Sections

Treatment

Approach Considerations

No specific emergency department (ED) treatment is indicated for viral hepatitis, other than supportive care that includes intravenous (IV) rehydration. A liver abscess calls for IV antibiotic therapy directed toward the most likely pathogens and consultation for possible surgical or percutaneous drainage.

Admit patients with hepatitis if they are showing any signs or symptoms suggestive of severe complications. Admit and evaluate for hepatic encephalopathy any patients with altered mental status, agitation, behavior or personality changes, or changes in their sleep-wake cycle. Other admission criteria that are suggestive of severe disease include a prothrombin time (PT) longer than 3 seconds, a bilirubin level greater than 30 mg/dL, and hypoglycemia.

Admit any patients with intractable vomiting, significant electrolyte or fluid disturbances, or significant comorbid illness; those who are immunocompromised; and those who are older than 50 years.

Certain patients may benefit from pharmacologic therapy. For chronic hepatitis B virus (HBV) and chronic hepatitis C virus (HCV) infections in particular, the goals of therapy are to reduce liver inflammation and fibrosis and to prevent progression to cirrhosis and its complications. Because the treatment regimens for hepatitis are being actively researched, medication recommendations, indications, and dosages are all subject to change. Consultations with a gastroenterologist, hepatologist, or general surgeon may be indicated.

Most patients with viral hepatitis can be monitored on an outpatient basis. Ensure that patients can maintain adequate hydration, and arrange close follow-up care with primary care physicians. Instruct patients to refrain from using any potential hepatotoxins (eg, ethanol or acetaminophen). Advise patients to avoid prolonged or vigorous physical exertion until their symptoms improve. Patients who are found subsequently to have HBV or HCV should be referred to a gastroenterologist or a hepatologist for further evaluation and treatment.

Acute Hepatitis A

Treatment for acute hepatitis caused by hepatitis A virus (HAV) is necessarily supportive in nature, because no antiviral therapy is available. Hospitalization is warranted for patients whose nausea and vomiting places them at risk for dehydration. Patients with acute liver failure require close monitoring to ensure they do not develop fulminant hepatic failure (FHF), which is defined as acute liver failure that is complicated by hepatic encephalopathy.

Acute Hepatitis B

As is the case for acute hepatitis A virus (HAV) infection, no well-established antiviral therapy is available for acute hepatitis B virus (HBV) infection. Supportive treatment recommendations are the same for acute hepatitis B as for acute hepatitis A. Lamivudine, adefovir dipivoxil, and other antiviral therapies appear to have a positive impact on the natural history of severe cases of acute HBV infection. A study by Schmilovitz-Weiss described a rapid clinical and biochemical response in 13 of 15 patients with severe acute hepatitis B who received lamivudine.^[62]

Chronic Hepatitis B

Ideally, treatment of chronic hepatitis B would routinely achieve loss of hepatitis B surface antigen (HBsAg). Indeed, loss of HBsAg is associated with a decreased incidence of hepatocellular carcinoma (HCC) and a decreased incidence of liver-related death in patients with hepatitis B virus (HBV)-induced cirrhosis.^[63]However, loss of HBsAg is only achieved in relatively small percentages of patients with chronic hepatitis B, that is, about 3-7% of those treated with pegylated interferon (PEG-IFN)^{[64, 65, 66]}and 0-5% of those treated with oral nucleosides or nucleotides.^[67]

At present, the key goal of antiviral treatment of HBV is the inhibition of viral replication. This is marked by the loss of hepatitis B e antigen (HBeAg) in patients with HBeAg-positive chronic hepatitis B and by the suppression of HBV DNA levels. Secondary aims are to reduce symptoms, if any, and to prevent or delay the progression of chronic hepatitis to cirrhosis or HCC.

Agents currently used to treat hepatitis B include PEG-IFN alfa-2a and the oral nucleoside or nucleotide analogues. Typically, PEG-IFN treatment is continued for 48 weeks for both HBeAg-positive and HBeAg-negative chronic hepatitis. Oral agents may be used for as short as 1-2 years; however, most HBeAg-positive chronic hepatitis patients and almost all HBeAg-negative chronic hepatitis patients require indefinite therapy with these agents. Withdrawal of oral nucleoside/nucleotide analogue therapy in these individuals usually results in virologic relapse.

Therapy for treatment-naïve patients

Lamivudine for 8 weeks followed by lamivudine and IFN-alpha for 16 weeks or lamivudine alone for 52 weeks can be used to treat hepatitis B. HBeAg seroconversion at week 52 was shown to be higher in patients receiving combination therapy with interferon plus lamivudine.

Lamivudine with PEG-IFN combination therapy has been shown to improve virologic response at the end of therapy.

Entecavir with PEG-IFN therapy has been shown to increase viral response compared to entecavir alone.^[68]

The combination of PEG-IFN and tenofovir disoproxil fumarate has helped patients infected with HBV genotype A.^[69]

A trial involving 24 patients who were treated with 48 weeks of combination therapy followed by 96 weeks of adefovir monotherapy found marked decrease in HBV DNA.^[70]

Resources

More detailed information regarding management of chronic hepatitis B is beyond the scope of this emergency medicine topic. The reader is referred to the following references:

Pyrsopoulos NT, Reddy KR. Hepatitis B. Medscape Drugs & Diseases. Updated: October 20, 2022. Available at: https://emedicine.medscape.com/article/177632-treatment.
Terrault NA, Bzowej NH, Chang KM, et al. AASLD guidelines for treatment of chronic hepatitis B. Hepatology. 2016 Jan. 63(1):261-83.^[4]
Terrault NA, Lok ASF, McMahon BJ, et al. Update on prevention, diagnosis, and treatment of chronic hepatitis B: AASLD 2018 hepatitis B guidance. Hepatology. 2018 Apr. 67(4):1560-99.^[71]
World Health Organization. Guidelines for the prevention, care and treatment of persons with chronic hepatitis B infection. 2015 Mar.^[5]

Acute Hepatitis C

Acute hepatitis C virus (HCV) infection is detected infrequently. When it is identified, early interferon (IFN) therapy should be considered. In one study, 44 patients with acute hepatitis C were treated with IFN alfa-2b at 5 million U/day subcutaneously (SC) for 4 weeks and then three times per week for another 20 weeks.^[72]About 98% of patients developed a sustained virologic response (SVR), defined as an undetectable level of serum HCV RNA 6 months after completion of antiviral treatment. Most experts now equate achievement of an SVR with viral eradication or cure of HCV infection.^{[72, 73]}

Goals

Antiviral therapy has several major goals, including the following:

Decrease viral replication or eradicate HCV
Prevent progression of disease
Reduce the prevalence of cirrhosis
Decrease the frequency of hepatocellular carcinoma (HCC) as a complication of cirrhosis
Ameliorate symptoms, such as fatigue and joint pain
Treat extrahepatic complications of HCV infection, such as cryoglobulinemia or glomerulonephritis

Simplified HCV treatment for treatment-naïve adults without cirrhosis

Eligibility/ineligibility criteria

The American Association for the Study of Liver Diseases (AASLD) and the Infectious Diseases Society of America (IDSA) indicate that adults with hepatitis C without cirrhosis and who have not been treated previously are eligible for simplified treatment.^[74]However, patients with any of the following characteristics are not eligible for simplified treatment^[74]:

Previously received treatment for hepatitis C
Cirrhosis
Positive for infection with human immunodeficiency virus (HIV) or positive for hepatitis B surface antigen (HBsAg)
Currently pregnant
Known or suspected diagnosis of hepatocellular carcinoma (HCC)
Previously received liver transplantation

Note that the AASLD/IDSA provides guidance on pretreatment assessment as well as follow-up (for patients who achieve virologic cure [sustained virologic response (SVR)] and those who do not achieve SVR).

Recommended regimens

The AASLD/IDSA recommend the following simplified regimens^[74]:

Glecaprevir 300 mg / pibrentasvir 120 mg for 8 weeks, taken with food
Sofosbuvir 400 mg / velpatasvir 100 mg for 12 weeks

On-treatment monitoring

Monitor for hypoglycemia. Patients on diabetes medication should be made aware of the possibility of symptomatic hypoglycemia occurring.

Monitor the international normalized ratio (INR) of patients on warfarin for subtherapeutic anticoagulation. Inform patients on warfarin of the possibility of changes in their anticoagulation status.

Other patients do not require laboratory monitoring.

If needed, patients may schedule in-person or telehealth/phone visits for patient support, symptomatic assessment, and/or new medications.

Posttreatment evaluation

It is recommended that quantitative HCV RNA and a hepatic function panel be evaluated 12 weeks or more after treatment completion to confirm virologic cure (undetectable HCV RNA) and transaminase normalization.

Evaluate for other causes of liver disease in the setting of elevated transaminase levels following achievement of SVR.

Other treatment regimens for HCV infection

Interferon-based regimens comprise many side effects, including psychiatric illness. Therefore, interferon-free regimens are preferred in patients with hepatitis C. Direct antiviral treatment regimens are frequently used to HCV infection with and without the presence of cirrhosis.

In a study including 100 patients with HCV were divided into two cohorts. In cohort A, 60 non-cirrhotic, treatment-naïve patients received sofosbuvir plus ledipasvir (Harvoni) for 8 weeks (group 1), sofosbuvir plus ledipasvir and ribavirin for 8 weeks (group 2), or sofosbuvir plus ledipasvir for 12 weeks (group 3). In cohort B, 40 patients who previously had virological failure after receiving a protease inhibitor regimen received sofosbuvir plus ledipasvir for 12 weeks (group 4) or sofosbuvir plus ledipasvir and ribavirin for 12 weeks (group 5). In cohort A, SVR12 was achieved by 95% in group 1, by 100% in group 2, and by 95% in group 3. In cohort B, SVR12 was achieved by 95% in group 4 and 100% in group 5. These findings suggest that fixed-dose combination of sofosbuvir-ledipasvir alone or with ribavirin has the potential to cure most patients with genotype-1 HCV.^[75]

In phase 3 open label study, once-daily ledipasvir-sofosbuvir with or without ribavirin for 12 or 24 weeks was highly effective in previously untreated patients with HCV genotype 1 infection.^[76]

Ledipasvir 90mg and sofosbuvir 400 mg (Harvoni) is highly effective for both treatment-naïve and treatment-experienced patients with genotype 1 infection in the setting of cirrhosis. The duration of therapy is 12 weeks for treatment-naïve and noncirrhotic treatment-experienced patients and 24 weeks for cirrhotic treatment-experienced patients.^[77]

A double-blind, placebo-controlled study included 624 patients who were treated with sofosbuvir-velpatasvir. Once-daily sofosbuvir-velpatasvir for 12 weeks provided high rates of sustained virologic response among both previously treated and untreated patients infected with HCV genotype 1, 2, 4, 5, or 6, including those with compensated cirrhosis.^[78]

In a randomized controlled trial including 377 treatment-naïve non cirrhotic patients, 12 weeks of sofosbuvir, 400 mg, and velpatasvir, 100 mg, was well-tolerated and resulted in high SVR in patients infected with HCV genotypes 1 to 6.^[79]

Sofosbuvir (400 mg) and the NS5A inhibitor velpatasvir (100 mg) (Epclusa) given for 12 weeks is highly effective for both treatment-naïve and experienced patients with genotype 1 infection.^{[80, 81]}

In a randomized open controlled trial including 1208 patients, once-daily treatment with glecaprevir-pibrentasvir for either 8 weeks or 12 weeks achieved high rates of sustained virologic response among patients with HCV genotype 1 or 3 infection who did not have cirrhosis.^[82]

Glecaprevir (300 mg) and the NS5A inhibitor pibrentasvir (120 mg) for 12 weeks has attained SVR rate of 98-99% and is one of the preferred regimens for treatment-naïve and -experienced genotype 1-infected patients with and without compensated cirrhosis.^{[83, 84]}

Once-daily fixed-dose combination of the NS5A inhibitor elbasvir and the NS3/4A protease inhibitor grazoprevir is highly effective among treatment-naïve and experienced genotype 1-infected patients with and without cirrhosis. Duration of treatment depends on presence of NS5A resistance-associated substitutions (RASs). Patients with subtype 1 A infection, regimen given for 12 weeks. for those without RAS’s but is given for 16 weeks with weight-based ribavirin to those with RASs. SVR rate of 95% achieved by this regimen.^{[85, 86]}

In the absence of cirrhosis, 12 weeks of ombitasvir-paritaprevir-ritonavir plus dasabuvir with weight-based ribavirin results in SVR rates in excess of 95%.^{[87, 88]}In the open-label TURQUOISE-II trial, 380 treatment-naïve and experienced patients with cirrhosis were randomly assigned to receive 12 or 24 weeks of this regimen SVR rates were 92% and 96% for 12 and 24 weeks of treatment, respectively.^[89]

In a trial of patients who had previously failed an NS5A inhibitor-containing regimen, sofosbuvir-velpatasvir-voxilaprevir for 12 weeks resulted in SVR rates of 96% and 100% for genotypes 1a (n = 101) and 1b (n = 45), respectively.^[90]Sofosbuvir-velpatasvir-voxilaprevir regimen is usually well tolerated, except mild adverse events are headache, fatigue, diarrhea, and nausea.^[91]

The interferon-free combination of the protease inhibitor simeprevir (150 mg orally once daily) plus the NS5B inhibitor sofosbuvir (400 mg orally once daily) is given for 12 weeks to those without cirrhosis and for 24 weeks to those with cirrhosis.^[92]Addition of ribavirin to simeprevir and sofosbuvir regimen can be used in patients with suboptimal response to antiviral therapy (eg, cirrhosis, obesity, Black race, unfavorable IL28B genotype).

The combination of the NS5A inhibitor daclatasvir plus the NS5B inhibitor sofosbuvir is effective for hepatitis C infection. In an open label trial that included 82 treatment-naïve genotype 1-infected patients treated with daclatasvir plus sofosbuvir for 12 weeks, SVR rates were high (95% and 100% with or without ribavirin, respectively).^[93]Daclatasvir plus sofosbuvir for 24 weeks with or without ribavirin has also been demonstrated to be effective among patients who failed prior therapy with a protease inhibitor combined with peginterferon and ribavirin (98% of 42 individuals).

Interferon (IFN) was the drug of choice for the treatment of hepatitis C. It is often used in combination with ribavirin. Successful IFN-based therapy, resulting in a sustained virologic response (SVR), can improve the natural history of chronic hepatitis C and may reduce the risk of HCC in patients with HCV-induced cirrhosis.^{[94, 95]}

IFN-based therapy reduced the rate of fibrosis progression in patients with HCV infection.^[96]A cohort of 96 patients with biopsy-proven HCV-induced cirrhosis who were treated with IFN-based therapy experienced regression of cirrhosis.^[97]At a median interval of 17 months after the conclusion of antiviral therapy, patients underwent a second biopsy. Overall, 18 patients (19%) had a decrease in fibrosis score on follow-up biopsy, from stage 4 to less than stage 2, and SVR had been achieved in 17 patients. With a median follow-up of 118 months, these patients were found to have decreased liver-related morbidity and mortality compared with patients who were not histologic responders.^[97]

When considering treatment of HCV infection, both the clinician and the patient must be clear about the goals of therapy. For example, in the patient with advanced fibrosis or cirrhosis, the goal of treatment is virologic cure in the hope of preventing progressive liver disease. Unfortunately, SVR cannot be achieved for everyone. Achievement of SVR, although always desirable, is not always necessary to obtain a desired clinical result. Indeed, partial suppression of HCV through antiviral therapy may be all that is needed to stabilize renal function in a patient with HCV-related glomerulonephritis or to prevent the progression of malignancy in a patient with HCV-related non-Hodgkin lymphoma.

Summary of HCV treatment regimens for treatment-naïve patients

To summarize, the following treatment regimens for HCV have demonstrated safety and efficacy in treatment-naïve patients:

Elbasvir/grazoprevir for 12 weeks, grazoprevir/pibrentasvir for 8 weeks, ledipasvir and sofosbuvir for 12 weeks, ledipasvir and sofosbuvir for 8 weeks, and sofosbuvir and velpatasvir for 12 weeks is recommended for treatment-naïve patients with genotype 1a without cirrhosis.
Elbasvir and grazoprevir for 12 weeks, ledipasvir and sofosbuvir for 12 weeks, sofosbuvir and velpatasvir for 12 weeks, grazoprevir and pibrentasvir for 8 weeks is used for treatment-naïve genotype 1 a with compensated cirrhosis.
Elbasvir and grazoprevir for 12 weeks, glecaprevir and pibrentasvir for 8 weeks, ledipasvir and sofosbuvir for 12 weeks, sofosbuvir and velpatasvir for 12 weeks in treatment-naïve patients genotype 1b without cirrhosis.
Elbasvir and grazoprevir for 12 weeks, ledipasvir and sofosbuvir for 12 weeks, sofosbuvir and velpatasvir for 12 weeks, glecaprevir and pibrentasvir for 8 weeks for genotype 1 b with compensated cirrhosis.
Glecaprevir and pibrentasvir for 8 weeks, sofosbuvir and velpatasvir for 12 weeks for treatment-naïve genotype 2 without cirrhosis.
Sofosbuvir and velpatasvir for 12 weeks, glecaprevir and pibrentasvir for 8 weeks for treatment-naïve genotype 2 with compensated cirrhosis.
Glecaprevir and pibrentasvir for 8 weeks, sofosbuvir and velpatasvir for 12 weeks for treatment-naïve genotype 3 patients without cirrhosis.
Glecaprevir and pibrentasvir for 8 weeks, sofosbuvir and velpatasvir for 12 weeks for treatment-naïve genotype 3 with compensated cirrhosis.
Elbasvir and grazoprevir for 12 weeks, glecaprevir and pibrentasvir for 8 weeks, ledipasvir and sofosbuvir for 12 weeks, sofosbuvir and velpatasvir for 12 weeks for treatment-naïve genotype 4 patients without cirrhosis.
Sofosbuvir and velpatasvir for 12 weeks, glecaprevir and pibrentasvir for 8 weeks, elbasvir and grazoprevir for 12 weeks, ledipasvir and sofosbuvir for 12 weeks for treatment-naïve genotype 4 patients with compensated cirrhosis.
Glecaprevir and pibrentasvir for 8 weeks, sofosbuvir and velpatasvir for 12 weeks, ledipasvir and sofosbuvir for 12 weeks for genotype 5 and 6.

Treatment-experienced patients

For patients who failed sofosbuvir-based treatment with or without compensated cirrhosis, retreatment with fixed dose combination of sofosbuvir, velpatasvir and voxilaprevir for 12 weeks is well tolerated and effective.^[98]The main exception is persons with genotype 3 and cirrhosis, in whom addition of ribavirin to sofosbuvir/velpatasvir/voxilaprevir for 12 weeks is recommended. Glecaprevir/pibrentasvir for 16 weeks is an alternative regimen.

For patients who failed glecaprevir and pibrentasvir treatment, daily fixed dose combination of glecaprevir and pibrentasvir plus daily sofosbuvir and weight-based ribavirin is recommended. Fixed dose combination of sofosbuvir, velpatasvir and voxilaprevir is another option.

Patients with HIV/HCV coinfection

HCV medications such as direct antiviral medications should be used with antiretroviral medications without interactions.

Daily fixed-dose combination of elbasvir (50 mg)/grazoprevir (100 mg) can be used with antiretroviral medications (eg, abacavir, bictegravir, dolutegravir, doravirine, emtricitabine, lamivudine, maraviroc, raltegravir, rilpivirine and tenofovir).

Daily fixed-dose combination of glecaprevir (300 mg)/pibrentasvir (120 mg) can be used with antiretroviral medications (eg, abacavir, bictegravir, dolutegravir, doravirine, emtricitabine, lamivudine, maraviroc, raltegravir, rilpivirine and tenofovir).

Daily fixed-dose combination of sofosbuvir (400 mg)/velpatasvir (100 mg) can be used with most antiretroviral medications.

Daily fixed-dose combination of ledipasvir (90 mg)/sofosbuvir (400 mg) can be used with most antiretrovirals (do not use efavirenz, etravirine or nevirapine).

Daily fixed-dose combination of sofosbuvir (400 mg)/velpatasvir (100 mg)/voxilaprevir (100 mg) should be used with antiretroviral drugs with which they do not have substantial interactions, such as abacavir, bictegravir, dolutegravir, doravirine, emtricitabine, lamivudine, maraviroc, raltegravir, rilpivirine, and tenofovir alafenamide.

Treatment of Hepatitis D and E

Treatment of patients coinfected with hepatitis B virus (HBV) and hepatitis delta virus (HDV) has not been well studied. The only effective treatment for HBV/HDV coinfection is pegylated interferon (PEG-IFN)^{[4, 5]}; antiviral nucleos(t)ide analogues have limited or no effect on HDV replication.^[5]However, multiple small studies have demonstrated that patients with HBV-HDV coinfection are less responsive to IFN therapy than patients with HBV infection alone.^[5]Treatment with PEG-IFN alfa-2b produced HDV RNA negativity in only 17-19% of patients.^{[89, 90]}Lamivudine appears to be ineffective against HBV-HDV coinfection.^{[99, 100]}

Treatment of patients infected with hepatitis E virus (HEV) infection is supportive in nature.

Hepatitis A

Improved sanitation, strict personal hygiene, and hand washing all may help prevent transmission of hepatitis A virus (HAV). The virus is inactivated by household bleach or by heating to 85°C (185°F) for 1 minute. In addition, travelers to endemic areas should not drink untreated water or ingest raw seafood or shellfish. Fruits and vegetables should not be eaten unless they are cooked or can be peeled.

Vaccination

In 1995, the US Food and Drug Administration (FDA) approved the first vaccine for HAV. Beginning in 1996, the Centers for Disease Control and Prevention (CDC) recommended vaccination against HAV for the following individuals:

People traveling to regions where HAV is endemic
Men who have sex with men
Users of illicit drugs

Beginning in 1999, the CDC recommended vaccination for children living in 17 states with consistently elevated rates of HAV infection. Since 2006, the CDC has recommended vaccination for all children at age 1 year as well as encouraged catchup vaccination programs for unvaccinated children.^[101]

Active immunization with HAV vaccine is also recommended for the following individuals:

Persons with an occupational risk of infection (eg, persons working with HAV-infected primates)
Patients who may receive clotting factor concentrates
Susceptible persons with chronic liver disease^[101]
Susceptible persons who are either awaiting or have received liver transplants^[101]

The third recommendation stemmed from the observation that patients with chronic liver disease, although not at an increased risk for exposure to HAV, were at increased risk for fulminant hepatic failure (FHF) if they were infected with the virus.^[102]Notably, there are data to suggest that workers exposed to raw sewage do not have a higher prevalence of antibodies to HAV than a comparator population.^[101]

The inactivated HAV vaccines Havrix and Vaqta are administered as 1-mL (0.5-mL in children) intramuscular (IM) injections given more than 1 month before an anticipated travel to an endemic area. This approach results in a better-than-90% likelihood of stimulating production of immunoglobulin G (IgG) antibody to HAV (anti-HAV), with resulting immunity against HAV infection.

A booster dose of the vaccine is recommended 6 months after the initial vaccination. Whether HAV vaccine administration should be mandated in children (as HBV vaccination is) remains unclear.

An alternative vaccine, containing inactivated HAV and recombinant hepatitis B virus (HBV) vaccines, is Twinrix. This product is immunogenic against both HAV and HBV. The FDA has approved its use in adults. Typical administration involves three injections of 1 mL given IM on a 0-, 1-, and 6-month schedule. Alternatively, a four-dose schedule can be used, with Twinrix administered on days 0, 7, and 21-30, followed by a booster dose at month 12.^[103]

Immune globulin

Passive postexposure immunization with hepatitis A immune globulin (HAIG) is an alternative to active immunization with HAV vaccine.^[104]Its effectiveness is highest when it is given within 48 hours of exposure, but it may be helpful when given as far as 2 weeks into the incubation period.

Postexposure prophylaxis with HAIG is appropriate for household and intimate contacts of patients with HAV. It is also recommended for contacts at daycare centers and institutions. The typical dosing of HAIG is 0.02 mL/kg IM as a single dose. Postexposure prophylaxis is not recommended for the casual contacts of patients, such as classmates or coworkers.

For travelers who anticipate spending less than 3 months in an HAV-endemic region, the dose is 0.02 mL/kg IM. Travelers who are planning to spend more than 3 months in a region where HAV is endemic should receive 0.06 mL/kg IM every 4-6 months.

Hepatitis B

The primary strategies for prevention of hepatitis B are to reduce transmission of the disease and to improve health outcomes for individuals who are already infected with hepatitis B.^[9]

Vaccination

Plasma-derived and recombinant HBV vaccines use hepatitis B surface antigen (HBsAg) to stimulate the production of anti-HBs in noninfected individuals. The vaccines are highly effective, with a greater than 95% rate of seroconversion. Vaccine administration is recommended for all infants as part of the usual immunization schedule, as well as for adults at high risk of infection (eg, those receiving dialysis and healthcare workers). Recommendations for hepatitis B vaccination are available from the CDC^[105]and the World Health Organization (WHO).^[5]

Recombivax HB and Engerix-B (referred to as conventional hepatitis B vaccines) are currently being used worldwide. They use an aluminum adjuvant and typically require three doses over a six-month period to provide protection. In November 2017, a new recombinant hepatitis B vaccine (designated HepB-CpG; sold as Heplisav-B) received approval for use in adults 18 years of age and older.

Studies comparing HepB-CpG (the recombinant vaccine that uses a novel immunostimulatory adjuvant) with the recombinant hepatitis B vaccine Engerix-B found that seroprotective anti-HBs levels (>10 milli-international units/mL) were achieved in 90-100% of patients receiving HepB-CpG versus 70-90% of those receiving Engerix-B.^[106]The proportion of subjects with seroprotective anti-HBs after two doses of HepB-CpG versus three doses of Engerix-B were 95.4% versus 81.3% in the overall cohort, respectively.

The recommended vaccination schedule for infants consists of an initial vaccination at the time of birth (ie, before hospital discharge), a repeat vaccination at 1-2 months, and another repeat vaccination at 6-18 months. The recommended vaccination schedule for adults consists of an initial vaccination, a repeat vaccination at 1 month, and another repeat vaccination at 6 months. If Twinrix (the combined HAV-HBV vaccine) is used, it is given according to the schedule previously described for hepatitis A.

Because of the nonresponse rate, many recommend that healthcare workers undergo postvaccination testing to confirm response within 1-2 months of receiving the vaccine. The duration of immunity conferred by the vaccine is not clearly known. Some clinicians recommend that a booster be given at 5-10 years.

Vaccination of children is an effective means of preventing HBV infection and its complications. For example, although HBV infection is endemic in Taiwan, the institution of universal vaccination for neonates in Taiwan in 1984 reduced the HBsAg carrier rate in children from 9.8% to 0.7% over a period of 15 years.^[107]There was also a resulting drop in the incidence of HCC in children from 0.54 to 0.20 per 100,000. Follow-up studies are needed to determine whether the overall incidence of HCC in Taiwan decreases as these children enter adulthood.

Vaccination is also recommended for older children and adolescents who were not vaccinated as infants; adults with diabetes; and household contacts and intimate partners of individuals with chronic hepatitis B infection.

Prevention of perinatal transmission

Mother-to-child transmission of hepatitis B most commonly occurs at birth, when the neonate is exposed to maternal blood and bodily fluids, or during early childhood.^[5]Because acquiring hepatitis B infection early in life poses a high risk of developing chronic infection, strategies to reduce mother-to-child transmission are of vital importance. For such strategies to be effective, it is important that all pregnant women undergo screening for HBV infection so that they and their newborns may be treated appropriately.^[9]Administering hepatitis B vaccination within 12 hours of birth to neonates born to mothers with hepatitis B infection is 80-95% effective in preventing transmission of hepatitis B infection.^{[4, 5]}In some cases, depending upon the mother’s viral load and human immunodeficiency virus (HIV) status, there may be indications to treat the mother with antiviral agents during pregnancy.^{[4, 5]}

Immune globulin

Hepatitis B immune globulin (HBIG) is derived from plasma. It provides passive immunization for individuals who describe recent exposure to a patient infected with HBV. HBIG is also administered after liver transplantation to persons infected with HBV in order to prevent HBV-induced damage to the liver allograft.

Recommendations for postexposure prophylaxis for contacts of patients positive for HBsAg are as follows:

Perinatal exposure: HBIG plus HBV vaccine at the time of birth (90% effective)
Sexual contact with an acutely infected patient: HBIG plus HBV vaccine
Sexual contact with a chronic carrier: HBV vaccine
Household contact with an acutely infected patient: None
Household contact with an acutely infected person resulting in known exposure: HBIG, with or without HBV vaccine
Infant (age < 12 months) primarily cared for by an acutely infected patient: HBIG, with or without HBV vaccine
Inadvertent percutaneous or permucosal exposure: HBIG, with or without HBV vaccine

Improving health outcomes for those with HBV infection

Improving health outcomes for persons with HBV requires early identification so that they can be made aware of their infection and can receive appropriate treatment and education on risk reduction. To that end, it is recommended that individuals who are at high risk for HBV infection be offered appropriate testing and connection with care.^[9]

Hepatitis C

No vaccine against HCV is available, and immune globulin is not proven to prevent transmission. In fact, immune globulin administration has been associated with HCV. At present, the major means of preventing transmission of HCV is to prevent infected blood, organs, and semen from entering the donor pools. The CDC also recommends meticulous infection control practices within healthcare settings.^[9]Additionally, individuals who are at risk for HCV infection should be offered appropriate testing, treatment, and health education to reduce the risk of transmission.

Improving health outcomes for those with HCV infection

With newer treatments that can provide sustained viral response (SVR), health outcomes for individuals with HCV can be improved by linking them to care and providing appropriate treatment.^[9]Because many individuals may not be aware that they are infected with HCV, providers should offer testing to individuals at risk to include those with a history of injection drug use, persons infected with HIV, and healthcare workers with bloodborne exposures to HCV.^[108]Additionally, the CDC recommends one-time screening for all individuals born between 1945 and 1965 because this population is at high risk of HCV infection, and they are at highest risk for morbidity and mortality as a result of HCV infection.^[9]

Prevention of perinatal transmission

The finding of HCV among increasing numbers of women of childbearing age raises the concern that more infants will be at risk for HCV as a result of mother-to-child transmission.^[46]Providers should screen pregnant women to assess their risks for HCV and offer testing if they are deemed to be at risk; additionally, infants born to infected mothers should be tested for HCV. Women of childbearing age, pregnant women, and infants who test positive for HCV should be referred for care, monitoring, and treatment.^[46]

Hepatitis D and E

Because HDV can infect patients only when HBV is present, transmission of hepatitis D can be decreased by effectively immunizing patients against HBV. Unfortunately, at this time, no means of preventing HDV superinfection in patients with chronic HBV is known.

No vaccine exists for the prevention of HEV infection. Administration of immune globulin does not prevent the development of clinical disease.

Medication

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Media Gallery

Viral Hepatitis. Hepatitis A virus as viewed through electron microscopy.
Viral Hepatitis. Liver biopsy specimen showing ground-glass appearance of hepatocytes in a patient with hepatitis B.
Viral Hepatitis. Liver biopsy with hematoxylin stain showing stage 4 fibrosis (ie, cirrhosis) in a patient with hepatitis B.
Viral Hepatitis. Liver biopsy with trichrome stain showing stage 3 fibrosis in a patient with hepatitis B.
Viral Hepatitis. Hepatic carcinoma, primary. Large multifocal hepatocellular carcinoma in an 80-year-old man without cirrhosis.
Viral Hepatitis. Triple-phase computed tomography scan depicting liver cancer, revealing classic findings of enhancement during the arterial phase and delayed hypointensity during the portal venous phase.

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Table 1. Diagnostic Tests for Hepatitis B

Test	CHB HBeAg Positive	CHB HBeAg Negative	Inactive Carrier
HBsAg	+	+	+
Anti-HBs	-	-	-
HBeAg	+	-	-
Anti-HBe	-	+	+
Anti-HBc	+	+	+
IgM anti-HBc	-	-	-
HBV DNA	>2 × 10⁴ IU/mL* (>10⁵ copies/mL)	>2 × 10³ IU/mL (>10⁴ copies/mL)	< 2 × 10³ IU/mL (< 10⁴ copies/mL)
ALT level	Elevated	Elevated	Normal
ALT = alanine aminotransferase; anti-HBc = antibody to hepatitis B core antigen; anti-HBe = antibody to HBeAg; anti-HBs = antibody to HBsAg; CHB = chronic hepatitis B; HBV = hepatitis B virus; HBeAg = hepatitis B e antigen; HBsAg = hepatitis B surface antigen; IgM = immunoglobulin M. *Increasingly, experts in the field use IU/mL rather than copies/mL.

Table 2. Histologic Grading for Hepatitis C–Induced Liver Disease

Grade	Portal Inflammation	Interface Hepatitis	Lobular Necrosis
1 – Minimal	Mild	Scant	None
2 – Mild	Mild	Mild	Scant
3 – Moderate	Moderate	Moderate	Spotty
4 – Severe	Marked	Marked	Confluent

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Author

Naga Swetha Samji, MD Physician, Bellin Clinic, Bellin Health Systems

Naga Swetha Samji, MD is a member of the following medical societies: American College of Gastroenterology, American College of Physicians, Wisconsin Medical Society

Disclosure: Nothing to disclose.

Coauthor(s)

Adrienne M Buggs, MD, FACEP, FAAEM Medical Policy Advisor, Office of Merchant Mariner Credentialing, United States Coast Guard

Adrienne M Buggs, MD, FACEP, FAAEM is a member of the following medical societies: American Academy of Emergency Medicine, American College of Emergency Physicians, American College of Occupational and Environmental Medicine

Disclosure: Nothing to disclose.

Praveen K Roy, MD, MSc Clinical Assistant Professor of Medicine, University of New Mexico School of Medicine

Praveen K Roy, MD, MSc is a member of the following medical societies: Alaska State Medical Association, American Gastroenterological Association

Disclosure: Nothing to disclose.

Chief Editor

BS Anand, MD Professor, Department of Internal Medicine, Division of Gastroenterology, Baylor College of Medicine

BS Anand, MD is a member of the following medical societies: American Association for the Study of Liver Diseases, American College of Gastroenterology, American Gastroenterological Association, American Society for Gastrointestinal Endoscopy

Disclosure: Nothing to disclose.

Acknowledgements

Eugene Hardin, FAAEM, FACEP Former Chair and Associate Professor, Department of Emergency Medicine, Charles Drew University of Medicine and Science; Former Chair, Department of Emergency Medicine, Martin Luther King Jr/Drew Medical Center

Disclosure: Nothing to disclose.

Douglas M Heuman, MD, FACP, FACG, AGAF Chief of GI, Hepatology, and Nutrition at North Shore University Hospital/Long Island Jewish Medical Center; Professor, Department of Medicine, Hofstra North Shore-LIJ School of Medicine

Douglas M Heuman, MD, FACP, FACG, AGAF is a member of the following medical societies: American Association for the Study of Liver Diseases, American College of Physicians, and American Gastroenterological Association

Disclosure: Novartis Grant/research funds Other; Bayer Grant/research funds Other; Otsuka Grant/research funds None; Bristol Myers Squibb Grant/research funds Other; Scynexis None None; Salix Grant/research funds Other; MannKind Other

Julian Katz, MD Clinical Professor of Medicine, Drexel University College of Medicine

Julian Katz, MD is a member of the following medical societies: American College of Gastroenterology, American College of Physicians, American Gastroenterological Association, American Geriatrics Society, American Medical Association, American Society for Gastrointestinal Endoscopy, American Society of Law, Medicine & Ethics, American Trauma Society, Association of American Medical Colleges, and Physicians for Social Responsibility

Disclosure: Nothing to disclose.

Joseph K Lim, MD Associate Professor of Medicine, Director, Yale Viral Hepatitis Program, Section of Digestive Diseases, Yale University School of Medicine

Joseph K Lim, MD is a member of the following medical societies: American Association for the Study of Liver Diseases, American College of Gastroenterology, American College of Physicians, American Gastroenterological Association, and American Society for Gastrointestinal Endoscopy

Disclosure: Nothing to disclose.

Robert M McNamara, MD, FAAEM Chair and Professor, Department of Emergency Medicine, Temple University School of Medicine

Robert M McNamara, MD, FAAEM is a member of the following medical societies: American Academy of Emergency Medicine, American Medical Association, Pennsylvania Medical Society, and Society for Academic Emergency Medicine

Disclosure: Nothing to disclose.

Sandeep Mukherjee, MB, BCh, MPH, FRCPC Associate Professor, Department of Internal Medicine, Section of Gastroenterology and Hepatology, University of Nebraska Medical Center; Consulting Staff, Section of Gastroenterology and Hepatology, Veteran Affairs Medical Center

Sandeep Mukherjee, MB, BCh, MPH, FRCPC is a member of the following medical societies: Royal College of Physicians and Surgeons of Canada

Disclosure: Merck Honoraria Speaking and teaching; Ikaria Pharmaceuticals Honoraria Board membership

Francisco Talavera, PharmD, PhD Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Medscape Salary Employment

Rajeev Vasudeva, MD, FACG Clinical Professor of Medicine, Consultants in Gastroenterology, University of South Carolina School of Medicine

Rajeev Vasudeva, MD, FACG is a member of the following medical societies: American College of Gastroenterology, American Gastroenterological Association, American Society for Gastrointestinal Endoscopy, Columbia Medical Society, South Carolina Gastroenterology Association, and South Carolina Medical Association

Disclosure: Pricara Honoraria Speaking and teaching; UCB Consulting fee Consulting

David C Wolf, MD, FACP, FACG, AGAF Medical Director of Liver Transplantation, Westchester Medical Center; Professor of Clinical Medicine, Division of Gastroenterology and Hepatobiliary Diseases, Department of Medicine, New York Medical College

David C Wolf, MD, FACP, FACG, AGAF is a member of the following medical societies: American Association for the Study of Liver Diseases, American College of Gastroenterology, American College of Physicians, and American Gastroenterological Association

Disclosure: Nothing to disclose.

Viral Hepatitis Treatment & Management

Approach Considerations

Acute Hepatitis A

Acute Hepatitis B