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CME: Primary Care

Healing livers, saving lives

Hepatitis C screening in an era of cure

Boucher, Courtney M. MPAP, PA-C; Walsh, Anne MMSc, PA-C, DFAAPA; Forest, Christopher P. MSHS, PA-C, DFAAPA

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Journal of the American Academy of Physician Assistants: May 2016 - Volume 29 - Issue 5 - p 20-28
doi: 10.1097/01.JAA.0000482295.08412.4a
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Hepatitis C virus (HCV) is a bloodborne pathogen that can lead to acute or chronic liver infection. Between 15% and 26% of patients spontaneously clear the virus, typically within 3 months, with complete resolution.1 However, about 85% of infections are asymptomatic, and most patients fail to clear the virus in the acute phase, thereby progressing to chronic viral hepatitis.1 Chronic infection progresses over decades and ultimately leads to cirrhosis, liver failure, and hepatocellular carcinoma in 20% to 40% of patients. These patients will need to be referred for liver transplantation. In fact, HCV-related liver disease is the most common indication for liver transplant in the United States; 14,500 adults are on the waiting list, yet only 6,700 transplants are performed each year, with an average 5-year survival rate of 73%.2,3

The most common modes of transmission for HCV are blood transfusion, organ transplant, and needle sharing for IV drug use; 70% to 90% of older, former IV drug users have HCV.4 Transmission is possible, albeit less likely, from percutaneous exposures such as needle sticks, tattooing, body piercing, intranasal drug use, acupuncture, and manicure equipment. Other known risks are mucosal exposures to blood, including vertical transmission from an infected mother or sexual intercourse with an infected partner. IV drug use continues to remain the greatest risk factor for HCV infection and accounts for most new infections in the United States.

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Worldwide, 130 to 170 million people (2% to 3% of the population) are infected with HCV, and each year 500,000 people die of HCV-related complications.5 Before the virus was discovered in 1989, an estimated 300,000 people per year were infected primarily through IV drug use and transfusions, with what was called non-A non-B viral hepatitis. Based on retrospective studies of stored transfusion-associated hepatitis sera, up to 90% of these cases were caused by HCV.6,7 Because chronic HCV infection typically remains asymptomatic for many years, and about half of those infected are unaware of their status, most infections are untreated.5,8 Patients rarely present with classic symptoms of acute hepatitis, such as jaundice, scleral icterus, pruritus, fever, right upper quadrant pain, nausea, vomiting, and dark urine; such patients need a comprehensive workup for hepatobiliary disease, which is outside the scope of this article.

A marked change in the HCV screening and treatment paradigm over the last few years presents a perfect opportunity for primary care providers to substantially reduce HCV's effect on public health:

  • In 2012, the CDC revised HCV screening recommendations so that more patients meet screening criteria.
  • In 2013, the US Preventive Services Task Force (USPSTF) updated its screening guidelines for HCV to grade B status, recommending with high certainty that the net benefit is moderate to substantial.
  • In 2014, the Affordable Care Act increased the number of patients with access to care and now requires insurance companies to cover the cost of all USPSTF grade A and B screening recommendations.
  • Numerous new drugs developed within the last decade have been approved for treating HCV, and even more are in the pipeline. In general, they are highly effective, well tolerated, and have fewer contraindications than previous interferon-based regimens.

Despite these positive developments, screening compliance remains an issue. Primary care providers are in an ideal position to increase overall screening rates and improve patients' lives. However, a study of 8,981 patients and 154 physicians found that only 36% of primary care physicians followed the current HCV screening recommendations.9


In 1998, the CDC released the first screening criteria for patients with known risk factors for HCV. The criteria have been updated periodically and include:

  • patients with a history of IV drug use, including “one-time-only” use
  • patients with a history of intranasal drug use
  • patients with tattoos obtained in an unregulated setting
  • patients who have been incarcerated
  • patients who received clotting factors before 1987, or blood transfusions or solid organ transplants before 1992
  • patients with a history of long-term hemodialysis
  • healthcare workers who had needlestick injuries
  • patients infected with HIV
  • patients with elevated liver enzymes
  • children born to HCV-positive mothers.10

Screening based solely on disclosed risks may miss detection of a large number of infected patients, as many people with chronic HCV perceive themselves as low risk. Thus, recent recommendations include a one-time screening for baby boomers—those born between 1945 and 1965—who may be at increased risk due to undisclosed high-risk behaviors in their youth, such as IV drug experimentation. Though this population is at low risk for new infection, they are at high risk for sequelae of chronic liver disease given the length of time they have potentially been infected. Baby boomers as a cohort account for 75% of the deaths caused by HCV each year, and would thus gain the greatest benefit from screening and subsequent treatment before they become symptomatic.11 Although birth-cohort screening is less efficient than screening only people with known risk factors, the USPSTF and CDC predict that a substantial number of patients will benefit, estimating that 120,000 HCV-related deaths can be averted by birth-cohort screening and treatment.11 The USPSTF recognizes that increased screening will result in more diagnoses and treatment for patients who may never develop signs or symptoms of liver disease; however, this cost is deemed acceptable when weighed against the potential harms of underdiagnosis. Birth-cohort screening has a strong recommendation from the CDC and a grade B recommendation from USPSTF.10,12


Determining the patient's HCV antibody status is the first step in screening; a positive result indicates either past exposure or current infection. If the patient's status is negative and exposure is suspected, retest the patient's antibody status in 6 months to confirm absence of infection.1 Order a quantitative assay for HCV ribonucleic acid (HCV RNA) to detect whether an antibody-positive patient has a current infection. Positive RNA confirms the presence of virus and a diagnosis of chronic HCV. If HCV RNA is not detected in an antibody-positive patient, this indicates either a past infection that spontaneously cleared, or a false-positive result (Figure 1). HCV RNA can be detected as early as 1 to 3 weeks postexposure; however, HCV antibody seroconversion takes 8 to 9 weeks.13 Note that a positive antibody test does not mean the patient is immune; caution patients that a new HCV infection can be contracted regardless of antibody status.

Hepatitis C screening algorithm10

If a diagnosis of chronic HCV is confirmed, screen the patient for hepatitis B virus (HBV) with hepatitis B surface antigen (HBsAg), and for HIV with HIV antibody because they have common modes of transmission. Coinfection with either virus accelerates disease progression and affects the selection of treatment regimens.

Perform baseline testing

The following laboratory tests are indicated to estimate the degree of liver disease, screen for comorbidities including concomitant chronic liver disease, and determine treatment candidacy: complete blood cell count, serum aminotransferases (which may be normal), bilirubin, albumin, prothrombin time, ferritin, antinuclear antibody, creatinine, fasting glucose, lipid panel, and a pregnancy test for women of childbearing potential. Check antibody titers and provide immunization for hepatitis A and B if the patient is seronegative, as contracting either virus may result in fulminant liver failure in a patient with chronic HCV.

Determine genotype

Order HCV genotype testing, which is important for the selection of drug, dosing, and duration of therapy, once viremia has been confirmed. Of the six major genotypes, genotype 1 is the most prevalent in the United States and the most difficult to treat with interferon-based regimens. Newer medications minimize the effect of genotype on prognosis because they improve virologic response rates in all genotypes but therapy regimens are chosen specifically by genotype.

Assess the degree of fibrosis

One of several methods can be used to assess the degree of liver fibrosis in patients with confirmed chronic HCV.

Liver biopsy, performed under ultrasound guidance, is considered the gold standard for assessing fibrosis, and the decision whether to biopsy is most often made by consulting a gastroenterologist or hepatologist. The rendering pathologist will report the degree of inflammation (grade) and extent of scarring and fibrosis (stage), each typically rated from 0 to 4. Although biopsy provides useful information for treatment selection and prognosis, it is invasive, costly, uncomfortable, subject to sampling error, and includes risks of injury (to the bile duct or lung) and bleeding complications, especially in patients who may already be high-risk due to cirrhosis.

Serologic markers are increasingly being used in lieu of liver biopsy as a noninvasive method of assessing fibrosis. Various parameters that include tissue turnover markers, liver enzymes, and patient demographics are combined into one of several proprietary algorithms that generate the predictive score.

Ultrasound-based transient elastography is another noninvasive method of evaluating fibrosis. Inexpensive, quick, reproducible, and painless, it examines a large area of the liver tissue and may be easily repeated over time, unlike tissue biopsy. The process measures shear wave velocity through the liver, which is then converted to degree of liver stiffness.

Point-of-care calculators are simple, free, and can be helpful to primary care providers when counseling patients at initial diagnosis. One calculator uses the aspartate aminotransferase (AST)-to-platelet ratio index (APRI), and another uses AST, ALT, platelets, and patient age. The oldest, simplest estimate is simply the AST/ALT ratio. An important caveat with noninvasive testing is that patients who are actively drinking alcohol have higher AST levels, thus fibrosis scores may be falsely elevated.


A baseline abdominal ultrasound at diagnosis is important to assess for hepatomegaly/fatty liver, splenomegaly (surrogate marker for portal hypertension), cholelithiasis (increased in cirrhosis), and liver nodularity or masses. Patients with cirrhosis should be screened for hepatocellular carcinoma every 6 months with liver ultrasound, according to the 2015 American Association of the Study of Liver Disease (AASLD) guidelines.14 Nodules smaller than 1 cm should be followed every 3 months by repeat ultrasound. Nodules larger than 1 cm should be followed with dynamic contrast-enhanced MRI or four-phase multidetector CT.15


Most patients diagnosed with chronic HCV are asymptomatic, and learning of their diagnoses may result in significant emotional stress. Newly diagnosed patients should be assessed for depression (a common finding in patients with HCV) using any of the validated screening tools available to the provider. Identify and treat other medical conditions that can complicate the management of this disease, such as hypothyroidism, cardiovascular disease, and diabetes. The latter is three times more prevalent in patients with HCV than in the general population.16 Other systemic diseases that are associated with HCV infection include non-Hodgkin lymphoma, porphyria cutanea tarda, essential mixed cryoglobulinemia, leukocytoclastic vasculitis, and membranoproliferative glomerulonephritis. Patients with these conditions should be screened for HCV.

Educating the patient is critical, as asymptomatic patients may not understand the serious implications of HCV. Explain the modes of transmission, so patients know that sharing toothbrushes and razors, for example, can increase the risk of infecting other household members but casual contact, such as hugging or sharing a restroom, does not. Other important topics for patient education include weight management and smoking cessation (of both tobacco and cannabis) because smoking and obesity can stimulate hepatic fibrosis and speed the progression to cirrhosis.17,18

Recommend a healthful diet low in simple carbohydrates and fat; advise patients to abstain completely from alcohol and recreational drugs. Perform a Screening, Brief Intervention and Treatment (SBIRT) on every patient with HCV and refer patients to a 12-step or other recovery program if needed.11 Interestingly, consuming more than 2 cups of coffee per day has been shown to reduce the risk of hepatocellular carcinoma as well as the rate of hospitalization in patients with chronic liver disease.19 Coffee consumption also increases virologic response in patients receiving interferon-based therapies.20 Although these findings do not imply a recommendation for increased coffee consumption, they may provide the patient some relief to know it is safe to continue enjoying coffee when other substances are restricted.

Because of the risk of bleeding and hepatotoxicity, patients with advanced liver disease should avoid taking nonsteroidal anti-inflammatory drugs. Acetaminophen is of concern due to the risk of liver damage at high doses; however, it can be used in patients with normal liver function (that is, albumin, PT/INR, and direct bilirubin; recall that ALT and AST are not representative of liver function, but instead, liver inflammation) as long as the dose does not exceed 2 g in 24 hours. Dose adjustment is not required in patients with normal hepatic function.

Patients will seek more information on the Internet, so guide them toward credible and accurate resources such as and


For the first time in the history of HCV management, guidelines recommend that all patients with chronic HCV be treated, barring contraindications or limited life expectancy.21 The goal of antiviral therapy is to achieve a sustained virologic response, which is essentially a clinical cure. A sustained virologic response is defined as an undetectable HCV RNA measured 6 months after completion of therapy. Most patients who achieve a sustained virologic response will continue to have undetectable serum HCV RNA in long-term follow-up and are considered cured. Although no recommendations exist for continued monitoring of viral load in patients with a sustained virologic response due to relapse rates of less than 1%, data regarding long-term relapse are still limited.

Antiviral therapy

The most important indication for beginning antiviral therapy is the presence of advanced fibrosis or cirrhosis, due to the risk of hepatic decompensation and progression to hepatocellular carcinoma. Achieving a sustained virologic response in patients with compensated cirrhosis has been shown to reduce the risk of hepatic decompensation, leading to improved survival rates.22

All patients with chronic HCV should be referred for specialty care upon diagnosis; most payers will not cover medications unless they are ordered by a specialist. However, as broader screening identifies more patients needing treatment, primary care providers may play an active role in disease management. Special populations of patients with HCV, including those with HIV, HBV, chronic kidney disease, decompensated cirrhosis, pre- and postliver transplant, and patients who have not responded to previous therapy, present specific treatment challenges and should be managed by an experienced gastroenterology or hepatology specialist.

Despite the availability of interferon therapy for over 20 years, mortality from HCV infection in the United States has continued to increase because treatment was medically contraindicated for many patients, only half of treated patients responded, and a large portion of those who did not respond progressed to end-stage disease. These outcomes speak to the need for the development of better-tolerated, more effective treatment options.

Novel therapies

The new direct-acting antiviral agents (DAAs) have brought about remarkable success with regard to achieving a sustained virologic response in patients of all genotypes. In addition to improved rates of sustained virologic response, DAAs reduce pill burden, allow for the option of interferon-free therapy, shorten treatment duration, and increase treatment success.23,24 Although the presence of frank cirrhosis, genotype 1 subtype a, and some genotype 3 patients have somewhat lower response rates, no longer are nonmodifiable patient factors, such as age, sex, race, viral load, IL28 genotype, or degree of fibrosis direct predictors of response to DAAs, as with the previous interferon-based regimens.25 DAAs have some limitations, including drug-drug interactions and the development of resistance mutations. However, DAAs have rapidly become the standard of care treatment for most patients with chronic HCV, from the newly diagnosed treatment-naïve, to post-transplant retreatment patients, including those who have not responded to multiple regimens and those who have relapsed after treatment.23Table 1 summarizes approved treatment regimens.

Regimens to treat chronic HCV in treatment-naive patients

The DAAs target multiple sites of nonstructural HCV proteins that control viral replication. They prohibit HCV replication specifically by acting on translation and polyprotein processing (NS3/4A), HCV genome replication (NS5B polymerase and NS5A), and viral assembly (NS5A).26

The first NS3/4A protease inhibitors were approved in 2011. Boceprevir and telaprevir were shown to be superior against genotype 1 HCV infection when combined with pegylated interferon/ribavirin in treatment-naïve and treatment-experienced patients. Adverse reactions include anemia and nausea; telaprevir can cause severe pruritus and contains a black box warning for Stevens-Johnson syndrome and toxic epidermal necrolysis. These medications were removed from the treatment guidelines just 3 years after approval due to the emergence of better-tolerated therapies.

Improved adverse reaction profiles were achieved with the second group of NS3/4A inhibitors, including simeprevir, which was approved in 2013 in combination with peginterferon alfa and ribavirin for genotype 1; approved indications include genotype 4 and HCV-HIV coinfection.

Although the NS3/4A class provided promising results, research continued for drugs that went beyond inactivating a protein and focused on halting the virus' ability to replicate. In 2013, sofosbuvir became the first approved NS5B polymerase inhibitor, characterized for its high potency and genetic barriers to resistance. Sofosbuvir combined with ribavirin achieved an interferon-free regimen for patients with genotype 2 or 3 HCV. This drug also can be used in combination with pegylated interferon/ribavirin for 12 weeks in patients with genotype 1. Sofosbuvir has demonstrated sustained virologic response rates as high as 93% (95% CI, 85 to 98) with a 12-week course for genotype 2, and 85% (95% CI, 80 to 89) for genotype 3 in a 24-week therapy.27 Specific regimens vary based on genotype, stage of fibrosis, patient age, and whether cirrhosis is present. Although the drug may cause adverse reactions—most commonly, fatigue, headache, nausea, insomnia, and pruritus—most patients find these reactions manageable, and the rate of discontinuation of therapy is less than 1%.27Table 2 lists adverse reactions to HCV therapies.

Adverse reactions to HCV therapies reported by more than 10% of patients

Even patients with difficult-to-treat genotype 1 HCV who have previously been treated with an interferon-based therapy and did not reach sustained virologic response, termed nonresponders, have shown excellent success with new interferon-free therapy. In a phase 3 study, patients were randomly assigned a combination of ledipasvir, an NS5A inhibitor, and sofosbuvir, an NS5B inhibitor, in a once-daily dose for either 12 or 24 weeks with or without the addition of ribavirin. The rates of sustained virologic response were high in all treatment groups: 94% (95% CI, 87 to 97) and 96% (95% CI, 91 to 99) in 12-week therapies without and with ribavirin, respectively, and 99% (95% CI, 95 to 100) in 24-week therapies without and with ribavirin.23

In October 2014, the FDA approved ledipasvir-sofosbuvir, a combination pill, as the first all-oral treatment for HCV without either pegylated interferon or ribavirin. In December 2014, ombitasvir, paritaprevir, and ritonavir tablets copackaged with dasabuvir tablets, were approved for use with or without ribavirin for genotype 1. Another all-oral treatment, daclatasvir, was approved in July 2015 for use with sofosbuvir in the treatment of genotypes 1, 2, and 3. Also new in July 2015 was the first all-oral treatment approved for genotype 4: a fixed-dose combination containing ombitasvir, an NS5A inhibitor; paritaprevir, an NS3/4A protease inhibitor; and ritonavir, a CYP3A inhibitor, to be used with ribavirin in patients without cirrhosis. An additional protease inhibitor-NS5A combination drug, grazoprevir-elbasvir, was approved with or without ribavirin in January 2016 for the treatment of genotypes 1 and 4. With such rapid evolution of new antivirals, providers are advised to review the most up-to-date treatment regimens from the AASLD and the Infectious Diseases Society of America (IDSA) website:

Cost of treatment

Although the benefits of therapy are clear, the notable limitation of the new DAA medications is cost: a single course of treatment can cost from $25,000 to $189,000 based on medications and length of therapy.24 Cost of therapy should be weighed against the cost of caring for the medical complications resulting from untreated HCV, keeping in mind that HCV is a systemic disease, not simply a liver disease, and patients with chronic HCV have increased rates of all-cause mortality.8

Estimates of healthcare spending per person with chronic HCV infection are as high as $20,961 per year.28 Care for a patient with cirrhosis complicated by hepatocellular carcinoma costs $43,671 annually.29 Patients with cirrhosis could accrue up to $270,000 in medical expenses as they progress to end-stage liver disease.24 The cost of medical care for a liver transplant recipient is about $93,609 annually, which does not include the actual surgical and postsurgical costs, totaling upwards of $500,000.24,29

Direct medical expenditures for HCV in the United States are estimated to be $10.7 billion for the 10-year period from 2010 to 2019.28 Over the same time period, indirect costs associated with HCV-related deaths in patients younger than age 65 years are estimated to reach $54.2 billion.28 DAAs, though expensive, still cost substantially less than the treatment of HCV-related complications. These drugs have the potential to reduce the high economic burden that HCV infection imposes on the US healthcare system, particularly government payers, as most insured patients with HCV are covered under Medicare, Medicaid, or the Veterans Administration. Although treatment costs are high, the cost of not treating also is high when considering all-cause mortality, health-related quality of life, new infection transmission, premature death, and disability.30 In this new age of HCV treatment, although patients may be unable to access therapy due to social, political, and economic barriers, providers should continue to advocate for treatment, as there are virtually no clear medical reasons to withhold therapy, as was the case with interferon-based regimens.31


Current guidelines recommend a one-time screening for HCV in all patients born between 1945 and 1965, for whom perceived risk may be low yet the potential for complications is high. Early identification and treatment in this cohort, as well as in patients with known risk factors, has become increasingly important, as the new antiviral drugs are highly efficacious and have minimal adverse reactions compared with previous therapies. The new all-oral, once-daily DAAs offer a short duration of treatment with good tolerability and excellent efficacy, curing this indolent infection at the highest rates ever for all genotypes. Primary care providers should intentionally broaden their screening practices and refer all infected patients for treatment. Adopting this new paradigm will significantly reduce the profound morbidity, mortality, and societal burden of chronic HCV.


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                          hepatitis C; HCV; direct-acting antivirals; sofosbuvir; ledipasvir; screening

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