1 Lesson 1: Chronic Hepatitis C Virus InfectionCore Competency 3: Screening, Testing, Diagnosis, and Clinical Evaluation of HCV Infection among PLWH Lesson 1: Chronic Hepatitis C Virus Infection PLWH = People Living with HIV July 2017

2 Lesson Objectives By the end of this lesson, the learner will be able to: Define chronic HCV Screen and diagnose chronic HCV Identify factors that increase morbidity and mortality associated with chronic HCV Recognize clinical manifestations of chronic HCV Evaluate chronic HCV, including taking a history, performing a physical examination, and ordering laboratory and imaging studies

3 Two Cases Mr. B. Boomer is a 60-year-old man with a past medical history of diabetes and hypertension. He presents for an annual physical and health maintenance evaluation. Mr. Y. Man is a 21-year- old man who identifies as bisexual. He was recently diagnosed with HIV during an ED evaluation for an influenza-like illness. He has been referred to clinic for HIV evaluation and care. These two cases illustrate two very different individuals who warrant HCV screening for different reasons.

4 Commonality? Two individuals with different health histories and needsBoth warrant HCV screening While each of these individuals have different medical histories and have different reasons for presenting for health care, they both meet criteria for HCV screening and testing. Should these individuals be diagnosed with HCV, the approach and content of clinical evaluation will be very similar for each individual, though the findings may differ significantly.

5 Screening RecommendationsMr. B. Boomer was born between 1945 and 1965. Mr. Y. Man is HIV infected. The CDC recommends that all people born between 1945 and 1965 (Baby Boomers) receive at least once screening test for HCV infection. Approximately 75% of those infected with HCV were born in these years. This group is often referred to as the “birth cohort.” All PLWH should be screened for HCV infection, as well.

6 Definition of Chronic HCV1-3Infection with HCV and detectable/quantifiable HCV RNA at least 6 months after infection For many patients, the initial date of HCV infection cannot be identified Active HCV infection is defined when infection with HCV is detected with a detectable or quantifiable HCV ribonucleic acid (RNA) test. HCV infection is defined as chronic when HCV RNA remains detectable >6 months from the time a person is infected, though this may be difficult to define in many clinical cases do not have defined exposures. The next lesion will address acute HCV, which includes active infection <6 months from the time a person is infected. In the absence of symptoms, significant fluctuations in liver aminotransferases, significant fluctuations in HCV RNA, or a defined exposure, many HCV infections are considered chronic at the time of initial evaluation.

7 Screening and Diagnosis1-4Anti-HCV test Antibody negative; no concerns for acute infection No further testing required unless risk exposures in future Antibody negative; acute infection suspected Evaluate with sensitive RNA test Antibody positive Confirm with sensitive RNA test RNA negative and no concerns for acute infection No further testing required RNA negative and acute infection suspected Repeat RNA test in near future Screening is most commonly performed using an anti-HCV test, though persons with specific risk exposures within the past 3-6 months may also be screened with HCV RNA testing. Initial screening includes an anti-HCV test (i.e. HCV antibody serologic testing) If a HCV antibody is abnormal (i.e. positive), HCV RNA should be obtained for further evaluation. Persons acutely infected with HCV may have falsely negative anti-HCV tests or transiently negative HCV RNA tests. See Lesson 3.2 for further details. In most persons with a positive anti-HCV antibody but negative HCV RNA, no further testing is necessary without recent or defined exposures. As noted previously, acute HCV infections may have transiently negative HCV RNA; as such, repeat testing may be appropriate in these patients. Many sites have adopted “reflex testing” to reduce burden and additional decision making by providers. In reflex testing, a positive antibody results automatically triggers the performance of a RNA test without an additional provider order. This is an example of best practice, as many persons who have a positive antibody never get a confirmatory RNA test performed if testing requires subsequent provider review, provider order, and a repeat laboratory test.

8 Risk Factors for HCV Infection1-3Risk Exposures Persons on long-term hemodialysis Persons with percutaneous/ parenteral exposures Occupational health exposures Children born to HCV-infected women Transfusion/organ recipient prior to July 1992 Clotting factor concentrate recipients prior to 1987 Persons ever incarcerated PLWH Risk Behaviors Injection drug use (current or ever) Intranasal illicit drug use Sexually active individuals considering PrEP for HIV Birth Cohort Persons born between 1945 and 1965 Other Groups Unexplained chronic liver disease and/or chronic hepatitis Solid organ donors (deceased and living) PrEP = Pre-Exposure Prophylaxis HCV risk factors fall into three major groups: risk exposures; risky behaviors; and the birth cohort. Individuals infected with HIV are at risk for having been exposed to HCV in the same way, whether by blood or body fluid contact. Thus, HCV screening is indicated in this patient population Individuals considering pre-exposure prophylaxis due to risk of HIV transmission have demonstrated high rates of sexually transmitted infections and hepatitis C at time of initial evaluation; as such, they should be counselled regarding transmission risk for not only HIV and sexually transmitted infections but for HCV as well. Thus, HCV screening may be beneficial in this group. Individuals with undefined liver disease or solid organ donors are additional groups that should be considered for HCV screening.

9 Natural History of HCV Mono-infection5HCC = Hepatocellular carcinoma ESLD = End Stage Liver Disease Majority infected will develop chronic infection Minority will develop cirrhosis, hepatocellular carcinoma, and/or end-stage liver disease Most cirrhosis, hepatocellular carcinoma, and end-stage liver disease occurs after many years of infection Source: Hepatitis C Online (www.hepatitis.uw.edu)

10 Natural History of HCV Mono-infection5 (Continued)HCC = Hepatocellular carcinoma ESLD = End Stage Liver Disease Majority infected will develop chronic infection Minority will develop cirrhosis, hepatocellular carcinoma (HCC), and/or end-stage liver disease (ESLD) Most cirrhosis, HCC, and ESLD occurs after many years of infection

11 Natural History of HIV/HCV Co-infection6-10Increased likelihood of developing advanced fibrosis, cirrhosis, and end-stage liver disease Faster progression to fibrosis In some longitudinal cohorts, nearly 70% of HIV/HCV co-infected patients developed cirrhosis by the end of the study period. In one study, persons with HIV/HCV co-infection had liver fibrosis stages similar to persons with HCV mono-infection a decade older.

12 Immune-Related Extrahepatic Manifestations of HCV11,12Mixed cryoglobulinemia Autoantibody production (i.e., cryoglobulins, rheumatoid factor, and antinuclear, anticardiolipin, antithyroid and anti-smooth muscle antibodies) Cryoglobulinemic vasculitis B-cell non-Hodgkin lymphoma Sicca syndrome Arthralgia/myalgia Monoclonal gammopathies Polyarteritis nodosa Immune thrombocytopenia Extrahepatic manifestations are important to recognize for appropriate diagnosis, medical care, as well as risk/benefit analysis. Extrahepatic manifestations are increasingly being recognized as important endpoints for HCV infection. These extrahepatic manifestations may impact both persons with HCV mono-infection as well as HIV/HCV co-infection. Many extrahepatic manifestations are thought to be due to immune system activation and/or autoimmune activity triggered by HCV. Examples of these conditions are listed here. While it is not necessary for all individuals involved in HCV care to be familiar with the details related to extrahepatic manifestations, it is important to recognize that HCV’s impact goes far beyond liver outcomes.

13 Inflammation-Related Extrahepatic Manifestations of HCV11,12Diabetes mellitus type 2 Impaired quality of life Insulin resistance Polyarthritis/fibromyalgia Glomerulonephritis Cardiovascular disorders (i.e., stroke, ischemic heart disease) Renal insufficiency Fatigue Cognitive impairment Depression As noted in the previous slide, it is not necessary that all individuals involved in HCV care to be familiar with the details of extrahepatic manifestations, it is important to recognize that HCV’s impact goes far beyond liver outcomes. There are many major causes of morbidity and mortality noted above (including diabetes, ischemic heart disease, and stroke). The cost-benefit evaluation of HCV screening, diagnosis, evaluation, and treatment will need to incorporate these factors in the future as better outcome data becomes available related to these issues.

14 Risk Factors for HCV Disease Progression5,13HIV co-infection HBV co-infection Older age at time of infection Male gender Metabolic disease (including obesity and insulin resistance) Alcohol use Infection with HCV genotype 3 Individuals with these demographic factors, co-infections, or environmental exposures are more likely to progress to advanced liver disease, cirrhosis, end stage liver disease, and/or hepatocellular carcinoma. Unfortunately, many of these are not modifiable once HCV infection occurs. Social determinants of health may also impact the likelihood of appropriate screening, diagnosis, evaluation, and or treatment of persons with HCV, which in turn may also impact overall disease progression and outcomes. See core competency 6 for more on addressing barriers related to HCV care.

15 Linkage to Care1 All persons screening HCV positive warrant linkage to care and further evaluation Counseling, evaluation, treatment, and follow-up are all essential components of the continuum Linkage to care models and options vary locally, regionally, and nationally Limited data available on models of best practice Once a person screens positive for HCV, that person should be referred and linked to care for appropriate evaluation. It may not be feasible for individuals to receive counseling, education, and/or treatment in one setting. For instance, some persons have no access to expert providers who can provide evaluation and treatment. In these cases, education and counseling for persons screened positive for HCV can still benefit from education and counseling. There are wide varieties of linkage to care models. Options for referral also vary drastically in different regions. Local/county health departments, state health departments, patient advocacy groups (i.e. American Liver Foundation), and HIV service organizations may be appropriate resources to contact to determine linkage to care options.

16 Linkage to Care1 and TreatmentBarriers Strategies Comorbidities Competing priorities Loss to follow-up Perceived adverse effects Lack of knowledge regarding new therapies Lack of access to treatment Lack of experienced practitioners Payer restrictions on prescribing practices Counseling and education for persons living with HCV Co-localization of services Improved therapies Novel care delivery models System interventions for access Practitioner education and support for HCV treatment Advocacy to limit payer restrictions There are many barriers to linkage to care. Comorbidities such as medical comorbidities, substance use, and/or psychiatric disease may limit treatment. Competing priorities may make patients and practitioners prioritize other issues over HCV. Patients may be lost to follow-up after diagnosis when referred to a different setting for care. The length of treatment may be a barrier in some locations, though it is much shorter in most cases than it has been historically. Adverse effects may limit patients’ willingness to be treated and providers’ willingness to prescribe. Lack of knowledge among many providers (i.e. belief that interferon and/or ribavirin-based therapies remain primary therapeutic options despite their adverse effects) may limit enthusiasm for diagnosis and/or referral. The cost of treatment may limit accessibility due to patient, payer, or system factors. Practitioners may not feel comfortable or sufficiently skilled to prescribe HCV therapy. Some payers restrict prescribing to specific provider groups (i.e. gastroenterologists or infectious disease physicians) regardless of provider expertise or experience. There are multiple strategies that may be considered to effectively deliver care. Patient counseling and education is fundamental to many behavioral changes to improve care and reduce transmission risk. Co-localization of services may limit issues such as comorbidities, loss to follow-up, long treatment duration, as well as others. Improved therapies are shortening treatment duration and limiting side effects. Novel delivery models, such as HCV therapy at opioid replacement therapy clinics or directly observed therapy, may provide unique solutions. System interventions at patient, payer, pharmaceutical, and policy levels remain critical to empowering access. Practitioner education and support, through Project-ECHO, telemedicine, AETC, and other outlets, remain critical to addressing workforce dynamics. Advocacy to limit payer restrictions may be important in certain regions with certain payers.

17 Clinical Manifestations of HCV4,14Most persons with acute HCV are asymptomatic See Lesson 3.2 Many persons with chronic HCV (>6 months of infection) are asymptomatic before end-organ dysfunction occurs Nonspecific symptoms: Fatigue Joint pain Abdominal pain Depression Many patients with HCV remain asymptomatic. Most symptoms attributed to HCV are nonspecific. They may or may not be due to HCV even if the person is infected with HCV. Other symptoms have been reported to be related HCV, though they are not common. Persons with end stage liver disease and/or hepatocellular carcinoma related to HCV may become symptomatic from those processes.

18 Clinical Evaluation for HCVHistory Physical Exam Laboratory Assessment Staging The four key parts of the clinical evaluation of a person infected with HCV include taking a history, performing a physical exam, assessing laboratory studies, and determining the stage of liver fibrosis present.

19 History 4,14 Prior treatment for HCV Risk factors for infectionSymptoms, extrahepatic manifestations, and/or complications of liver disease Prior assessment for HCV Prior treatment for HCV What agents? Clinical response? Adverse effects? Medical comorbidities Other medical conditions, including co-infections Psychiatric disease Alcohol and drug use Medications being taken When obtaining a history from a person with HCV, risk factors for infection should be assessed in order to determine the likely modality of infection, duration of infection, and potential risk factors for reinfection in the future should the patient be cured with HCV therapy. While many patients may be asymptomatic, others may attribute clinical symptoms to HCV (whether HCV is truly the etiology or not). Extrahepatic manifestations should be assessed as well as potential complications of liver disease, such as ascites, spontaneous bacterial peritonitis, and/or gastrointestinal bleeding. Some patients may have been assessed for HCV previously, and documentation of this assessment may provide context and prevent duplications of therapy. Some patients may have been treated for HCV in the past. The type of therapy, clinical response, and adverse effects may subsequently impact selection of current therapy. Other medical comorbidities, including co-infections, psychiatric disease, and substance use, should be assessed at this point in order to optimize medical care for these individuals. Providers should be that stigma may limit the utility of obtaining history. See lesson 6.1to learn more about the impact of stigma on HCV co-infected PLWH.

21 Laboratory Assessment 4,14Non-hepatic Laboratory Testing Complete blood counts, including platelets Serum creatinine Consider TSH and vitamin D Hepatic Function Testing ALT AST Total bilirubin Direct bilirubin Alkaline phosphatase Serum albumin Prothrombin time (PT) / INR HCV Confirmation and Genotyping HCV antibody HCV RNA HCV genotype Co-infection Evaluation HAV antibody HBV surface antigen HBV core antibody HBV surface antibody Consider HIV RNA and CD4 T-cell count in HIV co-infected if not done recently This slide highlights laboratory considerations for assessment of individuals with HCV. Subsequent slides will discuss these in further detail. This curriculum is for those with HIV/HCV co-infection, but HIV antibody should be done for those with unknown HIV status (ie, HCV mono-infection) TSH = Thyroid-Stimulating Hormone ALT = Alanine Aminotransferase AST = Aspartate Aminotransferase RNA = Ribonucleic Acid HAV = Hepatitis A Virus HBV = Hepatitis B Virus

22 Non-hepatic Laboratory Testing 4,14Complete blood counts, including platelets Serum creatinine Consider TSH and vitamin D Complete blood counts should be assessed for leukopenia, anemia, and/or thrombocytopenia, as all may be associated with chronic liver disease. Serum creatinine should be assessed for comorbidity assessment as well as to assist in appropriate medication dosing. Thyroid disease is commonly associated with HCV-related liver disease, and baseline thyroid assessment was essential in the interferon treatment era as this intervention could cause thyroid dysfunction. Testing with a TSH may be considered in the appropriate clinical circumstance. Vitamin D deficiency is common among individuals with HCV disease. Repletion of vitamin D used to be an important step to optimize the likelihood of sustained virologic response with interferon-based therapies. While vitamin D repletion may or may not impact SVR rates on new direct acting antivirals, providers may consider screening for vitamin D deficiency in this high risk population.

23 Hepatic Function Testing 4,14ALT AST Total bilirubin Direct bilirubin Alkaline phosphatase Serum albumin Prothrombin time (PT) / INR Hepatic function testing is essential to assess the degree of inflammation and intrinsic liver function in a person with HCV. ALT and AST levels define the degree of active inflammation via laboratory testing. ALT is more consistently associated with viral hepatitis than AST, which may be more prominently elevated by alcohol or other processes. Total bilirubin may be elevated due to intrinsic liver dysfunction. Direct bilirubin and alkaline phosphatase may be necessary to distinguish whether an obstructive liver process is present as well. Serum albumin and prothrombin time (PT) / international normalized ratio (INR) are markers of protein production by the liver. If low and prolonged, respectively, liver synthetic function may have been harmed by liver disease. ALT = Alanine Aminotransferase AST = Aspartate Aminotransferase

24 Hepatitis C Confirmation1,3,4,14 and GenotypingHCV antibody HCV RNA HCV genotype HCV infection should be assessed as noted in the algorithm earlier in this lesson. All individuals with a positive HCV antibody should have active infection confirmed with a HCV RNA test. The hepatitis C genotype result helps determine the prognosis and treatment options for individuals infected with HCV. While it is the standard of care to obtain a genotype prior to prescribing HCV therapy currently, the increasing availability of pangenotypic HCV treatment regimens may impact the necessity and/or timing of this test in the future. It is important to note that pangenotypic treatment regimens are currently available that can facilitate treatment of HCV-infected persons if HCV genotype testing is not available.

25 Co-infection Evaluation 4,14HAV antibody Consider HIV RNA and/or CD4 T-cell count if not recently done HBV surface antigen HBV core antibody HBV surface antibody HIV antibody (in HCV mono-infected) All individuals infected with HCV have been exposed to a blood-borne pathogen in some capacity. As such, hepatitis B and HIV testing are recommended in HCV-exposed individuals. Exposure to HCV does not necessarily mean that an individual is high risk for hepatitis A virus (HAV), as HCV is primarily blood borne (though rarely may be spread in other body fluids), while HAV is spread via the fecal-oral route. However, an individual infected with HCV is at higher risk for fulminant liver disease should infection occur. Also, certain subgroups, including men who have sex with men, are at higher risk for HAV and immunization may be recommended regardless of HCV status. All HCV-infected persons should be immunized for HAV and HBV if eligible. HIV testing should be obtained in all HCV-exposed persons. In HIV/HCV co-infected persons, HIV control and a healthy immune system limit the progression of HCV disease. As such, assessment of current HIV activity, HIV suppression, and/or immune function should be considered when evaluating HCV. For more on the viral viability of HCV see lesson 2.1.

26 Three Methods of Staging 4,14,15Pathology Laboratory Imaging Staging, when discussed in regard to liver disease assessment, is the study of the degree of scarring (i.e. fibrosis) from an underlying diseases state. While treatment for HCV may be performed without staging, there may be uncertainties in how best to care for individuals with HCV during the course of treatment and after. When considered in relation to HCV disease, staging helps determine the urgency of treatment, the choice of or duration of treatment, treatment eligibility for some payers, and the need for advanced liver disease care. There are multiple methods of staging. The most common categories are via pathology, laboratory, and imaging tests.

27 Pathology Staging: Liver Biopsy 4,14,15Historical gold standard Aids in evaluating other causes of liver disease Results may be impacted by quality of specimen (i.e., length of biopsy, fragmentation during processing) Limited by invasive nature of test, cost, and access to procedure Used less often now with availability of noninvasive staging techniques Liver biopsy is the historical gold standard for staging liver fibrosis. It may be used to assess other, noninfectious liver diseases. While the gold standard, the results of a liver biopsy may be impacted by a variety of factors, including the quality of the specimen, as well as sampling error. The test itself is costly, is invasive with risks of serious adverse effects, and may not be easily accessible to all persons.

28 Laboratory Staging 4,14,15 Examples include direct biomarkers using publicly available calculations (e.g., APRI, FIB-4) as well as proprietary tests (FibroTest/FibroSure) Allows staging without invasive procedures or specialized imaging Vary in utility and accuracy Not accepted by all groups (including payers) as acceptable staging method Use in combination with other staging tools (e.g., vibration-controlled transient liver elastography) when possible Multiple laboratory based tests may be used for the purposes of estimating liver fibrosis. Some tests rely on publicly available calculators (such as AST-to-Platelet Ratio Index [APRI] and FIB-4) that use easily accessible demographic data such as age as well as laboratory data such as ALT, AST, and platelet count to estimate the degree of fibrosis. Some tests such as FibroTest/FibroSure use proprietary calculations to estimate the degree of fibrosis. These tests and others vary in utility and accuracy. These tests are often more accurate on the extreme ends of the fibrosis scale. Said another way, laboratory staging is better at distinguishing “no/mild fibrosis” (F0-F1 on Metavir scale) from “advanced/severe fibrosis” (F3-F4 on Metavir scale) than it is when discriminating between individual stages (i.e. F2 vs. F3). While commonly used in clinical practice as at least an adjunct to other staging techniques, these calculations are not accepted by all clinicians or payers as acceptable sole means of staging liver disease.

29 Anatomic Imaging 4,14-18 Examples include ultrasound, computed tomography (CT), and magnetic resonance imaging (MRI) Low sensitivity for fibrosis staging and even cirrhosis Ultrasound had 38% sensitivity for cirrhosis while CT had 77% and MRI had 68% in one study) Parenchymal disease identified likely corresponds to true disease Allows screening for HCC prior to treatment Anatomic imaging, such as ultrasound, CT, and/or MRI, are not sensitive for detecting fibrosis or even cirrhosis; in lay terms, this means that advanced fibrosis or cirrhosis may be present in an individual’s liver without any noted abnormalities on imaging. If these studies demonstrate anatomical abnormalities consistent with cirrhosis, this is typically consistent with true advanced fibrosis. These imaging modalities are most appropriate for screening for hepatocellular carcinoma.

30 Elastography for Staging 4,14,15Assesses mechanical shear wave velocity, which is proportional to liver stiffness Multiple types and related methods of varying accuracy and availability Transient elastography (i.e., FibroScan®) Magnetic resonance elastography Acoustic radiation force impulse (ARFI) Elastography may allow staging through noninvasive means. There are multiple types available, which vary in their test characteristics, accuracy, and availability. For instance, many major metropolitan areas have limited access to different elastography mechanisms, and many suburban or rural areas do not have these studies available locally.

31 Who and When to Treat: Considerations13,19Patient Factors Readiness Risk of reinfection System Factors Access Affordability Payer coverage Future alternatives Hepatic Factors Disease stage Anticipated progression Urgency of therapy Other Medical Factors Age Limited life expectancy Comorbid conditions Multiple different factors should be considered when considering a person’s eligibility for HCV treatment (as noted above) Readiness Some persons may not be ready for treatment due to competing medical, social, economic, or other reasons. Even if treatment is in the client’s/patient’s best interests, that individual may prioritize other activities (i.e. work, family care, etc.) over medical evaluation and treatment for HCV. In this case, efforts should be made to retain clients/patients in care while closely monitoring for progression of disease. Persons likely to die from illnesses unrelated to HCV and liver disease may not benefit from HCV therapy. Individuals with life expectancies <12 months are unlikely to benefit unless their underlying condition(s) is related to HCV. In that case, evaluation and/or treatment should be conducted in consultation with an expert.

33 Hepatocellular Carcinoma 21,22Major cause of morbidity and mortality among people infected with HCV AASLD-IDSA HCV Guidance recommends surveillance in: Persons with chronic HCV infection who have advanced fibrosis or cirrhosis (Metavir stage F3 or F4) Persons with advanced fibrosis or cirrhosis after achieving sustained virologic response (SVR) for HCV Surveillance may be performed with: Ultrasound every 6 months Computed tomography (CT) with triple phase contrast every 12 months Magnetic resonance imaging with contrast every 12 months Due to the significant morbidity and mortality associated with hepatocellular carcinoma (even among those who have achieved sustained virologic response), screening remains an important element of care for these patients during the initial evaluation, through the course of treatment, and even post-treatment.

34 References – 1 AASLD-IDSA. HCV testing and linkage to care. Recommendations for testing, managing, and treating hepatitis C. Available at: Accessed May 15, 2017. Spach DH. Recommendations for hepatitis C screening. Hepatitis C Online. Available at: Updated August 30, Accessed May 15, 2017. Spach DH. Hepatitis C diagnostic testing. Hepatitis C Online. Available at: diagnosis/diagnostic-testing/core-concept/all. Updated October 21, Accessed May 15, 2017. Bräu N. Evaluation of the hepatitis C virus-infected patient: the initial encounter. Clin Infect Dis Mar;56(6): Thornton K. Natural history of hepatitis C infection. Hepatitis C Online. Available at: staging-monitoring/natural-history/core-concept/all. Updated September 21, Accessed May 15, 2017. Di Martino V, Rufat P, Boyer N, et al. The influence of human immunodeficiency virus coinfection on chronic hepatitis C in injection drug users: a long-term retrospective cohort study. Hepatology Dec;34(6): Graham CS, Baden LR, Yu E, et al. Influence of human immunodeficiency virus infection on the course of hepatitis C virus infection: a meta-analysis. Clin Infect Dis Aug 15;33(4):562-9. De Lédinghen V, Barreiro P, Foucher J, et al. Liver fibrosis on account of chronic hepatitis C is more severe in HIV-positive than HIV-negative patients despite antiretroviral therapy. J Viral Hepat Jun;15(6): Kirk GD, Mehta SH, Astemborski J, et al. HIV, age, and the severity of hepatitis C virus-related liver disease: a cohort study. Ann Intern Med May 7;158(9): Fierer DS, Dieterich DT, Fiel MI, et al. Rapid progression to decompensated cirrhosis, liver transplant, and death in HIV-infected men after primary hepatitis C virus infection. Clin Infect Dis Apr;56(7): Cacoub P, Comarmoud C, Domont F, Savey L, Desbois AC, Saadoun D. Extrahepatic manifestations of chronic hepatitis C virus infection. Ther Adv Infect Dis Feb;3(1):3-14. Fox RK. Extrahepatic conditions related to hepatitis C. Hepatitis C Online. Available at: staging-monitoring/extrahepatic-conditions/core-concept/all. Updated July 1, Accessed May 15, 2017.

35 References – 2 AASLD-IDSA. When and in whom to initiate HCV therapy. Recommendations for testing, managing, and treating hepatitis C. Available at: Accessed May 15, 2017. Ramers CB. Initial evaluation of persons with chronic hepatitis C. Hepatitis C Online. Available at: Updated March 27, Accessed May 15, 2017. Cox-North PP, Shuhart MC. Evaluation and staging of liver fibrosis. Hepatitis C Online. Available at: Updated October 21, Accessed May 15, 2017. Sanford NL, Walsh P, Matis C, Baddeley H, Powell LW. Is ultrasonography useful in the assessment of diffuse parenchymal liver disease? Gastroenterology Jul;89(1): Celle G, Savarino V, Picciotto A, Magnolia MR, Scalabrini P, Dodero M. Is hepatic ultrasonography a valid alternative tool to liver biopsy? Report on 507 cases studied with both techniques. Dig Dis Sci Apr;33(4): Kudo M, Zheng RQ, Kim SR, et al. Diagnostic accuracy of imaging for liver cirrhosis compared to histologically proven liver cirrhosis. A multicenter collaborative study. Intervirology. 2008;51 Suppl 1:17-26. Scott JD, Woolston SL. Making a decision on when to initiate HCV therapy. Hepatitis C Online. Available at: Updated March 7, Accessed May 15, 2017. Thornton K. Evaluation and prognosis of patients with cirrhosis. Hepatitis C Online. Available at: Updated July 14, Accessed May 15, 2017. AASLD-IDSA. Monitoring patients who are starting hepatitis C treatment, are on treatment, or have completed therapy. Recommendations for testing, managing, and treating hepatitis C. Fox RK. Surveillance for hepatocellular carcinoma. Hepatitis C Online. monitoring/surveillance-hepatocellular-carcinoma/core-concept/all. Updated October 21, Accessed May 15, 2017.

36 Resources AASLD and IDSA. HCV Guidance: Recommendations for Testing, Managing, and Treating HCV. Hepatitis C Online. Online training modules and resource library cover topics including screening, diagnosis, evaluation, staging, treatment, complications and comorbidities. From the CDC and University of Washington. Free CME and CEUs. Hepatitis C Online as well as AASLD/IDSA HCV Guidance provide additional information and recommendations regarding the surveillance of hepatocellular carcinoma as related to HCV infection.

37 Authors and Funders This presentation was prepared by Cody Chastain, MD (Southeast AETC) for the AETC National Coordinating Resource Center in July 2017. This presentation is part of a curriculum developed by the AETC Program for the project: Jurisdictional Approach to Curing Hepatitis C among HIV/HCV Co- infected People of Color (HRSA ), funded by the Secretary's Minority AIDS Initiative through the Health Resources and Services Administration HIV/AIDS Bureau.

38 Disclaimer and PermissionsUsers are cautioned that because of the rapidly changing medical field, information could become out of date quickly. You may use or present this slide set and other material in its entirely or incorporate into another presentation if you credit the author and/or source of the materials. The complete HIV/HCV Co-infection: An AETC National Curriculum is available at: https://aidsetc.org/hivhcv