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Hepatitis C in 2019: Are We There Yet?
The Journal for Nurse Practitioners xxx (xxxx) xxx
Contents lists available at ScienceDirect
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Feature Article
Hepatitis C in 2019: Are We There Yet? Donald Gardenier, DNP, FNP-BC, Mary C. Olson, DNP, ANP-BC a b s t r a c t Keywords: hepatitis C infectious disease public screening treatment
Chronic hepatitis C is the most common blood-borne pathogen worldwide. Upwards of half of the individuals infected with hepatitis C have not been diagnosed, and rates of screening remain low. Incidence, which had been declining, began increasing in 2011, mirroring the current opioid epidemic. Once infected, people with chronic hepatitis C are at risk for developing complications including end-stage liver disease and hepatocellular carcinoma, leading to morbidity and mortality. These public health consequences of the hepatitis C epidemic are expected to increase over the coming decade. Innovation has resulted in highly tolerable medications of 8 to 16 weeks’ duration with over 90% efficacy. Experts have determined that the eradication of hepatitis C would be feasible and have laid out strategies to move us toward that goal. Significant and disparate barriers remain, including access to treatment and an increase in incidence related to the opioid epidemic. An underresourced approach to surveillance and screening, provider shortages, and payer restrictions are among the obstacles to eliminating hepatitis C as a public health problem in the United States. © 2018 Elsevier Inc. All rights reserved.
Natural History Hepatitis C is a blood-borne virus. Infection occurs as the result of transmission from an infected individual to an uninfected individual. The majority of hepatitis C infections in the United States took place in the course of percutaneous injection of illicit drugs, which continues to account for 75% of hepatitis C incidence. Worldwide risk factors include the reuse or inadequate sterilization of medical equipment including syringes. Other risk factors include transfusions before 1990 and vertical transmission (Table 1). Neither frequency nor remoteness of exposure are associated with the likelihood of transmission, so a single remote exposure should still be considered significant when assessing risk for chronic infection.2 After infection, acute symptoms such as nausea, vomiting, and/ or jaundice are rare. The host immune response results in spontaneous resolution in approximately 20% of acute infections. In the remaining approximately 80% of cases, hepatitis C infection becomes chronic, and spontaneous clearance is rare. The chronic phase is generally recognized to be asymptomatic, although nonspecific symptoms such as fatigue are common. In most cases, there is no specific sign or symptom indicating hepatitis C. Once in the bloodstream, the virus releases RNA into hepatocytes, viral replication takes place, new RNA strands are released into the bloodstream, and additional hepatocytes become infected.1 Antibodies to the hepatitis C virus develop during the acute phase, or the first 6 months after exposure. If acute infection is suspected, a quantitative hepatitis C RNA test (viral load) and transaminases should be used to screen the patient for exposure because an antibody response may not yet have occurred. Once the patient is beyond the acute phase, hepatitis C antibodies indicate https://doi.org/10.1016/j.nurpra.2018.12.009 1555-4155/© 2018 Elsevier Inc. All rights reserved.
prior exposure to the virus and, unless there is a prior history of treatment, suspected chronic infection. Infection is confirmed by a viral load. Hepatitis C virus is also characterized by genotypes numbered 1 through 6. In the US, approximately 70% is genotype 1. Genotype distributions vary by region worldwide. Patients who become aviremic either by spontaneous clearance or after treatment will have no detectable RNA but usually retain antibodies that do not confer immunity from reinfection should the individual be reexposed to the hepatitis C virus.1 Chronic inflammation leads to hepatocyte damage, including fibrosis production and loss of liver function that in most cases occur gradually over time. Inflammation can cause an elevation in hepatic transaminases. A concomitant source of liver inflammation, such as alcohol use, hepatitis B coinfection, or nonalcoholic fatty liver disease, can increase both the rate and severity of liver inflammation and damage. Coinfection with human immunodeficiency virus also leads to faster progression. Infection without transaminase elevation is not unusual and should not be taken as evidence of no damage. RNA quantification has not been associated with the rate or degree of liver damage. The likelihood of developing cirrhosis and other complications increases as the patient with chronic infection ages.1 Complications of chronic hepatitis C infection are those that are common in cirrhosis, including volume overload with ascites and lower extremity edema, portal hypertension, esophageal varices, coagulopathies, deficient protein synthesis, and encephalopathy. Extrahepatic manifestations of chronic hepatitis C have also been recognized and are listed in Table 2.4 The risk for developing hepatocellular carcinoma is 1% to 5% per year. Once hepatocellular carcinoma has been diagnosed, the patient has a 33% probability of dying within a year.1
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Table 1 Hepatitis C Risk Factors1 People who have ever injected drugs People who have ever used intranasal drugs Recipients of infected blood, organs, or blood products Transfusions before 1992 Clotting factor concentrates made before 1987 Organs donated by hepatitis Cepositive donors People who have undergone percutaneous invasive procedures in health care settings with inadequate or unreliable infection control practices Children born to mothers infected with hepatitis C or with risk factors People with sexual partners infected with hepatitis C or with risk factors People with human immunodeficiency virus infection Prisoners or previously incarcerated persons People who have had tattoos or piercings People with elevated liver enzymes People born between 1945 and 1965 People who have ever undergone hemodialysis Health care worker, first responder, or public safety workers who Ever had a percutaneous (needlestick) injury Ever splashed with blood or blood products
Epidemiology Approximately 130 million people worldwide are chronically infected with the hepatitis C virus. Significant variation between regions exists, both in the prevalence and likely infection patterns and risk factors. The highest prevalence in the world is in Egypt (15%-20%), whereas the lowest is in the United Kingdom and Scandinavia (0.01%-0.1%).1 In the US, approximately 5 million are thought to be chronically infected with the hepatitis C virus. Official surveillance data, which are lower, are considered likely to be undercounts because they sampled only the domiciled civilian noninstitutionalized population and therefore omitted the homeless, the incarcerated, and those admitted to hospitals or nursing homes. Active military personnel were also excluded. Approximately 75% of those infected in the US are baby boomers, born between 1945 and 1965. Most baby boomers, also referred to as the birth cohort, were infected remotely (more than 10 years ago), and have had largely asymptomatic disease courses. Men and racial and ethnic minorities are disproportionately affected, as are medically underserved populations including the incarcerated, homeless, and those with concomitant mental illness and substance use, all groups that were underrepresented as a result of the official surveillance methodology.3 Hepatitis C infection causes inflammatory liver disease, fibrosis, and eventually cirrhosis. In turn, cirrhosis progresses to end-stage liver disease and, in some cases, hepatocellular carcinoma, which Table 2 Extrahepatic Manifestations of Hepatitis C3 Sign/Symptom
Potential Hepatitis Cerelated Etiology
Hypertension
Membranoproliferative glomerulonephritis Nephropathy Cryoglobulinemia Lichen planus Porphyria cutanea tarda Leukocytoclastic vasculitis Cryoglobulinemic vasculitis Cryoglobulinemic vasculitis Leukocytoclastic vasculitis Membranoproliferative glomerulonephritis Cryoglobulinemia Membranoproliferative glomerulonephritis Cryoglobulinemia Lymphoproliferative disorder Cryoglobulinemic vasculitis Lymphoproliferative disorder Cryoglobulinemia Lymphoma
Dermatitis
Purpura Peripheral neuropathy Renal insufficiency Hematuria Lymphadenopathy Fever Arthralgia Weakness
together are among the top 10 leading causes of death. Hepatitis C is estimated to be the etiology of 27% of cirrhosis and 25% of hepatocellular carcinoma cases worldwide. Because hepatitis Cerelated complications are still developing in a significant percentage of infected individuals, end-stage complication rates in the population are expected to continue to increase over the coming years.1 Because acute infection is most often asymptomatic and surveillance methodology varies, tracking hepatitis C incidence has been difficult. Therefore, reported cases are supplemented by statistically modeled estimates of true incidence, which are considered by epidemiologists to more accurately reflect incidence rates. In the US, incidence peaked in 1989 and then declined by approximately 80% through 2005. Incidence remained relatively stable from 2005 through 2011 but has increased since, paralleling opioid use disorder, and thus is likely associated with the opioid epidemic currently underway in the US.5 Incidence as reported to the Centers for Disease Control and Prevention (CDC) as well as estimates of the actual incidence of hepatitis C from 2011 through 2016 are shown in the Figure (available online at http://www.npjournal.org).6 A long period of asymptomatic chronicity is most often associated with hepatitis C infection, delaying the onset of complications well beyond the time of infection. For this reason, the major disease burden associated with chronic hepatitis C has not yet peaked. Similarly, the death rate from chronic hepatitis C in the US is also rising and has been projected to peak at 36,000 per year sometime between 2030 and 2035.7 Chhatwal et al8 modeled hepatitis C disease burden in the US given the most recent relevant changes, such as the advent of direct-acting antiviral (DAA) medications and the Patient Protection and Affordable Care Act of 2010. According to their model, the number of noninstitutionalized viremic individuals in the US dropped from 2.5 million in 2010 to 1.9 million in 2015. That number is expected to drop to less than 1 million by 2020; however, more than 500,000 of those remaining viremic individuals will remain undiagnosed. An estimated 1.8 million individuals will undergo treatment by 2030. They concluded that, despite the availability of effective treatment, 157,000 individuals will develop hepatocellular carcinoma, 203,000 will progress to decompensated cirrhosis, and 320,000 people will die of chronic hepatitis C over the coming 35 years.8 Screening Routine screening for nonacute hepatitis C as recommended in the US is based on risk factors and is a 3-step process. Individuals are first screened for risk factors (Table 1). Those with 1 or more risk factor(s) are tested for serologic presence of hepatitis C antibodies. Those with antibodies are then tested for the presence of hepatitis C virus RNA. The presence of RNA in the serum indicates chronic disease. The presence of antibodies without RNA indicates an infection that has resolved, either spontaneously or after successful treatment.1 Risk factorebased screening misses between 31% and 47% of hepatitis C cases according to the National Hepatitis Screening Survey. Epidemiologic data revealed that 67% of hepatitis C cases were among individuals born between 1945 and 1965, thereby adding individuals in the birth cohort to those at elevated risk. This recognition led the CDC and the US Preventive Services Task Force, in 2012 and 2013, respectively, to recommend the screening of individuals in the birth cohort even in the absence of additional risk factors.5 Hepatitis C screening rates are low. The CDC estimates that between 45% and 85% of those chronically infected with hepatitis C are unaware of their diagnosis.4 Screening rates since 2012, when birth cohort screening was first recommended, have increased only
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marginally. Data collected between 2013 and 2015 in the National Health Interview Surveys (N ¼ 85,210) showed that the screening rate in the birth cohort was 11.5% to 12.8%, with slightly higher rates among those younger than the birth cohort and lower rates among those who are older. In addition to age, there were significant disparities associated with sex and race/ethnicity.9 Interventions to improve screening have been undertaken successfully. For example, in 1 academic practice, baseline data showed that screening was completed in only 23.5% of patients, and providers elected to screen in only 50% to 62.5% of individuals who met screening criteria. After a quality improvement project was implemented, the screening rate increased to over 90%. One year later, the screening rate remained at 88%.5 A consensus committee convened by the National Academies of Sciences, Engineering, and Medicine studied the feasibility of eliminating hepatitis B and C as a public health problem in the US. Among a broad array of proposals, the committee recommended improved surveillance and increased screening. Screening identifies those who are infected and is the essential first step in treating those who are most at risk of progression because of active infection.1 The National Viral Hepatitis Roundtable, 1 of the sponsors of the National Academies report, also encourages increased screening with a focus on underserved populations in which hepatitis C is endemic, such as the incarcerated.10 Treatment Once chronic hepatitis C infection has been diagnosed with a positive viral load, the patient needs to be evaluated for treatment. Untreated hepatitis C leads to progression of liver disease and hepatocellular carcinoma, has extrahepatic manifestations, and has been shown to cause a decrease in quality of life. Studies have also shown that patients’ quality of life improves after successful treatment. The likelihood of extrahepatic manifestations also decreases after treatment. Real-world database studies have verified high rates of cure observed in the DAA clinical trials.11 Therefore, it is important to consider all patients with chronic hepatitis C to be candidates for treatment. It is important to determine the genotype and stage of fibrosis. The stage of fibrosis can be assessed with noninvasive tests, including transient elastography if available. There are also blood tests that can be done to estimate the degree of fibrosis. A thorough medical history, including any hepatitis C treatment history, current medical problems, and all medications and supplements that the patient is taking, is needed to identify any potential drug-drug interactions. Coinfection with human immunodeficiency virus and concomitant alcohol use also need to be considered. Patients with decompensated cirrhosis should be referred to a qualified hepatology specialist or a liver transplant center to be further evaluated. Prior authorization for treatment is required by most insurance companies. All DAAs have black box warnings about the risk of activation of hepatitis B virus that can result in fulminant hepatitis, hepatic failure, and death. Therefore, all patients need to be screened for hepatitis B and treated if indicated before hepatitis C treatment.12 Once evaluated, a treatment regimen can be selected. DAA regimens with once-daily dosing for 8 to 12 weeks and 95% or greater rates of sustained viral response (SVR12, defined as no detectable virus 12 weeks after completing treatment, which is synonymous with cure), makes adherence to treatment less challenging and more likely to be successful than previous regimens. DAA regimens combine drugs that inhibit viral replication by binding to viral proteases or polymerases at specific locations. They are classified by these locations (NS3/4A or NS5A/B). Treatment is individualized based on genotype; viral load; and patient factors,
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including prior treatment history, comorbid conditions, stage of liver fibrosis, and any potential interactions with the patient’s existing medications.12 Three pangenotypic regimens have been approved since 2016: sofosbuvir 400 mg/velpatasvir 100 mg (SOF/VEL), glecaprevir 100 mg/pibrentasvir 40 mg (GLE/PIB), and sofosbuvir 400 mg/velpatasvir 100 mg/voxilaprevir 100 mg (SOF/VEL/VOX). GLE/PIB and SOF/VEL are first-line regimens with different treatment durations based on genotype, treatment history, and stage of liver fibrosis. SOF/VEL/VOX is recommended for the retreatment of patients who previously failed a DAA regimen. SOF/VEL and SOF/VEL/VOX are dosed 1 tablet daily for 12 weeks. GLE/PIB is dosed 3 tablets daily for 8, 12, or 16 weeks.12 SOF/VEL combines an NS5B inhibitor and an NS5A inhibitor. In phase 3 trials, SOF/VEL was studied for 12 weeks. Patients with genotypes 1-6, with or without prior treatment and with or without compensated cirrhosis were included. The sustained viral response (SVR) rate was 99%. Therefore, this regimen is dosed as 1 tablet once daily for 12 weeks for all genotypes. The most common adverse events were headache, fatigue, nasopharyngitis, and nausea.13 SOF/VEL/VOX, approved in 2017, adds an NS3/4A protease inhibitor to SOF/VEL. In 2 phase 3 trials patients who had previously failed a DAA-containing regimen were given SOF/VEL/VOX for 12 weeks. The SVR12 rate was 96%-98%, showing a high response rate for these patients. The most common adverse events were headache, fatigue, diarrhea, and nausea.14 GLE/PIB combines an NS3/4 protease inhibitor and an NS5A inhibitor. The antiviral activity is pangenotypic with a high barrier to resistance. A phase 2 trial of GLE/PIB for 8 weeks included genotypes 1-6 in treatment-naive and treatment-experienced patients without cirrhosis. The SVR12 rates were 97%-100%.15 In 2 phase 3 trials, GLE/PIB was evaluated for 8 or 12 weeks in patients with genotype 1 or 3, both treatment naive and treatment experienced without cirrhosis. The SVR12 rate for genotype 1 was 99.1% for 8 weeks and 99.78% for 12 weeks. For genotype 3, the SVR12 rate was 95% for both 8- and 12-week durations. In another trial, treatment-naive and treatment-experienced patients with compensated cirrhosis, genotypes 1, 2, 4, 5, or 6 were given GLE/PIB for 12 weeks. The SVR rate was 99%.16 A phase 3 study included genotype 3 patients with compensated cirrhosis; treatment naive and treatment experienced were treated with GLE/PIB for 12 or 16 weeks respectively. The SVR12 rates were 98% in the 12-week group and 96% in the 16-week group.17 The most common adverse events were fatigue and headache. GLE/PIB is absorbed in an acidic environment and should be taken with food.18 Two other regimens are approved for genotypes 1 and 4. The combination of SOF, an NS5B inhibitor, with ledipasvir, an NS5A inhibitor, was tested in trials that included treatment-naive and treatment-experienced patients with and without compensated cirrhosis. The results showed that 97% and 94%, respectively, achieved an SVR12 after 12 weeks.19,20 In genotype 4, treatment-naive and treatment-experienced patients with and without advanced fibrosis were treated for 12 weeks; the SVR12 rate was 95%.21 Further evaluation showed that SOF/ledipasvir can be given for 8 weeks in genotype 1 treatment-naive patients with a viral load < 600,000 IU/mL. The most common adverse events were fatigue, headache, insomnia, and nausea.22 The other regimen recommended for genotypes 1 and 4 is grazoprevir 100 mg (GRZ), an NS3/4A protease inhibitor, in combination with elbasvir 50 mg (EBR), an NS5A inhibitor. The phase 3 C-Edge study evaluated treatment-naive and treatmentexperienced patients with genotypes 1, 4, and 6 with or without cirrhosis. After 12 weeks of treatment, the SVR12 rates for treatment naive patients by genotype were 92% for 1a, 99% for 1b, and 100% for 4.23 EBR/GRZ was given to the treatment experienced
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Table 3 First-line Regimens for Treatment-naive Patients With Chronic Hepatitis C With or Without Compensated Cirrhosis13 Regimen Medications and Dosing
Brand Name
Duration
Consideration
EBR 50 mg GZR 100 mg 1 tablet Once daily GLE/PIB GLE 100 mg PIB 40 mg 3 tablets Once daily SOF/LDV SOF 400 mg LDV 90 mg 1 tablet Once daily SOF/VEL SOF 400 mg VEL 100 mg 1 tablet Once daily
Zepatier (Merck, Sharp and Dohme Corp., Whitehouse Station, NJ)
12 weeks with and without cirrhosis
Genotypes 1a (no NS5a RASb), 1b, 4
Mavyret (Abbvie Inc., North Chicago, IL)
8 weeks without cirrhosis 12 weeks with cirrhosis
Genotypes 1-6 Take with food
Harvoni (Gilead Sciences, Foster City, CA)
12 weeks with and without cirrhosis 8 weeks without cirrhosis, nonblack, no HIV infection, with HCV RNA <6,000,000 at baseline 12 weeks with and without cirrhosis
Genotypes 1, 4, 5, 6
EBR/ GZRa
Epclusa (Gilead Sciences, Foster City, CA)
Genotypes 1-6
EBR ¼ elbasvir; HCV ¼ hepatitis C virus; HIV ¼ human immunodeficiency virus; GLE ¼ glecaprevir; GZR ¼ grazoprevir; LDV ¼ ledipasvir; PIB ¼ pibrentasvir; RAS ¼ Resistanceassociated substitutions; SOF ¼ sofosbuvir; VEL ¼ velpatasvir. a EBR/GZR for G1a with NS5A RASs is given with weight-based ribavirin for 16 weeks. b RASs.
genotype 1 patients for 12 or 16 weeks with or without ribavirin. The SVR rate for both 12 and 16 weeks of EBR/GRZ without ribavirin was 92.4%. The SVR rates for EBR/GZR for 12 and 16 weeks with ribavirin were 94.2% and 98.1%. respectively. The response rates to this regimen was affected by baseline-resistant variants in patients with genotype 1a. The SVR12 rate for the 12-week duration without ribavirin in genotype 1b was 98.6%. Among patients with genotype 1a, baseline testing for NS5A-resistant variants was highly effective in predicting the outcome of the 12-week regimen. The SVR12 rate for patients with genotype 1a without baseline resistance was 99%, and for patients with baseline resistance who were treated with EBR/GZR/RBV for 16 weeks, it was 100%. The adverse events were fatigue, nausea, and headache.24 Table 3 lists the 4 first-line treatment regimens with key considerations. Once a regimen has been selected, a baseline treatment visit should be conducted with an updated history and a physical examination to determine any new medical issues that may have occurred since the pretreatment evaluation. The patient should be assessed for motivation to ensure that the entire course of treatment and posttreatment evaluation will be completed. An updated review of any new over-the-counter and prescribed medications as well as any herbal products is important to confirm that there will be no drug/drug interactions. Patient education should include dosing, importance of adherence, and management of missed doses and side effects. A visit at treatment week 4 is important to determine tolerance to the regimen. A viral load can be drawn at this point to ascertain adherence.12 At the end of treatment, a complete blood count, chemistry, and viral load should be drawn. A viral load should again be drawn at 4 and 12 weeks posttreatment to determine if the patient has achieved an SVR12. Posttreatment management of patients who have been cured of hepatitis C is evolving. Those with advanced fibrosis or cirrhosis will need posttreatment follow-up to monitor for decompensation and should be referred to a qualified hepatology specialist. Those who are not cured should be assessed and considered for retreatment.12 Challenges Because there is no vaccine for hepatitis C, prevention is considered to be especially important, particularly among those who inject drugs and account for 75% of new cases of hepatitis C. A
key prevention intervention with documented efficacy and costeffectiveness is needle and syringe exchange as part of a harm reduction approach.25 Another key intervention is the elimination of barriers to hepatitis C treatment. Although cost-effective, medications used to treat hepatitis C are expensive and, as a result, significant barriers erected by payers prevent or substantially delay access by many patients to treatment. Treatment delays result in increased rates of progression to cirrhosis and related complications. Because people remain infected for longer, treatment delays also increase incidence. Conversely, the unrestricted treatment access that would result from the elimination of barriers has the potential to reduce new cases of hepatitis C by 90% by 2030. In addition to prevention and the removal of barriers to treatment, the establishment of an office at the national level to oversee and coordinate efforts to eliminate hepatitis C as a public health problem was considered by an expert panel to be critical, as were increased surveillance and increased efforts to reach high-prevalence populations with limited access to care, such as the incarcerated.1 All of these interventions would require significant changes in national policies and funding. Durham et al26 developed a transmission model to assess the impact of increased screening and treatment on hepatitis C prevalence in the US. In addition to the need to increase capacity, complete elimination of hepatitis C transmission in the US would require screening of all people who inject drugs, a group that traditionally has had poor access to care in the US. Evidence supports successful treatment and low rates of relapse and reinfection in individuals who inject drugs, as well as those on opioid agonist therapy, suggesting that barriers to treatment based on active injection drug use are not evidence based and hinder progress toward the public health goal of eliminating chronic hepatitis C.27 The task remains to implement methods to reach this traditionally marginalized population more effectively and comprehensively. Bruggmann and Litwin28 examined a number of models that have shown success in adapting usual health care models to meet the unique needs of individuals who inject drugs. The models share key components, including identifying and eliminating stigma, integrating care and services, peer support, and taking a multidisciplinary approach. Programs that have had successful outcomes vary widely, with a structure and approach based on the specific needs of the patient populations they serve. These include incorporating directly observed therapy, substance use treatment,
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structured peer support services, and colocated psychiatric and substance use treatment.28 Success in reaching traditionally excluded high-prevalence populations has been achieved using care delivery innovations. Innovations take a variety of forms, and data support incorporating specific program elements that have been used successfully into new or existing care delivery models based on the needs of the patients they serve. In a qualitative study conducted among patients in an opioid substitution program, for example, there was unanimous perceived benefit in the use of peer educators.29 Another program used a team approach, including patient navigators, a registered nurse, and an experienced specialty pharmacy to achieve a 93% approval rate in prior authorizations for treatment medications for their patients, 69% of whom were covered by Medicaid.30 The National Viral Hepatitis Action Plan’s goals include the prevention of new infections, the reduction of deaths, and improvement of the health of individuals living with chronic hepatitis C. Additional goals include reducing health disparities among those with hepatitis C and coordination and monitoring of efforts undertaken to achieve the goal of eliminating the public health problem of viral hepatitis.31 Use of these recommendations should assist providers and administrators on need-based structural elements for their care delivery models as they work to reach those with chronic hepatitis C and link them to care. Engaging with community organizations and public health resources will also facilitate needs-based models of care. Conclusion Chronic hepatitis C infection is both curable and preventable. Advances have led to an increased number of pharmaceutical options with high efficacy and tolerability. However, their high cost is a barrier that has prevented their full potential in combating the hepatitis C from being realized. A shortage of providers qualified to treat hepatitis C is also a barrier. Although there is no vaccine, risks for hepatitis C transmission are known, and education geared toward prevention, especially efforts that take a harm reduction approach, have been shown to be effective. Nevertheless, hepatitis C remains a public health problem in the US and worldwide, one that experts agree can and should be eradicated. Changes in screening recommendations have not resulted in significantly higher numbers of individuals screened, and more than half of those infected with chronic hepatitis C remain undiagnosed. Innovation in care delivery has shown promise, particularly in reaching populations in which hepatitis C has a disparate impact. A concurrence of expert opinion and evidence suggests that strategies to achieve the elimination of hepatitis C as a public health problem are within reach. The task of making hepatitis C a public health priority remains before us. It will require care innovation, focus in the policy-making arena, and greater resource allocation in order to prevent the much more serious consequences that have been predicted for the coming years and decades. Supplementary Data Supplementary Figure associated with this article can be found in the online version at https://doi.org/10.1016/j.nurpra.2018.12.009. References 1. Gardenier D, Kwong J, Olson M, Epstein R. Epidemiology, screening, and pretreatment evaluation of the patient with chronic hepatitis C infection. J Nurse Pract. 2015;11:109-115. 2. National Academies of Sciences, Engineering, and Medicine. A National Strategy for the Elimination of Hepatitis B and C: Phase 2 Report. Washington, DC: The National Academies Press; 2017.
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3. Edlin B, Eckhardt B, Shu M, Holmberg S, Swan T. Toward a more accurate estimate of the prevalence of hepatitis C in the United States. Hepatology. 2015;62:1353-1363. 4. Polo M, Laufer N. Extrahepatic manifestations of HCV: the role of direct acting antivirals. Expert Rev Anti Infect Ther. 2017;15(8):737-746. 5. Trinh J, Turner N. Improving adherence to hepatitis C screening guidelines. BMJ Open Qual. 2018;7(2):e000108. 6. Zibbell J, Asher A, Patel R, et al. Increases in acute hepatitis C virus infection related to a growing opioid epidemic and associated injection drug use, United States, 2004-2014. Am J Public Health. 2018;108(2):175-181. 7. Rein D, Wittenborn J, Weinbaum C, Sabin M, Smith B, Lesesne S. 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. 8. Chhatwal J, Wang X, Ayer T, et al. Hepatitis C disease burden in the United States in the era of direct-acting antivirals. Hepatology. 2016;64(5):1442-1450. 9. Kasting ML, Giuliano AR, Reich R, et al. Hepatitis C screening trends: serial cross-sectional analysis of the National Health Interview Survey population, 2013-2015. Cancer Epidemiol Biomarkers Prev. 2018;27(4):1-11. 10. National Viral Hepatitis Roundtable. Elimination of hepatitis B and C: a national strategy. 2017. http://www.nvhr.org. Accessed September 6, 2018. 11. Younossi Z, Stepanova M, Asselah T, et al. Hepatitis C in patients With minimal or no hepatic fibrosis: the impact of treatment and sustained virologic response on patient-reported outcomes. Clin Infect Dis. 2018;66(11):1742-1750. 12. American Association for the Study of Liver Disease/Infectious Disease Society of America. HCV Guidance: Recommendations for Testing, Managing, and Treating Hepatitis C. https://www.hcvguidelines.org/. March 23, 2018. Accessed September 6, 2018. 13. Feld J, Jacobson I, Hezode C, et al. Sofosbuvir and velpatasvir for HCV genoytpe 1, 2, 4, 5, and 6 infection. N Engl J Med. 2015;373(27):2599-2607. 14. Bourliere M, Gordon S, Flamm S, et al. Sofosbuvir, velpatasvir, and voxilaprevir for previously treated HCV Infection. N Engl J Med. 2017;376(22):2134-2146. 15. Kwo P, Poordad F, Astryan F, et al. Glecaprevir and pibrentasvir yield high response rates in patients with HCV genotype 1-6 without cirrhosis. J Hepatol. 2017;67:263-271. 16. Forns X, Lee S, Valdes J, et al. Glecaprevir plus pibrentasvir for chronic hepatitis C virus genotype 1, 2, 4, 5, or 6 infection in adults with compensated cirrhosis (EXPEDITION-1): a single-arm, open-label, multicenter phase 3 trial. Lancet. 2017;17:1062-1068. 17. Wyles D, Poordad F, Wang S, et al. Glecaprevir/Pibrentasvir for hepatitis C virus genotype 3 patients with cirrhosis and/or prior treatment experience: A partially randomized phase 3 clinical trial. Hepatology. 2018;67(2):514-523. 18. Zeuzem S, Foster G, Wang S, et al. Glecaprevir-pibrentasvir for 8 or 12 2eeks in HCV genotype 1 or 3 infection. N Engl J Med. 2018;378(4):354-369. 19. Afdahl N, Zeuzem S, Kwo P, et al. Ledipasvir and sofosbuvir for untreated HCV genotype 1 infection. N Engl J Med. 2014;370(20):1889-1898. 20. Afdahl N, Reddy R, Nelson D, et al. Ledipasvir and sofosbuvir for previously treated HCV genotype 1 infection. N Engl J Med. 2014;370(16):1483-1493. 21. Kohi A, Kapoor A, Sims R, et al. Ledipasvir and sofosbuvir for hepatitis C genotype 4: a proof-of-concept, single centre, open-label cohort study. Lancet Infect Dis. 2015;15(9):1049-1054. 22. Terrault N, Zeuzem S, DiBisceglie A, et al. Effectiveness of ledipasvir-sofosbuvir combination in patients with hepatitis C virus infection and factors associated with sustained virologic response. Gastroenterology. 2016;151(6):1131-1140. 23. Zeuzem S, Ghalib R, Reddy R. Grazoprevir-elbasvir combination therapy for treatment-naive cirrhotic and noncirrhotic patients with chronic hepatitis C genotype 1, 2, or 6 infection. Ann Intern Med. 2015;163(1):1-13. 24. Kwo P, Gane E, Peng C, et al. Effectiveness of elbasvir and grazoprevir combination, with or without ribavirin, for treatment-experienced patients with chronic hepatitis C infection. Gastroenterology. 2017;152(1):164-175. 25. Centers for Disease Control and Prevention. www.cdc.gov. Accessed September 15, 2018. 26. Durham D, Skrip L, Bruce R, et al. The iImpact of enhanced screening and treatment on hepatitis C in the United States. Clin Infect Dis. 2016;62:298-304. 27. Dore G, Altice F, Litwin A, et al. Elbasvir-grazoprevir to treat hepatitis C infection in persons receiving opioid agonist therapy. Ann Intern Med. 2016;165(9):625-636. 28. Bruggmann P, Litwin A. Models of care for the management of hepatitis C virus among people who inject drugs: one size does not fit all. Clin Infect Dis. 2013;57:S56-S61. 29. Batchelder A, Cockerman-Colas L, Peyser D, et al. Perceived benefits of the hepatitis C peer educators: a qualitative investigation. Harm Reduct J. 2017;14(67):1-7. 30. Vu T, Toribio W, Riazi F, et al. Increasing access to hepatitis C virus medications: a program model using patient navigators and specialty pharmacy to obtain prior authorization approval. J Manag Care Spec Pharm. 2018;24(4):329-333. 31. Department of Health and Human Services. Responding to the threat of viral hepatitis in the United States. www.hhs.gov. Accessed September 15, 2018.
Donald Gardenier, DNP, FNP-BC, FAANP, FAAN, is a nurse practitioner at Eisenhower Health in Palm Springs, CA. He is available at [email protected]. Mary C. Olson, DNP, ANP-BC is a nurse practitioner at New York University Langone Health in New York City. In compliance with national ethical guidelines, the authors report no relationships with business or industry that would pose a conflict of interest.
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45000 40000 35000 30000 25000
Reported Acute HCV
20000
Actual New HCV Cases (est)
15000 10000 5000 0 2011
2012
2013
2014
2015
2016
Figure. Hepatitis C incidence in the US from 2011 to 2016 (reported cases and estimated actual number).3
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Feature Article
Hepatitis C in 2019: Are We There Yet? Donald Gardenier, DNP, FNP-BC, Mary C. Olson, DNP, ANP-BC a b s t r a c t Keywords: hepatitis C infectious disease public screening treatment
Chronic hepatitis C is the most common blood-borne pathogen worldwide. Upwards of half of the individuals infected with hepatitis C have not been diagnosed, and rates of screening remain low. Incidence, which had been declining, began increasing in 2011, mirroring the current opioid epidemic. Once infected, people with chronic hepatitis C are at risk for developing complications including end-stage liver disease and hepatocellular carcinoma, leading to morbidity and mortality. These public health consequences of the hepatitis C epidemic are expected to increase over the coming decade. Innovation has resulted in highly tolerable medications of 8 to 16 weeks’ duration with over 90% efficacy. Experts have determined that the eradication of hepatitis C would be feasible and have laid out strategies to move us toward that goal. Significant and disparate barriers remain, including access to treatment and an increase in incidence related to the opioid epidemic. An underresourced approach to surveillance and screening, provider shortages, and payer restrictions are among the obstacles to eliminating hepatitis C as a public health problem in the United States. © 2018 Elsevier Inc. All rights reserved.
Natural History Hepatitis C is a blood-borne virus. Infection occurs as the result of transmission from an infected individual to an uninfected individual. The majority of hepatitis C infections in the United States took place in the course of percutaneous injection of illicit drugs, which continues to account for 75% of hepatitis C incidence. Worldwide risk factors include the reuse or inadequate sterilization of medical equipment including syringes. Other risk factors include transfusions before 1990 and vertical transmission (Table 1). Neither frequency nor remoteness of exposure are associated with the likelihood of transmission, so a single remote exposure should still be considered significant when assessing risk for chronic infection.2 After infection, acute symptoms such as nausea, vomiting, and/ or jaundice are rare. The host immune response results in spontaneous resolution in approximately 20% of acute infections. In the remaining approximately 80% of cases, hepatitis C infection becomes chronic, and spontaneous clearance is rare. The chronic phase is generally recognized to be asymptomatic, although nonspecific symptoms such as fatigue are common. In most cases, there is no specific sign or symptom indicating hepatitis C. Once in the bloodstream, the virus releases RNA into hepatocytes, viral replication takes place, new RNA strands are released into the bloodstream, and additional hepatocytes become infected.1 Antibodies to the hepatitis C virus develop during the acute phase, or the first 6 months after exposure. If acute infection is suspected, a quantitative hepatitis C RNA test (viral load) and transaminases should be used to screen the patient for exposure because an antibody response may not yet have occurred. Once the patient is beyond the acute phase, hepatitis C antibodies indicate https://doi.org/10.1016/j.nurpra.2018.12.009 1555-4155/© 2018 Elsevier Inc. All rights reserved.
prior exposure to the virus and, unless there is a prior history of treatment, suspected chronic infection. Infection is confirmed by a viral load. Hepatitis C virus is also characterized by genotypes numbered 1 through 6. In the US, approximately 70% is genotype 1. Genotype distributions vary by region worldwide. Patients who become aviremic either by spontaneous clearance or after treatment will have no detectable RNA but usually retain antibodies that do not confer immunity from reinfection should the individual be reexposed to the hepatitis C virus.1 Chronic inflammation leads to hepatocyte damage, including fibrosis production and loss of liver function that in most cases occur gradually over time. Inflammation can cause an elevation in hepatic transaminases. A concomitant source of liver inflammation, such as alcohol use, hepatitis B coinfection, or nonalcoholic fatty liver disease, can increase both the rate and severity of liver inflammation and damage. Coinfection with human immunodeficiency virus also leads to faster progression. Infection without transaminase elevation is not unusual and should not be taken as evidence of no damage. RNA quantification has not been associated with the rate or degree of liver damage. The likelihood of developing cirrhosis and other complications increases as the patient with chronic infection ages.1 Complications of chronic hepatitis C infection are those that are common in cirrhosis, including volume overload with ascites and lower extremity edema, portal hypertension, esophageal varices, coagulopathies, deficient protein synthesis, and encephalopathy. Extrahepatic manifestations of chronic hepatitis C have also been recognized and are listed in Table 2.4 The risk for developing hepatocellular carcinoma is 1% to 5% per year. Once hepatocellular carcinoma has been diagnosed, the patient has a 33% probability of dying within a year.1
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Table 1 Hepatitis C Risk Factors1 People who have ever injected drugs People who have ever used intranasal drugs Recipients of infected blood, organs, or blood products Transfusions before 1992 Clotting factor concentrates made before 1987 Organs donated by hepatitis Cepositive donors People who have undergone percutaneous invasive procedures in health care settings with inadequate or unreliable infection control practices Children born to mothers infected with hepatitis C or with risk factors People with sexual partners infected with hepatitis C or with risk factors People with human immunodeficiency virus infection Prisoners or previously incarcerated persons People who have had tattoos or piercings People with elevated liver enzymes People born between 1945 and 1965 People who have ever undergone hemodialysis Health care worker, first responder, or public safety workers who Ever had a percutaneous (needlestick) injury Ever splashed with blood or blood products
Epidemiology Approximately 130 million people worldwide are chronically infected with the hepatitis C virus. Significant variation between regions exists, both in the prevalence and likely infection patterns and risk factors. The highest prevalence in the world is in Egypt (15%-20%), whereas the lowest is in the United Kingdom and Scandinavia (0.01%-0.1%).1 In the US, approximately 5 million are thought to be chronically infected with the hepatitis C virus. Official surveillance data, which are lower, are considered likely to be undercounts because they sampled only the domiciled civilian noninstitutionalized population and therefore omitted the homeless, the incarcerated, and those admitted to hospitals or nursing homes. Active military personnel were also excluded. Approximately 75% of those infected in the US are baby boomers, born between 1945 and 1965. Most baby boomers, also referred to as the birth cohort, were infected remotely (more than 10 years ago), and have had largely asymptomatic disease courses. Men and racial and ethnic minorities are disproportionately affected, as are medically underserved populations including the incarcerated, homeless, and those with concomitant mental illness and substance use, all groups that were underrepresented as a result of the official surveillance methodology.3 Hepatitis C infection causes inflammatory liver disease, fibrosis, and eventually cirrhosis. In turn, cirrhosis progresses to end-stage liver disease and, in some cases, hepatocellular carcinoma, which Table 2 Extrahepatic Manifestations of Hepatitis C3 Sign/Symptom
Potential Hepatitis Cerelated Etiology
Hypertension
Membranoproliferative glomerulonephritis Nephropathy Cryoglobulinemia Lichen planus Porphyria cutanea tarda Leukocytoclastic vasculitis Cryoglobulinemic vasculitis Cryoglobulinemic vasculitis Leukocytoclastic vasculitis Membranoproliferative glomerulonephritis Cryoglobulinemia Membranoproliferative glomerulonephritis Cryoglobulinemia Lymphoproliferative disorder Cryoglobulinemic vasculitis Lymphoproliferative disorder Cryoglobulinemia Lymphoma
Dermatitis
Purpura Peripheral neuropathy Renal insufficiency Hematuria Lymphadenopathy Fever Arthralgia Weakness
together are among the top 10 leading causes of death. Hepatitis C is estimated to be the etiology of 27% of cirrhosis and 25% of hepatocellular carcinoma cases worldwide. Because hepatitis Cerelated complications are still developing in a significant percentage of infected individuals, end-stage complication rates in the population are expected to continue to increase over the coming years.1 Because acute infection is most often asymptomatic and surveillance methodology varies, tracking hepatitis C incidence has been difficult. Therefore, reported cases are supplemented by statistically modeled estimates of true incidence, which are considered by epidemiologists to more accurately reflect incidence rates. In the US, incidence peaked in 1989 and then declined by approximately 80% through 2005. Incidence remained relatively stable from 2005 through 2011 but has increased since, paralleling opioid use disorder, and thus is likely associated with the opioid epidemic currently underway in the US.5 Incidence as reported to the Centers for Disease Control and Prevention (CDC) as well as estimates of the actual incidence of hepatitis C from 2011 through 2016 are shown in the Figure (available online at http://www.npjournal.org).6 A long period of asymptomatic chronicity is most often associated with hepatitis C infection, delaying the onset of complications well beyond the time of infection. For this reason, the major disease burden associated with chronic hepatitis C has not yet peaked. Similarly, the death rate from chronic hepatitis C in the US is also rising and has been projected to peak at 36,000 per year sometime between 2030 and 2035.7 Chhatwal et al8 modeled hepatitis C disease burden in the US given the most recent relevant changes, such as the advent of direct-acting antiviral (DAA) medications and the Patient Protection and Affordable Care Act of 2010. According to their model, the number of noninstitutionalized viremic individuals in the US dropped from 2.5 million in 2010 to 1.9 million in 2015. That number is expected to drop to less than 1 million by 2020; however, more than 500,000 of those remaining viremic individuals will remain undiagnosed. An estimated 1.8 million individuals will undergo treatment by 2030. They concluded that, despite the availability of effective treatment, 157,000 individuals will develop hepatocellular carcinoma, 203,000 will progress to decompensated cirrhosis, and 320,000 people will die of chronic hepatitis C over the coming 35 years.8 Screening Routine screening for nonacute hepatitis C as recommended in the US is based on risk factors and is a 3-step process. Individuals are first screened for risk factors (Table 1). Those with 1 or more risk factor(s) are tested for serologic presence of hepatitis C antibodies. Those with antibodies are then tested for the presence of hepatitis C virus RNA. The presence of RNA in the serum indicates chronic disease. The presence of antibodies without RNA indicates an infection that has resolved, either spontaneously or after successful treatment.1 Risk factorebased screening misses between 31% and 47% of hepatitis C cases according to the National Hepatitis Screening Survey. Epidemiologic data revealed that 67% of hepatitis C cases were among individuals born between 1945 and 1965, thereby adding individuals in the birth cohort to those at elevated risk. This recognition led the CDC and the US Preventive Services Task Force, in 2012 and 2013, respectively, to recommend the screening of individuals in the birth cohort even in the absence of additional risk factors.5 Hepatitis C screening rates are low. The CDC estimates that between 45% and 85% of those chronically infected with hepatitis C are unaware of their diagnosis.4 Screening rates since 2012, when birth cohort screening was first recommended, have increased only
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marginally. Data collected between 2013 and 2015 in the National Health Interview Surveys (N ¼ 85,210) showed that the screening rate in the birth cohort was 11.5% to 12.8%, with slightly higher rates among those younger than the birth cohort and lower rates among those who are older. In addition to age, there were significant disparities associated with sex and race/ethnicity.9 Interventions to improve screening have been undertaken successfully. For example, in 1 academic practice, baseline data showed that screening was completed in only 23.5% of patients, and providers elected to screen in only 50% to 62.5% of individuals who met screening criteria. After a quality improvement project was implemented, the screening rate increased to over 90%. One year later, the screening rate remained at 88%.5 A consensus committee convened by the National Academies of Sciences, Engineering, and Medicine studied the feasibility of eliminating hepatitis B and C as a public health problem in the US. Among a broad array of proposals, the committee recommended improved surveillance and increased screening. Screening identifies those who are infected and is the essential first step in treating those who are most at risk of progression because of active infection.1 The National Viral Hepatitis Roundtable, 1 of the sponsors of the National Academies report, also encourages increased screening with a focus on underserved populations in which hepatitis C is endemic, such as the incarcerated.10 Treatment Once chronic hepatitis C infection has been diagnosed with a positive viral load, the patient needs to be evaluated for treatment. Untreated hepatitis C leads to progression of liver disease and hepatocellular carcinoma, has extrahepatic manifestations, and has been shown to cause a decrease in quality of life. Studies have also shown that patients’ quality of life improves after successful treatment. The likelihood of extrahepatic manifestations also decreases after treatment. Real-world database studies have verified high rates of cure observed in the DAA clinical trials.11 Therefore, it is important to consider all patients with chronic hepatitis C to be candidates for treatment. It is important to determine the genotype and stage of fibrosis. The stage of fibrosis can be assessed with noninvasive tests, including transient elastography if available. There are also blood tests that can be done to estimate the degree of fibrosis. A thorough medical history, including any hepatitis C treatment history, current medical problems, and all medications and supplements that the patient is taking, is needed to identify any potential drug-drug interactions. Coinfection with human immunodeficiency virus and concomitant alcohol use also need to be considered. Patients with decompensated cirrhosis should be referred to a qualified hepatology specialist or a liver transplant center to be further evaluated. Prior authorization for treatment is required by most insurance companies. All DAAs have black box warnings about the risk of activation of hepatitis B virus that can result in fulminant hepatitis, hepatic failure, and death. Therefore, all patients need to be screened for hepatitis B and treated if indicated before hepatitis C treatment.12 Once evaluated, a treatment regimen can be selected. DAA regimens with once-daily dosing for 8 to 12 weeks and 95% or greater rates of sustained viral response (SVR12, defined as no detectable virus 12 weeks after completing treatment, which is synonymous with cure), makes adherence to treatment less challenging and more likely to be successful than previous regimens. DAA regimens combine drugs that inhibit viral replication by binding to viral proteases or polymerases at specific locations. They are classified by these locations (NS3/4A or NS5A/B). Treatment is individualized based on genotype; viral load; and patient factors,
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including prior treatment history, comorbid conditions, stage of liver fibrosis, and any potential interactions with the patient’s existing medications.12 Three pangenotypic regimens have been approved since 2016: sofosbuvir 400 mg/velpatasvir 100 mg (SOF/VEL), glecaprevir 100 mg/pibrentasvir 40 mg (GLE/PIB), and sofosbuvir 400 mg/velpatasvir 100 mg/voxilaprevir 100 mg (SOF/VEL/VOX). GLE/PIB and SOF/VEL are first-line regimens with different treatment durations based on genotype, treatment history, and stage of liver fibrosis. SOF/VEL/VOX is recommended for the retreatment of patients who previously failed a DAA regimen. SOF/VEL and SOF/VEL/VOX are dosed 1 tablet daily for 12 weeks. GLE/PIB is dosed 3 tablets daily for 8, 12, or 16 weeks.12 SOF/VEL combines an NS5B inhibitor and an NS5A inhibitor. In phase 3 trials, SOF/VEL was studied for 12 weeks. Patients with genotypes 1-6, with or without prior treatment and with or without compensated cirrhosis were included. The sustained viral response (SVR) rate was 99%. Therefore, this regimen is dosed as 1 tablet once daily for 12 weeks for all genotypes. The most common adverse events were headache, fatigue, nasopharyngitis, and nausea.13 SOF/VEL/VOX, approved in 2017, adds an NS3/4A protease inhibitor to SOF/VEL. In 2 phase 3 trials patients who had previously failed a DAA-containing regimen were given SOF/VEL/VOX for 12 weeks. The SVR12 rate was 96%-98%, showing a high response rate for these patients. The most common adverse events were headache, fatigue, diarrhea, and nausea.14 GLE/PIB combines an NS3/4 protease inhibitor and an NS5A inhibitor. The antiviral activity is pangenotypic with a high barrier to resistance. A phase 2 trial of GLE/PIB for 8 weeks included genotypes 1-6 in treatment-naive and treatment-experienced patients without cirrhosis. The SVR12 rates were 97%-100%.15 In 2 phase 3 trials, GLE/PIB was evaluated for 8 or 12 weeks in patients with genotype 1 or 3, both treatment naive and treatment experienced without cirrhosis. The SVR12 rate for genotype 1 was 99.1% for 8 weeks and 99.78% for 12 weeks. For genotype 3, the SVR12 rate was 95% for both 8- and 12-week durations. In another trial, treatment-naive and treatment-experienced patients with compensated cirrhosis, genotypes 1, 2, 4, 5, or 6 were given GLE/PIB for 12 weeks. The SVR rate was 99%.16 A phase 3 study included genotype 3 patients with compensated cirrhosis; treatment naive and treatment experienced were treated with GLE/PIB for 12 or 16 weeks respectively. The SVR12 rates were 98% in the 12-week group and 96% in the 16-week group.17 The most common adverse events were fatigue and headache. GLE/PIB is absorbed in an acidic environment and should be taken with food.18 Two other regimens are approved for genotypes 1 and 4. The combination of SOF, an NS5B inhibitor, with ledipasvir, an NS5A inhibitor, was tested in trials that included treatment-naive and treatment-experienced patients with and without compensated cirrhosis. The results showed that 97% and 94%, respectively, achieved an SVR12 after 12 weeks.19,20 In genotype 4, treatment-naive and treatment-experienced patients with and without advanced fibrosis were treated for 12 weeks; the SVR12 rate was 95%.21 Further evaluation showed that SOF/ledipasvir can be given for 8 weeks in genotype 1 treatment-naive patients with a viral load < 600,000 IU/mL. The most common adverse events were fatigue, headache, insomnia, and nausea.22 The other regimen recommended for genotypes 1 and 4 is grazoprevir 100 mg (GRZ), an NS3/4A protease inhibitor, in combination with elbasvir 50 mg (EBR), an NS5A inhibitor. The phase 3 C-Edge study evaluated treatment-naive and treatmentexperienced patients with genotypes 1, 4, and 6 with or without cirrhosis. After 12 weeks of treatment, the SVR12 rates for treatment naive patients by genotype were 92% for 1a, 99% for 1b, and 100% for 4.23 EBR/GRZ was given to the treatment experienced
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Table 3 First-line Regimens for Treatment-naive Patients With Chronic Hepatitis C With or Without Compensated Cirrhosis13 Regimen Medications and Dosing
Brand Name
Duration
Consideration
EBR 50 mg GZR 100 mg 1 tablet Once daily GLE/PIB GLE 100 mg PIB 40 mg 3 tablets Once daily SOF/LDV SOF 400 mg LDV 90 mg 1 tablet Once daily SOF/VEL SOF 400 mg VEL 100 mg 1 tablet Once daily
Zepatier (Merck, Sharp and Dohme Corp., Whitehouse Station, NJ)
12 weeks with and without cirrhosis
Genotypes 1a (no NS5a RASb), 1b, 4
Mavyret (Abbvie Inc., North Chicago, IL)
8 weeks without cirrhosis 12 weeks with cirrhosis
Genotypes 1-6 Take with food
Harvoni (Gilead Sciences, Foster City, CA)
12 weeks with and without cirrhosis 8 weeks without cirrhosis, nonblack, no HIV infection, with HCV RNA <6,000,000 at baseline 12 weeks with and without cirrhosis
Genotypes 1, 4, 5, 6
EBR/ GZRa
Epclusa (Gilead Sciences, Foster City, CA)
Genotypes 1-6
EBR ¼ elbasvir; HCV ¼ hepatitis C virus; HIV ¼ human immunodeficiency virus; GLE ¼ glecaprevir; GZR ¼ grazoprevir; LDV ¼ ledipasvir; PIB ¼ pibrentasvir; RAS ¼ Resistanceassociated substitutions; SOF ¼ sofosbuvir; VEL ¼ velpatasvir. a EBR/GZR for G1a with NS5A RASs is given with weight-based ribavirin for 16 weeks. b RASs.
genotype 1 patients for 12 or 16 weeks with or without ribavirin. The SVR rate for both 12 and 16 weeks of EBR/GRZ without ribavirin was 92.4%. The SVR rates for EBR/GZR for 12 and 16 weeks with ribavirin were 94.2% and 98.1%. respectively. The response rates to this regimen was affected by baseline-resistant variants in patients with genotype 1a. The SVR12 rate for the 12-week duration without ribavirin in genotype 1b was 98.6%. Among patients with genotype 1a, baseline testing for NS5A-resistant variants was highly effective in predicting the outcome of the 12-week regimen. The SVR12 rate for patients with genotype 1a without baseline resistance was 99%, and for patients with baseline resistance who were treated with EBR/GZR/RBV for 16 weeks, it was 100%. The adverse events were fatigue, nausea, and headache.24 Table 3 lists the 4 first-line treatment regimens with key considerations. Once a regimen has been selected, a baseline treatment visit should be conducted with an updated history and a physical examination to determine any new medical issues that may have occurred since the pretreatment evaluation. The patient should be assessed for motivation to ensure that the entire course of treatment and posttreatment evaluation will be completed. An updated review of any new over-the-counter and prescribed medications as well as any herbal products is important to confirm that there will be no drug/drug interactions. Patient education should include dosing, importance of adherence, and management of missed doses and side effects. A visit at treatment week 4 is important to determine tolerance to the regimen. A viral load can be drawn at this point to ascertain adherence.12 At the end of treatment, a complete blood count, chemistry, and viral load should be drawn. A viral load should again be drawn at 4 and 12 weeks posttreatment to determine if the patient has achieved an SVR12. Posttreatment management of patients who have been cured of hepatitis C is evolving. Those with advanced fibrosis or cirrhosis will need posttreatment follow-up to monitor for decompensation and should be referred to a qualified hepatology specialist. Those who are not cured should be assessed and considered for retreatment.12 Challenges Because there is no vaccine for hepatitis C, prevention is considered to be especially important, particularly among those who inject drugs and account for 75% of new cases of hepatitis C. A
key prevention intervention with documented efficacy and costeffectiveness is needle and syringe exchange as part of a harm reduction approach.25 Another key intervention is the elimination of barriers to hepatitis C treatment. Although cost-effective, medications used to treat hepatitis C are expensive and, as a result, significant barriers erected by payers prevent or substantially delay access by many patients to treatment. Treatment delays result in increased rates of progression to cirrhosis and related complications. Because people remain infected for longer, treatment delays also increase incidence. Conversely, the unrestricted treatment access that would result from the elimination of barriers has the potential to reduce new cases of hepatitis C by 90% by 2030. In addition to prevention and the removal of barriers to treatment, the establishment of an office at the national level to oversee and coordinate efforts to eliminate hepatitis C as a public health problem was considered by an expert panel to be critical, as were increased surveillance and increased efforts to reach high-prevalence populations with limited access to care, such as the incarcerated.1 All of these interventions would require significant changes in national policies and funding. Durham et al26 developed a transmission model to assess the impact of increased screening and treatment on hepatitis C prevalence in the US. In addition to the need to increase capacity, complete elimination of hepatitis C transmission in the US would require screening of all people who inject drugs, a group that traditionally has had poor access to care in the US. Evidence supports successful treatment and low rates of relapse and reinfection in individuals who inject drugs, as well as those on opioid agonist therapy, suggesting that barriers to treatment based on active injection drug use are not evidence based and hinder progress toward the public health goal of eliminating chronic hepatitis C.27 The task remains to implement methods to reach this traditionally marginalized population more effectively and comprehensively. Bruggmann and Litwin28 examined a number of models that have shown success in adapting usual health care models to meet the unique needs of individuals who inject drugs. The models share key components, including identifying and eliminating stigma, integrating care and services, peer support, and taking a multidisciplinary approach. Programs that have had successful outcomes vary widely, with a structure and approach based on the specific needs of the patient populations they serve. These include incorporating directly observed therapy, substance use treatment,
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structured peer support services, and colocated psychiatric and substance use treatment.28 Success in reaching traditionally excluded high-prevalence populations has been achieved using care delivery innovations. Innovations take a variety of forms, and data support incorporating specific program elements that have been used successfully into new or existing care delivery models based on the needs of the patients they serve. In a qualitative study conducted among patients in an opioid substitution program, for example, there was unanimous perceived benefit in the use of peer educators.29 Another program used a team approach, including patient navigators, a registered nurse, and an experienced specialty pharmacy to achieve a 93% approval rate in prior authorizations for treatment medications for their patients, 69% of whom were covered by Medicaid.30 The National Viral Hepatitis Action Plan’s goals include the prevention of new infections, the reduction of deaths, and improvement of the health of individuals living with chronic hepatitis C. Additional goals include reducing health disparities among those with hepatitis C and coordination and monitoring of efforts undertaken to achieve the goal of eliminating the public health problem of viral hepatitis.31 Use of these recommendations should assist providers and administrators on need-based structural elements for their care delivery models as they work to reach those with chronic hepatitis C and link them to care. Engaging with community organizations and public health resources will also facilitate needs-based models of care. Conclusion Chronic hepatitis C infection is both curable and preventable. Advances have led to an increased number of pharmaceutical options with high efficacy and tolerability. However, their high cost is a barrier that has prevented their full potential in combating the hepatitis C from being realized. A shortage of providers qualified to treat hepatitis C is also a barrier. Although there is no vaccine, risks for hepatitis C transmission are known, and education geared toward prevention, especially efforts that take a harm reduction approach, have been shown to be effective. Nevertheless, hepatitis C remains a public health problem in the US and worldwide, one that experts agree can and should be eradicated. Changes in screening recommendations have not resulted in significantly higher numbers of individuals screened, and more than half of those infected with chronic hepatitis C remain undiagnosed. Innovation in care delivery has shown promise, particularly in reaching populations in which hepatitis C has a disparate impact. A concurrence of expert opinion and evidence suggests that strategies to achieve the elimination of hepatitis C as a public health problem are within reach. The task of making hepatitis C a public health priority remains before us. It will require care innovation, focus in the policy-making arena, and greater resource allocation in order to prevent the much more serious consequences that have been predicted for the coming years and decades. Supplementary Data Supplementary Figure associated with this article can be found in the online version at https://doi.org/10.1016/j.nurpra.2018.12.009. References 1. Gardenier D, Kwong J, Olson M, Epstein R. Epidemiology, screening, and pretreatment evaluation of the patient with chronic hepatitis C infection. J Nurse Pract. 2015;11:109-115. 2. National Academies of Sciences, Engineering, and Medicine. A National Strategy for the Elimination of Hepatitis B and C: Phase 2 Report. Washington, DC: The National Academies Press; 2017.
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3. Edlin B, Eckhardt B, Shu M, Holmberg S, Swan T. Toward a more accurate estimate of the prevalence of hepatitis C in the United States. Hepatology. 2015;62:1353-1363. 4. Polo M, Laufer N. Extrahepatic manifestations of HCV: the role of direct acting antivirals. Expert Rev Anti Infect Ther. 2017;15(8):737-746. 5. Trinh J, Turner N. Improving adherence to hepatitis C screening guidelines. BMJ Open Qual. 2018;7(2):e000108. 6. Zibbell J, Asher A, Patel R, et al. Increases in acute hepatitis C virus infection related to a growing opioid epidemic and associated injection drug use, United States, 2004-2014. Am J Public Health. 2018;108(2):175-181. 7. Rein D, Wittenborn J, Weinbaum C, Sabin M, Smith B, Lesesne S. 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. 8. Chhatwal J, Wang X, Ayer T, et al. Hepatitis C disease burden in the United States in the era of direct-acting antivirals. Hepatology. 2016;64(5):1442-1450. 9. Kasting ML, Giuliano AR, Reich R, et al. Hepatitis C screening trends: serial cross-sectional analysis of the National Health Interview Survey population, 2013-2015. Cancer Epidemiol Biomarkers Prev. 2018;27(4):1-11. 10. National Viral Hepatitis Roundtable. Elimination of hepatitis B and C: a national strategy. 2017. http://www.nvhr.org. Accessed September 6, 2018. 11. Younossi Z, Stepanova M, Asselah T, et al. Hepatitis C in patients With minimal or no hepatic fibrosis: the impact of treatment and sustained virologic response on patient-reported outcomes. Clin Infect Dis. 2018;66(11):1742-1750. 12. American Association for the Study of Liver Disease/Infectious Disease Society of America. HCV Guidance: Recommendations for Testing, Managing, and Treating Hepatitis C. https://www.hcvguidelines.org/. March 23, 2018. Accessed September 6, 2018. 13. Feld J, Jacobson I, Hezode C, et al. Sofosbuvir and velpatasvir for HCV genoytpe 1, 2, 4, 5, and 6 infection. N Engl J Med. 2015;373(27):2599-2607. 14. Bourliere M, Gordon S, Flamm S, et al. Sofosbuvir, velpatasvir, and voxilaprevir for previously treated HCV Infection. N Engl J Med. 2017;376(22):2134-2146. 15. Kwo P, Poordad F, Astryan F, et al. Glecaprevir and pibrentasvir yield high response rates in patients with HCV genotype 1-6 without cirrhosis. J Hepatol. 2017;67:263-271. 16. Forns X, Lee S, Valdes J, et al. Glecaprevir plus pibrentasvir for chronic hepatitis C virus genotype 1, 2, 4, 5, or 6 infection in adults with compensated cirrhosis (EXPEDITION-1): a single-arm, open-label, multicenter phase 3 trial. Lancet. 2017;17:1062-1068. 17. Wyles D, Poordad F, Wang S, et al. Glecaprevir/Pibrentasvir for hepatitis C virus genotype 3 patients with cirrhosis and/or prior treatment experience: A partially randomized phase 3 clinical trial. Hepatology. 2018;67(2):514-523. 18. Zeuzem S, Foster G, Wang S, et al. Glecaprevir-pibrentasvir for 8 or 12 2eeks in HCV genotype 1 or 3 infection. N Engl J Med. 2018;378(4):354-369. 19. Afdahl N, Zeuzem S, Kwo P, et al. Ledipasvir and sofosbuvir for untreated HCV genotype 1 infection. N Engl J Med. 2014;370(20):1889-1898. 20. Afdahl N, Reddy R, Nelson D, et al. Ledipasvir and sofosbuvir for previously treated HCV genotype 1 infection. N Engl J Med. 2014;370(16):1483-1493. 21. Kohi A, Kapoor A, Sims R, et al. Ledipasvir and sofosbuvir for hepatitis C genotype 4: a proof-of-concept, single centre, open-label cohort study. Lancet Infect Dis. 2015;15(9):1049-1054. 22. Terrault N, Zeuzem S, DiBisceglie A, et al. Effectiveness of ledipasvir-sofosbuvir combination in patients with hepatitis C virus infection and factors associated with sustained virologic response. Gastroenterology. 2016;151(6):1131-1140. 23. Zeuzem S, Ghalib R, Reddy R. Grazoprevir-elbasvir combination therapy for treatment-naive cirrhotic and noncirrhotic patients with chronic hepatitis C genotype 1, 2, or 6 infection. Ann Intern Med. 2015;163(1):1-13. 24. Kwo P, Gane E, Peng C, et al. Effectiveness of elbasvir and grazoprevir combination, with or without ribavirin, for treatment-experienced patients with chronic hepatitis C infection. Gastroenterology. 2017;152(1):164-175. 25. Centers for Disease Control and Prevention. www.cdc.gov. Accessed September 15, 2018. 26. Durham D, Skrip L, Bruce R, et al. The iImpact of enhanced screening and treatment on hepatitis C in the United States. Clin Infect Dis. 2016;62:298-304. 27. Dore G, Altice F, Litwin A, et al. Elbasvir-grazoprevir to treat hepatitis C infection in persons receiving opioid agonist therapy. Ann Intern Med. 2016;165(9):625-636. 28. Bruggmann P, Litwin A. Models of care for the management of hepatitis C virus among people who inject drugs: one size does not fit all. Clin Infect Dis. 2013;57:S56-S61. 29. Batchelder A, Cockerman-Colas L, Peyser D, et al. Perceived benefits of the hepatitis C peer educators: a qualitative investigation. Harm Reduct J. 2017;14(67):1-7. 30. Vu T, Toribio W, Riazi F, et al. Increasing access to hepatitis C virus medications: a program model using patient navigators and specialty pharmacy to obtain prior authorization approval. J Manag Care Spec Pharm. 2018;24(4):329-333. 31. Department of Health and Human Services. Responding to the threat of viral hepatitis in the United States. www.hhs.gov. Accessed September 15, 2018.
Donald Gardenier, DNP, FNP-BC, FAANP, FAAN, is a nurse practitioner at Eisenhower Health in Palm Springs, CA. He is available at [email protected]. Mary C. Olson, DNP, ANP-BC is a nurse practitioner at New York University Langone Health in New York City. In compliance with national ethical guidelines, the authors report no relationships with business or industry that would pose a conflict of interest.
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45000 40000 35000 30000 25000
Reported Acute HCV
20000
Actual New HCV Cases (est)
15000 10000 5000 0 2011
2012
2013
2014
2015
2016
Figure. Hepatitis C incidence in the US from 2011 to 2016 (reported cases and estimated actual number).3