HEPATITIS C: AN IMPROVED TREATMENT JACQUELINE KOSTICK, PHARM.D.

Transcription

1 HEPATITIS C: AN IMPROVED TREATMENT JACQUELINE KOSTICK, PHARM.D.

2 HEPATITIS C: AN IMPROVED TREATMENT ACTIVITY DESCRIPTION The hepatitis C virus (HCV) causes an infection that injures the liver. It affects more than 170 to 200 million people worldwide 3% of the world s population and over 3.2 million individuals in the United States. The hepatitis C viral disease causes liver inflammation and if untreated can lead to cirrhosis or liver cancer. Recently, the U.S. Food and Drug Administration (FDA) approved several oral medications with the potential to change HCV history. TARGET AUDIENCE The target audience for this activity is pharmacists, pharmacy technicians and nurses in hospital, community, and retail pharmacy settings. LEARNING OBJECTIVES After completing this activity, the pharmacist and nurse will be able to: Outline the history, frequency, and diagnosis of chronic hepatitis C virus (HCV) infection Review the recently approved medications to treat HCV (e.g., mechanism of action, duration of treatment, and potential adverse effects) Review the importance of HCV medication adherence and the cost of HCV treatment After completing this activity, the pharmacy technician will be able to: List medications used to treat chronic HCV List routes of administration for these HCV medications ACCREDITATION PHARMACY PharmCon, Inc. is accredited by the Accreditation Council for Pharmacy Education as a provider of continuing pharmacy education. NURSING PharmCon, Inc. is approved by the California Board of Registered Nursing (Provider Number CEP 13649) and the Florida Board of Nursing (Provider Number ). Activities approved by the CA BRN and the FL BN are accepted by most State Boards of Nursing. CE hours provided by PharmCon, Inc. meet the ANCC criteria for formally approved continuing education hours. The ACPE is listed by the AANP as an acceptable, accredited continuing education organization for applicants seeking renewal through continuing education credit. For additional information, please visit Universal Activity No.: H01-P&T Credits: 2 contact hours (0.2 CEU) Release Date: April 27, 2015 Expiration Date: April 27, 2017 ACTIVITY TYPE Knowledge-Based Home Study Monograph FINANCIAL SUPPORT BY Pharmaceutical Education Consultants, Inc. 1

3 ABOUT THE AUTHOR Jacqueline Kostick PharmD is a pharmacist and medical writer. As the owner of JK Medical Writing, she has written and researched pharmacy-related material (e.g., medical newsletters, drug monographs, medical website content) for organizations including Medscape, the American Society of Health-System Pharmacists (ASHP), CVS/Caremark, and United HealthCare. Jacqueline Kostick, PharmD J K Medical Writing FACULTY DISCLOSURE It is the policy of PharmCon, Inc. to require the disclosure of the existence of any significant financial interest or any other relationship a faculty member or a sponsor has with the manufacturer of any commercial product(s) and/or service(s) discussed in an educational activity. Jacqueline Kostick reports no actual or potential conflict of interest in relation to this activity. Peer review of the material in this CE activity was conducted to assess and resolve potential conflict of interest. Reviewers unanimously found that the activity is fair balanced and lacks commercial bias. Please Note: PharmCon, Inc. does not view the existence of relationships as an implication of bias or that the value of the material is decreased. The content of the activity was planned to be balanced and objective. Occasionally, authors may express opinions that represent their own viewpoint. Participants have an implied responsibility to use the newly acquired information to enhance patient outcomes and their own professional development. The information presented in this activity is not meant to serve as a guideline for patient or pharmacy management. Conclusions drawn by participants should be derived from objective analysis of scientific data presented from this monograph and other unrelated sources. 2

4 Hepatitis Comparison The name hepatitis is Greek for liver inflammation. 1 It also refers to a family of viral infections that affect the liver: hepatitis A, B, C, D, and E. 1 In the United States, the most widely reported types include: hepatitis A, hepatitis B, and hepatitis C as hepatitis D and E are rarely reported in our country. 3,4 Presently, the only hepatitis vaccines approved for use in the United States are for hepatitis A and B, as vaccines to treat hepatitis C, D, and E unavailable. 1,3,4 The World Health Organization reports that China has a vaccine to prevent the hepatitis E virus, but it is not approved for use in the United States. 4 Depending on the hepatitis disease, infection can occur after contact with contaminated blood, water, or food. For example, hepatitis A is spread after the ingestion of tiny amounts of contaminated fecal matter, which could be found in bad food or tainted drinking water. 5 It can also occur after sexual contact with a hepatitis A infected person. 5 Fortunately, hepatitis A resolves in the acute stage and does not progress to a chronic liver illness. 5 Hepatitis B can be transmitted after contact with infected blood or body fluid (e.g., sexual contact, sharing needles, mother to baby). In some people it can shift from acute to chronic hepatitis B. 6 Hepatitis C is usually transmitted to individuals after contact with infected blood via an injection; however, it can also spread through sex involving blood with an HCV-infected person and from a mother to her baby during childbirth. 1 HCV usually progresses from an acute to chronic disease. 1 Hepatitis D can spread after contact with infected blood or body fluid. 3 The hepatitis D virus can also transition from an acute to chronic disease in certain individuals. 3 Hepatitis E, similar to hepatitis A, can infect individuals after the ingestion of small amounts of contaminated fecal matter (i.e., bad food or water). 4 Usually, a hepatitis E infection results in a self-limited, acute illness. 4 Acute vs. Chronic HCV The hepatitis C virus is divided into two sections: acute and chronic HCV. 1 Acute HCV is a shortterm illness that occurs within 6 months of HCV exposure and usually progresses to chronic HCV infection. 1 Around 75 to 85% of people with acute HCV develop chronic HCV; however, the remaining 15 to 25% acute HCV cases are self-resolving as the individual s immune system is able to clear the virus. 1,7,8 Of note, the likelihood of a HCV resolution in the acute stage is reportedly associated by several 3

5 factors, such as the speed of decline of HCV RNA and high blood levels of interferon-gamma protein 10 (IP-10). 7,8 Chronic HCV is a long-term illness that begins after 6 months of persistent HCV RNA blood levels. 1 Long-term chronic HCV can lead to liver cirrhosis, which may prompt further complications such as liver cancer. 1 Chronic HCV infections are currently the leading indication for liver transplantations in the United States. 1 Among chronic HCV patients, 15 to 30% will develop cirrhosis over time according to the Centers for Disease Control and Prevention (CDC). 1 Of note, once cirrhosis has developed there is a 1 to 5% annual risk of liver cancer. 1 HCV Pathophysiology HCV is a spherical, enveloped, single-stranded RNA virus that was first described in ,9 It belongs to the Flaviviridae family and Flavivirus genus. 9 The hepatitis C virus can enter a susceptible host after a HCV-contaminated blood injection, via sexual contact that involves infected blood, or transmission from a HCV-infected mother to her baby during delivery. 1,7,9 The virus then penetrates hepatocytes (liver cells) as the viral receptor. 7,9,10 A single HCV polyprotein of 3011 aminoacids is translated, and then cleaved by cellular and viral proteases into three structural proteins (core, E1, and E2) and seven non-structural proteins (p7, NS2, NS3, NS4A, NS4B, NS5A, and NS5B). 7,9,10,11 After uptake, the virus uncoats and releases the viral genome to begin HCV viral replication. 10,11 When ready to replicate, the HCV RNA virus forms a complex with the non-structural proteins. 7,9,11 Of note, the HCV non-structural proteins listed will play a key role in the mechanism of action of the recently FDAapproved oral HCV treatment medications. HCV Genotypes There are at least six HCV genotypes and more than 50 subtypes that are associated with different geographical regions. 1,7,9 Although all genotypes are distributed worldwide, the most common HCV genotype in the United States is genotype 1 (a and b), which is found in 60 to 80% of the HCV population. 1,2,9 Of note, genotype 1 is also associated with more severe form of liver disease along with a higher risk of hepatocellular carcinoma. 1,2,9 Globally, genotypes 1, 2, 4, and 5 are endemic in Africa, whereas genotypes 3 and 6 are most commonly reported in Asia. 9 Of note, each HCV genotype responds 4

6 to treatment differently. 2,7 For example, HCV genotype 1 is not as responsive to HCV therapy as genotypes 2 and 3. 7 HCV genotype distribution in the United States include the following: 1 Genotype 1a: Occurs in 50 to 60% of patients Genotype 1b: Occurs in 15 to 20% of patients Genotype 1c: Occurs in less than 1% of patients Genotype 2 (a, b,c): Occurs in 10 to 15% of patients (most responsive to medication) Genotype 3 (a, b): Occur in 4 to 6% of patients Genotypes 4 to 6: Each occur in less than 5% of patients HCV Signs/Symptoms HCV has been referred to as a silent epidemic, because most people in the early HCV stages are asymptomatic. 1 The most common HCV symptoms reported in the early stages are fatigue and muscle pain. 1 If symptoms occur, the average time is 6 to 7 weeks after HCV exposure, but this time period can range from 2 weeks to 6 months. 7 Usually, 10 to 14 weeks after HCV infection, an increase in liver serum aminotransaminase levels may occur. 7 Long-term chronic HCV effects from years of liver cell inflammation can take several years or even decades to symptomatically develop. Chronic HCV symptoms may include: fever, loss of appetite, nausea, vomiting, stomach pain, dark (tea-colored) urine, clay-colored stools, and jaundice a yellow color in skin or eyes. 1 HCV History Over 20 years after the discovery of the hepatitis C virus, methods to improve HCV screening and reduce the number of HCV cases have evolved. 7,10,11,12 In the 1960s and 1970s, scientists developed blood tests to identify hepatitis A and hepatitis B, but many of the blood samples taken for posttransfusion illness tested negative for hepatitis A and hepatitis B. 13 Therefore, this unknown hepatitis strain was called the non-a, non-b hepatitis (NANB). 10 In 1986, a pilot trial with interferon was used to treat NANB hepatitis, because during this time interferon was used to treat hepatitis B. 9,10,11 In 1989, the hepatitis C virus was discovered by scientists working at the CDC and within the pharmaceutical industry. 1,11,12,13,14 In 1990, the U.S. began testing the blood supply for HCV and two years later it was 5

7 officially declared out of the U.S. blood supply. 1 After the discovery of HCV and the dawn of HCV interferon treatments, hepatitis C infection cases declined by 80% in However, as of 2007, the number of deaths from HCV surpassed HIV in the United States for the first time, as rates of new HCV cases declined but deaths due to HCV increased. 1 During this time, HIV treatments improved, but also many individuals with untreated chronic HCV faced the end-stage liver effects from years of HCV damage. Transmission Hepatitis C virus is a contagious liver disease that is usually transmitted via blood by individuals sharing needles, syringes, or other injection equipment. For example, it can be transmitted after an accidental HCV infected-blood needle-stick injury in a healthcare or laboratory setting. 1 HCV can also be transferred from HCV-infected mothers to their babies. 1 In rare cases, HCV can also be transmitted by sexual contact, or by individuals sharing razors or toothbrushes infected with HCV-blood. 1 Of note, HCV is not spread by food or water, nor by sharing utensils, breastfeeding, hugging, kissing, or coughing. 1 HCV can survive outside the body at room temperature, on environmental surfaces, for at least 16 hours but no longer than four days, according to the CDC. 1 A 2010 study reported that the hepatitis C virus can even live in a sealed tuberculin syringe for up to 63 days. 15 Therefore, in healthcare settings, blood spills involving HCV-infected blood should be immediately cleaned up with a dilution of one part bleach to 10 parts water. 1 In addition, the person cleaning up the blood must wear gloves. 1 Populations at Risk for HCV The majority of individuals at risk for HCV are current or past injection drug users. 1 In addition, other populations that may have a HCV risk include: long-term hemodialysis patients, individuals who received blood or a transplanted organ prior to July 1992, and people who received a clotting factor concentrate produced before ,16 The CDC reports that certain HIV patients may also be at risk for HCV as 50 to 90% of HIV-infected persons who use injection drugs are reportedly also co-infected with HCV. 17 HCV can also be transmitted to individuals who have received a body-piercing or tattoo, if given with HCV-blood infected instruments (e.g., a prison or in an unsterile setting). 1,16 6

8 HCV Testing In 2012 and 2013, the CDC and the US Preventive Services Task Force (USPSTF), respectively, recommended a one-time HCV test for baby boomers born between 1945 and ,18 While anyone can contract HCV, the CDC reported that up to 75% of adults infected with HCV were born in this time frame. 16 Within this baby boomer generation, the CDC reports that, infections are five times more common than in the general population. 16 It is estimated that this one-time HCV test for this population could identify nearly 808,600 additional people with chronic HCV. 16 The CDC also recommends that, those treated for a blood clot prior to 1987 and those who received a blood transfusion or organ transplant prior to July 1992 should also receive a one-time HCV test. 16 HIV patients, especially if they have ever used injection drugs, are another sub-population that should receive an HCV test. 1,17 Initially, HCV testing should begin with an anti-hcv test. 16 A positive test result could indicate one of the following results: a current HCV infection, a past unresolved HCV infection, or false positivity. For those with positive test results, the anti-hcv test should be followed with an HCV RNA test along with HCV genotype testing. 16 Treatment Goals- SVR Definition HCV treatment efficacy is measured by a sustained virological response (SVR). 14,19 HCV guidelines currently define a SVR as, an undetectable HCV RNA level 12 weeks after finishing therapy. 19 Until recently, the SVR was defined as an undetectable viral load 24 weeks after the completion of HCV therapy; however, the 2014 HCV guidelines changed the SVR time frame from 24 to 12 weeks due to recent outcome trials. 14,19 Several recent HCV articles have combined the definitions and refer to the SVR as, an undetectable HCV RNA 12 or 24 weeks after stopping therapy. 19,20 Another key HCV treatment goal is to prevent chronic HCV progression to cirrhosis or liver cancer, and eliminate the need for a liver transplant. 19 7

9 There are other HCV therapy definitions to describe how an individual reacts to HCV treatment. For example, a null response to HCV therapy is defined as: a 2 log decline in HCV RNA after 12 weeks of HCV therapy. 20 A non-response to HCV treatment is when an individual continues to have a detectable HCV RNA level after 12 weeks of HCV therapy. 20 A viral breakthrough is a detectable HCV RNA after previously undetectable levels. 20 In addition, a partial response to HCV therapy is defined as: greater than 2-log decline in HCV RNA, but a detectable HCV RNA after 12 weeks of HCV therapy. 20 If the HCV RNA level is undetectable or if a greater than 2-log-fold reduction in HCV RNA level is present, continue therapy, as up to 65% of patients will eventually develop a SVR, recommended researchers in a recent HCV study. 21 Interferon Interferon received its name because it was known to interfere with antiviral functions. In 1986, interferon was first used to treat NANB hepatitis presently known as hepatitis C in a pilot study, because, at the time, it was used to treat hepatitis B. 10,11,22 Interferon activates human type 1 interferon receptor to induce specific and nonspecific immune responses against HCV, which inhibits viral replication. 12,13,14 However, it also causes unnecessary actions in the body as it can suppress cell cycle progression and stimulate cytotoxic T-lymphocytes. 12,13,14 Early HCV interferon therapy, a subcutaneous (under-the-skin) injection given three times per week, was FDA-approved for the treatment of chronic HCV in the 1990s. 10,11,12 In 1991, the FDA approved the first alfa-2a interferon (Intron-A ) to treat hepatitis C. Throughout the 1990s, other interferons were also approved for HCV treatment: Roferon-A (1996) and Infergen (1997). Unfortunately, the probability of a successful treatment with interferon alfa was relatively low, with a reported SVR less than 10% for HCV genotype 1 patients and around 30% for HCV genotypes 2 and Of note, in the 1990s the SVR was defined as the HCV RNA blood level 6 months post-treatment, which differs from the current definition in which the HCV RNA response is measured after only 12 weeks of treatment. 8

10 PEG-IFN Pegylation is a process that involves the attachment of polyethylene glycol, a biologically inert compound, to a molecule to make it less likely to be cleared from the bloodstream. 22,23 A pegylated interferon can increase interferon levels and the sustained virologic response, when compared to standard interferon. 22 The addition of a PEG molecule to interferon changed the frequency of dosing from three time weekly injection to once weekly. 22,23 In the early 2000s, several subcutaneous pegylated interferons were approved for HCV treatment including: PEG-IFN alfa-2b (PEG-Intron ) and PEG-IFN alfa- 2a (Pegasys ). 23 Ribavirin Ribavirin (RBV; Copegus, Rebetol ) is an oral antiviral approved to treat HCV when used in combination with other agents (e.g., PEG-IFN). 6,24 When ribavirin is given along with an IFN, the combination has a synergistic effect to stop HCV from spreading in the body and boost the SVR. 24 The mechanism of action of ribavirin is not fully understood; however, it likely has both direct and indirect effects on HCV virus replication. 19,24 Ribavirin is approved for use along with interferon in all HCV genotypes. 19 Ribavirin comes as a tablet, a capsule, and an oral solution to take by mouth. 24,25 It is usually taken with food twice a day, in the morning and the evening. 24 Some serious adverse effects from ribavirin therapy include anemia and birth defects; 12,24 therefore, during ribavirin therapy, patients should be monitored with complete blood cell count tests. 24 If the patient is anemic while on ribavirin, consider a ribavirin dose reduction or treatment with erythropoietin. 19 PEG-IFN and RBV Since the early 2000s, the gold-standard HCV treatment was a pegylated interferon (PEG-IFN; Pegasys, PegIntron ), a subcutaneous injection given once per week, along with oral ribavirin given with food twice daily. 13,21,22,23 The reported SVR from the PEG-IFN and RBV combination therapy for HCV genotype 1 patients is around 40 to 50% after 48 weeks of therapy. 23,24 For patients with HCV genotype 2 and 3, the reported SVR was around 60 to 70% after 24 weeks of combination PEG-IFN and ribavirin therapy. 23,24 Side effects reported from PEG-IFN alone include: increased infection risk; psychiatric problems including depression and mood and suicidal thoughts; ischemic disorders such as chest pain or 9

11 a heart attack; an unmasking or worsening of an autoimmune disorders that may affect the blood, joints, kidneys, liver, lungs, muscles, skin, or thyroid gland, and blood disorders such as neutropenia and thrombocytopenia. 23 Unfortunately, the PEG-IFN/RBV combination caused additional adverse effects including: anemia, birth defects, and eye problems (e.g., blindness). 23,24 Due to the multiple side effects reported from the combination of PEG-IFN and RBV, certain medications were approved to help patients on this HCV regimen. For example, eltrombopag (Promacta ) was approved for thrombocytopenia in HCV patients who will begin or must continue IFN therapy. 26 It stimulates bone marrow platelet production during IFN therapy. 26 Initially, the dose is 25 mg by mouth every day on an empty stomach (one hour before or two hours after a meal), which may be increased every 2 weeks as needed up to 100 mg per day to achieve target platelet. 26 Of note, patients must allow at least a four-hour interval between taking eltrombopag and medications or foods that contain polyvalent cations such as antacids, calcium rich dairy products and calcium fortified juices, or vitamin supplements containing iron, calcium, aluminum, magnesium, selenium, and zinc. 26 Protease Inhibitors: Treatment Shift- Stop Viral Replication Given the adverse effects and the lack of efficacy from the standard HCV therapy IFN and ribavirin in certain HCV patients, scientists began to study other ways to stop HCV replication. 13 Direct antiviral agents and medications that target viral replication, including HCV protease inhibitors, became the focus of HCV research. 13 HCV protease inhibitors block the HCV NS3/NS4 serine protease, which is responsible for HCV polyprotein processing. 13,19 Even though HCV protease inhibitors still required the combination of PEG-IFN and ribavirin during treatment, they also introduced a new oral HCV treatment option. First-generation HCV protease inhibitors to treat HCV genotype 1, boceprevir (Victrelis ) and telaprevir (Incivek ), were approved by the FDA in ,13,27,28 Boceprevir, an oral agent, when given along with PEG-IFN and ribavirin raised the SVR to around 60% in patients with HCV genotype 1; however, it had a low genetic barrier to resistance and required three times a day dosing. 10,13 Telaprevir, an oral medication also given three times a day with a standard fat meal, was given along 10

12 with PEG-IFN and ribavirin and also increased the SVR to 60-70%. 28 Even though first-generation HCV protease inhibitors provided a significant SVR boost for HCV genotype 1 patients, they also contributed to increased rates of adverse events and multiple drug interactions. 14 For example, first-generation protease inhibitors were associated with anemia that required complete blood cell count monitoring. 14 In addition, 35% of boceprevir patients reported dysgeusia (alteration of taste) and up to 56% telaprevir patients reported a rash while on therapy. 27,28 In 2014, telaprevir was discontinued by the manufacturer due to currently available alternative HCV treatments and diminishing market demands. 29 In addition, the American Association for the Study of Liver Diseases (AASLD) and the Infectious Diseases Society of America (IDSA) HCV guidelines (2014) no longer recommend regimens containing either boceprevir or telaprevir, because they are inferior to the latest HCV medications. 19 Simeprevir Simeprevir (Olysio ), a second generation protease inhibitor, was approved by the FDA in November It is an HCV NS3/4A protease inhibitor approved for use in combination with PEG-IFN and ribavirin to treat patients with HCV genotype Simeprevir is available as a 150-mg capsule and should be taken with food once a day. 30 It is given for 12 weeks along with PEG-IFN/ RBV for an additional 12 or 36 weeks depending on a patient s previous treatment history and viral response to therapy. 30 Since, its mechanism of action is similar to that of boceprevir and telaprevir, it should not be used in patients who have previously failed therapy with either of these two agents due to viral crossresistance. 30 Simeprevir can also be given as an all-oral regimen with sofosbuvir in patients without cirrhosis for 12 weeks or for those with cirrhosis for 24 weeks. 30 Of note, patients with genotype 1a infection with Q80K polymorphism should not be given simeprevir, as it appears to be much less effective in these individuals. 30 Clinicians should inform patients taking simeprevir to limit sun exposure and use protective sun exposure measures, as photosensitivity reactions can occur with this medication. 30 Simeprevir in combination with PEG-IFN and ribavirin or along with sofosbuvir has been proven safe and effective in multiple clinical trials. 31,32,33 In the QUEST-1 study, simeprevir given along with PEG- IFN and ribavirin in treatment-naïve genotype 1 patients resulted in a SVR of 80%. 31 In addition, the duration of HCV therapy was shortened with this regimen and the reported adverse effects were 11

13 relatively mild (e.g., fatigue, headache). 31 In the QUEST-2 study, HCV participants reported a SVR of 81%. 32 In the COSMOS trial, simeprevir was given along with sofosbuvir and achieved a SVR greater than 90%. 33 Approved simeprevir HCV dosing regimens include: simeprevir 150 mg PO QD with PEG-IFN alfa (Pegasys ) and ribavirin- SVR: ~80% 31,23 simeprevir 150 mg PO QD in combination with sofosbuvir (Sovaldi ) - SVR: ~90% 19,33 Polymerase Inhibitors In 2013, the FDA approved a breakthrough, oral, once-daily HCV polymerase inhibitor that treats multiple HCV genotypes: sofosbuvir (Solvaldi ). 34,35 Sofosbuvir is a uridine nucleotide prodrug NS5B polymerase inhibitor. 34 It inhibits a RNA dependent polymerase NS5B competitively by binding to the catalytic site of HCV polymerase. 34,35 HCV NS5B polymerase plays an essential role in HCV replication. Since, HCV is a RNA virus that forms a complex with non-structural proteins p7, NS2, NS3, NS4A, NS4B, NS5A, NS5B when ready to replicate, sofosbuvir slips into the HCV RNA through the NS5B polymerase and acts as a chain terminator to stop viral replication. 34 Unlike, HCV protease inhibitors that are only FDA-approved to treat HCV genotype 1, sofosbuvir is approved to treat patients with HCV genotypes 1, 2, 3, or Sofosbuvir is also used along with ribavirin in HCV patients with liver cancer awaiting a liver transplant to treat HCV and reduce the risk of re-infection after the transplant. 34 Sofosbuvir is also approved for HCV patients co-infected with HIV. 34 In addition, it can be used in patients who have previously failed a protease-inhibitor based regimen. 34 The SVR from sofosbuvir when given in combination with other HCV agents is greater than 90% after only 12 weeks of therapy. 34,35 Sofosbuvir is available as a 400-mg tablet to be taken once daily with or without food in combination with other HCV agents. 34 Currently, it is used in combination with PEG-IFN and ribavirin for HCV genotypes 1 and 4. 34,35 For HCV genotypes 2 and 3, sofosbuvir can be used in combination with ribavirin alone without the need for an interferon. 34 The duration of therapy is generally 12 or 24 weeks, depending on the patient s HCV genotype. 34 Sofosbuvir HCV dosing regimens include: 12

14 Genotypes 1 or 4: 400 mg PO QD for 24 weeks with PEG-IFN and ribavirin Genotype 2: 400 mg PO QD + ribavirin for 12 weeks Genotype 3: 400 mg PO QD + ribavirin for 24 weeks Sofosbuvir therapy requires certain drug interactions precautions. For example, it should not be given along with the following medications: carbamazepine (Carbatrol, Tegretol ), oxcarbazepine (Trileptal ), phenobarbital, phenytoin (Dilantin, Phenytek ), rifabutin (Mycobutin ), rifampin (Rifadin, Rimactane ), St. John s wort, or tipranavir (Aptivus ). 34 Of note, sofosbuvir should not be given along with amiodarone (Cordarone, Pacerone ) as serious bradycardia may occur. 34 In addition, sofosbuvir only when given in combination with ribavirin can cause fetal harm due to the ribavirin component; therefore, patients taking this combination must be advised to use two methods of birth control to prevent pregnancy during treatment with these medications and to the continue the birth control for six months after treatment. 34 Ledipasvir/ Sofosbuvir (Harvoni ) Even though the SVR from sofosbuvir-combination HCV therapy was significant (greater than 90%), researchers sought a higher SVR and ideally, a virologic cure. Focusing on the HCV viral replication process led scientists to discover another potent medication: ledipasvir. 36,37 Ledipasvir is an HCV NS5A inhibitor that also stops the HCV virus life cycle by blocking a key step in replication. 36,37 It inhibits HCV NS5A, which may affect modulation of viral RNA replication and assembly and regulation of the endogenous interferon response. 36,37 When ledipasvir blocks NS5A and sofosbuvir blocks NS5B were given together, the two different anti-viral mechanisms of action had a synergistic effect that increased the SVR to 94-99% in HCV genotype 1 patients after 12 to 24 weeks of therapy. 36,37,38 HCV genotype 1 patients given the oral combination of ledipasvir and sofosbuvir in clinical trials consistently reported SVRs greater than 90%. 37,38,39 In the ION-1 study, 865 previously untreated HCV patients with or without cirrhosis achieved an SVR of 97%. 37 In the ION-2 study, 440 HCV treatmentexperienced patients were treated with sofosbuvir and ledipasvir without ribavirin for 12 weeks achieved a SVR of 93%. 38 Also, in the ION-3 study, 647 treatment-naive patients without cirrhosis with genotype 1 infection who were treated for only 8 weeks achieved a SVR of 94%

15 The combination of ledipasvir and sofosbuvir has a remarkable side effect profile, as the majority of side effects reported in studies included tiredness and headache. 36,37,38,39 In HCV studies, none of the patients quit the ledipasvir and sofosbuvir study due to adverse effects after 12 weeks of treatment, and only 1% stopped after 24 weeks. 36,37 The duration of therapy for the combination of ledipasvir and sofosbuvir is 8 to 24 weeks as it depends on if the patient has cirrhosis and is treatmentnaïve. 36 A duration of treatment of 8 weeks can be given to treatment-naive patient without cirrhosis who has a baseline HCV RNA level less than 6 million IU/mL. 36 In October 2014, the FDA-approved the oral, fixed-combination of ledipasvir and sofosbuvir (Harvoni ) for HCV genotype 1 patients. 36 It can be given orally, once daily without regards to food. 36 In addition, dosage adjustments for renal or hepatic impairment are not required. 36 Of note, the package insert states that the combination of ledipasvir and sofosbuvir does not have any contraindications to treatment; however, there are several significant drug-drug interactions, especially with P-gp inducers (e.g., St. John's wort and rifampin). 36 The manufacturer strongly recommends not to administer the following medications along with ledipasvir/sofosbuvir (Harvoni ): amiodarone (Cordarone, Pacerone ), carbamazepine (Tegretol ), oxcarbazepine (Trileptal ), phenobarbital, phenytoin (Dilantin ), digoxin (Lanoxin ), efavirenz (Sustiva ), emtricitabine (Emtriva ), tenofovir (Viread ), elvitegravir (Sustiva), cobicistat (Tybost), lopinavir, ritonavir (Norvir ), tipranavir (Aptivus ), rifabutin (Mycobutin ), rifampin (Rifadin ), rifapentine (Priftin ), rosuvastatin (Crestor ), simeprevir (Olysio ), and St. John s wort. 36 Also, tell the patient to take antacids containing aluminum hydroxide or magnesium hydroxide (Maalox, Mylanta, Tums, others), 4 hours before or 4 hours after ledipasvir and sofosbuvir. 36 Viekira Pak In December 2014, Viekira Pak was approved to treat chronic HCV genotype It is an all-oral regimen comprised of four medications: ombitasvir, paritaprevir, ritonavir, and dasabuvir. 40 Ombitasvir is a NS5A inhibitor with potent pangenotypic picomolar antiviral activity. 40 It stops the virus that causes hepatitis C from spreading inside the body. 40 Paritaprevir is a NS3/4A serine protease inhibitor and dasabuvir is a non-nucleoside NS5B polymerase inhibitor. 40 Unlike the other medications in this 14

16 regimen, ritonavir does not prevent HCV viral replication, but it is a potent CYP3A4 inhibitor. 40 It is used as a pharmacologic booster to maintain paritaprevir blood levels. 40 Viekira Pak is available as a package with two different tablets. 40 The dosing regimen for Viekira Pak in HCV genotype 1 patient includes: two fixed-combination ombitasvir, paritaprevir, ritonavir tablets taken in the morning with food and one dasabuvir tablet taken in the morning and evening with food. 40 Viekira Pak can be used with or without ribavirin to treat HCV genotype Of note, Viekira Pak is not approved for HCV patients with decompensated (severe) cirrhosis; however, it can be used in those with compensated cirrhosis. 40 The SVR for Viekira Pak in genotype 1 patients is 91 to 100%; however, the package insert states an SVR of 97%. 40 In the SAPPHIRE-II study, 96% of non-cirrhotic previous non-responders to PEG-IFN and ribavirin achieved SVR while taking Viekira Pak. 41 Viekira Pak has several important safety precautions to consider before prescribing to a HCV genotype 1 patient. For example, it is contraindicated in patient with severe hepatic impairment. 40 In addition, individuals taking an estrogen based birth control must stop prior to beginning treatment and for two weeks after treatment with Viekira Pak and switch to another form of birth control. 40 Additional drug interactions associated with Viekira Pak that may require dose adjustments include: alprazolam (Xanax ), amiodarone (Cordarone ), amlodipine (Norvasc ), atazanavir (Reyataz ), buprenorphine and naloxone (Suboxone ), cyclosporine (Neoral ), darunavir (Prezista ), disopyramide (Norpace ), flecainide, fluticasone (Flonase ), furosemide (Lasix ), ketoconazole (Nizoral ), lidocaine (Xylocaine ), lopinavir, mexiletine, omeprazole (Prilosec ), pravastatin (Pravachol ), propafenone (Rhythmol ), quinidine, rilpivirine (Edurant ), ritonavir (Norvir ), rosuvastatin (Crestor ), salmeterol (Serevent ), tacrolimus (Astagraf XL ), and voriconazole (Vfend ). 39 Major side effects reported from Viekira Pak include: tiredness, itching, lack of energy, and nausea. 40 Other HCV Genotypes in the US The majority of new direct antiviral agents approved to treat HCV are for individuals with HCV genotype 1; however, HCV genotypes 2 and 3 represent 20 to 29% of the reported HCV infections in the United States. 2,18 Traditionally, the standard of care for genotypes 2 and 3 was PEG-IFN along with ribavirin for up to 24 weeks of therapy. 2 On this regimen, those with genotype 2 usually had a higher SVR than those with genotype 3. Of note, genotype 3 HCV patients with cirrhosis usually have a higher 15

17 risk of viral relapse an undetectable HCV RNA on therapy with detectable HCV RNA after stopping therapy than patients infected with other HCV genotypes; therefore, fewer patients with genotype 3 achieved a SVR. 18 In a recent HCV trial, genotype 2 HCV patients were given the all-oral regimen of sofosbuvir and ribavirin for 12 weeks and the reported SVR was 82 to 93%. 34 Genotype 3 patients were also given sofosbuvir and ribavirin and the SVR after 24 weeks of therapy was 80 to 95%. 34 Of note, sofosbuvir and ribavirin given for 12 weeks is effective for genotype 2 individuals, but a longer treatment period of 24 weeks is required for genotype 3 patients to achieve a SVR greater than 90%. 7 Therefore, the HCV guidelines currently recommend sofosbuvir with ribavirin for HCV genotypes 2 and 3 due to these recent HCV studies HCV Clinical Guidelines HCV clinical guidelines are changing rapidly due to the recent approval of several HCV treatment medications and new clinical studies. The Infectious Diseases Society of America (IDSA) and American Association for the Study of Liver Diseases (AASLD), in collaboration with the International Antiviral Society USA (IAS USA), developed a web-based process for the formulation of evidence-based, expertdeveloped recommendations for hepatitis C management. 18 According to AASLD/IDSA/IAS, these guidelines will continually be updated to the rapid changes in therapy and are considered a "living document." 19 AASLD/IDSA/IAS. AASLD Practice Guidelines. Diagnosis, Management, and Treatment of Hepatitis C: An Update. Available at: Cost of HCV Medication Treatment The goal of achieving a SVR, or a HCV virologic cure, is possible with the recently-approved HCV medications; however, the cost of these new treatment options is controversial. 42,43,44 For example, many individuals have called into question the cost of sofosbuvir (Sovaldi ) at $1000 per tablet and 16

18 sofosbuvir ledipasvir (Harvoni ) at $1125 per tablet, when these HCV agents were released by the manufacturer. 43,44 Based on the HCV guidelines, here is a list of several HCV treatment regimen costs wholesale acquisition costs for 12 weeks of HCV therapy: 43,44 ledipasvir/sofosbuvir (Harvoni )= $94,500 sofosbuvir (Sovaldi ) + PEG IFN α-2 (Pegasys ) + ribavirin (generic)= $93,950 sofosbuvir (Sovaldi ) and simeprevir (Olysio ) +/- ribavirin (generic)= $151,000 or if taken with generic ribavirin (an additional $700) to $151,700 ombitasvir- paritaprevir- ritonavir dasabuvir (Viekira Pak ) +/- ribavirin (generic)= $83,319 or if taken with generic ribavirin (an additional $700) to $84,019 Due to the expense, these new HCV agents may be restricted to certain HCV populations. 44 At least 35 U.S. states only permit HCV treatments for Medicaid patients with advanced-stage disease because of the cost of these medications. 44 A recent HCV study stated that the cost-effectiveness of these latest HCV treatments depends on the insurance type. 45 For example, the study found that sofosbuvir ledipasvir (Harvoni ), a fixed-combination, once-daily tablet may be cost-effective in patients with Medicaid, Medicare, and the Veterans Health Administration patients as these populations have a longer patient enrollment period than private payers. 45 In addition, the study reported that sofosbuvir ledipasvir (Harvoni ) would significantly benefit the following HCV subgroups: genotype 1 HCV individuals, HCV patients in advanced stages of disease, or young HCV patients. 45 The cost of new HCV medications HCV protease and polymerase inhibitors may affect the resources of government health groups such as Medicaid and Medicare. 46 Since, the USPSTF gave HCV testing in baby boomers and others at risk for infection a grade B, the 2010 Patient Protection and Affordable Care Act (Affordable Care Act) requires private health plans to cover clinical preventive services that are given an A or B grade. 19,46 The Affordable Care Act also provides incentives for Medicaid programs to cover these services. 46 In addition, the CDC initiative of HCV testing baby boomers, may cause the number of Medicare patients with HCV to increase. 18,46 17

19 Medical costs for untreated HCV patients or for individuals who have not achieved a SVR are significant. 47,48,49 In one study, researchers found that the average annual cost (e.g., inpatient care costs, ambulatory care costs) for an HCV patient was around $23,000, which excludes the cost of HCV treatment or the cost of adverse events due to treatment. 47,48 In another study that examined HCV direct healthcare costs, via medical and pharmacy claims, the average annual expense for those with end-stage liver disease was around $60, If the HCV infection progresses to decompensated (severe) cirrhosis, a liver transplant is an alternative, albeit expensive, option. 49,50 According to the United Network for Organ Sharing (UNOS) Transplant Living Website, the estimated U.S. average of billed charges per liver transplant in 2011 was $577, Counseling HCV Patients Many HCV patients in the early HCV stages are asymptomatic; therefore, these individuals may not seek medical attention or adhere to medication schedules. Clinicians should explain to HCV patients the possible long-term HCV effects, if their condition is left untreated or if a sustained virologic response is not achieved. 51,52 One study reported that, based on pharmacy refill data, HCV patients with a medication adherence rate of 85% or greater to pegylated-ifn and ribavirin treatment had an increased HCV viral suppression load. 51 HCV treatment failure may not only occur from a virologic nonresponse, but due to virologic resistance from non-adherence. 51,52 The rate of HCV mutation is similar to viruses such as HIV; therefore, any missed doses during treatment can contribute to viral resistance. 51,52 In addition, studies report that adverse effects from HCV treatments may contribute to nonadherence. 51,52 For example, it is reported that high doses of ribavirin can have a negative effect on adherence due to adverse effects such as depression or anemia-related fatigue. 51 Therefore, it is important to discuss with patients if they have missed any HCV-medication doses and if they have had any possible side effects to therapy. The CDC recommends that all HCV patients abstain from alcohol due to the effects on the liver. 1 In addition, HCV patients should talk to their doctor and/or pharmacist to verify if any of their medications are liver-metabolized and whether a dose adjustment or medication change may be required. 1 HCV patients should also check with their doctor before they receive a hepatitis A or B 18

20 vaccine. 1 Since HCV is transmitted via blood, remind HCV patients not to donate blood, organs, or semen and to practice safe sex. 1 Conclusion Twenty years after the discovery of hepatitis C and an all-oral HCV virologic cure is available to treat this illness. For years, the combination of interferon and ribavirin was the standard treatment for all HCV genotypes; however, this regimen was ineffective for many individuals and associated with serious adverse effects. New direct acting HCV agents, HCV protease inhibitors and HCV polymerase inhibitors, are associated with a high SVR and fewer side effects than previous HCV treatments. In addition, the duration of HCV treatment with these new oral agents has decreased from 48 weeks to 8 to 24 weeks. Direct-acting HCV oral agents may replace the need for complicated and lengthy treatments and help the millions of patients with chronic HCV. 19

21 References 1. Centers for Disease Control and Prevention (CDC). Hepatitis C FAQs for Health Professionals. Available at: 2. Wendt A, Adhoute X, Castellani P. Chronic hepatitis C: future treatment. Clinical Pharmacology: Advances and Applications. 2014: Centers for Disease Control and Prevention (CDC). Hepatitis D FAQs for Health Professionals. Available at: 4. World Health Organization. Hepatitis E Jun. Available at: 5. Centers for Disease Control and Prevention (CDC). Hepatitis A FAQs for Health Professionals. Available at: 6. Centers for Disease Control and Prevention (CDC). Hepatitis B FAQs for Health Professionals. Available at: 7. Webster DP, Klenerman P, Dusheiko GM. Hepatitis C. Lancet 2015; 385: Beinhardt S, Payer BA, Datz C, et al. A diagnostic score for the prediction of spontaneous resolution of acute hepatitis C virus infection. J Hepatol. 2013; 59: Simmonds P. Genetic diversity and evolution of hepatitis C virus 15 years on. J Gen Virol. 2004; 85: Strader DB, Seeff LB. A brief history of the treatment of viral hepatitis C. Clinical Liver Disease. 2012; 2: Davis GL, Balart L, Schiff E, et al. Treatment of chronic hepatitis C with recombinant interferon alfa. A multicenter, randomized, controlled trial. Hepatitis Intervention Therapy Group. N Engl J Med. 1989; 321: Liang TJ, Rehermann B, Seef LB, et al. Pathogenesis, natural history, treatment, and prevention of hepatitis C. Ann Intern Med Feb; 132: Hoofnagle JH, Mullen KD, Jones DB, et al. Treatment of chronic non-a, non B hepatitis with recombinant human alpha interferon. N Engl J Med. 1986; 315: Liang TJ, Ghany MG. Current and Future Therapies for Hepatitis C Virus Infection. N Engl J Med. 2013; 368 (20): Paintsil E, He H, Peters C, et al. Survival of hepatitis C virus in syringes: implications for transmission among injection drug users. J Infect Dis. 2010; 202:

22 16. Centers for Disease Control and Prevention (CDC). Testing Recommendations for Hepatitis C Virus Infection. Available at: Centers for Disease Control and Prevention (CDC). HIV/AIDS and Viral Hepatitis. Available at: US Preventive Services Task Force. Screening for Hepatitis C Virus Infection in Adults Summary. Available at: AASLD/IDSA/IAS. AASLD Practice Guidelines. Diagnosis, Management, and Treatment of Hepatitis C: An Update Available at: Kohli A, Shaffer A, Sherman A. et al. Treatment of Hepatitis C. JAMA. 2014; 312 (6): Fried MW, Shiffman ML, Reddy KR, et al. Peginterferon alfa-2a plus ribavirin for chronic hepatitis C virus infection. N Engl J Med. 2002;347(13): Manns MP, McHutchison JG, Gordon SC, et al. Peginterferon alfa-2b plus ribavirin compared with interferon alfa-2b plus ribavirin for initial treatment of hepatitis C. Lancet. 2001; 358: Merck. Pegintron (interferon alpha) prescribing information. Whitehouse Station, NJ; 2015 Jan. Available at: Merck. Rebetol (ribavirin) prescribing information. Whitehouse Station, NJ; 2014 Dec. Available at: U.S. Food and Drug Administration. Orange Book: Approved Drug Products with Therapeutic Equivalence Evaluations. Available at Accessed 2015 Apr Glaxo Smith Kline. Promacta (eltrombopag) prescribing information. Research Triangle Park, NC; 2014 Aug. Available at: Merck. Victrelis (boceprevir) capsules prescribing information. Whitehouse Station, NJ; 2014 Jul Vertex Pharmaceuticals Inc. Incivek (telaprevir) prescribing information. Cambridge, MA; 2012 Dec. Available at: 29. News Release: Hepatitis C Drug to be discontinued Aug Janssen Products. Olysio (simeprevir) prescribing information. Titusville, NJ; 2014 Nov. 21

23 31. Jacobson IM, Dore GJ, Foster, GR, et al. Simeprevir with pegylated interferon alfa 2a plus ribavirin in treatment-naïve patients with chronic hepatitis C virus genotype 1 infection (QUEST- 1): a phase 3, randomized, double-blind, placebo-controlled trial. Lancet. 2014; 384 (9941): Manns M, Marcellin P, Poordad F, et al. Simeprevir with pegylated interferon alfa 2a or 2b plus ribavirin in treatment-naïve patients with chronic hepatitis c virus genotype 1 infection (QUEST- 2): a randomized, double-blind, placebo-controlled phase 3 trial. Lancet. 2014; 384 (9941): Lawitz E, Sulkowski MS, Ghalib R, et al. Simeprevir plus sofosbuvir, with or without ribavirin, to treat chronic infections with hepatitis c virus genotype 1 in non-responders to pegylated interferon and ribavirin and treatment-naïve patients: the COSMOS randomized trial. Lancet Nov; 384 (9956): Gilead Sciences, Inc. Sovaldi (sofosbuvir) tablets prescribing information. Foster City, CA; 2014 Nov. 35. Lawitz E, Mangia A, Wyles D, et al. Sofosbuvir for Previously Untreated Chronic Hepatitis C Infection. N Engl J Med. 2013; 368: Gilead Sciences. Harvoni (ledipasvir and sofosbuvir) prescribing information. Foster City, CA; 2015 Mar. 37. Afdal N, Zeuzem S, Kwo P, ION- 1 Investigators, et al. Ledipasvir and sofosbuvir for untreated HCV genotype 1 infection. N Engl J Med. 2014; 370: Afdhal N, Reddy KR, Nelson DR, ION-2 Investigators, et al. N Engl J Med Apr 17;370(16): Kowdley KV, Gordon SC, Reddy KR, et al. Ledipasvir and Sofosbuvir for 8 or 12 Weeks for Chronic HCV without Cirrhosis. N Engl J Med May; 370: Abbvie. Viekira Pak (ombitasvir, paritaprevir, and ritonavir along with dasabuvir) prescribing information. North Chicago, IL; 2015 Mar. 41. Zeuzem S, Jacobson IM, Baykal T, et al. Retreatment of HCV with ABT-450/r-Ombitasvir and Dasabuvir with Ribavirin. N Engl J Med. 2014; 370: Reau NS, Jensen DM. Sticker Shock and the Price of New Therapies for Hepatitis C: Is It Worth It? Hepatology. 59; 4: 2014: International Antiviral Society and the University of Washington. Medications to Treat HCV: 2015 Wholesale Costs. 22

24 44. Japsen B. As pricey hepatitis pill Harvoni joins Sovaldi, states erect Medicaid hurdles. Forbes. 10 October Available at: Chhatwal J, Kanwal F, Roberts MS, et al. Cost-Effectiveness and Budget Impact of Hepatitis C Virus Treatment With Sofosbuvir and Ledipasvir in the United States. Ann Intern Med. 2015;162(6): Ngo-Metzger Q, Ward JW, Valdiserri RO. Expanded hepatitis C virus screening recommendations promote opportunities for care and cure [Editorial]. Ann Intern Med. 2013; 159: El Khoury AC, Vietri J, Prajapati G. The Burden of Untreated Hepatitis C Virus Infection: A US Patients Perspective. Dig Dis Sci. (2012) 57: Gordon SC, Pockros PJ, Terrault NA, et al. Impact of Disease Severity on Healthcare Costs in Patients With Chronic Hepatitis C (CHC) Virus Infection. Hepatology Nov; 56(5): Mathes T, Antoine S, Pieper D. Factors influencing adherence in Hepatitis-C infected patients: a systematic review. Infectious Diseases. 2014, 14: UNOS Transplant Living. Available at: Lo Re V, Amorosa VK, Localio AR, et al. Adherence to Hepatitis C Virus Therapy and Early Virologic Outcomes. Clin Infect Dis Jan 15; 48 (2): Weiss JJ, Brau N, Stivala A, et al. Adherence to medication for chronic hepatitis C building on the model of human immunodeficiency virus antiretroviral adherence research. Aliment Pharmacol Ther Jul; 30 (1):

25 ACTIVITY TEST 1. How many people in the United States are infected with the hepatitis C virus? A. 2 million people B. 300,000 people C. 170 million people D. 3.2 million people 2. What percentage of acute HCV cases progress to chronic HCV? A % B % C % D % 3. What is the most common HCV genotype in the United States? A. genotype 1a B. genotype 2 C. genotype 3a D. genotype 4 4. Which of the following answers is correct? HCV can be transmitted from. A. sharing utensils B. a baby born to a mother with HCV C. breastfeeding D. hugging 5. Which of the following is a possible chronic HCV symptom? A. jaundice (yellow color in skin or eyes) B. sneezing C. itchy palms D. cough 24

26 6. Which of the following is a counseling recommendation for a HCV patient? A. Share needles B. Share blood-tinged razors and toothbrushes C. Donate blood D. Avoid Alcohol 7. Which of the following treatment options has the highest reported sustained virologic response (SVR) for HCV genotype 1 patients? A. ledipasvir/ sofosbuvir (Harvoni ) B. simeprevir (Olysio ) with PEG-IFN alfa-2a (Pegasys ) and ribavirin (Rebetol ) C. PEG-IFN alfa-2a (Pegasys ) and ribavirin (Rebetol ) D. interferon alfa-2a (Roferon-A ) 8. Which medication combination was the standard HCV treatment for over a decade? A. simeprevir (Olysio ) with PEG-IFN alfa-2a (Pegasys ) and ribavirin (Rebetol ) B. PEG-IFN alfa-2a (Pegasys ) and ribavirin (Rebetol ) C. acyclovir (Zovirax ) and ribavirin (Rebetol ) D. boceprevir (Victrelis ) and ribavirin (Rebetol ) 9. What is the approved duration of treatment for HCV patients taking ledipasvir/sofosbuvir (Harvoni )? A weeks B weeks C. 4-6 weeks D. 52 weeks 10. Which of the following medications was one of the first FDA-approved options for HCV treatment? A. acyclovir (Zovirax ) B. interferon alfa-2a (Roferon-A ) C. boceprevir (Victrelis ) D. telaprevir (Incivek ) 25

27 11. Which of the following types of hepatitis has an FDA-approved vaccine to prevent infection? A. hepatitis A B. hepatitis C C. hepatitis D D. hepatitis E 12. Based on the 2014 HCV guidelines, which of the following options is the definition of a sustained virological response (SVR)? A. An undetectable HCV RNA 6 months after finishing HCV therapy B. An undetectable HCV RNA 12 weeks after finishing HCV therapy C. An undetectable HCV RNA 1 year after finishing HCV therapy D. A detectable HCV RNA levels 12 weeks after finishing HCV therapy 13. In 2012, the CDC recommended a one-time HCV test for individuals born in this time frame. A B C. 1930s D Which of the following medications is approved to treat interferon-related thrombocytopenia? A. ribavirin (RBV; Copegus, Rebetol ) B. eltrombopag (Promacta ) C. acyclovir (Zovirax ) D. ibuprofen (Advil ) 15. Chronic HCV is defined as a persistent HCV RNA levels after how many months? A. 3 months B. 6 weeks C. 1 year D. 6 months 26

28 16. Which of the following HCV medications was discontinued in 2014 by the manufacturer? A. boceprevir (Victrelis ) B. telaprevir (Incivek ) C. PEG-IFN (Pegasys ) D. rifabutin (Rebetol ) 17. Which HCV medication is approved for HCV genotype 1, 2, 3, and 4 patients (when given in HCV combination therapy)? A. boceprevir (Victrelis ) B. telaprevir (Incivek ) C. sofosbuvir (Sovaldi ) D. simeprevir (Olysio ) 18. How frequently is pegylated interferon (PEG-IFN) given for HCV treatment? A. Twice weekly B. Once weekly C. Once monthly D. Three times weekly 19. Which of the following medications are included in Viekira Pak? A. ombitasvir, paritaprevir, ritonavir, and dasabuvir B. sofosubir and simeprevir C. acyclovir and ribavirin D. boceprevir and ribavirin 20. Which of the following HCV non-structural proteins are blocked by ledipasvir and sofosbuvir? A. NS2 and NS3 B. NS4A and NS4B C. NS5A and NS4A D. NS5A and NS5B Please submit your final responses on freece.com. Thank you. 27