Update, November 5, 2014: The US Food and Drug Administration (FDA) approved the combination of Janssen’s Olysio™(simeprevir) and Gilead’s Sovaldi® (sofosbuvir) to treat patients with chronic hepatitis C virus, genotype 1. Previously, they were approved only for use separately, in combination with pegylated interferon and/or ribavirin. The all-oral daily therapy should be taken for 12 weeks for patients without cirrhosis and 24 weeks for patients with cirrhosis.
Update, October 10, 2014: On October 10, 2014, the US Food and Drug Administration (FDA) approved Harvoni™, a combination of ledipasvir, an NS5A inhibitor, and sofosbuvir, a polymerase inhibitor, to treat patients with chronic hepatitis C virus (HCV) infection, genotype 1. The drug, manufactured by Gilead, is the first combination pill to treat HCV. It is also the first to do so without the use of interferon or ribavirin, previously considered the gold standard for treatment. Treatment-experienced patients, those who have been on previous HCV drug regimens, are expected to take the pill for 12 or 24 weeks, achieving sustained virological response (SVR), an indication that they have been cured.
Update, September 2014: Vertex Pharmaceuticals, Inc., announced in a letter to providers that it would discontinue the sale and distribution of Incivek® in the US in mid-October 2014. “This decision has been taken in view of available alternative treatments and the diminishing demand for Incivek,” wrote Charles Johnson, vice president of global medical affairs at Vertex, in the letter. Patients will be allowed to complete their treatments. They should consult with their physicians regarding next steps.
Update, January 2014: On January 29, 2014, the American Association for the Study of Liver Diseases (AASLD), in partnership with the Infectious Diseases Society of America (IDSA) and the International Antiviral Society—USA (IAS-USA), announced the creation of a website to keep clinicians apprised of the latest developments in the fast-growing field of new therapies for treating hepatitis C virus (HCV) infection. According to the AASLD press release, the site will provide “rapid formulation and dissemination of evidence-based expert-developed resources for hepatitis C management.” Although targeted to healthcare providers, the new website can be accessed by patients and their families.
Original article: After a nearly 10-year drought in drug development for patients with hepatitis C virus (HCV), two drugs signal a sea change in therapy. The new drugs, approved by the US Food and Drug Administration (FDA) in May 2011, are boceprevir, trade name Victrelis™, manufactured by Merck; and telaprevir, trade name Incivek™, made by Vertex Pharmaceuticals Inc. They are protease inhibitors, oral drugs that prevent HCV from replicating when taken with the standard of care, peginterferon (PegIFN) and ribavirin (RBV).
People with hemophilia who are co-infected with HCV are candidates for the new therapy. However, because they were not included in the drugs’ clinical trials, it is not known how they will respond. They will need to work closely with their physician to individualize their therapy to achieve the best results. Those with other conditions, such as HIV, will need to be monitored closely for drug interactions.
Standard of Care
For years, the standard of care for patients with chronic HCV has been the combination of two antiviral drugs—PegIFN, which is injected weekly, and RBV, a pill taken twice daily. During the typical 48-week regimen, most patients felt lousy as they coped with debilitating side effects, ranging from fatigue and flulike symptoms to depression. It’s no wonder that many abandoned the regimen early. For those who did persevere, only about 40%–50% with HCV genotype 1, the most common type, cleared the virus.
Introducing Protease Inhibitors
An alternative was needed that could boost sustained viral response (SVR) rates—the ability to clear HCV—and shorten the treatment period. Protease inhibitors have accomplished both. “These designer drugs are the first in a class of medicine called direct-acting antiviral agents that target particular proteins that are essential for the hepatitis C virus to replicate,” says Paul Kwo, MD, professor of medicine and medical director of liver transplantation at the Indiana University School of Medicine in Indianapolis.
Protease inhibitors prevent the serine protease enzyme from cutting a long protein into the smaller functional units HCV needs to reproduce. Preventing HCV from reproducing has led to higher SVR rates, which are cure rates, Kwo says. “The cure rates for patients on these protease inhibitors in combination with PegIFN/RBV are now about 70%–75% for genotype 1.”
HCV is notorious for creating mutations that can result in new variants that resist drug therapy. Taking boceprevir or telaprevir alone can trigger the proliferation of these variants. “The reason patients don’t break through in the majority of cases is because the combination PegIFN/RBV inhibits resistant variants,” Kwo says.
Results of studies on the triple drug combination of PegIFN/RBV and a protease inhibitor show very encouraging results. According to the 2011 practice guidelines issued by the American Association for the Study of Liver Diseases (AASLD), most patients can stop therapy after 24 weeks if HCV is undetectable after four weeks and remains so during the following 20 weeks. But each of the protease inhibitors is taken differently. Stopping points have been established for each drug if patients’ viral loads remain too high.
Before starting the combination therapy including these protease inhibitors, it’s important to take such factors into consideration as: your race and genotype; whether you’re treatment-naïve (never treated before) or treatment-experienced; and your degree of liver impairment. All of these factors will best determine treatment.
Genotype Influences Interferon Response
“We’ve known for many years that African Americans don’t respond well to interferon and that Asians do,” says Kenneth Sherman, MD, PhD, Gould Professor of Medicine and director of the Division of Digestive Diseases at the University of Cincinnati College of Medicine. Now we know why. A change in a single nucleotide, the smallest unit on a chromosome, occurs on chromosome 19 in the region of IL28B, which codes for a type of interferon that is part of the body’s innate immune response, he says.
Your response to interferon can be predicted by which combination of the nucleotides cytosine (C) or thymine (T) you inherit from your parents. Those with the CC genotype, such as Asians, have the highest response. “People with the CC gene are more likely to be treated for short durations of therapy,” Kwo says. “They have an intrinsic ability to get rid of the virus.”
Although African Americans typically have the lower-responding TT or CT, even those with HCV showed significant improvement in SVR while on the triple drug therapy with telaprevir. “In treatment-naïve patients, the response rates of over 60% were seen in African Americans in two phase 3 trials,” Sherman says. That’s compared to studies showing SVR of approximately 25% on PegIFN/RBV alone.
A patient’s response to the new therapy can be forecast at the gene level. IL28B genotype blood testing can determine a patient’s response to interferon. “IL28B predicts what happens with the viral therapy,” says Kwo. Your HCV subtype, 1a or 1b, also influences your treatment response. “Patients with subtype 1a are harder to treat. They are more likely to get resistance than those who have 1b,” Kwo says. (See “What’s Your Genotype?” HemAware Spring 2010, p. 26.)
Kwo was lead author of a 2010 study in Lancet of treatment-naïve patients taking PegIFN/RBV and boceprevir. “With that study, we achieved about a 75% cure rate with 48 weeks of treatment,” he says.
Patients on the therapy take PegIFN/RBV initially for four weeks before boceprevir is added to the regimen. Reasons for this so-called “lead-in phase” include reducing the viral load early to achieve a higher response rate later and for its predictive value. “If you have a meaningful response—if your viral load goes down by at least 90%—your chance of cure is 70% to 80%,” Kwo says. It also can determine whether you should continue. “If you can’t tolerate the PegIFN/RBV, you know before you add a very expensive drug.”
The thought of cutting treatment time in half is a cause for celebration among chronic HCV patients. However, before crossing off the weeks on your calendar, you have to achieve extended rapid virological response (eRVR) at weeks 4 and 12 or weeks 8 and 24, depending on the protease inhibitor. “If the conditions are met for response-guided therapy, the treatment can be shortened from 48 weeks to 24 in most patients with identical outcomes, with identical results,” Sherman says. He was lead author of a 2011 study published in the New England Journal of Medicine that showed of 540 treatment-naïve patients on telaprevir, 352 (65%) achieved eRVR. The overall SVR rate was 72%.
Previously treated patients don’t do as well as their treatment-naïve peers when it comes to SVR rates on triple therapy. But many are still in the running for re-treatment. The AASLD guidelines recommend re-treating partial responders, those whose viral loads dropped while on PegIFN/RBV but were still detectable at the end of the study, and relapsers, those whose viral loads became undetectable during treatment but reappeared later. Both groups tend to show high SVR rates with the protease inhibitor triple therapy. To avoid drug resistance in treatment-experienced patients, AASLD recommends these stopping points: week 12 for patients on boceprevir who have detectable HCV RNA higher than 100; weeks 4 or 12 for patients on telaprevir whose HCV RNA is greater than 1,000 IU.
Null responders, those whose viral load didn’t drop by a set amount midway through previous PegIFN/RBV therapy, however, should be considered for therapy on an individual basis, especially those with bridging fibrosis (advanced liver scarring) and cirrhosis. These people respond the poorest, achieving a cure rate of about 30% to 35% with either telaprevir or boceprevir. “The responses are lower in the setting of advanced fibrosis,” Kwo says. “They are not particularly PegIFN/RBV-responsive.”
Drug Adherence Factors
Patients on protease inhibitors take one pill three times a day, along with twice-daily RBV pills and weekly PegIFN injections.
Maintaining this routine for 24, or possibly 48, weeks can lead to “pill fatigue,” a lapse in medication adherence. A 2011 study in the Annals of Internal Medicine of more than 5,700 patients with HCV on PegIFN/RBV showed that as time went by, subjects tended to miss doses of RBV. The study, led by Vincent Lo Re, MD, MSCE, assistant professor of infectious disease and epidemiology at the University of Pennsylvania in Philadelphia, revealed a correlation between contentment and compliance. Patients whose side effects were addressed by medical personnel and then properly managed felt better and were more likely to stick with the regimen. The researchers noted that the findings are applicable to patients now on the triple drug therapy.
Another major concern is the combined cost and added co-pays for these new drugs. A 24-week round of PegIFN/RBV is about $15,000. Incivek costs about $4,100 per week or $49,200 for a 12-week regimen. Victrelis runs about $1,100 weekly or approximately $26,400 for a 24-week regimen. The steep out-of-pocket cost could cause some patients to take less of their medications to try to make it last longer. (See “Costs and Coverage of New Hepatitis C Drugs,” HemAware Fall 2011, p. 13.)
Specific Side Effects
Adding a protease inhibitor to PegIFN/RBV ratchets up the risk of generic side effects, such as fatigue, nausea and anemia.
It also causes distinctive drug-specific side effects. The main side effect for patients on boceprevir was dysgeusia, a change in their sense of taste. For telaprevir patients, an eczema-like rash with itching occurred in more than half of study subjects. In 4% of cases, the rash was extensive, covering more than 50% of the body. “The severe cases are relatively rare, but patients must be monitored for that and the drug discontinued if that’s seen,” Sherman says.
But it’s the embarrassing side effects that can be the most trying for telaprevir patients. Nearly one-third of patients experienced anorectal symptoms, including diarrhea, hemorrhoids and perianal burning.
Another complication is drug interactions. Protease inhibitors can disrupt drug-metabolizing enzymes in the liver, causing problems with immunosuppressants, statins and opportunistic infection drugs. “Boceprevir and telaprevir interfere tremendously with HIV drugs, in some cases,” says Sherman. “That’s why there has to be very specific guidance.”
Cured, Still Needing Care
After completing the therapy, patients can’t wave good-bye to their treaters just yet. “The typical follow-up is the determination of SVR, which is typically 12 weeks to 24 weeks after the therapy is complete,” Sherman says. He repeats the tests six months later. “If the virus is still gone, then you pronounce that patient cured.”
However, patients with later-stage fibrosis, a measure of scar tissue buildup in the liver, probably should be monitored for life, says Sherman. “That patient needs to be followed on a regular basis by a hepatologist looking for evidence of liver cancer and other signs of hepatic decompensation (permanent liver damage).”
In its guidelines, the AASLD notes the lack of data on “special populations”—people co-infected with HCV and HIV, those with decompensated liver cirrhosis and liver transplant patients. It recommends that such people be treated cautiously and with more frequent monitoring.
“They are going to require more intensive support,” Kwo says. Many of these patients are immunosuppressed and their red blood cell production is compromised. More of these people are going to require erythropoietin because the anemias are going to be more severe, he says. There are two main issues when using these agents: They are expensive and not FDA-approved for treating HCV. (See “Pumping Iron,” HemAware Summer 2010, p. 30.)
Although there are no data yet for patients with bleeding disorders, Kwo and Sherman say clinical trials are beginning soon at their institutions (See “Access to Hepatitis C Clinical Trials,” posted on hemaware.org, February 2011.) Some of the data from studies of nonhemophilic patients are useful, especially for those with HCV and HIV. “The drugs appear at week 24 to be very effective and safe, with no other new unexpected side effects or adverse effects,” says Sherman. Data still need to be gathered for the 48-week regimen for these patients and to determine SVR rates, he says.
People with bleeding disorders may present some unique issues that need to be addressed. “Patients with hemophilia and hepatitis C may be implicitly different than other hepatitis C patients because they had massive exposures to lots of strains of HCV and lots of blood products, which are thought to affect the immune system,” Sherman says.
The final determinant of which patients receive the thumbs up for therapy may be their liver condition. “Prior treatment null responders with advanced liver disease have very poor responses—in the 14%–15% range,” Sherman says. “In general, they probably should be held for studies with even better agents.” Others have such advanced liver disease that they have only one option. “Those that have developed ascites (fluid in the abdomen) and variceal bleeding (in the esophagus) should be evaluated for transplant,” says Sherman. (See “In for the Long Haul,” HemAware May/June 2009, p. 20.)
Patients with hemophilia and HCV have reasons for feeling they’re riding the crest of a long wave. Sherman attended The Liver Meeting® 2011, hosted by AASLD in San Francisco, November 4–8, and sensed the excitement. “There was a flood of new information on the next several waves of new drugs for hepatitis C and new combinations. The next three years will represent a time of rapid change.”
[Related: New Hepatitis C Drugs Mark Major Advancement.]