Chronic Hepatitis C Assessment and Treatment: Algorithms for Primary Care Providers

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Susan Ferguson, PA-C Physician Assistant Santa Rosa Gastroenterology, Santa Rosa Beach, FL.

In the past, chronic hepatitis C (CHC) was a challenge to manage as treatment protocols were complicated and medications had severe side effects. Primary care providers are often the first medical professionals who screen for CHC, but patients are frequently referred to specialists after hepatitis C is diagnosed. Moreover, health care providers in safety-net clinics should be screening their patients as low-income individuals are disproportionately affected by CHC. The new generation of CHC medications makes treatment options more feasible and cost-effective. Assessment and treatment protocols for CHC have been developed to serve the needs of primary care providers in private practice as well as safety-net clinics.

Chronic hepatitis C (CHC) affects 3.4 to 6 million Americans.1 The prevalence of CHC is four times higher in populations that are below the federal poverty level in comparison to those who are two times the federal poverty level.2 Therefore, clinics that serve low-income patients should have a high priority for screening and treatment of CHC.2 Moreover, the cure rates for CHC increased when medical providers within safety net clinics had a comprehensive care plan when treating patients for CHC.1
The new CHC therapies have lower side effect profiles and can be prescribed to a larger selection of patients.3 The advent of pangenotypic medications for CHC enable primary care providers, whether in safety-net clinics or private practice, to effectively treat a larger cohort of patients.

Moreover, assessment and treatment algorithms can aid primary care providers in determining when it is appropriate to refer patients to specialists for CHC treatment.

In 2016, there were 2,967 reported cases of acute hepatitis C in the United States.4 The overall incidence rate for new cases was 1.0 per 100,000, which is an increase from 0.8 cases per 100,000 in 2015.4 Furthermore, it is estimated that the actual number of cases are most likely 13.9 times greater than reported.4

There are more than 71 million people worldwide who have CHC.5 Approximately 70% of individuals with CHC were born between the years of 1945 to 1965.6 In the United States, males have approximately double the prevalence rate of CHC compared to women.6

Hepatitis C virus (HCV) is the most common blood-borne infection in the United States.6 Common exposures to the virus include injection drug use, needle sticks, transfused infected blood product before 1992, and maternal transmission during birth.4 The hepatitis C virus can infrequently be transmitted through the use of personal hygiene products belonging to infected individuals, unregulated tattoos, and sexual intercourse with infected individuals.4 There is a common misconception that CHC is prevalent in the “baby boomer” generation as a result of high-risk behaviors, such as tattooing, sexual practices, and injection drug use.7 To the contrary, members of the high-risk group born between 1945 and 1965 were approximately 5 years old when the peak of Genotype 1A HCV occurred in 1950.7 The likely peak in 1950 occurred as a result of medical procedures performed during and after World War II, and the transition to disposable plastic syringes in the 1950s through the 1960s correlated with a decline in HCV incidence rates.7 However, the role of recreational injection drug use from 1920 to the late 1960s was contributory.7

Hepatitis C is transmitted parentally through blood and body fluids.8 Acute presentations of the illness may result in jaundice, which occurs in approximately 20% of individuals.8 The average incubation period for HCV is between six and seven weeks. The incubation time can be difficult to assess as infected individuals are often asymptomatic, and there is not a precise serological marker of early infection.9 Spontaneous resolution of the virus occurs in approximately 15% to 45% of infected individuals, and clearance usually happens within six months of contracting the virus.8 Moreover, clearance of HCV is bifurcated by gender with females having a 40% spontaneous clearance rate compared with 19% of males.6 Spontaneous clearance is influenced by genetic inheritance of the IL28b and DQB1 0301 allele on the class II2 major histocompatibility complex.10

Interestingly, patients who present with clinical symptoms of acute hepatitis C demonstrate higher rates of spontaneous clearance of the virus.10 For individuals who do not clear the virus, the annual rates of fibrosis progression are between 0.1 and 0.2 stages per year.10 Approximately 20% to 25% of CHC cases progress to cirrhosis.8 Out of every 100 infected individuals with CHC, 10 to 20 will develop cirrhosis, and there is a 1% to 5% annual risk of developing hepatocellular carcinoma.4 The progression from cirrhosis to hepatocellular carcinoma is due to several factors. Specific viral proteins act upon cell signaling pathways and inhibit tumor suppressor genes, signaling pathways that up-regulate cell growth and division are activated, and the loss of the tumor suppressor genes p53 and retinoblastoma cause increased carcinogenesis.11

Signs and Symptoms
Most individuals with CHC are asymptomatic, or they may have non-specific symptoms, such as lethargy or depression.4 However, CHC is linked to extrahepatic disorders, such as arthritic-like pain, kidney, cardiovascular, neuropsychiatric, and gastrointestinal conditions.12 Many individuals with CHC will eventually present with liver disease. Chronic hepatitis C was the known etiology for 17% of the reported cases of hepatocellular carcinoma in the United States from the years 2000 to 2010.13 Patients with advanced liver disease may manifest symptoms, such as ascites, jaundice, variceal bleeding, altered mental status, and pruritus.14


The presence of HCV antibody (anti-HCV) can indicate active HCV infection, either acute or chronic; past infection that resolved with spontaneous clearance or treatment; or a false positive.15 Therefore, the World Health Organization (WHO) and the Centers for Disease Control and Prevention (CDC) recommend that serological testing for CHC should include both anti-HCV and nucleic acid testing for the presence of HCV RNA.16,17 The American Gastroenterology Association (AGA) recommends testing for anti-HCV, HCV RNA, HCV genotype, complete metabolic panel (CMP), INR, hepatitis B studies, and HIV antibody.14

Assessment of liver disease
The 2016 WHO guidelines state that assessment for fibrosis and cirrhosis in CHC infected individuals is necessary to properly stratify individuals into appropriate treatment protocols.17 The American Association for the Study of Liver Diseases (AASLD) and the Infectious Diseases Society of America (IDSA) collectively composed guidelines for evaluation of advanced liver disease, including fibrosis and cirrhosis. Liver disease can be assessed with liver biopsy, imaging, and/or non-invasive markers.18 The AGA recommends right upper quadrant ultrasound for initial imaging before treatment.14 Fibrosis staging can also be assessed with newer non-invasive technologies, such as transient elastography and magnetic resonance elastography.14 However, aspartate aminotransferase to platelet ratio index (APRI) or fibrosis-4 (FIB-4) testing can be utilized when medical resources are scarce.14,17 Both the APRI and FIB-4 tests have low and high cutoff values that can be utilized to assess the severity of fibrosis, and the APRI scoring system can also be utilized to estimate a patient’s probability of having cirrhosis.17 The cutoff values aid providers in the assessment of liver disease secondary to HCV and can be utilized to stratify patients for treatment.17 An APRI score below the low cut-off value of 0.5 indicates that a patient has only an 18% probability of having advanced fibrosis, and a FIB-4 score lower than 1.45 indicates an 11% probability of having advanced fibrosis.17 Moreover, the WHO guidelines stated that treatment could be deferred in patients who score below the low cut-off values on APRI and FIB-4 tests.17 However, patients with an APRI score above the high cutoff value of 2 have a 94% probability of having cirrhosis, and these patients would benefit greatly from treatment.17 Patients who have APRI or FIB-4 scores that fall between the low and high cut-off values can either be treated or monitored, depending on the availability of medications.17

Treatment Options for Chronic Hepatitis C
There are six separate genotypes for HCV (1- 6), and approximately 70% of all cases of CHC are Genotype 1.18 The prior treatment for CHC utilized interferon alfa-2a plus ribavirin, but these medications have severe side effects associated with them and achieve cure in only about 40% to 50% of patients.19 In 2009, the first direct-acting antivirals (DAAs), which directly target HCV replication, were approved for the treatment of CHC.20 By 2017, there were six different DAA combination therapies available for specific genotypes of CHC.19 The advent of pangenotypic medications for CHC almost obviates the need to genotype the virus; however, in certain CHC patients, viral genotyping is still necessary. Additionally, cirrhotic patients should be assessed for the severity of cirrhosis utilizing the Child-Pugh score.21 While glecaprevir/pibrentasvir is pangenotypic for non-cirrhotic, treatment-naive patients, genotyping is still necessary for treatment-experienced and/or cirrhotic patients as the duration of therapy has to be adjusted based on these parameters.22 Conversely, sofosbuvir/velpatasvir is a pangenotypic medication that can be utilized for non-cirrhotic or Child-Pugh A cirrhotic patients who are treatment-naive or experienced.23 Although there are other medicinal treatments for CHC, this review will be limited to the pangenotypic class of CHC medications as they enable providers to more easily treat patients at the primary care level.

NS5B inhibitors
The AASLD and IDSA collectively recommend sofosbuvir (SOF) for treatment of all genotypes of HCV.18 Sofosbuvir is administered orally, once a day.19 Sofosbuvir inhibits the HCV NS5B RNA-dependent RNA polymerase by incorporating into the HCV RNA, whereby it terminates the RNA chain.24 Sofosbuvir demonstrated an advantage over the first-generation DAA class of HCV medications because of its high genetic barrier to viral resistance.18 Furthermore, sustained viral response (SVR) improved when SOF was used in combination therapy.25 There is a low risk for medication interactions with SOF as it does not inhibit or induce the P450 cytochrome system; however, amiodarone is contraindicated with SOF because of the risk for fatal bradycardia.19 Additionally, given the fact that SOF is excreted through the renal system, it should be used with caution in renal patients and should not be given to patients with glomerular filtration rates (GFR) less than 30.19

NS5A inhibitors
There are numerous functions of the HCV viral NS5A protein, including roles in viral replication, assembly, and interactions with cellular functions.26 Velpatasvir (VEL), an NS5A inhibitor used in conjunction with SOF, is efficacious on all genotypes of HCV.19,20 Because less than 1% of VEL is renally excreted, there are no dosing adjustments in the context of renal dysfunction; however, caution should still be taken as VEL is given in conjunction with SOF.19 Concomitant administration of rifampin, efavirenz, or St. John’s Wort may decrease levels of SOF/VEL and should not be taken concurrently.19 Conversely, SOF/VEL may decrease therapeutic levels of digoxin so treatment levels should be monitored closely.19 Additionally, proton pump inhibitors (PPIs) should be discontinued during therapy with SOF/VEL as VEL concentration levels decrease with increases in gastric pH.23

NS3/4 protease inhibitor combination therapy
The AASLD and IDSA guidelines recommend the combination of glecaprevir (GLE) and pibrentasvir (PIB) for all genotypes of HCV.18 Glecaprevir is a second-generation NS3/4 protease inhibitor and PIB is a second-generation NS5A inhibitor.27 The GLE/PIB combination regimen has a high genetic barrier to resistance compared with first-generation medications27 and is excreted through the biliary system with minimal renal excretion.28 Moreover, GLE/PIB is designed for once-daily dosing, and treatment-naive patients without cirrhosis need only take the medication for 8 weeks.22 The GLE/PIB combination medication is not recommended for individuals with Child-Pugh B scores and is contraindicated for patients with Child-Pugh C scores.22 Additionally, GLE/PIB is contraindicated with concurrent use of rifampin or atazanavir.22

Challenges of Treating Chronic Hepatitis C Co-infection
Co-infection with hepatitis B (HBV) and/or human immunodeficiency virus (HIV) is associated with worse prognosis of CHC.18 Additionally, there is the possibility of a reactivation of HBV after initiating HCV therapy in patients who are co-infected with hepatitis B and C.18 Therefore, the WHO recommends that individuals who test positive for the hepatitis B surface antigen (HBsAg) be treated for HBV before they are treated for HCV.17

Concomitant alcohol or drug use
The WHO guidelines recommend performing alcohol and illicit drug intake assessments before initiating treatment.17 Moreover, U.S. Department of  Veterans Affairs (VA) recommends that patients who have histories of substance or alcohol disorders be considered on a case-by-case basis for treatment.29 The AASLD and IDSA guidelines contend that there is a lack of evidence supporting the practice of withholding treatment for HCV infected individuals who intake alcohol or illicit drugs.18 Moreover, the VA guidelines discourage providers from disqualifying patients for treatment based solely on the length of abstinence from alcohol or illicit drugs. Patients with active substance or alcohol disorders may be treated for CHC but coordination with substance treatment professionals is imperative for treatment success.29

Treatment experienced patients
Treatment-experienced patients need to be stratified by the type of prior failed therapy, the specific HCV genotype, and stage of liver disease.18 Once daily dosing of GLE/PIB can be utilized for treatment-experienced patients; however, the duration of therapy is between 8 and 16 weeks based on prior treatment failures, viral genotype, and liver disease state.22 In contrast to GLE/PIB therapy, SOF/VEL has a once daily dosing for 12 weeks, independent of genotype, prior therapy, or liver disease state.23

Patients with cirrhosis
The VA asserts that all CHC infected individuals are potential candidates for HCV therapy, including individuals with cirrhosis. Furthermore, patients with advanced liver disease are likely to benefit the most from therapy.29 However, HCV infected individuals with decompensated cirrhosis need to be evaluated by specialists in the management of complex liver disease before treatment is initiated.18

Treatment Monitoring and Curative Metrics
The WHO guidelines state that a complete blood count (CBC), renal function test, liver function test, and HCV RNA quantity be performed as a baseline before starting treatment and again at week 4 of treatment with the exception of HCV RNA quantity.17 However, the AGA guidelines assert that patients receiving treatment should be tested at week 4 with a CBC, CMP, and HCV RNA quantity.14 If HCV RNA is detectable at week 4, therapy should continue for 2 more weeks with a repeated HCV RNA quantity test at week 6.18 Therapy should be discontinued if there is a greater than 10-fold increase of HCV RNA from baseline at week 6; however, there are no set guidelines to discontinue therapy if there is less than a 10-fold increase of HCV RNA.18 Moreover, a 10-fold increase in ALT levels from baseline at any time during therapy should prompt discontinuation of treatment.18 For patients on either 12-week or 16-week regimens, HCV RNA quantity should be tested at week 12 and week 16 respectively.14 All patients should be tested for HCV RNA quantity at 12 weeks post-therapy.14,17,18

Sustained viral response at 12 weeks post-therapy (SVR12) is defined as an undetectable HCV RNA level in the blood and is considered the primary endpoint of treatment success.29 Pradat et al.5 stated that the use of direct acting antiviral agents (DAAs) achieved a 90% cure rate. Moreover, Evon et al.12 asserted that that DAA medications for CHC demonstrated a 95% cure rate. Kosloski et al.28 contended that the combination of GLE and PIB achieved a 99% cure rate in compensated cirrhotic patients treated for 12 weeks for all genotypes except genotype 3, for which a greater than 96% rate was achieved. Furthermore, Osawa et al.27 demonstrated a 93% cure rate of GLE and PIB combination therapy in treatment-experienced, non-cirrhotic patients who experienced prior virologic failure on DAA medication regimens. However, the cure rate decreased to 83% in treatment-experienced, cirrhotic patients.27 Treatment-naive patients with or without cirrhosis who were given SOF/VEL had cure rates of 95% to 99% depending on HCV genotype.19 Moreover, Feld et al.30 demonstrated a 99% cure rate with SOF/VEL in treatment-experienced patients.

Figure 1, “The Assessment Algorithm for Chronic Hepatitis C”, is designed in a decision-tree format for ease of use. The decision-tree contains common scenarios that primary care providers may encounter in assessing patients for possible chronic hepatitis C therapy. There may be circumstances in rural or resource scarce areas where specialty providers, including infectious disease specialists, are limited. In such cases, providers can refer patients to their local health department for further evaluation if need be. However, most areas do have gastroenterologists who can assist with both liver disease and complex treatment protocols.

Figure 2, “The Treatment Algorithm for Chronic Hepatitis C”, utilizes the currently available combination therapy of sofosbuvir/velpatisvir. Sofosbuvir/velpatisvir has a relative ease of use because it can be prescribed for any genotype of the hepatitis C virus. Additionally, the dosing durations are the same regardless of whether a patient is non-cirrhotic or has Child-Pugh A cirrhosis. Moreover, the medication has the same dosing duration whether or not the patient is treatment-naive or had unsuccessful treatments for CHC in the past. The side effects are minimal in comparison to prior CHC therapies and dosing is once a day.

Patients with cirrhosis are in more urgent need of HCV therapy as their risk for conversion to decompensated cirrhosis or hepatocellular carcinoma is elevated, in comparison to non-cirrhotic individuals with CHC.29 However, the AASLD and IDSA guidelines recommend treatment for all individuals with CHC except those with short life expectancies who cannot be reasonably and positively affected by HCV therapy, liver transplant, or other directed therapy.18

Primary care providers are on the front lines for hepatitis C screening and need to have the proper tools to manage the disease process. Given the new medications available to treat CHC, treatment protocols have never been easier to administer. One of the main challenges of treating CHC patients at the primary care level is knowing when to refer patients for more specialized care. The assessment algorithm included in this article addresses the situations that may require specialty referrals. Additionally, the treatment algorithm utilizes SOF/VEL, which has a low side-effect profile; less onerous monitoring schedules; and does not require viral genotyping. Primary care providers can effectively utilize these algorithms to treat a much larger cohort of CHC patients both in private practices and safety-net clinics.

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