Daclatasvir, Elbasvir, and Grazoprevir in the Treatment of Chronic Hepatitis C

DACLATASVIR, ELBASVIR, AND GRAZOPREVIR IN THE TREATMENT OF CHRONIC HEPATITIS C

Noah Carpenter, MD Dr. Noah Carpenter is a Thoracic and Peripheral Vascular Surgeon practicing in Brandon, Manitoba. He is known for the development of surgical techniques. He attended the University of Manitoba where he graduated with the B.Sc. in chemistry, completed medical school and did his surgical residency and fellowship at the University and Affiliated Hospitals in Edmonton, Alberta. Dr. Carpenter did an additional fellowship at the University of Edinburgh, Scotland in Adult Cardiovascular and Thoracic Surgery, and has specialized in microsurgical techniques, vascular endoscopy, laser and laparoscopic surgery in Vancouver, British Columbia, Canada and Colorado, Texas, Vancouver, and Los Angeles. He has an Honorary Doctorate of Law from the University of Calgary, and was appointed a Citizen Ambassador to China, and has served as a member of the Native Physicians Association of Canada, the Canadian College of Health Service Executives, the Science Institute of the Northwest Territories, the Canada Science Council, and the International Society of Endovascular Surgeons, among others. He has been an inspiration to youth, motivating them to understand the importance of achieving higher education.

ABSTRACT

Hepatitis C virus can cause acute and chronic liver disease. The primary treatment of chronic hepatitis C is antiviral therapy. New antiviral therapy can generally eradicate the virus through an easier and shorter course of care than with prior methods and offer a different approach — targeting the virus itself to fight off the disease — that is proving successful in the fight against hepatitis C. An important consideration for patients diagnosed with chronic hepatitis C viral infection includes ongoing surveillance for liver fibrosis and other complications that can lead to significant morbidity and mortality. 1

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This activity has been planned and implemented in accordance with the policies of NurseCe4Less.com and the continuing nursing education requirements of the American Nurses Credentialing Center's Commission on Accreditation for registered nurses. It is the policy of NurseCe4Less.com to ensure objectivity, transparency, and best practice in clinical education for all continuing nursing education (CNE) activities.

Continuing Education Credit Designation

This educational activity is credited for 2.5 hours. Nurses may only claim credit commensurate with the credit awarded for completion of this course activity. Pharmacology content is 2.5 hours.

Statement of Learning Need

Clinicians need to be informed of the new medications being offered for the treatment of hepatitis C that target the hepatitis C virus, effectively reduce viral load over a shorter period of time, have milder side effects, and have a higher success rate to cure hepatitis C. An understanding of the hepatitis C virus, it’s transmission, risk factors and diagnosis, are critical to clinical decision-making and early treatment to prevent serious liver damage.

Course Purpose

To provide health clinicians with knowledge of chronic hepatitis C etiology, diagnosis, and options for new treatment.

nursece4less.com nursece4less.com nursece4less.com nursece4less.com Target Audience

Advanced Practice Registered Nurses and Registered Nurses (Interdisciplinary Health Team Members, including Vocational Nurses and Medical Assistants may obtain a Certificate of Completion)

Course Author & Planning Team Conflict of Interest Disclosures

Noah Carpenter, MD, William S. Cook, PhD, Douglas Lawrence, MA Susan DePasquale, MSN, FPMHNP-BC – all have no disclosures

Acknowledgement of Commercial Support

There is no commercial support for this course.

Please take time to complete a self-assessment of knowledge, on page 4, sample questions before reading the article. Opportunity to complete a self-assessment of knowledge learned will be provided at the end of the course.

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1. Daclatasvir is a direct-acting antiviral drug approved for use to treat

a. adult patients with chronic Hepatitis C virus (HCV). b. patients with HCV genotypes 5 or 6. c. patients with chronic HCV but only after previous interferon-based therapy has failed. d. a person in the acute phase of HCV.

2. Is daclatasvir safe and effective for treating individuals with HIV and HCV co-infection?

a. Yes, its effectiveness and safety have been well-studied. b. Its effectiveness and safety in co-infected individuals has not been determined. c. No, it cannot be prescribed for co-infected individuals because it interacts poorly with most HIV drugs. d. Yes, but only in patients with advanced liver damage.

3. Daclatasvir is effective only if it is administered

a. with food. b. without food. c. by itself. d. with other Hepatitis C medications.

4. Hepatitis C patients who have responded best to treatment with daclatasvir include those who

a. failed to respond to other, prior drug treatments. b. took the drug as a stand-alone treatment. c. responded well to interferon based therapy. d. had mild or moderate liver fibrosis.

5. Reported side effects of daclatasvir indicate that the medication

a. is well-tolerated with no known specific side effects. b. has serious side effects of its own. c. causes dizziness and moderate to severe muscle pain. d. causes insomnia or difficulty staying asleep.

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Introduction

Daclatasvir (Daklinza) is a medication taken orally and used in combination with other medications to treat hepatitis C virus (HCV). Daclatasvir works as one of the new direct-acting antiviral (DAA) drugs. Elbasvir and grazoprevir are used in combination to treat hepatitis C genotypes 1 and 4 and considered useful for patients diagnosed with cirrhosis, human immunodeficiency virus (HIV), and kidney disease. There are factors that predict how well a patient will respond to either of these drug treatments.

Treating Hepatitis C with Daclatasvir

Daclatasvir has the brand name Daklinza and is indicated for chronic hepatitis C (genotype 1a or 1b) at varied doses ranging from 60 mg orally daily with concomitant sofosbuvir or Peginterferon/ribavirin-experienced patients for 12 weeks in treatment naive individuals without cirrhosis for 12 weeks and in patients with decompensated cirrhosis at 60 mg once daily with concomitant sofosbuvir and ribavirin for 12 weeks. Treatment may be extended to 24 weeks for patients who are ribavirin-ineligible. In Canada, patients with genotype 1b, with or without compensated cirrhosis, may receive daclatasvir when used concomitantly with asunaprevir [Canadian product] for a recommended 24 weeks; if used concomitantly with asunaprevir, peginterferon alfa, and ribavirin in patients with genotypes 1 or 4 (with or without compensated cirrhosis), the 2017 labeled treatment recommendation duration is 24 weeks.35

Side Effects

Side effects can include headache and fatigue, however, the choice to take daclatasvir would consider that benefits outweigh the risks and side effects. Successful treatments can reduce the risk of long-term complications of 5

nursece4less.com nursece4less.com nursece4less.com nursece4less.com hepatitis C, which includes liver cancer or the need of a liver transplant.34,35 There are other off-label uses that will not be addressed here, but are well covered in the prescribing information and other current prescribing resources for clinicians with helpful patient handouts.

HCV Life Cycle

Daclatasvir works as one of the new direct-acting antiviral drugs. It targets different steps of the HCV lifecycle, and interferes with a protein the virus uses to reproduce. Daclatasvir is the first-ever approved HCV NS5A replication complex inhibitor.1

Daclatasvir should be combined with other medications.1 As mentioned, this can include other direct-acting antivirals that work differently, such as sofosbuvir or the HCV protease inhibitor asunaprevir, or pegylated interferon and ribavirin. Those who can use daclatasvir are adults with chronic hepatitis C (lasting more than six months). Its use is approved for people with HCV was initially approved only for genotype 3 in 2015 and expanded in 2016 to include Genotype 1 and Genotype 3, including individuals with human immunodeficiency virus (HIV) coinfection or advanced cirrhosis, or after liver transplant. Genotype 3 is harder to contract than Genotype 1, and Genotype 3 is also the hardest genotype to treat.2,34,35

Daclatasvir can be used by both patients who are treatment-naive, that is, who are being treated for hepatitis C for the first time, and patients who are treatment-experienced - patients who previously received a course of treatment for hepatitis C. Patients are reported to be treatment-experienced if they have been previously treated and relapsed, partially responded to treatment, or did not respond at all to treatment. Individuals who underwent

nursece4less.com nursece4less.com nursece4less.com nursece4less.com incomplete treatment for HCV due to dropping out of treatment and noncompliance would also be considered as treatment-experienced.

Co-infection and Daclatasvir

The safety and effectiveness of daclatasvir has not been determined yet in individuals with HIV and HCV co-infection, and this is currently being tested. According to studies, daclatasvir does not have a problematic interaction with the most widely used HIV drugs. If a person has HIV and HCV co- infection and wants to take daclatasvir, the person should be under the care of a medical clinician who has experience treating both HCV and HIV.

People with all stages of compensated liver disease can use daclatasvir. This includes those people who have cirrhosis. Daclatasvir works better for people with less advanced liver damage. The drug is being tested for people with chronic hepatitis C and waiting for or who have received a liver transplant.

Dosing and Duration of Treatment

Patient instruction for taking daclatasvir is that the treatment of hepatitis C with this drug involves a once per day administration to be given with sofosbuvir and other drugs, as noted. Daclatasvir is available in 30 and 60 mg tablets. The usual dose is 60 mg once daily with or without food.

As mentioned, daclatasvir must be used in combination with other hepatitis C medications and is not effective if taken alone. Some of the medication combinations used with daclatasvir are listed below.34,35

Genotype 1: Daclatasvir & sofosbuvir

● 12 weeks (no cirrhosis) - 24 weeks (with cirrhosis)

nursece4less.com nursece4less.com nursece4less.com nursece4less.com Genotype 1: Daclatasvir & sofosbuvir & ribavirin

● 12 weeks (post-liver transplant, no cirrhosis)

● 12 weeks (with cirrhosis A or B)

● 24 weeks (with decompensated cirrhosis)

Genotype 2 - Daclatasvir & sofosbuvir

● Evidence lacking to make a recommendation on duration; at least 12 weeks.

Genotype 3 - Daclatasvir & sofosbuvir

● 12 weeks (no cirrhosis)

Genotype 3 - Daclatasvir & sofosbuvir & ribavirin

● 12 weeks (post-transplant, no cirrhosis)

● 24 weeks (with cirrhosis)

Genotype 4 - Daclatasvir & sofosbuvir

● 12 weeks (no cirrhosis)

● 24 weeks (with cirrhosis)

Genotype 4 - Daclatasvir & sofosbuvir & ribavirin

● 12 weeks (post-transplant or with cirrhosis A or B)

● 24 weeks (with decompensated cirrhosis)

Genotype 4 - Alternative

● Daclatasvir plus weekly pegylated interferon injections and ribavirin pills for 24 weeks is another option. Slow responders should continue on pegylated interferon and ribavirin for 48 weeks.

nursece4less.com nursece4less.com nursece4less.com nursece4less.com Some patients respond better than others to daclatasvir. Some of the factors that predict how well a patient responds include HCV genotype, previous treatment history, and extent of liver damage. Someone with liver cirrhosis will not respond as well as someone with mild or moderate liver fibrosis.

People who are new to treatment may have a better chance of being cured than those with little or no response to previous treatment. A person’s response to treatment with daclatasvir also depends on which drug(s) is/are combined with daclatasvir. The factors that traditionally predict poor response to interferon based therapy do not apply or make much difference with interferon-free treatments. Overcoming these factors is possible by prolonging treatment or adding another direct-acting antiviral drug or ribavirin.

Daclatasvir and Treatment Response

Concerning daclatasvir and treatment response, patients who have a sustained virological response, who still have undetectable HCV viral load 12 weeks after finishing treatment (known as 'SVR12'), are considered cured. A phase 2 study included people with HCV genotype 1 who were previously untreated and those already treated with pegylated interferon and ribavirin, plus the older HCV protease inhibitors boceprevir or telaprevir. One hundred percent of people in both groups treated for either 12 or 24 weeks were cured with daclatasvir plus sofosbuvir.1-3

During testing of daclatasvir plus sofosbuvir for 24 weeks, a small number was tested and included previously untreated people with HCV genotype 2 or 3. When treated with daclatasvir plus sofosbuvir alone, 96 percent of people with genotype 2 were cured. Of those with genotype 3, 98 percent were

nursece4less.com nursece4less.com nursece4less.com nursece4less.com cured. When ribavirin was added to daclatasvir and sofosbuvir, the cure rate for genotype 3 was 100 percent.7-9

Daclatasvir was tested in combination with pegylated interferon and ribavirin for previously untreated people with HCV genotype 4 in the COMMAND-4 trial. For those with and without cirrhosis about 80 percent were cured with this triple combination. This was a cure rate of twice as many as those taking interferon and ribavirin alone. In actual medical case reports and not a clinical trial the cure rate and effectiveness of daclatasvir can be lower in part as patients could be more ill or have other conditions that complicate treatment.3,6

Drug Interactions and Warnings

Reported side effects of daclatasvir indicate that the medication is generally well-tolerated with no known specific side effects of its own. Fatigue, nausea, and headache were the most common side effect in people taking daclatasvir with sofosbuvir. If a patient is taking daclatasvir with interferon and ribavirin, the patient can experience side effects that include fever, muscle and joint aches, itching, depression, anemia (low hemoglobin level), and neutropenia (low white blood cell count). Ribavirin can also cause birth defects. A patient who is pregnant or her male partners should not use the medication.34,35

Daclatasvir can interact with other drugs that are processed with the same gut and liver enzymes. This includes some tuberculosis (TB), antibiotic, and anti-seizure drugs, as well as herbal products that contain St John’s wort.36 There are cases where a drug dose adjustment can overcome these interactions. Some medications should not be used with daclatasvir.

nursece4less.com nursece4less.com nursece4less.com nursece4less.com The other medications used in combination with daclatasvir - sofosbuvir, ribavirin, and interferon - is a choice of combination treatment that varies depending on the virus type and whether the person has cirrhosis. These combination therapies contain NS5A inhibitors.38 Common side effects with sofosbuvir and daclatasvir include headache, feeling tired, and nausea. With daclatasvir, sofosbuvir, and ribavirin the most common side effects are headache, feeling tired, nausea, and red blood cell breakdown.37

Cost of Therapy

When daclatasvir should be started to treat hepatitis C depends on several factors. The severity of liver damage is an important factor to determining treatment and can be obtained through use of a FibroScan (non-invasive device that assesses liver hardness) or liver biopsy. Daclatasvir received approval for use in the United States and India in 2015 and in Europe in 2014. It is on the List of Essential Medicines (the most effective and safe medications) needed in a health system, as maintained by the World Health Organization (WHO).39 Hill, et al., noted that as of January 2016, a twelve- week course costs around $63,000 in the United States, $39,000 in the United Kingdom, $37,000 in France, and $525 in Egypt.40

Elbasvir and Grazoprevir

This section discusses the use of elbasvir and grazoprevir for treating hepatitis C and addresses genotypes 1 or 4, how the medication is taken, and the drug side effects. These medications are useful for a patient who has cirrhosis, HIV, and kidney disease.41 According to the University of Washington medicine section that reviews elbasvir-grazoprevir (Zepatier), the drug provides a safe, effective, well-tolerated, treatment option for patients with genotype 1 or 4 infection. The drug is taken in a single pill

nursece4less.com nursece4less.com nursece4less.com nursece4less.com form and once daily. For a patient with genotype 1a, the patient needs resistant virus testing before starting therapy.41

Resistant Viruses

These newly formed resistant viruses have a selective growth advantage that allows them to replicate in the presence of antiviral drugs. In a subset of patients with chronic HCV infection, viral variants harboring substitutions associated with resistance to HCV direct-acting antivirals are detectable prior to antiviral therapy and, particularly in the case of NS5A inhibitor-containing regimens, may negatively impact treatment response. These substitutions often are referred to as baseline resistance-associated substitutions (RASs).

A patient with genotype 1a is 10 to 15 percent likely to have the presence of a substitution at amino acid positions 28, 30, 31, or 93. This requires the addition of ribavirin and extension of therapy from 12 to 16 weeks. This can be a particularly good option for a patient with HCV and severe renal impairment and when sofosbuvir-based regimens may not be optimal.41

Elbasvir-grazoprevir is an oral fixed-dose combination of an NS5A replication complex inhibitor (elbasvir) and a “later”-generation HCV NS3/4A protease inhibitor (grazoprevir). Elbasvir was formerly MK-8742 and is a small molecule inhibitor of nonstructural protein 5A. It possesses in vitro activity against most major HCV genotypes and some viral variants resistant to earlier NS5A inhibitors. Grazoprevir is a macrocyclic compound that reversibly binds to the HCV NS3/4A protease, an enzyme responsible for cleaving and processing the HCV-encoded polyprotein. It is distinct from earlier-generation protease inhibitors due to its in vitro activity against a broader array of HCV genotypes, as well as activity against some of the

nursece4less.com nursece4less.com nursece4less.com nursece4less.com major resistance-associated variants (R155K and D168Y) resulting from failure with first-generation protease inhibitors.41,65

Adverse Effects

Pooled data from phase 2 and phase 3 trials revealed that the most commonly observed adverse effect in patients receiving elbasvir-grazoprevir were fatigue (11%), headache (10%), and nausea (5%). For 1 percent of subjects, elevations in alanine aminotransferase (ALT) levels to greater than 5 times the upper limit of normal typically occurred at or after 8 weeks of therapy. In most cases this resolved at or after the completion of therapy. Rash and photosensitivity noted with earlier protease inhibitors have not been found to be a problem.42-44,65

Drug Precaution and Warning

Before taking elbasvir and grazoprevir, special precautions that patients should take include informing their medical clinician whether they are allergic to elbasvir, grazoprevir, any other medications, or any of the ingredients in elbasvir and grazoprevir tablets. A patient should also report to a clinician when taking atazanavir, carbamazepine, cyclosporine, darunavir, efavirenz, lopinavir, phenytoin, rifampin, saquinavir, St. John's wort, or tipranavir. Taking one or more of these medications may lead to the medical decision to not prescribe elbasvir and grazoprevir.

For a person who is a candidate for therapy with elbasvir and grazoprevir there is an important warning. This warning states that a patient could already be infected with hepatitis B but have no symptoms of the condition. In such a case, taking a combination of elbasvir and grazoprevir could increase the risk that the infection may become more serious or life-

nursece4less.com nursece4less.com nursece4less.com nursece4less.com threatening, and patients taking the drug could also be at increased risk of developing symptoms.45

Patients who have or had a hepatitis B viral infection should convey this to their medical clinician. As mentioned previously, blood testing to determine the presence of hepatitis B infection can be done. The patient should be monitored for signs of a hepatitis B infection during and for several months after treatment and symptoms of excessive tiredness, yellowing of the skin or eyes, loss of appetite, nausea or vomiting, pale stools, stomach pain, or dark urine should be reported to a patient’s medical clinician.

Goal of Therapy

A combination of elbasvir and grazoprevir is used alone or in combination with ribavirin to treat chronic and long-term hepatitis C infection. Elbasvir is in a class of antiviral medications called HCV NS5A inhibitors, and works to stop HCV from spreading.41,65 Grazoprevir is in a class of medications called protease inhibitors, working by decreasing the amount of HCV in the body. It is not known whether elbasvir and grazoprevir prevent the spread of hepatitis C.

Elbasvir and grazoprevir can be taken with or without food once a day for 12 to 16 weeks and should be taken at about the same time every day.41 Patients taking elbasvir and grazoprevir should continue to take the medication even when feeling well. The length of treatment depends on the patient’s condition, response to treatment, and whether any undesirable side effects are encountered.

A patient should also report to interdisciplinary health team members when taking or planning to take nutritional supplements, vitamins, and herbal

nursece4less.com nursece4less.com nursece4less.com nursece4less.com products. This should include bosentan, cobicistat taken along with elvitegravir, emtricitabine, and tenofovir, etravirine, and medications to treat high cholesterol, ketoconazole, modafinil, nafcillin, tacrolimus, and warfarin. Doses of medications may need to be changed and the patient monitored carefully for side effects. Other medications can also interact with elbasvir and grazoprevir. A patient should report all medications taken even if they do not appear on the list of those with warnings.

Additional Considerations

Patients should report to their medical clinician any type of existing disease other than Hepatitis C. This could determine whether elbasvir and grazoprevir should be prescribed or not. In addition, a patient should report whether he or she had or is waiting for a liver transplant, has human immunodeficiency virus (HIV), or is pregnant, breastfeeding, or planning to become pregnant. A patient should report if she becomes pregnant while taking elbasvir and grazoprevir.41,65

If a dose is missed, the patient should take the missed dose as soon as possible; however, if it is almost time for the next dose, the missed dose should be skipped, and the patient should continue the regular dosing schedule. A double dose should not be taken to make up for a missed one.

There are no special dietary instructions when taking elbasvir and grazoprevir. However, side effects may include gut issues, such as diarrhea, and headache, difficulty falling asleep or staying asleep. These symptoms should be reported if they are severe or do not go away.

Cost of Therapy 15

nursece4less.com nursece4less.com nursece4less.com nursece4less.com The acquisition cost for elbasvir-grazoprevir has been reported to be $54,600 and notably lower than other first-line regimens. Merck & Co., Inc. manufactures elbasvir and grazoprevir (Zepatier) and the list price is for a 12-week treatment course. A 16 week course costs $72,800 and patient assistance is available for those who cannot obtain or afford elbasvir- grazoprevir.41

Case Study

A 52-year-old female was diagnosed with an HCV genotype 1b infection over 10 years. Comorbid health concerns during history and physical revealed diabetes mellitus and chronic pancreatitis. Diabetes was regulated with insulin 24 units daily and gabapentin 600 mg daily for blood sugar level control and complications of pain from diabetic neuropathy, respectively. On occasion, trazodone was taken for difficulty sleeping and ibuprofen at bedtime for breakthrough pain if interfering with sleep.

The patient was reported to be an interferon-treatment naïve patient and received prior treatment of ledipasvir 90 mg daily and sofosbuvir 400 mg daily 7 months previously. Unfortunately, there were cardiac side effects such as rapid heart rate after just a few days of treatment, which required that treatment be stopped. The patient was referred to a cardiologist for work up and required no long-term cardiac treatment and the rapid heart rate did not recur. The laboratory data before proceeding with retreatment showed complete blood count with mild anemia and a comprehensive metabolic panel with glucose level 180 and mild kidney disease with a GFR range of 75 percent with serum potassium level at the high end of normal. The patient had no signs of cirrhosis. Testing for HCV indicated a HCV NS5A resistant-associated variant (RAV).

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The patient was educated about the benefits and risks of starting grazoprevir and elbasvir, including risk of fatigue, headache, nausea and a lower risk of elevations in serum alanine aminotransferase greater than five times the upper level of normal and elevated bilirubin, as well as possible re-infection with HCV. The patient signed an informed consent to start grazoprevir 100 mg daily and elbasvir 50 mg daily to be administered orally for 12 weeks. The patient completed the full course of treatment without major adverse events and only moderate nausea initially that was easily alleviated with ondansetron 4 mg orally as needed twice daily.

The patient’s estimated glomerular filtration rate (eGFR) was unchanged during the therapy. There was rapid virologic response (RVR) and the serum HCV RNA was negative at week 4 was achieved after commencing treatment and SVR at 12 weeks and the end of treatment.

Discussion

Grazoprevir and elbasvir given once daily is known to provide effective and tolerable treatment for HCV infected patients. In the case of the patient above, she did not have cirrhosis and showed good response to treatment; however, if cirrhosis were to develop grazoprevir and elbasvir would still have been considered effective treatment. Patients with renal disease and patients with HIV co-infection may use grazoprevir and elbasvir for the treatment of HCV. Grazoprevir and elbasvir is considered a promising regimen for HCV treatment.

Summary

Daclatasvir is a medication taken orally and used in combination with other

nursece4less.com nursece4less.com nursece4less.com nursece4less.com medications to treat hepatitis C virus. Daclatasvir works as one of the new direct-acting antiviral drugs and is indicated for chronic HCV genotype 1a or 1b at varied doses and durations for treatment naive individuals without cirrhosis and with decompensated cirrhosis. Elbasvir and grazoprevir are used in combination to treat hepatitis C genotypes 1 and 4. Elbasvir and grazoprevir are useful for a patient who has cirrhosis, HIV, and kidney disease. There are factors that predict how well a patient will respond to either of these drug treatments. Some patients respond better than others to daclatasvir. Factors that predict how well a patient responds include HCV genotype, previous treatment history, and the extent of liver damage.

HCV infection continues to be a major health concern worldwide. HCV can lead to chronic liver disease, and in some cases it can cause hepatic cirrhosis. The advent of direct-acting antivirals has improved patient outcomes, and they are well well-tolerated medications with high cure rates. However, these medications are expensive and barriers exist to treatment that prevent successful completion of a treatment course of care and HCV cure. More could be said about the efficacy of HCV drug treatment and patient compliance with treatment and accessibility to treatment in future research and clinical studies.

Please take time to help NurseCe4Less.com course planners evaluate the nursing knowledge needs met by completing the self-assessment of Knowledge Questions after reading the article, and providing feedback in the online course evaluation.

Completing the study questions is optional and is NOT a course requirement. 1. Daclatasvir is a direct-acting antiviral drug approved for use to treat

a. adult patients with chronic hepatitis C virus. 18

nursece4less.com nursece4less.com nursece4less.com nursece4less.com b. patients with HCV genotypes 5 or 6. c. patients with chronic HCV but only after previous interferon-based therapy has failed. d. a person in the acute phase of HCV.

2. Is daclatasvir safe and effective for treating individuals with HIV and HCV co-infection?

3. Daclatasvir is effective only if it is administered

a. with food. b. without food. c. by itself. d. with other hepatitis C medications.

4. Hepatitis C patients who have responded best to treatment with daclatasvir include those who

a. failed to respond to other, prior drug treatments. b. took the drug as a stand-alone treatment. c. responded well to interferon based therapy. d. had mild or moderate liver fibrosis.

5. Reported side effects of daclatasvir indicate that the medication

6. One of the most commonly observed adverse effect in patients receiving elbasvir-grazoprevir is

a. nausea. 19

nursece4less.com nursece4less.com nursece4less.com nursece4less.com b. fatigue. c. muscle pain. d. insomnia.

7. A patient taking elbasvir and grazoprevir should

a. take the medication only when symptomatic. b. not take the medication with food. c. continue taking the medication even if the patient feels well. d. take the medication only in the morning.

8. True or False: There are no special dietary instructions when taking elbasvir and grazoprevir.

a. True b. False

9. For patients receiving elbasvir-grazoprevir, some may have

a. debilitating photosensitivity. b. severe rash requiring cessation of treatment. c. elevated alanine aminotransferase (ALT) levels. d. All of the above

10. Daclatasvir can interact with other drugs that are processed with the same enzymes in the intestines and liver, such as

a. sofosbuvir. b. ribavirin. c. some tuberculosis medications. d. pegylated interferon.

11. Daclatasvir works best in patients who have

a. advanced, end-stage liver damage. b. less advanced liver damage. c. decompensated liver disease. d. received a liver transplant.

12. A patient receiving daclatasvir to treat hepatitis C is considered treatment-naive if the patient

nursece4less.com nursece4less.com nursece4less.com nursece4less.com a. are being treated for hepatitis C for the first time. b. were previously treated for hepatitis C but relapsed. c. did not complete a prior hepatitis C treatment. d. All of the above

13. True or False: A common side effect of daclatasvir co- administered with sofosbuvir, and ribavirin is red blood cell breakdown.

a. True b. False

14. Elbasvir and grazoprevir are used as a combination drug that

a. must be used alone to treat hepatitis C virus (HCV). b. prevents the spread of HCV. c. includes elbasvir because it is a protease inhibitor. d. may be combined with ribavirin to treat chronic and long-term HCV infection.

15. The length of treatment with elbasvir and grazoprevir

a. is a preset regimen that is used uniformly for each patient. b. cannot extend beyond 12 weeks. c. should be stopped as soon as the patient feels well. d. depends on the patient’s response to treatment.

CORRECT ANSWERS:

nursece4less.com nursece4less.com nursece4less.com nursece4less.com 1. Daclatasvir is a direct-acting antiviral drug approved for use to treat

a. adult patients with chronic hepatitis C virus.

“Those who can use daclatasvir are adults with chronic hepatitis C (lasting more than six months).”

2. Is daclatasvir safe and effective for treating individuals with HIV and HCV co-infection?

b. Its effectiveness and safety in co-infected individuals has not been determined.

“The safety and effectiveness of daclatasvir has not been determined yet in individuals with HIV and HCV co-infection, and this is currently being tested.”

3. Daclatasvir is effective only if it is administered

d. with other hepatitis C medications.

“Daclatasvir is available in 30 and 60 mg tablets. The usual dose is 60 mg once daily with or without food. As mentioned, it must be used in combination with other hepatitis C medications and is not effective if taken alone.”

4. Hepatitis C patients who have responded best to treatment with daclatasvir include those who

d. had mild or moderate liver fibrosis.

“Some patients respond better than others to daclatasvir. Some of the factors that predict how well a patient responds include HCV genotype, previous treatment history, and extent of liver damage. Someone with liver cirrhosis will not respond as well as someone with mild or moderate liver fibrosis. People who are new to treatment may have a better chance of being cured than those with little or no response to previous treatment.”

nursece4less.com nursece4less.com nursece4less.com nursece4less.com

5. Reported side effects of daclatasvir indicate that the medication

a. is well-tolerated with no known specific side effects.

“Reported side effects of daclatasvir indicate that the medication is generally well-tolerated with no known specific side effects of its own.”

6. One of the most commonly observed adverse effect in patients receiving elbasvir-grazoprevir is

b. fatigue.

“Pooled data from phase 2 and phase 3 trials revealed that the most commonly observed adverse effect in patients receiving elbasvir-grazoprevir were fatigue (11%), headache (10%), and nausea (5%).”

7. A patient taking elbasvir and grazoprevir should

c. continue taking the medication even if the patient feels well.

“Patients taking elbasvir and grazoprevir should continue to take the medication even when feeling well.”

8. True or False: There are no special dietary instructions when taking elbasvir and grazoprevir.

a. True

“There are no special dietary instructions when taking elbasvir and grazoprevir.”

9. For patients receiving elbasvir-grazoprevir, some may have

c. elevated alanine aminotransferase (ALT) levels.

“For 1 percent of subjects, elevations in alanine aminotransferase (ALT) levels to greater than 5 times the upper limit of normal typically occurred at or after 8 weeks of therapy. In most cases this resolved at or after the completion of therapy. Rash and photosensitivity noted with earlier protease inhibitors have not been found to be a problem.”

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10. Daclatasvir can interact with other drugs that are processed with the same enzymes in the intestines and liver, such as

c. some tuberculosis medications.

“Daclatasvir can interact with other drugs that are processed with the same gut and liver enzymes. This includes some tuberculosis (TB), antibiotic, and anti-seizure drugs, as well as herbal products that contain St John’s wort. There are cases where a drug dose adjustment can overcome these interactions. Some medications should not be used with daclatasvir.”

11. Daclatasvir works best in patients who have b. less advanced liver damage.

“People with all stages of compensated liver disease can use daclatasvir. This includes those people who have cirrhosis. Daclatasvir works better for people with less advanced liver damage. The drug is now being tested for people with chronic hepatitis C and waiting for or having received a liver transplant.”

12. A patient receiving daclatasvir to treat hepatitis C is considered treatment-naive if the patient a. are being treated for hepatitis C for the first time.

“Daclatasvir can be used by both patients who are treatment-naive, that is, who are being treated for hepatitis C for the first time, and patients who are treatment-experienced - patients who previously received a course of treatment for hepatitis C. Patients are reported to be treatment-experienced if they have been previously treated and relapsed, partially responded to treatment, or did not respond at all to treatment. Individuals who underwent incomplete treatment for HCV due to dropping out of treatment and noncompliance would also be considered as treatment-experienced.”

13. True or False: A common side effect of daclatasvir co- administered with sofosbuvir, and ribavirin is red blood cell breakdown. a. True

nursece4less.com nursece4less.com nursece4less.com nursece4less.com “Common side effects with sofosbuvir and daclatasvir include headache, feeling tired, and nausea. With daclatasvir, sofosbuvir, and ribavirin the most common side effects are headache, feeling tired, nausea, and red blood cell breakdown.” 14. Elbasvir and grazoprevir are used as a combination drug that d. may be combined with ribavirin to treat chronic and long-term HCV infection.

“A combination of elbasvir and grazoprevir is used alone or in combination with ribavirin to treat chronic and long-term hepatitis C infection. Elbasvir is in a class of antiviral medications called HCV NS5A inhibitors, and works to stop HCV from spreading. Grazoprevir is in a class of medications called protease inhibitors, working by decreasing the amount of HCV in the body. It is not known whether elbasvir and grazoprevir prevent the spread of hepatitis C.”

15. The length of treatment with elbasvir and grazoprevir d. depends on the patient’s response to treatment.

“Elbasvir and grazoprevir can be taken with or without food once a day for 12 to 16 weeks and should be taken at about the same time every day. Patients taking elbasvir and grazoprevir should continue to take the medication even when feeling well. The length of treatment depends on the patient’s condition, response to treatment, and whether any undesirable side effects are encountered.”

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Reference Section

The References below include published works and in-text citations of published works that are intended as helpful material for your further reading. [References are for a multi-part series on the NEW HEPATITIS C VIRUS THERAPIES.]

1. Facente, SN, et al. (2018). New Treatments Have Changed the Game: Hepatitis C Treatment in Primary Care. Infect Dis Clin North Am. 2018 Jun;32(2):313-322. 2. Chopra, S. and Pockros, M. (2017). Overview of the Management of Chronic Hepatitis C Virus Infections. UpToDate. Retrieved from https://www.uptodate.com/contents/overview-of-the-management-of- chronic-hepatitis-c-virus- infection?search=hepatitis%20C&source=search_result&selectedTitle= 1~150&usage_type=default&display_rank=1 3. Zuckerman, A, et al. (2018). Increasing success and evolving barriers in the hepatitis C cascade of care during the direct acting antiviral era. PLoS ONE 13 (6): e0199174. https://doi.org/10.1371/journal.pone.0199174 4. Mayo Clinic (2018). Hepatitis C. Patient Care & Health Information. Hepatitis C Care at Mayo Clinic. Retrieved from https://www.mayoclinic.org/diseases-conditions/hepatitis-c/symptoms -causes/syc-20354278 5. Pierce, BG, et al. (2016). Global mapping of antibody recognition of the hepatitis C virus E2 glycoprotein: Implications for vaccine design. Proc Natl Acad Sci U S A. 2016 Oct 26. pii: 201614942. 6. Pockros, P. (2018). Direct-acting antivirals for the treatment of hepatitis C virus infection. UpToDate. Retrieved from https://www.uptodate.com/contents/direct-acting-antivirals-for-the-tr eatment-of-hepatitis-c-virus-infection 7. American Liver Foundation (2016). Advances in medications to treat Hepatitis C. Retrieved from http://hepc.liverfoundation.org/treatment/the-basics-about-hepatitis- c-treatment/advances-in-medications/ 8. American Liver Foundation (2016). Can Hepatitis C Be Cured? Retrieved from http://hepc.liverfoundation.org/diagnosis/can-hepatitis-c-be-cured/ 26

nursece4less.com nursece4less.com nursece4less.com nursece4less.com 9. Lanini, S., et al. (2018). Members of the Lazio Region HCV treatment group. Impact of new DAA therapy on real clinical practice: a multicenter region-wide cohort study. BMC Infect Dis.;18(1):223. 10. Fuerst, TR, et al (2018). Designing a B Cell-Based Vaccine against a Highly Variable Hepatitis C Virus. Front Microbiol. 2018 Jan 15;8:2692. 11. Welzel, T., et al. (2016). Daclatasvir plus sofosbuvir, with or without ribavirin, achieved high sustained virological response rates in patients with HCV infection and advanced liver disease in a real-world cohort. Gut. 2016 Nov;65(11):1861-1870. doi: 10.1136/gutjnl-2016-312444. Retrieved from https://www.ncbi.nlm.nih.gov/pubmed/27605539 12. Simon, S. (2015). Pruritus in Hepatitis C: Tips to help with itching. Retrieved from https://hepatitisc.net/living/pruritus/ 13. Mazoff, C. (2014). Pruritus (itching). Retrieved from http://hcvadvocate.org/hepatitis/factsheets_pdf/pruritus.pdf 14. Olysio.com. (2017). What are the possible side effects of Olysio? Retrieved from https://www.olysio.com/common-side-effects 15. Chopra, S. and Arora, S. (2018). Patient evaluation and selection for antiviral therapy for chronic hepatitis C virus infection. UpToDate. Retrieved online at https://www.uptodate.com/contents/patient-evaluation-and-selection- for-antiviral-therapy-for-chronic-hepatitis-c-virus-infection?search=he patitis%20c%20treatment%20and%20side%20effects&source=search _result&selectedTitle=5~150&usage_type=default&display_rank=5. 16. Liu, CY, et al. (2016). Utilization and prescription patterns of traditional Chinese medicine for patients with hepatitis C in Taiwan: a population-based study. BMC Complement Altern Med. 2016;16(1):397. 17. MedlinePlus (2018). Daclatasvir. U.S. National Library of Medicine Retrieved from https://medlineplus.gov/druginfo/meds/a615044.html 18. MedlinePlus (2018). Hepatitis. U.S. National Library of Medicine. Retrieved from https://medlineplus.gov/hepatitis.html 19. World Health Organization. (2016). What is hepatitis ? 2018 WHO. Retrieved from http://www.who.int/features/qa/76/en/ 20. National Institute of Allergy and Infectious Disease (2015). Hepatitis. NIH. Retrieved from https://www.niaid.nih.gov/diseases- conditions/hepatitis 21. World Health Organization. (2017). Hepatitis B. 2018 WHO. Retrieved from http://www.who.int/mediacentre/factsheets/fs204/en/ 22. World Health Organization. (2017). New hepatitis data highlight need for urgent global response. 2018 WHO. Retrieved from http://www.who.int/news-room/fact-sheets/detail/hepatitis-c 23. Nguyen, T., et al. (2016). The Worsening Profile of Alcoholic Hepatitis in the United States. Alcohol Clin Exp Res. 2016 Jun;40(6): 1295-1303. Retrieved from 27

nursece4less.com nursece4less.com nursece4less.com nursece4less.com https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4918810/ 24. Can, C. (2017). Hepatitis A Outbreaks Appearing Across the Nation. U.S. Department of Health and Human Services. Retrieved from https://www.hhs.gov/hepatitis/blog/2017/08/08/hepatitis-a-outbreaks -appearing-across-the-country.html 25. MedlinePlus (2018). Alcoholic liver disease. U.S. National Library of Medicine. Retrieved from https://medlineplus.gov/ency/article/000281.htm 26. Ogholikhan, S. and Schwarz, K. (2016). Vaccines (Basel). Hepatitis Vaccines. 2016 Mar; 4(1): 6. Retrieved from https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4810058/ 27. Koff, R. (2018). Immunizations for patients with chronic liver disease. UpToDate. Retrieved from https://www.uptodate.com/contents/immunizations-for-patients-with- chronic-liver-disease?search=hepatitis%20a%20and%20%20b%20vac cines&source=search_result&selectedTitle=8~150&usage_type=defaul t&display_rank=8. 28. Ippolito, AM, et al (2017). HCV clearance after direct-acting antivirals in patients with cirrhosis by stages of liver impairment: The ITAL-C network study. Dig Liver Dis. 2017 Sep;49(9):1022-1028. 29. Chopra, S. and Muir, AJ. (2018). Treatment regimens for chronic hepatitis C virus genotype 1 infection in adults. UpToDate. Retrieved from https://www.uptodate.com/contents/treatment-regimens-for- chronic-hepatitis-c-virus-genotype-1-infection-in- adults?search=direct%20acting%20antivirals&source=search_result&s electedTitle=6~150&usage_type=default&display_rank=6. 30. World Health Organization. (2017). WHO endorses direct-acting antivirals for treatment of hepatitis C. 2018 WHO. Retrieved from http://www.who.int/hepatitis/news-events/direct-acting-antiviral-cure- hepatitis-c/en/ 31. Pockros, P. (2017). Direct-acting antivirals for the treatment of hepatitis C virus infection. UpToDate. Retrieved from https://www.uptodate.com/contents/direct-acting-antivirals-for-the- treatment-of-hepatitis-c-virus-infection 32. Applegate, TL, Farado, E., and Sacks, JA. (2018). Hepatitis C Virus Diagnosis and the Holy Grail. Infect Dis Clin North Am.;32(2):425-445. 33. Jakobsen, J., Nielsen, E., et al. (2017). Direct-acting antivirals for chronic hepatitis C. Cochrane Library. Retrieved from http://www.natap.org/2017/HCV/CD012143%2033.pdf 34. National Institute of Health (2018). Daclatasvir. NIH. Retrieved from https://pubchem.ncbi.nlm.nih.gov/compound/Daclatasvir 35. Lexicomp (2018). Daclatasvir. UpToDate. Retrieved from https://www.uptodate.com/contents/daclatasvir-patient-drug-informat ion?search=daclatasvir&source=search_result&selectedTitle=2~21&us 28

nursece4less.com nursece4less.com nursece4less.com nursece4less.com age_type=default&display_rank=2. 36. The American Society of Health-System Pharmacists. (2016). Daclatasvir Dihydrochloride 37. Food and Drug Administration (2016). Daclatasvir label. FDA. Retrieved from https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/206843s 006lbl.pdf 38. Electronic Medicines Compendium. (2016). Daklinza film-coated tablets - Summary of Product Characteristics 39. World Health Organization. (2015). WHO Model List of Essential Medicines (19th List). 40. Hill, A., Simmons, B., et al. (2016). Rapid reductions in prices for generic sofosbuvir and daclatasvir to treat hepatitis C. J Virus Erad. 2 (1): 28–31. 41. Hepatitis C Online. (2018). Elbasvir-grazoprevir. University of Washington. Retrieved from https://www.hepatitisc.uw.edu/page/treatment/drugs/elbasvir-grazopr evir. 42. Bruchfeld, A., et al. (2017). Elbasvir plus grazoprevir in patients with hepatitis C virus infection and stage 4-5 chronic kidney disease: clinical, virological, and health-related quality-of-life outcomes from a phase 3, multicentre, randomised, double-blind, placebo-controlled trial. Lancet Gastroenterol Hepatol. 2017;2:585-594. 43. Buti, M., et al. (2016). Grazoprevir, Elbasvir, and Ribavirin for Chronic Hepatitis C Virus Genotype 1 Infection After Failure of Pegylated Interferon and Ribavirin. Clin Infect Dis. 2016 Jan 1;62(1):32-6. doi: 10.1093/cid/civ722. Retrieved from https://www.ncbi.nlm.nih.gov/pubmed/26371152 44. Carrion, A., and Martin, P. (2016). Safety and efficacy of elbasvir and grazoprevir for treatment of hepatitis C. Expert Opin Drug Saf. 2016;15:883-90 45. MedlinePlus (2018). Elbasvir and Grazoprevir. U.S. National Library of Medicine. Retrieved from https://medlineplus.gov/druginfo/meds/a616016.html 46. Hepatitis C Online (2018). Glecaprevir-Pibrentasvir (Mavyret). University of Washington. Retrieved from https://www.hepatitisc.uw.edu/page/treatment/drugs/glecaprevir- pibrentasvir 47. MedlinePlus (2018). Glecaprevir and Pibrentasvir. U.S. National Library of Medicine. Retrieved from https://medlineplus.gov/druginfo/meds/a617039.html 48. Afdhal, N., et al. (2014). Ledipasvir and Sofosbuvir for Previously

nursece4less.com nursece4less.com nursece4less.com nursece4less.com Treated HCV Genotype 1 Infection. N Engl J Med 2014; 370:1483- 1493. Retrieved from http://www.nejm.org/doi/full/10.1056/nejmoa1316366 49. MedlinePlus (2018). Ledipasvir and Sofosbuvir. U.S. National Library of Medicine. Retrieved from https://medlineplus.gov/druginfo/meds/a614051.html 50. Westermann, C., Wendeler, D., Nienhaus, A. (2018). Hepatitis C in healthcare personnel: secondary data analysis of therapies with direct- acting antiviral agents. J Occup Med Toxicol; 2018:13(16). Retrieved from https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5970510/. 51. MedlinePlus (2018). Ombitasvir, Paritaprevir, and Ritonavir. U.S. National Library of Medicine. Retrieved from https://medlineplus.gov/druginfo/meds/a615036.html 52. Hézode, C., et al. (2015). Ombitasvir plus paritaprevir plus ritonavir with or without ribavirin in treatment-naive and treatment-experienced patients with genotype 4 chronic hepatitis C virus infection (PEARL-I): a randomised, open-label trial. The Lancet. Volume 385, Issue 9986, 20–26 June 2015, Pages 2502-2509. Retrieved from https://www.sciencedirect.com/science/article/pii/S014067361560159 3 53. Hepatitis C Online (2018). Ombitasvir-Paritaprevir-Ritonavir and Dasabuvir (Viekira Pak). University of Washington. Retrieved from https://www.hepatitisc.uw.edu/page/treatment/drugs/3d 54. MedlinePlus (2018). Ombitasvir, Paritaprevir, Ritonavir, and Dasabuvir. U.S. National Library of Medicine. Retrieved from https://medlineplus.gov/druginfo/meds/a614057.html 55. Feld, J., et al. (2015). Sofosbuvir and Velpatasvir for HCV Genotype 1, 2, 4, 5, and 6 Infection. NEJM. Retrieved from http://www.nejm.org/doi/full/10.1056/NEJMoa1512610 56. MedlinePlus (2018). Sofosbuvir and Velpatasvir. U.S. National Library of Medicine. Retrieved from https://medlineplus.gov/druginfo/meds/a616034.html 57. The American Society of Health-System Pharmacists. (2017). Sofosbuvir and Velpatasvir. Retrieved from https://www.ashp.org/- /media/ahfs/docs/ahfs-essentials- monograph.ashx?la=en&hash=F8AF588A6C01709ABB3045DC5780293 5DAF7F9A3 58. Rajagopal, D., (2016). US Gilead faces competition from Bangladesh’s Beacon pharma. The Economic Times. Retrieved from https://economictimes.indiatimes.com/industry/healthcare/biotech/ph armaceuticals/us-gilead-faces-competition-from-bangladeshs-beacon- pharma/articleshow/53407488.cms 59. World Health Organization. (n.d.). Sofosbuvir/Velpatasvir for the

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nursece4less.com nursece4less.com nursece4less.com nursece4less.com (2012). Viral Hepatitis: A through E and Beyond. NIH. Retrieved from https://www.niddk.nih.gov/health-information/liver-disease/viral- hepatitis 72. Rosen, H. (2011). Clinical practice. Chronic hepatitis C infection. NEJM. 364 (25): 2429–38. doi:10.1056/NEJMcp1006613 73. World Health Organization (2015). Hepatitis C Fact Sheet N°164. 74. GBD 2015 Disease and Injury Incidence and Prevalence Collaborators (2015). Global, regional, and national incidence, prevalence, and years lived with disability for 310 diseases and injuries, 1990-2015: a systematic analysis for the Global Burden of Disease Study 2015". Lancet. 388 (10053): 1545–1602. doi:10.1016/S0140-6736(16)31678-6. Retrieved from http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(16)3 1678-6/abstract 75. American Liver Foundation (2016). Advances in medication to treat hepatitis C. Retrieved from http://hepc.liverfoundation.org/treatment/the-basics-about-hepatitis- c-treatment/advances-in-medications/ 76. Naderi, M., Gholipour, N., et al. (2014). Hepatitis C Virus and Vaccine Development. Int J Mol Cell Med. 2014 Autumn; 3(4): 207–215. Retrieved from https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4293608/ 77. Billerbeck, E., et al. (2013). Animal models for hepatitis C. Curr Top Microbiol Immunol. 2013;369:49-86. doi: 10.1007/978-3-642-27340- 7_3. Retrieved from https://www.ncbi.nlm.nih.gov/pubmed/23463197 78. Mohd Hanafiah, K., Flaxman, D., and Wiersma, S. (2013). "Global epidemiology of hepatitis C virus infection: new estimates of age- specific antibody to HCV seroprevalence". Hepatology. 57 (4): 1333– 42. doi:10.1002/hep.26141. PMID 23172780. 79. American Liver Foundation (2018). Testing to diagnose Hepatitis C. Retrieved from http://hepc.liverfoundation.org/diagnosis/who-should- get-tested/testing-for-hep-c/ 80. Centers for Disease Control and Prevention. (2014). U.S. 2014 Surveillance Data for Viral Hepatitis, Statistics & Surveillance, Division of Viral Hepatitis. 81. Centers for Disease Control and Prevention. (2016). Hepatitis C Kills More Americans than Any Other Infectious Disease. CDC. Retrieved from https://www.cdc.gov/media/releases/2016/p0504-hepc- mortality.html 82. Blackier, M., Leleu, H., et al. (2013). "The burden of liver disease in Europe: a review of available epidemiological data". J. Hepatol. 58 (3): 593–608. doi:10.1016/j.jhep.2012.12.005. PMID 23419824 83. Welzel, T., et al. (2016). Daclatasvir plus sofosbuvir, with or without

nursece4less.com nursece4less.com nursece4less.com nursece4less.com ribavirin, achieved high sustained virological response rates in patients with HCV infection and advanced liver disease in a real-world cohort. Gut. 2016 Nov;65(11):1861-1870. doi: 10.1136/gutjnl-2016-312444. Retrieved from https://www.ncbi.nlm.nih.gov/pubmed/27605539 84. Filskov, J., et al. (2017). Broadening CD4+ and CD8+ T Cell Responses against Hepatitis C Virus by Vaccination with NS3 Overlapping Peptide Panels in Cross-Priming Liposomes. J Virol. 2017 Jun 26;91(14). pii: e00130-17. doi: 10.1128/JVI.00130-17. Print 2017 Jul 15. Retrieved from https://www.ncbi.nlm.nih.gov/pubmed/28446674 85. Bellier, B. and Klatzmann, D. (2013). Virus-like particle-based vaccines against hepatitis C virus infection. Expert Rev Vaccines. 2013 Feb;12(2):143-54. doi: 10.1586/erv.13.10. Retrieved from https://www.ncbi.nlm.nih.gov/pubmed/23414406 86. Lee, H., et al. (2017). Preclinical evaluation of multi antigenic HCV DNA vaccine for the prevention of Hepatitis C virus infection. Sci Rep. 2017; 7: 43531. Retrieved from https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5339862/ 87. Wijesundara, D. and Jason Gummow, J., et al. (2018). Induction of genotype-cross reactive, hepatitis C virus-specific cell mediated immunity in DNA-vaccinated mice. Journal of Virology. Retrieved from http://jvi.asm.org/content/early/2018/02/01/JVI.02133- 17.short?rss=1 88. Sjøgren, K. (2015). A virus from horses is bringing us closer to a vaccine against Hepatitis C. Science Nordic. Retrieved from http://sciencenordic.com/virus-horses-bringing-us-closer-vaccine- against-hepatitis-c 89. Naderi, M., et al. (2014). Hepatitis C Virus and Vaccine Development. J Mol Cell Med. 2014 Autumn; 3(4): 207–215. Retrieved from https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4293608/ 90. Highlights in the Treatment of Hepatitis C Virus From the 2016 AASLD Liver Meeting (2016). Gastroenterology & Hepatology Volume 12, Issue 12, Supplement 6 December 2016. Retrieved from http://www.gastroenterologyandhepatology.net/files/2017/01/gh1216 sup6-1.pdf. 91. Chopra, S. (2018). Characteristics of the hepatitis C virus. UpToDate. Retrieved from https://www.uptodate.com/contents/characteristics-of-the-hepatitis-c- virus?search=quasispecies&source=search_result&selectedTitle=1~12 &usage_type=default&display_rank=1. 92. Poordad, F., et al. (2017). Glecaprevir and pibrentasvir for 12 weeks

nursece4less.com nursece4less.com nursece4less.com nursece4less.com for hepatitis C virus genotype 1 infection and prior direct- acting antiviral treatment. Hepatology 2017; 66(2):389-397. Retrieved from https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5573922/. 93. Fathi, H. et al (2017). Effectiveness of current and future regimens for treating genotype 3 hepatitis C virus infection: a large-scale systematic review. BMC Infect Dis. 2017; 17: 722. Retrieved from https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5691805/. 94. Taraoa, K. and Satob, A. (2017). A Hepatitis C Virus-Associated Chronic Hepatitis Patient Developing Various Adverse Events Including Severe Gingivitis, Gingival Bleeding, and Inflammation of Genital Vulva during the Course of Antiviral Therapy with Elbasvir/Grazoprevir. Case Rep Gastroenterol. 2017 Sep-Dec; 11(3): 736–741. 95. Grebely, J., et al. (2018). Sofosbuvir-Based Direct-Acting Antiviral Therapies for HCV in People Receiving Opioid Substitution Therapy: An Analysis of Phase 3 Studies. Open Forum Infect Dis. 2018; 5(2). Retrieved from https://www.ncbi.nlm.nih.gov/pubmed/29450210. 96. Kanda, T., et al. (2017). Retreatment of patients with treatment failure of direct-acting antivirals: Focus on hepatitis C virus genotype 1b. World J Gastroenterol. 2017 Dec 14;23(46):8120-8127. doi: 10.3748/wjg.v23.i46.8120. Retrieved from https://www.ncbi.nlm.nih.gov/pubmed/29290649. 97. Bourlière, M., et al. (2017). Sofosbuvir, Velpatasvir, and Voxilaprevir for Previously Treated HCV Infection. N Engl J Med 2017; 376:2134- 2146. Retrieved from https://www.nejm.org/doi/10.1056/NEJMoa1613512?url_ver=Z39.88- 2003&rfr_id=ori:rid:crossref.org&rfr_dat=cr_pub%3dwww.ncbi.nlm.ni h.gov. 98. Lawitz, E. (2016). Efficacy of Sofosbuvir, Velpatasvir, and GS-9857 in Patients With Genotype 1 Hepatitis C Virus Infection in an Open-Label, Phase 2 Trial. Gastroenterology. 2016 Nov;151(5):893- 901. Retrieved from https://www.ncbi.nlm.nih.gov/pubmed/27486034.

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