Hepatitis C Treatment: Issues for the Emergency Physician
AUTHORS
Kevin Tin, MD, MBA, Division of Gastroenterology, Department of Medicine, Maimonides Medical Center, Brooklyn, NY.
Eiei Soe, MD, Division of Gastroenterology, Department of Medicine, Maimonides Medical Center, Brooklyn, NY.
James Park, MD, Division of Gastroenterology, Department of Medicine, NYU Langone Medical Center, New York, NY.
Hillel Tobias, MD, Division of Gastroenterology, Department of Medicine, NYU Langone Medical Center, New York, NY.
PEER REVIEWER
Ramesh K. Gandhi, MD, Clinical Associate Professor, Wright State University, Boonshoft School of Medicine, Dayton, OH.
Statement of Financial Disclosure
To reveal any potential bias in this publication, and in accordance with Accreditation Council for Continuing Medical Education guidelines, we disclose that Dr. Farel (CME question reviewer) owns stock in Johnson & Johnson. Dr. Schneider (editor) is employed by the American College of Emergency Physicians. Dr. Park (author) serves on the speaker’s bureau for Abbvie, Merck, Gilead, and BMS. Dr. Tobias (author) serves on the speaker’s bureau for Gilead, Abbvie, and Merck. Dr. Gandhi (peer reviewer) serves on the speaker’s bureau for Salix Pharmaceuticals and Allergan. Dr. Stapczynski (editor), Ms. Fessler (nurse planner), Dr. Tin (author), Dr. Soe (author), Ms. Mark (executive editor), and Ms. Coplin (executive editor) report no financial relationships with companies related to the field of study covered by this CME activity.
Emergency physicians are experienced in evaluating patients with chronic diseases who are on or should be on daily treatment; think of how common diabetes, hypertension, or hyperlipidemia are in your emergency department (ED) patient population. We always check patients’ blood pressure and often check glucose, and if the results are elevated, we talk with the patients about treatment and compliance. We do this because effective compliant treatment reduces complications and prolongs life. Now we can add hepatitis C to the list of chronic disorders for which a daily oral course of therapy for 12-24 weeks is highly effective in reducing morbidity and mortality associated with this chronic infection. This issue is written to provide you with the knowledge to be able to ask and educate patients with hepatitis C about the highly effective treatment available for most all infected patients.
— J. Stephan Stapczynski, MD, FACEP, Editor
Hepatitis C virus (HCV) infection can cause both acute and chronic hepatitis. In most people, the acute infection is asymptomatic, but instead of full recovery, the majority of patients transition into a long-term, chronic infection with persistent viremia. There is no vaccine for HCV, so the best way to prevent hepatitis C is by avoiding behaviors that can spread the disease, especially injection drug use. With the development of direct-acting antiviral (DAA) agents, most people with chronic infection can now be cured from HCV infection.
Pathogenesis and Genotypes
Hepatitis C virus is a spherical, enveloped, positive-strand RNA virus that belongs to the family of flaviviruses. The natural targets of HCV are hepatocytes and, possibly, B lymphocytes. Virus replication occurs through an RNA-dependent RNA polymerase that lacks a “proofreading” function, resulting in the rapid evolution of diverse but related quasispecies within an infected person. This presents a major challenge with respect to immune-mediated control of HCV and vaccine development.1,2
In 1989, the virus was identified as the major etiological agent responsible for post-transfusion non-A and non-B hepatitis.4-7 The natural history of HCV infection has been difficult to assess because of the commonly silent onset of the acute phase as well as the frequent lack of symptoms during the early stages of chronic infection. Following primary HCV infection, persistent viremia and chronic hepatitis develop in the majority of cases, with spontaneous clearance of viremia in only rare cases.8 With time, patients are at risk of developing progressive hepatic fibrosis, cirrhosis, and death from liver failure, as well as the advent of hepatocellular carcinoma (HCC).9 It is estimated that cirrhosis will develop in 15-20% of those infected, and once cirrhosis is established, the risk of hepatocellular carcinoma is around 1-4% per year. Hepatocellular carcinoma can occur in those without cirrhosis but the majority of HCV-associated HCC patients most often will have at least advanced fibrosis.1
Six distinct but related HCV genotypes (GTs) and multiple subtypes have been identified on the basis of molecular relatedness that has geographic variation. (See Figure 1.) In the United States and Western Europe, GTs 1a and 1b are most common, followed by GTs 2 and 3. Genotype 4 is commonly found in Egypt, GT 5 in South Africa, and GT 6 is common in Southeast Asia.3 Knowledge of the GT is important because it has predictive value in terms of the response to antiviral therapy.1
Figure 1. HCV Genotype by Geographic Location3
Epidemiology
Hepatitis C infection affects 170 million persons worldwide, and an estimated 2.2 million to 3.2 million persons in the United States are chronically infected with HCV.1,10 (See Figure 2.) However, these numbers are most likely underestimates because most studies of HCV prevalence are from blood donors who are not completely representative of the U.S. population. The number of new annual HCV infections in the United States was high during the 1980s, when an estimated 230,000 individuals were newly infected each year. Many of these infections were due to blood transfusions. The testing of donated blood with HCV serologic screening tests, initially developed in 1990, has markedly reduced the number of new infections.11
Figure 2. Prevalence of Hepatitis C Globally
Source: Centers for Disease Control and Prevention: Available at: https://wwwnc.cdc.gov/travel/yellowbook/2016/infectious-diseases-related-to-travel/hepatitis-c
Persons with HCV infection have all-cause mortality more than twice that of HCV-negative persons. In the United States, the number of annual deaths related to HCV recently has increased substantially, to approximately 15,000 people per year. (See Table 1.) In 2007 the number of deaths related to hepatitis C surpassed those related to human immunodeficiency virus-1 (HIV). The number of hepatitis C-related deaths is at least eight-fold greater than the number of deaths related to hepatitis B. Among the HCV-related deaths in recent years, more than 70% have involved persons 45-64 years of age.12
Table 1. Prevalence of Hepatitis C in the United States
Reported New Cases of HCV |
||||||||
|
* Current information indicates these represent a fraction of deaths attributable in whole or in part to chronic hepatitis C |
||||||||
|
2005 |
2006 |
2007 |
2008 |
2009 |
2010 |
2011 |
2012 |
2013 |
|
694 |
802 |
849 |
878 |
781 |
853 |
1,230 |
1,778 |
2,138 |
Estimated Actual New Cases of HCV |
||||||||
|
2011 (estimated) |
2012 (estimated) |
2013 (estimated) |
||||||
|
16,500 (7,200-43,400) |
24,700 (19,600–84,400) |
29,700 (23,500–101,400) |
||||||
|
Estimated Number of Chronic Cases in the United States |
Number of Death Certificates Listing HCV as Cause |
|||||||
|
2.7–3.9 million |
2010 |
2011 |
2012 |
2013 |
||||
|
16,627* |
17,721* |
18,650* |
19,368* |
|||||
It is projected that 1.76 million people with chronic HCV infection, if untreated, will progress to cirrhosis during the next 40-50 years. The predicted incidence peak of end-stage liver disease (ESLD) will occur in 2030, with about 38,600 cases per year. The prevalence with ESLD also is anticipated to peak in 2030, with an estimated 131,300 persons living with ESLD. Liver transplants for HCV-related hepatic failure are expected to peak around 2032-2033 at a level of 3,200 transplants per year.13
Risk Factors and Prevention
Prevention targets those at risk of acquiring the virus and involves providing education, risk reduction counseling, HCV screening, and substance abuse treatment. Counseling on HCV treatment, reducing alcohol usage, and immunizing with hepatitis A, hepatitis B, pneumococcal, and influenza vaccines is recommended.14-16 HCV-infected persons should be informed of the precautions needed to avoid exposing others to infected blood, as this is the primary mode of HCV transmission. The Centers for Disease Control and Prevention (CDC) estimates the risk of infection after a single needlestick contaminated with HCV-infected blood to be about 1.8%. (See Table 2.) This precaution about blood exposure is particularly important for persons who use injection drugs, given that HCV transmission in this population primarily results from the sharing of needles and other infected instruments. Recently, epidemics of acute HCV due to sexual transmission in HIV-infected men who have sex with men also have been described.14
Table 2. Estimated Infection Risk After Single Needlestick
Virus |
Risk of Infection |
Comments |
|
SOURCE: https://www.cdc.gov/oralhealth/infectioncontrol/faq/bloodborne_exposures.htm |
||
|
Hepatitis B (HBV) |
6-30% |
Risk is for HBV unvaccinated persons and depends on the hepatitis B e antigen (HBeAg) status of the source blood; both hepatitis B surface antigen (HBsAg) and HBeAg positive have more virus in the blood and are more likely to transmit HBV. |
|
Hepatitis C (HCV) |
1.8% |
Estimated based on limited studies |
|
HIV |
0.3% |
About 1:300 |
HCV is not spread by sneezing, hugging, holding hands, coughing, or sharing eating utensils or drinking glasses, nor is it transmitted through food or water. However, persons with HCV infection should be counseled to avoid sharing toothbrushes and dental or shaving equipment and be cautioned to cover any bleeding wound to prevent the possibility of others coming into contact with their blood. Household surfaces and implements contaminated with visible blood from an HCV-infected person should be cleaned using a dilution of 1 part household bleach to 9 parts water.14
High Prevalence Groups
As with screening for other chronic diseases, it would make sense initially to target populations at increased risk for HCV infection. But such risk-based testing has not proven to be optimal for many reasons. A significant portion of individuals with HCV infection report having no specific risk factors for HCV infection; in an analysis of data from a national health survey, 45% of individuals with evidence of HCV infection reported no known exposure risk.17,18 In addition, even among individuals who have high risk exposure to HCV, many remain untested, as demonstrated by a study in which 72% of 1,033 injection drug users who had a reactive HCV antibody test when tested during trial enrollment were previously unaware of their diagnosis. In another study within a managed care network that included more than 55,000 adults, only 29% of those who had at least one identifiable HCV risk factor underwent testing for HCV.19
Surveillance data have suggested that individuals born between 1945 and 1965 (the “baby boomer generation”) in the United States reflect a disproportionate percentage of the total population of adults chronically infected with HCV. In a study of NHANES data from 2003 to 2010, persons born between 1945 and 1964 accounted for 81% of the total estimated population of chronically HCV-infected adults.20-22 The prevalence of HCV RNA positivity among individuals in this birth cohort is estimated at 2.6%, six times higher than individuals born in other years. Hence, there is a call to perform routine screening on patients born within these two decades, regardless of the presence of risk factors, to identify a significant proportion of the chronically infected HCV population in the United States.23-25 In a study involving more than 4,700 patients presenting to an ED in Maryland, antibody testing of excess blood samples identified 204 patients with undocumented HCV infection.24 Of those, 26% would have been identified by risk-based testing (history of injection drug use or HIV infection), whereas an additional 49% would have been identified by screening based on birth between 1945 and 1965.
HIV-infected Individuals. Coinfection with HIV and HCV is common because of mutual routes of transmission; coinfection is about 25% in HIV-infected patients overall and up to 50-90% in HIV-infected injection drug users. In contrast to the low potential of sexual transmission of HCV in general, increasing evidence has shown a substantial risk of sexual transmission of HCV among HIV-infected men who have sex with men. In addition, coinfection is associated with higher rates of fibrosis progression, decompensated liver disease, and liver-related morbidity and mortality compared with infection with HCV alone.
Dialysis Patients. Historically, the prevalence of HCV among patients undergoing hemodialysis has been higher than that in the general population, although the incidence is thought to be decreasing.
Incarcerated Individuals. In the United States, an estimated 16-41% of inmates have serological evidence of HCV exposure and 12-35% have chronic infection.26,27 Thus, some advocate routine screening for HCV in correctional facilities.
The CDC has released recommendations for HCV testing. (See Table 3.)
Table 3. CDC Recommendations for HCV Testing
Category |
Recommendation |
|
Adults born between 1945 and 1965 |
One-time HCV test |
|
Risk factors for HCV:
|
One-time HCV test |
|
Persons who inject drugs and HIV-seropositive men who have unprotected sex with men |
Annual HCV testing |
|
Uncertain risk factors for HCV infection:
|
Uncertain need for HCV testing |
|
Not considered risk factors for HCV infection:
|
Routine HCV testing is not recommended (unless they have risk factors for infection) |
Clinical Manifestations
The majority of persons with acute HCV infection usually have no symptoms. A minority will have mild symptoms, typically within seven to eight weeks (range two to 26 weeks) after exposure to HCV. Among those who have symptoms, the most frequent complaint is fatigue, followed by less common manifestations including myalgia, arthralgia, nausea, anorexia, and weight loss. The symptoms rarely are debilitating and may be difficult to attribute to liver disease itself.
A number of extrahepatic diseases have been associated with chronic HCV infection. Most cases appear to be directly related to the viral infection. These include:
- Hematologic diseases, such as essential mixed cryoglobulinemia and lymphoma;
- Renal disease, particularly membranoproliferative glomerulonephritis;
- Autoimmune disorders, such as thyroiditis and the presence of autoantibodies;
- Dermatologic conditions, such as porphyria cutanea tarda and lichen planus;
- Diabetes mellitus.
Once patients develop cirrhosis they are at risk of decompensation. Hepatic decompensation is characterized by the development of certain liver-related complications, including ascites, variceal bleeding, and encephalopathy. In patients with chronic HCV infection, jaundice is almost always a sign of advanced liver disease. Almost all HCV-infected patients who develop these complications have cirrhosis; however, not all patients with cirrhosis develop these complications.
Serologic Diagnosis
Two major types of serologic tests are utilized: IgG assays for HCV antibodies and nucleic acid amplification testing to detect HCV RNA in blood. Assays for anti-HCV-IgM to detect early or acute infection are unavailable. About 75-85% of patients who seroconvert to anti-HCV, indicative of acute infection, will progress to chronic infection and will develop detectable viremia. As a positive HCV antibody test cannot discriminate between someone who previously was infected with clearing of the infection and someone with current infection, therefore it is important that HCV RNA testing follow a positive HCV antibody test to assess current HCV infection. The HCV nucleic acid test is used to detect viremia, confirm current HCV infection, and guide clinical management, including initiation of HCV treatment. False-negative antibody test results, while uncommon, may occur early in acute infection, commonly in the initial 15 weeks after exposure and infection.14
HCV RNA testing also should be performed in patients with a negative anti-HCV test who are either immunocompromised (i.e., persons receiving chronic hemodialysis) or who might have been exposed to HCV within the last six months because these patients may be anti-HCV negative. An HCV RNA test also is required to detect reinfection in anti-HCV-positive persons after previous spontaneous or treatment-related viral clearance.1
Factors Associated with Disease Progression
Several factors appear to be determinants of fibrosis progression in HCV-infected patients, including baseline liver histology, age, ethnic background, gender, alcohol intake, comorbidities such as obesity or viral coinfection, and HCV-specific cellular immune response. As an example, young women and children infected with HCV tend to have slower rates of fibrosis progression. Patients with mild inflammation (portal inflammation alone or with only focal periportal extension) and no fibrosis had only a 1.2% annual risk of progressing to cirrhosis. Patients with moderate chronic hepatitis (periportal inflammation usually involving more than 30% of the limiting plate) had an increased annual risk of developing cirrhosis at 4.6%, of which more than 90% developed cirrhosis within 20 years of the time of the biopsy. Nearly all patients with severe inflammation or bridging fibrosis developed cirrhosis within 10 years.28,29
The daily consumption of more than 50 grams of alcohol has a high probability of worsening fibrosis. A standard alcoholic drink contains approximately 14 grams of alcohol, which is equivalent to 12 ounces of beer (~5% alcohol), 8.5 ounces of malt liquor (~9% alcohol), 5 ounces of wine (~12% alcohol), 3.5 ounces of fortified wine (e.g., sherry or port), or 1.5 ounces of liquor (distilled spirits; ~40% alcohol). So 50 grams of alcohol per day translates into 3.5 standard drinks per day. There are studies suggesting that daily consumption of smaller amounts of alcohol also has a negative impact on the liver; however, these data are controversial. Excess alcohol intake also has been shown to cause steatohepatitis.30 Thus, HCV-infected persons identified as abusing alcohol and having alcohol dependence require treatment and referral to an addiction specialist.
Hepatitis B virus and HIV coinfection have been associated with poorer prognosis of HCV in cohort studies. Because of overlapping risk factors for these infections and additional benefits of their diagnosis and treatment, persons with HCV should be tested for HIV antibody and hepatitis B surface antigen (HBsAg) using standard assays for screening and should be counseled on how to decrease their risk of acquiring these infections, including through HBV vaccination.14
Patients who are obese and have components of metabolic syndrome have underlying insulin resistance and are more prone to have nonalcoholic fatty liver disease, which is a risk factor for fibrosis progression in HCV-infected persons. Therefore, HCV-infected persons who are overweight or obese (defined by a body mass index of 25 kg/m2 or higher or 30 kg/m2 or higher, respectively) should be counseled regarding strategies to reduce weight and improve insulin resistance via diet, exercise, and medical therapies. Patients with HCV infection and hyperlipidemia or cardiovascular comorbidities also may benefit from various lipid-lowering drugs. Prospective studies have illustrated the safety and efficacy of statins in patients with chronic HCV and others with compensated chronic liver disease.31 Therefore, these agents should not be withheld in HCV-infected patients.
The Model for End-Stage Liver Disease (MELD) is a scoring system for assessing the severity of chronic liver disease. Initially it was developed to predict mortality within three months of surgery in patients who had undergone a transjugular intrahepatic portosystemic shunt (TIPS) procedure, and subsequently was found to be useful in determining prognosis and prioritizing for receipt of a liver transplant. This score is used by the United Network for Organ Sharing (UNOS) and Eurotransplant for prioritizing allocation of liver transplants.32 The original MELD score is calculated by:
MELD = 3.78 × ln[serum bilirubin (mg/dL)] + 11.2 × ln[INR] + 9.57×ln[serum creatinine (mg/dL)] + 6.43.
A web-based calculator of the original MELD score can be found at: http://www.mdcalc.com/meld-score-original-pre-2016-model-end-stage-liver-disease/.
The higher the MELD score, the higher is the observed three-month mortality in hospitalized patients; a score of > 40 has a 70% mortality compared to a score of < 9, which has a 2% mortality.
In January 2016, the MELD score was updated to include serum sodium as a factor in the calculation. Web-based calculators of the updated version can be found at: https://optn.transplant.hrsa.gov/resources/allocation-calculators/meld-calculator/ or http://www.mdcalc.com/meld-score-model-end-stage-liver-disease-12-older/.
Treatment
Successful hepatitis C treatment is achievable now in nearly all HCV-infected patients and is reflected by a sustained virological response (SVR), defined as the continued absence of detectable HCV RNA for 12 weeks after completion of therapy.36 An SVR is associated with a 99% chance of being HCV RNA negative during long-term follow-up and, therefore, patients can be considered cured of the HCV infection.37 Patients who are cured of their HCV infection experience numerous health benefits, including a decrease in liver inflammation, regression of fibrosis, and, for some, even resolution of cirrhosis.38 An SVR is associated with a more than 70% reduction in the risk of HCC and a 90% reduction in the risk of liver-related mortality and liver transplantation.39-41
In the past, drug therapy for HCV-infection was performed using a combination of peg-interferon alpha 2a or 2b plus ribavirin. The pharmacologic action of both agents was nonspecific; peg-interferon produces antiviral, antiproliferative, and immunomodulatory effects, while ribavirin inhibits viral RNA polymerase and viral protein synthesis. The clinical benefits were poor, with low overall cure rates and high rates of early discontinuation because of adverse reactions.
The new direct-acting antivirals (DAAs) specifically inhibit hepatitis C viral proteins and offer not only a shorter duration of treatment with fewer adverse reactions, but also greatly improved overall cure rates as high as 96%.42 Development of the DAAs required identification of the four structural and six nonstructural proteins of HCV, which was possible only after the HCV RNA genome was sequenced. DAAs target the specific nonstructural components of HCV such as the NS3-4A (serine protease and cofactor), the NS5A (replication complex), and NS5B (RNA-dependent RNA polymerase). Combinations of two or more of these drugs have been shown to be highly effective in curing more than 90% of patients to achieve and maintain SVR across all genotypes.43
Because sequence diversity in the HCV genome exists at all times, even within individual patients, combination therapy is used. Most of these agents are available in the United States only in combination tablets. (See Table 4.) Regimens are chosen based on HCV genotype, the presence or absence of cirrhosis, whether cirrhosis is compensated or decompensated, the presence of anemia, and whether the patient is intolerant to ribavirin. Treatment can last from 12-24 weeks. The DAAs often are combined with ribavirin in some regimens.
Table 4. Commercially Available Direct Acting Antivirals in the United States
Generic |
Trade Name |
Tablet Size and Typical Adult Dose |
Mechanism of Action |
|
Simeprevir |
Olysio® |
150 – PO daily |
NS3-4A protease inhibitor |
|
Daclatasvir |
Daklinza® |
60 – PO daily |
NS5A inhibitor |
|
Sofosbuvir |
Sovaldi® |
400 – PO daily |
NS5B nucleoside polymerase inhibitor |
|
Ledipasvir/sofosbuvir |
Harvoni® |
90/400 – PO daily |
NS5A inhibitor/ NS5B nucleoside polymerase inhibitor |
|
Elbasvir/grazoprevir |
Zepatier® |
50/100 – PO daily |
NS5A inhibitor/ NS3-4A protease inhibitor |
|
Ombitasvir, paritaprevir, ritonavir |
Technivie® |
12.5/75/50 – 2 tabs PO daily |
NS5A inhibitor/NS3-4A protease inhibitor/protease inhibitor boosting |
|
Dasabuvir, ombitasvir, paritaprevir, ritonavir |
Viekira XR® |
200/8.33/50/3.33 – |
NS5B Non-nucleoside polymerase inhibitor/ NS5A inhibitor/NS3-4A protease inhibitor/protease inhibitor boosting |
|
Velpatasvir/sofosbuvir |
Epclusa® |
400/100 – PO daily |
NS5A inhibitor/ NS5B nucleoside polymerase inhibitor |
A practical limitation to HCV treatment is the current cost of these oral agents. For patients who lack insurance coverage and pay full retail price, a 12-week course of treatment would cost between $75,000 to $95,000. Since a majority of U.S. residents have some medical insurance coverage (although the same might not be said for HCV-infected patients), the out-of-pocket cost to the patient could be considerably less depending on the drug coverage in the particular insurance plan. The American Association for the Study of Liver Diseases (AASLD) and the Infectious Diseases Society of America (IDSA) have an overview of cost, reimbursement, cost-effectiveness, and affordability available at: http://www.hcvguidelines.org/full-report/overview-cost-reimbursement-and-cost-effectiveness-considerations-hepatitis-c-treatment.
This analysis concludes that the incremental cost-effectiveness ratio for DAA treatment is within the range of other accepted medical practices for genotype 1, the most common HCV genotype in the United States. However, this document concludes, “Although the wholesale acquisition costs of HCV drugs often make treatment appear unaffordable, the reality is that insurers, PBMs [pharmacy benefit managers], and government agencies negotiate pricing and few actually pay the much-publicized WAC [wholesale acquisition cost] (retail). However, the negotiated pricing and cost structure for pharmaceutical products in the United States are not transparent, and it is therefore difficult to estimate the true cost and cost-effectiveness of HCV drugs. Whatever the actual current cost of HCV DAAs, competition and negotiated pricing have not improved access to care for many persons with HCV infection and continue to limit the public health impact of these new therapies. Insurers, government, and pharmaceutical companies should work together to bring medication prices to the point where all of those in need of treatment are able to afford and readily access it.”
The choice between combination regimens also depends primarily on the potential for drug interactions and drug toxicity. There are a few specific cautions and warnings with some agents:
- Ribavirin is teratogenic, so two effective forms of contraception should be used by both men and women of child-conceiving potential during treatment and six months after treatment with ribavirin-containing regimens.46 Ribavirin also should be dosed accordingly to weight and glomerular filtration rate (GFR). Complete blood counts (CBCs) should be followed on a routine basis due to the possibility of anemia.
- Sofosbuvir is a substrate of P-glycoprotein (P-gp), so it should not be used with drugs that are potent P-gp inducers, such as rifampin and St. John’s wort. It also should not be used with amiodarone as there have been reported cases of bradyarrhythmias.47
- Dose adjustments of daclatasvir (DCV) are warranted with moderate CYP3A inducers and strong CYP3A inhibitors (see Table 5), so consideration should be given before initiating these medications by prescription upon ED discharge.
Table 5. Commonly Prescribed CYP3A Inducers and Inhibitors
Inducers |
Inhibitors |
|
Strong Inducers Carbamazepine Phenobarbital Phenytoin Rifampin St. John’s wort |
Strong Inhibitors Clarithromycin Fluvoxamine Grapefruit juice (in large amounts, > 1 liter a day, and in high concentrations) Itraconazole Ketoconazole Telithromycin Voriconazole |
|
Moderate Inducers Modafinil Nafcillin |
Moderate Inhibitors Ciprofloxacin Diltiazem Erythromycin Fluconazole Grapefruit juice (in lower concentrations and smaller amounts) Verapamil |
|
CYP3A Weak Inducers Echinacea Prednisone Topiramate |
CYP3A Weak Inhibitors Alprazolam Amiodarone Amlodipine Atorvastatin Cimetidine Dihydroergotamine Ergotamine Fluoxetine Ginkgo biloba Goldenseal (Hydrastis canadensis root) Imipramine Isoniazid Oral contraceptives Ranitidine |
The safety profiles to date of all recommended regimens are excellent. Across numerous Phase III studies, less than 1% of patients without cirrhosis discontinued treatment early, and adverse events were mild, usually consisting of mild fatigue and headache. Adequate water intake commonly alleviates these symptoms. Most adverse events occurred in treatment regimens that included RBV, which may account for anemia in up to 10%.37
Adverse Side Effects of HCV Treatment Agents
As noted, the DAAs have a low adverse side effect incidence. If symptoms do occur, patients may come to the ED seeking explanation. The noted symptoms should be considered only representative and the prevalence only approximate. (See Table 6.) The symptoms noted during clinical studies vary according to severity and incidence, depending on duration of treatment and coadministered drugs. In addition, similar symptoms were noted in patients receiving placebo treatment. Daily oral ribavirin is given in combination with peg-interferon infusions weekly for the duration of treatment, so it is not possible to identify adverse reactions due to ribavirin from the common adverse reactions due to peg-interferon.
Table 6. Adverse Reactions Associated with HCV Oral Treatment Agents
Drug |
Common Reactions (all severity) |
Serious Reactions |
|
SOURCE: Prescribing Information for these drugs and combinations |
||
|
Ribavirin (Rebetol®) as part of peg-interferon treatment regimen |
Fatigue: 67% Headache: 50% Nausea: 40% Chills: 39% Insomnia: 38% Fever: 35% Anorexia: 29% Myalgias/arthralgias: 27% |
Hemolytic anemia Depression Suicidal ideation |
|
Simeprevir (Olysio®) |
Headache: 17-23% Fatigue: 16-32% Nausea: 13-14% Rash including photosensitivity: 12-16% |
Serious symptomatic bradycardia when coadministered with sofosbuvir and amiodarone |
|
Daclatasvir (Daklinza®) |
Headache: 14% Fatigue: 14% Nausea: 8% |
Serious symptomatic bradycardia when coadministered with sofosbuvir and amiodarone |
|
Sofosbuvir (Sovaldi®) |
Fatigue: 30-38% Headache: 24-30% Nausea: 13-22% Pruritus: 11-27% Diarrhea: 9-12% |
Serious symptomatic bradycardia when coadministered with amiodarone and another HCV DAA |
|
Ledipasvir/sofosbuvir (Harvoni®) |
Fatigue: 13-18% Headache: 11-17% Nausea: 6-9% Diarrhea: 3-7% Insomnia: 3-6% |
Symptomatic bradycardia, as well as fatal cardiac arrest and cases requiring pacemaker intervention, when amiodarone is coadministered |
|
Elbasvir/grazoprevir (Zepatier®) |
Fatigue: 5-11% Headache: 9-11% Nausea: 11% |
ALT elevations |
|
Ombitasvir/paritaprevir/ ritonavir (Technivie®) |
Asthenia: 25-29% Fatigue: 7-15% Nausea: 9-14% Insomnia: 5-13% Pruritus: 5-7% |
Hepatic decompensation in patients with cirrhosis |
|
Dasabuvir/ombitasvir/ paritaprevir/ritonavir (Viekira XR®) |
Fatigue: 34% Nausea: 16-22% Pruritus: 13-18% Rash: 16% Insomnia: 12-14% Asthenia: 9-14% |
Hepatic decompensation in patients with cirrhosis |
|
Sofosbuvir/velpatasvir (Epclusa®) |
Headache: 11-22% Fatigue: 15-32% Nausea: 9-15% Insomnia: 5-11% Asthenia: 5% |
Serious symptomatic bradycardia has been reported in patients taking amiodarone who initiated treatment with sofosbuvir in combination with another HCV DAA |
Considerations in Specific Populations
Patients with Cirrhosis. Treatment of HCV in patients with compensated cirrhosis is a high priority because of the risk of developing severe liver-related complications. For patients with hepatitis C-related cirrhosis, treatment of hepatitis C is associated with significant reversal in hepatic fibrosis and decreased risk of developing HCC, especially when the patient achieves an SVR with therapy.38
Options are limited for patients with decompensated cirrhosis, and antiviral treatment should be undertaken only by an expert in the management of such patients, preferably at a transplant center. Patients with decompensated cirrhosis or a MELD score greater than 10 should be evaluated for liver transplantation prior to initiation of HCV therapy.
HIV-HCV Coinfection. In patients with chronic hepatitis C, coinfection with HIV can accelerate the progression of hepatic fibrosis. Hence, treatment of HCV should be a high priority in coinfected patients. Drug-drug interactions between antiretroviral agents and HCV antiviral agents may be significant. For coinfected patients whose CD4 cell counts are less than 200 cells/mm3, it may be advisable to wait for further immune reconstitution prior to initiating HCV therapy, particularly since most HCV treatment trials have excluded such patients.80,81
Patients with Renal Impairment. Renal function, including an estimation of CrCl or GFR, must be assessed before initiating any hepatitis C treatment. Based on the estimated CrCl or GFR value, patients with renal impairment are classified as having mild (50-80 mL/min), moderate (30-50 mL/min), or severe (less than 30 mL/min) disease.
Based on the available limited data, the AASLD/IDSA hepatitis C guidance provides recommendations for the treatment of patients with severe renal disease, including those with ESRD.
- Patients with Mild Renal Impairment (CrCl 50-80 mL/min): No dosage adjustment needed when using any of the recommended agents or regimens to treat HCV.
- Patients with Moderate Renal Impairment (CrCl 30-50 mL/min): No dosage adjustment needed with DAAs when using standard dosing. The ribavirin dosing should be reduced to a schedule of 200 mg alternating with 400 mg every other day.
- Patients with Severe Renal Impairment (CrCl less than 30 mL/min) or ESRD: Recommended regimens vary according to genotype, if the patient does not have cirrhosis, and if renal transplantation is not an immediate option. Patients with hepatitis C infection who require renal transplantation should be evaluated for hepatitis C treatment; the treatment of hepatitis C prior to renal transplantation is strongly preferred over treatment of hepatitis C after renal transplantation. Several trials are underway for the treatment of HCV in patients with severe renal disease.82-84
Monitoring During DAA Regimens
For patients receiving hepatitis C therapy, the AASLD/IDSA recommends obtaining a quantitative HCV RNA level at baseline, at four weeks after starting therapy, and at 12 weeks after completing therapy.37 Some experts do not routinely recheck the HCV RNA after a detectable level at week 4 in patients believed to have reliable adherence, since the vast majority of these patients achieve SVR. However, if adherence is a concern, it is recommended to recheck the HCV RNA in two weeks, and if there is a greater than 10-fold increase, then obtain expert consultation and consider stopping therapy.
For patients evaluated in the ED, it is common to obtain chemistry panels that include serum bilirubin and liver enzyme levels. If an elevation in the alanine aminotransferase (ALT) is seen, medication adjustment or close follow-up may be required.
- Asymptomatic Increases in ALT Levels Less than 10-Fold: Patients with an increase in ALT levels that is less than 10 times the upper limit of normal, but without symptoms suggestive of acute hepatitis (weakness, nausea, vomiting, or jaundice), should have close surveillance and repeat ALT levels checked at treatment week 6 and week 8. If the ALT levels remain persistently elevated, discontinuation of therapy should be considered.
- Symptomatic Increase in ALT Levels of Less than 10-Fold: If a patient has any increase in ALT levels less than 10 times the upper limit of normal that is accompanied either by symptoms suggestive of acute hepatitis or increases in other hepatic function panel labs, HCV therapy should be discontinued promptly and the patient should undergo close monitoring for liver toxicity.
- A 10-fold or Greater Increase in ALT Levels: Patients who have a 10-fold or greater increase in ALT levels, regardless of the presence of clinical symptoms, should have HCV therapy discontinued promptly and undergo close monitoring for liver toxicity.
Conclusion
Hepatitis C is highly prevalent in the Western world and is the leading indication for liver transplantation in the United States. Patients affected can progress to having hepatic fibrosis, liver cirrhosis, and then HCC. There have been six identified genotypes that vary geographically. Initial diagnostic tests include an HCV antibody and, if reactive, then will include RNA quantitative testing as well as genotyping. Historially, hepatitis C has been known as a tough-to-treat entity given the lack of sustained viral remission with the previous drugs and the number of adverse reactions to those drugs, including ribavirin and interferon. Within the past couple of years, with the advent of DAA agents, treatment success rates exceed 90%. Treatment options then are based on the genotype, degree of fibrosis, treatment-naïve vs. treatment experienced, and comorbid conditions. Given the high efficacy of DAAs, screening efforts should be continued, especially in high-risk cohorts, to halt the progression of hepatitis C and to prevent further morbidity and mortality.
REFERENCES
- Lauer GM, Walker BD. Hepatitis C virus infection. N Engl J Med 2001;345:41-52
- Castera L, Vergniol J, Foucher J, et al. Prospective comparison of transient elastography, Fibrotest, APRI, and liver biopsy for the assessment of fibrosis in chronic hepatitis C. Gastroenterology 2005;128:343-350.
- Messina JP, Humphreys I, Flaxman A, et al. Global distribution and prevalence of hepatitis C virus genotypes. Hepatology 2015;61:77-87.
- Alter HJ, Purcell RH, Shih JW, et al. Detection of antibody to hepatitis C virus in prospectively followed transfusion recipients with acute and chronic non-A, non-B hepatitis. N Engl J Med 1989;321:1494-1500.
- Kuo G, Choo QL, Alter HJ, et al. An assay for circulating antibodies to a major etiologic virus of human non-A, non-B hepatitis. Science 1989;244:362-364.
- van der Poel CL, Reesink HW, Lelie PN, et al. Anti-hepatitis C antibodies and non-A, non-B post-transfusion hepatitis in The Netherlands. Lancet 1989;2:297-298.
- Alter MJ, Margolis HS, Krawczynski K, et al. The natural history of community-acquired hepatitis C in the United States. The Sentinel Counties Chronic non-A, non-B Hepatitis Study Team. N Engl J Med 1992;327:1899-1905.
- Bruix J, Barrera JM, Calvet X, et al. Prevalence of antibodies to hepatitis C virus in Spanish patients with hepatocellular carcinoma and hepatic cirrhosis. Lancet 1989;2:1004-1006.
- Denniston MM, Jiles RB, Drobeniuc J, et al. Chronic hepatitis C virus infection in the United States, National Health and Nutrition Examination Survey 2003 to 2010. Ann Intern Med 2014;160:293-300.
- Alter MJ, Kruszon-Moran D, Nainan OV, et al. The prevalence of hepatitis C virus infection in the United States, 1988 through 1994. N Engl J Med 1999;341:556-562.
- Ly KN, Xing J, Klevens RM, et al. The increasing burden of mortality from viral hepatitis in the United States between 1999 and 2007. Ann Intern Med 2012;156:271-278.
- Rein DB, Wittenborn JS, Weinbaum CM, et al. Forecasting the morbidity and mortality associated with prevalent cases of pre-cirrhotic chronic hepatitis C in the United States. Dig Liver Dis 2011;43:66-72.
- Viral Hepatitis C. US: CDC. Available at: http://www.cdc.gov/ncidod/diseases/hepatitis/c/plan/Prev_Control.htm. Accessed Oct. 20, 2016.
- Backmund M, Reimer J, Meyer K, et al. Hepatitis C virus infection and injection drug users: Prevention, risk factors, and treatment. Clin Infect Dis 2005;40(Suppl 5):S330-S335.
- Edlin BR, Kresina TF, Raymond DB, et al. Overcoming barriers to prevention, care, and treatment of hepatitis C in illicit drug users. Clin Infect Dis 2005;40(Suppl 5):S276-S285.
- Smith BD, Morgan RL, Beckett GA, et al. Recommendations for the identification of chronic hepatitis C virus infection among persons born during 1945-1965. MMWR Recomm Rep 2012;61:1.
- Smith BD, Yartel AK, Krauskopf K, et al. Hepatitis C virus antibody positivity and predictors among previously undiagnosed adult primary care outpatients: Cross-sectional analysis of a multisite retrospective cohort study. Clin Infect Dis 2015;60:1145.
- Roblin DW, Smith BD, Weinbaum CM, Sabin ME. HCV screening practices and prevalence in an MCO, 2000-2007. Am J Manag Care 2011;17:548.
- Spradling PR, Rupp L, Moorman AC, et al. Hepatitis B and C virus infection among 1.2 million persons with access to care: Factors associated with testing and infection prevalence. Clin Infect Dis 2012;55:1047.
- Armstrong GL, Wasley A, Simard EP, et al. The prevalence of hepatitis C virus infection in the United States, 1999 through 2002. Ann Intern Med 2006;144:705.
- Denniston MM, Jiles RB, Drobeniuc J, et al. Chronic hepatitis C virus infection in the United States, National Health and Nutrition Examination Survey 2003 to 2010. Ann Intern Med 2014;160:293.
- Galbraith JW, Franco RA, Donnelly JP, et al. Unrecognized chronic hepatitis C virus infection among baby boomers in the emergency department. Hepatology 2015;61:776.
- Hsieh YH, Rothman RE, Laeyendecker OB, et al. Evaluation of the Centers for Disease Control and Prevention Recommendations for Hepatitis C Virus Testing in an Urban Emergency Department. Clin Infect Dis 2016;62:1059.
- Lyons MS, Kunnathur VA, Rouster SD, et al. Prevalence of diagnosed and undiagnosed hepatitis C in a Midwestern urban emergency department. Clin Infect Dis 2016;62:1066.
- Weinbaum C, Lyerla R, Margolis HS, Centers for Disease Control and Prevention. Prevention and control of infections with hepatitis viruses in correctional settings. Centers for Disease Control and Prevention. MMWR Recomm Rep 2003;52:1.
- Spaulding AC, Thomas DL. Screening for HCV infection in jails. JAMA 2012;307:1259.
- Davis GL, Lau JY. Factors predictive of a beneficial response to therapy of hepatitis C. Hepatology 1997;26(Suppl 1):122S–127S.
- Poynard T, Marcellin P, Lee SS, et al. Randomised trial of interferon alpha2b plus ribavirin for 48 weeks or for 24 weeks versus interferon alpha2b plus placebo for 48 weeks for treatment of chronic infection with hepatitis C virus. International Hepatitis Interventional Therapy Group (IHIT). Lancet 1998;352:1426-1432.
- Ostapowicz G, Watson KJ, Locarnini SA, Desmond PV. Role of alcohol in the progression of liver disease caused by hepatitis C virus infection. Hepatology 1998;27:1730.
- Everhart JE, Lok AS, Kim HY, et al. Weight-related effects on disease progression in the hepatitis C antiviral long-term treatment against cirrhosis trial. Gastroenterology 2009;137:549.
- Malinchoc M, Kamath PS, Gordon FD, et al. A model to predict poor survival in patients undergoing transjugular intrahepatic portosystemic shunts. Hepatology 2000;31:864-871.
- Lin ZH, Xin YN, Dong QJ, et al. Performance of the aspartate aminotransferase-to-platelet ratio index for the staging of hepatitis C-related fibrosis: An updated meta-analysis. Hepatology 2011;53:726.
- Rossi E, Adams L, Prins A, et al. Validation of the FibroTest biochemical markers score in assessing liver fibrosis in hepatitis C patients. Clin Chem 2003;49:450.
- Talwalkar JA, Kurtz DM, Schoenleber SJ, et al. Ultrasound-based transient elastography for the detection of hepatic fibrosis: Systematic review and meta-analysis. Clin Gastroenterol Hepatol 2007;5:1214.
- Swain MG, Lai MY, Shiffman ML, et al. A sustained virologic response is durable in patients with chronic hepatitis C treated with peginterferon alfa-2a and ribavirin. Gastroenterology 2010;139:1593.
- AASLD/IDSA. Initial treatment of HCV infection. Recommendations for testing, management, and treating hepatitis C. Available at: www.hcvguidelines.org. Accessed Jan. 3, 2017.
- Poynard T, McHutchison J, Manns M, et al. Impact of pegylated interferon alfa-2b and ribavirin on liver fibrosis in patients with chronic hepatitis C. Gastroenterology 2002;122:1303-1313.
- Morgan RL, Baack B, Smith BD, et al. Eradication of hepatitis C virus infection and the development of hepatocellular carcinoma: A meta-analysis of observational studies. Ann Intern Med 2013;158(5 Pt 1):329-337.
- van der Meer AJ, Veldt BJ, Feld JJ, et al. Association between sustained virological response and all-cause mortality among patients with chronic hepatitis C and advanced hepatic fibrosis. JAMA 2012;308:2584-2593.
- Veldt BJ, Heathcote EJ, Wedemeyer H, et al. Sustained virologic response and clinical outcomes in patients with chronic hepatitis C and advanced fibrosis. Ann Intern Med 2007;147:677-684.
- Boucher CM, Walsh A, Forest CP. Healing livers, saving lives: Hepatitis C screening in an era of cure. JAAPA 2016;29:20-28.
- Ara AK, Paul JP. New direct-acting antiviral therapies for treatment of chronic hepatitis C virus infection. Gastroenterol Hepatol 2015;11:458-466.
- Elfiky AA, Elshemey WM, Gawad WA, Desoky OS. Molecular modeling comparison of the performance of NS5b polymerase inhibitor (PSI-7977) on prevalent HCV genotypes. Protein J 2013;32:75-80.
- Noell BC, Besur SV, deLemos AS. Changing the face of hepatitis C management — the design and development of sofosbuvir. Drug Des Devel Ther 2015;9:2367-2374.
- Lawitz E, Mangia A, Wyles D, et al. Sofosbuvir for previously untreated chronic hepatitis C infection. N Engl J Med 2013;368:1878.
- Roberts SS, Miller RK, Jones JK, et al. The Ribavirin Pregnancy Registry: Findings after 5 years of enrollment, 2003-2009. Birth Defects Res A Clin Mol Teratol 2010;88:551-559.
- Fontaine H, Lazarus A, Pol S, et al. Bradyarrhythmias associated with sofosbuvir treatment. N Engl J Med 2015;373:1886-1888.
- Zeuzem S, Mizokami M, Pianko S, et al. Prevalence of pre-treatment NS5A resistance associated variants in genotype 1 patients across different regions using deep sequencing and effect on treatment outcome with LDV/SOF [Abstract 91]. 66th Annual Meeting of the American Association for the Study of Liver Diseases (AASLD). November 13-17, 2015; San Francisco, CA.
- Jacobson IM, Asante-Appiah E, Wong P, et al. Prevalence and impact of baseline NS5A resistance associated variants (RAVs) on the efficacy of elbasvir/grazoprevir (EBR/GZR) against GT1a infection [Abstract LB-22]. 66th Annual Meeting of the American Association for the Study of Liver Diseases (AASLD). November 13-17, 2015; San Francisco, CA.
- Zeuzem S, Rockstroh JK, Kwo PY, et al. Predictors of response to grazoprevir/elbasvir among HCV genotype 1 (GT1)–infected patients: Integrated analysis of Phase 2-3 trials [Abstract 700]. 66th Annual Meeting of the American Association for the Study of Liver Diseases (AASLD). November 13-17, 2015; San Francisco, CA.
- Zeuzem S, Ghalib R, Reddy KR, et al. Grazoprevir-elbasvir combination therapy for treatment-naive cirrhotic and noncirrhotic patients with chronic hepatitis C virus genotype 1, 4, or 6 infection: A randomized trial. Ann Intern Med 2015;163:1-13.
- Kwo P, Gane EJ, Peng C-Y, et al. Efficacy and safety of grazoprevir/elbasvir +/- RBV for 12 weeks in patients with HCV G1 or G4 infection who previously failed peginterferon/RBV: C-edge treatment-experienced trial. J Hepatol 2015;62(Suppl 2):S674-S675.
- Lawitz E, Matusow G, DeJesus E, et al. Simeprevir plus sofosbuvir in patients with chronic hepatitis C virus genotype 1 infection and cirrhosis: A phase 3 study (OPTIMIST-2). Hepatology 2016;64:360-369.
- Andreone P, Colombo MG, Enejosa JV, et al. ABT-450, ritonavir, ombitasvir, and dasabuvir achieves 97% and 100% sustained virologic response with or without ribavirin in treatment-experienced patients with HCV genotype 1b infection. Gastroenterology 2014;147:359-365.
- Wyles D, Pockros P, Morelli G, et al. Ledipasvir-sofosbuvir plus ribavirin for patients with genotype 1 hepatitis C virus previously treated in clinical trials of sofosbuvir regimens. Hepatology 2015;61:1793-1797.
- Dalgard O, Bjøro K, Ring-Larsen H, et al. Pegylated interferon alfa and ribavirin for 14 versus 24 weeks in patients with hepatitis C virus genotype 2 or 3 and rapid virological response. Hepatology 2008;47:35-42.
- Foster GR, Pianko S, Brown A, et al. Efficacy of sofosbuvir plus ribavirin with or without peginterferon-alfa in patients with hepatitis C virus genotype 3 infection and treatment-experienced patients with cirrhosis and hepatitis C virus genotype 2 infection. Gastroenterology 2015;149:1462-1470.
- Sulkowski MS, Gardiner DF, Rodriguez-Torres M, et al. Daclatasvir plus sofosbuvir for previously treated or untreated chronic HCV infection. N Engl J Med 2014;370:211-221.
- Foster GR, Afdhal N, Roberts SK, et al. Sofosbuvir and velpatasvir for HCV genotype 2 and 3 infection. N Engl J Med 2015;373:2608-2617.
- AASLD/IDSA. Recommendations for testing, management, and treating hepatitis C. Retreatment of persons in whom prior therapy has failed. Available at: http://www.hcvguidelines.org/full-report/retreatment-persons-whom-prior-therapy-has-failed. Accessed Jan. 3, 2017.
- Zeuzem S, Dusheiko GM, Salupere R, et al. Sofosbuvir and ribavirin in HCV genotypes 2 and 3. N Engl J Med 2014;370:1993-2001.
- Leroy V, Angus P, Bronowicki JP, et al. Daclatasvir, sofosbuvir, and ribavirin for hepatitis C virus genotype 3 and advanced liver disease: A randomized phase III study (ALLY-3+). Hepatology 2016;63:1430-1441.
- Nelson DR, Cooper JN, Lalezari JP, et al. All-oral 12-week treatment with daclatasvir plus sofosbuvir in patients with hepatitis C virus genotype 3 infection: ALLY-3 phase III study. Hepatology 2015;61:1127-1135.
- Pianko S, Flamm SL, Shiffman ML, et al. Sofosbuvir plus velpatasvir combination therapy for treatment-experienced patients with genotype 1 or 3 hepatitis C virus infection: A randomized trial. Ann Intern Med 2015;163:809-817.
- Al-Ali J, Siddique I, Varghese R, Hasan F. Pegylated interferon-alpha2b plus ribavirin for the treatment of chronic hepatitis C virus genotype 4 infection in patients with normal serum ALT. Ann Hepatol 2012;11:186-193.
- Hézode C, Asselah T, Reddy KR, et al. 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. Lancet 2015;385:2502-2509.
- Feld JJ, Jacobson IM, Hézode C, et al. Sofosbuvir and velpatasvir for HCV genotype 1, 2, 4, 5, and 6 infection. N Engl J Med 2015;373:2599-2607.
- Antaki N, Hermes A, Hadad M, et al. Efficacy of interferon plus ribavirin in the treatment of hepatitis C virus genotype 5. J Viral Hepat 2008;15:383-386.
- Bonny C, Fontaine H, Poynard T, et al Effectiveness of interferon plus ribavirin combination in the treatment of naive patients with hepatitis C virus type 5. A French multicentre retrospective study. Aliment Pharmacol Ther 2006;24:593-600.
- Lam KD, Trinh HN, Do ST, et al. Randomized controlled trial of pegylated interferon-alfa 2a and ribavirin in treatment-naive chronic hepatitis C genotype 6. Hepatology 2010;52:1573-1580.
- Abergel A, Asselah T, Metivier S, et al. Ledipasvir-sofosbuvir in patients with hepatitis C virus genotype 5 infection: An open-label, multicentre, single-arm, phase 2 study. Lancet Infect Dis 2016;16:459-464.
- Gane EJ, Hyland RH, An D, et al. Efficacy of ledipasvir and sofosbuvir, with or without ribavirin, for 12 weeks in patients with HCV genotype 3 or 6 infection. Gastroenterology 2015;149:1454-1461.e1.
- Kwo PY. Regimens for cirrhotic patients. Clin Liver Dis 2015;19:657-667.
- Chung RT, Andersen J, Volberding P, et al. Peginterferon Alfa-2a plus ribavirin versus interferon alfa-2a plus ribavirin for chronic hepatitis C in HIV-coinfected persons. N Engl J Med 2004;351:451.
- Carrat F, Bani-Sadr F, Pol S, et al. Pegylated interferon alfa-2b vs standard interferon alfa-2b, plus ribavirin, for chronic hepatitis C in HIV-infected patients: A randomized controlled trial. JAMA 2004;292:2839.
- Sulkowski M, Pol S, Mallolas J, et al. Boceprevir versus placebo with pegylated interferon alfa-2b and ribavirin for treatment of hepatitis C virus genotype 1 in patients with HIV: A randomised, double-blind, controlled phase 2 trial. Lancet Infect Dis 2013;13:597.
- Sulkowski MS, Sherman KE, Dieterich DT, et al. Combination therapy with telaprevir for chronic hepatitis C virus genotype 1 infection in patients with HIV: A randomized trial. Ann Intern Med 2013;159:86.
- Dieterich D, Rockstroh JK, Orkin C, et al. Simeprevir (TMC435) with pegylated interferon/ribavirin in patients coinfected with HCV genotype 1 and HIV-1: A phase 3 study. Clin Infect Dis 2014;59:1579.
- Sulkowski MS, Naggie S, Lalezari J, et al. Sofosbuvir and ribavirin for hepatitis C in patients with HIV coinfection. JAMA 2014;312:353.
- Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents. Department of Health and Human Services. Considerations for antiretroviral use in patients with confections: Hepatitis C (HCV)/HIV coinfection. April 8, 2015.
- Panel on Opportunistic Infections in HIV-Infected Adults and Adolescents. Guidelines for the prevention and treatment of opportunistic infections in HIV-infected adults and adolescents: Recommendations from the Centers for Disease Control and Prevention, the National Institutes of Health, and the HIV Medicine Association of the Infectious Diseases Society of America. Hepatitis C virus infection. Oct. 28, 2014.
- Fabrizi F, Messa P, Martin P. Recent advances on hepatitis C virus in dialysis population. Kidney Blood Press Res 2014;39:260-271.
- Fabrizi F, Messa P. Therapy of hepatitis C by direct-acting anti-virals: The end of HCV in dialysis population? Expert Rev Clin Pharmacol 2015;8:785-793.
- Fabrizi F, Penatti A, Messa P, Martin P. Treatment of hepatitis C after kidney transplant: A pooled analysis of observational studies. J Med Virol 2014;86:933-940.
- European Association for the Study of the Liver. EASL recommendations on treatment of hepatitis C 2015. J Hepatol 2015;63:199-236.
This issue is written to provide you with the knowledge to be able to ask and educate patients with hepatitis C about the highly effective treatment available for most all infected patients.
Subscribe Now for Access
You have reached your article limit for the month. We hope you found our articles both enjoyable and insightful. For information on new subscriptions, product trials, alternative billing arrangements or group and site discounts please call 800-688-2421. We look forward to having you as a long-term member of the Relias Media community.