What Are the Hepatitis C Genotypes?

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What Are the Hepatitis C Genotypes and Where Are They Found?

Today, approximately 2% of the world's population is infected with Hepatitis C. Like other viruses, hepatitis C has evolved into distinct subgroups, which has made the virus difficult to treat with a universal drug.

Doctors recognize six major genotypes, although there may be as many as 11. Because genotypes are the result of evolution, distinct types are often clustered in certain parts of the world and distributed elsewhere through migration. Genotypes 1, 2 and 3 are common in North America, but are also seen across the globe. Genotype 4 primarily exists in the Middle East, Egypt and Central Africa; genotype 5 is largely confined to South Africa and genotype 6 to Southeast Asia.

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How Does Genotype Impact Health Outcomes?

Historically, patients with genotype 1 were the most difficult to treat, but that changed with the recent wave of new medicines called direct-acting antivirals. This new generation of drugs, the first of which was approved in 2011, dramatically improved the odds for patients with genotype 1, and new drugs and drug combinations followed.

In June, the FDA announced a major advancement for patients with all genotypes with the approval of a new drug called Epclusa, the first pan-genotypic hepatitis C medication that can be taken as a single pill. "The introduction of Epclusa into the market today presents clinicians who are new to the field a simplicity of treatment, both from the patient's and clinician's perspective," said Hugo Vargas, M.D., chair and director of hepatology of the Mayo Clinic in Arizona.

Today, patients of all genotypes have a good chance of being cured by taking direct-acting antivirals, although some genotypes have been harder to tackle than others. The next six slides will describe the differences between hepatitis C genotypes and which of the new direct-acting antiviral treatments are best for each. Below is a general overview; some patients who have previously tried and failed treatment and those who have some level of liver damage (cirrhosis) may need specialized treatment.

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Genotype 1

Genotype 1 is the most common type of hepatitis C infection, accounting for nearly half of all cases in the world. A majority of genotype 1 infections appear in East Asia, the Americas and Europe. Genotype 1 also contains two prominent subtypes, called 1a and 1b, although most drugs approved today for genotype 1 can cure both subtypes with high success rates.

These drugs are combination regimens; some are packaged as one pill and some as multiple pills. Single-pill options include sofosbuvir/velpatasvir (Epclusa), elbasvir/grazoprevir (Zepatier) and sofosbuvir/ledipasvir (Harvoni). Patients can also take the multi-pill combo packed comprised of paritaprevir/ritonavir/ombitasvir and dasabuvir (Viekira Pak), or a combination of sofosbuvir (Sovaldi) with simeprevir (Olysio).

All of these options have excellent and highly comparable cure rates, so for genotype 1 patients the preferred option will likely come down to each patient's insurance plan and other mitigating factors, such as the presence of kidney disease or advanced liver disease, said Kevin Korenblat, M.D., professor of medicine, Division of Gastroenterology, Washington University School of Medicine in St. Louis.

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Genotype 2

Genotype 2 accounts for about 9% of all hepatitis C infections worldwide. It is the most common type of infection in West Africa, although the greatest number of cases is in East Asia where it is less common but still represents a sizable percentage of all infections. In the United States, genotype 2 accounts for nearly 15% of infections.

In the prior era of peginterferon and ribavirin treatments, patients with genotype 2 infections were the easiest to treat. Today, even higher cure rates exist with new direct-acting antivirals. The best option is the one-pill combination of sofosbuvir/velpatasvir. An alternative is the combination of sofosbuvir and daclatasvir (Daklinza).

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Genotype 3

Genotype 3 is the second more common subtype of hepatitis C after genotype 1. In South Asia, genotype 3 accounts for nearly 72% of the infected population. Genotype 3 is also common in Australasia, Central Asia, Western Europe and Latin America. Approximately 10% of hepatitis C patients in the United States are infected with genotype 3.

At first, genotype 3 patients did not respond as well to the new class of medications, especially if they already had some liver damage. These patients would be prescribed a six-month-long course of treatment with sofosbuvir, but cure rates were still not as good as in patients with genotypes 1 or 2.

But then the pan-genotypic drugs daclatasvir and velpatasvir were developed, providing the first good options for genotype 3 patients. Both need to be paired with sofosbuvir for a high cure rate, and velpatasvir is available in combination with sofosbuvir as a single pill (Epclusa).

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Genotype 4

While genotypes 1, 2 and 3 can be found in relatively high numbers all over the world, genotype 4 is found almost exclusively the Middle East, Egypt and Central Africa. Still, there are so many infected patients in that part of the globe that genotype 4 comprises nearly 20% of cases worldwide. For example, approximately 15% of Egyptians have hepatitis C, compared with a 2% infection rate globally.

Patients can be treated with the drug regimens ombitasvir/paritaprevir/ritonavir (Technivie), sofosbuvir/velpatasvir, elbasvir/grazoprevir or sofosbuvir/ledipasvir.

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Genotype 5

Genotype 5 is the least common hepatitis C subtype, comprising less than 1% of global infections. Nonetheless, it is the most common type of infection in Southern Africa, where it represents more than half of all infections.

Although fewer clinical studies have been conducted with patients who have genotype 5 infection, current guidelines suggest that genotype 5 patients with or without liver damage should start treatment with sofosbuvir/ledipasvir or sofosbuvir/velpatasvir.

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Genotype 6

Genotype 6 is the last of the widely recognized hepatitis C subgroups. The small Southeast Asian country of Laos is the only country in which genotype 6 infects a majority of hepatitis C patients, although genotype 6 is also found in China, Korea, Taiwan and elsewhere in Southeast Asia. Genotype 6 comprises 5.4% of cases worldwide.

As with genotype 5, more data is needed to better support the best course of treatment for genotype 6 patients, but the evidence available shows relatively good cure rates with either sofosbuvir/ledipasvir or sofosbuvir/velpatasvir.

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The Future

The approval of sofosbuvir/velpatasvir as Epclusa, a pan-genotypic regimen, will eliminate the need for genotype testing prior to treatment and could reduce treatment errors, said Vargas. Now that all genotypes are fairly well covered by available direct-acting antivirals, the next treatment challenge to address will be those small numbers of patients who fail treatment, he continued. All of the direct-acting antivirals approved today have at least a 95% cure rate, which means some patients will need to be re-treated.

Gilead Sciences, the makers of Epclusa, are planning to combine it with a new experimental drug called voxilaprevir, and this combination might one day be an option for patients who don't respond to currently available treatments, Vargas said. Moreover, Epclusa is essentially a stepping-stone in Gilead's plans for a future three-drug regimen that is pan-genotypic and does not include ribavirin, said Korenblat.

Merck, the makers of elbasvir/grazoprevir (Zepatier), are also testing the combination of elbasvir/grazoprevir and a "nuc" drug that will fill the same role as Gilead's sofosbuvir, the backbone of Harvoni and Epclusa. Overall, Vargas is impressed with the breakneck pace of drug development in hepatitis C. "I never would have imagined that we would be at this very nice space this early," he said. "The future is shaping itself very nicely."

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