Treatment of Hepatitis C virus infection

Hepatitis C virus

Inflammation of the liver (Hepatitis) is mainly caused by viral infections. In the 1940’s it was thought there are two main types of infectious hepatitis, namely hepatitis A transmitted by polluted water or food having little long-term impact on the patient, and the second type transmitted through blood and bodily fluids, which was a serious condition that can lead to a chronic condition, with the development of cirrhosis and liver cancer. In the 1960’s, Baruch Blumberg determined that one form of bloodborne hepatitis was caused by a virus which was labelled as Hepatitis B virus. In 1976, Blumberg received Nobel Prize for this discovery.

Still a significant number of patients used to develop chronic hepatitis following blood transfusions due to an unknown infectious agent that had the characteristics of a virus. This mysterious condition used to be referred to as ‘non-A, non-B’ hepatitis. Following a comprehensive search and an arduous methodical work, Harvey J Alter demonstrated that an unknown virus was a common cause of chronic hepatitis. Michael Houghton isolated the genome of the new virus and was named Hepatitis C virus. Charles M Rice provided the final evidence demonstrating that Hepatitis C virus could cause hepatitis. This work was carried out between 1970 and 1990. The Nobel Prize in Physiology or Medicine 2020 was awarded jointly to Harvey J. Alter, Michael Houghton and Charles M. Rice “for the discovery of Hepatitis C virus¹ .

Hepatitis C virus (HCV) is an RNA flavivirus, responsible for hepatitis C infection. HCV spreads by contact with blood and blood products. Acute manifestations following hepatitis C infection are unusual. Often HCV infection may be discovered incidentally in asymptomatic persons when the patient has developed chronic liver disease. Most individuals exposed to HCV become chronically infected and spontaneous viral clearance does not occur.

HCV RNA antigen can be demonstrated in 2-4 weeks after acute infection and anti-HCV antibodies develop after a period of 6-12 weeks. There are six virus genotypes which are distributed worldwide in a variable fashion. Though genotype has no effect on progression of liver disease, it exhibits variable response to treatment.

Antiviral therapy

Antiviral therapy is given to the patients as chronic HCV infection may result in chronic hepatitis, cirrhosis, and end-stage liver disease (ESLD) and hepatocellular carcinoma (HCC). Cirrhosis develops in nearly 20 per cent of patients following establishment of chronic infection and it is noted after a period of 10 to 20 years² . The aim of treatment is to eradicate infection. It is called ‘cure’ when there is undetectability of HCV RNA in the serum 24 hours after completion of treatment.

The term sustained virological response (SVR) is used when there is undetectable serum HCV RNA six months after the end of therapy. Such a clearance in HCV prevents progression of fibrosis, and reduces the risk of hepatic decompensation and HCC. However, it does not confer protective immunity against re-infection with HCV³ .

Antiviral treatment with the combination of peginterferon and ribavirin has been recommended for patients with chronic HCV infection⁴ . Interferon has broad antiviral effects decreasing in HCV RNA levels, and lowering serum aminotransferase levels. The condition is treated with pegylated alpha-interferon, administered weekly subcutaneously. Ribavirin, a synthetic nucleoside analogue is administered simultaneously orally. Ribavirin though has little effect on serum HCV RNA levels, brings about improvements in aminotransferase levels. The length of treatment and efficacy depend on viral genotype. The above combination with full doses of ribavirin is given for 48 weeks in patients infected with HCV genotype 1 or 4 to achieve a sustained virologic response. In patients infected with genotypes 2 and 3, a sustained virologic response can be achieved with a 24-week course and reduced doses of ribavirin.

National Institute for Health and Clinical Excellence Technology (NICE) has recommended a single course of treatment for 48 weeks for genotypes 1 or 4 and 24 weeks for genotype 2 or 3 HCV. The SVR rates are nearly 45% and 80% respectively⁵ . It is recommended to test for an improvement in the circulating HCV viral load. The treatment can be discontinued if there is no adequate response by week 12 of therapy. Such a method minimizes the risk of adverse effects⁶ .

Adverse events

Ribavirin can give rise to haemolytic anaemia as main side effect. It must be remembered that it is potentially teratogenic. Side effects of interferon include nonspecific flu-like symptoms such as myalgia, arthralgia, fatigue, headache and fever, and nonpsychiatric manifestations such as anxiety, irritability and depression. There may also be a risk of myelosuppression and autoimmune conditions. Persons who exhibit uncontrolled depression, or autoimmune conditions and recipients of solid organ transplants are not candidates to receive this treatment.

Response rate

The treatment response rates are lower in those exhibiting higher baseline viral load, more advanced liver disease, higher body mass index, continued consumption of alcohol, co-infection with HIV, non-Caucasians and patients who are not interested to take full course of the treatment⁷ . Those individuals who exhibit a rapid virological response, the duration of treatment may be reduced if they are exhibiting an undetectable viral load after four weeks of treatment

Newer agents

Since the current therapy for chronic HCV infection is effective in less than 50% of patients infected with HCV genotype 1, attempts to improve the outcomes are made with introduction of new agents.

Telaprevir

Telaprevir is an orally bioavailable, a protease inhibitor specific to the HCV non-structural 3/4A serine protease, has shown to reduce rapidly HCV RNA levels⁸ . It resembles the HCV polypeptide that is cleaved by the viral protease, a necessary step in replication of the virus. In cell culture and in animal models, telaprevir exhibited profound effects on HCV replication⁹ . The results of two clinical trials carried out by McHutchison and colleagues in the United States and Hezode and co-workers in Europe have been recently published^10,11.

In Protease Inhibition for Viral Evaluation 1 (PROVE 1) multicenter study in the USA, McHutchison et al, assigned patients infected with HCV genotype 1 to one of three telaprevir groups or to the control group⁹ . Control group received peginterferon alpha-2 (180 mcg per week) and ribavirin (1000 or 1200 mg per day according to body weight) for 48 weeks, plus telaprevirmatched placebo for first 12 weeks. The telaprevir groups received telaprevir 1250 mg on day 1 and 750 mg every 8 hours thereafter for 12 weeks, as well as peginterferon alpha-2a and ribavirin (1000 or 1200 mg per day according to body weight) for the same 12 weeks (first), or 24 weeks (second) or 48 weeks (third). The primary outcome was a sustained virologic response (an undetectable HC RNA level 24 weeks after the end of therapy).

The rates of sustained virologic response was 41% in the control group as compared with 61%, in the telaprevir second group, 67% in telaprevir third group, and 35% in telaprevir first group. Patients receiving telaprevir had maculopapular rash, and pruritus as a side effect which often led to discontinuation of the drug. The investigators concluded that treatment with a telaprevirbased regimen significantly improved sustained virologic response rates in patients with genotype-1 HCV despite higher rates of discontinuation because of adverse events. The duration of therapy can be reduced from 48 weeks to 24 weeks for most patients while maintaining an improved sustained virologic response.

Patients with chronic infection with HCV genotype-1, who had not been treated previously, in PROVE-2 study, Hezode et al randomly assigned 334 patients assigned to receive one of four treatments involving various combinations of telaprevir (1250 mg on day 1, then 750 mg every 8 hours), peginterferon alfa-2a (180 mcg weekly) and ribavirin according to body weight¹¹. The study was carried out in France, Germany, the United Kingdom, and Austria. Patients of group 1 received telaprevir, peginterferon alfa-2a and ribavirin for 12 weeks, followed by peginterferon alfa-2a and ribavirin for 12 more weeks. The group 2 received telaprevir, peginterferon alfa-2a and ribavirin for 12 weeks. The third group received telaprevir and peginterferon alfa-2a without ribavirin for 12 weeks. The fourth group, as control, received peginterferon alfa-2a and ribavirin for 48 weeks. The primary end point was a sustained virologic response compared between the control group and the combined groups

The rate of sustained virologic response for the second and third group combined was 48%, as compared with 46% in the control group. The rate was 60% in the first group. The adverse events with increased frequency in the telaprevir-based groups were pruritus, rash and anaemia. The study concluded that addition of telaprevir to peginterferon alfa-2a and ribavirin in patients infected with hepatitis C genotype 1 who had not been treated previously showed a significantly higher rate of sustained virologic response, and the response rates were lowest with the regimen that did not include ribavirin.

The above 2 studies have shown the beneficial effect of addition of telaprevir to the combination of peginterferon and ribavirin in bringing about sustained virologic response in patients with a chronic HCV genotype 1 infection. It has been able to achieve a sustained virologic response of 65% and has permitted therapy to be limited to 24 weeks. It supports undertaking larger, and longer phase 3 trial of telaprevir in combination with peginterferon alfa-2a and ribavirin. Telaprevir is a major advance in the therapy of hepatitis C.

Boceprevir

Boceprevir, a potent oral HCV- ketoamide serine protease inhibitor has been evaluated recently. Poordad and colleagues for the SPRINT-2 (Serine Protease Inhibitor Therapy-2) investigators carried out a double-blind study in which previously untreated adults with HCV genotype 1 infection were treated with peginterferon alfa-2b (1.5 microgram per kg of body weight subcutaneously once a week) and ribavirin (600 to 1200 mg per day in divided doses orally) for 4 weeks as the lead-in period followed by either placebo plus peginterferon-ribavirin for 44 weeks (Group 1), or boceprevir (800 mg three times daily taken with food) plus peginterferon-ribavirin for 24 weeks, and those with a detectable HCV RNA level between weeks 8 and 24 with placebo plus peginterferon-ribavirin for an additional 20 weeks (Group 2) and boceprevir plus peginterferonribavirin for 44 weeks (Group 3)¹². The addition of boceprevir to standard therapy with peginterferonribavirin, as compared with standard therapy along, significantly increased the rates of sustained virologic response in previously untreated adults with chronic HCV genotype 1 infection. The rates were similar with 24 weeks and 44 weeks of boceprevir. The regimens that included boceprevir exhibited increased rates of anaemia and dysgeusia.

In another study boceprevir was administered in previously treated chronic HCV genotype 1 infection. Patients who had suboptimal response with peginterferon-ribavirin, received boceprevir that binds to the HCV non-structural 3 active stie. Bacon and colleagues for the HCV RESPONSE 2 (Retreatment with HCV Serine Protease Inhibitor Boceprevir and Peg Intron/ Rebetol-2) investigators tried to assess the effect of the combination of boceprevir and peginterferonribavirin for retreatment of patients with chronic HCV genotype 1 infection¹³. The patients received per interferon alfa-2b and ribavirin for 4 weeks as the lead-in period. Subsequently group 1 received placebo plus per interferon-ribavirin for 44 weeks (control group). Group 2 received boceprevir plus peginterferon-ribavirin for 32 weeks and patients with a detectable HCV RNA level at week 8 received placebo plus peginterferon-ribavirin for an additional 12 weeks and group received boceprevir plus peginterferon-ribavirin for 44 weeks.

The rate of sustained virologic response was significantly higher in the two boceprevir groups (group 2, 59%, group 3, 66%) than in the control group (21%). Among patients with an undetectable HCV RNA level at week 8, the rate of SVR was 86% after 32 weeks of triple therapy and 88% after 44 weeks of triple therapy. The study has shown that the addition of boceprevir to peginterferonribavirin therapy leads to high rates of sustained virologic response among patients in whom prior treatment had failed. Rates of anaemia were higher among patients receiving boceprevir-containing regimens than among controls.

Sofosbuvir

Standard care of all patients with HCV infection is 24-48 weeks of treatment with peginterferon-2 alpha in combination with ribavirin. Treatment with subcutaneous injections of interferon is associated with troublesome side effects (influenza-like symptoms, depression, fatigue and cytopaenia)¹⁴. Sofosbuvir is a direct acting nucleotide polymerase inhibitor. It is developed as an oral drug for the treatment of hepatitis C. Nucleotide analogues are phosphorylated within the host hepatocytes to the active nucleoside triphosphate which competes with the natural nucleotides thereby causing termination of RNA replication in the nascent viral genome.

Monotherapy with sofosbuvir at a dose of 400 mg for 7 days resulted in profound reduction in the level of HCV RNA in patients with HCV genotype 1 infection¹⁵. 12-weeks treatment with sofosbuvir in combination with peginterferon and ribavirin resulted in substantial decrease in the level of HCV RNA during therapy leading to a sustained virologic response at 24 weeks after treatment in 92% of patients with HCV genotype 2 or 3 infection¹⁶. The same regimen followed by 12 weeks of treatment with peginterferon and ribavirin resulted in a sustained virology response in 24 weeks after treatment in89% of patients with HCV genotype 1 infection¹⁷.

It has been found sofosbuvir plus ribavirin for 12 weeks may be effective in previously untreated patients with HCV genotype 1, 2 or 3 infection¹⁸. 12 weeks therapy with a combination of a protease inhibitor, a nucleoside polymerase inhibitor and ribavirin may be effective for treatment of HCV genotype 1 infection¹⁹.

In two phase-3 trials for treatment with sofosbuvir and ribavirin in patients with HCV genotype 2 or 3 infection for whom treatment with peginterferon was not an option and in those who did not have a response to prior interferon treatment, it was found 12 or 16 weeks of treatment was effective. Efficacy was increased among patients with HCV genotype 2 patients and those without cirrhosis. In previously treated patients with genotype 3 infection, 16 weeks of therapy was significantly more effective than 12 weeks²⁰.

In a study of sofosbuvir combined with peginterferon-ribavirin patient with predominantly genotype 1 or 4 HCV infection showed a rate of sustained virologic response of 90% at 12 weeks.

In a noninferiority trial, patients with genotype 2 or 3 infection who received either sofosbuvir or peginterferon with ribavirin had nearly identical rates of response (67%) and adverse events were less frequent with sofosbuvir than with peginterferon²¹.

CONCLUSION

The incidence of chronic infection with HCV is increasing. Therapeutic intervention can be undertaken as there is a long interval between infection and development of cirrhosis and cancer. Treatment can bring about a sustained virological response. Though the treatment is expensive, it is worth undertaking the treatment to reduce progression of liver disease.

Identification of specific proteins involved in the replication of hepatitis C virus has enabled to target them protease and polymerase inhibitors. Emergence of two new serine protease inhibitors-telaprevir and boceprevir-to standard therapy consisting of peginterferon-alpha 2 and ribavirin has shown significantly increased rates of sustained virologic response. This represents a major advance in the treatment of chronic HCV infection. The phase-3 clinical trials have paved the way for a new era of therapy for hepatitis C virus infection. Peginterferonfree regimens have the potential to improve both the safety and efficacy of HCV therapy. However, protease inhibitors do not show any antiviral activity in HCV genotypes other than predominant genotype 1. Further they can promote viral resistance, thus making the treatment a failure. These agents are to be administered with peginterferon and ribavirin.

The studies on Sofosbuvir, a novel polymerase inhibitor in treating patients with HCV genotype 2 or 3 have shown that there is a sustained virologic response at 12 weeks of therapy. Such a therapy has shown a great promise in the treatment of HCV infection with genotypes 2 or 3.