Module 6: Treatment options - section 5

In this document:

Overview of conventional treatment

Activity: Presentation, group work and discussion
Section Time: Approximately 40 minutes

This section, largely presented in lecture format (but also encourages interaction and contributions from participants) gives an overview of current recommended treatment and regime for chronic HCV infection and how this has been established on the basis of evidence on effectiveness and safety from international clinical trials. 

Optimal treatment

Using Slide 6.9 (Optimal treatment of chronic HCV infection) to outline how trials inform the current optimal treatment of chronic HCV infection:


 

Genotyping for optimal treatment response

Present Slide 6.10 (Recommendations for HCV genotyping) to indicate how genotyping is recommended to inform optimal treatment responses:

 


Show and talk to Slide 6.11(HCV Genotypes) to give an overview on genotypes:


Facilitate discussion by explaining:

  • Hepatitis C shows significant genetic variation in worldwide populations
  • There is evidence of its frequent rates of mutation and rapid evolution
  • These changes may help it evade attack from an infected persons immune system
  • There are six basic genotypes of HCV
  • Genotype prevalence varies across different regions of the world

Show and talk to Slide 6.12 (Distribution of hepatitis C genotypes):


Supporting content:

Hepatitis C shows significant genetic variation in worldwide populations, evidence of its frequent rates of mutation and rapid evolution and changes that may help it evade attack from an infected person’s immune system. There are six basic genotypes of HCV, with 15 recorded subtypes, which vary in prevalence across different regions of the world.

Each genotype has variations, called subtypes. Subtypes are named by lower-case letter (i.e. a, b, c, etc). One genotype cannot change into another, but it is possible for a person to catch more than one genotype at the same time, or to catch a different genotype from that they were previously infected with. It is possible to be re-infected with the same genotype after successfully clearing the virus with treatment.

In order to prescribe a treatment plan with the highest chances of success, a person must have their particular Hepatitis C genotype and subtype identified.

Trials have defined several key components of therapy, namely the appropriate dose of the drugs, the optimal duration of therapy and the need for a different regimen for patients with genotype 1 and genotype 2 and 3 infections. Additionally, knowing the exact strain of HCV is helpful in defining its epidemiology, which can inform individually tailored treatment approaches. There appears to be little difference in the severity of disease or outcome of patients infected with different genotypes. However, genotype can have a bearing on the course and outcome of treatment and people with genotypes 2 and 3 are more likely to respond to interferon treatment.

The optimal duration of treatment for patients with genotype 1 or 4 is 48 weeks. For patients with genotype 2 or 3, 24 weeks is the standard. Patients with genotype 1 infection who fail to achieve an early viral response at 12 weeks have a less than five per cent chance of achieving a sustained viral response. Patients with genotype 2 and 3 infection who achieve a rapid viral response (HCV RNA negative) at four weeks can receive 12 or 16 weeks of pegylated IFN and ribavirin therapy with similar results to 24 weeks of treatment.

 

Combination therapy

Establish small groups, show Slide 6.13 (Group work) and ask them to answer the questions and record on flip chart:


Allow 5 minutes for small group work and another 5 for large group feedback before presenting Slide 6.14 (Interferons) ; 6.15 (Pegylated interferon) and 6.16 (Ribavirins) to summarise the characteristics of drugs used in interferon based treatments:




 

Treatment regimes

Present Slide 6.17 (Treatment regimens) to outline recommended treatment regimes:


Supporting content:

Interferons are a group of naturally occurring proteins that form an essential part of the immune system. Interferons operate in two primary ways, firstly they directly hinder the replication process of the virus and secondly they enhance the immune response. They hinder the replication process by binding to receptors that are present on nearly all cell types and preventing a virus from entering the cell and replicating within it. They enhance the immune response by stimulating activity of immune cells and rendering virus-infected cells more susceptible to the responses of the immune system. The three types of interferon are referred to by Greek letters - alpha, beta and gamma.

In its naturally occurring form, alpha interferon is produced by the body to fight infections, notably flu, and is responsible for many of the symptoms associated with flu, such as headaches, fever and shivering. As a treatment for hepatitis C, it is synthetically produced in a laboratory and administered by injection under the skin in doses considerably higher than occur naturally.

Laboratory-produced standard interferon is broken down relatively fast by the body. As a result, its effectiveness decreases, allowing the hepatitis C virus to multiply in between injections. Pegylation is a process whereby a large molecule chain is attached to the interferon to slow the rate at which it is broken down. This molecule chain is made up of essentially inactive chemicals and does not change the basic nature of the interferon but it allows consistent levels of the drug to circulate in the body and consequently maintain a consistent attack on the virus. It also means that, whereas standard interferon needs to be taken 3 times a week, pegylated interferon only has to be injected once a week.

There are two types of pegylated interferon which are similar but not identical:

  1. Alpha-2a is manufactured by Roche and sold under the trade name ‘Pegasys’. Pegasys is a liquid that comes in one vial and is stored in the refrigerator. The same dose of Pegasys is prescribed to those treated, regardless of their weight.
  2. Alpha-2b is manufactured by Merck/Schering Plough and sold under the trade name ‘PegIntron’ or ‘ViraferonPeg’. PegIntron is a powder that has to be reconstituted with purified water, both of which come in separate vials. PegIntron is dosed by weight.

Different formulations have been studied differently in patients with different severity of disease. They have not been compared directly, and so it is difficult to know whether one may be better than another in different circumstances.

Ribavirin is a synthetic antiviral nucleoside analogue that works very successfully with interferon but is ineffective against hepatitis C on its own. Its efficacy when used with interferon was first noted in 1990 and since 1998 it has been incorporated into standard treatment for hepatitis C. Ribavirin inhibits viral growth, has anti-viral properties and interrupts the way hepatitis C absorbs genetic material when it replicates.

In the majority of cases ribavirin is used alongside interferon for the treatment of hepatitis C. Ribavirin comes in 200mg pill or capsule form and is taken orally, twice daily, with dose dependent on patient weight and genotype. Brand names for ribavirin include Copegus, Rebetrol and Ribasphere.

 

Treatment effectiveness

Present Slides 6.18 (Effectiveness of combination therapy for HCV1) and 6.19 (Effectiveness of combination therapy graph) to illustrate how treatment effectiveness has improved irrespective of genotype with the advent of combination therapy although there are variations in effectiveness across genotypes:



Supporting content:

The most effective pharmaceutical treatment for hepatitis C consists of taking two drugs, pegylated interferon and ribavirin, and is known as dual or combination therapy. In trials, it has been shown to be effective in 55% of cases. Effective here means that the hepatitis C virus was no longer detectable in blood 6 months after treatment ended (known as a sustained virological response or SVR). 55% is an overall figure: the SVR was about 40% for people with genotype 1 (although the latest trials are now producing figures of 50% for genotype 1) and around 80% for those with genotype 2 or 3.

In addition, treatment has been shown in trials to reduce both inflammation and fibrosis. This even happens in patients who do not have an SVR, although only in about half the number of cases. Even in cases of cirrhosis, which until recently was believed to be irreversible, there is evidence that it can sometimes be reversed through treatment.

 

Treating cirrhosis

Although treatment is more effective during acute infection treatment can and should be offered to people with moderate liver damage and those with compensated cirrhosis. Present Slide 6.20 (Treating cirrhosis) explaining how more recently that, with some limitations, treatment benefits can be achieved in those with some liver damage:


Supporting content:

HCV treatment is more effective when given during acute infection and treatment should be offered to people with moderate liver damage, since they are at risk of progression to cirrhosis. People with compensated cirrhosis can be treated, but treatment is less likely to be effective, and side effects may be worse. Careful monitoring is needed. People with decompensated cirrhosis cannot be safely treated for hepatitis C, which is when a liver transplant is usually the only possible option.

Until recently it was generally thought that treating people with HCV-induced decompensated cirrhosis with pegylated interferon was not worthwhile as the response rates tended to be low, the risks of severe side effects and the possibility that treatment might accelerate the deterioration of the liver. However, recent studies suggest that treatment may help carefully selected patients with decompensated cirrhosis, who have not previously had treatment and who currently have few options other than liver transplantation.

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