Hepatitis C and Hemophilia

In May 2011, the FDA approved boceprevir (trade name Victrelis) and telaprevir (trade name Incivek), both protease inhibitors. Learn more about these new hepatitis C drugs.

One of the toughest things about having a chronic disease is figuring out the best time to seek treatment. Should you infuse before a long weekend, or wait to see if you have a bleed? Should you have a painful joint replaced now, or try to get a few more years out of it?

Similarly, people with bleeding disorders who have contracted the hepatitis C virus (HCV) face tough choices. There are wide variations in individual responses to the disease, and the treatment, which causes fatigue, is only sometimes effective.

“Any time you are dealing with a chronic illness, the more variables you have to manage, the more complicated things are,” says Phillip Kucab, a 28-year-old with severe factor VIII deficiency who contracted HCV in the early 1980s.

In 2006, Kucab was completing his undergraduate studies at the University of Michigan, applying for graduate school and, like his peers, preparing for life beyond graduation. But he was also preparing himself to undergo a rigorous drug treatment regimen that would attack his hepatitis C infection. Although he had no signs of liver trouble beyond a little jaundice, his decision to seek treatment—11 months of Interferon alpha-2a to enhance the immune system and the antiviral ribavirin—was based mainly on what would happen in 10 years if he did nothing.

“With hemophilia, you’re looking at treatment for the rest of your life,” says Kucab, former National Hemophilia Foundation Board member and now a consultant to NHF. “The good thing about HCV treatment is that it is temporary and it often results in no longer having to worry about the disease.”

Hepatitis C and Hemophilia

New developments in the understanding and treatment of hepatitis C are important for the bleeding disorders community. As many as 80% of people receiving factor products to treat hemophilia prior to 1992 were infected with hepatitis C virus.

In 2009, The U.S. Centers for Disease Control and Prevention (CDC) summarized in its Universal Data Collection (UDC) Project National Report that there were 6,513 people with bleeding disorders and HCV—6,196 with hemophilia, 317 with von Willebrand disease. With the implementation of hepatitis C testing in 1992, as well as other improvements in donor screening and product safety, the risk of HCV transmission from plasma-derived clotting factor has been greatly reduced. No seroconversions to HCV have been reported with any of the FVIII products currently marketed in the U.S.

But once infected, the course of this disease varies greatly from one person to the next. It can run the gamut from spontaneous remission to extensive scarring of the liver and, in some cases, death.

The initial infection by the hepatitis C virus is subtle, with vague symptoms such as fatigue, muscle or joint pain, irritability and headaches that are often mistaken for a mild case of flu. Some people clear the virus from their blood after this initial infection period. Others develop a chronic condition. Chronic HCV infection may progress slowly. Many people may have no symptoms and lead relatively normal lives. However, a 2008 study of 777 patients with hemophilia and HCV at 34 hemophilia treatment centers revealed that after a median 40 years of infection with HCV, almost 25% had liver fibrosis.

“Those with HIV infection have a slightly higher rate of fibrosis—about 1.4 times higher than those who are HIV negative,” says principal investigator of the unpublished study, Margaret Ragni, MD, MPH, professor of medicine at the University of Pittsburgh and director of the Hemophilia Center of Western Pennsylvania. Ragni is a member of NHF’s Medical and Scientific Advisory Council (MASAC). HIV accelerates liver damage, but the mechanism is not known. It may be that the virus increases production of cytokines, which speed up repair and fibrosis. Too much of a good thing, Ragni says, might lead to liver damage.

The progression from minimal fibrosis to symptomatic cirrhosis (scarring), an indication of end-stage liver disease (ESLD) may be slowed. In a study published in Haemophilia in March 2009, Ragni and colleagues showed that the use of highly activated antiretroviral therapy (HAART) in men with hemophilia and HIV/HCV co-infection delayed onset of ESLD for 30.3 years compared with 20 years in the control group. The rate for developing ESLD was comparable to what men who were HIV negative experienced.

Research on people with bleeding disorders who are HCV positive shows that in one out of 10, the virus disappears spontaneously. The other nine do not clear the virus and will experience chronic infections and hepatitis. When this happens, individuals respond in a variety of ways: some remain in a “carrier state” with no measurable damage to the liver, while in others widespread scarring (fibrosis) occurs, which is a symptom of cirrhosis.

Late-stage chronic HCV infection can result in liver cancer or liver failure. Some patients require liver transplants. (See “In For the Long Haul,” HemAware May/June 2009.)

“We really don’t have many answers as to why there is such a wide range of outcomes in people with HCV,” says Ragni. “We suspect that there might be some genetic differences in patients that make someone blind to the virus, prevent HCV from entering the cell, interrupt reproduction or prevent HCV from being released from the cell after reproduction. Further, if you drink alcohol, take too much pain medication or have HIV, you won't respond as well. These are all critical issues.”

Now You See It, Now You Don’t

A set of several circumstances can affect the likelihood of a person’s body being able to rid itself of hepatitis C. For reasons not entirely understood, the younger a patient is at initial exposure to the virus, the higher the probability of clearing it. Women may get over the infection more often than men. Those who do not have co-infections with other viruses, especially HIV, can more effectively fight off HCV infections.

“Once you have a chronic infection, most of what happens next is not directly due to the virus,” says Kenneth Sherman, MD, PhD, a member of NHF's MASAC and Gould Professor of Medicine and director of the Division of Digestive Diseases at the University of Cincinnati Academic Health Center. “The development of liver disease is really dependent on a person’s immune response to the viral infection and the ongoing efforts of the body to clear it. This process includes a deposition of collagen (scar), which alters blood flow through the liver, leading to signs and symptoms of advanced liver disease.”

“Humans are very different from one person to the next, and because of these differences we are bound to see differences in how the body responds,” says T. Jake Liang, MD, chief of the Liver Disease Branch of the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), a division of the National Institutes of Health, in Bethesda, Maryland. “Some get infected and never develop serious disease, while others progress to end-stage liver disease with major complications.”

One theory suggests that development of liver disease depends on an individual’s immune response to the infection. To fight off the disease, the body produces chemicals and proteins that lead to the development of scar tissue in the liver. Eventually this scarring becomes so extensive that it affects blood flow in the liver, triggering end-stage liver disease.

“Everyone doesn’t scar the same,” says Sherman. “If you took a razor and made a standard cut on 100 people, you always find some who heal with no sign you made the cut, some would have a visible scar and others would have excessive tissue and a very lumpy and bumpy scar. We don’t yet know why similar injuries result in different levels of scarring.”

Sherman notes that the best predictor of who will develop scarring is the previous occurrence of it. Liver biopsies look for fibrosis. If a person has chronic HCV infection with little or no scarring, then he or she is at a lower risk for the complications of HCV.

Use of liver biopsies to stage fibrosis is safe in most patients with bleeding disorders, even on an outpatient basis. However, the need for factor infusions prior to the procedure means that it will be more expensive for someone with a bleeding disorder. (See “Is Liver Biopsy Better?” HemAware March/April 2008.)

Hepatitis C Treatment Options

Hepatitis C is a unique virus in that it is the only one that causes a chronic disease that can be “cured.” The bad news is that current gold-standard treatments work only about half the time. The main predictor of treatment success in the individual is the genotype, or family, of the virus.

“There are currently six major genotypes of HCV, with types 1, 2 and 3 seen most often in the US and type 1 being the most common,” says Ragni. “It turns out that standard treatment is less likely to be successful with genotype 1, requiring much longer treatment times. Types 2 and 3 have a slightly different makeup that responds much better to medication.”

Two different drugs are currently the standard cocktail treatment for HCV. Interferon fights viral infections by interfering with the virus’ ability to reproduce; PEG-Intron (pegylated interferon-alfa-2b) and PEGASYS (pegylated-interferon-alfa-2a) are commonly used to treat HCV. Being pegylated makes the interferon stay in the body longer. Studies have yet to show any significant clinical differences between the two treatments.

The second standard medication is ribavirin, an oral antiviral drug that can be used against a broad range of viruses. Interestingly, it has little effect on HCV by itself. However, when ribavirin is combined with interferon, it increases response rate by two to three times.

Although current guidelines suggest treatment for 24 weeks for people infected by either HCV type 2 or 3 and up to 48 weeks for those with type 1 virus, physicians are reviewing viral loads earlier to see if treatment should be discontinued. “New paradigms have been established that say we should be checking viral loads in the blood at four weeks to look for viral clearance,” says Sherman. This rapid viral response (RVR), he says, is accurate in predicting sustained viral response. Further, if a patient fails to achieve complete clearance by 12 weeks, he says, the chance of a sustained viral response (cure) within 48 weeks of standard treatment is very low.

Another new approach is to tailor treatment length to individual patients. “For example, many experts believe that if the patient achieves RVR, treatment can be shortened to 24 weeks,” Sherman says. Conversely, if someone fails to achieve RVR, the physician might recommend extending treatment beyond 48 weeks, up to 72 weeks, he says.

“Before someone starts on the medications, they need to understand that they are probably making a year-long commitment,” says Daniel Reilly, 41, former co-infection coordinator at Hep C Connection in Denver (an education, prevention and support network) and president of the Hemophilia Society of Colorado. “People need to know they will not feel their best and that it will be very unpredictable how they will feel from one day to the next.”

Reilly has severe factor VIII deficiency and started experiencing symptoms of HCV infection in 1983. After going through two shortened rounds of treatment with interferon and ribavirin, which initially cleared the virus only to have it return again, he tried a third time for 11 months. The treatment finally worked, and he has been clear of the virus for nearly six years.

“Even though I had to go through a total of 96 weeks of a very unpleasant treatment, I would jump back on it tomorrow if need be,” says Reilly.

The most common side effects of the combined therapy include flulike symptoms, nausea, diarrhea, insomnia, changes in how things taste, irritability and hair loss. It can also suppress bone marrow function, which leads to anemia. (See sidebar, “Coping with Side Effects of Treatment.”)

A more  severe complication is decreased platelet counts. This, in turn, can lead to spontaneous bleeding. If indicated, medications that stimulate production of platelets can be added or the doses of the drugs can be adjusted. Another concern is that HCV treatments can trigger episodes of major depression, with the rare possibility of suicide.

Fatigue is the side effect that probably has the most impact on both the people receiving the treatment and those around them.

Patients planning to undergo treatment for hepatitis C need to carefully research side effects to mentally prepare themselves (and their families, friends and co-workers) about what to expect during the treatment’s course.

Researching the Future

New drugs are currently in various stages of testing and show promise in treating HCV, hopefully with fewer side effects.

The group that is furthest along, and closest to being available, are called protease inhibitors. This class of drugs inhibits enzymes that the hepatitis virus needs to reproduce and releases new virus particles from cells that have been infected.

A third group of drugs that could be added to the standard treatment to improve efficacy are cyclophilin inhibitors, which prevent the protein cyclophilin from promoting replication of the hepatitis C virus.

Polymerase inhibitors are a second class of prospective drugs to treat HCV. They are similar to protease inhibitors, but they interfere with the viral polymerase enzyme, which acts on different parts of the virus’s life and reproduction cycles.

Updates on recent clinical trials:

• Boceprevir, trade name Victrelis,^TM is a protease inhibitor from Merck, which was approved by the US Food and Drug Administration (FDA) in May 2011. In two Phase 3 clinical trials of the drug, which was combined with pegylated interferon and ribavirin, 2/3 of the 1,500 adult patients in the study showed undetectable levels of the hepatitis C virus in their blood 24 weeks after treatment ended. Early responders were able to stop treatment after 28 or 36 weeks instead of the standard 48 weeks. The most common side effects were fatigue, low red blood cell count, nausea and headache. The pill needs to be taken three times a day with food.
• Telaprevir, trade name Incivek,^TM is a protease inhibitor from Vertex Pharmaceuticals that was also approved by the FDA in May 2011. The drug was studied in three Phase 3 clinical trials of about 2,250 adult patients who were previously untreated or who had received prior therapy. The drug was combined with pegylated interferon and ribavirin. Of the previously untreated patients, 79% no longer had detectable levels of HCV in their blood at 24 weeks. The sustained virologic response for all the patients in all three studies was between 20% and 45% higher than current standard of care. Early responders were able to stop at 24 weeks—half the time of the standard 48 weeks. The most common side effects were rash, low red blood cell count, nausea, fatigue, headache, diarrhea, itching (pruritus), and anal or rectal irritation and pain. The rash can sometimes be serious and require stopping treatment. The pill needs to be taken three times a day with food.
• Debio 025 is a cyclophilin inhibitor from Debiopharm Group in Switzerland. In Phase 2 trials, when combined with pegylated interferon and ribavirin, it produced significant antiviral response in patients who had previously been nonresponders. This was enhanced in patients who received a “loading dose” of Debio 025 for one week prior to the triple combination therapy.
• The combination of two oral antivirals, RG7128, a polymerase inhibitor, and RG7227, a protease inhibitor, from Roche in collaboration with InterMune and Pharmasset, has shown promising results in the INFORM-1 trial. During the twice daily shortened therapy—only 14 days—there was no resistance or serious adverse effects. Patients resumed ribavirin and peg-interferon after the initial two weeks. “It looks like for short-term therapy you can spare interferon and drop viral load in rates similar to peg-interferon regimens,” Sherman says. Roche expects to conduct longer term studies in the INFORM-2 trials, which will measure viral clearance in patients on the oral drugs alone, with pegylated interferon, with ribavirin or with both, beginning in the first quarter of 2010.

“Though current treatments are not easy, people should not delay treatment while waiting for the new generations of products,” says Sherman. “The ­current generation can be curative, stop the progression of the disease and may be lifesaving in the long run.”

When new medications do reach the market, the consensus among those interviewed for this article is that the drugs will most likely be used as an addition to the current treatment instead of as a replacement. Experience using similar drugs in people with HIV and indications from the early studies in HCV suggest that there are high rates of viral mutation and drug resistance if the newer medications are used alone.

There is also ongoing research into the genetic makeup of both the virus and the host. Scientists are researching how changes in a person’s genes may affect their response to HCV. A study published in the August 2009 online version of Nature indicated that there is a racial difference in response to the pegylated interferon-ribavirin combination based on gene variants inherited near the interferon gene, IL28B. The study found that 75% of East Asians experience a successful round of the combination therapy compared with 55% in Americans of European descent and 25% of African Americans. In the future, the development of a diagnostic test to screen the presence of genetic variants could predict which patients will respond well to the combination therapy. Others are trying to find genetic variations in the virus itself that may hold clues to new treatment options. In both of these areas, the studies are too new with too few results to have an immediate impact.

“A big area of research is noninvasive markers of fibrosis,” says Sherman. “We would like to identify ways to be able to stage the disease without performing a liver biopsy.”

A noninvasive imaging method called elastography shows promise. In this procedure, sound waves are bounced off the liver, measuring how stiff it is, a trait of fibrosis. There are two types of elastography: ultrasound and magnetic resonance. Although ultrasound-based elastography is widely used in Europe, neither type has yet been approved for use in the U.S., says Sherman.

Other areas of interest include looking for chemicals in the blood that indicate fibrosis formation. However, the early results have not been consistent, potentially lessening their overall usefulness.

“We are on the verge of a revolution in treatments of hepatitis C with a large number of agents in the drug pipe line,” says Sherman. “This represents a significant area of hope for patients with hemophilia and hepatitis C.”