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Antivirals: Treatment, Prophylaxis and Pandemic Control

Antivirals in treatment and prophylaxis of influenza

Table 13 presents a comparison between the different antiviral drugs available for treatment (amantadine, rimantadine and oseltamivir) and prophylaxis (amantadine, rimantadine, oseltamivir and zanamivir) of influenza. Again, only oseltamivir and zanamivir are effective against both influenza A and B. The UK National Institute for Clinical Excellence (NICE) no longer approves the use of amantadine for treatment of influenza, 5 x National Institute for Clinical Excellence. Guidance on the use of zanamivir, oseltamivir and amantadine for the treatment of influenza. In. Flu – zanamivir (review), amantadine and oseltamivir 58 (2003) (www.nice.org.uk) while the USA and Canada have also recently changed the recommendations for prophylaxis and treatment with amantidine and rimantidine, the reasons for which will be discussed below.

Table 13 Comparison of antiviral drugs for prophylaxis and treatment of influenza. source: Reproduced from La Rosa AM and Whimbey E. Respiratory viruses. In: Cohen J, Powderly WG, editors. Infectious Diseases, 2nd edn, 2003 with permission from Elsevier.

Comparison of antiviral drugs for prophylaxis and treatment of influenza
Drug Trade name Influenza type Dosing for prophylaxis Dosing for treatment Main side effects
Amantadine Symmetrel® A Age 1–9 years: Age 1–9 years: Central nervous system
5 mg/kg/day, p.o. div b.i.d. 5 mg/kg/day, p.o. div b.i.d.
Age 9 and up: Age 9 and up:
100 mg p.o. b.i.d. 100 mg p.o. b.i.d.
Rimantadine Flumadine® A Age 1–10 years: Adults: Central nervous
5 mg/kg/day, p.o. q.d. 100 mg p.o. b.i.d. system
Age 10 and up:
100 mg p.o. b.i.d.
Zanamivir Relenza® A and B N/A Age >7 years: Bronchial
10 mg inhaled b.i.d.
Oseltamivir Tamiflu® A and B Age 1–12 years: Age 1–12 years: Gastrointestinal
dose per weight dose per weight
Age ≥ 13 years: Age 13 and up:
75 mg p.o. q.d. 75 mg p.o. b.i.d.

References in context

  • Table 13 presents a comparison between the different antiviral drugs available for treatment (amantadine, rimantadine and oseltamivir) and prophylaxis (amantadine, rimantadine, oseltamivir and zanamivir) of influenza.
    Go to context

*For children who weigh <15 kg the dose is 30 mg b.i.d.; for those who weigh 15–23 kg, it is 45 mg b.i.d.; for those who weigh 23–40 kg, it is 60 mg b.i.d.; and for those who weigh >40 kg, it is 75 mg b.i.d.

The influenza antiviral drugs should only be used to treat patients if the clinical picture meets the criteria for influenza-like illness (ILI) and if influenza activity has been reported in the area. Table 14 lists indications for influenza antivirals.

Table 14 Indications for antiviral drugs against influenza. source: Adapted from CDC, Prevention and control of influenza. Recommendations ACIP. MMWR Recomm Rep 2004; 53 (RR-6): 1–40.

Indications for antiviral drugs against influenza
  • Patients at risk and their household contacts, who have not (yet) been vaccinated at the time when influenza infections are becoming widespread in an area.
  • Control of an outbreak in a (semi-)closed community (e.g. nursing home).
  • Patients at risk with a known hypersensitivity to chicken proteins (contraindication for vaccination).
  • Vaccine mismatch between vaccine component and circulating virus strain.
  • Pandemic threat with no vaccine (yet) available.

References in context

  • The influenza antiviral drugs should only be used to treat patients if the clinical picture meets the criteria for influenza-like illness (ILI) and if influenza activity has been reported in the area. Table 14 lists indications for influenza antivirals.
    Go to context

Treatment of influenza

All influenza antiviral agents have to be administered within 24–48 hours of disease onset. The drugs are given orally, except for zanamivir, which is inhaled. Influenza antiviral drugs diminish the severity of clinical symptoms and shorten the duration of uncomplicated influenza disease by an average of 1 day (from about 7 to 6 days). To reduce the risk of development of drug resistance (see below), amantadine or rimantadine should be discontinued as soon as clinically appropriate, usually after 3–5 days or within 24–48 hours after the disappearance of symptoms. For zanamivir and oseltamivir, the recommended duration of treatment is 5 days.

Evidence for the effectiveness of these four antiviral agents is based primarily on studies of uncomplicated influenza in adults. 6 x Food and Drug Administration. Subject: safe and appropriate use of influenza drugs [Public Health Advisory] (US Department of Health and Human Services, Food and Drug Administration, Rockville, MD, 2000) None of the drugs has been shown to prevent serious complications, such as pneumonia or the exacerbation of underlying disease. Data are limited regarding their effectiveness in the treatment of influenza among people at high risk of serious complications and among paediatric populations.

Both M2 channel blockers interact with a variety of different medicines, which can exacerbate their toxicity, including antihistamines, anticholinergics, co-trimoxazole, triamterene, quinine, quinidine, monoamine oxidase inhibitors, cimetidine, aspirin and paracetamol. When drugs such as antihistamines, antidepressants or minor tranquillizers are co-administered, patients should be monitored closely for CNS side effects.

Adverse effects

The most common side effects of the M2 inhibitors are CNS complaints (anxiety, difficulty concentrating, insomnia, dizziness, headache and jitteriness) and gastrointestinal upset. While the CNS complaints are minor in younger adults, these symptoms may be very prominent in the elderly, particularly with the use of amantadine. Reduction of these symptoms depends on dose adjustments based on creatinine clearance. Patients who receive amantadine may develop antimuscarinic effects, orthostatic hypotension and congestive heart failure. Particularly in the elderly or those with renal failure, serious CNS side effects due to amantadine (and less often rimantadine) include confusion, disorientation, mood alterations, memory disturbances, delusions, nightmares, ataxia, tremors, seizures, coma, acute psychosis, slurred speech, visual disturbances, delirium, oculogyric episodes and hallucinations. 1 x FG Hayden, FY Aoki. Amantadine, rimantadine, and related agents. SL Barriere (Ed.) Antimicrobial Therapy and Vaccines (Williams & Wilkins, Baltimore, 1999) (1344 - 1365) Amantadine causes CNS side effects in about 15–30% of people, as well as dose-related abnormalities in psychomotor testing. Amantadine (and possibly rimantadine) may increase the risk of seizures in those with a history of seizures.

In general, NAIs have fewer adverse effects than the M2 channel blockers. Oseltamivir is normally well tolerated but may induce gastrointestinal side effects, including nausea and vomiting, especially if the drug is not taken with food. Other infrequent possible adverse events include insomnia, vertigo and fever. Postmarketing reports suggest that oseltamivir may be associated rarely with skin rash, hepatic dysfunction or thrombocytopenia.

The inhaled zanamivir may induce bronchospasm (potentially severe) in those with underlying lung disease. Current guidelines advise against the use of zanamivir in patients with hyperreactive airways, unless the patient is closely monitored and has a fast-acting inhaled broncho-dilator available when inhaling zanamivir. 7 x Prevention and control of influenza: Recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR 51 (2002) (1) Other less frequent side effects include diarrhoea, nausea, headache and dizziness. Zanamivir is associated with low bioavailability and no clinically significant drug interactions have been recognized.

Influenza prophylaxis with antivirals

As indicated above, under specific conditions, influenza antivirals may be used for prevention of influenza infection. Both of the M2 blockers are 70–90% effective in preventing illness from influenza A infection in healthy adults. 8 x V Demicheli, T Jefferson, D Rivetti, J Deeks. Prevention and early treatment of influenza in healthy adults. Vaccine 18 (2000) (957 - 1003) When used as prophylaxis, they permit subclinical infection (whilst preventing illness) and allow development of protective antibodies. Both drugs have been studied extensively as a component of influenza outbreak-control programmes and can limit the spread of influenza in nursing homes. 9 x KG Nicholson. Use of antivirals in influenza in the elderly: prophylaxis and therapy. Gerontology 42 (1996) (280 - 289) Crossref.

Despite the fact that, of the NAIs, only oseltamivir has been approved for prophylaxis, both drugs have been shown to be similarly effective (82–84%) in preventing influenza in community studies of healthy adults. 10, x AS Monto, ME Pichichero, SJ Blanckenberg, et al.. Zanamivir prophylaxis: an effective strategy for the prevention of influenza types A and B within households. J Infect Dis 186 (2002) (1582 - 1588) Crossref. 11 x FG Hayden, RL Atmar, M Schilling, et al.. Use of the selective oral neuraminidase inhibitor oseltamivir to prevent influenza. New Engl J Med 341 (1999) (1336 - 1343) Crossref. Few data are available regarding their prophylactic use in closed settings or among patients with chronic medical conditions, but one study with oseltamivir reported a 92% reduction in influenza illness among nursing-home residents. 12 x PH Peters Jr, S Gravenstein, P Norwood, et al.. Long-term use of oseltamivir for the prophylaxis of influenza in a vaccinated frail older population. J Am Geriatr Soc 49 (2001) (1025 - 1031) Crossref.

There are no data regarding prophylactic efficacy of any of the four antiviral agents among people with severe immunosuppression. In these cases, prophylaxis can be considered for those expected to have an inadequate antibody response to influenza vaccine, including HIV-positive individuals, in particular those with advanced disease. Such patients should be monitored closely for interactions with other drugs used to treat HIV-positive individuals.

For the purposes of prevention, after an outbreak has been reported, vulnerable adults can be vaccinated and simultaneously receive prophylactic treatment for 2–3 weeks until sufficient antibodies have been generated by vaccination. 13, x PA Gross, C Russo, S Dran, P Cataruozolo, G Munk, SC Lancey. Time to earliest peak serum antibody response to influenza vaccine in the elderly. Clin Diagn Lab Immunol 4 (1997) (491 - 492) 14 x KA Brokstad, RJ Cox, J Olofsson, R Jonsson, LR Haaheim. Parenteral influenza vaccination induces a rapid systemic and local immune response. J Infect Dis 171 (1995) (198 - 203) Crossref. In individuals who remain unvaccinated, the drug must be taken each day for the duration of influenza activity in the community to be maximally effective as prophylaxis. Children under 9 years old receiving the influenza vaccine for the first time can require 6 weeks of prophylaxis, i.e. for 4 weeks after the first dose of vaccine and an additional 2 weeks after the second.

Control of influenza outbreaks in (semi-)closed settings

In closed institutions the use of antiviral drugs both for treatment and prophylaxis is a key component in the control of influenza outbreaks. When an outbreak occurs in a nursing home, all residents should receive prophylaxis, whether or not they have been vaccinated, as vaccination is only ∼60% effective in preventing laboratory-confirmed influenza illness among elderly people in this setting. 15 x R Guy, S Lambert, H Kelly. Estimating influenza vaccine effectiveness in an outbreak when anti-viral medications were used as a control measure. Aust NZ J Public Health 29 (2005) (540 - 543) Crossref. This should continue for a minimum of 2 weeks and until approximately 1 week after the last case has been identified. Prophylaxis should also be considered for all unvaccinated staff, and, in the case of outbreaks caused by a variant strain not well matched by the vaccine, prophylaxis should be considered for all employees, both vaccinated and unvaccinated. The dose of drug should be determined on an individual basis. 16 x R Dolin. Influenza – interpandemic as well as pandemic disease. New Engl J Med 353 (2005) (2535 - 2537) Crossref. Prevention can also be considered for controlling outbreaks in, for example, dormitories, schools, cruise ships.

Cost-effectiveness of treatment with antivirals

A recent review article addressed the cost-effectiveness of treatment of ILI with antiviral agents. 17 x LD Lynd, R Goeree, BJ O'Brien. Antiviral agents for influenza; a comparison of cost-effectiveness data. Pharmacoeconomics 23 (2005) (1083 - 1106) Crossref. Treatment with amantadine, zanamivir or oseltamivir was examined in eight studies. Several further studies investigated treatment vs a test-and-treat strategy or vs vaccination. One study included an economic analysis of prophylactic use of antivirals instead of, or on top of, vaccination. 18 x D Turner, A Wailoo, A Nicholson, et al.. Systematic review and economic decision modelling for the prevention and treatment of influenza A and B (National Institute of Clinical Excellence (NICE), Leicester (UK), 2002) Analyses were mostly directed at net costs per symptom-day averted or quality-adjusted life-year (QALY) gained. In some cases net costs were estimated per death averted or life-year gained. A large variation in cost-effectiveness ratios was observed, related to differences in perspectives chosen, populations targeted and diagnostic accuracy assumed. For example, one specific study estimated acceptable incremental net costs per QALY of antivirals compared to standard care at US$18,500, US$28,000 and US$44,000 for amantidine, zanamivir and oseltamivir, respectively, whereas for children, all antivirals exhibited cost-effectiveness over US$150,000 per QALY gained. 18 x D Turner, A Wailoo, A Nicholson, et al.. Systematic review and economic decision modelling for the prevention and treatment of influenza A and B (National Institute of Clinical Excellence (NICE), Leicester (UK), 2002) An analysis of oseltamivir prophylaxis in a Canadian long-term care facility during an influenza A outbreak showed that oseltamivir resulted in less ILI than amantadine prophylaxis, and that oseltamivir prophylaxis saved costs at Can$1,200 per 100 patients compared with amantadine and $3,400 per 100 patients compared with no prophylaxis. 19 x NA Risebrough, SK Bowles, AE Simor, et al.. Economic evaluation of oseltamivir phosphate for postexposure prophylaxis of influenza in long-term care facilities. J Am Geriatr Soc 53 (2005) (444 - 451) Crossref.

 
x

Table 13 Comparison of antiviral drugs for prophylaxis and treatment of influenza. source: Reproduced from La Rosa AM and Whimbey E. Respiratory viruses. In: Cohen J, Powderly WG, editors. Infectious Diseases, 2nd edn, 2003 with permission from Elsevier.

Comparison of antiviral drugs for prophylaxis and treatment of influenza
Drug Trade name Influenza type Dosing for prophylaxis Dosing for treatment Main side effects
Amantadine Symmetrel® A Age 1–9 years: Age 1–9 years: Central nervous system
5 mg/kg/day, p.o. div b.i.d. 5 mg/kg/day, p.o. div b.i.d.
Age 9 and up: Age 9 and up:
100 mg p.o. b.i.d. 100 mg p.o. b.i.d.
Rimantadine Flumadine® A Age 1–10 years: Adults: Central nervous
5 mg/kg/day, p.o. q.d. 100 mg p.o. b.i.d. system
Age 10 and up:
100 mg p.o. b.i.d.
Zanamivir Relenza® A and B N/A Age >7 years: Bronchial
10 mg inhaled b.i.d.
Oseltamivir Tamiflu® A and B Age 1–12 years: Age 1–12 years: Gastrointestinal
dose per weight dose per weight
Age ≥ 13 years: Age 13 and up:
75 mg p.o. q.d. 75 mg p.o. b.i.d.

References in context

  • Table 13 presents a comparison between the different antiviral drugs available for treatment (amantadine, rimantadine and oseltamivir) and prophylaxis (amantadine, rimantadine, oseltamivir and zanamivir) of influenza.
    Go to context

*For children who weigh <15 kg the dose is 30 mg b.i.d.; for those who weigh 15–23 kg, it is 45 mg b.i.d.; for those who weigh 23–40 kg, it is 60 mg b.i.d.; and for those who weigh >40 kg, it is 75 mg b.i.d.

Table 14 Indications for antiviral drugs against influenza. source: Adapted from CDC, Prevention and control of influenza. Recommendations ACIP. MMWR Recomm Rep 2004; 53 (RR-6): 1–40.

Indications for antiviral drugs against influenza
  • Patients at risk and their household contacts, who have not (yet) been vaccinated at the time when influenza infections are becoming widespread in an area.
  • Control of an outbreak in a (semi-)closed community (e.g. nursing home).
  • Patients at risk with a known hypersensitivity to chicken proteins (contraindication for vaccination).
  • Vaccine mismatch between vaccine component and circulating virus strain.
  • Pandemic threat with no vaccine (yet) available.

References in context

  • The influenza antiviral drugs should only be used to treat patients if the clinical picture meets the criteria for influenza-like illness (ILI) and if influenza activity has been reported in the area. Table 14 lists indications for influenza antivirals.
    Go to context

References

Label Authors Title Source Year
1

References in context

  • Amantadine and rimantadine were the first generation of influenza antiviral agents.1 These compounds specifically block the ion channel function of the M2 protein of influenza A virus (see Chapter 2), thus interfering with corresponding specific steps in the viral life cycle.
    Go to context

  • Particularly in the elderly or those with renal failure, serious CNS side effects due to amantadine (and less often rimantadine) include confusion, disorientation, mood alterations, memory disturbances, delusions, nightmares, ataxia, tremors, seizures, coma, acute psychosis, slurred speech, visual disturbances, delirium, oculogyric episodes and hallucinations.1 Amantadine causes CNS side effects in about 15–30% of people, as well as dose-related abnormalities in psychomotor testing.
    Go to context

  • Emergence of resistant virus does not appear to cause a rebound in illness in immunocompetent adults, but may be associated with protracted illness and shedding in immunocompromised hosts.22 Importantly, resistant virus can be spread to others and has caused failures of antiviral prophylaxis under close contact conditions, as in nursing homes23 and households.1 The resistant viruses appear to retain wild-type pathogenicity and cause an influenza illness indistinguishable from that caused by susceptible strains.
    Go to context

FG Hayden, FY Aoki. Amantadine, rimantadine, and related agents. SL Barriere (Ed.) Antimicrobial Therapy and Vaccines (Williams & Wilkins, Baltimore, 1999) (1344 - 1365) 1999
5

References in context

  • The UK National Institute for Clinical Excellence (NICE) no longer approves the use of amantadine for treatment of influenza,5 while the USA and Canada have also recently changed the recommendations for prophylaxis and treatment with amantidine and rimantidine, the reasons for which will be discussed below.
    Go to context

National Institute for Clinical Excellence. Guidance on the use of zanamivir, oseltamivir and amantadine for the treatment of influenza. In. Flu – zanamivir (review), amantadine and oseltamivir 58 (2003) (www.nice.org.uk) 2003
6

References in context

  • Evidence for the effectiveness of these four antiviral agents is based primarily on studies of uncomplicated influenza in adults.6 None of the drugs has been shown to prevent serious complications, such as pneumonia or the exacerbation of underlying disease.
    Go to context

Food and Drug Administration. Subject: safe and appropriate use of influenza drugs [Public Health Advisory] (US Department of Health and Human Services, Food and Drug Administration, Rockville, MD, 2000) 2000
7

References in context

  • Current guidelines advise against the use of zanamivir in patients with hyperreactive airways, unless the patient is closely monitored and has a fast-acting inhaled broncho-dilator available when inhaling zanamivir.7 Other less frequent side effects include diarrhoea, nausea, headache and dizziness.
    Go to context

Prevention and control of influenza: Recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR 51 (2002) (1) 2002
8

References in context

  • Both of the M2 blockers are 70–90% effective in preventing illness from influenza A infection in healthy adults.8 When used as prophylaxis, they permit subclinical infection (whilst preventing illness) and allow development of protective antibodies.
    Go to context

V Demicheli, T Jefferson, D Rivetti, J Deeks. Prevention and early treatment of influenza in healthy adults. Vaccine 18 (2000) (957 - 1003) 2000
9

References in context

  • As indicated above, under specific conditions, influenza antivirals may be used for prevention of influenza infection.
    Go to context

KG Nicholson. Use of antivirals in influenza in the elderly: prophylaxis and therapy. Crossref. Gerontology 42 (1996) (280 - 289) 1996
10

References in context

AS Monto, ME Pichichero, SJ Blanckenberg, et al.. Zanamivir prophylaxis: an effective strategy for the prevention of influenza types A and B within households. Crossref. J Infect Dis 186 (2002) (1582 - 1588) 2002
11

References in context

FG Hayden, RL Atmar, M Schilling, et al.. Use of the selective oral neuraminidase inhibitor oseltamivir to prevent influenza. Crossref. New Engl J Med 341 (1999) (1336 - 1343) 1999
12

References in context

PH Peters Jr, S Gravenstein, P Norwood, et al.. Long-term use of oseltamivir for the prophylaxis of influenza in a vaccinated frail older population. Crossref. J Am Geriatr Soc 49 (2001) (1025 - 1031) 2001
13

References in context

  • For the purposes of prevention, after an outbreak has been reported, vulnerable adults can be vaccinated and simultaneously receive prophylactic treatment for 2–3 weeks until sufficient antibodies have been generated by vaccination.13,14 In individuals who remain unvaccinated, the drug must be taken each day for the duration of influenza activity in the community to be maximally effective as prophylaxis.
    Go to context

PA Gross, C Russo, S Dran, P Cataruozolo, G Munk, SC Lancey. Time to earliest peak serum antibody response to influenza vaccine in the elderly. Clin Diagn Lab Immunol 4 (1997) (491 - 492) 1997
14

References in context

  • For the purposes of prevention, after an outbreak has been reported, vulnerable adults can be vaccinated and simultaneously receive prophylactic treatment for 2–3 weeks until sufficient antibodies have been generated by vaccination.13,14 In individuals who remain unvaccinated, the drug must be taken each day for the duration of influenza activity in the community to be maximally effective as prophylaxis.
    Go to context

KA Brokstad, RJ Cox, J Olofsson, R Jonsson, LR Haaheim. Parenteral influenza vaccination induces a rapid systemic and local immune response. Crossref. J Infect Dis 171 (1995) (198 - 203) 1995
15

References in context

  • When an outbreak occurs in a nursing home, all residents should receive prophylaxis, whether or not they have been vaccinated, as vaccination is only ∼60% effective in preventing laboratory-confirmed influenza illness among elderly people in this setting.15 This should continue for a minimum of 2 weeks and until approximately 1 week after the last case has been identified.
    Go to context

R Guy, S Lambert, H Kelly. Estimating influenza vaccine effectiveness in an outbreak when anti-viral medications were used as a control measure. Crossref. Aust NZ J Public Health 29 (2005) (540 - 543) 2005
16

References in context

  • The dose of drug should be determined on an individual basis.16 Prevention can also be considered for controlling outbreaks in, for example, dormitories, schools, cruise ships.
    Go to context

  • In addition, the efficacy of these drugs in the absence of vaccination in the very young16 and the very old31 also remain in question in both pandemic and interpandemic influenza seasons.
    Go to context

R Dolin. Influenza – interpandemic as well as pandemic disease. Crossref. New Engl J Med 353 (2005) (2535 - 2537) 2005
17

References in context

  • A recent review article addressed the cost-effectiveness of treatment of ILI with antiviral agents.17 Treatment with amantadine, zanamivir or oseltamivir was examined in eight studies.
    Go to context

LD Lynd, R Goeree, BJ O'Brien. Antiviral agents for influenza; a comparison of cost-effectiveness data. Crossref. Pharmacoeconomics 23 (2005) (1083 - 1106) 2005
18

References in context

  • One study included an economic analysis of prophylactic use of antivirals instead of, or on top of, vaccination.18 Analyses were mostly directed at net costs per symptom-day averted or quality-adjusted life-year (QALY) gained.
    Go to context

  • One study included an economic analysis of prophylactic use of antivirals instead of, or on top of, vaccination.18 Analyses were mostly directed at net costs per symptom-day averted or quality-adjusted life-year (QALY) gained.
    Go to context

D Turner, A Wailoo, A Nicholson, et al.. Systematic review and economic decision modelling for the prevention and treatment of influenza A and B (National Institute of Clinical Excellence (NICE), Leicester (UK), 2002) 2002
19

References in context

  • A recent review article addressed the cost-effectiveness of treatment of ILI with antiviral agents.17 Treatment with amantadine, zanamivir or oseltamivir was examined in eight studies.
    Go to context

NA Risebrough, SK Bowles, AE Simor, et al.. Economic evaluation of oseltamivir phosphate for postexposure prophylaxis of influenza in long-term care facilities. Crossref. J Am Geriatr Soc 53 (2005) (444 - 451) 2005

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