Hepatitis C: Throwing Light on the Shadow Epidemic

  • Hepatitis C (HCV) is an infectious disease, often asymptomatic, affecting primarily the liver.
  • As a chronic infection, it can lead to liver scarring, cirrhosis and, ultimately, liver failure, liver cancer, or life-threatening esophageal and gastric varices.
  • HCV is spread primarily by blood-to-blood contact associated with intravenous drug use, poorly sterilized medical equipment, and transfusions.
  • An estimated 150–200 million people worldwide are infected with hepatitis C including about 3.2 million Americans.
  • Hepatitis C is the leading reason for liver transplantation in the U.S.

Hepatitis C has been called a shadow epidemic because it is the most common chronic bloodborne infection in the U.S.and 80% of those infected show no symptoms (1, 2). To put it in perspective, one in a thousand Americans has been infected with Hepatitis C. The global landscape is shocking: One in fifty people worldwide has been infected with Hepatitis C. The symptoms are generally mild, often resembling the flu, so only a small fraction of the 20% of symptomatic cases may be recognized and treated early.

The asymptomatic nature of hepatitis C is one of the reasons that it is so prevalent. If the infection remains unrecognized then precautions may be not taken to avoid spreading the disease. The most common risk factors for hepatitis C are common to other bloodborne pathogens: sharing needles with intravenous drug users, needle-stick injuries in a healthcare setting, birth by a mother who has hepatitis C, sexual contact, sharing personal care items such as toothbrushes and razors, and poorly regulated tattoo and piercing facilities. Donated blood and organs were not tested for hepatitis C before 1992 and recipients before that date are at particular risk. Surprisingly, three out of four Americans with hepatitis C are baby boomers born between 1946 and 1964.

The asymptomatic nature of hepatitis C is also responsible for its high rate of mortality. Left untreated, hepatitis C leads to liver damage, cirrhosis, and liver cancer. Illness and death caused by complications from hepatitis C infection are more common than we realize. Lou Reed and Allen Ginsberg died of liver cancer caused by chronic hepatitis C infection. In an effort to bring awareness to the disease, Pamela Anderson, Anita Pallenberg, Natalie Cole, Stephen Tyler, Marianne Faithfull, and Keith Richards have publicly acknowledged that they also have hepatitis C.

The genomic variability of hepatitis C makes it very difficult to treat effectively. There are six strains of Hepatitis C and multiple sub-strains, each with unique genomic RNA sequences. The variability in genomic sequence imparts an advantage to some strains so that they are able to evade current drugs. Each part of the world has a unique distribution of the six genotypes. Genotype 1 is most prevalent in the U.S., Europe, and Eastern Asia and is historically the most difficult to treat. Genotype 4 is more common in Africa, and genotype 6 is common in Southeast Asia (4).

Hepatitis C | The Distribution of different Hepatitis C genotypes around the World

The Distribution of different Hepatitis C genotypes around the World.

Hepatitis C | The Distribution of different Hepatitis C genotypes around the World

The Distribution of different Hepatitis C genotypes around the World.

Hepatitis C | The Distribution of different Hepatitis C genotypes around the World

The Distribution of different Hepatitis C
genotypes around the World.

Hepatitis C | The Distribution of different Hepatitis C genotypes around the World

The Distribution of different Hepatitis C genotypes around the World.

There is no vaccine for hepatitis C and until a few years ago the available treatments were non-specific and brought severe side effects. The standard regimen was to receive weekly injections of pegylated (plastic-coated) interferon alpha and oral ribavirin, an analog of an RNA building block that inhibits viral replication via unknown mechanism (6). Positive response was measured as the amount of viral RNA in the blood after 24 weeks. Only 50 – 70% of treated patients showed a positive response after months of grueling injections (7).

In 2011, the first direct-acting antivirals (DAAs) were brought to market to specifically treat hepatitis C. These oral antivirals, boceprevir (trade name: Victrelis) and telaprevir (trade name: Incivek), are inhibitors of a viral protease enzyme that interferes with host immune signaling and thereby contributes to viral escape (8). Used early and in combination with peg-interferon alpha and ribarivin, these DAAs are able to cure 75% of the patients infected (7). They are combined with the older standard of care because only a few sequence mutations are enough for the virus to gain resistance. This approach is like using a set of tweezers (the DAAs) and a heavy blunt object like a mallet (the traditional standard of care) to remove a splinter. The first generation of DAAs offered only slightly higher response rates and very little advance in the duration of treatment and serious side effects.

Hepatitis C virus (HCV) undergoes a number of steps in order to infect a host cell and replicate. New direct-acting antiviral agents can block the process at different points, offering hope of a sustained virologic response (ie, a cure) with an all-oral regimen. (Medical Illustrator: David Schumick)

Hepatitis C Viral Replication

Hepatitis C virus (HCV) undergoes a number of steps in order to infect a host cell and replicate. New direct-acting antiviral agents can block the process at different points, offering hope of a sustained virologic response (ie, a cure) with an all-oral regimen (Medical Illustrator: David Schumick). Source: Hepatitis C virus: Here comes all-oral treatment (Cleveland Clinic Journal of Medicine, 81 (3): 159-172.)

Hepatitis C virus (HCV) undergoes a number of steps in order to infect a host cell and replicate. New direct-acting antiviral agents can block the process at different points, offering hope of a sustained virologic response (ie, a cure) with an all-oral regimen. (Medical Illustrator: David Schumick)

Hepatitis C Viral Replication
Hepatitis C virus (HCV) undergoes a number of steps in order to infect a host cell and replicate. New direct-acting antiviral agents can block the process at different points, offering hope of a sustained virologic response (ie, a cure) with an all-oral regimen (Medical Illustrator: David Schumick). Source: Hepatitis C virus: Here comes all-oral treatment (Cleveland Clinic Journal of Medicine, 81 (3): 159-172.)

Hepatitis C virus (HCV) undergoes a number of steps in order to infect a host cell and replicate. New direct-acting antiviral agents can block the process at different points, offering hope of a sustained virologic response (ie, a cure) with an all-oral regimen. (Medical Illustrator: David Schumick)

Hepatitis C Viral Replication
Hepatitis C virus (HCV) undergoes a number of steps in order to infect a host cell and replicate. New direct-acting antiviral agents can block the process at different points, offering hope of a sustained virologic response (ie, a cure) with an all-oral regimen (Medical Illustrator: David Schumick). Source: Hepatitis C virus: Here comes all-oral treatment (Cleveland Clinic Journal of Medicine, 81 (3): 159-172.)

Hepatitis C virus (HCV) undergoes a number of steps in order to infect a host cell and replicate. New direct-acting antiviral agents can block the process at different points, offering hope of a sustained virologic response (ie, a cure) with an all-oral regimen. (Medical Illustrator: David Schumick)

Hepatitis C Viral Replication
Hepatitis C virus (HCV) undergoes a number of steps in order to infect a host cell and replicate. New direct-acting antiviral agents can block the process at different points, offering hope of a sustained virologic response (ie, a cure) with an all-oral regimen (Medical Illustrator: David Schumick). Source: Hepatitis C virus: Here comes all-oral treatment (Cleveland Clinic Journal of Medicine, 81 (3): 159-172.)

Since the first DAAs were made available, the pharmaceutical industry has been racing to develop once-a-day antiviral pills targeting hepatitis C that do not require concurrent interferon. For the pharmaceutical industry, this is an opportunity to positively affect the lives of millions of patients worldwide and achieve a hefty financial reward.

Only two years later, at the end of 2013, the next generation of DAAs hit the market. Unlike the protease inhibitors from the first generation of DAAs, sofosbuvir (trade name: Sovaldi) was developed as an RNA mimic. It is incorporated by the virus during RNA replication but does not allow strand elongation, effectively throwing a wrench in the replication machinery. Due to the genomic variability of hepatitis C, sofosbuvir is still used in combination with existing drugs. Genotypes 2 and 3 are allowed an all-oral alternative with sofosbuvir and ribavirin for 3 – 6 months. Sofosbuvir was less effective against genotype 1, which still required the concurrent use of interferon and ribarivin for 3 months. Within months, the Food and Drug Administration (FDA) had approved a second oral DAA targeting hepatitis C: simeprevir (trade name: Olysio). Simeprevir builds off of the first generation of DAAs and is a protease inhibitor that is best used in combination with sofosbuvir for treatment of genotype 1 hepatitis C (9).

Hailed as the first all-oral, non-interferon treatment for hepatitis C, sofosbuvir and simeprevir are marketed with a premium price tag. Sofosbuvir is sold at $1000 per pill, or around $84,000 per treatment course. In the U.S. insurance companies have been reluctant to reimburse the cost for sofosbuvir. In Australia, the government has rejected subsidized access to the drug. Worldwide, only the wealthiest patients have been able to access this new drug. Considering the worldwide burden of hepatitis C, the availability and expense of treatments is especially controversial. Three weeks ago, on September 15, 2014, the producer of sofosbuvir (Gilead Sciences) announced that they will distribute a generic version of the drug manufactured in India to 91 countries at reduced cost (10).

The race is on. By the end of next week, on October 10, 2014, the FDA will decide whether to approve a third oral option: ledipasvir [Note from the Editor: Drug was approved by the FDA on October 10th, 2014]. Ledipasvir (no current trade name) is a once-daily pill that will be used in combination with the existing sofosbuvir for treatment of genotype 1 hepatitis C. In December 2014, the FDA will decide whether to approve a fourth oral option: ABT-450 (no current trade name). The genomic variability of hepatitis C will require combination therapies that provide a multi-pronged attack for maximum efficacy against a dynamically evolving virus. Although the cost of treatment may be prohibitively high, doctors are already suggesting that non-critical patients forgo current treatment options and wait a few months for the new all-oral regimes. Patients and providers are still waiting in the shadows but facing the light with hope.

References

  1. Celine Gounder (2013). A better treatment for hepatitis C. The New Yorker, December 9.
  2. Using advanced molecular techniques for rapid identification of hepatitis C outbreaks; FY 2014 Advanced Molecular Detection Projects: Detecting Hepatitis C [Centers for Disease Control and Prevention]
  3. Image of the hepatitis C virus
  4. Hepatitis C Genotypes and Quasispecies [U.S. Department of Veterans Affairs]
  5. Global Distribution of Hepatitis C Genotypes [Stop HEP C]
  6. Helen S. Te, Glenn Randall, Donald M. Jensen (2007). Mechanism of action of Ribavarin in the treatment of chronic hepatitis C. Gastroenterology and Hepatology, 3 (3): 218-25.
  7. Mohannad Dugum and Robert O’Shea (2014). Hepatitis C virus: Here comes all-oral treatment. Cleveland Clinic Journal of Medicine, 81 (3): 159-172.
  8. Image of the viral replication mechanism and potential for inhibition: Reference 7, Dugum and O’Shea 2014.
  9. Ivan Gentile, Federico Borgia, Antonio Riccardo Buonomo, Emmanuela Zappulo, Giuseppe Castaldo, Guglielmo Borgia (2014). ABT-450: A novel protease inhibitor for the treatment of hepatitis C virus infection. Current Medicinal Chemistry, 21: 3261-70.
  10. OLYSIO™ (simeprevir) Receives FDA Approval for Combination Treatment of Chronic Hepatitis C [Johnson & Johnson]
  11. $1,000-a-pill hep C treatment to be cheaper abroad [2014-09-16; Liz Szabo, USA Today]

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Juliesta Sylvester, Ph.D. is a biochemist who promotes innovation and technology transfer at the interface of academia and industry. Her research has spanned pharmaceutical discovery, molecular diagnostics, bioinformatics, and quantitative systems analysis. She is an avid world traveler, invited speaker at national and international meetings, and enthusiastic consultant for startups.

Juliesta Sylvester, Ph.D. is a biochemist who promotes innovation and technology transfer at the interface of academia and industry. Her research has spanned pharmaceutical discovery, molecular diagnostics, bioinformatics, and quantitative systems analysis. She is an avid world traveler, invited speaker at national and international meetings, and enthusiastic consultant for startups.

Juliesta Sylvester, Ph.D. is a biochemist who promotes innovation and technology transfer at the interface of academia and industry. Her research has spanned pharmaceutical discovery, molecular diagnostics, bioinformatics, and quantitative systems analysis. She is an avid world traveler, invited speaker at national and international meetings, and enthusiastic consultant for startups.

Juliesta Sylvester, Ph.D. is a biochemist who promotes innovation and technology transfer at the interface of academia and industry. Her research has spanned pharmaceutical discovery, molecular diagnostics, bioinformatics, and quantitative systems analysis. She is an avid world traveler, invited speaker at national and international meetings, and enthusiastic consultant for startups.

The Michelson Medical Research Foundation‘s Viewpoint blog is brought to you thanks to the generous support of Dr. Gary K. Michelson and his wife, Alya Michelson.
The Michelson Medical Research Foundation‘s Viewpoint blog is brought to you thanks to the generous support of Dr. Gary K. Michelson and his wife, Alya Michelson.
The Michelson Medical Research Foundation‘s Viewpoint blog is brought to you thanks to the generous support of Dr. Gary K. Michelson and his wife, Alya Michelson.
The Michelson Medical Research Foundation‘s Viewpoint blog is brought to you thanks to the generous support of Dr. Gary K. Michelson and his wife, Alya Michelson.