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

In diagnosing the condition, your doctor will work to identify the type you have in order to provide the best treatment possible. Discover the differences in hepatitis C and learn how new medications are changing the way doctors treat the infection.

Expert answers are provided by Dr. Hirsch, who has extensive clinical practice serving patients with the hepatitis C virus (HCV).

Q: Hepatitis C has different “genotypes.” What is a genotype?


Hepatitis C virus (HCV) is a single-stranded RNA virus. That means that 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, a plant, or an 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 upon differences in particular regions of the viral genome. There are additional branching subcategories within a genotype. They include subtype and quasispecies.   

Q: What’s the difference between hep C genotypes?


Scientists have identified between 6 and 11 distinct HCV genotypes. 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, genotype is a predictor of the outcome of treatment.

Genotype is a predictor of 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 specific for particular genotypes.

Q: 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 patient’s immune system. Its goal is to rally the immune system to recognize and eliminate cells infected with HCV. 

As mentioned earlier, there can be variations of HCV in a single person. So every variation of the virus 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 itself. Direct-acting antiviral (DAA) therapy uses small molecules designed to specifically inhibit these viral proteins. 

Many DAA drugs have been under development over the past decade. Each targets one of the handful of essential HCV proteins. The first two DAA drugs, boceprivir and telaprivir, were approved for use in the United States in 2011. Both target a particular type of HCV enzyme known as proteases. These drugs are used in combination with PEG/ribavirin.

Both of these new medications are most effective against HCV genotype 1. They’re moderately effective versus 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.

Since then, additional DAA drugs have been approved for use in conjunction 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 greater than 90 percent of people treated for only 12 weeks.

Sofosbuvir has a very high potency for to suppress viral replication, regardless of genotype (among those studied). Due to the drug’s success, Europe has recently changed its treatment guidelines. They now recommend a 12-week course of treatment for all uncomplicated HCV patients 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 genotype 2 patients, or 24 weeks in genotype 3 patients.

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


Maybe … or maybe not. 

Each of HCV’s essential proteins works 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 on the target protein it binds. The effectiveness of those agents that bind most directly to the protein’s active site are least likely to be impacted 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 patient’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. 

Q: 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 impact the likelihood of treatment success.  Some of the more significant ones include:

  • amount of HCV virus in your blood
  • severity of liver damage prior to treatment
  • the condition of your immune system (HIV, corticosteroids, transplantation all affect immunity)
  • age
  • race
  • ongoing alcohol abuse
  • response to prior therapies 

Having certain genes can also predict how well treatment works. In people with genotype 1, a gene known as IL28B is one of the strongest predictors of response to PEG/ribavirin treatment. A given person will have one of three possible configurations of the gene:

  • CC
  • CT
  • TT

A person with the CC configuration responds well to PEG/ribavirin. In fact, they

are two to three times more likely than 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 in the presence of a non-CC IL28B gene. This is because in general, PEG/ribavirin works sufficiently well against these genotypes. So, the impact of IL28B status doesn’t change the likelihood of treatment efficacy.

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


Possibly.  Some evidence suggests that people infected with genotype 1 HCV (particularly 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, often occurring 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 patient 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 M.D. 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 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.