The goal of treatment for chronic hepatitis C is to eliminate the HCV virus from the body permanently. This is measured by evaluating blood for the presence of the virus after treatment has finished. If no virus is detected, patients have achieved sustained viral response (SVR) and are presumed to be cured. Current guidelines indicate the earliest interval for SVR testing is three months following therapy completion. The specific treatment regimen typically includes multiple medications and is determined by a patient's genotype (or viral strain) and previous treatment history, as well as the degree of liver damage.
Traditionally, HCV was treated with a combination of injectable interferon and oral ribavirin. In 2011, a new class of medications (oral protease inhibitors) was approved for patients with genotype 1. These drugs dramatically increased the rate of SVR, or viral cure, when compared to previously available options. Since that time, a number of additional oral medications with various mechanisms of action have been approved for genotypes 1 through 4.
Each of these iterations brought additional benefits to HCV treatment, improving cure rate and tolerability as well as shortening the length of therapy.
Oral Viral Inhibitors
This class of new antivirals is generally referred to as direct-acting antivirals, meaning these drugs work directly on the virus to stop the growth of HCV. Within this class, the drugs can be subdivided by the way they work against HCV (or their mechanism of action).
Olysio (simeprevir), Victrelis (boceprevir)
Protease inhibitors block an important step in HCV replication (or growth). In order to grow, the virus has to be cut into smaller pieces for processing, copying and reassembly. Protease inhibitors stop this viral cleavage by binding to the protease enzyme so it cannot cut, similar to covering scissor blades with glue.
Side effects of HCV protease inhibitors vary according to the particular drug but some possible symptoms include low blood cells, rash, itching and upset stomach.
Polymerase inhibitors also work by blocking viral replication (or growth). In order for HCV to continue growing and infecting new cells, the virus must first make new copies of itself. Polymerase is a naturally occurring enzyme in human cells whose job is to assemble the building blocks of DNA and RNA. When a cell becomes infected with HCV, the virus hijacks this enzyme and uses it to start the HCV viral copying process instead. Polymerase inhibitors work by blocking the enzyme and preventing the creation of new virus particles and the spread of HCV to healthy cells.
Side effects of HCV polymerase inhibitors may vary but some possible symptoms include headache and fatigue.
Combination, Direct-Acting Antivirals
Newer products, such as Viekira Pak and Harvoni, combine multiple medications with varying mechanisms of action to increase treatment efficacy and reduce the risk of HCV resistance. These combination products offer short-course treatment lengths similar to other recently available HCV medications. Not only does this approach provide effective treatment, but it also adds convenient, fixed-dose regimens to make complying with HCV treatment even easier.
Similar to the newer single-product antivirals, side effects of these combination therapies are considerably less intense as compared to traditional interferon-based HCV treatment. While side effects may vary, patients taking Viekira Pak may experience nausea, itching, or insomnia. Similar symptoms, such as headache and fatigue, may occur with Harvoni.
Interferon is a protein made by the immune system which interferes with viral reproduction and boosts the body's natural response to disease. During HCV treatment, pegylated interferon (a manmade version of the natural protein) is given by weekly injections, for up to 12 months. These increased concentrations of interferon in the body (naturally occurring + the injected manmade product) can produce various adverse effects. These include flu-like symptoms, low blood cells, as well as psychiatric problems (e.g. depression, irritability, insomnia, moodiness). The good news is that clinicians have years of experience with side effect management and many strategies are available to help improve tolerance to this therapy.
Ribavirin is a molecule that mimics some of the building blocks of DNA. It is administered orally and is typically taken twice daily in a dose based on weight. Although it is not effective against hepatitis C when used alone, ribavirin plays an important role in HCV combination treatment. While scientists have not discovered exactly how it works, it is clear that adding ribavirin boosts cure rates and reduces the risk of HCV relapse.
The major side effect of ribavirin is anemia, or low red blood cells. Ribavirin also causes severe birth defects, so it cannot be used by pregnant or breastfeeding women or by their male partners. Birth control for both male and female patients taking ribavirin is essential while on therapy and for six months after treatment ends.
New Treatments on the Horizon
Scientists continue to work to find more effective, more tolerable and shorter HCV treatment options. All-oral, interferon-free treatments in the late stages of clinical investigation include:
- Daclatasvir (Bristol-Myers Squibb)
o Oral, once daily
o NS5A inhibitor to be used in combination with other medications (i.e., Sovaldi)
o Studied in genotypes 1 and 3
- Daclatasvir/asunaprevir/beclabuvir (Bristol-Myers Squibb)
o Oral, fixed dose, twice daily combination
o Combination of NS5a inhibitor/protease inhibitor/non-nucleoside polymerase inhibitor
o Studied in genotype 1
- Grazoprevir/elbasvir (Merck)
o Oral, once daily combination
o Combination of second generation protease inhibitor/NS5A inhibitor
o Studied in genotype 1