach IDU's should be carried out, since this population does not access medical care in the general manner.

3.3.3 Public Policy

Public policies as well as harm reduction strategies have so far not been very successful in almost all countries. The paramount reason behind that remains that even if there is a slight probability of syringe sharing, there will be the risk of transmission of HCV. This remains the case with IDU's and requires urgent attention.

Effective measures are needed that can intervene and prevent people that are at a risk of taking injectable forms of drugs. Solutions based on the regulatory aspect of such substances remain highly controversial. Some feel that the best way out is to decriminalize the possession of these drugs and to treat patients that are caught with possession rather than put them behind bars.

3.3.4 Immunoprophylaxis

Although there is no doubt that a vaccine for Hepatitis C will not only bring the disease under control, but will also account for a significant reduction in the extent to which this disease has spread. However, the obstacles to this seem daunting because HCV has a high rate of mutation during RNA polymerisation. HCV RNA has a hyper-variable region that codes for the exposed portion of its exposed protein. Slight changes in this exposed area cause minor constraints for the virus and therefore it can exist in swarms of closely related quasi-species in the same host. Currently, extensive research is being carried out in order to obtain a vaccine, but experts predict that it may take up to a decade or more before a vaccine hits the market.

(4268 words)

Antiviral therapy for Hepatitis C

It is proven that effective antiviral therapy can not only cure HCV, but can also prevent cirrhosis, reduce the risk of developing hepatocellular carcinoma (HCC) and can reverse the severity of fibrosis. A combination of pegylated-interferon (PEG-INF) along with ribavirin is the standard treatment that is recommended to patients with chronic hepatitis C (CHC). There have been indications that possibly a triple therapy with the addition of small molecule HCV antivirals (STAT-C agent) to the current PEG-INF/ribavirin therapy is likely to improve the results against HCV genotype 1 infection, the current emphasis revolves around optimisation of the existing combination therapy (Teoh, N. C. et al. 2010).

Since the introduction of the combination therapy, an individual approach for treatment has been advocated and the dosage and duration of the therapy is estimated after taking several factors into consideration. These factors include determination of HCV genotype, the presence or absence of cirrhosis, and the HCV RNA titre in blood (viral load). A full dose of PEG-IGF along with 800mg/day of ribavirin (irrespective of weight of patient) for a period of 24 weeks is generally recommended for genotypes 2 and 3, while a dose full dose of PEG-IGF along with a weight-based dose of ribavirin for 48 weeks is generally recommended for genotypes 1 and 4.

However, optimal results require an individual approach for each patient since some respond to the treatment in less than 6 months while others require an extended of 72 weeks. It has also been observed that factors such as ethnicity (Afro-Americans show poor response to the treatment while Asians show a much better response), insulin resistance, old age, and obesity have a certain degree of impact on the chances of showing a sustained antiviral response (SVR).

A key issue to ensure successful combination therapy is to deliver optimal doses of both agents that provide sufficient antiviral protection, and at the same time to ensure that the side-effects are limited to minimal. This is crucial in order to prevent chances of relapse. A significant advance in the treatment has been the regular monitoring of viral load that can be used to measure the antiviral response and hence predict whether the therapy can be shortened if possible or needs to be lengthened.

4.1 Intra-treatment monitoring of virologic response

Since the individual response of patients to the antiviral therapy varies considerably (Table 3), monitoring of the viral load is crucial during treatment. Reverse-transcriptase PCR with a molecular assay which is sensitive to 50IU/ml of HCV RNA is used to determine the presence of the virus. It is recommended that this test is performed at 4, 12, and 24 weeks during treatment. Successful SVR is achieved when there are no detectable levels of HCV RNA found after 24 weeks of discontinuing therapy.

Table 3. (Different kinds of virological response)

(Teoh, N.C. et al. 2010)

4.1.1 HCV viral kinetics during therapy

Serum HCV RNA levels decline soon after the commencement of the combination therapy. This decline, when plotted as a curve, indicates two distinct phases (Figure 4.1.1). A rapid fall in HCV RNA levels followed by a slower second fall has been observed in the first 48 hours and this may last several weeks before the HCV RNA levels fall below detectable levels. The significance of such kinetics is that is the rate of decrease of HCV RNA can be used to predict the outcome of the treatment. Differences in viral kinetics between different genotypes have been observed.

Figure 4.1.1 (HCV viral kinetics during therapy)

(Teoh, N.C. et al. 2010)

4.1.2 Benefits of a shortened treatment course

Tolerability for the patient is a key factor that ensures compliance throughout the therapy. A shortened treatment course means the side-effects are reduced significantly, therefore encouraging the patients to complete the therapy. Several audits on the combination therapy have suggested that patient compliance is significantly higher in a 24 week course as compared to a 48 week course. Other advantages of shortened treatment course are reduced medical costs and fewer visits to the doctor.

4.1.3 Predicting treatment outcome using RVR

It has been observed that the probability of SVR depends on the speed of decline of viral load. A rapid decline of HCV RNA to undetectable levels provides the added advantage of a longer duration of therapy while virus suppression has taken place. In the case of infection with HCV RNA genotype 2 and 3, it was observed that between 85-100% patients achieve SVR after 24 weeks of PEG-IFN/ribavirin therapy, while in the case of infection with HCV RNA genotype 1, about 88% achieved SVR after 48 weeks of therapy.

4.2 Factors affecting Rapid Viral Response

4.2.1 Assay sensitivity

Sensitivity of the assay plays an important role in various studies that are carried out to calculate rates of SVR. In the case of a less sensitive assay, more patients will show RVR and this in turn will lead to lower rates of SVR. The treatment decisions such as shortening of therapy are more reliable when a highly sensitive assay is used. Therefore sensitive assays of about 50IU/ml are preferred for the purpose.

4.2.2 Dosage of PEG-IFN and ribavirin

Studies have indicated that the dosage of PEG-IFN and ribavirin play an important role in achieving SVR and also in preventing relapse. A standard dose of PEG-INF (1800 mg/week of PEG-INF-α2a or 1µg/kg/week of PEG-INF-α2b) and a weight based dose of ribavirin (800 mg/day for patients weighing up to 65 kilograms with an additional 200 mg/day for every 20 kilograms) are sufficient and reduce risk of relapse to minimal levels. Thus it is important to use these doses for optimum results and dose reductions should not be carried out unless the patient suffers from major adverse-effects. In case of reduction of dose, it is advisable to abstain from truncation of therapy.

4.2.3 Viral genotype

RVR is more difficult to achieve in the case of infection with HCV genotype 1, as compared to HCV genotypes 2 and 3. Studies conducted in Europe and China indicated the RVR in genotype 1 ranged between 20-29% in European patients and up to 44% in Chinese patients while RVR in genotype 2 and 3 ranged between 65-80% in European patients and 80-85% in Chinese patients. Therefore it is evident that viral genotype plays a role in RVR along with the ethnicity of patient.

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