HCV over 3 decades: From a disease with no name to a cure

To mark our 30th anniversary, Infectious Disease News will be examining some of the infectious diseases that have defined and changed the field over the past 3 decades.

At the American Association for the Study of Liver Diseases annual meeting in 2011, Ed Gane, MBChB, MD, FRACP, MNZM, presented data on PS7977, an antiviral agent for the treatment of hepatitis C virus infection. The treatment approach changed slightly across patient groups — some participants were treated for longer than others, and some received PS7977 in combination with ribavirin and pegylated interferon — but the results were always the same.

In all, Gane, deputy director of the New Zealand Liver Transplant Unit at Auckland City Hospital and clinical professor of medicine at the University of Auckland School of Medicine, presented data on 40 patients; all 40 were cured of HCV.

“As soon as he presented the data on the last group of patients, it was so quiet you could hear a pin drop,” Mitchell L. Shiffman, MD, of the Liver Institute of Virginia, told Infectious Disease News. “It was only quiet for about 5 seconds, probably, but it seemed like 5 minutes.”

The data on PS7977 — later known as Sovaldi (sofosbuvir, Gilead Sciences) — led to the direct-acting antiviral (DAA) revolution in HCV. This revolution, however, has taken place in the last several years. When HCV was first discovered in 1989, it was known only as non-A, non-B hepatitis.

This trajectory is “nothing short of a miracle,” according to Zobair M. Younossi, MD, MPH, chairman of the department of medicine at Inova Fairfax Hospital and vice president for research at Inova Health System in Falls Church, VA.

Zobair M. Younossi

“In the span of 30 years or so, we’ve gone from discovering the most common cause of liver disease, liver cancer and liver transplantation in the United States to providing a cure for it,” Younossi said.

The DAA revolution

Michael Houghton, PhD, of the University of Alberta, and colleagues discovered HCV in 1989. Shortly after that, researchers began investigating whether interferon was an effective treatment.

“Interferon was exciting, on one hand, because you could cure some people, but the side effects were so awful that a lot of patients didn’t complete the full course or had a lot of trouble tolerating therapy,” Michael S. Saag, MD, the Jim Straley Chair in AIDS Research and Director of the Center for AIDS Research at the University of Alabama at Birmingham, said in an interview. “Then they switched from interferon to pegylated interferon, but you still had to use ribavirin. Cure rates were around 40% for genotype 1.”

Infectious Disease News 30th Anniversary
Click to enlarge

Early use of interferon required a lot of coaching, according to both Saag and Shiffman.

“Back then, a physician had to be the cheerleader to get people through therapy,” Shiffman said. “We could tell that people were responding to interferon, and we knew that, if the virus became undetectable, there was a good chance of cure. But if you didn’t want to deal with the side effects, and if the physician wasn’t an advocate, the patient didn’t have a chance. The cure rate was 40%. That’s not nearly good enough, but it’s not insignificant.”

The barriers associated with interferon — and the lack of a wide-reaching cure — made interferon-free treatment the “holy grail” in HCV. The first-generation DAAs, Victrelis (boceprevir, Merck) and Incivek (telaprevir, Vertex), were approved by the FDA in May 2011. However, side effects remained a problem.

“The first-generation DAAs were pretty good — and much better than the therapies we had in the past — but were associated with significant side effects that prevented a lot of people from taking the medication,” Younossi said.

As a result, the approval of sofosbuvir in December 2013 for genotypes 1 through 4 — and the second- and third-generation DAAs that followed — was “a game-changer,” according to Saag.

The approval of sofosbuvir was preceded by Olysio (simeprevir, Janssen) in November 2013. In all, nine DAAs have been approved since late 2013.

“The second- and third-generation DAAs are associated with very few side effects,” Younossi told Infectious Disease News. “Cure rates are approaching 100%, and the duration of treatment is short, at only 3 months for most patients.”

In addition to improving cure rates, the DAA revolution has changed the use of interferon and ribavirin. There is no longer a role for interferon in this setting, according to Saag and Younossi, and the circumstances in which ribavirin is still used are limited and will continue to fade, according to Shiffman.

Michael S. Saag

“There are still some situations where adding ribavirin is effective,” Shiffman said. “But the next generation of therapies will not use ribavirin at all, in any patients.”

The barrier of cost

Despite the progress of the last several years, there are still barriers that prevent the use of DAAs in all patients. Cost is the “fundamental hurdle” that prevents every patient from receiving treatment, according to Saag.

An analysis from November 2015 shows that Harvoni (ledipasvir/sofosbuvir, Gilead Sciences) can range from $63,000 for an 8-week course of therapy to $189,000 for 24 weeks. A 12-week course of sofosbuvir costs $84,000, or $1,000 per pill.

The cost of DAAs has led insurance companies to put restrictions in place before they are willing to pay for treatment, Saag told Infectious Disease News. These restrictions vary depending on the patient’s insurance, but they include fibrosis score, mandatory sobriety for active drug and alcohol users and limitations on which providers can prescribe DAAs.

“The payers say, ‘We don’t want to spend money on everyone right now, so let’s just treat the sickest people.’ They create all these hurdles that you have to go through to get access to the drug, solely because it’s expensive,” Saag said. “That theory is like saying, in someone who has a pre-cancerous condition, ‘We’re going to wait until it develops into cancer before we do anything.’ That doesn’t make any sense.”

However, “even those restrictions have become less and less rigid over the past couple of years,” according to Younossi.

The shift in coverage has become most apparent in the past year, Shiffman said.

“Most insurance carriers, although not all, will treat everybody, with no fibrosis restrictions,” he said.

As efficacy continues to improve and restrictions on therapy decrease, the primary issues that remain in the fight against HCV relate to identifying patients who are infected and bringing them into care. Strategies for resolving these issues — and, as a result, curing more people of HCV — can be found in another infectious disease: HIV.

Testing, treating all patients

Like HCV, HIV was once a disease with no name and no cure. Strategies that have been developed in the management of HIV have already translated to progress in the management of HCV, and more lessons to be learned. The biggest impact that HIV has had in HCV is in the development of effective treatment, according to Saag.

Mitchell L. Shiffman

“All the DAAs were based, to some degree, on the model for treating HIV and the technology used to develop the nucleoside reverse transcriptase inhibitors, non-nucleoside reverse transcriptase inhibitors and protease inhibitors,” he said.

One of the most significant hurdles that remains in managing HCV is testing everyone and treating all individuals who test positive. This is another area in which the strategies employed in HIV may prove successful.

Saag believes the cascade of care model used in HIV may be an effective strategy to increase the number of patients with HCV who are aware of their infection status and receive treatment.

“There is a universe of people with HCV, including 4 million in the U.S., and most don’t know they’re infected,” he said. “They have trouble getting linked to care and getting treatment. The difference with HCV is that, once treatment is prescribed, it’s only for about 12 weeks, and the cure rate is 90% to 98%.”

Recent efforts to test more individuals for HCV have focused, in part, on baby boomers, or adults born between 1945 and 1965, as well as people who inject drugs. The rate of HCV antibodies among baby boomers is 3.25%, which is five times higher than the rate among adults born outside of that age cohort. Young people aged 17 to 35 years who inject drugs are considered “the second wave” of patients with HCV; as much as 90% of new infections worldwide have been attributed to injection drug use. The prevalence of HCV in this population is between 60% and 80%.

“We have testing recommendations for baby boomers, and we screen those patients,” Shiffman said. “We’re making a huge impact. But HCV is now on the rise again, after 20 years of decline, because of intravenous drug use in young people. We have no recommendations for screening young people who may have used drugs in the past. We have to identify them when they enroll in drug abuse programs and get them treatment.”

Looking ahead

The advent of DAA therapy has turned a disease with no name into one that can be cured. Current efforts focus on testing and treating all patients, and there are two other areas in which improvements can still be made, according to Younossi: Effective therapy for all genotypes and even shorter durations of therapy.

“We still have regimens where you have to check the patient’s genotype and adjust treatment based on that,” he said. “The next regimens will be pangenotypic.”

The first pangenotypic regimen for HCV, Epclusa (sofosbuvir/velpatasvir, Gilead Sciences), was approved in June 2016.

“The other goal is to shorten the treatment,” Younossi continued. “We have a pretty short duration of treatment now, at 3 months, but there is a possibility that the treatment could be even shorter, at only 8 weeks.”

That said, achievements to date have made HCV “a very easy disease to treat,” according to Shiffman.

“I think it’s just a matter of a commitment by the health care system to identify people and get everyone linked to care and treated. That’s what we need to focus on,” he said. “We have excellent therapies. For people who fail first-line therapy, we also have salvage therapies. It’s hard to improve upon 97% or 98% sustained response rates.” – by Julia Ernst, MS

Disclosures: Saag reports receiving research grants through his institution from Bristol-Myers Squibb, Gilead Sciences and Merck, and serving on advisory boards for Bristol-Myers Squibb, Gilead Sciences and Merck. Shiffman reports serving in advisory, investigator and speaker roles for AbbVie, Gilead Sciences and Merck. Younossi reports serving as a consultant for AbbVie, Bristol-Myers Squibb, Gilead Sciences and Intercept.

To mark our 30th anniversary, Infectious Disease News will be examining some of the infectious diseases that have defined and changed the field over the past 3 decades.

At the American Association for the Study of Liver Diseases annual meeting in 2011, Ed Gane, MBChB, MD, FRACP, MNZM, presented data on PS7977, an antiviral agent for the treatment of hepatitis C virus infection. The treatment approach changed slightly across patient groups — some participants were treated for longer than others, and some received PS7977 in combination with ribavirin and pegylated interferon — but the results were always the same.

In all, Gane, deputy director of the New Zealand Liver Transplant Unit at Auckland City Hospital and clinical professor of medicine at the University of Auckland School of Medicine, presented data on 40 patients; all 40 were cured of HCV.

“As soon as he presented the data on the last group of patients, it was so quiet you could hear a pin drop,” Mitchell L. Shiffman, MD, of the Liver Institute of Virginia, told Infectious Disease News. “It was only quiet for about 5 seconds, probably, but it seemed like 5 minutes.”

The data on PS7977 — later known as Sovaldi (sofosbuvir, Gilead Sciences) — led to the direct-acting antiviral (DAA) revolution in HCV. This revolution, however, has taken place in the last several years. When HCV was first discovered in 1989, it was known only as non-A, non-B hepatitis.

This trajectory is “nothing short of a miracle,” according to Zobair M. Younossi, MD, MPH, chairman of the department of medicine at Inova Fairfax Hospital and vice president for research at Inova Health System in Falls Church, VA.

Zobair M. Younossi

“In the span of 30 years or so, we’ve gone from discovering the most common cause of liver disease, liver cancer and liver transplantation in the United States to providing a cure for it,” Younossi said.

The DAA revolution

Michael Houghton, PhD, of the University of Alberta, and colleagues discovered HCV in 1989. Shortly after that, researchers began investigating whether interferon was an effective treatment.

“Interferon was exciting, on one hand, because you could cure some people, but the side effects were so awful that a lot of patients didn’t complete the full course or had a lot of trouble tolerating therapy,” Michael S. Saag, MD, the Jim Straley Chair in AIDS Research and Director of the Center for AIDS Research at the University of Alabama at Birmingham, said in an interview. “Then they switched from interferon to pegylated interferon, but you still had to use ribavirin. Cure rates were around 40% for genotype 1.”

Infectious Disease News 30th Anniversary
Click to enlarge

Early use of interferon required a lot of coaching, according to both Saag and Shiffman.

“Back then, a physician had to be the cheerleader to get people through therapy,” Shiffman said. “We could tell that people were responding to interferon, and we knew that, if the virus became undetectable, there was a good chance of cure. But if you didn’t want to deal with the side effects, and if the physician wasn’t an advocate, the patient didn’t have a chance. The cure rate was 40%. That’s not nearly good enough, but it’s not insignificant.”

The barriers associated with interferon — and the lack of a wide-reaching cure — made interferon-free treatment the “holy grail” in HCV. The first-generation DAAs, Victrelis (boceprevir, Merck) and Incivek (telaprevir, Vertex), were approved by the FDA in May 2011. However, side effects remained a problem.

“The first-generation DAAs were pretty good — and much better than the therapies we had in the past — but were associated with significant side effects that prevented a lot of people from taking the medication,” Younossi said.

As a result, the approval of sofosbuvir in December 2013 for genotypes 1 through 4 — and the second- and third-generation DAAs that followed — was “a game-changer,” according to Saag.

The approval of sofosbuvir was preceded by Olysio (simeprevir, Janssen) in November 2013. In all, nine DAAs have been approved since late 2013.

“The second- and third-generation DAAs are associated with very few side effects,” Younossi told Infectious Disease News. “Cure rates are approaching 100%, and the duration of treatment is short, at only 3 months for most patients.”

In addition to improving cure rates, the DAA revolution has changed the use of interferon and ribavirin. There is no longer a role for interferon in this setting, according to Saag and Younossi, and the circumstances in which ribavirin is still used are limited and will continue to fade, according to Shiffman.

Michael S. Saag

“There are still some situations where adding ribavirin is effective,” Shiffman said. “But the next generation of therapies will not use ribavirin at all, in any patients.”

The barrier of cost

Despite the progress of the last several years, there are still barriers that prevent the use of DAAs in all patients. Cost is the “fundamental hurdle” that prevents every patient from receiving treatment, according to Saag.

An analysis from November 2015 shows that Harvoni (ledipasvir/sofosbuvir, Gilead Sciences) can range from $63,000 for an 8-week course of therapy to $189,000 for 24 weeks. A 12-week course of sofosbuvir costs $84,000, or $1,000 per pill.

PAGE BREAK

The cost of DAAs has led insurance companies to put restrictions in place before they are willing to pay for treatment, Saag told Infectious Disease News. These restrictions vary depending on the patient’s insurance, but they include fibrosis score, mandatory sobriety for active drug and alcohol users and limitations on which providers can prescribe DAAs.

“The payers say, ‘We don’t want to spend money on everyone right now, so let’s just treat the sickest people.’ They create all these hurdles that you have to go through to get access to the drug, solely because it’s expensive,” Saag said. “That theory is like saying, in someone who has a pre-cancerous condition, ‘We’re going to wait until it develops into cancer before we do anything.’ That doesn’t make any sense.”

However, “even those restrictions have become less and less rigid over the past couple of years,” according to Younossi.

The shift in coverage has become most apparent in the past year, Shiffman said.

“Most insurance carriers, although not all, will treat everybody, with no fibrosis restrictions,” he said.

As efficacy continues to improve and restrictions on therapy decrease, the primary issues that remain in the fight against HCV relate to identifying patients who are infected and bringing them into care. Strategies for resolving these issues — and, as a result, curing more people of HCV — can be found in another infectious disease: HIV.

Testing, treating all patients

Like HCV, HIV was once a disease with no name and no cure. Strategies that have been developed in the management of HIV have already translated to progress in the management of HCV, and more lessons to be learned. The biggest impact that HIV has had in HCV is in the development of effective treatment, according to Saag.

Mitchell L. Shiffman

“All the DAAs were based, to some degree, on the model for treating HIV and the technology used to develop the nucleoside reverse transcriptase inhibitors, non-nucleoside reverse transcriptase inhibitors and protease inhibitors,” he said.

One of the most significant hurdles that remains in managing HCV is testing everyone and treating all individuals who test positive. This is another area in which the strategies employed in HIV may prove successful.

Saag believes the cascade of care model used in HIV may be an effective strategy to increase the number of patients with HCV who are aware of their infection status and receive treatment.

“There is a universe of people with HCV, including 4 million in the U.S., and most don’t know they’re infected,” he said. “They have trouble getting linked to care and getting treatment. The difference with HCV is that, once treatment is prescribed, it’s only for about 12 weeks, and the cure rate is 90% to 98%.”

Recent efforts to test more individuals for HCV have focused, in part, on baby boomers, or adults born between 1945 and 1965, as well as people who inject drugs. The rate of HCV antibodies among baby boomers is 3.25%, which is five times higher than the rate among adults born outside of that age cohort. Young people aged 17 to 35 years who inject drugs are considered “the second wave” of patients with HCV; as much as 90% of new infections worldwide have been attributed to injection drug use. The prevalence of HCV in this population is between 60% and 80%.

“We have testing recommendations for baby boomers, and we screen those patients,” Shiffman said. “We’re making a huge impact. But HCV is now on the rise again, after 20 years of decline, because of intravenous drug use in young people. We have no recommendations for screening young people who may have used drugs in the past. We have to identify them when they enroll in drug abuse programs and get them treatment.”

Looking ahead

The advent of DAA therapy has turned a disease with no name into one that can be cured. Current efforts focus on testing and treating all patients, and there are two other areas in which improvements can still be made, according to Younossi: Effective therapy for all genotypes and even shorter durations of therapy.

“We still have regimens where you have to check the patient’s genotype and adjust treatment based on that,” he said. “The next regimens will be pangenotypic.”

The first pangenotypic regimen for HCV, Epclusa (sofosbuvir/velpatasvir, Gilead Sciences), was approved in June 2016.

“The other goal is to shorten the treatment,” Younossi continued. “We have a pretty short duration of treatment now, at 3 months, but there is a possibility that the treatment could be even shorter, at only 8 weeks.”

That said, achievements to date have made HCV “a very easy disease to treat,” according to Shiffman.

“I think it’s just a matter of a commitment by the health care system to identify people and get everyone linked to care and treated. That’s what we need to focus on,” he said. “We have excellent therapies. For people who fail first-line therapy, we also have salvage therapies. It’s hard to improve upon 97% or 98% sustained response rates.” – by Julia Ernst, MS

Disclosures: Saag reports receiving research grants through his institution from Bristol-Myers Squibb, Gilead Sciences and Merck, and serving on advisory boards for Bristol-Myers Squibb, Gilead Sciences and Merck. Shiffman reports serving in advisory, investigator and speaker roles for AbbVie, Gilead Sciences and Merck. Younossi reports serving as a consultant for AbbVie, Bristol-Myers Squibb, Gilead Sciences and Intercept.

    See more from Infectious Disease News 30th Anniversary