Dramatic advances have been made in the treatment of hepatitis C since the virus that caused it was first identified in 1989.
The most exciting new advance is a two-drug combo named Harvoni, which combines sofosbuvir and another antiviral drug called ledipasvir, and offers a cure for hepatitis C in as little as eight weeks. It was approved by the Food and Drug Administration in late 2014. Patients taking the new drug only need to take a pill once a day, and they run a much lower risk of serious side effects associated with the standard treatment for hepatitis C. Unfortunately, the high cost of the medicine means that some patients who need it may not be eligible for it, but it has been hailed as a major breakthrough in hepatitis C treatment.
The current treatment for most patients is a combination of two drugs: pegylated alpha interferon and ribavirin. Together, these two drugs have been shown to slow or stop the progress of hepatitis C in some, but not all, patients. Although far from perfect treatments, they offer new hope to people with the disease.
Pegylated interferon (peginterferon)
Alpha interferon is a substance produced by the immune system in response to viral infections. Researchers have developed techniques to synthesize alpha interferon that can be used as a drug. The newest form has been chemically modified by the addition of a molecule of polyethylene glycol. The process — pegylation — creates a form of alpha interferon, called peginterferon that remains in the blood longer. Levels of peginterferon in the blood are also much more constant than those of previous forms of alpha interferon. For that reason, pegylated interferon can be administered as an injection just once weekly. The new form of the drug is also better than previous forms at inhibiting the hepatitis C virus. More patients respond to peginterferon than previous forms of synthetic alpha interferon.
Ribavirin is an antiviral drug given in pill form. It acts against a variety of viruses, including herpes and influenza. Alone, it has little effect against the hepatitis C virus. But the combination of ribavirin and peginterferon has been shown to produce an antiviral effect two to three times more powerful than peginterferon alone. Ribavirin is typically given twice a day in 200-mg capsules. The total dose is based on a person’s body weight. Someone who weighs 145 pounds, for example, is given 1000 mgs.
Combination therapy (peginterferon and ribavirin)
For patients treated with the combination of peginterferon and ribavirin, the length of treatment depends on the genotype of the virus. Patients with genotype 1, the most common form found in the US, are usually given the drugs for 48 weeks. Those with genotypes 2 and 3 usually respond better to the combined treatment, and are typically given the drugs for 24 weeks. The optimal dose of ribavirin also varies depending on genotype. Patients with genotypes 2 and 3 are typically prescribed a dose of 800 mg, while those with genotype 1 typically receive 1000-mg doses.
Some patients shouldn’t receive peginterferon. These include people with autoimmune hepatitis or liver disease in which the liver is starting to fail, or those who have had an allergic reaction to alfa interferon in the past, or to products derived from E. coli.
An important caution about both alpha interferon and ribavirin: They can cause serious complications in pregnant women and severe birth defects. Birth control is essential for both men and women taking these drugs. Neither pregnant women nor the female partners of men on this therapy should take these drugs, and both groups should be extremely careful to avoid becoming pregnant for six months after the therapy is discontinued. Male partners of pregnant women should not take these drugs, either.
In addition, some patients cannot tolerate ribavirin because the drug can cause dangerous reactions in people with kidney disease or serious heart disease. In this case, pegylated alpha interferon alone is recommended for a period of 48 weeks.
How well do the treatments work?
In seven out of 10 patients, the hepatitis C virus can no longer be detected (using HCV RNA blood tests) after treatment is completed. Liver enzyme levels return to normal. In some patients, the virus begins to multiply again once treatment is stopped, but 55 percent of patients given combination therapy have a sustained response. That is, the virus remains undetectable for six months or more after treatment is stopped. About 35 percent of patients given alpha interferon alone have a sustained response.
Are there side effects to treatment?
Yes. Like almost all effective treatments, the drugs used against hepatitis C have side effects and complications. Most are mild to moderate in severity, and can be managed by your doctor. Side effects are typically the worst after the first injection and during the first few weeks of treatment.
Side effects of combination therapy that occur in 10 percent or more of patients include:
- Muscle aches
- Nausea and vomiting
- Skin irritation at the injection site
- Low-grade fever
- Weight loss
- Skin rashes
- Nasal stuffiness, cough, and asthma-like symptoms
- Mild bone marrow suppression
- Temporary hair loss
- Sexual dysfunction in men
Are there other treatments for hepatitis C?
Yes. Other treatments include interferon alone, standard interferon plus ribavirin, and standard interferon plus amantadine. These drugs are sometimes used to treat people whose infection has relapsed, or who don’t respond to the peginterferon and ribavirin combination therapy.
Recent research on a hepatitis C-specific protease inhibitor called telaprevir forecasts a new era in the treatment of this disease. In April 2009, the New England Journal of Medicine reported on a study that showed significant improvement in the chances of being cured when telaprevir was added to the current standard therapy, and treatment took only half the time. If further studies confirm these results, telaprevir could soon be approved by the Food and Drug Administration.
A closer look at hepatitis C treatment and depression
In some cases, side effects can be severe enough to force people to stop taking the medications. In a 2003 study of 39 patients with life-threatening liver disease, for instance, one in three people became so depressed after several months of interferon therapy that they stopped taking their medication. The depression showed up suddenly and at almost the same time in most of the patients — usually two or three months after starting the drug treatments. Researchers suspect that interferon may deplete levels of the mood-related brain chemical serotonin. Studies suggest that patients who experience serious depression during treatment may be less likely to clear the virus from their system.
Be sure to call your doctor immediately if you develop signs of depression or feel suicidal during treatment; become unusually irritable, anxious or aggressive; or experience other unusual mood or behavior changes.
Fortunately, depression triggered by hepatitis C drugs can be treated. Researchers at the Northwest Hepatitis C Resource Center of the Portland VA Medical Center in Portland, Oregon, who conducted the depression study, gave the affected patients the commonly used antidepressant citalopram (Celexa). Within five to six weeks, 11 out of 13 patients were no longer depressed. The drug, like other selective serotonin reuptake inhibitors (SSRIs), helps make more serotonin available to brain cells. A Canadian report in September 2009 summarized nine trials and also concluded that evidence suggests SSRIs are safe and effective in treating depression during HCV treatment.
Many of the other moderate side effects associated with HCV treatment can also be eased or eliminated. For example, acetaminophen can relieve the muscle aches, headaches, and low-grade fever that sometimes accompany treatment. The dosage of ribavirin can be reduced if the asthma-like symptoms become severe. Even when side effects can’t be eliminated, they usually go away within a few weeks after treatment is completed.
More serious side effects
Less commonly, ribavirin, peginterferon, and the combination of the two drugs can cause more serious complications. In most patients, ribavirin causes a small percentage of red blood cells to die. The severity of this side effect varies widely among patients. In most people, the loss of red blood cells can cause anemia. Symptoms of anemia can include fatigue, shortness of breath, irregular heartbeat, and headaches. Doctors closely monitor red blood cell counts, or hemoglobin, during treatment. In rare cases, the drop in red blood cells can cause chest pain, heart attacks, or strokes. (That’s why ribavirin is not prescribed to people with serious heart or cerebral vascular disease.)
Other uncommon side effects of peginterferon and combination therapy include:
- Autoimmune disease
- Bacterial infections
- Thrombocytopenia, or loss of blood platelets
- Neutropenia, or loss of blood cells called neutrophils
- Retinopathy, or damage to tiny blood vessels in the retina
- Hearing loss and ringing in the ears
In rare cases, therapy for hepatitis C has been associated with heart failure, kidney failure, and vision loss, among other complications. It’s important to remember that these side effects occur very rarely. For most people with hepatitis C, the benefits of treatment outweigh the risks.
In addition, many of the unwanted side effects of combination therapy can be relieved. Doctors can prescribe red blood cell growth factors to treat anemia, for instance. Acetaminophen helps ease the muscle aches and reduce low-grade fever. Doctors can also adjust the dose of both peginterferon and ribavirin to lessen side effects.
When should I contact my doctor about side effects?
Stop using interferon and ribavirin and call your doctor immediately or seek emergency medical help if you have:
- an allergic reaction such as swelling of your lips, tongue, or face; difficulty breathing; hives; or throat constriction
- chest pain or shortness of breath
- depression, suicidal thoughts, unusual aggressiveness, or uncontrollable mood changes
- In addition, talk to your doctor if you notice thinning hair, a rash or itchiness, nausea, dizziness, nervousness, irritability, insomnia, or pain or redness at the injection site.
What should I discuss with my doctor before using peginterferon and ribavirin?
Before taking this combination therapy, tell your doctor if you have had blood problems such as anemia, high blood pressure, heart problems; a history of depression or another mental illness; drug abuse; lung or breathing problems; kidney disorders; diabetes; thyroid problems; autoimmune disorders; psoriasis; eye problems; pancreatitis; an active infection, liver disease (other than hepatitis C); or bone marrow suppression, which is marked by low red or white blood cells or platelets.
These conditions mean that you might not be a candidate for combination therapy, or that your dosage might need to be adjusted.
Who should be treated — and when?
Surprisingly, this is one of the most difficult and controversial questions in hepatitis C care. Most diseases are treated immediately after they are diagnosed. But because hepatitis C can infect people for years without causing any symptoms, let alone liver damage — and because the treatments pose risks of their own — many experts say it makes sense for some patients to wait.
At the same time, it’s true that some patients do develop serious liver damage. For them, treatment can be life-saving. Unfortunately, it’s not easy for doctors to determine who is at highest risk. Even a high level of the virus in the bloodstream isn’t an indication of the seriousness of the infection.
In 2002, hepatitis C experts met to establish guidelines for treatment. The group, called the National Institutes of Health Consensus Development Conference Panel, recommended that treatment be limited to patients with elevated aminotransferase levels and evidence of progressive liver disease. The determining test is a liver biopsy, which removes a very small piece of liver tissue which can be obtained with a relatively non-invasive procedure called a needle aspiration. If the results show significant fibrosis (fibrous strands in the liver) or moderate to severe inflammation and dying liver cells, treatment is recommended.
As doctors learn more about hepatitis C, they gain additional useful insights into optimal treatment regimens. A study published in 2003 in the Journal of the American Medical Association showed that early treatment may make more sense for men than for women. Scientists found that the probability an infected man will develop cirrhosis over a 30-year period is between 13 and 46 percent. The same risk for a woman is only between 1 and 29. Also, the older people are at the time they become infected, researchers found, the more likely they are to develop serious liver problems.
In another recent advance, researchers at Baylor University Medical Center in Dallas, Texas, reported that it may be possible to predict how well the treatment will work even before the course of therapy is completed. In a study reported in the journal Hepatology, experts found that patients most likely to have a complete response were those who saw a significant drop in viral activity during the first 12 weeks of treatment. Patients who experienced little or no change in virus activity during that same period of time were unlikely to have a complete response, even if the treatment was continued for up to nine months.
In August 2009, scientists at Duke University Medical Center reported that they had identified the first genetic marker that predicts who is most likely to respond to hepatitis C treatment. This discovery provides valuable information for patients and doctors making decisions about the course of treatment.
Who shouldn’t be treated?
Many people infected with hepatitis C virus aren’t sick enough to justify treatment, while those with advanced liver disease are too sick to benefit from interferon/ribavirin, but may be eligible for liver transplant. For patients with certain other medical conditions, the risks of treatment may outweigh the benefits in some instances. Doctors often decide whether treatment is appropriate on a patient-by-patient basis. As a guide, the National Institutes of Health Consensus Development Conference Panel determined that treatment was NOT advisable for:
- Patients with advanced cirrhosis of the liver as a result of hepatitis C
- Patients infected with HCV, but who have normal aminotransferase levels (indicating healthy liver function)
- Patients who have received a kidney, liver, heart, or other solid-organ transplant
- Patients with a high risk of having serious adverse reactions to either peginterferon or ribavirin. This includes patients with severe depression, advanced coronary artery disease, or severe anemia.
- Ribavirin can cause severe birth defects, so women who are unable to stick to a birth control regimen should not take the drug. And because alcohol consumption interferes with peginterferon treatment and worsens the prognosis for people with hepatitis C, patients with a drinking problem should not be treated until they have stopped drinking, usually for a period of six months.
A new push to expand treatment
Guidelines for treatment are likely to change as researchers assess new findings. One controversy is whether patients with normal aminotransferase levels should be treated. The official guidelines say no. But approximately 30 percent of patients with chronic hepatitis C have normal aminotransferase levels. In general, normal or only moderately elevated aminotransferase levels indicate that the disease is progressing very slowly.
Yet a small percentage of patients with normal levels do develop advanced fibrosis or cirrhosis. Such patients are likely to benefit from treatment. Some experts argue that combination therapies are proving to be so successful that they should be offered to more patients.
Official guidelines are just that, of course. Doctors ultimately decide, in consultation with their patients, the best course of treatment. The decision is based on many factors, including the patient’s age, test results, symptoms, and wishes.
The importance of staying informed
Only two decades since hepatitis C virus was identified, doctors have made giant strides in treating the infection. The prognosis for people with the disease has improved dramatically. It’s likely to get even better as doctors learn to increase the benefits of existing drugs, and as new medications come along. Even now, new drug protocols and new drugs are being tested. The standard of care is likely to change as researchers refine their knowledge, so staying informed is a crucial part of staying healthy.
Everyone with hepatitis C, even if mild and nonprogressive, should make sure to see their doctor at least once or twice a year to get blood tests and to learn if there are any new developments in this rapidly changing field.
Chronic Hepatitis C: Current Disease Management. National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK). http://digestive.niddk.nih.gov/ddiseases/pubs/chronichepc/
Seeff et al. The National Institutes of Health Consensus Development Conference management of hepatitis C 2002, Clinical Liver Disease, Feb 2003, pp 261-87
Foy, E. et al. Regulation of interferon regulatory factor-3 by the hepatitis C virus serine protease, Science 2003 300: 1145-1148
Raison CL, et al. Depressive Symptoms and Viral Clearance in Patients Receiving Interferon-alpha and Ribavirin for Hepatitis C. Brain, Behavior, and Immunity. January 2005; 19(1): 23 – 27.
American Liver Foundation. Hepatitis C. October 24, 2007. http://www.liverfoundation.org/abouttheliver/info/hepatitisc/
McHutchison, JG et al. Telaprevir with peginterferon and ribavirin for chronic HCV Genotype 1 infection. New England Journal of Medicine. April 2009.
New Biomarker Predicts Response to Hepatitis C Treatment. http://www.dukehealth.org/health_library/news/new_biomarker_predicts_response_to_hepatitis_c_treatment
Sockalingam S and Abbey SE. Managing depression during hepatitis C treatment. Canadian Journal of Psychiatry. September 2009; 54(9): 614-25.
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