Hepatitis C: current management and emerging therapies

Hepatitis C: current management and emerging therapies
September 22, 2011


'Progression of liver disease occurs over several decades, and is accelerated in the presence of cofactors such as older age of acquisition, obesity, alcohol consumption, diabetes mellitus (to which HCV itself predisposes) and human immunodeficiency virus (HIV) co-infection'
Dr Stephen Stewart and Dr Mary-Teresa O’Neill offer a comprehensive overview of the diagnosis and treatment of HCV and look at new therapy options.

Hepatitis C virus (HCV) infection is one of the main causes of chronic liver disease worldwide. It affects 2.35 per cent of the world’s population, or 160 million individuals. Hepatitis C was first identified in 1989 and became a notifiable disease in Ireland under the Infectious Diseases Amendment Regulations in 2004.

Since then, there have been approximately 9,661 notified cases of hepatitis C. Some 67 per cent of notified cases in 2011 were male and the median age for notification was 36 years for males and 32 years for females.

Prior to the 1990s, the primary routes of HCV infection were via blood transfusion and intravenous drug use. These modes of transmission account for approximately 70 per cent of cases in developed countries. Screening of blood products for HCV has virtually eradicated transfusion-transmitted hepatitis C in European countries. Approximately 1,700 people have been identified as being infected with HCV through the receipt of contaminated blood and blood products in Ireland. These include women infected through anti-D immunoglobulin, recipients of blood transfusion, patients with haemophilia and other blood-clotting disorders and those who received haemodialysis. At present, new HCV infections are mainly due to intravenous or nasal drug use.

In Ireland, approximately seven in every 10 injecting drug users receiving drug treatment test positive for antibodies to HCV. Perinatal and heterosexual transmission risk is low. In fact, the risk of sexual transmission is sufficiently low that the use of barrier protection is generally not advised among monogamous couples. Promiscuous sexual activity may be related to increased risk of HCV infection.

Natural history
Six major genotypes of HCV have been defined, as well as more than 50 subtypes, the most frequent subtypes being 1a, 1b, 2a and 2b. Genotype 1 is the most common genotype in Europe and the United States with 60-70 per cent prevalence while genotype 3a is common in European intravenous drug users. HCV genotype is an important determinant of the patient’s response to treatment.

Acute HCV infection is asymptomatic in 50-90 per cent of cases. Fulminant liver injury is rare and occurs in less than 1 per cent of patients. An average of 26 per cent of patients with acute hepatitis C experience spontaneous clearance of the virus, an event that occurs primarily during the first three months after clinical onset of disease. Spontaneous resolution is more common among infected infants and young women.

Other host factors influence the likelihood of spontaneously clearing the virus, in particular, certain polymorphisms of a site close to the IL28B gene. The IL28B gene encodes interferon lambda, which is an anti-viral cytokine and the gene is upregulated by interferons.

One study of 1,008 patients showed that those with the C/C genotype were associated with spontaneous clearance rates of 50-55 per cent compared with only 16-20 per cent in those with the T/T genotype. The C allele was more common in patients of European descent compared to African descent. These polymorphisms are also associated with response to treatment with pegylated interferon and ribavirin.

Some 55-85 per cent of individuals who develop acute hepatitis C will develop chronic HCV infection. The high prevalence of chronic infection may be due to the genetic diversity of the virus and its tendency towards rapid mutation, allowing HCV to escape immune recognition.

Progression of liver disease occurs over several decades, and is accelerated in the presence of cofactors such as older age of acquisition, obesity, alcohol consumption, diabetes mellitus (to which HCV itself predisposes) and human immunodeficiency virus (HIV) co-infection.

Between 10-40 per cent of patients with chronic HCV infection will develop cirrhosis. Once cirrhosis occurs, there is a risk for the development of hepatic decompensation (30 per cent over 10 years) and also hepatocellular carcinoma (1-3 per cent per year).

Screening
The optimal approach to detecting HCV infection is to screen those with a history of risk of exposure to the virus. All intravenous drug users, as well as intranasal drug users, who share paraphernalia should be tested for HCV infection. Individuals who have received a blood or blood component transfusion before routine screening of blood products for HCV was introduced in Ireland in 1991 should be tested.

The Anti-D/Hepatitis C National Screening Programme was initiated in 1994 to offer testing to recipients of Blood Transfusion Service Board Anti-D immunoglobulin. Patients with unexplained elevations of aminotransferase levels, those on haemodialysis, children born to HCV-infected mothers, or those with HIV infection should also be screened.

Diagnosis of HCV infection is based on the detection of both anti-HCV antibodies by enzyme immunoassay, and of HCV RNA by a sensitive molecular method, ideally a real-time polymerase chain reaction (PCR) assay. HCV RNA testing is necessary for monitoring the response to HCV treatment.

The presence of symptoms or jaundice, and whether or not there was a prior history of ALT elevation, can assist to distinguish acute HCV infection from chronic infection. After exposure, HCV RNA is usually detectable before the antibody; HCV RNA can be identified as soon as two weeks following exposure, whereas anti-HCV is generally not detectable before 8-12 weeks.

Rarely, in immunosuppressed patients, anti-HCV antibodies are not detected and HCV RNA alone is present. HCV genotyping should be performed in all HCV-infected persons prior to treatment in order to determine the dose and duration of therapy and to estimate the likelihood of response.

Although a liver biopsy is not necessary for the diagnosis of hepatitis C, it is useful to stage the liver disease prior to initiation of therapy. It is particularly important to identify patients with cirrhosis, as their response to therapy is reduced and they also require surveillance for HCC and portal hypertension, including oesophageal varices. Staging should be performed regardless of ALT levels, as significant fibrosis may be present in patients with repeatedly normal ALT.

As well as the grade, the stage of the liver injury can also be assessed by biopsy. The grade defines the extent of necroinflammatory activity, while the stage establishes the extent of fibrosis or the presence of cirrhosis. Steatosis and excess hepatocellular iron can also be identified on biopsy and may influence the likelihood of response to treatment.

A liver biopsy is not necessary in genotypes 2 and 3, as 80 per cent of these patients achieve a sustained virological response (SVR) to standard-of-care treatment.

Although liver biopsy has been regarded as the ‘gold standard’ for defining liver disease stage, the procedure is not risk-free. Alternative non-invasive methods can now be used to assess liver disease severity. Blood marker panels measuring both indirect and direct markers of fibrosis are useful for establishing the presence of minimal fibrosis or cirrhosis but are less helpful in assessing the mid-ranges of fibrosis or for tracking fibrosis progression.
Transient elastography is a rapid non-invasive technique that uses ultrasound and low-frequency elastic waves to measure liver stiffness. Its accuracy is greater in those with normal body weight and it may provide an alternative to liver biopsy in certain patient populations.

Determination of IL28B polymorphisms prior to treatment assists in evaluating a patient’s likelihood of response to treatment with pegylated interferon alpha, ribavirin and also protease inhibitors, particularly in genotype 1 disease.

Treatment
Both the European Association for the Study of the Liver and American Association for the Study of Liver Diseases have similar recommendations regarding who should be considered for antiviral therapy. Adults positive for HCV RNA with a liver biopsy showing chronic hepatitis and significant fibrosis should be offered treatment, in the setting of compensated liver disease. Patient compliance and the absence of concurrent alcohol or illicit drug use should also be verified prior to initiation of treatment. Patients with early stages of fibrosis, decompensated liver disease or relative contraindications are considered on a case-by-case basis.

The goal of antiviral therapy is to eradicate HCV infection in order to prevent the complications of HCV-related liver disease. The endpoint of therapy is a sustained virological response (SVR), which is defined as an undetectable HCV RNA 24 weeks after cessation of treatment. An SVR is associated with a 99 per cent chance of being HCV RNA negative during long-term follow-up.

Intermediate endpoints are used during treatment to assess the likelihood of an SVR and adjust treatment duration accordingly. They include HCV RNA level measurements at four, 12, and 24 weeks of therapy, which are compared to the baseline HCV RNA level. Successful treatment halts necroinflammation and fibrosis progression in the liver.


Prior to the 1990s, the primary routes of HCV infection were via blood transfusion and intravenous drug use'
First-line treatment of chronic hepatitis C is the combination of pegylated interferon alpha (IFN) and ribavirin. Alpha interferons induce interferon-stimulated genes that establish an antiviral state within cells, though the response is not virus-specific. There are two pegylated IFN molecules that can be used; IFN-α2a and IFN-α2b.

There is no conclusive evidence that one is superior to the other. Ribavirin, a purine analogue, is incorporated into the RNA of replicating virions, thereby increasing the mutation frequency and reducing the specific infectivity of new virions. The cost of combination therapy in Ireland is approximately €1,950 per month.

SVR is achieved in 40-54 per cent of patients infected with HCV genotype 1 after 48 weeks of treatment, while patients infected with HCV genotypes 2 or 3 achieve SVR in 65-82 per cent of cases after 24 weeks. Multivariate analyses have identified two major predictors of an SVR: the viral genotype, namely genotype 2 and 3, and a pretreatment viral load of less than 600,000 IU/ml. As mentioned earlier, IL28B polymorphisms are significant independent predictors of response to treatment.

Multiple studies have shown that patients with the CC genotype at the polymorphic site have higher SVR rates than patients with the CT or TT genotypes. One study done in a large cohort of patients with chronic HCV genotype 1 infection showed an SVR of 69 per cent in Caucasian patients with CC IL-28 genotype compared with 33 per cent in CT genotype and 27 per cent in TT genotype.

Other characteristics associated with a favourable response include female gender, age less than 40 years, non African-American race, normal body weight (≤75 kg), no evidence of insulin resistance and the absence of bridging fibrosis or cirrhosis on liver biopsy.

Treatment duration varies depending on the virological response. Treatment for all genotypes should be stopped if there is less than a 2 log drop in HCV RNA (ie less than 99 per cent decrease of the baseline value) at week 12 and at week 24 if HCV RNA is still detectable. Patients with genotype 1 are usually treated for 48 weeks unless they have a rapid virological response (RVR), i.e. undetectable HCV RNA at week 4 of therapy, in which case it may be reduced to 24 weeks.

Genotype 2 and 3 patients are usually treated for 24 weeks’ duration. Relapsers are patients who achieve an end-of-treatment response (undetectable HCV RNA) but subsequently relapse and did not achieve an SVR, whereas persons who fail to decrease HCV RNA by at least a 2 log drop after 12 weeks of therapy are classed as null responders.

Side-effects
Adverse events are common during treatment. In the initial trials of peginterferon alfa-2a and 2b with ribavirin, 10-14 per cent of patients discontinued therapy as a result of side effects. Interferon causes influenza-like side effects such as fatigue, headache, fever and rigours, and psychiatric side effects such as depression can occur in up to 30 per cent of patients. Haematological and biochemical side effects of treatment include neutropaenia, anaemia, thrombocytopaenia and ALT flares.

Anaemia occurs in one-third of patients, reaching a nadir within six-eight weeks. This is multifactorial and includes ribavirin-induced haemolysis. Ribavirin is also teratogenic and accumulates in gonadal tissues, therefore all patients need to use contraception both during, and for six months after treatment.

New and emerging treatments
More recently, two new agents have completed phase III clinical trials for the treatment of chronic hepatitis C in combination with pegylated IFN-alpha and ribavirin. Telaprevir and boceprevir are both NS3/4A (non-structural) serine protease inhibitors. The NS3/4A HCV viral protein contains a serine protease activity that is required for cleavage of the viral polyprotein at four sites into mature viral proteins. Telaprevir (Incivek, Incivo) and boceprevir (Victrelis) were approved by the FDA in May 2011.

The European Medicines Agency approved boceprevir in August 2011 and telaprevir is currently awaiting market authorisation. These agents will be used in triple therapy for the treatment of genotype 1 chronic hepatitis C in patients who are treatment-naïve or who have previously been treated with interferon-based treatment and not responded adequately.

The ADVANCE trial demonstrated SVR rates of 75 per cent in treatment naïve genotype 1 patients who received telaprevir in combination with IFN and ribavirin for 12 weeks followed by IFN and ribavirin alone, compared with 44 per cent in patients who received standard-of-care treatment.

The REALIZE trial evaluated telaprevir in patients with HCV genotype 1 infection who had no response or a partial response to previous therapy or who had a relapse after an initial response. Rates of SVR were significantly higher in both telaprevir groups than in the control group among all groups of patients.

The HCV SPRINT 2 trial evaluated boceprevir in treatment-naïve genotype 1 patients and showed an SVR of 66 per cent for patients who received peginterferon alpha/ribavirin alone for four weeks, followed by the addition of boceprevir for 44 more weeks, compared to an SVR of 38 per cent for the standard of care group.

The SVR rates were higher in Caucasians. RESPOND-2 was a phase III trial, which evaluated boceprevir in patients who were prior partial responders or relapsers with peginterferon and ribavirin. Boceprevir or placebo was started after a four-week lead-in of peginterferon and ribavirin. Null responders were not included in the trial. SVR rates were significantly higher in all patients who received boceprevir.

These agents are associated with the rapid emergence of viral resistance, which is substantially reduced by combination therapy with IFN and ribavirin. Telaprevir causes cutaneous reactions including rash and pruritus in up to half of patients, but these are usually mild to moderate.

Telaprevir has also been associated with anaemia beyond that seen with peginterferon and ribavirin therapy alone (36 per cent versus 14 per cent, respectively). The most common side effects of boceprevir include fatigue, anaemia, nausea and headache. Trials investigating NS5A and NS5B polymerase inhibitors, cyclophilin inhibitors, new forms of interferon, derivatives of ribavirin and therapeutic vaccines are in progress.

Conclusion
The burden of hepatitis C on our healthcare service is likely to increase in the future as many patients progress to develop cirrhosis and end stage liver disease. Treatment of hepatitis C is rapidly evolving, particularly with the imminent introduction of the directly-acting anti-viral protease inhibitors. These, in combination with ongoing developments in this area, may help to eradicate hepatitis C as a chronic illness.

There are significant concerns about the rising costs of treatment, particularly in the current economic climate. Difficult decisions will need to be made, comparing the cost of eradication of the disease with costs frequently incurred in the longer term in these patients.

References on request.

Dr Mary-Teresa O’Neill is a Liver Research Fellow and Dr Stephen Stewart is a Consultant Hepatologist at the Centre for Liver Disease at the Mater Misericordiae University Hospital, Dublin 7.