Hepatitis C is a viral infection that causes inflammation of the liver. The virus is transmitted through blood and rarely through sexual contact. There are many different types of the hepatitis C virus. But all forms of hepatitis C share important similarities.

After you receive a diagnosis of hepatitis C, your doctor will work to identify the type you have so you’ll get the best treatment.

Discover the differences in hepatitis C types. Expert answers are provided by Dr. Hirsch, who has extensive clinical practice working with people who have hepatitis C.

Hepatitis C has different “genotypes.” What does this mean?

Hepatitis C virus (HCV) is a single-stranded RNA virus. That means the genetic code of each virus particle is contained within one continuous piece of the nucleic acid RNA.

Every strand of a nucleic acid (RNA or DNA) is made up of a chain of building blocks. The sequence of these blocks determines the proteins that an organism requires, whether it’s a virus, plant, animal.

Unlike HCV, the human genetic code is carried by double-stranded DNA. The human genetic code goes through strict proofreading during the process of DNA replication. Random changes (mutations) to the human genetic code occur at a low rate. That’s because most mistakes of DNA replication are recognized and corrected.

In contrast, HCV’s genetic code is not proofread when it’s replicated. Random mutations occur and stay in the code. HCV reproduces very quickly — up to one trillion new copies per day. So certain parts of HCV genetic code are highly varied and change frequently, even within a single infected person.

Genotypes are used to identify particular strains of HCV. They’re based on differences in particular regions of the viral genome. There are additional branching subcategories within a genotype. They include subtype and quasispecies. 

What’s the difference between hepatitis C genotypes?

According to the Centers from Disease Control and Prevention (CDC), at least six distinct HCV genotypes, and more than 50 subtypes, have been identified.

The different HCV genotypes and subtypes have different distributions throughout the world.

Genotypes 1, 2, and 3 are found worldwide. Genotype 4 occurs in the Middle East, Egypt, and central Africa. Genotype 5 is present almost exclusively in South Africa. Genotype 6 is seen in Southeast Asia.

Genotype 1 is the most common HCV genotype in the United States. It’s found in nearly 75 percent of all HCV infections in the country. Most of the remaining people in the United States with HCV infection carry genotypes 2 or 3.

The HCV genotype isn’t absolutely related to the rate of liver damage, or the likelihood of eventually developing cirrhosis. However, it can help predict the outcome of treatment.

The genotype can help predict the outcome of anti-HCV therapy with interferon-based treatment regimens. Genotype has also helped to determine treatment. In some formulations, the recommended doses of ribavirin and pegylated interferon (PEG) are for people with specific HCV genotypes.

What is the current research into genotypes and treatments for each type?

The most widely used anti-HCV therapy, PEG/ribavirin, doesn’t target the virus itself. This treatment regimen primarily affects the person’s immune system. Its goal is to rally the immune system to recognize and eliminate cells infected with HCV. However, variations of HCV in a single person won’t necessarily “look the same” to the immune system. This is one of the reasons that HCV infections persist and become chronic infections.

Even with this genetic diversity, researchers have identified proteins that are required for the reproduction of HCV in the body. These proteins are present in essentially all of the many HCV variants. The new treatments for HCV target these proteins. That means they target the virus. Direct-acting antiviral (DAA) therapy uses small molecules designed to specifically inhibit these viral proteins.

Many DAA drugs have been under development during the past decade. Each drug targets one of the handful of essential HCV proteins. The first two DAA drugs, boceprevir and telaprevir, got approval for use in the United States in 2011. Both target a particular type of HCV enzyme known as protease. These drugs are used in combination with PEG/ribavirin.

Both of these new medications are most effective for HCV genotype 1. They’re moderately effective for genotype 2, and not effective for genotype 3. Initially, they were only approved for use in people with genotype 1 HCV in combination with PEG/ribavirin.

Additional DAA drugs have been approved for use along with PEG/ribavirin. These newer drugs target several additional HCV proteins. One of these drugs is sofosbuvir.

With PEG/ribavirin treatment alone, genotype 1 HCV used to require the longest duration of treatment with the least likelihood of success. With sofosbuvir, genotype 1 is now curable in more than 90 percent of people treated for only 12 weeks.

Sofosbuvir has a very high potency for suppressing viral replication, regardless of genotype (among those studied). Due to the drug’s success, Europe recently changed its treatment guidelines. It now recommends a 12-week course of treatment for all people with uncomplicated HCV who have not been previously treated.

With sofosbuvir, the FDA also approved the first interferon-free combination therapy (sofosbuvir plus ribavirin). This therapy is used for 12 weeks in people with genotype 2, or 24 weeks in people with genotype 3.

Does genotype predict response to DAA therapy like it did for interferon therapy?

Maybe … maybe not.

Each of HCV’s essential proteins work the same, regardless of genotype. These essential proteins may be structurally different due to small mutations. Because they’re essential for the HCV life cycle, the structure of their active sites is least likely to change due to random mutation.

Because a protein’s active site is relatively consistent between different genotypes, how well a particular DAA agent works is affected by where it binds on the target protein. The effectiveness of those agents that bind most directly to the protein’s active site is least likely to be affected by virus genotype.

All DAA drugs suppress ongoing HCV replication, but they don’t eject the virus from its host cell. They also don’t remove infected cells. This job is left to the person’s immune system.

The variable effectiveness of interferon treatment indicates that the immune system is able to clear cells infected with some genotypes better than those infected by others.

Genotype usually determines the type of treatment a person receives. Are there other factors that affect treatment?

Aside from genotype, there are many variables that can affect the likelihood of treatment success. Some of the more significant ones include:

  • amount of HCV virus in your blood
  • severity of liver damage before treatment
  • the condition of your immune system (Coinfection with HIV, treatment with corticosteroids, or having had an organ transplant can all lower your immunity.)
  • age
  • race
  • ongoing alcohol abuse
  • response to prior therapies

Certain human genes can also predict how well treatment may work. The human gene known as IL28B is one of the strongest predictors of response to PEG/ribavirin treatment in people with HCV genotype 1. People have one of three possible configurations of IL28B:

  • CC
  • CT
  • TT

People with the CC configuration respond well to treatment with PEG/ribavirin. In fact, they are 2 to 3 times more likely than people with other configurations to have a complete response to treatment.

Determining the IL28B configuration is important in the decision to treat with PEG/ribavirin. However, people with genotypes 2 and 3 can often be treated with PEG/ribavirin even if they don’t have the CC configuration. This is because in general, PEG/ribavirin works well against these genotypes. So, IL28B configuration doesn’t change the likelihood of treatment effectiveness.

Does my genotype affect the likelihood that I’ll develop cirrhosis or liver cancer?

Possibly. Some research suggests that people who are infected with HCV genotype 1 (particularly those with subtype 1b) have a greater incidence of cirrhosis than those infected with other genotypes. Regardless of whether this observation is true, the recommended management plan doesn’t change significantly.

The progression of liver damage is slow. It often happens over decades. So, anyone newly diagnosed HCV should be assessed for liver damage. Liver damage is an indication for therapy.

The risk of developing liver cancer doesn’t appear to be related to HCV genotype. In chronic HCV infection, hepatocellular carcinoma (liver cancer) only develops once cirrhosis has been established. If an infected person is effectively treated before they develop cirrhosis, then the infecting genotype isn’t a factor.

However, in people who have already developed cirrhosis, there is some data suggesting that genotypes 1b or 3 may increase the risk of cancer. Screening for liver cancer is recommended for everyone who has HCV with cirrhosis. Some doctors recommend more frequent screening for those infected with genotypes 1 and 3.

About the Doctor

Dr. Hirsch earned his MD from Washington University in St. Louis, Mo. He did postgraduate training in both internal medicine and hepatology at the University of California, San Francisco (UCSF). He did additional postgraduate training at the NIH in Allergy & Immunology. He also served as the Chief of Hepatology at the Washington VAMC. Dr. Hirsch has held faculty appointments at the medical schools of both Georgetown and George Washington Universities.

Dr. Hirsch has extensive clinical practice serving patients with the hepatitis C virus (HCV). He also has years of experience in pharmaceutical research. Dr. Hirsch has served on advisory boards for industry, national medical societies, and regulatory bodies.