Antiviral Medications, Part 3: Evidence-Based Treatment of Hepatitis B.
HBV is transmitted through infected blood and body fluids. It can be passed to others through unprotected sex, use of contaminated needles, and direct contact with blood. It also can be passed from an infected woman to her baby during pregnancy, childbirth, and breastfeeding (Hepatitis B Foundation, 2017). HBV also is a major occupational hazard for healthcare workers (Adams, Holland, & Urban, 2017).
Approximately half of people with newly acquired HBV infection are asymptomatic and can spread the virus unknowingly to others (CDC, 2015). HBV infection can be acute and self-limiting, or progress to chronic disease and eventually become fatal from cirrhosis and liver cancer (World Health Organization [WHO], 2015). In part 2 of the antiviral medication series, Penkalski, Felicilda-Reynaldo, and Patterson (2017) presented evidence-based guidelines for assessment, monitoring, and pharmacotherapeutic management of HBV infection.
Pathophysiology and Diagnosis of Hepatitis B
HBV contains deoxyribonucleic acid (DNA) and the enzyme DNA polymerase needed for the virus to replicate itself. HBV DNA represents viral load in the bloodstream and is the most reliable indicator of HBV infection. Viral load is detectable in the blood before symptoms of the infection begin, as well as briefly during the acute illness. DNA polymerase is briefly present in the blood. It may remain detectable for years in persons with CHB and serve as a good indicator of infectivity (Grossman & Porth, 2014).
The virus also contains antigens that trigger production of antibodies: hepatitis B surface antigen ([HB.sub.s]Ag), hepatitis B core antigen ([HB.sub.c]Ag), and hepatitis B e antigen ([HB.sub.e]Ag). A positive blood test for [HB.sub.s]Ag confirms HBV infection. [HB.sub.s]Ag is detectable in the blood before symptoms of the infection begin; it peaks after symptoms develop and then becomes undetectable in 3-6 months. Continued presence of [HB.sub.s]Ag in the blood for more than 6 months indicates CHB, continued replication of the virus, and communicability. [HB.sub.c]Ag remains in liver cells to direct the assembly of new virus and is not detectable in the blood. [HB.sub.e]Ag is detectable in the blood soon after [HB.sub.s]Ag and is another indicator of active replication of the virus (Grossman & Porth, 2014; McCance, Huether, Brashers, & Rote, 2010; Terrault et al., 2016).
HBV antigens result in development of multiple antibodies, including IgG anti-[HB.sub.s], IgM and IgG anti-HB , and anti-HB . IgG anti-HB appears in the blood after clearance of [HB.sub.s]Ag and indicates recovery from the infection, noncommunicability, and protection from future HBV infection. IgG anti-[HB.sub.s] is also detectable in persons who have been immunized successfully against HBV. IgM anti-[HB.sub.c] is detectable in the blood before symptoms begin and at about the same time as the amount of alanine aminotransferase (ALT) increases. IgM anti-[HB.sub.c] later is replaced by IgG anti-[HB.sub.c]. Anti-[HB.sub.e] appears in the blood soon after [HB.sub.e]Ag becomes undetectable and indicates resolution of the acute illness (Grossman & Porth, 2014; McCance et al., 2010; Terrault et al., 2016). HBV antigens and antibodies are used as serologic markers to diagnose and monitor progression of HBV infection. Interpretation of serologic test results for HBV infection are summarized in Table 1.
The incubation period from time of exposure to symptom onset for HBV is 6 weeks-6 months (CDC, 2015). During the first stage of infection, the virus evades the immune system and attaches to a liver cell. Once attached, the virus penetrates the liver cell and invades its nucleus. Inside the nucleus, the virus converts the cell's DNA to HBV DNA which allows the virus to replicate, enter the bloodstream (viral load), and infect more liver cells. In immunocompetent people, the immune system attacks infected liver cells and causes inflammatory and fibrotic changes in the liver. The extent of liver injury is determined by age at the time of infection and strength of the immune response (Oakes, 2014a). Persons with a prompt and strong immune response during acute infection sustain liver injury but eliminate the virus. Those with a decreased immune response (e.g., young children, older adults, persons with human immunodeficiency virus [HIV]) sustain little or no liver injury, are less able to eliminate the virus, and become carriers or develop CHB (Grossman & Porth, 2014).
HBV infection has four distinct phases that reflect the immunocompetence of the host and the degree of viral replication. The immune tolerant phase lasts 10-30 years in persons infected perinatally, and is absent or short for those infected as children or adults. Liver injury is minimal because the immune system tolerates the virus. The immune active phase occurs when the immune system no longer tolerates HBV and attacks infected liver cells. Most people seek treatment in this phase. Some develop new strains of virus, continue to make new virus, and have progressive liver damage. This phase carries the highest risk for cirrhosis, liver failure, and liver cancer. Seroconversion occurs when [HB.sub.e]Ag becomes undetectable in the blood and anti-[HB.sub.e] appears. Seroconversion occurs within 5-10 years of entering this phase and signals transition to the inactive carrier phase. In the inactive carrier phase, [HB.sub.e]Ag and [HB.sub.s]Ag become undetectable in the blood. Anti-[HB.sub.e] and anti-[HB.sub.s] antibodies become detectable, viral load is low or undetectable, ALT value normalizes, and liver inflammation and fibrosis improve. The reactivation phase can occur spontaneously or result from immunosuppression from a variety of causes (e.g., chemotherapy, another viral infection). Diagnostic findings for each phase of HBV infection are summarized in Table 2.
Evidence-Based Guidelines for Evaluation and Monitoring of CHB Infection
All persons with CHB infection should be evaluated thoroughly by a primary care provider and referred to a specialist if abnormalities are detected. Initial evaluation should include history and physical examination, laboratory tests, serology/ virology, and imaging/staging studies. The history and physical examination should identify signs and symptoms of cirrhosis, use of alcohol, metabolic risk factors, family history of liver failure, and vaccination history. Recommended laboratory tests include complete blood count, platelet count, international normalized ratio, liver transaminases, total bilirubin, alkaline phosphatase, albumin, ALT, and gamma glutamyl transferase. Serology/ virology evaluation should include HBV viral load, all hepatitis antigens and antibodies, screening for other types of hepatitis, and existence of HIV. Fibroscan is an accurate, quick, and noninvasive way to measure liver stiffness that occurs with inflammation and cirrhosis (use not appropriate in pregnancy and persons with ascites) (Oakes, 2014b; Terrault et al., 2016).
Evidence-Based Guidelines for Antiviral Therapy for HBV Infection
Goals of pharmacologic treatment for HBV infection are to decrease viral load, reduce risk of transmission, and decrease liver damage (Oakes, 2014b). Undetectable viral load results in normalization of ALT values, loss of [HB.sub.e]Ag, seroconversion, and decreased liver inflammation. Although loss of [HB.sub.s]Ag and an undetectable viral load represent immunological cure, a virological cure for HBV is not possible because HBV cannot be eradicated from liver cells (Terrault et al., 2016).
The American Association for the Study of Liver Diseases (AASLD) (Terrault et al., 2016) published several recommendations for treatment and monitoring of CHB based on the phase of disease.
* Adults with immune-active disease should receive pegylated interferon (Pegasys[R]), entecavir (Baraclude[R]), or tenofovir disopoxil fumarate (Viread[R]) as initial therapy regardless of [HB.sub.e]Ag status (low quality/certainty of evidence; strong recommendation).
* Adults with immune-tolerant disease should not be treated with antiviral therapy unless over age 40 with normal ALT and elevated viral load, and liver biopsy showing significant inflammation and fibrosis not caused by other liver disease. ALT values should be monitored every 6 months to assess transition to immune-active or immune-inactive disease (moderate quality/certainty of evidence; strong recommendation).
* Adults who are [HB.sub.e]Ag-positive but do not have cirrhosis who convert to anti-[HB.sub.e] on therapy should discontinue the antiviral after at least 12 months of persistently normal ALT and undetectable viral load. Viral load, ALT values, and occurrence of seroconversion and clinical presentation should be monitored every 3 months (very low quality/certainty of evidence; conditional recommendation).
* Adults with cirrhosis who are [HB.sub.e]Ag-positive and who seroconvert to anti-[HB.sub.e] on antiviral therapy should continue therapy indefinitely due to increased risk for disease progression and death (very low quality/certainty of evidence; conditional recommendation).
* Adults with [HB.sub.e]Ag-negative immune-active disease should continue antiviral therapy indefinitely. However, discontinuation of therapy may be considered in those who have lost [HB.sub.s]Ag; these persons should be monitored every 3 months for at least a year to detect increased viral load and ALT, and assess clinical presentation (low quality/certainty of evidence; conditional recommendation).
* Entecavir and tenofovir disoproxil fumarate are preferred equally in adults with potential long-term risks of renal and bone complications (very low/low quality/certainty of evidence; conditional recommendation).
* Adults with persistently low viral load taking entecavir or tenofovir disoproxil fumarate alone should continue doing so regardless of ALT value. Those whose viral load increases should switch to another drug with a higher barrier to resistance or add a second antiviral drug that is not cross-resistant (very low quality/certainty of evidence; conditional recommendation).
* Adults with compensated cirrhosis and low viral load should be treated with antiviral therapy to reduce disease progression, regardless of ALT value. Entecavir or tenofovir disoproxil fumarate is safer than pegylated interferon in these persons resistant (very low quality/certainty of evidence; conditional recommendation).
* Adults with [HB.sub.s]Ag-positive decompensated cirrhosis should be treated indefinitely with antiviral therapy, regardless of viral load, [HB.sub.e]Ag status, or ALT value to reduce risk of additional liver complications (moderate quality/certainty of evidence; strong recommendation).
* Pregnant women who are [HB.sub.s]Ag-positive and have high viral load should be treated with antiviral therapy at 28-32 weeks gestation to reduce risk of perinatal transmission (low quality/certainty of evidence; conditional recommendation).
In the past, several types of medications were used to treat HBV infection. These included corticosterioids, hepatoprotective agents, and those that suppressed, stimulated, or modified the immune response. Of these, pegylated interferon was most effective but also caused serious side effects, such as bone marrow suppression and depression (Terrault et al., 2016). Current antiviral medications used to treat CHB are summarized in Table 3.
NRTIs and NNRTIs
Antiviral drugs used to treat CHB are classified as nucleoside reverse transcriptase inhibitors (NRTIs) or nonnucleoside reverse transcriptase inhibitors (NNRTIs). NRTIs include entecavir, lamivudine (Epivir HBV[R]), and ribavirin (RibaTab[R]). NNRTIs include tenofovir and adefovir dipivoxil (Hepsera[R]). NRTIs and NNRTIs are slightly different chemically. However, they effectively block DNA polymerase needed for HBV replication (Karch, 2017; Kee, Hayes, & McCuistion, 2015).
Entecavir and tenofovir disoproxil fumarate are first-line (prototype) antiviral medications because they reduce viral load and normalize ALT more effectively than other antivirals in antiviral naive, [HB.sub.e]Ag-positive patients; those who are [HB.sub.e]Ag negative; and those coinfected with HIV, other types of hepatitis (hepatitis C [HCV], hepatitis D [HDV]), and tuberculosis (TB). Tenofovir disoproxil fumarate has the highest probability of achieving low or undetectable viral load in individuals who are lamivudine-resistant. Use of only tenofovir disoproxil fumarate in persons resistant to other antivirals simplifies disease management and increases adherence to treatment (Vallerand, Sanoski, & Deglin, 2013).
Entecavir and tenofovir are administered orally once daily. Entecavir should be taken on an empty stomach at least 2 hours before or after a meal. Tenofovir should be taken with meals. Serious side effects of entecavir and tenofovir are uncommon but usually liver-related; they include enlargement, fatty infiltration, reactivation and exacerbation of hepatitis, hepatotoxicity, and hyperglycemia. Signs of liver involvement include jaundice, dark urine, light-colored stools, fatigue, anorexia, nausea, vomiting, lower stomach pain, and in severe cases, ascites and edema. Signs of hyperglycemia include unexplained weight loss, excessive hunger and thirst, and frequent urination. In severe cases, hyperglycemia can cause changes in level of consciousness. Lactic acidosis may occur but is rare. Signs of lactic acidosis include increased serum lactate, weakness, fatigue, unusual muscle pain, shortness of breath, stomach pain, tachycardia, and arrhythmias (Vallerand et al., 2013).
Entecavir and tenofovir have a low observed rate of drug resistance. Resistance to entecavir occurs most often in patients resistant to lamivudine. Lamivudine has the highest rate of drug resistance, especially in Asians and Pacific Islanders who have a high rate of HBV infection. Resistance to tenofovir occurs most often in patients who are non-adherent (WHO, 2015).
Nursing Management throughout Antiviral Therapy
Safety and success of antiviral therapy depends on thorough assessment and patient education before, during, and after treatment. AASlD (Terrault et al., 2016) and WHO (2015) guidelines recommend assessment of the severity of liver damage (presence and extent of cirrhosis or fibrosis), viral load, presence of co-infections (e.g., HIV, HCV, HDV, TB), comorbidities (especially related to immunosuppression), family history of liver cancer, lifestyle choices (e.g., alcohol use, protected sex), risk factors for renal and liver dysfunction, and baseline liver and renal function. These guidelines do not recommend liver biopsy to confirm liver damage before initiation of antiviral therapy, but support use of serum markers of fibrosis (e.g., aspartate aminotransferase [AST]-to platelet ratio index [APRI]) to select appropriate therapy, determine duration of treatment, and monitor disease progression and treatment response. AASLD and WHO guidelines recommend continuous assessment for cirrhosis (in those without cirrhosis at the start of antiviral therapy) (Terrault et al., 2016; WHO, 2015).
[HB.sub.s]Ag, [HB.sub.e]Ag, viral load, and liver function (ALT and AST for APRI) should be monitored to gauge treatment response, and identify side effects and adverse reactions. Monitoring for side effects, adverse reactions, and treatment response should occur at every visit to the healthcare provider, usually every 3 months during the first year and then at least annually. HBV increases the risk of death from cirrhosis and liver cancer. Liver cancer may be asymptomatic until it is advanced. Liver ultrasound and AFP are used to monitor for liver cancer. Although there is no agreement on the frequency of monitoring for persons with HBV, evidence suggests semi-annual monitoring improves survival rates (Vallerand et al., 2013; WHO, 2015).
Antiviral medications are excreted unchanged by the kidneys, underscoring the importance of monitoring renal function. Persons at low or no risk for renal toxicity should be monitored annually. Those at high risk of renal toxicity should be monitored every 6 months, and more often if there is evidence of decreased renal function. Closer renal monitoring is especially important for persons with decreased creatinine clearance (< 50 mL/min). Renal monitoring may include urine dipsticks for proteinuria and glycosuria for persons without diabetes and for those with well-controlled diabetes, serum creatinine, estimated decline in glomerular filtration rate, serum phosphate, and urine protein-to-creatinine ratio. Minimum recommend ed monitoring includes annual urine dipstick testing and creatinine measurement. Tenofovir should not be used with adefovir dipivoxil or other nephrotoxic drugs (e.g., aminoglycosides, furosemide [Lasix[R]]). Entecavir should be used instead of tenofovir or the dose of tenofovir reduced in persons with long-term diabetes, uncontrolled hypertension, or severe osteoporosis (Vallerand et al., 2013; WHO, 2015).
Adherence to antivirals also should be assessed at each visit to the healthcare provider, especially for persons with cirrhosis. Reactivation of HBV may occur after discontinuing antiviral medications. Retreatment is recommended if consistent signs of reactivation are present: [HB.sub.s]Ag or [HB.sub.e]Ag becomes positive, ALT increases, or viral load becomes detectable. Individuals or their caregivers should be asked directly about the number of doses missed since their last appointment. Nonadherence also may be identified by reviewing pharmacy refill records. More frequent monitoring of adherence is recommended for persons who do not meet the criteria for antiviral treatment, such as those who have periodically abnormal ALT values or viral loads that fluctuate between 2,000 IU/mL and 20,000 IU/mL, and who are coinfected with HIV. Monitoring for adherence, treatment response, and treatment failure is recommended every 3 months during the first year for persons with cirrhosis. Primary treatment failure occurs when antiviral therapy fails to decrease viral load within 3 months. Secondary treatment failure is reflected in a rebound of viral load from its lowest level in persons receiving antivirals. More frequent monitoring is recommended for persons who discontinue treatment and anytime treatment adherence is a concern (Terrault et al., 2016; WHO, 2015).
Medical-surgical nurses should be knowledgeable about clinical guidelines for antiviral therapy for patients diagnosed with CHB. Knowledge of first-line therapies, requirements to monitor clinical progress, and nursing management for antiviral therapy drug administration will allow medical-surgical nurses to provide optimal care to their patients. It also will help patients continue to be adherent to drug therapies to achieve best outcomes. USED
Instructions For Continuing Nursing Education Contact Hours
Antiviral Medications, Part 3: Evidence-Based Treatment of Hepatitis B
Deadline for Submission: December 31, 2019
To Obtain CNE Contact Hours
1. For those wishing to obtain CNE contact hours, you must read the article and complete the evaluation through the AMSN Online Library. Complete your evaluation online and print your CNE certificate immediately, or later. Simply go to www.amsn.org/library
2. Evaluations must be completed online by December 31, 2019. Upon completion of the evaluation, a certificate for 1.2 contact hour(s), which includes 1.2 hours of pharmacology credit, may be printed.
After completing this learning activity, the learner will be able to discuss antiviral medications used to manage hepatitis B.
Learning Engagement Activity
Download and review:
World Health Organization (WHO). (2015). Guidelines for the prevention, care, and treatment of persons with chronic hepatitis B infection. http://apps.who.int/iris/bitstream710665/154590/1/9789241549059_eng.pdf
The author(s), editor, editorial board, content reviewers, and education director reported no actual or potential conflict of interest in relation to this continuing nursing education article.
This educational activity is jointly provided by Anthony J. Jannetti, Inc. and the Academy of Medical-Surgical Nurses (AMSN).
Anthony J. Jannetti, Inc. is accredited as a provider of continuing nursing education by the American Nurses Credentialing Center's Commission on Accreditation.
Anthony J. Jannetti, Inc. is a provider approved by the California Board of Registered Nursing, provider number CEP 5387. Licensees in the state of California must retain this certificate for four years after the CNE activity is completed.
This article was reviewed and formatted for contact hour credit by Rosemarie Marmion, MSN, RN-BC, NE-BC, AMSN Education Director.
Adams, M., Holland, N., & Urban, C. (2017). Pharmacology for nurses: A pathophysiologic approach (5th ed.). Boston, MA: Pearson.
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Frandsen, G., & Pennington, S.S. (2014). Abrams' clinical drug therapy: Rationales for nursing practice (10th ed.).
Philadelphia, PA: Wolters Kluwer. Grossman, S.C., & Porth, C.M. (2014). Porth's pathophysiology: Concepts of altered health states (9th ed.). Philadelphia, PA: Wolters Kluwer.
Hepatitis B Foundation. (2017). What is hepatitis B? Retrieved from http://www.hepb. org/what-is-hepatitis-b/what-is-hepb/
Karch, A.M. (2017). Focus on nursing pharmacology (7th ed.). Philadelphia, PA: Wolters Kluwer.
Kee, J.L., Hayes, E.R., & McCuistion, L.E. (2015). Pharmacology: A patient-centered approach. St. Louis, MO: Elsevier Saunders.
Kumar, R., Perez -Del-Pulgar, S., Testoni, S., Lebosse, F., & Zoulim, F. (2016). Clinical relevance of the study of hepatitis B virus covalently closed circular DNA. Liver International, 36(Suppl. 1), 72-77. doi: 10.1111/liv.13001
McCance, K.L., Huether, S.E., Brashers, V.L., & Rote, N.S. (2010). Pathophysiology: The biologic basis for disease in adults and children (6th ed.). Maryland Heights, MO: Mosby Elsevier.
Moon, W.R., Moon, D.S., Kim, J.A., Yoon, Y, Choi, B.S., Chung, C.H., & Park, S.G. (2015). Reactivation of hepatitis B (reverse seroconversion) after melphalan/dexamethasone therapy for primary amyloidosis: A case report. Journal of Medical Case Reports, 9(122), 2-4. doi:10.1186/s13256-015-0610-z
Oakes, K. (2014a). Chronic hepatitis B part 1: Hepatitis B: Prevalence and pathophysiology. Nursing Times, 110(7), 12-16.
Oakes, K. (2014b). Chronic hepatitis B part 2: Management of chronic hepatitis B virus. Nursing Times, 110(8), 20-24.
Penkalski, M.R., Felicilda-Reynaldo, R.F., & Patterson, K. (2017). Antiviral medications, part 2: HIV antiretroviral therapy. MEDSURG Nursing, 26(5), 327-331.
Terrault, N.A., Bzowej, N.H., Chang, K.M., Hwang, J.P., Jonas, M.M., & Murad, M.H. (2016). AASLD guidelines for treatment of chronic hepatitis B. Hepatology, 63(1), 261-283.
Vallerand, A.H., Sanoski, C.A., & Deglin, J.H. (2013). Davis's drug guide for nurses (13th ed.). Philadelphia, PA: F.A. Davis.
World Health Organization (WHO). (2015). Guidelines for the prevention, care, and treatment of persons with chronic hepatitis B infection. Retrieved from http:// apps.who.int/iris/bitstream/10665/ 154590/1 /9789241549059_eng.pdf
Jo Ellen Branstetter-Hall, PhD, RN, is Assistant Professor, School of Nursing, Missouri State University, Springfield, MO.
Rhea Faye D. Felicilda-Reynaldo, EdD, RN, is Associate Professor, School of Nursing and Dental Hygiene, University of Hawaii at Manoa, Honolulu, HI; and a MEDSURG Nursing Editorial Board Member. For comments and to suggest topics for the "Nursing Pharmacology" feature, contact her at firstname.lastname@example.org
TABLE 1. Serologic Markers [HB.sub.s]Ag Total IgM Anti- Interpretation anti- anti- [HB.sub.s] [HB.sub.c] [HB.sub.c] - - - - Never infected + ([dagger]) - - - Early acute infection or up to 18 days post -vaccination + + + - Acute infection - + + - Recovered from past infection and immune + + - - Chronic infection - + - - False positive (susceptible) ;past infection; low-level chronic infection [double dagger]; passive transfer to baby - - - + Immune if concentration is >10 Miu/Ml; passive transfer after HB immune globulin ([dagger]) Should be confirmed to rule out false positive ([double dagger]) Persons positive for only anti-HBc are not usually infective except through blood transfusion or organ transplantation. Source: CDC, 2015 TABLE 2. Diagnostic Findings by Phase of HBV Infections Phase Viral Load [HB.sub.s]Ag Anti-[HB.sub.s] 1 (Immune High Pos Neg tolerant) 2 (Immune Fluctuating Neg Neg active) 3 (Inactive Low or Neg Neg Pos carrier) 4 (Reactivation) Spikes Pos Below protective level Phase [HB.sub.e]Ag Anti-[HB.sub.e] ALT 1 (Immune Pos Neg Normal tolerant) 2 (Immune Neg Pos Increased active) 3 (Inactive Neg Pos Normal carrier) 4 (Reactivation) Neg Neg Increased Phase Liver Inflammation and/or Fibrosis 1 (Immune None or minimal tolerant) 2 (Immune Increased risk active) 3 (Inactive None or improved carrier) 4 (Reactivation) Moderate to severe ALT=alanine aminotransferase; Neg=negative; Pos=positive Sources: Kumar, Perez-Del-Pulgar, Testoni, Lebosse, & Zoulim, 2016; Moon et al., 2015; Oakes, 2014a; Terrault et al., 2016 TABLE 3. Current Antiviral Medications Drug ([dagger]) First-Line Second-Line Classification Entecavir X NRTI (Baraclude[R]) ([dagger]) Tenofovir disoproxil X NNRTI fumarate (Viread[R]) ([dagger]) Adefovir dipivoxil X NNRTI (Hepsera[R]) Lamivudine (Epivir[R], X NRTI Epivir-HBV[R]) Ribavirin (RibaTab[R]) X NRTI Telbivudine (Tyzeka[R]) X NRTI NRTI = nucleoside reverse transcriptase inhibitors, NNRTI = nonnucleoside reverse transcriptase inhibitors (NNRTIs) Source: Terrault et al., 2016
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|Author:||Branstetter-Hall, Jo Ellen; Felicilda-Reynaldo, Rhea Faye D.|
|Article Type:||Disease/Disorder overview|
|Date:||Nov 1, 2017|
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