What is the impact of antibiotics or vaccines in the prevention and control of hepatitis?

Hepatitis A

There are no recommendations for universal vaccination of health care workers.

Hepatitis B

Health care workers

Hepatitis B is an occupational risk for health care workers. Prior to the availability of vaccinations against hepatitis B, the incidence of hepatitis B in health care workers with frequent exposure to blood was reported as 1% per year in the US. The hepatitis B vaccination was introduced in 1982 in the US. The Centers for Disease Control and Prevention (CDC) recommends that health care workers should be vaccinated against hepatitis B. Surveillance of vaccination utilization revealed that in the US, 75% of health care workers in 2002 to 2003 were vaccinated against hepatitis B. There has been a decline in hepatitis B infections in health care workers in the US. In 1983 the incidence of hepatitis B infection among health care workers was 386 per 100,000 and this declined to 9.1 per 100,000 in 1995. The hepatitis B vaccination, along with the implementation of infection control precautions and post-exposure prophylaxis has made a significant impact in the incidence of hepatitis B infections in healthcare workers.

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Hemodialysis

Hepatitis B transmission between patients and staff has been recognized in dialysis units. In 1974, the incidence of hepatitis B newly acquired in hemodialysis patients was reported to be 6.2% in the US. With the introduction of the first guidelines in 1997 to control hepatitis B in the hemodialysis setting, including periodic HBsAg testing, isolation of HBsAg patients, and cleaning and disinfection practices, by 1980, the incidence of hepatitis B was reduced to 1% in the hemodialysis population. In 1982, vaccination against hepatitis B was recommended for hemodialysis patients and staff and by 2001, the incidence of hepatitis B infection was reduced to 0.05%. The hepatitis B vaccination has made a significant impact on the incidence of hepatitis B infection in hemodialysis patients and staff.

Which antibiotics or vaccine preparations play a major role in the prevention and control of hepatitis?

Hepatitis A vaccine preparations

There are two hepatitis A vaccine preparations available: Vaqta and Havrix. In an open-label randomized trial in adults, Vaqta and Havrix demonstrated similar immunogenicity. There have been no studies to compare Vaqta and Havrix specifically in the health care setting. There are no recommendations for routine vaccination of health care workers against hepatitis A.

Hepatitis B vaccine preparations

There are two hepatitis B vaccinations available: Energix-B and Recombivax HB. A literature review revealed that Energix-B and Recombivax HB have similar seroprotective effect. There have been no studies to compare Energix-B and Recombivax HB specifically in the health care setting.

What are the common antibiotics (or vaccines) used to prevent and control hepatitis, and what are key distinguishing features?

See Table I, Table II, and Table III for a summary of the common agents.

Table I.
Havrix Vaqta
Dose, interval Children and adolescents (> 12 months of age): 0.5mL Intramuscular (IM) at 0 and 6-12 monthsAdults: 1 mL IM at 0 and 6-12 months. Children and adolescents (>12 months): 0.5mL IM at 0 and 6-18 monthsAdults: 1mL IM at 0 and 6-18 months
Common side effects Children 12 to 25 months:- Injection site tenderness and redness. – Irritability- Drowsiness- Loss of appetiteAge ≥ 2 years: – Injection site tenderness- Headache Children 12 to 23 months: – Injection site tenderness- FeverAge ≥ 2 years:- Injection site tenderness- Headache
Contraindications Allergic reaction to:- Previous dose of any hepatitis A containing vaccine- Any component of Havrix- Neomycin Allergic reaction to:- Previous dose of any hepatitis A containing vaccine- Any component of Vaqta- Neomycin
Table II.
Recombivax HB Energix-B
Dose, interval 0-19 years of age: 5 mcg IM at 0, 1, 6 months (Pediatric/Adolescent formulation)11-15 years of age: 10 mcg at 0, 4-6 months (Adult formulation)≥ 20 years of age: 10 mcg at 0, 1, 6 months (Adult formulation)Predialysis and dialysis patients: 40mcg at 0, 1, 6 months (dialysis formulation)* 0-19 years of age: 10mcg at 0, 1, 6 months≥ 20 years of age: 20 mcg at 0, 1, 6 monthsAdults on hemodialysis: 40 mcg at 0, 1, 2, 6 months*
Common side effects Injection site: tenderness, swelling, rednessSystemic symptoms: fever, fatigue, headache, nausea, diarrhea, upper respiratory infection Injection site tendernessFatigue
Contraindications Allergic reaction to:- Any component of the Recombivax HB vaccine- Yeast Allergic reaction to:- Previous dose of any hepatitis B containing vaccine- Any component of Energix-B- Yeast

* The CDC recommends annual antibody testing for dialysis patients and a booster vaccination should be give when antibody levels decline to < 10 mIU/mL.

Table III.
Twinrix
Dose, intervals > 18 years of age:1 mL IM (deltoid) at 0, 1, 6 months
Common side effects – Injection site soreness, redness-Headache- Fatigue
Contraindications Allergic reaction to:- Previous dose of any hepatitis A-containing or hepatitis B-containing vaccine, or to any component of Twinrix- Yeast

Infants born to HBsAg positive mothers should also receive hepatitis B immune globulin (HBIG)

Twinrix is a combination vaccination against both hepatitis A and B and can be used in patients age 18 years or older that require immunization against both hepatitis A and B.

Current CDC recommendations for hepatitis A and hepatitis B vaccination

Hepatitis A vaccination is recommended for:

  • All children at age 1

  • Children and adolescents ages 2-18 who live in states or communities with a high incidence of disease

  • Travelers to intermediate or high rates of hepatitis A

  • Men who have sex with men

  • Users of illegal injection and non-injection drugs

  • Persons with clotting factor disorders

  • Persons how work with hepatitis A infected primates or with hepatitis A in a research laboratory

  • Persons with chronic liver disease

  • Anyone else who seeks long-term protection

Hepatitis B vaccination is recommended for:

  • All infants beginning at birth

  • Older children not previously vaccinated

  • Sex partners of people that are hepatitis B surface antigen positive

  • Men who have sex with men

  • People seeking evaluation or treatment of a sexually transmitted disease

  • Injection drug user

  • People with chronic liver disease

  • Patients with HIV

  • Patients with end stage renal disease, including predialysis, hemodialysis, peritoneal dialysis and home dialysis

  • Household contacts of people that are hepatitis B surface antigen positive

  • Healthcare and public safety workers exposed to blood or blood-contaminated body fluids

  • Residents and staff in institutions for the developmentally disabled persons

  • Travelers to intermediate or high rates of hepatitis B

  • Anyone else seeking long term protection

Available treatments, and the features that distinguish them, including efficacy and safety.

Acute hepatitis A

There is no specific treatment for hepatitis A, as most cases resolve spontaneously. The management of hepatitis A is symptomatic care and maintaining adequate hydration. Nausea is a common symptom of patients with hepatitis A, and it is imperative to maintain adequate hydration. Patients should also avoid hepatotoxic medications and practice good hand washing and cleaning.

Hepatitis A post-exposure prophylaxis with hepatitis A immune globulin or hepatitis A vaccination:

Hepatitis A immune globulin is effective in 80-90% of cases if given within 14 days of exposure. The CDC recommends hepatitis A immune globulin for post-exposure prophylaxis for contacts not previously vaccinated that are > 40 years of age, children < 12 months of age, immunocompromised people, those with chronic liver disease and in patients with a contraindication to hepatitis A vaccination. The hepatitis A vaccination is recommended for contacts 12 months to 40 years of age. Hepatitis A immune globulin is contraindicated in IgA deficiency due to the risk of anaphylaxis.

Acute hepatitis B

If acute viral hepatitis B precipitates acute liver failure, treatment with a nucleos(t)ide analog is a treatment option. If a patient develops prolonged prothrombin time or hepatic encephalopathy, these are indications of severe liver injury and high risk of acute liver failure respectively and one can consider treatment with lamivudine or telbivudine if the treatment duration is likely to be short; entecavir is another option. Given that patients with severe acute hepatitis B may need a liver transplant, reduction in hepatitis B (HBV) DNA would be one rationale for treatment. However, in the absence of features of acute liver failure, treatment is not indicated, as it does not change the natural history of the virus, and most patients spontaneously clear the virus.

Chronic hepatitis B

See Table IV and Table V.

Table IV.
PEG-IFNα Tenofovir Entecavir Lamivudine Adefovir Telbivudine
Dose, duration 180 mcg qw, 48 weeks 300 mg OD, 48 weeks 0.5 mg OD, 48 weeks 100 mg OD, 48-52 weeks 10 mg OD, 48 weeks 600 mg OD, 52 weeks
Loss of serum HBV DNA 25% 76% 67% 40-44% 21% 60%
HBeAb seroconversion 30% 21% 21% 16-21% 12% 22%
Durability of response NA NA 69% 50-80% 90% 80%

NB: Dosing information is for adult patients.

Table V.
PEG-IFNα Tenofovir Entecavir Lamivudine Adefovir Telbivudine
Dose, duration 180 mcg qw, 48 weeks 300 mg OD, 48 weeks 0.5 mg OD, 48 weeks 100mg OD 48-52 weeks 10 mg OD, 48 weeks 600 mg OD 52 weeks
Loss of serum HBV DNA 63% 93% 90% 60-73% 51% 88%
Durability of response 20% NA 3% < 10% 5% NA

NB: Dosing information is for adult patients.

Summary of the available agents with important PK/PD data, dosing information for prevention vs. treatment, drug-drug interactions, and adverse reactions.

See Table VI for a summary of the dose and side effects of chronic hepatitis B therapy agents.

Table VI.
Pharmacologic agent

Class of medication

 Dose Side effects
Pegylated Interferon α

Anti-viral, anti-proliferative, immunomodulator

 180 mcg subcutaneous once weekly for 48 weeks Influenza-like syndrome:FatigueWeight lossHair lossMyelosuppressionCan cause flare in ALT in 30-40% of patientsDepression, anxiety, suicidal tendency
Tenofovir

Nucleotide analog

 300 mg PO ODDose adjust if CrCl < 50 ml/min Reports of Fanconi’s syndromeRenal insufficiencyOsteomalacia
Entecavir

Nucleoside analog

 0.5 mg PO ODDose adjust if CrCl < 50 ml/min Well tolerated
Lamivudine

Nucleotide analog

 100 mg PO OD* no HIV co-infectionDose adjust if CrCl < 50ml/min Well tolerated
Adefovir

Nucleotide analog

 10mg PO ODDose adjust if CrCl < 50ml/min Possible nephrotoxicity
Telbivudine

Nucleoside analog

 600 mg PO ODDose adjust if CrCl < 50 ml/min Well toleratedCase reports of myopathy and peripheral neuropathy

Interactions of drugs used in the treatment of hepatitis B:

The reader is referred to the website: www.hep-druginteractions.org for a comprehensive list of interactions of the drugs used in the management of hepatitis B.

What controversies surround the key agents, if any, and what are the pros and cons for each drug?

Hepatitis A

Not applicable

Chronic hepatitis B

It is important to chose drugs that have minimal side effects and low resistance rates. Table VII summarizes the treatment duration, route of administration and resistance rates for drugs used to treat chronic hepatitis B.

Table VII.
PEG-IFNα Tenofovir Entecavir Lamivudine Adefovir Telbivudine
Duration of treatment:

HBeAg positive chronic hepatitis

 12 months ≥ 1 year * ≥ 1 year * ≥ 1 year * ≥ 1 year * ≥ 1 year *

HBeAg negative chronic hepatitis

 12 months > 1 year > 1 year > 1 year > 1 year > 1 year
Route of administration subcutaneous oral oral oral oral oral
Drug resistance — 3 years: 0% 5 years: 1% 5 years: 70% 5 years: 29% 2 years: 24%

* Treat for at least one year and continue for at least 6 months after anti-HBe seroconversion. There is however discussion that perhaps a more robust treatment endpoint in HBeAg positive chronic hepatitis should be considered.

Are there specific guidelines for the use of some or all of these agents?

Hepatitis A

Not applicable.

Chronic hepatitis B

First line therapy of chronic hepatitis B includes: tenofovir, entecavir and PEG-IFNα (in the absence of cirrhosis). The use of other nucleos(t)ide analogues including lamivudine, adefovir and telbivudine have higher resistance rates and can be used, although not preferred. See Table VIII.

Table VIII.
HBeAg HBV DNA ALT Management
+ > 20,000 IU/mL ≤ 2 x ULN – Observe and treat when ALT elevated- Consider a liver biopsy if: >40 years of age, ALT persistently high, or family history of HCC- Consider treatment if HBV DNA > 20,000 IU/mL and liver biopsy reveals moderate/severe inflammation or significant fibrosis
+ > 20,000 IU/mL > 2 x ULN – Observe 3-6 months and if no spontaneous HBeAg loss, treat- Consider liver biopsy prior to treatment if compensated- Treat if icteric or development of clinical decompensation
– > 20,000 IU/mL > 2 x ULN Recommend treatment
– > 2,000 IU/mL 1->2 x ULN Consider liver biopsy and treat if moderate to severe necroinflammation or significant fibrosis
– ≤ 2,000 IU/mL ≤ ULN Observe and treat if HBV DNA or ALT increase
+/- Detectable Cirrhosis

Compensated:

HBV DNA > 2,000 IU/mL: recommend treatment

HBV DNA < 2,000 IU/mL: If ALT elevated, consider treatment

Decompensated:

Discuss treatment and referral for liver transplant with a liver transplant center.
+/- Undetectable Cirrhosis

Compensated:

Observe

Decompensated:

Refer for liver transplant

Abbreviations: ULN – upper limit of normal

Monitoring for response to treatment:

If patients to not achieve a decrease in serum HBV DNA by at least 2 log after 6 months of nucleos(t)ide therapy, it is suggested to switch to a different treatment or add another medication.

Monitor for resistance to treatment:

  • Test HBV DNA by PCR every 3-6 months

  • Check medication compliance if breakthrough

  • Confirm antiviral resistance with genotype testing

Treatment considerations in special populations:

(i) Hepatitis B and HIV co-infection:

Co-infection of hepatitis B and HIV leads to faster progression of liver injury. Some oral nucleos(t)ide analogs have activity against hepatitis B and HIV. If treatment of chronic hepatitis B is indicated, the treatment choice is based on whether Highly Active Antiretroviral Therapy (HAART) will be used. It is important to be mindful that if HAART is used, in first 4-8 weeks, immune reconstitution may induce an immune response to HBV and result in liver damage. However there is no evidence to initiate HBV control before HAART. If HAART is not indicated, it is recommended to use drugs without any effect on HIV to reduce resistance.

(ii) Hepatitis B and hepatitis C co-infection:

Hepatitis C usually dominates in hepatitis B and hepatitis C co-infection, however, there are few data to guide therapy in this subset of patients.

(iii) Prophylactic treatment for immunosuppressive or chemotherapeutic therapy:

Hepatitis B can reactivate in hepatitis B carrier patients on immunosuppression or chemotherapy. Risk factors for reactivation include younger age, males, high pre-treatment ALT and HBV DNA. Prophylaxis with antiviral therapy should be initiated in hepatitis B carriers that are treated with chemotherapy or immunosuppressive therapy and treatment duration is guided by baseline HBV DNA. A meta-analysis of lamivudine prophylaxis reduced clinical and virologic reactivation by more than 90% and reduced mortality. For the duration of chemotherapy or immunosuppression of <12 months with baseline undetectable HBV DNA, lamivudine is recommended and telbivudine is another option. If longer treatment with chemotherapy or immunosuppression is required, tenofovir or entecavir are recommended.

References

Gibas, A, Blewett, DR, Schoenfeld, DA, Dienstag, JL. “Prevalence and incidence of viral hepatitis in health workers in the pre-hepatitis B vaccination era”. Am J Epidemiol. vol. 136. 1992. pp. 603-10. (An epidemiology paper that outlines the prevalence and incidence of viral hepatitis B in the healthcare setting in the US prior to the availability of hepatitis B vaccination.)

Simard, EP, Miller, JT, George, PA. “Hepatitis B vaccination coverage levels among healthcare workers in the United States, 2002-2003”. Infect Control Hospital Epidemiol. vol. 28. 2007. pp. 783-90. (A study that highlights vaccination coverage and differences in uptake among health care workers.)

Dinits-Pensy, M, Forrest, GN, Cross, AS, Hise, MK. “The use of vaccines in adult patients with renal disease”. Am J Kidney Dis. vol. 46. 2006. pp. 997-1011. (A review article that provides a summary of hepatitis B vaccination recommendations and efficacy in patients with renal disease.)

Braconier, JH, Wennerholm, S, Norrby, SR. “Comparative immunogenicity and tolerance of Vaqta and Havrix”. Vaccine. vol. 17. 1999. pp. 2181-4. (An open-label randomized trial comparing Havrix and Vaqta which revealed similar immunogenicity of these vaccinations against hepatitis A.)

Coates, T, Wilson, R, Patrick, G, Andre, F, Watson, V. “Hepatitis B Vaccines: Assessment of the seroprotective efficacy of two recombinant DNA vaccines”. Clinical Therapeutics. vol. 23. 2001. pp. 392-403. (A retrospective review of the literature to assess and compare the efficacy of Recombivax HB and Energix-B.)

Lok, AS, McMahon, BJ. “AASLD Practice Guideline Update. Chronic Hepatitis B: Update 2009”. Hepatology. vol. 50. 2009. pp. 1-33. (This reference summarizes the American Association for the Study of Liver Diseases (AASLD) guidelines on the management of chronic hepatitis B including treatment recommendations, medication dosing, efficacy and resistance.)

Boyer, TD, Manns, MP, Sanyal, AJ. “Zakim and Boyer's Hepatology: A textbook of liver disease”. Elsevier. 2012. pp. 531-63. (The chapters on Hepatitis A and Hepatitis B provide the reader with a thorough overview on the epidemiology, pathogenesis, diagnosis and management of hepatitis A and B.)

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