Hepatitis Screening

Number: 0835

Table Of Contents

Policy Applicable CPT / HCPCS / ICD-10 Codes Background References

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Policy

Scope of Policy

This Clinical Policy Bulletin addresses hepatitis screening.

1. Medical Necessity

   Aetna considers following interventions medically necessary:

   1. Hepatitis B virus (HBV) screening for the following individuals:
      1. Current or former hemodialysis individuals
      2. Donors of blood, plasma, organs, tissues, or semen
      3. Household, needle-sharing, or sexual contacts of persons known to be HBV-positive
      4. Individuals born in Asia, Africa, and other geographic regions with a 2 % or higher prevalence of chronic HBV infection
      5. Infants born to HBV infected mothers
      6. Individuals with a recognized exposure such as health care workers, emergency medical personnel or public safety workers after needle sticks, sharps or mucosal exposures to HBV positive blood
      7. Individuals with chronically elevated amino alanine transferase (ALT) or aspartate amino transferase (AST) of unknown etiology
      8. Individuals with HIV
      9. Injection drug users
      10. Men who have sexual contact with men
      11. Persons needing immunosuppressive therapy, including chemotherapy, immunosuppression related to organ transplantation, and immunosuppression for rheumatologic or gastroenterologic disorders
      12. Persons who are the sources of blood or body fluids resulting in an exposure (e.g., needlestick, sexual assault) that might require post-exposure prophylaxis
      13. Pregnant women
      14. U.S. born persons not vaccinated as infants whose parents were born in regions with high HBV endemicity (greater than or equal to 8 %), such as sub-Saharan Africa, southeast and central Asia, and China.

   2. Hepatitis C virus (HCV) screening for the following individuals:

      1. Children born to HCV infected mothers
      2. Children from a region with high prevalence of HCV infection
      3. Current or former hemodialysis individuals
      4. Individuals who received blood transfusions or organ transplants prior to July 1992 or who received blood from a donor who later tested positive for HCV infection
      5. Individuals who received clotting factor concentrates produced before 1987
      6. Individuals with HIV
      7. Individuals with persistently abnormal ALT levels
      8. Individuals with a recognized exposure such as health care workers, emergency medical personnel or public safety workers after needle sticks, sharps or mucosal exposures to HCV positive blood
      9. Injection drug users
      10. Pregnant women
      11. Present sexual partners of HCV-infected persons.

      Aetna considers one-time testing without prior ascertainment of HCV risk medically necessary for adults aged 18 years and older.

   3. Hepatitis D virus (HCV) screening:

      Aetna considers screening for hepatitis D (delta) infection medically necessary for individuals with hepatitis B infection (HBsAg-positive) and significant risk factors (intravenous drug users, HBV-DNA of less than 2,000 IU/ml, alanine aminotransferase (ALT) of greater than 40 U/L, and HDV endemic country of origin).

2. Experimental, Investigational, or Unproven

   Aetna considers hepatitis E virus (HEV) screening in peri-transplant period experimental, investigational, or unproven because the effectiveness of this approach has not been established.

3. Related Policies

   • CPB 0048 – Hepatitis A Vaccine
   • CPB 0410 – Hepatitis B Vaccine

Table:

CPT Codes / HCPCS Codes / ICD-10 Codes

Code Code Description

Hepatitis B Virus (HBV) screening:

CPT codes covered if selection criteria are met:

86704 Hepatitis B core antibody (HBcAb); total 86705 IgM antibody 86706 Hepatitis B surface antibody (HBsAb) 87340 Infectious agent antigen detection by immunoassay technique, (eg, enzyme immunoassay [EIA], enzyme-linked immunosorbent assay [ELISA], immunochemiluminometric assay [IMCA]) qualitative or semiquantitative, multiple-step method; hepatitis B surface antigen (HBsAg) 87341 hepatitis B surface antigen (HBsAg) neutralization

HCPCS codes covered if selection criteria are met:

G0499 Hepatitis b screening in non-pregnant, high risk individual includes hepatitis b surface antigen (hbsag) followed by a neutralizing confirmatory test for initially reactive results, and antibodies to hbsag (anti-hbs) and hepatitis b core antigen (anti-hbc)

ICD-10 codes covered if selection criteria are met:

B20 Human immunodeficiency virus [HIV] disease B97.35 Human immunodeficiency virus, type 2 [HIV 2] as the cause of diseases classified elsewhere F11.10 – F11.99 Opioid related disorders [injecting drug users] F13.10 – F13.99 Sedative, hypnotic, or anxiolytic related disorders [injecting drug users] F14.10 – F14.99 Cocaine related disorders [injecting drug users] F15.10 – F15.99 Other stimulant related disorders [injecting drug users] O10.011 – O16.9 Edema, proteinuria and hypertensive disorders in pregnancy, childbirth and the puerperium O20.0 – O29.93 Other maternal disorders predominantly related to pregnancy R74.01 – R74.2 Nonspecific elevation of levels of transaminase or lactic acid dehydrogenase [LDH][ALT or AST] Z20.2 Contact with and (suspected) exposure to infections with a predominantly sexual mode of transmission Z20.5 Contact with and (suspected) exposure to viral hepatitis Z20.6 Contact with and (suspected) exposure to human immunodeficiency virus [HIV] Z21 Asymptomatic human immunodeficiency virus [HIV] infection status Z22.4 Carrier of infections with a predominantly sexual mode of transmission Z22.50 – Z22.59 Carrier of viral hepatitis Z34.00 – Z34.93 Encounter for supervision of normal pregnancy Z51.11 Encounter for antineoplastic chemotherapy Z72.51 – Z72.53 High-risk sexual behavior Z77.21 Contact with and (suspected) exposure to potentially hazardous body fluids Z94.0 – Z94.9 Transplanted organ and tissue status Z99.2 Dependence on renal dialysis

Hepatitis C Virus (HCV) screening:

CPT codes covered if selection criteria are met:

86803 Hepatitis C antibody 86804 Confirmatory test (eg, immunoblot)

HCPCS codes covered if selection criteria are met:

G0472 Hepatitis C antibody screening for individual at high risk and other coverage indication(s)

ICD-10 codes covered if selection criteria are met (not all inclusive):

B20 Human immunodeficiency virus [HIV] disease B97.35 Human immunodeficiency virus, type II [HIV-2] D65 – D69.9 Coagulation defects, purpura and other hemorrhagic conditions F11.10 – F11.99 Opioid related disorders [injecting drug users] F13.10 – F13.99 Sedative, hypnotic, or anxiolytic related disorders [injecting drug users] F14.10 – F14.99 Cocaine related disorders [injecting drug users] F15.10 – F15.99 Other stimulant related disorders [injecting drug users] O00.00 – O9A.53 Pregnancy, childbirth and the puerperium T80.61X+ Other serum reaction due to administration of blood products [Blood transfusion, without reported diagnosis] Z11.59 Encounter for screening for other viral diseases [hepatitis C] Z20.5 Contact with and (suspected) exposure to viral hepatitis Z22.50 – Z22.59 Carrier of viral hepatitis Z34.00 – Z34.93 Encounter for supervision of normal pregnancy Z94.0 – Z94.9 Transplanted organ or tissue status Z99.2 Dependence on renal dialysis

Screening for hepatitis D (delta) infection:

CPT codes covered if selection criteria are met:

86692 Antibody; hepatitis, delta agent

ICD-10 codes covered if selection criteria are met:

B16.0 – B16.9 Acute hepatitis B B17.0 Acute delta-(super) infection of hepatitis B carrier B18.1 – B18.2 Chronic viral hepatitis B B19.10 – B19.11 Unspecified viral hepatitis B Z11.59 Encounter for screening for other viral diseases

Hepatitis E Virus (HEV) screening:

CPT codes not covered for indications listed in the CPB:

Hepatitis E screening – no specific code:

ICD-10 codes not covered if indications listed in the CPB:

Z94.0 – Z94.9 Transplanted organ and tissue status

Background

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Hepatitis refers to inflammation of the liver and also refers to a group of viral infections that affect the liver. The most common types are Hepatitis A, Hepatitis B, and Hepatitis C, although Hepatitis D and E viruses have also been identified. An estimated 4.4 million Americans are living with chronic hepatitis, the majority of whom do not know they are infected. Viral hepatitis is the leading cause of liver cancer and the most common reason for liver transplantation (CDC Division of Viral Hepatitis, 2012).

Transmission of hepatitis A, which is caused by hepatitis A virus (HAV), occurs by the fecal-oral route through direct contact with an HAV-infected person or by ingestion of HAV-contaminated food or water. Foodborne or waterborne hepatitis A outbreaks are relatively uncommon in the United States, but food handlers with hepatitis A are frequently identified, and evaluation of the need for immuno-prophylaxis and implementation of control measures are a considerable burden on public health resources. It is also notable that HAV-contaminated food may be the source of hepatitis A for an unknown proportion of persons whose source of infection is not identified (Fiore, 2004).

Torner et al (2012) reported that although hepatitis A mass vaccination effectiveness is high, outbreaks continue to occur. They investigated the association between duration and characteristics of hepatitis A outbreaks reported between 1991 and 2007. An outbreak was defined as greater than or equal to 2 epidemiologically-linked cases with greater than or equal o 1 case laboratory-confirmed by detection of HA immunoglobulin M (IgM) antibodies. Between 1991 and 2007, 268 outbreaks (rate 2.45 per million persons-year) and 1,396 cases (rate 1.28 per 10(5) persons-year) were reported. Factors associated with shorter duration were time to intervention (odds ratio [OR] = 0.96; 95 % confidence interval [CI]: 0.94 to 0.98) and school setting (OR = 0.39; 95 % CI: 0.16 to 0.92). However, the authors also noted that in person-to-person transmission outbreaks, only time to intervention was associated with shorter outbreak duration (OR = 0.96; 95 % CI: 0.95 to 0.98). Torner et al concluded that making confirmed HA infections statutory reportable for clinical laboratories could diminish outbreak duration.

Wiersma et al (2011) reported that most of the estimated 350 million people with chronic hepatitis B virus (HBV) live in resource-constrained settings and that up to 25 % of those persons will die prematurely of hepatocellular carcinoma or cirrhosis. They further state that an informal World Health Organization consultation of experts concluded that chronic HBV is a major public health problem in emerging nations, all HIV-infected persons should be screened for HBV infection, HIBV/HBV co-infected persons should be treated with therapies active against both viruses and that reduce the risk of resistance, and that standards for the management of chronic HBV infection should be adapted to resource-constrained settings.

Hepatitis B, which is caused by infection with the HBV, is found in highest concentrations in blood and in lower concentrations in other body fluids (e.g., semen, vaginal secretions, and wound exudates). HBV is efficiently transmitted by percutaneous or mucous membrane exposure to infectious blood or body fluids that contain blood. In adults, approximately half of newly acquired HBV infections are symptomatic, and approximately 1 % of reported cases result in acute liver failure and death. Risk for chronic infection is inversely related to age at infection, with approximately 90 % of infected infants and 3 0% of infected children aged less than 5 years becoming chronically infected, compared with 2 % to 6 % of adults. Among persons with chronic HBV infection, the risk for premature death from cirrhosis or hepatocellular carcinoma is 15 % to 25 %. The primary risk factors that have been associated with infection are unprotected sex with an infected partner, birth to an infected mother, unprotected sex with more than one partner, men who have sex with other men, history of other sexually transmitted diseases, and illegal injection drug use (CDC Division of Viral Hepatitis, 2012). The United States Preventive Services Task Force (USPSTF) strongly recommends screening for HBV in pregnant women at their first prenatal visit. The USPSTF recommends against routinely screening the general asymptomatic population for chronic HBV infection (USPSTF, 2004).

Weinbaum et al (2009) reported that “early identification of persons with chronic HBV infection enables infected persons to receive necessary care to prevent or delay onset of liver disease, and enables the identification and vaccination of susceptible household contacts and sex partners, interrupting ongoing transmission.” The authors emphasized that testing had been recommended previously to enable primary prevention of HBV infection among close contacts for pregnant women, household contacts and sex partners of HBV-infected persons, persons born in countries with hepatitis B surface antigen (HBsAg) prevalence of more than 8 %, persons who are the source of blood or body fluid exposures that might warrant post-exposure prophylaxis (e.g., needlestick injury to a healthcare worker or sexual assault), and to enable appropriate treatment for infants born to HBsAg-positive mothers and persons infected with human immunodeficiency virus. With the increasing availability of efficacious hepatitis B treatment, the CDC published updated recommendations for public health evaluation and management for chronically infected persons and their contacts which extended testing recommendations to include persons born in geographic regions with HBsAg prevalence of greater than 2 %, men who have sex with men, and injection drug users.

The CDC, in collaboration with the New York City (NYC) Department of Health and Mental Hygiene (DOHMH), conducted a chronic HBV surveillance, selecting a random sample of newly reported cases and collecting more detailed information from the patients’ clinicians. Analysis was presented on 180 randomly selected HBV cases reported during June 2008 to November 2009. Approximately two-thirds (67 %) of the patients were Asian, and the most commonly reported reason for HBV testing was the patient’s birth country or race/ethnicity (27 %). In 70 % of cases, the clinician did not know of any patient risk factors and 62 % did not know their patient’s hepatitis A vaccination status despite recommendations. Sixty-nine percent of clinicians stated that they counseled their patients about notifying close contacts about their infection, and 75 % counseled about transmission and prevention. This surveillance effort provided quantitative data on health disparities, illustrating that not all patients received recommended prevention and treatment services. In response to these findings, DOHMH now routinely distributes HBV patient education materials to populations in need (CDC, 2012).

HCV infection is the most common chronic bloodborne infection in the United States, with approximately 3.2 million persons chronically infected. Sixty to 70 % of persons newly infected with HCV typically are asymptomatic or have a mild clinical illness. HCV RNA can be detected in blood within 1 to 3 weeks after exposure, the average time from exposure to antibody to HCV (anti-HCV) seroconversion is 8 to 9 weeks, and anti-HCV can be detected in greater than 97 % of persons by 6 months after exposure. Chronic HCV infection develops in 70 % to 85 % of HCV-infected persons and 60 % to 70 % of chronically infected persons have evidence of active liver disease. Although the majority of infected persons may not be aware of their infection, infected persons serve as a source of transmission to others and are at risk for chronic liver disease or other HCV-related chronic diseases decades after infection occurs. HCV is most efficiently transmitted through large or repeated percutaneous exposure to infected blood (e.g., through transfusion of blood from unscreened donors or through use of injecting drugs). Although much less frequent, occupational, perinatal, and sexual exposures also can result in transmission of HCV (CDC Division of Viral Hepatitis, 2012).

Smith et al (2012) reported that many of the 2.7 to 3.9 million persons living with HCV infection, an increasing cause of morbidity and mortality in the United States, are unaware they are infected and do not receive care (e.g., education, counseling, and medical monitoring) and treatment. The CDC estimates that although persons born between 1945 to1965 comprise an estimated 27 % of the population, they account for approximately three-fourths of all HCV infections in the United States, 73 % of HCV-associated mortality, and are at greatest risk for hepatocellular carcinoma and other HCV-related liver disease. The CDC is augmenting previous recommendations for HCV testing to recommend one-time testing without prior ascertainment of HCV risk for persons born during 1945 to1965. These recommendations do not replace previous guidelines for HCV testing that are based on known risk factors and clinical indications, but rather define an additional target population for testing: persons born during 1945 to 1965. The CDC developed these recommendations with the assistance of a work group representing diverse expertise and perspectives. The recommendations are informed by the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) framework, an approach that provides guidance and tools to define the research questions, conduct the systematic review, assess the overall quality of the evidence, and determine the strength of the recommendations.

The United States Centers for Disease Control currently has in place recommendations regarding screening for both hepatitis B and hepatitis C. The USPSTF (Moyer, 2013) recommended screening for HCV infection in persons at high risk for infection. The USPSTF also recommended offering 1-time screening for HCV infection to adults born between 1945 and 1965. (B recommendation).

The North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition (NASPGHAN)’s practice guidelines on “Diagnosis and management of hepatitis C infection in infants, children, and adolescents” (Mack et al, 2012) noted that children from a region with high prevalence of HCV infection as well as present sexual partners of HCV-infected persons should be screened for HCV infection.

Updated USPSTF recommendations on screening for HBV were published in May, 2014. These recommendations are based on current evidence on the benefits and harms of antiviral therapy, the benefits of education on behavior change counseling, and the association between improvements in intermediate and clinical outcomes after antiviral therapy. The recommendation updates are focused on high-risk populations and reflect current evidence the USPSTF identified that HBV vaccination is effective for decreasing disease acquisition in high-risk populations. The risk for HBV infection varies substantially by country of origin in foreign-born persons in the United States (US), particularly persons born in countries with a prevalence of HBV infection of 2% or greater. The recommendations further note that lack of vaccination in infancy in US-born persons with parents from a country or region with high prevalence (≥ 8%). including sub-Saharan Africa, central and southeast Asia, and China, is an important risk factor (USPSTF, 2014).

The Centers for Medicare and Medicaid (CMS) issued a National Coverage Determination on June 2, 2014 stating that “the evidence is adequate to conclude that screening for HCV, in accord with the USPSTF recommendations, is reasonable and necessary for the prevention or early detection of an illness or disability and is appropriate for individuals entitled to benefits under Part A or enrolled under Part B.” Therefore, CMS will cover screening for HCV for beneficiaries who are adults at high risk for HCV infection, high risk being defined as a current or past history of illicit injection drug use or a history of receiving blood transfusion prior to 1992, CMS will also cover a single screening test for adults who do not meet the CMS definition of high risk, but who were born from 1945 through 1965.

Hwang et al (2015) provided a revised opinion on “Hepatitis B virus screening for patients with cancer before therapy” based on the American Society of Clinical Oncology (ASCO) panel’s consensus opinion in the context of an evolving database. This updated provisional clinical opinion introduced a risk-adaptive strategy to identify and treat patients with HBV infection to reduce their risk of HBV re-activation. Medical providers should screen by testing patients for HBV infection before starting anti-CD20 therapy or hematopoietic cell transplantation. Providers should also screen patients with risk factors for HBV infection. Screening should include both hepatitis B surface antigen (HBsAg) and hepatitis B core antibody (anti-HBc), because re-activation can occur in patients who are HBsAg positive/anti-HBc positive or HBsAg negative/anti-HBc positive. Either total anti-HBc or anti-HBc immunoglobulin G (not immunoglobulin M) test should be used. Clinicians should start anti-viral therapy for HBsAg-positive/anti-HBc-positive patients before or contemporaneously with cancer therapy and monitor HBsAg-negative/anti-HBc-positive patients for re-activation with HBV DNA and ALT levels, promptly starting anti-virals if re-activation occurs. Clinicians can initiate anti-virals for HBsAg-negative/anti-HBc-positive patients anticipating cancer therapies associated with a high risk of re-activation, or they can monitor HBV DNA and ALT levels and initiate on-demand anti-virals. For patients who neither have HBV risk factors nor anticipate cancer therapy associated with a high risk of re-activation, current evidence does not support HBV screening before initiation of cancer therapy.

The ASCO panel suggests HBV screening for patients with cancer and HBV risk factors before initiation of systemic cancer therapy. Risk groups include the following:

• Persons born in countries and regions with prevalence of HBV infection greater than or equal to 2 %
• US-born persons not vaccinated as infants whose parents were born in regions with high prevalence of HBV infection (greater than or equal to 8 %; e.g., sub-Saharan Africa, southeast and central Asia)
• HIV-positive persons
• Injection drug users
• Men who have sex with men
• Those with household or sexual contact with persons with HBV infection.

The American Gastroenterological Association (AGA)’s guideline on “The prevention and treatment of hepatitis B virus reactivation during immunosuppressive drug therapy” (Reddy et al, 2015) recommended screening for HBV (HBsAg and anti-HBc, followed by a sensitive HBV DNA test if positive) in patients at moderate or high risk who will undergo immunosuppressive drug therapy. The AGA recommended against routinely screening for HBV in patients who will undergo immunosuppressive drug therapy and are at low risk.

The Centers for Medicare and Medicaid Services (CMS, 2016) has determined that a screening test is covered for asymptomatic, nonpregnant adolescents and adults at high risk for HBV infection. “High risk” is defined as persons born in countries and regions with a high prevalence of HBV infection (i.e., ≥ 2%), U.S.-born persons not vaccinated as infants whose parents were born in regions with a very high prevalence of HBV infection (i.e., ≥ 8%), HIV-positive persons, men who have sex with men, injection drug users, household contacts or sexual partners of persons with HBV infection. In addition, CMS has determined that repeated screening would be appropriate annually only for beneficiaries with continued high risk (i.e., men who have sex with men, injection drug users, household contacts or sexual partners of persons with HBV infection) who do not receive hepatitis B vaccination.

CMS (2016) has stated that a screening test at the first prenatal visit is covered for pregnant women and then rescreening at time of delivery for those with new or continuing risk factors. In addition, CMS has determined that screening during the first prenatal visit would be appropriate for each pregnancy, regardless of previous hepatitis B vaccination or previous negative hepatitis B surface antigen (HBsAg) test results.

Hepatitis C Virus Screening

The USPSTF reports that the estimated prevalence of chronic HCV infection is approximately 1.0% (2013 to 2016), with an estimated 44,700 new HCV infections that occurred in the US in 2017. The USPSTF state that cases of acute HCV infection have increased approximately 3.8-fold (2010 to 2017) over the last decade because of increasing injection drug use and improved surveillance, with the most rapid increase found in young adults aged 20 to 39 years who inject drugs (USPSTF, 2020).

In March 2020, the US Preventative Services Task Force (USPSTF) updated their 2013 recommendations to include a category B recommendation for the screening of HCV infection in adults aged 18 to 79 years. This recommendation applies to all asymptomatic adults in that age category without known liver disease. This recommendation is based on a systematic evidence review and examination of the evidence on adolescents. The main outcomes and measures of the review included mortality, morbidity, quality of life, screening and treatment harms, and screening diagnostic yield. Eight RCTs of direct-acting antiviral (DAA) therapy vs placebo or an outdated antiviral regimen, 48 other treatment studies, and 33 cohort studies, with a total of 179 230 participants, were included. No study evaluated effects of HCV screening vs no screening. One new study since the 2013 review (n = 5917) found similar diagnostic yield of risk-based screening and birth cohort screening, assuming perfect implementation. Ten open-label studies (n = 3292) reported small improvements in some quality-of-life and functional outcomes after DAA treatment compared with before treatment. Two cohort studies (n = 24 686) found inconsistent associations of antiviral therapy vs no therapy with risk of hepatocellular carcinoma. Forty-nine treatment studies (n = 10 181) found DAA regimens associated with pooled sustained virologic response (SVR) rates greater than 95% across genotypes, and low short-term rates of serious adverse events (1.9%) and withdrawal due to adverse events (0.4%). An SVR after antiviral therapy was associated with decreased adjusted risk of all-cause mortality (13 studies, n = 36 986) and hepatocellular carcinoma (20 studies, n = 84 491) vs no SVR. The study reflected that direct evidence on the effects of HCV screening on clinical outcomes remains unavailable, but that all-oral DAA regimens were associated with sustained virologic response (SVR) rates greater than 95% and few short-term harms relative to older antiviral therapies. An SVR after antiviral therapy was associated with improved clinical outcomes compared with no SVR. (Chou et al., 2020).

The USPSTF concluded with moderate certainty that screening for HCV infection in adults aged 18 to 79 years has substantial net benefit. Most adults need to be screened only once. Persons with continued risk for HCV infection (e.g., persons who inject drugs) should be screened periodically. There is limited information about the specific screening interval that should occur in persons who continue to be at risk for new HCV infection or how pregnancy changes the need for additional screening. This recommendation incorporates new evidence and replaces the 2013 USPSTF recommendation, which recommended screening for HCV infection in persons at high risk for infection and 1-time screening in adults born between 1945 and 1965 (B recommendation). Thus, the 2020 USPSTF recommendation expands the ages for screening to all adults from 18 to 79 years. According to the USPSTF, the Centers for Disease Control and Prevention is in the process of updating its HCV screening guidelines (USPSTF, 2020).

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In April 2020, the Centers for Disease Control and Prevention (CDC) recommends universal hepatitis C screening at least once in a lifetime for all adults aged 18 years and older, except in settings where the prevalence of HCV infection (HCV RNA‑positivity) is less than 0.1%. The CDC also recommends universal hepatitis C screening for all pregnant women during each pregnancy, except in settings where the prevalence of HCV infection (HCV RNA‑positivity) is less than 0.1%. Determining prevalence: In the absence of existing data for hepatitis C prevalence, healthcare providers should initiate universal hepatitis C screening until they establish that the prevalence of HCV RNA positivity in their population is less than 0.1%, at which point universal screening is no longer explicitly recommended but may occur at the provider’s discretion. In addition, the CDC recommends one-time hepatitis C testing regardless of age or setting prevalence among people with recognized conditions or exposures such as people with HIV, who ever injected drugs and shared needles, syringes, or other drug preparation equipment, including those who injected once or a few times many years ago; people with selected medical conditions including people who ever received maintenance hemodialysis and people with persistently abnormal ALT levels; prior recipients of transfusions or organ transplants, including people who received clotting factor concentrates produced before 1987, people who received an organ transplant before July 1992, people who were notified that they received blood from a donor who later tested positive for HCV infection; healthcare, emergency medical, and public safety personnel after needle sticks, sharps, or mucosal exposures to HCV-positive blood; children born to mothers with HCV infection; routine periodic testing for people with ongoing risk factors, while risk factors persist, such as people who currently inject drugs and share needles, syringes, or other drug preparation equipment, and people with selected medical conditions, including, people who ever received maintenance hemodialysis; any any person who requests hep C testing regardless of disclosure of risk because many persons may be reluctant to disclose stigmatizing risks (CDC, 2020; Schillie et al, 2020).

Hepatitis E Virus Screening in Peri-Transplant Period

Scotto and co-workers (2015) examined the sero-virological prevalence and clinical features of hepatitis E virus (HEV) infection in end-stage renal failure patients and in the healthy population. HEV infection is a viral disease that can cause sporadic and epidemic hepatitis. Previous studies unexpectedly showed a high prevalence of HEV antibodies in immunosuppressed subjects, including hemodialysis (HD) patients and patients who had undergone kidney transplant. In a cohort/case-control study, these researchers determined the sero-prevalence of HEV in 801 subjects; 231 HD patients, 120 kidney transplant recipients (KTRs), and 450 health individuals. All HD patients and KTRs were attending the Departments of Nephrology and Dialysis at 2 hospitals located in Southern Italy, and were included progressively in this study. Serum samples were tested for HEV antibodies (IgG/IgM); in the case of positivity they were confirmed by a Western blot assay and were also tested for HEV-RNA, and the HEV genotypes were determined. A total of 30/801 (3.7 %) patients were positive for anti-HEV Ig (IgG and/or IgM) and by Western blot. The healthy population presented with a prevalence of 2.7 %, HD patients had a prevalence of 6.0 %, and KTRs had a prevalence of 3.3 %. The overall combined HEV-positive prevalence in the 2 groups with chronic renal failure was 5.1 %. The rates of exposure to HEV (positivity of HEV-IgG/M in the early samples) were lower in the healthy controls, but the difference among the 3 groups was not statistically significant (p > 0.05). Positivity for anti-HEV/IgM was detected in 4/30 (13.33 %) anti-HEV Ig positive individuals, in 2/14 HD patients, in 1/4 KTRs, and in 1/12 of the healthy population. The relative risk (RR) of being HEV-IgM-positive was significantly higher among KTRs compared to the other 2 groups (OR = 65.4, 95 % CI: 7.2 to 592.7, p < 0.001), but the subjects with HEV-IgM positivity were numerically too few to calculate a significant difference. No patient presented with chronic hepatitis from HEV infection alone. The authors concluded that this study indicated a higher, but not significant, circulation of HEV in hemodialysis patients versus the healthy population; and chronic hepatitis due to the HEV virus was not observed.

Sue and associates (2016) stated that autochthonous HEV infection has been reported in over 200 solid organ transplant (SOT) recipients since 2006, yet little is known about the burden of HEV among SOT recipients in North America. In a retrospective, single-center, cross-sectional study, these investigators examined the prevalence and risk factors associated with HEV infection among SOT recipients at their institution. Children and adults (n = 311) who received allografts between 1988 and 2012 at the Johns Hopkins Hospital were assessed for evidence of HEV infection by testing post-transplantation serum samples for HEV antibody by enzyme immunoassay and HEV RNA by reverse transcription quantitative polymerase chain reaction (rt-qPCR). Individuals with evidence of post-transplant HEV infection (presence of anti-HEV IgM antibody, anti-HEV IgG sero-conversion, or HEV RNA) were compared with individuals without evidence of infection and assessed for risk factors associated with infection. A total of 12 individuals (4 %) developed post-transplant HEV infection. Post-transplant HEV infection was associated with an increased risk for graft rejection (OR, 14.2; p = 0.03). No individuals developed chronic infection. The authors concluded that SOT recipients in the United States are at risk for post-transplant HEV infection. Moreover, they stated that a prospective, multi-center, study is needed to supplement the findings of this retrospective, single-center study and to better understand HEV infection among SOT recipients in North America.

The authors stated that this study had several drawbacks. Due to its retrospective design, detailed data on exposures and potential routes of HEV transmission were not available. In addition, as this study was limited to a single center, these investigators did not capture potential regional differences in HEV exposure and risk of infection. A disproportionate number of KTRs were represented within this cohort. Among these, a high proportion of KTR were HLA-mismatched, highly sensitized individuals at increased risk for graft rejection and required higher levels of immunosuppression. As such, it is possible that the association the authors observed between HEV infection and graft rejection was particularly exaggerated in this population, although this association was also observed among other transplant types in this study. Transmission of HEV infection through contaminated blood products has been previously described and as such, it was possible that a number of infected individuals within this cohort may have been exposed to HEV via contaminated blood products. However, these researchers were unable to test blood products received by individuals for the presence of HEV, given the retrospective nature of this study as well as the lack of blood donor screening for HEV.

In regards to HEV sero-conversions, these investigators considered the possibility that anti-HEV IgG may have been transmitted through intravenous immunoglobulin (IVIG) administration after transplantation and contributed to a number of the observed sero-conversions. To address this concern, these researchers reviewed the records of the 6 individuals diagnosed by sero-conversion, and these investigators noted that only 2 received IVIG within 2 months before initial specimen testing. Of these 2 cases, 1 individual underwent plasmapheresis immediately after IVIG administration (making IVIG an unlikely cause of sero-conversion), resulting in 1 individual within this cohort who may have sero-converted secondary to recent IVIG administration. To evaluate the likelihood of anti-HEV IgG sero-conversion secondary to recent IVIG administration in this individual, the authors reviewed records of all anti-HEV IgG sero-negative subjects (i.e., no evidence of sero-conversion) for evidence of prior IVIG exposure. These researchers found that 61 % (162 of 254) of sero-negative individuals previously received IVIG with no evidence of anti-HEV IgG sero-conversion with the authors’ assay. Of these, 18 % (29 of 162) received IVIG within the 8 weeks preceding specimen collection; but yet remained anti-HEV IgG negative. Thus, the authors concluded that recent administration of IVIG was unlikely to be a significant source for anti-HEV IgG sero-conversion in the individual above.

These investigators stated that although it is likely that the majority of the observed HEV infections were due to genotype 3 virus, they were unsuccessful in their attempts to genotype the PCR-positive isolates in this cohort. These researchers attributed this to the relatively lower levels of viremia we noted among the isolates as well as the decreased sensitivity of the genotyping assay for HEV compared with RT-qPCR. These researchers were also surprised to not observe any PCR (+) chronic infections. Circulating HEV RNA may have been reduced to undetectable levels as a result of plasma dilution in the setting of IVIG administration and plasmapheresis for ABO- or HLA-incompatible living donor transplant. This may have contributed to the absence of HEV RNA in the serial samples tested. Finally, the use of rituximab in over 1/3 of this cohort of KTR may have contributed to the low prevalence of anti-HEV IgM and led to an under-estimation of recent post-transplant infections in this study compared with others.

Ankcorn and co-workers (2018) noted that persistent HEV genotype 3 (HEV G3) infections affect SOT recipients and hematopoietic stem cell transplant (HSCT) recipients, but the burden in these cohorts in the United Kingdom (UK) is unknown. These investigators established an audit to determine the point prevalence of HEV viremia in SOT and HSCT patients in the UK and compared different testing approaches to inform screening strategies. Between January 5, 2016, and September 21, 2016, a total of 3,044 patients undergoing therapeutic drug monitoring at a single transplant center were screened for HEV ribonucleic acid (RNA) in mini-pools. A total of 2,822 patients who could be characterized included 2,419 SOT patients, 144 HSCT patients and 259 patients with no available transplant history; HEV RNA-positive samples were characterized by serology and genomic phylogeny. HEV antigen (HEV-Ag) testing was performed on RNA-positive samples, 420 RNA-negative samples and 176 RNA-negative blood donor samples. A total of 19 of 2,822 patients were viremic with G3 HEV giving a prevalence of 0.67 %. The median alanine aminotransferase (ALT) was significantly higher in the HEV viremic patients (p < 0.0001); however, 2 viremic patients had an ALT value within the normal range at the time of screening. The HEV-Ag assay identified 18/19 viremic patients and all those patients with proven viremia longer than 4 weeks. The authors concluded that transplant recipients in the UK were at a low but significant risk of HEV infection; HEV-Ag detection could be an alternative to RNA detection where the goal is to identify established persistent HEV infection, particularly where expertise, facilities, or cost prohibit RNA testing.

Reekie and colleagues (2018) noted that HEV is a common cause of acute viral hepatitis worldwide. Typically associated with a self-limiting illness, infection may persist in immunosuppressed populations with significant morbidity and mortality. Based on clinical data published world-wide, UK blood safety guidance recommends the universal screening for HEV RNA of blood donors and donors of tissue, organs and stem cells. In a cross-sectional study, these researchers determined the point prevalence of HEV viremia and clinical course of viremic patients in the peri-transplant period in SOT and HSCT recipients transplanted between 2013 and 2015. Nucleic acid extracts of whole blood from patients undergoing SOT or HSCT were tested by an in-house real-time rt-PCR assay for HEV RNA. Samples were tested at baseline (time of transplant), 30, 60 and 90 days post-transplant. A total of 870 patients (259 HSCT, 262 liver and 349 kidney transplant) were included with 2,554 samples meeting the inclusion criteria. No kidney transplant patients had HEV viremia at time of testing; 1 HSCT and 3 liver transplant patients were found to be HEV RNA-positive. Overall this represented 0.46 % of the patients testing positive for HEV viremia. The authors concluded that prevalence of HEV viremia in SOT and HSCT patients in UK although higher than in the general population was low at baseline and remained low throughout the early post-transplant phase; clearance of viremia can be maintained despite ongoing immunosuppression. These investigators stated that prospective UK studies are needed to inform screening policies in this population.

Hepatitis C Virus Screening in Pregnancy

In a systematic review, Andes et al (2021) examined recent demographic characteristics of HCV infection during pregnancy and the effectiveness of risk-based versus universal screening. These investigators searched PubMed, Embase, and Cochrane Library to identify relevant studies. Studies that recognized hepatitis C as a primary or secondary outcome, with pregnant women as the population and written in English, were included. Studies were excluded if they were abstracts only, written in foreign language, or published before 1992. Two researchers independently screened all the studies by titles, abstracts, and full text. Conflicts were settled by a 3rd researcher. A total of 698 studies were identified with 78 fitting inclusion criteria. In total, 69 epidemiologic and 9 comparison studies were found. Identified risk factors for HCV infection included intravenous (IV) or illicit drug use, sexually transmitted co-infection, high-risk behaviors in the partners, high parity, and history of miscarriages or abortions. Demographic characteristics associated with HCV included non-Hispanic white race, American Indian or Alaskan Native ethnicity, and increasing age. Providers may fail to adequately screen for each risk factor, and up to 2/3 of women with a known risk factor were not screened under current guidelines. Finally, up to 27 % of HCV-positive women had no identifiable risk factors for infection. The authors concluded that there is evidence that risk-based screening failed to identify a large proportion of HCV-positive women in pregnancy and that pregnant women with HCV risk factors and consistent with current screening guidelines failed to be tested. These investigators urged for the adoption of universal screening to identify these women and offer treatment.

Bushman et al (2021) stated that despite the CDC and USPSTF recommending universal HCV screening in pregnancy, Society for Maternal-Fetal Medicine (SMFM) and American College of Obstetricians and Gynecologists (ACOG) continue to endorse risk-based screening for HCV in pregnancy. In a retrospective cohort study, these researchers hypothesized that universal screening is associated with increased HCV diagnosis and post-partum linkage to HCV care compared with risk-based screening. This trial included pregnant women screened for HCV at a single tertiary-care center. These investigators defined 2 cohorts: women managed with risk-based (January 2014 to October 2016) or universal HCV screening (November 2016 to December 2018). Screening was carried out with ELISA antibody testing and viremia confirmed with HCV ribonucleic acid (RNA) polymerase chain reaction (PCR). Primary outcomes were the rate of HCV screen positivity and post-partum linkage to care. From 2014 to 2018, a total of 16,489 women delivered at the authors’ institution, of whom 166 screened positive for HCV. A total of 7,039 pregnant women were screened for HCV: 266 with risk-based and 6,773 with universal screening; 29 % (76/266) were positive HCV antibody screening (HCVAb + ) in the risk-based cohort and 1.3 % (90/6,773) in the universal cohort. HCVAb+ women in the risk-based cohort were more likely to have a positive drug screen. Only 69 % (62/90) of HCVAb+ women in the universal cohort met the criteria for risk-based testing. Of the remaining 28 women, 6 (21 %) had active viremia (HCV RNA+). Of the 166 HCVAb+ women, 64 % (103/166) were HCV RNA+-51 of 266 (19 %) in the risk-based and 52 of 6,773 (0.8 %) in the universal cohort. Of HCVAb+ women, 75 % (125/166) were referred post-partum for HCV evaluation and 27 % (34/125) were linked to care. Only 9 % (10/103) of women with viremia-initiated treatment within 1 year of delivery. The authors concluded that universal HCV screening in pregnancy identified an additional 31 % of HCVAb+ women compared with risk-based screening. Given low rates of HCV follow-up and treatment regardless of screening modality, further studies are needed to address barriers to post-partum linkage to care.

Hepatitis D (Delta) Virus Screening

Da et al (2021) noted that the American Association for the Study of Liver Diseases (AASLD; Terrault et al, 2018) recommended hepatitis D virus (HDV) screening in certain high-risk groups; however, the effectiveness is unknown. These investigators carried out a study of North American patients with HBV referred to the NIH to identify risk factors associated with HDV infection. Active HDV was “confirmed” by serum HDV RNA or histologic HDV antigen staining. A total of 651 cases were studied, of which 91 were HDV “confirmed”. Independent risk factors for HDV included: intravenous drug users, HBV-DNA of less than 2,000 IU/ml, alanine aminotransferase (ALT) of greater than 40 U/L, and HDV endemic country of origin. The authors concluded that North American patients with HBV and significant risk factors should be screened for HDV.

Brichler et al (2024) stated that chronic hepatitis D infection is the most severe form of viral hepatitis and can rapidly progress to cirrhosis or hepatocellular carcinoma (HCC). Despite recommendations for systematic screening of HBsAg-positive individuals, data from real-world studies have reported a low frequency of HDV screening. In retrospective, a cross-sectional study, these researchers examined the diagnostic cascade for hepatitis D infection in tertiary centers and described the characteristics of HDV-positive patients. A total of 6,772 individuals who tested HBsAg positive for the 1st time between 2018 and 2022 were included; demographic, clinical as well as laboratory data were analyzed. A total of 5,748 HBsAg-positive individuals (84.9 %) were screened for HDV infection. The screening rate varied from 63 % to 97 % according to the screening strategy used in the centers including or not HDV reflex testing. The prevalence of HDV infection was 6.3 %. HDV RNA levels were determined in 285 of the 364 (78.3 %) HDV antibody screening-positive patients, and 167 (58.6 %) had active HDV infection. A total of 66.8 % were men, with a mean age of 44.9 years. A total of 97.5 % were born abroad, and 92.9 % were HBeAg-negative. At the time of diagnosis, HDV RNA levels were 6.0 Log UI/ml; 60.1 % had ALT of greater than 40 U/L, and 56.3 % had significant fibrosis (≥ F2), including 41.6 % with cirrhosis. The most common genotype was HDV-1 (75.4 %). Co-infections were not uncommon: 7.4 % were HIV-positive, and 15.0 % were HCV antibody-positive. The authors concluded that the findings of this study highlighted the need for increased screening and monitoring of HDV infection; reflex testing aided in identifying HDV-infected individuals.

Wong et al (2024) stated that current U.S. guidelines recommend risk-based testing for HDV in individuals with chronic hepatitis B (CHB). While there is debate as to whether a risk-based or universal testing approach is most effective, limited data exist on universal HDV testing programs in the U.S. In a 1-year, single-center, pilot study, these researchers examined the outcomes of a universal HDV testing approach among U.S. veterans with CHB. All consecutive adults with CHB receiving care at hepatology clinics at a Veterans Affairs (VA) Health System from October 1, 2022 to September 30, 2023 were prospectively tested for anti-HDV antibody (anti-HDV). Patients who were anti-HDV Ab-positive were subsequently tested for HDV RNA. Comparison of HDV testing between groups employed Chi-square testing. A total of 91 consecutive CHB patients (90.0 % men, mean age of 60.9 ± 14.1 years, 73.9 % Asian, 26.1 % non-Asia, 16.5 % cirrhosis, and 17.1 % with active or past history of drug use) had anti-HDV ordered. Overall, 76.9 % (n = 70) completed anti-HDV testing; 4.3 % (n = 3) were positive. HDV RNA testing was ordered in all 3 patients; 2 patients completed HDV RNA testing and 1 had detectable HDV RNA. No significant differences in completion of anti-HDV testing was observed by age, sex, race/ethnicity, cirrhosis status, or drug-use history. The authors concluded that in a prospective, single-center, cohort study piloting a universal HDV testing approach, 1 patient with viremic HDV was identified. These researchers stated that implementing true reflex testing of all CHB patients with anti-HDV, followed by automated HDV RNA testing for anti-HDV-positive patients would improve the HDV testing cascade and timely diagnosis of HDV.

Kushner and Andrews (2024) noted that infection with the HDV, a unique RNA virus that requires HBV antigens for its assembly, replication, and transmission, could result in severe viral hepatitis. Compared to HBV mono-infection, HDV infection increases the risk of severe liver disease, necessity for liver transplantation (LTx), and mortality. Global HDV prevalence estimates vary from 5 % to 15 % among individuals with HBV; however, screening guidelines for HDV are inconsistent – some recommend risk-based screening, while others recommend universal screening for all individuals with HBV. Among primary care providers (PCPs) in the U.S., there is a lack of awareness and/or insufficient adherence to current recommendations for the screening of HDV infection and management of chronic HDV. Studies were identified by carrying out literature searches between July and August 2022 using the PubMed database and by manual searches of the retrieved literature for additional references. Information was synthesized to highlight HDV screening and management strategies for PCPs. Best practices for PCPs based on current guidelines and co-management strategies for patients with HBV and HDV infection were summarized. These investigators recommend universal screening for HDV in patients positive for hepatitis B surface antigen. Confirmed HDV infection should prompt evaluation by a liver specialist, if available, with whom the PCP can comanage the patient. PCPs should counsel patients on the expected course of the disease, lifestyle factors that may influence liver health, need for consistent disease monitoring and follow-up, and risk of disease transmission. Screening is suggested for sexual partners, household contacts, and family members, with HBV immunization recommended for those found to be susceptible. There are currently no Food and Drug Administration (FDA)-approved therapies for HDV infection; therefore, management is limited to treatments for chronic HBV infection plus long-term monitoring of liver health. The authors concluded that PCPs can be a valuable point of care (POC) for patients to access HDV/HBV screening, HBV immunization, and education, and can comanage patients with HBV and/or HDV infection.

Furthermore, an UpToDate review on “Epidemiology, clinical manifestations and diagnosis of hepatitis D virus infection” (Negro and Lok, 2024) states that “We perform routine screening for HDV in all patients with chronic HBV. Initial testing should assess for total anti-HDV antibody; if positive, HDV infection should be confirmed by testing for serum HDV RNA. Identifying persons with chronic HDV/HBV is important since patients with coinfection may have more severe liver disease, and the presence of HDV coinfection can impact treatment decisions. This information can also be used for counseling purposes so patients without HDV infection can reduce behaviors that might put them at risk for HDV superinfection”.

Appendix

Table: Geographic Regions with an HBsAg prevalenceFootnote 1* RegionFootnote 2** CountriesFootnote 3*** Africa All AsiaFootnote 4† All Australia and South Pacific All except Australia and New Zealand Middle East All except Cyprus and Israel Eastern Europe All except Hungary Western Europe Malta, Spain, and indigenous populations in Greenland North America Alaska natives and indigenous populations in northern Canada Mexico and Central America Guatemala and Honduras South America Ecuador, Guyana, Suriname, Venezuela, and Amazonian areas of Bolivia, Brazil, Colombia, and Peru Caribbean Antigua and Barbuda, Dominica, Grenada, Haiti, Jamaica, St. Kitts and Nevis, St. Lucia, and Turks and Caicos Islands

Adapted from Weinbaum et al, 2008.

Footnote 1* Estimates of prevalence of HBsAg, a marker of chronic hepatitis B virus infection, are based on limited data and might not reflect current prevalence in countries that have implemented childhood hepatitis B vaccination. In addition, HBsAg prevalence might vary within countries by subpopulation and locality.

Footnote 2** The regions with the highest prevalence (>5%) are sub-Saharan Africa and central and southeast Asia.

Footnote 3*** A complete list of countries in each region is available at the CDC’s “Vaccines. Medicines. Advice” webpage.

Footnote 4† Asia includes three regions: Southeast Asia, east Asia, and northern Asia.

References

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