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195 Cards in this Set
- Front
- Back
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What is Influenza named after?
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Haemophilus influenzae b/c it was originally thought to be bacterial.
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What problems are inherant to how influenza is perceived by patients and healthcare providers?
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1. Patients doubt the seriousness of influenza.
2. Patients have inappropriate fear of vaccine. 3. Physicians do not translate knowledge to action. 4. Physicians still not comfortable with antiviral therapy. |
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How do seasonal influenza and pandemic influenza differ in mortality among patient populations?
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Seasonal influenza mortality is highest among patients 65 and over.
During pandemic influenza 50% of mortality occurs in patients under age 65 |
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Direct cost of influenza due to increased medical care is roughly ___ % of total cost.
Indirect costs, including ____ and ____, account for ___ % of total cost. |
10%
lost productivity employee absenteeisn 90% |
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Complications of Influenza
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* Exacerbation of underlying chronic medical conditions
* Upper respiratory tract disease (sinusitis, otitis media, croup) * Lower respiratory tract disease (pneumonia, bronchiolitis, status asthmaticus) - Primary influenza viral pneumonia - Secondary Bacterial Pneumonia (Most frequent: S. pneumococcus, S. aureus, H. influenzae) * Cardiac (myocarditis, pericarditis) * Musculoskeletal (myositis, rhabdomyolysis) * Neurologic (acute and post-infectious encephalopathy, encephalitis, febrile seizures, status epilepticus, Guillain-Barré Syndrome ) |
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Primary influenza pneumonia vs. Secondary bacterial pneumonia
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Primary influenza pneumonia:
- Occurs when influenza virus infection directly involves the lung - Typically producing a severe pneumonia - Clinical suspicion for primary influenza pneumonia should be raised when symptoms persist and increase instead of resolving in a patient with acute influenza - High fever, dyspnea, and even progression to cyanosis can be seen. Secondary bacterial pneumonia — The influenza virus appears to affect tracheobronchial epithelium, directly leading to a decrease in the size of the cells and loss of cilia. These events can predispose to bacterial infection of the lung (secondary bacterial pneumonia). |
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Factors Affecting Symptoms and Course of Disease
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A wide range of factors make the symptoms and the general course of influenza variable among individual patients. Age, immune system status, and the presence of underlying diseases may cause a more severe illness. In addition, viral strains and subtypes may differ in their virulence and in their presenting symptoms.
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Influenza Morphology
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1. Hemagglutinins (H):
- Bind to glycoproteins of epithelial cells - 3 human and 15 animal subtypes identified 2. Neuraminidases (N): - Aid in cell budding from the plasma membrane - 2 human and 7 animal subtypes identified 3. Matrix Protiens (M): - ~3000 within the lipid bilayer - Uncoating of virus and endocytosis related activities |
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Influenza Virology
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Orthomyxoviridae family
Cause respiratory illness in humans and animals 3 Genera: A, B, C |
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Is influenza A a human pathogen or animal pathogen?
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both
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Is influenza B a human pathogen or animal pathogen?
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human only
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Is influenza C a human pathogen or animal pathogen?
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No, neither
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Do antigenic shift and/or antigenic drift occur in influenza A?
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yes both
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Do antigenic shift and/or antigenic drift occur in influenza B?
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drift only
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Do antigenic shift and/or antigenic drift occur in influenza C?
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drift only
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What is Antigenic shift?
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Antigenic shift is the process by which at least two different strains of a virus (or different viruses), especially influenza, combine to form a new subtype having a mixture of the surface antigens of the two original strains. (genetic reassortment)
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What is Antigenic drift?
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Antigentic drift is a point mutation of hemagglutinin and neuraminidase gene.
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How is Novel H1N1 a product of Triple Reassortment
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~ 1998, classical swine (H1N1) reassorted with human A(H3N2) and an avian virus to create a triple reassortant H3N2 swine virus
Shortly after 1998, classical swine H1N1 reassorted again with triple reassortant H3N2 swine virus resulted in the generation of further triple reassortant swine A(H1N1) and A(H1N2) viruses Since 1999, there has been significant antigenic drift within the various triple reassortant H1 viruses |
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How is Novel H1N1 a product of Triple Reassortment
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~ 1998, classical swine (H1N1) reassorted with human A(H3N2) and an avian virus to create a triple reassortant H3N2 swine virus
Shortly after 1998, classical swine H1N1 reassorted again with triple reassortant H3N2 swine virus resulted in the generation of further triple reassortant swine A(H1N1) and A(H1N2) viruses Since 1999, there has been significant antigenic drift within the various triple reassortant H1 viruses |
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Was H1N1 new to humans?
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No
A(H1N1) viruses circulated in humans from 1918 until the A(H2N2) influenza pandemic of 1957. During this period there was substantial antigenic drift of A(H1N1) viruses in humans away from the 1918 virus (2, 13). A(H1N1) influenza viruses from the early 1950s reemerged in humans in 1977 (14). From 1977 to 2009, there was substantial further antigenic evolution of the human A(H1N1) viruses that was sufficient to warrant eight updates of the H1 component of the influenza virus vaccine (15). This Substantial antigenic drift of A(H1N1) in humans away from the 1918 virus caused an Antigenic gap between swine H1 and human seasonal H1. Swine became a reservoir with pandemic potential that we have little immunity to |
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How is influenza activity measured?
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1. Office, clinic, or ER visits for febrile respiratory disease
- Increased Antibiotic usage - Vaccination decreases antibiotic use of influenza associated illnesses by 25% 2. School Absenteeism: - Children share germs effectively and therefore are important piece of viral dissemination - > 50% of isolates during initial phases of epidemic 3. Industrial losses: - Vaccination reduces cost from work absenteeism. - Reductions of 34-44% in MD visits and 32-45% in lost work days. 4.Excess morbidity/mortality: - Influenza A causes winter epidemics - Hospitalization rates linearly related to death rates attributable to influenza and pneumonia |
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In a typical year, during the peak of the season, how many deaths are due to influenza?
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approx. 10%
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Influenza Transmission & Replication
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* 1-4 day incubation period (average = 2 days)
* Transmitted via aerosolized droplets to next victim(Maximum communicability occurs 1-2 days before onset to 4-5 days after) * Invades respiratory tract epithelial cells * Replication leads to nasal and tracheobronchial epithelial injury |
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Supportive Care for influenza:
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1. APAP—for aches, not fever. The fever is an effective host defense because it slows viral replication. Obviously high fevers or fevers in children prone to febrile convulsions should be suppressed. (See A for brief discussion of temperature dependence of influenza virus replication.)
Warm Environment--This has to do with keeping the virus out of the lungs by keeping the temperature of the bronchial epithelium as high as possible. The only death in the 1976 Swine Flu virus outbreak at Ft. Dix, New Jersey, occurred in an Army recruit who was on a strenuous march during a very cold night. He probably "sucked" the virus down into his lungs while his lower respiratory tract epithelium was cooled below core body temperature. Drink lots of Fluids--Maintaining hydration helps maintain the "tracheal toilet." (Pulmonary mucous secretions amount to about 200 cc/day which are pushed up the trachea by the ciliated epithelium and swallowed.) The mucous flow helps protect the lungs. Cough Suppressants--There is controversy about the use of cough suppressants. Some pulmonologists object to the use of cough suppressants in almost all situations, while others believe they are appropriate for dry non-productive coughs such as those that occur early in influenza. We are in the latter group. Rest is needed because physical activity increases oxygen requirements and therefore breathing. This has two effects: 1) deep breathing is more apt to "suck" the virus down the respiratory tract into terminal bronchi and alveoli; 2) deep breathing cools the epithelium, thereby increasing the efficiency of viral replication. Flu viruses grow very poorly at 37 degrees C and best at 33-35 degrees C. |
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Which s/sxn is indicative of peak viral shedding?
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Abrupt onset
Fever, usually over 100 F Nonproductive cough |
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Which s/sxn is indicative of Cytokine release?
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Chills and/or sweats
Headache Myalgia Sore throat Substantial soreness Photophobia, ocular problems |
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Time Course of Influenza Symptoms
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The onset of illness usually begins 18 to 72 hours after incubation, depending on the concentration of transmitted virus.
fever days 2-5 HA, malaise, myalgia days 2-5 Nasal obstruction & discharge, Throat pain, Cough days 2 - 10 |
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Influenza vs. Common Cold S/SXN
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Onset:
- Influenza - Sudden - Cold - Gradual Fever: - Influenza - characteristic high fever (over 101 deg) lasts 3-4 days - Cold - rare Cough: - Influenza - nonproductive, may become severe - Cold - hacking Headache: - Influenza - prominent - Cold - rare Myalgia - Influenza - usual, often severe - Cold - slight Fatigue; weakness - Influenza - can last 2 -3 weeks - Cold - very mild Extreme exhaustion - Influenza - Early and prominent - Cold - never Chest discomfort - Influenza - common - Cold - mild to moderate Stuffy nose - Influenza - soemtimes - Cold - common Sneezing - Influenza - sometimes - Cold - usual Sore throat - Influenza - sometimes - Cold - common |
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How do s/sxn differ in children vs other populations affected by influenza?
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Children tend to experience similar symptoms, although abdominal symptoms and myalgia may occur more frequently. Their maximum temperatures may also be higher, prompting febrile convulsions. However, clinicians should be aware that symptoms such as headache and malaise are difficult for children to verbalize and thus, they may actually occur much earlier than it first appears
Typical signs and symptoms in adults include an abrupt onset of symptoms, fever usually >100ºF that peaks within 24 hours and persists from 1 to 5 days, nonproductive cough, chills, headache, myalgia, sore throat, anorexia, and malaise. Malaise may be severe and last for several days, differentiating influenza infection from other common respiratory illnesses. Other symptoms may include substernal soreness, photophobia, and other ocular problems, and GI distress, including nausea, abdominal pain, and diarrhea, although these symptoms are rarely prominent. |
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Diagnosing Influenza
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* Symptoms + epidemiology
- “Classical symptoms” during influenza season Test available when Nonclassical symptoms or classical sxn not in season * Antigen-based rapid tests (<30 minutes) * Direct fluorescent antibody (DFA) (0.5-3 hours) * PCR (6-24 hours, When maximal sensitivity desired) * Culture (24-48 hours, Confirm antigen/DFA; obtain isolates for surveillance) |
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Influenza Vaccination
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* Immunization is the primary method for preventing influenza and complications.
* Intramuscular Injection (deltoid preferred for adults) * Composition: - Trivalent (Contains two type A and one type B antigen) - Two Preparations: Subvirion and purified surface-antigen - Grown in embryonated hens’ eggs * Prime Time: - Influenza season occurs during fall/winter months - Vaccinate at beginning of season because it takes 2 weeks to mount an effective immune response - (Children:Sept; Elderly: Sept-Oct) |
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Vaccine Components
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Standardized to contain hemagglutinins and neuraminidases of strains likely to be circulating in the U.S. during the upcoming season
Virus has been made noninfectious. You can not get influenza from the vaccine. Do not give to individuals with an allergy to eggs or history of GBS. Best to avoid administration to acutely ill patients because immune system is already working overtime. The current vaccine is made from purified and formalin-inactivated viruses that have been grown in embryonated chicken eggs. Another vaccine is in development using a live but weakened influenza virus. Most preparations contain thimerosal as a preservative. Today there is a limited supply of thimerosal free influenza vaccine but manufacturers are expected to increase this supply. |
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Recommendations from the CDC Advisory Committee on Immunization Practices
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* Annual vaccination of all persons ≥6 months in age
- Persons at higher risk (i.e. target groups) should continue to be focus of vaccination efforts & take priority if vaccine shortages * Children aged 6 months to 8 years: 2 doses of a 2010-11 seasonal influenza vaccine (minimum interval: 4 weeks) recommended for: - Unknown vaccination status - Those who have never received seasonal influenza vaccine - Those who received seasonal vaccine for first time in 2009-10 but received only 1 dose - Those who did not receive at least 1 dose of the 2009-10 H1N1 monovalent vaccine regardless of previous influenza vaccine history |
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Target Patients for Influenza Vaccination
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1. Persons at high risk for complications (priority patients)
- Persons > 65 years old - Adults and children with metabolic diseases (DM, immunosuppression, renal impairment, hemoglobinopathies) that required medical treatment the preceding year for their disease - Residents of Long Term Care (LTC) facilities - Adults AND children > 6 months old with chronic pulmonary or cardiovascular conditions (including asthma) - Children/teenagers (6 mo. - 18 years) receiving long-term aspirin therapy - Women in the 2nd or 3rd trimester of pregnancy during influenza season 2. People who may transmit influenza - Physicians, nurses, and others in LTC facilities; hospital, clinic, and emergency departments who have patient contact - Home care providers - Household members living with priority patients - Household contacts of children 0-5 months old. 3. Persons age 50-64 - Have increased prevalence of high-risk conditions. - Will still benefit from vaccination: - less missed work - fewer medical visits and expenses - decreased risk of passing the virus to friends who are priority patients. |
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Influenza Vaccine Efficacy
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Immunocompetent:
- 70-90% efficacy in healthy (> 6 years of age) - Variable antibody response among high risk children Elderly (> 65 years): - 58% efficacy vs. respiratory illness, but may be less - 50-60% effective in preventing hospitalization for P/I among LTC residents and 80% effective in preventing death |
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Influenza Vaccine Adverse Effects
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* Injection site soreness
-suggest premedication to reduce incidence * Systemic febrile reaction * Hypersensitivity reaction to egg protein * Guillain-Barre syndrome (1/1,000,000) |
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Guillain-Barré Syndrome and TIV
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* 1976 swine influenza vaccine associated with 1 additional case of GBS per 100,000 persons
* No consistent evidence for causal relation between subsequent vaccines and GBS * Influenza virus infection is a known trigger of GBS - Frequency of influenza-related GBS is ~4-7 times higher than vaccine-associated GBS * Persons with prior GBS have a greater likelihood of subsequent GBS - Persons not at high risk for severe influenza and known to have had GBS within 6 weeks should not be vaccinated |
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Intranasal Influenza Vaccine (FluMist™ – MedImmune)
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* Live vaccine
- Antigenically representative viruses (A/H1N1, A/H3N2, B) - Cold-adapted - Temperature-sensitive - Attenuated * Intranasal administration induces protective mucosal and serum antibodies * Efficacy 85-100% * Indicated for prevention of influenza in: - Healthy children and adolescents 2-17 years of age - Healthy adults 18-49 years of age * Contraindicated in: - Children <2 and adults 50 years of age - Children <5 with possible reactive airways disease - Children or adults with significant risk factors for influenza illness & complications - Immunocompromised patients or those receiving immunosuppressive drugs - Children receiving aspirin or aspirin-containing therapy - History of allergy to eggs or egg products * Most common adverse effects = runny nose, nasal congestion, headache, cough |
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Fluzone High-Dose® Vaccine
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* Indicated in patients ≥65 years of age
* Covers same viral strains as standard vaccines but contains four time the quantity of antigenic viral proteins (hemagglutinin) * Intended to produce more vigorous immune response in older patients * Elicits significantly greater antibody titer, but no data concerning whether more effective than standard-dose vaccines |
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Pharmacologic Agents for treatment of influenza
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* M2 protein Inhibitors(Adamantanes)
- Amantadine (Symmetrel®) - Rimantadine (Flumadine®) * Neuraminidase Inhibitors - Zanamivir (Relenza®) - Oseltamivir (Tamiflu®) |
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Pharmacologic Treatment of Influenza
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* None definitely proven to prevent influenza-related complications in adults
* Must be administered within 2 days of onset of flu-like symptoms - Preferably 36 hours after onset of symptoms * Reduces symptom duration by ~ 1-1.5 day * Duration of treatment is 5 days * To reduce resistance, M2 inhibitors should be discontinued appropriately (Discontinue within 3-5 days after start of therapy or 24-48 hrs after symptoms are gone to minimize risk of resistance.) |
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Amantadine Pharmacology and Pharmicokinetics
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* MOA: Interferes with uncoating of influenza A through inhibition of viral M2 protein; may also interfere with viral assembly after replication
* Renal excretion * GI and CNS adverse Effects (5-10%) * Symmetrical tricyclic amine * These antivirals concentrate in lysosomes, increasing the lysosomal pH and interfering with membrane fusion. It appears to inhibit latestage uncoating of influenza A virions. Influenza B lacks the M2 protein. * A single amino acid change in the M2 protein results in resistance to both Amantadine and Rimantadine * Cost: $11 per 5 day course |
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Rimantadine Pharmacology and Pharmicokinetics
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* Similar MOA to amantadine: Interferes with uncoating of influenza A through
inhibition of viral M2 protein; may also interfere with viral assembly after replication * Hepatic excretion, minimal renal excretion * GI and CNS adverse effects less frequent (3-5%) & milder * Symmetrical tricyclic amine * These antivirals concentrate in lysosomes, increasing the lysosomal pH and interfering with membrane fusion. It appears to inhibit latestage uncoating of influenza A virions. Influenza B lacks the M2 protein. * A single amino acid change in the M2 protein results in resistance to both Amantadine and Rimantadine * Cost: $21 per 5 day course |
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M2 Protein Inhibitors:
Indications |
Amantadine: Children & Adults for both treatment & prophylaxis
Rimantadine: Adults: treatment & prophylaxis Children: Prophylaxis only |
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M2 Protein Inhibitors:
Adult Dose |
Amantadine:
Based on CrCl: If >80 ml/min, 100 mg BID Rimantadine 100mg BID in healthy; 100mg QD if CrCl <10 or severe hepatic dysfunction |
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M2 Protein Inhibitors:
Renal Excretion |
Amantadine
Excreted unchanged in urine Rimantadine Partially excreted in urine |
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M2 Protein Inhibitors:
Hepatic Excretion |
Amantadine
None Rimantadine Mostly metabolized in liver |
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M2 Protein Inhibitors
Adverse Effects |
* CNS AE incidence increased in elderly
* Amantadine Confusion, lightheadedness, nervousness, insomnia; urinary retention; dry mouth, nausea, constipation, diarhea Rimantadine Same, but less than amantadine |
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Neuraminidase Inhibitors:
MOA |
Neuraminidase on the surface of the virus breaks down sialic acid in the epithelial cell, facilitating the release of newly formed virus and transmission across the mucous lining of the respiratory tract. By inhibiting this enzyme activity in both influenza type A and type B viruses, neuraminidase inhibitors effectively stop viral replication. The “selectivity” denotes their lack of activity against human neuraminidase
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Zanamivir (Relenza®) pharmacology and pharmcokinetics
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Treatment of influenza A & B for patients >7 years old
Prophylaxis of influenza A & B for patients >5 years old Dosage form: Inhaler Dose: 2 puffs (10 mg) BID for 5 days AE: H/A, cough, bronchospasms Caution in patients with asthma or COPD Advantage: Non-systemic, good for pregnant females Cost: $48/5-day course |
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Oseltamivir (Tamiflu®)
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* Treatment and prophylaxis of influenza A & B for patients >1 y.o.
* Dosage form: 75 mg capsule * Dose: 75 mg BID for 5 days. (If CrCl < 30ml/min, 75 mg QD for 5 days) * AE: N/V; Administer with food to decrease * Advantage: Ease of use, safe for high risk pulmonary patients * Oseltamivir is a Prodrug that undergoes activation via hepatic ester hydrolysis * At the recommended dose oseltamivir 75 mg twice daily for 5 days, there was a 1.3-day (30%) difference in the median time to improvement in subjects receiving Tamiflu compared with subjects receiving placebo twice daily for 5 days. Another study published in the same journal the previous year gave similar results. * Cost: $60/5-day course |
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Influenza in Children
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* High infection rates
* Frequent complications - Otitis media - Sinusitis - Late-onset bacterial pneumonia - Progressive primary viral pneumonia * Excess hospitalizations * Increased outpatient visits * Increased antibiotic use |
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Oseltamivir Therapy in Children
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* 36% reduction in median time to alleviation of symptoms
* 40% reduction in physician-diagnosed complications * 40% reduction in the risk of otitis media * 24% reduction in patients receiving antibiotic prescriptions |
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Oseltamivir Dosing in Children
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Weight based dosing:
15 kg or less (33 lbs) 30 mg bid 16 kg - 23 kg (34-51 lbs) 45 mg bid 24 kg - 40 kg (52-88 lbs) 60 mg bid > 40 kg (>88lbs) 75 mg bid |
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T or F
Chemoprophylaxis is similar to vaccination and is a reasonable substitute. |
FALSE
Not a vaccine substitute, but provides protection from variant strains not well-matched by vaccine. |
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Chemoprophylaxis
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* Chemoprophylaxis is NOT a substitute for vaccination
* Provides protection against variant strains not covered by vaccine * Critical adjunct in prevention and control of influenza during peak season. - Amantadine and rimatadine are 70-90% effective in preventing illness from Influenza A. - Oseltamivir – Protective efficacy estimated to be 74% - Although no formal FDA indication, prophylactic zanamivir has demonstrated a 79 percent rate of protection in unvaccinated patients. |
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Resistance of Influenza to Antiviral Drugs
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Data from 2007-08:
* Resistance to adamantanes = - 99.8% of influenza A (H3N2) viruses tested - 10.7% of A (H1N1) * Resistance to oseltamivir = - 10.9% of influenza A (H1N1) viruses tested -- Increased from 0.7% in 2006-07 -- Represents about 2% of all influenza viruses in 2007-08 -- No cross-resistance with adamantane-resistant viruses * 0% in A (H3N2) and influenza B * Resistance to zanamivir = 0% in all viruses tested 2009-2010 Season: * Novel H1N1, Seasonal A/H3N2, and Influenza B - resistant to Amantidine/Rimantidine * Seasonal A/H1N1 - resistant to Oseltamivir |
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Recommendations from the CDC Advisory Committee on Influenza Drug Treatment
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* The adamantanes (amantadine, rimantadine) were NOT recommended for treatment or prophylaxis of influenza during the 2009-2010 season b/c expected circulating strain of influenza A (H3N2) exhibited high resistance to these drugs
* Only oseltamivir and zanamivir were recommended b/c most resistance was in seasonal influenza A (H1N1), which was rarely seen last year * Recommendations for the 2010-11 season not yet available but should be similar |
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Antiviral Treatment for 2009 H1N1
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* All patients requiring hospitalization
* Patients at increased risk of complications - Children <2 years* - Adults 65 years and older - Pregnant women - Persons with immune suppression, chronic pulmonary (including asthma), cardiovascular (except hypertension), renal, hepatic, hematological (including sickle cell disease), neurologic, neuromuscular, or metabolic disorders (including diabetes mellitus) or > 65 years - Children <19 on chronic aspirin therapy * Early treatment with either oseltamivir or zanamivir * Clinicians should not wait for confirmatory tests to treat |
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Who should receive chemoprophylaxis?
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* All to LTC residents and unvaccinated staff during an institutional outbreak.
* Priority Patients vaccinated after influenza activity has begun and until immunity has developed. * Unvaccinated persons in frequent contact with priority patients. * Persons who have immune deficiencies. * Persons who have a contraindication to the vaccine and wish to avoid influenza illness. |
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Avian Influenza H5N1:
disease seen in birds |
Two types of disease seen in birds
* “Low pathogenic” form commonly causes mild symptoms. May easily go undetected * “High pathogenic” form causes disease affecting multiple organ systems. Mortality approaches 100%, often within 48 hours |
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Avian Influenza H5N1:
In humans |
* In humans, disease follows an unusually aggressive clinical course which resembles highly pathogenic form in birds. Most human cases have occurred in children and young adults
* Human-to-human transmission is apparently rare and always involves close contact of infected individual. True human-to-human transmission often impossible to prove |
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Epidemiology and Virulence of H5N1 Influenza
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* As of 10/18/10, 507 human cases reported in 15 countries
* 302 deaths = ~60% mortality |
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Why the high mortality with H5N1?
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* Infects lung cells very efficiently
* Incites extraordinary cytokine responses * Virulence factors appear to be linked to the H5 hemagglutinin gene |
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Clinical Features of Avian Influenza
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* Incubation appears to be longer than seasonal influenza = 2-8 days (possibly as long as 17 days) compared to 2-3 days
* Initial symptoms: high fever (>38oC) and influenza-like symptoms - Diarrhea, vomiting, abdominal pain, chest pain, bleeding from nose and gums have been reported in many patients - Watery diarrhea without blood appears to be common - Acute encephalitis has been reported as presenting symptom * Lower respiratory tract manifestations develop early - Dyspnea, respiratory distress usually develop within 5 days - Bloody sputum may be present - Other features of viral pneumonia common * Clinical deterioration is rapid, multi-organ dysfunction often develops - Leukopenia (usually lymphopenia) - mild-to-moderate thrombocytopenia - elevated aminotransferases - disseminated intravascular coagulation (DIC) |
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Role of Drug Therapy for Avian Influenza
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* Neuraminidase inhibitors
- Have activity against H5N1 strains - Clinical data very limited, currently favoring oseltamivir - Appear to improve survival if started early (<48 hrs) - Increased doses (oseltamivir 300 mg/day) recommended by some authorities for more severe cases - Duration = 5 days, but may be increased to 10 days if no improvement after initial regimen - Resistance negligible, but likely to increase with widespread use during pandemic * M2 inhibitors - Clinical data very limited, not recommended first-line therapy - Some H5N1 strains are already fully resistant * Combination therapy - No clinical data, but may be considered if clinical progression on monotherapy |
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Drug Therapy Regimens for Avian Influenza
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* Antivirals (either oseltamivir or zanamivir x 7-10 days after last exposure) recommended by WHO for chemoprophylaxis of infection in certain individuals:
- High risk exposure group (antivirals SHOULD be given): --Household or close family contacts of a strongly suspected or confirmed H5N1 patient, because of potential exposure to a common environmental or poultry source as well as exposure to the index case - Moderate risk exposure group (antivirals MAY be given): --Personnel involved in handling sick animals or decontaminating affected environments (including animal disposal) --Individuals with unprotected and very close direct exposure to sick or dead animals infected with the H5N1 virus --Health care or laboratory personnel in close contact with strongly suspected or confirmed H5N1 patients, or handling inadequately screened/sealed body fluids without any or with insufficient personal protective equipment |
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H5N1 Vaccine
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* First human H5N1 vaccine approved in U.S. on 4/17/06
* Vaccine could provide early limited protection during pandemic while another vaccine tailored to the actual pandemic strain of the virus could be developed and produced * Vaccine produced from human strain by Sanofi Pasteur Inc. * Intended for adults 18-64 years of age at increased risk of exposure to virus * Two 90 mcg IM injections, given approximately one month apart * Vaccine will not be sold commercially. Purchased by federal government for inclusion within the Strategic National Stockpile for distribution by public health officials if needed * Clinical evidence for vaccine efficacy: 45% of individuals who received the 90 mcg dose developed antibodies at a level expected to reduce the risk of disease |
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Prevention of Avian Influenza
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* In areas free of disease, poultry and poultry products can be prepared and consumed as usual
* In areas experiencing outbreaks: - Avoid all direct contact with birds, including poultry - Avoid touching surfaces contaminated with bird feces or fluids - Poultry must be properly prepared and thoroughly cooked - Forget “runny” yolks - Raw eggs should not be consumed in any form * Avoid places such as poultry farms and bird markets * Avoid areas where free-ranging poultry are present * Do not swim in water where ducks or other birds may have been present * Avoid other risky behaviors: slaughtering, defeathering, butchering, or preparation of birds for consumption |
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What would happen in the event of a global pandemic of avian influenza?
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* Mortality resulting from a global pandemic is likely to be very high, although no one has any clue what it would actually be
* Estimates of infection range from 25% to 50% of the global population, with mortality rates between 1% and 5% of infected individuals * Current H5N1 is not highly transmissible, but that could be changed through: - A “re-assortment” event in which genetic material from human and avian viruses is exchanged - “Adaptive mutation” during which the virus slowly mutates during successive human infections |
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What three conditions must be met for a pandemic?
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* Emergence of new influenza subtype
* New subtype infects humans and causes serious disease * New subtype spreads easily and sustainably among humans |
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Hepatitis B Virus
Is this an RNA or DNA virus? |
Partially dsDNA
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Hepatitis B Virus
Is this virus enveloped or non-enveloped? |
Enveloped
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Hepatitis B Virus classification
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Hepadnaviridae
Multiple Serotypes and Genotypes A-G |
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is HBV more or less infectious than HIV?
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HBV is 50-100 times more infectious than HIV
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What is the leading cause of HCC?
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Hepatitis B
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Risk Factors for HBV Infection
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* IV Drug Use
* Transfusion or transplantation * Occupational exposure * Use of non-disposable needles * Perinatal transmission * Sexual transmission |
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Who has a better prognosis:
Patient with HBeAg (+) or Patient with HBeAg (-)? |
The prognosis of CHB HBeAg (-) patients is reportedly poorer than HBeAg (+)
ones. |
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What does it mean that a pt is HBeAg (-) ?
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* HBV reverse transcriptase enzyme is sloppy, some patients develop mutations in
the HBV genome that prevent HBeAg formation despite active HBV replication. |
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Steps to HBV infection
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Step 1 – Viral Entry into Cell
- HBV binds to the host cell membrane - HBV fuses with the membrane and the core enters the cells cytoplasm - ds DNA genome is completed by enzymes contained with the core Step 2 – Intracellular Replication - Viral DNA enters the host nucleus - Transcription of DNA to genomic and messenger RNA - RNA enters cytoplasm - Viral proteins are translated - Core assembles around + sense RNA - + sense RNA copied to - sense DNA - - sense DNA partly copied to +sense Step 3 – New Virion Budding - Virus with partly ds DNA leaves the cell - Virus buds through the host cell membrane - Core associates with HbS antigen in the cell membrane |
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Hepatitis B – Clinical Features
Incubation period |
Average 60-90 days
Range 45-180 days |
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Hepatitis B – Clinical Features
Clinical illness |
jaundice
<5 yrs, <10% >5 yrs, 30%-50% |
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Hepatitis B – Clinical Features
Chronic infection |
<5 yrs, 30%-90%
>5 yrs, 2%-10% |
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Hepatitis B – Clinical Features
Premature mortality from chronic liver disease |
15%-25%
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Who Should be Screened for HBV?
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* Patients with elevated LFTs or evidence of active liver disease without an identified cause
* Anyone with one or more of the following risk factors: - Born in areas of high or intermediate risk (Asia, Africa, South Pacisic Isles, Middle east, Malta, Spain, the arctic, Canada, Alaska, Greenland, Caribbean, South America, central america, Eastern Europe) - US born and not vaccinated with parents born in high risk countries - Household and sexual contacts of HBsAg (+) persons - IVDA - multiple sex partners or hx of STDs - MSM - Inmates of correctional facilities - Chronically elevated Ast or ALT - Infected with HCV or HIV - Patients on renal dialysis - All pregnant women - Persons needing immunosuppressive therapy |
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Diagnosing HBV
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* Initial Screening: HBsAg, anti-HBc (IgG and IgM), anti-HBs
* All HBsAg+ subjects: HBeAg, anti-HBe, quantitative HBV DNA level by PCR * HBsAg+ > 6 months considered to have chronic Hepatitis B |
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Interpreting Diagnostic Tests for HBV:
HBsAg + Anti-HBs - HBeAg + Anti-HBe - Anti-HBc IgG + Anti-HBc IgM + HBV DNA (PCR) + |
Acute Infection
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Interpreting Diagnostic Tests for HBV:
HBsAg - Anti-HBs + HBeAg - Anti-HBe +/- Anti-HBc IgG + Anti-HBc IgM - HBV DNA (PCR) - |
Immunity due to past exposure and naturally clearing the virus
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Interpreting Diagnostic Tests for HBV:
HBsAg - Anti-HBs + HBeAg - Anti-HBe - Anti-HBc IgG - Anti-HBc IgM - HBV DNA (PCR) - |
Immunity due to vaccination
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Interpreting Diagnostic Tests for HBV:
HBsAg + Anti-HBs - HBeAg + Anti-HBe - Anti-HBc IgG + Anti-HBc IgM - HBV DNA (PCR) + |
Chronic HBV infection
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Interpreting Diagnostic Tests for HBV:
HBsAg + Anti-HBs - HBeAg - Anti-HBe - Anti-HBc IgG + Anti-HBc IgM - HBV DNA (PCR) + |
Chronic Precore Mutant
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Interpreting Diagnostic Tests for HBV:
HBsAg + Anti-HBs - HBeAg - Anti-HBe + Anti-HBc IgG + Anti-HBc IgM - HBV DNA (PCR) - |
Inactive carrier
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HBeAg(-) CHB: Mechanism of Precore Mutation
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The most common mutation is a guanine to adenine substitution at nucleotide 1896 in the precore region which results in a TAG stop codon which prevents HBeAg production
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Interpreting Liver Biopsies in HBV
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Graded by one of three systems:
- Ishak (0-6) - MERAVIR (0-4) - Knodell (0-4) 0 = No fibrosis 6 or 4 or 4 = cirrhosis note Knodell system has no "2" rating (0,1,3,4) |
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Other Baseline Evaluations for HBV
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* PT (INR), CBC, comprehensive metabolic panel, ferritin, TIBC, iron
* Anti-HAV (vaccinate if negative) * Anti-HCV * Screen for HCC: Ultrasound (AFP if US not available or cost is an issue) * Consider liver biopsy to grade and stage disease |
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Treatment of HBeAg+ Patient(Non-Cirrhotic) with < 20,000 IU/mL viral load, and normal ALT
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No treatment
Monitor Q6-12mos |
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Treatment of HBeAg+ Patient(Non-Cirrhotic) with < 20,000 IU/mL viral load, and elevated ALT
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Consider treatment
in those with significant histologic disease |
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Treatment of HBeAg+ Patient(Non-Cirrhotic) with > or = 20,000 IU/mL viral load, and elevated ALT
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Treat with
ETV, TDF, or PegINF |
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Treatment of HBeAg+ Patient(Non-Cirrhotic) with > or = 20,000 IU/mL viral load, and normal ALT
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Consider biopsy if
age>35, if biopsy shows significant inflammation or moderate fibrosis – treat Treatment with ETV, TDF, or PegINF preferred |
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Treatment of HBeAg- Patient(Non-Cirrhotic) with < 2,000 IU/mL viral load and normal ALT
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No treatment
Monitor Q6-12mos |
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Treatment of HBeAg- Patient(Non-Cirrhotic) with < 2,000 IU/mL viral load and elevated ALT
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Consider treatment
in those with significant histologic disease |
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Treatment of HBeAg- Patient(Non-Cirrhotic) with > or = 2,000 IU/mL viral load and normal ALT
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Consider biopsy if
age>35, if biopsy shows significant inflammation or moderate fibrosis – treat Treatment with ETV, TDF, or PegINF preferred |
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Treatment of HBeAg- Patient(Non-Cirrhotic) with > or = 2,000 IU/mL viral load and elevated ALT
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Treat with
ETV, TDF, or PegINF Long-term treatment required for NRTIs |
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Treatment for Patients with Compensated Cirrhosis
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Long term treatment
required Treat with TDF or ETV or combo (TDF + 3TC or ETV) |
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Treatment for Patients with decompensated Cirrhosis
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(ascites, jaundice,
variceal bleeding, hepatic encephalopathy) Waitlist for transplant Long term treatment required Treat with combo oral nucleosides, (TDF + 3TC or ETV) No interferon |
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Prognosis with Compensated vs. Decompensated Cirrhosis
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Much WORSE with decompensated
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Treatment Goals
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* Ultimate goal of treatment is to reduce risk of complications (cirrhosis and HCC) and to increase survival
GOALS: 1. Seroconversion from antigens to antibodies - Treatment Endpoint: HBeAg to anti-HBe, HBsAg to anti-HBs 2. Suppress viral replication - Treatment endpoint Lower the HBV DNA 3. Histologic / biologic improvement - Treatment endpoint: Less necrosis / inflammation on biopsy and normalize ALT |
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Anti-HBV Drugs
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* SQ Interferon and Pegylated Interferon
* FDA-approved Oral Nucleos(t)ide Analogues - Adefovir - Entecavir - Lamivudine - Telbivudine - Tenofovir |
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Advantages of pegylated interferons for treatment of HBV
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Longer t1/2
Weekly dosing Greater patient adherence Enhanced efficacy |
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Pegasys for treatment of HBV
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pegylated interferon alpha 2a
* 180 mcg SQ weekly x 48 weeks * Hepatically metabolized and renally cleared * Ready to use: 1-mL single dose vial containing 180 mcg / vial * Refrigerated |
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Peg Intron for treatment of HBV
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pegylated interferon alpha 2b
* 1.5 mcg/kg SQ weekly x 48 weeks * Renally cleared * Requires reconstitution: Single dose vials with lyophylized powder and 5 mL vials of sterile water diluent * Room temp until reconstituted then can be refrigerated for 24 hours prior to use |
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Interferon MOA
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* Activates Cellular Ribonucleases
- 2’ 5’ oligo A synthetase degrades viral mRNA - Protein kinase Suppresses viral replication * Increases HLA Class I antigen expression on the surface membranes of hepatocytes - Helps cytolytic T cells to recognize viral peptides - Enhances macrophage and natural killer cell activity |
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Adefovir (Hepsera)
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Adenosine analog
dose = 10 mg qd Note: nephrotoxicity |
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Entecavir
(Baraclude®) |
Guanosine analog
dose for treatment naïve = 0.5 mg QD dose for treatment experienced = 1 mg QD |
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Lamivudine
(Epivir-HBV®) |
Cytidine analog
dose = 100 mg QD Note: Drug of choice in pregnancy |
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Telbivudine
(Tyzeka®) |
Thymidine analog
dose = 600 mg QD Note: Myopathy, mitochondrial toxicity |
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Tenofovir
(Viread®) |
Adenosine analog
dose = 300 mg QD Note: Nephrotoxicity in HIV population |
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Advantages of pegylated interferons for treatment of HBV
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Longer t1/2
Weekly dosing Greater patient adherence Enhanced efficacy |
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Pegasys for treatment of HBV
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pegylated interferon alpha 2a
* 180 mcg SQ weekly x 48 weeks * Hepatically metabolized and renally cleared * Ready to use: 1-mL single dose vial containing 180 mcg / vial * Refrigerated |
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Peg Intron for treatment of HBV
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pegylated interferon alpha 2b
* 1.5 mcg/kg SQ weekly x 48 weeks * Renally cleared * Requires reconstitution: Single dose vials with lyophylized powder and 5 mL vials of sterile water diluent * Room temp until reconstituted then can be refrigerated for 24 hours prior to use |
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Interferon MOA
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* Activates Cellular Ribonucleases
- 2’ 5’ oligo A synthetase degrades viral mRNA - Protein kinase Suppresses viral replication * Increases HLA Class I antigen expression on the surface membranes of hepatocytes - Helps cytolytic T cells to recognize viral peptides - Enhances macrophage and natural killer cell activity |
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Adefovir (Hepsera)
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Adenosine analog
dose = 10 mg qd Note: nephrotoxicity |
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Entecavir
(Baraclude®) |
Guanosine analog
dose for treatment naïve = 0.5 mg QD dose for treatment experienced = 1 mg QD |
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Lamivudine
(Epivir-HBV®) |
Cytidine analog
dose = 100 mg QD Note: Drug of choice in pregnancy |
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Telbivudine
(Tyzeka®) |
Thymidine analog
dose = 600 mg QD Note: Myopathy, mitochondrial toxicity |
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Tenofovir
(Viread®) |
Adenosine analog
dose = 300 mg QD Note: Nephrotoxicity in HIV population |
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Nucleos(t)ide Analogues MOA
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* The nucleoside analog triphosphate anabolite competes with the endogenous nucleoside-triphosphates for uptake by viral reverse transcriptase and incorporation into viral DNA.
* If the drug-triphosphate is incorporated, the DNA chain cannot elongate because these agents lack the 3’ hydroxyl required for phosphodiester linkage and viral DNA chain elongation is terminated. * Without HBV reverse transcriptase synthesis of viral DNA, the cell cannot be productively infected with HBV and the HBV life-cycle is inhibited. |
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Factors to consider when choosing HBV treatment
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* Patient Willingness
* Efficacy and Durability * Development of Resistance * Side Effects * Genotype * Concomitant Meds / Disease States * Costs |
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Durability of response after HBeAg seroconversion
Pegylated interferon |
Unknown
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Durability of response after HBeAg seroconversion
Lamivudine (LAM) |
77%
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Durability of response after HBeAg seroconversion
Adefovir (ADV) |
91%
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Durability of response after HBeAg seroconversion
Entecavir (ETV) |
69%
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Durability of response after HBeAg seroconversion
Telbivudine (TLV) |
80%
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Durability of response after HBeAg seroconversion
Tenofovir (TDF) |
Unknown
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Serum HBV DNA loss
Pegylated interferon |
25%
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Serum HBV DNA loss
Lamivudine (LAM) |
44%
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Serum HBV DNA loss
Adefovir (ADV) |
21%
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Serum HBV DNA loss
Entecavir (ETV) |
67%
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Serum HBV DNA loss
Telbivudine (TLV) |
60%
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Serum HBV DNA loss
Tenofovir (TDF) |
76%
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HBeAg loss
PegINF |
30% at wk 48
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HBeAg loss
LAM |
32%
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HBeAg loss
ADV |
24%
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HBeAg loss
TLV |
26%
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HBeAg loss
TDF |
22%
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HBeAg loss
ETV |
22%
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HBeAg seroconversion
PegINF |
27% at wk 48
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HBeAg seroconversion
LAM |
16-18%
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HBeAg seroconversion
ADV |
12%
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HBeAg seroconversion
ETV |
21%
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HBeAg seroconversion
TLV |
22%
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HBeAg seroconversion
TDF |
21%
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HBsAg loss
PegINF |
3% at wk 72
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HBsAg loss
LAM |
<1%
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HBsAg loss
ADV |
0%
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HBsAg loss
ETV |
2%
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HBsAg loss
TLV |
<1%
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HBsAg loss
TDF |
3%
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ALT normalization
PegINF |
39%
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ALT normalization
LAM |
41-72%
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ALT normalization
ADV |
48%
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ALT normalization
ETV |
68%
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ALT normalization
TLV |
77%
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ALT normalization
TDF |
69%
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Histologic improvement
PegINF |
38%
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Histologic improvement
LAM |
49-56%
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Histologic improvement
ADV |
53%
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Histologic improvement
ETV |
72%
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Histologic improvement
TLV |
65%
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Histologic improvement
TDF |
74%
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List in order from the least to the highest viral replication:
HCV, HBV, HIV |
HIV < HCV < HBV
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What enzyme is associated with drug resistance?
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* HBV plymerase mutations cause drug resistance
* Significant, persistent, and progressive rise in HBV viral load by at least 1 log10 during treatment * Can result in hepatitis flare, rapid decline in liver function and disease progression |
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Which antivirals used to treat HBV have the lowest incidence of resistance?
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Entecavir (treatment naïve patients) < Tenofovir
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Adverse Effects of interferon
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Flu-like symptoms
Insomnia Psychiatric Disorders Depression, irritability Rash and Pruritis Anorexia Neutropenia Thrombocytopenia Thinning of hair Thyroid dysfunction |
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Adverse Effects NRTIs
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Well-tolerated
Nephrotoxicity (ADV, TDF) Myopathy (LdT) |
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pros and cons to treating HBV with Pegylated Interferon
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Pros
* Finite treatment duration * Not associated with the development of antiviral resistance * Genotypes A and B have higher rates of response than C and D Cons SQ Many adverse effects Cannot be used in patients with decompensated cirrhosis |
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Nucleos(t)ide Therapy pros vs cons
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Cons
Long-term therapy required Development of resistance Off treatment relapse or flares Some active against HIV Pros Oral Well tolerated 3TC drug of choice in pregnancy |
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Most expensive HBV drug
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Pegylated Interferon
$22497 |
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Monitoring During Treatment
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* HBV DNA and ALT Q12 weeks
* HBeAg/anti-HBe Q24 weeks in HBeAg + patients * If > or = 1 log IU/mL increase in serum HBV DNA in 2 consecutive samples taken 1 month apart - Order a genotype test to look for mutations in the HBV virus conferring drug resistance * HCC Screening - Q6 months with AFP and US particularly those at high risk – Asian men > 40 yrs and women > 50 yrs, Africans > 20 yrs, those with a family history of HCC, anyone > 40 yrs with ALT elevations, and HBV DNA > 2000 IU/mL |
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When to Stop Oral NRTI treatment?
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HBeAg+ (non-cirrhotic) Anti-HBe seroconversion
Stop 6-12 mos later |
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Indications for HBV Vaccination
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* Routine vaccination of infants
* Catch-up vaccination in children * Vaccination of adults at high risk of infection (or anyone who wants it) - Occupational risk (HCWs) - Hemodialysis patients - All STD clinic clients - >1 sex partner in previous 6 months - Household or sexual contact with HBV+ person - Inmates in Correctional settings - MSM - IDU - Institution for developmental disability - Travelers to countries with high or intermediate endemicity - Persons with HIV or chronic liver disease |
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Hepatitis B Vaccine
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* First recombinant vaccine ever used
- Antibody against a surface antigen * Protection - ~30-50% dose 1; 75% - 2; 96% - 3 - lower in older, immunosuppressive illnesses (e.g., HIV, chronic liver diseases, diabetes), obese, smokers - Patients on hemodialysis require a higher dose * Typically a 3 dose series, - Schedule: 0, 1-2, 4-6 months - no maximum time between doses (no need to repeat missed doses or restart) |
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HBV Vaccination Single Antigen Products
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Energix B
Recombivax HB |
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HBV Vaccination Combination Products
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Comvax (Hib)
Pediarix (DTaP, inactivated poliovirus) Twinrix (Hep A) |
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Which HBV Vaccination Products are recommended at birth?
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Only the single antigen products should be given to infants at birth
Energix B Recombivax HB |
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Decreased Immunogenecity response to vaccine
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* HIV or other form of immunosuppression
- 40-70% response, not related to CD4 count * Chronic Hemodialysis - 50-60% response |
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Testing for Vaccine Response HBV
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* Test for response in these populations and in those with suspected repeated exposures:
- Health care workers - IVDU - MSM - Infants born to HBsAg+ moms * Test 1-2 months after complete series (in infants > 9 months of age) |
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When should booster doses of HBV vaccine be administered?
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Booster doses when anti-HBs levels decline to <10 mIU/mL
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Who Should Be Considered for HBV Post-Exposure Prophylaxis?
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* Percutaneous (bite, needlestick) or mucosal exposure to HBsAg+ blood or body fluids
* Sex or needle-sharing * Victims of sexual assault/abuse * Infants born to HBsAg+ mothers * Preventing HBV recurrence post-transplant |
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HBV Post-Exposure Prophylaxis
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* Mainstay is vaccine
- Preferably within 24 hours - Efficacy diminished if > 7 days for needlestick or 14 days for sexual exposure * Some may receive a combination of vaccine and hepatitis B immune globulin (HBIG) to improve efficacy or just HBIG |
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HBIG
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* Attacks HBsAg and prevents HBV from entering hepatocytes
* Uses - Preventing vertical transmission - Reducing transplant recurrence |
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Perinatal Transmission of HBV
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* Related to HBV replication status of the mother
- 85-90% risk in infants born to HBeAg+ moms vs. 32% in infants born to HBeAg- moms * HBV DNA correlates with risk of transmission * No evidence that C section prevents transmission * Neither breastfeeding nor amniocentesis appear to increase the risk of transmission |
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Prevention of Perinatal Transmission
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* Passive immunization to newborns of carrier mothers
* HBIG 0.06 mL/kg and vaccine * Vaccine within 12 hours of birth * 2nd and 3rd vaccine dose at 1 and 6-12 months respectively * 95% protective efficacy |
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Reducing Transplant Recurrence
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* Give HBIG 10,000 IU IV daily for 1st week, weekly weeks 2-4, monthly thereafter (can use IM)
* Goal is to keep trough anti-HBs > 100 IU/mL * Recurrence rates are 20-25% with HBIG alone so it is coupled with pre- and post-transplant antiviral therapy - Rates of reinfection < 10% |
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SW is a 65 yo AAM who was referred to the hepatologist because his PCP noted that his serum ALT level was elevated during a routine visit. His only risk factor for Hep B is being sexually active starting at the age of 18 while serving in the army in Korea.
PMH: well controlled HTN on HCTZ 25 mg po QD. SHx: He rarely EtOH and has never smoked tobacco or used illicit substances. PE: WNL Laboratory studies: ALT: 70 IU/mL (ULN 50), HBsAg +, Anti-HBc IgM –, platelets = 125,000 Anti-hepatitis C virus (HCV) antibody: negative Anti-hepatitis A virus total antibody: positive Findings on liver US: echogenic; consistent with chronic liver disease. No gallstones. No liver mass lesions. No ascites. No splenomegaly. On the basis of SW’s history, laboratory studies, and results of liver ultrasound, which of following statements is most correct? 1. SW has acute Hepatitis B 2. The patient should continued to be monitored because he is asymptomatic 3. The patient probably has inactive HBV infection 4. The patient probably has active Hepatitis B infection |
4. The patient probably has active Hepatitis B infection
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