Hepatitis C Guidance 2019 Update: AASLD-IDSA Recommendations for Testing, Managing, and Treating Hepatitis C Virus Infection

Recommendations

• 1

  One-time, routine, opt out HCV screening is recommended for all individuals aged 18 years or older. (I, B)

  In light of the inadequacy of targeted HCV case finding using risk-based and birth cohort HCV screening,^{(24, 25)} investigators have modeled the cost-effectiveness of one-time universal HCV screening for adults aged ≥18 years. Independent studies using different modeling techniques demonstrate that one-time universal screening for adults aged ≥18 years is cost-effective (<$30,000/quality-adjusted life years) compared with birth-cohort screening.^{(20, 26)} Additionally, the cost-effectiveness of nontargeted HCV screening has proven robust in a variety of venues including correctional,⁽²⁷⁾ prenatal,^{(28, 29)} and primary care⁽³⁰⁾ settings, and substance use treatment centers.^{(31, 32)} Given the current epidemiology of HCV disease in the United States, the cost-effectiveness of universal HCV screening, the high efficacy of DAA therapy, and the myriad liver-related and other health benefits of virologic cure,^(33–38) the HCV guidance panel recommends universal, one-time, opt out HCV screening of adults aged ≥18 years. Although neither CDC nor the USPSTF currently recommend universal HCV screening in adults, CDC initiated a peer review process to consider such a recommendation in July 2019. Similarly, in August 2019, the USPSTF published a draft recommendation for universal HCV screening among adults aged 18–79 years. The USPSTF draft universal hepatitis C screening recommendation differs from that of the AASLD-IDSA HCV guidance by setting an upper age limit of 79 years. The HCV guidance panel does not recommend an age limit for universal adult HCV screening due to the excellent quality of life of many octogenarians and the association between advanced age and more rapid HCV disease progression.

  The HCV guidance panel’s new universal screening recommendation is intended to enhance HCV case finding among adults not included in the 1945 through 1965 birth cohort and aligns with the WHO and NASEM goals of eliminating HCV as a public health threat by 2030. This is particularly important for men and women aged 20–39 years due to the disproportionate overlapping impact of the opioid epidemic and associated injection drug use and the rising rate of incident HCV infections in this age group. Universal HCV screening also bypasses the inherent barriers in ascertaining an accurate risk factor assessment.

Recommendations

• 2

  One-time HCV testing should be performed for all persons younger than 18 years old with behaviors, exposures, or conditions or circumstances associated with an increased risk of HCV infection. (I, B)

• 3

  Periodic repeat HCV testing should be offered to all persons with behaviors, exposures, or conditions or circumstances associated with an increased risk of HCV exposure. (IIa, C)

• 4

  Annual HCV testing is recommended for all persons who inject drugs and for men with human immunodeficiency virus (HIV) infection who have unprotected sex with men. (IIa, C)

  One-time, risk-based HCV screening is recommended for persons younger than 18 years old with current or past behaviors, exposures, or conditions or circumstances associated with an increased risk of HCV infection (see Table 1). There is currently insufficient evidence to support universal HCV screening in the pediatric population.

  People with ongoing risk factor(s) for HCV infection remain vulnerable for as long as the behavior, exposure, condition, or circumstance persists, thereby warranting periodic repeat HCV testing. There is a paucity of data addressing the optimal frequency of repeat testing thereby leaving the periodicity to the clinician’s discretion on a case-by-case basis with consideration of an individual’s risk for HCV infection or reinfection. People who inject drugs (PWID) and men with HIV infection who have unprotected sex with men are exceptions to this guidance. Because of the high incidence and prevalence of HCV infection in these populations,^(39–47) at least annual HCV testing is recommended. Given that many PWID lack access to or eschew traditional healthcare delivery systems, integration of HCV testing services into substance use treatment programs, needle/syringe service programs, and acute detoxification programs expands the opportunities to accomplish periodic HCV testing in this key population.^(48–50)

Recommendations

• 5

  HCV-antibody testing with reflex HCV RNA polymerase chain reaction testing is recommended for initial HCV screening. (I, A)

• 6

  Among persons with a negative HCV-antibody test who were exposed to HCV within the prior 6 months, HCV-RNA or follow-up HCV-antibody testing 6 months or longer after exposure is recommended. HCV-RNA testing can also be considered for immunocompromised persons. (I, C)

• 7

  Among persons at risk for reinfection after previous spontaneous or treatment-related viral clearance, HCV-RNA testing is recommended because a positive HCV-antibody test is expected. (I, C)

• 8

  Persons found to have a positive HCV-antibody test and negative results for HCV RNA by polymerase chain reaction should be informed that they do not have evidence of current (active) HCV infection but are not protected from reinfection. (I, A)

• 9

  Quantitative HCV-RNA testing is recommended prior to initiation of antiviral therapy to document the baseline level of viremia (i.e., baseline viral load). (I, A)

• 10

  HCV genotype testing may be considered for those in whom it may alter treatment recommendations. (I, A)

  HCV-antibody testing using a U.S. Food and Drug Administration (FDA) approved assay (laboratory-based or point-of-care) is recommended for initial HCV screening.^{(51, 52)} The sensitivity and specificity of the lone FDA-approved point-of-care test (OraQuick HCV Rapid Antibody Test; OraSure Technologies Inc., Bethlehem, Pennsylvania) are similar to laboratory-based assays.^{(53, 54)} A positive HCV-antibody test indicates current (active) HCV infection (acute or chronic), a past resolved infection, or rarely a false positive result.⁽⁵⁵⁾ A test to detect HCV viremia is necessary to confirm active HCV infection (see Figure 1). Ideally, a positive HCV-antibody test automatically reflexes to HCV-RNA testing. This approach requires a single blood collection and avoids a return visit for confirmatory testing, a major barrier in the continuum of care.⁽⁵⁶⁾ Collection of dried blood spots is an option for sequential HCV-antibody and reflex HCV-RNA testing. Dried blood spot collection can be accomplished with a fingerstick rather than venipuncture and transport does not require an intact cold chain, making this an advantageous testing option in rural areas and among people for whom phlebotomy is a testing barrier.⁽⁵⁷⁾ An FDA-approved quantitative or qualitative HCV-RNA assay with a detection level of ≤25 IU/mL should be used.

  HCV-RNA testing is required to detect reinfection after previous spontaneous or treatment-related viral clearance because HCV-antibody positivity is expected (see Figure 1). Immunocompromised persons and those with possible HCV exposure in the prior 6 months may be HCV antibody negative due to delayed or failed seroconversion⁽⁵⁸⁾ or being in the seroconversion window period,⁽⁵²⁾ respectively. HCV-RNA testing is a consideration for these individuals, particularly for those with known risk factor(s).

  Persons who have a reactive HCV-antibody test and a negative (not detected) HCV-RNA test should be informed that they do not have evidence of current HCV infection. Although additional testing is typically unnecessary, HCV-RNA testing can be repeated for persons with ongoing HCV infection risk or if there is a high index of suspicion for recent infection. If either the clinician or patient wish to determine whether a positive HCV-antibody test in the absence of HCV viremia represents a resolved HCV infection or a biologic false positive, repeat testing with a different HCV-antibody assay can be undertaken. A false positive typically does not occur with two different assays.^{(51, 59)}

  Quantitative HCV-RNA testing is recommended prior to initiating antiviral therapy to determine baseline viremia (viral load), which may affect treatment duration with ledipasvir/sofosbuvir therapy. With the advent of pangenotypic DAA regimens, HCV genotyping is no longer universally required prior to treatment initiation. Pretreatment genotyping is recommended for persons with a prior HCV treatment failure because DAA regimen selection and duration may differ by genotype. Pretreatment genotyping is not required for treatment-naive patients without cirrhosis if a pangenotypic regimen is used.

Recommendations

• 11

  Persons with current HCV infection should receive education and interventions aimed at reducing liver disease progression and preventing HCV transmission. (IIa, B)

• 12

  Abstinence from alcohol and, when appropriate, interventions to facilitate cessation of alcohol consumption should be advised for all persons with HCV infection. (IIa, B)

• 13

  All persons with HCV infection should be provided education about how to prevent HCV transmission to others. (I, C)

• 14

  Evaluation for advanced fibrosis using noninvasive markers (or liver biopsy, if required) is recommended for all persons with HCV infection to facilitate an appropriate decision regarding HCV treatment strategy, and to determine the need for initiating additional measures for cirrhosis management (e.g., hepatocellular carcinoma screening). (I, A)

• 15

  Evaluation for other conditions that may accelerate liver fibrosis, including hepatitis B and HIV infections, is recommended for all persons with active HCV infection. (IIb, B)

• 16

  Vaccination against hepatitis A and hepatitis B is recommended for all susceptible persons with HCV infection. (IIa, C)

• 17

  Vaccination against pneumococcal infection is recommended for all persons with cirrhosis. (IIa, C)

  Upon diagnosis of active HCV infection, patients require counseling and certain clinical interventions prior to initiation of antiviral therapy. Prevention of further liver damage is crucial. To that end, counseling patients to abstain from alcohol takes priority because of associations between excess alcohol use and incident or progressive fibrosis, and the development of hepatocellular carcinoma (HCC).^(60–69) There is no known safe level of alcohol use for patients with chronic hepatitis C. All patients with chronic hepatitis C, especially those with advanced fibrosis or cirrhosis, should be advised to abstain from alcohol use.^(70–72) Persons suffering from alcohol use disorder require treatment for this condition; consider referring these individuals to an addiction specialist. Ongoing alcohol use, however, is not a contraindication to antiviral therapy. Data indicate that ongoing alcohol use does not affect therapeutic outcomes with DAA regimens among treatment-adherent patients.⁽⁷³⁾

  From a public health perspective, educating persons with HCV infection about how to avoid transmitting the virus to others (Table 2) serves as an essential primary prevention measure to curb and eventually eliminate the hepatitis C epidemic. Exposure to infected blood is the primary mode of HCV transmission. Epidemics of acute HCV due to sexual transmission in men with HIV infection who have sex with men have also been described.^(74–77)

  Assessing liver disease severity is an essential component of the workup for all persons with newly diagnosed chronic hepatitis C as this factor influences initial and follow-up evaluation. This assessment (i.e., presence or absence of cirrhosis) can usually be accomplished with noninvasive tests (Table 3). Liver biopsy is rarely required but is a consideration if other causes of liver disease are suspected.

  Persons with known or suspected cirrhosis are at increased risk for complications of advanced liver disease and require frequent follow-up. They should also avoid hepatotoxic drugs, such as excessive acetaminophen (>2 g/d) and certain herbal supplements. Nephrotoxic drugs (e.g., nonsteroidal anti-inflammatory drugs) should also be avoided. Ongoing imaging surveillance for HCC and gastroesophageal varices is recommended for patients with cirrhosis.^(78–80) Cirrhosis with portal hypertension portends a greater likelihood of developing future hepatic complications in untreated patients.^{(81, 82)} Transient elastography provides point-of-care information regarding liver stiffness and can reliably distinguish patients with a high versus low likelihood of cirrhosis.^(83–85)

  Screening for hepatitis B virus (HBV) with an FDA-approved hepatitis B surface antigen (HBsAg) assay and HIV with an FDA-approved HIV-antigen/antibody test is recommended because these coinfections are associated with a poorer HCV prognosis.^(86–90) Persons who test positive for HBsAg require additional monitoring during HCV treatment due to HBV reactivation risk.⁽⁹¹⁾ Anti-HBV therapy is another consideration for these patients. For persons who test negative for HBsAg but positive for hepatitis B core antibodies (with or without hepatitis B surface antibodies) have resolved HBV infection and no further workup or additional monitoring is needed.⁽⁹²⁾

  Primary prevention measures for persons without coinfection include counseling about how to avoid contracting HIV and HBV, and immunization against HBV and hepatitis A virus (HAV) as needed. CDC also recommends pneumococcal vaccination for all persons with chronic liver disease.⁽⁹³⁾

Recommendation

• 18

  Antiviral treatment is recommended for all adults with acute or chronic HCV infection, except those with a short life expectancy that cannot be remediated by HCV therapy, liver transplantation, or another directed therapy. (I, A)

  Eradicating hepatitis C infection results in numerous health benefits, including reduced rates of all-cause mortality, cirrhosis, hepatic decompensation, and HCC.^{(33, 37, 98–110)} Successful treatment also confers improvement in extrahepatic manifestations of HCV disease, including cryoglobulinemic vasculitis^(111–116) and HCV-related non-Hodgkin lymphoma and other lymphoproliferative disorders,^(117–125) as well as improved productivity and quality of life.^{(34, 35, 126–131)} Given these and other benefits associated with virologic cure, the HCV guidance panel strongly recommends antiviral treatment for all adults with acute or chronic HCV infection (except those with a short life expectancy that cannot be remediated). Importantly, this recommendation includes persons with ongoing substance use (alcohol or drugs). Several studies demonstrate that treatment-committed individuals in this disproportionately affected population achieve sustained virologic response (SVR) rates with DAA therapy comparable to those without known, current substance use.^{(73, 132–139)} The universal treatment recommendation represents a principal tenet of the HCV guidance along with newly recommended universal hepatitis C screening of adults. The HCV guidance panel urges healthcare providers caring for adults to encourage hepatitis C screening and treatment (if positive) because DAA therapy is safe and cures HCV infection in most people.⁽²⁾

Simplified HCV Treatment Algorithm for Treatment-Naive Adults Without Cirrhosis

The simplified HCV treatment algorithm for adults without cirrhosis (see Figure 2) applies to persons aged ≥18 years who have not been previously treated for their infection and do not have evidence of cirrhosis as defined by the noninvasive parameters specified in the HCV guidance. Evidence of cirrhosis includes a FIB-4 score >3.25 or any of the following findings from a previously performed test: transient elastography indicating cirrhosis (e.g., FibroScan [Echosens, Paris, France] stiffness >12.5 kPa); noninvasive serologic tests that exceed proprietary cutoffs (e.g., FibroSure [BioPredictive, Paris, France], Enhanced Liver Fibrosis Test [Siemens Healthcare, Erlangen, Germany], etc.); clinical evidence of cirrhosis (e.g., liver nodularity and/or splenomegaly on imaging, platelet count <150,000/mm³, etc.); and/or prior liver biopsy showing cirrhosis. This simplified treatment algorithm is not recommended for persons with HIV and/or HBV infection, prior liver transplantation, HCC, end-stage renal disease (i.e., eGFR <30 mL/min/m²), and/or current pregnancy because they require more nuanced care. See the online HCV guidance for management and treatment recommendations for these patients.

The pretreatment evaluation should include an assessment for cirrhosis, medication reconciliation, drug-drug interactions, and patient education regarding treatment administration and the importance of adherence, and transmission prevention. Recommended pretreatment laboratory testing is conducted to confirm chronic HCV infection and exclude decompensated liver disease, HBV and/or HIV coinfection, end-stage renal disease, and pregnancy prior to treatment initiation.

Clearance of HCV infection with DAA therapy can improve hepatic function and thereby affect the safety and efficacy of some concomitantly administered medications. Real-world data indicate an association between DAA therapy and reduced glycemia, particularly among people with diabetes.^(141–144) Patients taking diabetes medication(s) should be informed of the potential for symptomatic hypoglycemia during and after DAA therapy. Glucose monitoring during and after DAA treatment is recommended; dosage adjustments of diabetes medication(s) may be needed. Real-world data also indicate an association between DAA therapy and a clinically significant reduction in warfarin dose-response.^{(145, 146)} Patients taking warfarin should be informed of the potential for a change in their anticoagulation status. INR monitoring for subtherapeutic anticoagulation is recommended during and after DAA treatment; warfarin dosage adjustments may be needed. For others, on-treatment laboratory monitoring is not required unless a patient experiences treatment-related side effects or there are adherence concerns.

Several well-designed, robust clinical trials have demonstrated the safety⁽¹⁴⁷⁾ and high curative efficacy of glecaprevir/pibrentasvir^(148–158) and sofosbuvir/velpatasvir^(159–164) among treatment-naive persons without cirrhosis regardless of HCV genotype. These findings have been confirmed in real-world cohort studies for both glecaprevir/pibrentasvir^(165–167) and sofosbuvir/velpatasvir.^(167–171) Based on these data, 8 weeks of glecaprevir/pibrentasvir or 12 weeks of sofosbuvir/velpatasvir is recommended for adults eligible for the simplified treatment algorithm.

To assess treatment response, HCV-RNA and hepatic aminotransferase testing is recommended 12 or more weeks after completing DAA treatment. Undetectable HCV RNA represents SVR and virologic cure. In the absence of cirrhosis, persons who attain SVR require no liver-specific follow-up. For those with ongoing HCV risk factors, risk-reduction counseling is recommended as well as HCV-RNA testing annually or anytime an increase in hepatic aminotransferase levels occurs. Recurrent HCV viremia after attainment of SVR represents either reinfection or a relapse (i.e., reemergence of the originally infecting HCV strain).^{(172, 173)} With reinfection, treatment approaches are identical to those for initial treatment. If relapse is suspected or cannot be ruled out, such patients should be managed by clinicians with expertise in managing HCV treatment failure.

Persons who attain SVR but have persistently elevated hepatic aminotransferase levels require evaluation for other causes of liver disease. Individuals for whom treatment fails can often be successfully retreated; see the online HCV guidance for management and antiviral regimen recommendations for treatment-experienced persons. If retreatment is delayed or not feasible, assessment for liver disease progression every 6–12 months is recommended as specified in Figure 2. Advise all patients, regardless of SVR, to avoid excess alcohol intake to prevent liver damage.

Simplified HCV Treatment Algorithm for Treatment-Naive Adults With Compensated Cirrhosis

The simplified HCV treatment algorithm for adults with compensated cirrhosis (see Figure 3) applies to persons aged ≥18 years who have not been previously treated for their infection and have evidence of compensated cirrhosis (i.e., Child-Turcotte-Pugh [CTP] class A) but not decompensated cirrhosis (i.e., CTP class B or C). Noninvasive evidence of cirrhosis mirrors the parameters specified in the previous section and are shown in Figure 3. Calculation of the CTP score is recommended to differentiate compensated versus decompensated cirrhosis. A CTP score ≥7 or any history of decompensation disqualifies these patients for the simplified treatment algorithm. Recommended pretreatment assessment also includes clinical evaluation for ascites and hepatic encephalopathy, and ultrasound imaging of the liver within the prior 6 months to evaluate for HCC and subclinical ascites; any of these clinical or imaging findings are contraindications to use of the simplified treatment algorithm. See the online HCV guidance for treatment and management of persons with decompensated cirrhosis. Other circumstances and comorbid conditions that disqualify a patient for use of the simplified treatment algorithm mirror those described in the previous section and are shown in Figure 3. Similarly, medication reconciliation, assessment for potential drug-drug interactions, and pretreatment education and counseling are the same as for treatment-naive patients without cirrhosis (see Figure 3).

Pretreatment laboratory assessment of patients with compensated cirrhosis eligible for use of the simplified treatment algorithm includes CBC, INR, a hepatic function panel, and eGFR within 3 months of initiating antiviral therapy. Quantitative HCV RNA, HIV antigen/antibody, and HBsAg tests are recommended any time prior to initiating DAA therapy. Notably, pretreatment genotype testing is recommended if sofosbuvir/velpatasvir therapy is planned because of the necessity for baseline RAS testing in persons with cirrhosis and genotype 3 infection.

Because new-onset hepatic decompensation develops rarely during HCV DAA treatment, clinicians may opt for on-treatment blood tests to detect liver injury. Patients who experience deteriorating hepatic laboratory parameters and/or new-onset jaundice, ascites, encephalopathy, or other new liver-related signs or symptoms should promptly see a liver specialist. On-treatment monitoring of blood glucose levels and INR are recommended for persons on diabetes medications or warfarin, respectively, with dosage adjustments as warranted (see previous section for a more detailed discussion).

Multiple rigorous clinical trials have demonstrated the safety⁽¹³⁹⁾ and high curative efficacy of glecaprevir/pibrentasvir^{(148, 174–177)} and sofosbuvir/velpatasvir^{(160, 162–164, 171, 178–180)} among treatment-naive adults with compensated cirrhosis, regardless of HCV genotype. These findings have been confirmed in real-world cohort studies for both glecaprevir/pibrentasvir^{(153, 165–167, 181–183)} and sofosbuvir/velpatasvir.^{(169, 170, 184–189)} Based on these data, recommended regimens for adults eligible for the simplified treatment algorithm are 8 weeks of glecaprevir/pibrentasvir for patients with genotype 1–6, or 12 weeks of sofosbuvir/velpatasvir for those with genotype 1, 2, 4, 5, or 6. Pretreatment RAS testing is recommended for persons with genotype 3 because only those without a baseline NS5A Y93H RAS are eligible for a 12-week course of sofosbuvir/velpatasvir. Patients with genotype 3 and a baseline Y93H RAS should be treated with glecaprevir/pibrentasvir or an alternative regimen (see the online HCV guidance).

HCV-RNA and aminotransferase testing are recommended 12 or more weeks after completion of DAA therapy to assess treatment response. Undetectable HCV RNA represents SVR and virologic cure. Ultrasound surveillance for HCC (with or without alpha-fetoprotein testing) every 6 months after treatment completion is recommended for patients with cirrhosis, regardless of achieving SVR.⁽⁷⁸⁾ Upper endoscopic surveillance for esophageal varices is recommended, consistent with AASLD guidance on portal hypertensive bleeding in cirrhosis.⁽¹⁹⁰⁾ Advise all patients to abstain from alcohol use to reduce the risk of liver disease progression. Risk-reduction counseling is recommended for persons with ongoing HCV risk factors. HCV-RNA testing annually or anytime an increase in hepatic aminotransferase levels occurs is also recommended for these persons. Recurrent HCV viremia after attainment of SVR represents either reinfection or a relapse.^{(172, 173)} With reinfection, the treatment approaches are identical to those for initial treatment. If relapse is suspected or cannot be ruled out, such patients should be managed by clinicians with expertise in managing HCV treatment failure. Persons who attain SVR but experience persistently elevated hepatic aminotransferase levels require evaluation for other causes of liver disease.

Individuals in whom initial treatment fails should be evaluated by a specialist for retreatment, which often proves successful. See the online HCV guidance for management and antiviral regimen recommendations for treatment-experienced persons. If retreatment is delayed or not feasible, assessment for liver disease progression every 6–12 months is recommended as specified in Figure 3.

Recommendations

• 19

  All children born to women with acute or chronic hepatitis C should be tested for HCV infection. Antibody-based testing is recommended at or after 18 months of age. (I, A)

• 20

  Testing with an HCV-RNA assay can be considered in the first year of life, but the optimal timing of such testing is unknown. (IIa, C)

• 21

  Testing with an HCV-RNA assay can be considered as early as 2 months of age. (IIa, B)

• 22

  Repetitive HCV-RNA testing prior to 18 months of age is not recommended. (III, A)

• 23

  Children who are anti-HCV positive after 18 months of age should be tested with an HCV-RNA assay after age 3 to confirm chronic hepatitis C infection. (I, A)

• 24

  The siblings of children with vertically acquired chronic hepatitis C should be tested for HCV infection, if born from the same mother. (I, C)

  The HCV guidance panel recommends HCV-antibody testing at age ≥18 months for children born to women with HCV infection. Earlier antibody testing is not recommended due to maternal anti-HCV, which can persist in the infant’s serum for up to 18 months.^{(206, 207)} For infants with a positive HCV-antibody test at or after 18 months of age, the HCV guidance panel recommends HCV-RNA testing at age ≥3 years to determine chronic infection versus spontaneous viral clearance. Approximately 25%−50% of vertically infected infants spontaneously resolve HCV infection by 4 years of age,^{(191, 200, 208–211)} although spontaneous viral clearance can occur later in childhood.^(212–214)

  HCV-RNA testing can be considered in the first year beginning at 2 months of age, particularly in the setting of concern about loss to follow-up. Detectable HCV RNA during the first year of life reliably correlates to anti-HCV positivity at 18 months.⁽²¹⁵⁾ Repetitive HCV-RNA testing prior to 18 months of age is not recommended. Hepatitis C screening is indicated for siblings of children with vertically acquired, chronic HCV infection if born to the same mother and not previously tested for HCV infection.

Recommendations

• 25

  Parents should be informed that hepatitis C is not transmitted by casual contact and, as such, children with HCV infection do not pose a risk to other children and can participate in school, sports, and athletic activities, and engage in all other regular childhood activities without restrictions. (I, B)

• 26

  Parents should be informed that universal precautions should be followed at school and in the home of children with HCV infection. Educate families and children about the risk and routes of HCV transmission, and the techniques for avoiding blood exposure, such as avoiding the sharing of toothbrushes, razors, and nail clippers, and the use of gloves and dilute bleach to clean up blood. (I, B)

  Children with HCV infection often face discrimination and stigmatization in school and child-care settings, usually driven by public misconceptions about contracting hepatitis C. Further, well-intentioned parents and caregivers may limit the activities of a child with HCV infection due to concerns about their health.^{(216, 217)} Clinicians caring for these children should counsel and assure parents that their child poses no threat to others because HCV is not transmitted by casual contact in the absence of blood exposure. Children with HCV infection can and should fully participate in school and extracurricular activities of their choosing without restrictions. Educate parents and appropriately aged children and adolescents about how to prevent HCV transmission in the home and at school. This includes implementing universal precautions for preventing transmission of bloodborne pathogens, covering open wounds, cleaning blood-contaminated surfaces with dilute bleach, and avoiding sharing personal hygiene items that might be contaminated with blood, such as toothbrushes, razors, nail clippers, and so on (see Table 2).

  Sexual transmission of HCV occurs but inefficiently except among men with HIV infection who have unprotected sex with men.^(218–220) Encourage adolescents with HIV/HCV coinfection and those with multiple sexual partners and/or sexually transmitted infections (STIs) to use barrier precautions to prevent transmission of HCV and other STIs. Counsel other adolescents with HCV infection that the risk of sexual transmission is low, but barrier precautions are recommended to prevent HIV and other STIs.

Recommendations

• 27

  Routine liver biochemistries at initial diagnosis and at least annually thereafter are recommended to assess for HCV disease progression. (I, C)

• 28

  Appropriate vaccinations are recommended for children with HCV infection who are not immune to HBV and/or HAV to prevent these infections. (I, C)

• 29

  Disease severity assessment via routine laboratory testing and physical examination, as well as use of evolving noninvasive modalities (i.e., transient elastography, imaging, or serum fibrosis markers) is recommended for all children with chronic hepatitis C. (I, B)

• 30

  Children with cirrhosis should undergo HCC surveillance and endoscopic surveillance for varices per standard recommendations. (I, B)

• 31

  Hepatotoxic drugs should be used with caution in children with chronic hepatitis C after assessment of potential risks versus benefits of treatment. Use of corticosteroids, cytotoxic chemotherapy, or therapeutic doses of acetaminophen are not contraindicated in children with chronic hepatitis C. (II, C)

• 32

  Solid organ transplantation and bone marrow transplantation are not contraindicated in children with chronic hepatitis C. (II, C)

• 33

  Anticipatory guidance about the potential risks of alcohol for progression of liver disease is recommended for adolescents with chronic HCV infection and their families. Abstinence from alcohol and interventions to facilitate cessation of alcohol consumption, when appropriate, are advised for all persons with chronic HCV infection. (I, C)

  The initial assessment of children with chronic HCV infection includes exclusion of other causes of liver disease, assessment of HCV disease severity, and detection of extrahepatic manifestations of HCV (uncommon in children). Children with chronic HCV infection usually appear clinically well on physical examination; hepatomegaly occurs in ≤10% of patients.^{(221, 222)} Assessment of hepatic laboratory parameters, including albumin, aminotransferase levels, total bilirubin, INR, and platelet count, is recommended every 6–12 months. Persistently or intermittently elevated hepatic aminotransferase levels occur in approximately 50% of children with chronic HCV infection.⁽²²¹⁾ Serum aminotransferase levels, however, do not consistently correlate with HCV liver disease severity.⁽²²³⁾ Laboratory testing for concomitant infections with HBV (i.e., HBsAg, anti-HBc, and anti-HBs testing) and HIV (i.e., anti-HIV), and immunity to HAV (i.e., anti-HAV IgG) are also recommended due to shared risk factors and the need to vaccinate nonimmune children against HAV and HBV. Serum fibrosis markers hold promise to assess hepatic disease severity but require further validation in the pediatric population.^(224–226)

  For pediatric patients with suspected advanced liver disease, initial assessment using liver ultrasound imaging to evaluate for splenomegaly and/or venous collaterals is recommended to avoid ionizing radiation exposure. Although liver biopsy remains the gold standard to assess inflammation grade and fibrosis stage, sampling variability and potential adverse events (e.g., bleeding) are problematic.^(227–231) Additionally, most clinicians and patients (or their parents) prefer noninvasive alternatives to determine the presence or absence of cirrhosis, particularly in the pediatric population. Ultrasound-based, liver elastography appears increasingly promising for monitoring children and adolescents with chronic HCV infection.^(232–236)

  HCV-related liver disease generally progresses more slowly in children and adolescents compared to adults, although disease progression is unpredictable.^{(191, 221, 237–239)} Despite a paucity of data evaluating risk factors for HCV disease progression in the pediatric population, children with comorbid conditions (e.g., obesity with nonalcoholic fatty liver disease, congenital heart disease with elevated right heart pressures, and HIV and/or HBV coinfection) and those receiving hepatotoxic drugs require careful monitoring.^{(87–90, 191, 226, 240)}

  Advanced HCV-related liver disease develops infrequently in children and teens, usually occurring more than 30 years after initial infection.^(241–243) Cirrhosis is uncommon and HCC even more rare, occurring almost exclusively in those with cirrhosis.^{(213, 214, 242, 244–253)} Limited evidence suggests that children with chronic hepatitis C and a history of childhood leukemia may be at increased risk of developing HCC.^{(254, 255)} The HCV guidance panel recommends HCC surveillance using liver ultrasound imaging (with or without alpha-fetoprotein testing) every 6 months for pediatric HCV patients with cirrhosis, consistent with AASLD guidance for HCC surveillance in adults.⁽⁷⁸⁾ A baseline endoscopy to detect esophageal varices and every 3 years thereafter (in the absence viral clearance) is advisable for these patients. Successful HCV DAA therapy substantially reduces the risk for cirrhosis complications.^{(256, 257)}

  In children with HCV-related advanced fibrosis or cirrhosis, medications known to accelerate hepatic fibrosis (e.g., methotrexate) should be avoided, if possible. Although corticosteroids and other immunosuppressants may enhance HCV replication, they are not contraindicated in children with HCV infection and should be prescribed for appropriate indications based on the overall risks versus benefits. Notably, icteric flares of HCV—as reported in children and adults with chronic HBV infection—have not been reported in children receiving an organ transplant or cytotoxic chemotherapy. Although underlying liver disease is a risk factor for the development of hepatic veno-occlusive disease following bone marrow transplantation,^{(258, 259)} chronic HCV infection should not delay this therapy.

  No dosage adjustments are necessary for commonly prescribed medications such as antimicrobial, antiepileptic, and cardiovascular agents. Nonsteroidal anti-inflammatory drugs and aspirin should be avoided, if possible, for patients with cirrhosis and esophageal varices due gastrointestinal bleeding and nephrotoxicity risks. Acetaminophen is a safe and effective analgesic for children and adolescents with chronic HCV infection when dosed per packaging recommendations.

  Alcohol abstinence is strongly advised to reduce the risk for liver disease progression.^{(61, 63, 64, 66–72)} Similarly, counsel appropriately aged, untreated pediatric patients and their parents about the importance of maintaining a healthy body weight due to the deleterious effects of insulin resistance on HCV-related fibrosis progression.^(260–271)

Recommendations

• 34

  DAA treatment with an approved regimen is recommended for all children and adolescents with HCV infection aged ≥3 years as they will benefit from antiviral therapy, regardless of disease severity. (I, B)

• 35

  The presence of extrahepatic manifestations—such as cryoglobulinemia, rashes, and glomerulonephritis—as well as advanced fibrosis should lead to early antiviral therapy to minimize future morbidity and mortality. (I, C)

  Although advanced HCV-related liver disease occurs uncommonly in children and adolescents, hepatic fibrosis progresses over time and complications may develop during early adulthood. The rationale for treating persons with HCV infection in the pediatric population mirrors that for adults, i.e., to reduce disease-related morbidity and mortality. Additionally, curative DAA therapy during childhood or adolescence supports the HCV treatment as transmission prevention paradigm, a pillar of the 2017 NASEM hepatitis C elimination strategy.⁽⁴⁾ The extension of pediatric HCV antiviral treatment to 3- through 11-year-olds comes at a critical inflexion point in the hepatitis C epidemic, given the recent increase in HCV infection among women of childbearing age^(272–275) and the fact that an estimated 29,000 women with HCV infection gave birth each year from 2011 to 2014.⁽¹⁸⁾

Recommendations for Treatment-Naive and Interferon-Experienced Patients

• 36

  An 8-week course of the daily fixed-dose combination of glecaprevir (300 mg)/pibrentasvir (120 mg) is recommended for treatment-naive adolescents aged ≥12 years or weighing ≥45 kg with any HCV genotype, without cirrhosis or with compensated cirrhosis. (I, B)

• 37

  A 12-week course of the combination of ledipasvir/sofosbuvir (weight-based dosing, see Table 4) is recommended for treatment-naive or interferon-experienced children aged ≥3 years with HCV genotype 1, 4, 5, or 6 infection, without cirrhosis or with compensated cirrhosis. (I, B)

  The high rate of HCV clearance with DAA regimens previously demonstrated in adults are increasingly being replicated in the pediatric population. Eight weeks of the daily fixed-dose combination of glecaprevir (300 mg)/pibrentasvir (120 mg) gained FDA approval for use in treatment-naive or interferon-experienced adolescents aged ≥12 years or weighing ≥45 kg with any HCV genotype infection, without cirrhosis or with compensated cirrhosis (Child-Pugh A). Although the registration trial included only adolescents with genotype 1 through 4,⁽²⁷⁶⁾ glecaprevir/pibrentasvir garnered FDA approval for all genotypes based on the safety and efficacy of the regimen demonstrated in adults.^{(148–150, 152–157, 165–167, 277)} The recommendations for use of glecaprevir/pibrentasvir in treatment-experienced adolescents is also based on clinical trial data from adults.^{(154, 156, 176, 278–280)} Given its pangenotypic activity, and safety and efficacy records in adults, the HCV guidance panel recommends glecaprevir/pibrentasvir as the first choice for adolescent HCV treatment. Coadministration of carbamazepine, efavirenz-containing regimens, and St. John’s wort should be avoided because these compounds may decrease circulating concentrations of glecaprevir and pibrentasvir.

  In August 2019, the FDA approved an expansion of pediatric indications for ledipasvir/sofosbuvir to include the 3- through 11-year-old age group in addition to the ≥12 years adolescent group for specific clinical scenarios. Dosing is weight based (see Table 4). Twelve weeks of ledipasvir/sofosbuvir is recommended for treatment-naive children and adolescents aged ≥3 years with genotype 1, 4, 5, or 6, without cirrhosis or with compensated cirrhosis (Child-Pugh A). This regimen is also recommended for interferon-experienced (± ribavirin, with or without an HCV protease inhibitor) children and adolescents aged ≥3 years with genotype 1 or 4. A 12-week course is recommended for patients without cirrhosis; 24 weeks is recommended for those with compensated cirrhosis. Three clinical trials supporting the approval of ledipasvir/sofosbuvir in the pediatric population aged ≥3 years demonstrated high SVR12 rates comparable to those observed in adults.^(281–283) Limited real-world data further corroborate these findings.^{(284, 285)}

  In September 2019, the FDA newly approved weight-based sofosbuvir plus ribavirin for treatment-naive and interferon-experienced (± ribavirin) children aged ≥3 years with genotype 2 or 3, without cirrhosis or with compensated cirrhosis (Child-Pugh A). A 12-week course is recommended for pediatric patients without cirrhosis and 24 weeks is recommended for those with compensated cirrhosis (see the online HCV guidance for dosing recommendations). The registration trial conducted in children aged 3 to <12 years demonstrated an SVR12 of 98%.⁽²⁸⁶⁾ The use of sofosbuvir plus ribavirin is further supported by clinical trial data involving adolescents⁽²⁸⁷⁾ and adults with genotype 2 or 3 infection.^(288–291) At the time of manuscript preparation, sofosbuvir (plus ribavirin) remained the only FDA-approved DAA for children 3 through 11 years with genotype 2 or 3 infection. However, recent clinical trials evaluating weight-based dosing of sofosbuvir/velpatasvir⁽²⁹²⁾ and glecaprevir/pibrentasvir⁽²⁹³⁾ are expected to lead to FDA approval for children aged 3 through 11 years. The HCV guidance panel recommends awaiting approval of a pangenotypic regimen unless there is a compelling need for immediate antiviral treatment of children aged 3 through 11 years with genotype 2 or 3 infection.

  DAA-experienced pediatric HCV patients are rarely encountered in clinical practice. Due to a paucity of data in the pediatric population, DAA-experienced children and adolescents with HCV infection should be treated using the adult HCV guidance while under the supervision of a pediatric HCV specialist. Similarly, decompensated cirrhosis and recurrent HCV after liver transplantation are rare clinical scenarios; children and adolescents with these conditions require specialty care. See the online HCV guidance for additional information about treatment of these children and adolescents.

  As with adults, testing for active HBV infection (i.e., HBsAg, anti-HBc, and anti-HBs) is recommended prior to initiating HCV DAA therapy in pediatric patients due to the risk for HBV reactivation during or after treatment.^{(92, 294, 295)} Additionally, on-treatment and post-treatment glucose monitoring for hypoglycemia in children and adolescents with diabetes and INR monitoring in those taking warfarin is recommended due to potential alterations in dose-response relationships associated with DAA-related HCV viral clearance.^(141–146)

Recommendation

• 38

  HCV-antibody and HCV-RNA testing are recommended when acute HCV infection is suspected due to known exposure, clinical presentation, or elevated aminotransferase levels (see Figure 4). (I, C)

  HCV RNA typically becomes reliably detectable within 2–3 weeks after viral exposure^(306–309); HCV antibody seroconversion among immunocompetent persons typically occurs 2–3 months after exposure, on average.^(308–311) Therefore, the best laboratory evidence to support a diagnosis of acute HCV infection is a positive HCV-RNA test in the setting of a negative HCV-antibody test (identification during the seronegative window period) or a positive HCV-antibody test after a prior negative anti-HCV test (seroconversion).^{(51, 52, 312)} Rarely, these approaches may be misleading such as in immunosuppressed individuals with impaired antibody production.^{(58, 313, 314)}

  Laboratory-based diagnosis of acute HCV infection is most straightforward when there has been a discrete, known or suspected exposure (e.g., after new onset or a change in drug injection practice, a percutaneous needlestick exposure to HCV-infected blood, a potentially nonsterile tattoo, or sexual contact). Baseline HCV-antibody and HCV-RNA testing should be performed within 48 hours of the exposure to document baseline HCV infection status (see Figure 4).

  If baseline testing is negative, repeat testing for HCV antibody and HCV RNA is recommended. The frequency can be tailored based on management objectives (e.g., monthly testing to identify and treat acute infection). If the baseline HCV-antibody test is positive but HCV RNA is undetectable, repeat HCV-RNA and ALT testing is recommended to identify acute reinfection. When baseline HCV-antibody and HCV-RNA testing are both positive, the person most likely already has chronic infection from a prior exposure.

  Individuals suspected of having acute HCV infection often do not have a discrete exposure and/or have no prior baseline testing, making a definitive diagnosis of acute infection more challenging (see Table 5). Acute infection should be suspected if there is a new rise in the ALT level without an alternative cause.^{(315, 316)} Acute infection should also be suspected when there are low (especially <10⁴ IU/mL) or fluctuating (>1 log₁₀ IU/mL) HCV-RNA levels, or spontaneous clearance during follow-up. These patterns do not commonly occur outside of the acute phase of HCV infection.^{(300, 301, 317)} Patients suspected of having acute HCV infection also require laboratory evaluation to exclude other or coexisting causes of acute hepatitis (e.g., HAV, HBV, hepatitis delta virus superinfection if chronically infected with HBV, hepatitis E virus [in the correct clinical scenario], and autoimmune hepatitis).⁽³¹⁸⁾ HIV testing is also recommended.

Recommendations

• 39

  After the initial diagnosis of acute HCV with viremia (defined as quantifiable RNA), HCV treatment should be initiated without awaiting spontaneous resolution. (I, B)

• 40

  Counseling is recommended for patients with acute HCV infection to avoid hepatotoxic insults, including hepatotoxic drugs (e.g., acetaminophen) and alcohol consumption, and to reduce the risk of HCV transmission to others. (I, C)

• 41

  Referral to an addiction medicine specialist is recommended for patients with acute HCV infection related to substance use. (I, B)

  The HCV guidance panel newly recommends initiating DAA therapy upon initial diagnosis of acute HCV infection without awaiting possible spontaneous clearance (i.e., a test and treat strategy). Real-world data demonstrate a reduction in HCV viremia incidence and prevalence with unrestricted access to HCV therapy.^{(305, 319)} Mathematical modeling studies also suggest that scaling up DAA treatment can reduce HCV incidence and prevalence, especially among populations at highest risk of onward transmission (e.g., MSM and PWID).^{(303, 320–322)} Additionally, delay introduced by waiting for spontaneous clearance may increase the number of patients lost to follow-up.

  Counseling persons with acute HCV infection to reduce behaviors that could result in virus transmission (e.g., sharing injection equipment and engaging in high-risk sexual practices) is recommended. Because the risk of transmission of other bloodborne, sexually transmitted infections (e.g., HIV and HBV) is higher in the acute phase of infection, some experts counsel persons with acute HCV to consider using barrier precautions, even in a stable monogamous relationship. For persons with acute HCV infection who have a history of recent injection drug use, referral to harm reduction services and an addiction medicine specialist is recommended as needed.^(323–326)

  Monitoring with hepatic panels (ALT, AST, bilirubin, and INR in the setting of an increasing bilirubin level) is recommended at 2-week to 4-week intervals until resolution of acute hepatitis C.⁽³¹⁶⁾ Hepatic laboratory parameters typically improve rapidly with antiviral treatment. Alteration of dosages of concomitant medications that are metabolized by hepatic enzymes is unnecessary unless there is concern for developing acute liver failure (e.g., increasing bilirubin level and prolongation of INR). Acetaminophen and alcohol consumption should be avoided during acute HCV infection.^(327–329)

  Patients with acute HCV infection rarely require hospitalization unless nausea and vomiting are severe. Although acute liver failure is very rare (<1%), it represents a serious and life-threatening complication of acute HCV infection. Patients with an INR >1.5 and those who exhibit any signs of acute liver failure (e.g., hepatic encephalopathy) should be immediately referred to a liver transplant center. Use of HCV antiviral regimens in acute liver failure should be managed by a clinician experienced in HCV treatment, ideally in consultation with a liver transplant specialist.

  HCV infection spontaneously clears in 20%−50% of untreated patients.⁽³³⁰⁾ Clearance of acute HCV infection usually occurs within 6 months of the estimated time of infection. Only 11%–14% of those who remain viremic at 6 months spontaneously clear the infection at a later time.^{(331, 332)} Predictors of spontaneous clearance include presentation with jaundice, elevated ALT, HBsAg positivity, female sex, younger age, genotype 1 infection, and host genetic polymorphisms, most notably those near the IL28B gene.^{(330, 333)}

  Patients who experience spontaneous clearance do not require antiviral therapy. They do, however, require counseling about the risk of reinfection and testing at least annually for this development in the setting of ongoing risk behaviors. Notably, transient suppression of viremia sometimes occurs in persons with acute HCV infection, even among those who progress to chronic infection. Thus, a single undetectable HCV-RNA test result is insufficient to declare spontaneous clearance.^{(300, 333, 334)}

Recommendation

• 42

  Due to high efficacy and safety, the same regimens that are recommended for chronic HCV infection are recommended for acute infection. (IIa, C)

Data are emerging regarding treatment of acute HCV infection with abbreviated courses of DAA regimens in both HCV monoinfection and HIV/HCV coinfection.^(335–338) There are presently insufficient data, however, to recommend abbreviated courses of any approved DAA regimens. Until more definitive data are available, recommended treatment is as described for chronic hepatitis C infection in the online HCV guidance. Pangenotypic regimens, as recommended in the simplified HCV treatment section, represent the preferred choice for eligible patients. For patients who are ineligible for simplified HCV treatment, genotyping may be considered to guide DAA regimen selection.

Recommendations

• 43
  Informed consent should include the following elements (I, C):

  • Risk of transmission from an HCV-viremic donor (and with a U.S. Public Health Service defined increased risk donor, the potential risks for other viral infections)
  • Risk of liver disease if HCV treatment is not available or treatment is unsuccessful
  • Benefits, specifically reduced waiting time and possibly lower waiting list mortality
  • Unknown long-term consequences (hepatic and extrahepatic) of HCV exposure (even if cure is attained)
  • Risk of allograft failure
  • Risk of HCV transmission to partner

• 44
  Transplant centers should have a programmatic strategy to (I, C):

  • Document informed consent
  • Assure access to HCV treatment and retreatment(s), as necessary
  • Ensure long-term follow-up of recipients (beyond SVR12)

  The informed consent process for HCV-negative patients contemplating accepting an organ from an HCV-viremic donor must address not only the potential benefits and risks of the procedure itself but also the known HCV-specific risks as well as long-term uncertainties. Given the mismatch between the number of organ transplantation candidates and the pool of available organs, willingness to accept an allograft from an HCV-viremic donor can reduce waitlist time^{(345, 346)} and improve access to transplantation,⁽³⁴⁷⁾ thereby reducing the risk of dying while awaiting an available organ.^(348–350)

  To make an informed decision to consent to accepting an organ from an HCV-viremic donor, the recipient needs to understand the high risk of HCV infection. All donors undergo HCV-antibody testing and nucleic acid testing for HCV RNA. Donors who are HCV antibody positive and HCV RNA negative pose a very low risk of HCV transmission to the recipient.^(351–353) Rarely, high risk donors with very recent HCV exposure who are anti-HCV positive and HCV RNA negative may pose a transmission risk.⁽³⁵⁴⁾ These increased risk donors are identified according to guidelines issued by the U.S. Public Health Service.⁽³⁵⁵⁾ Increased risk donors may also pose a risk for HIV and HBV transmission depending on their specific risk factors. Patients who receive an allograft from an increased risk donor require monitoring after transplantation to detect HCV transmission^{(353, 355)} as well as possible HBV and/or HIV infection if the donor was at increased risk for these infections. HCV-viremic donors pose the highest risk for HCV transmission to allograft recipients.

  Transplant recipients need to understand the risks conferred on them in the event of iatrogenic HCV infection from the allograft. This includes the necessity of HCV antiviral therapy and the risk of liver disease if such treatment is unavailable or unsuccessful. Additionally, there is a risk of DAA-associated allograft rejection and possible loss,^(356–362) and/or reduced allograft function.^{(361, 363–366)} Because use of allografts from HCV-viremic donors in HCV-negative recipients is a recent development in transplant medicine, there are no data on possible long-term hepatic and extrahepatic adverse effects associated with HCV exposure, even among those cured of the infection. Allograft recipients who are HCV viremic can potentially sexually transmit the virus to their partner(s), particularly among MSM.^{(74, 367–372)}

  The HCV guidance panel recommends that all programs performing HCV-viremia discordant solid organ transplantations have a strategy to execute and document a rigorous informed consent process; assure access to HCV treatment and retreatment, as needed; and ensure long-term follow-up of organ recipients to monitor for potential late consequences of HCV exposure and allograft function.

Recommendation Regarding Timing of DAA Therapy

• 45

  Prophylactic/preemptive DAA therapy with a pangenotypic regimen is recommended. (II, B)

  Recommendations for DAA Therapy

• 46

  An 8-week course of the pangenotypic daily fixed-dose combination of glecaprevir (300 mg)/pibrentasvir (120 mg) is recommended. (I, C)

• 47

  A 12-week course of the pangenotypic daily fixed-dose combination of sofosbuvir (400 mg)/velpatasvir (100 mg) is recommended. (I, C)

• 48

  A 12-week course of the daily fixed-dose combination of ledipasvir (90 mg)/sofosbuvir (400 mg) is recommended for patients with genotype 1, 4, 5, or 6 only. (I, C)

  Initiation of DAA therapy for HCV-negative recipients of an allograft from an HCV-viremic donor can occur prophylactically/preemptively (i.e., perioperatively without confirmation of HCV viremia in the recipient) or reactively after documentation of HCV viremia. The goal is to undertake DAA therapy as early as clinically possible to avoid the development of acute hepatitis and other complications of HCV infection. Emerging data suggest that initiating prophylactic/preemptive DAA therapy before viremia occurs reduces the likelihood of complications, such as fibrosing cholestatic hepatitis.^{(359, 373–376)} The prophylactic/preemptive approach may also allow for a shorter duration of DAA treatment,^{(359, 377)} although this is not currently recommended outside of a clinical trial setting.

  Because genotyping of HCV-viremic donors is not routinely performed, only a pangenotypic DAA regimen (i.e., glecaprevir/pibrentasvir or sofosbuvir/velpatasvir) should be used if opting for a prophylactic/preemptive treatment approach. With the reactive treatment approach, genotyping can be used to guide DAA regimen selection if a pangenotypic regimen is not utilized. Although clinical trial data demonstrate the safety and efficacy of elbasvir/grazoprevir among HCV-negative kidney transplant recipients of allografts from HCV-viremic donors,^(378–381) it is recommended as an alternative regimen due to the necessity for baseline RAS testing and the need for addition of ribavirin to the regimen if RASs are present.

  Several other important considerations should be taken account when selecting a DAA regimen for these patients. Protease inhibitors should be avoided in the presence of moderate to severe liver dysfunction (i.e., Child-Pugh B or C).⁽³⁸²⁾ Assessment of drug-drug interactions is crucial as some medications are contraindicated or not recommended during DAA therapy (e.g., high-dose proton pump inhibitors [twice daily dosing], amiodarone [contraindicated with sofosbuvir-inclusive regimens], and certain statins [eg, atorvastatin], among others). Importantly, complex interactions occur between DAAs and calcineurin inhibitors.^(383–388) Coadministration of elbasvir/grazoprevir and cyclosporine leads to a 15-fold increase in grazoprevir and a 2-fold increase in elbasvir area under the concentration-time curve;⁽³⁸⁹⁾ this DAA regimen and immunosuppressant combination should be avoided. A 40%−50% increase in tacrolimus level is predicted with coadministration of elbasvir/grazoprevir⁽³⁸⁹⁾; no dosing adjustments are anticipated but tacrolimus levels should be monitored. Please see the online HCV guidance for additional information about drug-drug interactions between DAAs and immunosuppressants as well as other medications.

  Limited short-term data from liver,^{(340, 357, 390, 391)} kidney,^{(358, 378–380, 390–394)} heart,^{(359, 373, 390, 395)} and lung^{(359, 374)} transplant programs performing solid organ transplantations involving HCV-viremic donors and HCV-negative recipients are encouraging. However, the overall number of published cases is limited and treatment approaches varied. Known risks include DAA treatment failure with emergence of complex RASs and possible severe or rapidly progressive liver disease.^{(358, 374, 396, 397)} Due to the limited, heterogeneous experience to date and lack of long-term safety data, strong consideration should be given to performing these transplantations under institutional review board approved protocols as recommended by the American Society of Transplantation consensus panel.⁽³⁵³⁾