Lesson 2: Acute Hepatitis C Virus Infection Core Competency 3: Screening, Testing, Diagnosis, and Clinical Evaluation of HCV Infection among PLWH Lesson 2: Acute Hepatitis C Virus Infection PLWH = People Living with HIV July 2017

Lesson Objectives By the end of this lesson, the learner will be able to: Define acute HCV Describe the epidemiology of acute HCV Understand the natural history of acute HCV Recognize clinical manifestations of acute HCV Screen and diagnose acute HCV Evaluate acute HCV, including taking a history, performing a physical examination, and ordering laboratory and imaging studies Understand considerations for treatment of acute HCV This outline lists the order and subject matter of this lesson. This lesson will refer to specific aspects unique to acute HCV. In many instances, acute HCV is assessed in the same way as chronic HCV. For a broader review regarding the evaluation of HCV, learners should refer to the content within Lesson 3.1.

Definition of Acute HCV Infection1-4 6-month time frame after HCV infection Not defined by presence of symptoms Laboratory-based diagnosis Positive (detectable) HCV RNA with a negative HCV antibody Positive HCV antibody with a documented negative HCV antibody in the past 12 months Non-official clinically based diagnosis Fluctuating ALT levels without another cause Low HCV RNA or fluctuating HCV RNA levels Subsequent spontaneous clearance of HCV The preferred expert definition of acute HCV is the first six months after acquiring HCV infection. While symptoms may be present during the acute phase, they are not necessary to define an infection as acute. Laboratory-based diagnosis may be defined in two ways (as noted above). There are major limitations to this approach, as many patients do not have a record of prior testing or do not have HCV RNA testing performed in the setting of negative serology testing. Furthermore, false-negative antibody tests may occur early in the infection window (i.e. 6 weeks), HCV RNA results may fluctuate, and liver aminotransferase values may fluctuate (including normal values) during the acute infection phase. Acute HCV may be suspected on clinical grounds if ALT and/or HCV RNA levels are rapidly fluctuating. Spontaneous clearance of HCV also suggests recent infection as this is less likely to occur beyond 6 months of infection. Cases that meet criteria for acute HCV should be reported to the local health department, as this is an essential element of epidemiologic monitoring for HCV.

Reported Incidence5 This chart details the incidence of REPORTED acute hepatitis C by year. The definition of acute hepatitis C, along with natural history of the disease (where many persons are asymptomatic after infection), make the epidemiology of acute HCV difficult to accurately grasp.

Estimated Incidence and Risk Factors2-7 Annual estimated incidence peaked in the 1980s was ~230,0005 Annual estimated incidence in 2015 was 33,9006,7 Risk Factors More common Parenteral exposure (e.g., injection drug use) Men who have sex with men (best studied among HIV infected) Less common Occupational exposure Heterosexual exposure Note how the REPORTED number of acute hepatitis C cases on the prior slide is much lower than the ESTIMATED number of cases annually per the CDC. The change in estimated incidence between the 1980s and more recent estimates was likely due to safer health practices, the blood supply being effectively screened, and changes in the epidemiology of injection drug use nationally. Unfortunately, the incidence of acute HCV appears to be increasing, likely due to the opioid use epidemic nationally Risk factors for acute HCV are the same as for chronic HCV; however, common risk factors are noted above. Among MSM infected with HIV, acute HCV infection is associated with sero-sorting behavior, methamphetamine use, sexually transmitted infections, mucosal trauma, and CD4<500. The learner can review Lesson 1.1 for further details about HCV epidemiology in general and Lesson 5.1 for recommendations for HCV in pregnant and postpartum co-infected women.

Natural History2-4,8,9 Estimated 20-40% clear HCV spontaneously, though reports range from 10-60% Rates of spontaneous clearance among PLWH appear to be lower (~10% in recent reports)9 Median time to clearance is about 16 weeks Approximately 90% of those that clear do so by 6 months After 6 months, disease state is considered chronic Estimates for the number of patients who “spontaneously clear” infection vary between 10-60% in different studies. Expert opinion suggests that 20-40% is the likely range across the population. The likelihood of spontaneously clearance is dependent on a variety of factors, including age, race, medical comorbidities (including HIV), IL-28B genotype, and others. Half of all persons who will spontaneously clear infection do so by 16 weeks, and 90% who will spontaneously clear infection do so by 6 months. As the vast majority of persons who will spontaneously clear infection do so by the 6 month mark, the disease is considered chronic at that point (although a small proportion of patients may still clear the infection at later time). GUIDELINES and HCO and Kamal SM. Acute hepatitis C: a systematic review. Am J Gastroenterol. 2008;103(5):1283-1297. Steininger

Clinical Manifestations2-4,8 Most persons with acute HCV infection are asymptomatic Approximately 15-30% develop symptoms, usually within 4-12 weeks after exposure Symptoms may include jaundice, flu-like symptoms, dark urine, light-colored stool, nausea, and/or abdominal pain <1% develop acute liver failure

Screening and Diagnosis1,2,10 Diagnosis may be difficult unless suspected exposure noted See definition of acute HCV Diagnosis may require both HCV antibody and RNA (often with repeated values over time) Screening is often contingent on risk factor assessment Anti-HCV test and HCV RNA test should be assessed for screening and diagnosis Due to the lack of symptoms in many cases, effective screening is difficult to do. The definition of acute HCV means that many persons require laboratory testing at multiple time points, and many persons have not had this completed. While acute HCV is a reportable illness to local and state health departments, the strict definition and difficulty in assessing this clinically results in underreporting. Effective screening requires in depth discussion of risk factors and potential exposures. Even if a risk factors is identified and screening is performed, a HCV antibody may be falsely negative early in infection; furthermore, HCV RNA may fluctuate during the acute infection period and be falsely negative at points even for patients who may subsequently have chronic infection. Of note, if anti-HCV test and HCV RNA are abnormal within 48 hours of exposure, the individual likely had chronic infection PRIOR to the recent exposure. Again, cases that meet criteria for acute HCV should be reported to the local health department, as this is an essential element of epidemiologic monitoring for HCV.

Clinical Evaluation Specific to Acute HCV11,12 Check ALT, HCV RNA every 2-4 weeks after infection if early treatment is considered (i.e., after 12-16 weeks of monitoring) Check ALT, HCV RNA at least once 4-6 months after infection If a patient spontaneously clears infection, no treatment or further care recommended Negative HCV RNA documented once is not sufficient to identify spontaneous clearance If a person has detectable HCV RNA beyond 6 months, HCV infection is considered chronic This slide details the unique clinical evaluation specific to acute HCV. Additional physical exam, laboratory testing, and/or imaging may be appropriate; if so, see lesson 3.1 (chronic HCV) for additional details. Checking ALT and HCV RNA ever 2-4 weeks after infection is optimal in order to identify clearance prior to starting HCV therapy if early treatment (i.e. starting after 12-16 weeks of monitoring from time of defined exposure or diagnosis) is anticipated. If more frequent laboratory testing is not feasible, or if early treatment is not anticipated, persons should have ALT and HCV RNA checked at least once 4-6 months after infection. Of note, some persons with acute HCV infection have transiently undetectable HCV RNA levels. However, some persons may have detectable HCV RNA a short time later and develop chronic infection. A single HCV RNA test <6 months after infection may not be sufficient to define spontaneous clearance and rule out chronic infection. If a patient spontaneously clears infection, no further testing, monitoring, or treatment is recommended. Once a person is defined as having chronic HCV infection, further evaluation and/or treatment should be considered. (See Lesson 3.1)

Treatment of Acute HCV11,12 Treatment selection is the same as for chronic HCV based on current clinical evidence Historically, treatment of acute HCV had higher efficacy than treatment of chronic HCV Some providers opt to wait to treat once chronic infection defined Optimal treatment approach is being evaluated in clinical trials While treatment of acute HCV used to be favored in the interferon era due to higher cure rates with traditionally low-efficacy therapies, treatment for acute HCV is often deferred in the modern direct-acting antiviral era in light of high efficacy therapies as well as high cost. Treatment of acute HCV and/or other groups that are at high risk for transmission (i.e. persons actively injecting drugs) may reduce the frequency of transmission in communities and address HCV at the public health level (i.e. treatment as prevention). This approach and its impact is currently being evaluated.

Advantages of Treating Acute HCV11,12 Prevention of transmission Limitation of long-term clinical impact Opportunity to engage in care and treat co-morbidities Additional factors that apply to those with chronic HCV infection There are some settings when providers may consider treatment of acute HCV. Persons at high risk of transmitting HCV to others may warrant treatment. Special attention should be given to risk-reduction therapies to prevent reinfection. Persons at high risk of clinical worsening, such as those who already have active or chronic liver disease now with superimposed HCV (i.e. cirrhosis or chronic HBV infection), may benefit from earlier treatment. Some persons may be difficult to link to or retain in care in the future due to other factors. These persons may benefit from treatment if they are in an environment where treatment is possible. Other clinical factors, including those used when determining treatment for chronic HCV, should also be considered.

Resources AASLD and IDSA. HCV Guidance: Recommendations for Testing, Managing, and Treating HCV. http://hcvguidelines.org CDC and University of Washington. Hepatitis C Online. Online training modules and resource library covers topics including screening, diagnosis, evaluation, staging, treatment, management of complications and comorbidities. Free CME/CEUs. http://www.hepatitis.uw.edu 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.

References AASLD-IDSA. HCV testing and linkage to care. Recommendations for testing, managing, and treating hepatitis C. Fox RK. Diagnosis of acute HCV infection. Hepatitis C Online. Kamal SM. Acute hepatitis C: a systematic review. Am J Gastroenterol. 2008 May;103(5):1283-97. Sharma SA, Feld JJ. Acute hepatitis C: management in the rapidly evolving world of HCV. Curr Gastroenterol Rep. 2014 Feb;16(2):371. Center for Disease Control. Surveillance for Viral Hepatitis -- United States, 2014. Center for Disease Control. Surveillance for Viral Hepatitis -- United States, 2015. Campbell CA, Canary L, Smith N, Teshale E, Ryerson B, Ward J. State HCV Incidence and policies related to HCV preventive and treatment services for persons who inject drugs -- United States, 2015-2016. MMWR Morb Mortal Wkly Rep. 2017 May 12;66(18):465-469. Thornton K. Natural history of hepatitis C infection. Hepatitis C Online. Steininger K, Boyd A, Dupke S, et al. HIV-positive men who have sex with men are at high risk of development of significant liver fibrosis after an episode of acute hepatitis C. J Viral Hepat. 2017 Apr 25. [Epub ahead of print]. Spach DH. Hepatitis C diagnostic testing. Hepatitis C Online. AASLD-IDSA.. Management of acute HCV infection. Recommendations for testing, managing, and treating hepatitis C. Fox RK, Spach DH. Treatment of acute hepatitis C infection. Hepatitis C Online.

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 16-189), funded by the Secretary's Minority AIDS Initiative through the Health Resources and Services Administration HIV/AIDS Bureau.

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