Efficacy and Safety of Combination Therapies With Oseltamivir & Zanamivir or Oseltamivir & Amantadine Versus Oseltamivir Monotherapy in the Treatment of Seasonal Influenza A Infection

Neuraminidase inhibitors (NAI) are effective anti-influenza antiviral treatment. During their use in experimentally infected patients, it has been shown that the viral load detected in the nasal fluid is decreasing significantly faster than in non treated patients. During clinical practice, the emergence of NAI-resistant strains has been observed. These strains remain rare, but their emergence seemed to be related to the mis-use of the NAI products (insufficient duration or dosage). This observation as well as the detection of NAI-resistant viruses in the community raises concerns about putative emergence of resistant clones in the specific context of a pandemic, when the use of NAI will be very large in the aim of reducing transmission, and subsequently the impact of the emerging virus.

In this context, it is important to determine the putative interest of alternative strategies.

Although zanamivir and oseltamivir are both issued from the same class , this combination may lead to a more rapid viral clearance in the infected cases, and to a reduction in the emergence of resistant sub-clones, and alternatively, might lead to a competitive inhibition. The evaluation of these combinations needs to be conducted in vivo.

Among available anti influenza antivirals, M2 blockers have been previously used. Although their efficacy against A H5N1 remains to be ascertained, their use in combination with NAI should also be evaluated in the context of a preparation for a possible pandemic and determination of the stockpile.

Therefore, the evaluation of combination therapies in the treatment of a virologically suspected influenza will be investigated in primary care during the winter season 2008-2009.

Study Schedule:

* Patient's follow up: 7 days with 10 visits V1, V2, V3, V4, V5 every 12 hours V6, V7, V8, V9, V10 every 24 hours
* V1: conducted by the GP rapid test diagnostic for influenza A, urine pregnancy test for women, inclusion /randomisation, nasal sample, initiation of treatment.
* V2 to V9: conducted by a nurse at the patient's home; nasal sample, symptoms scoring, safety assessment (side effects)
* V 10: conducted by GP; medical evaluation (follow up evaluation)

Eligibility Criteria:
Inclusion Criteria:

* Influenza season declared
* Subjects aged\>18 years and \< 65 years presenting within 36h documented of onset influenza illness
* Who have fever \>38°C
* Who present at least one of the following respiratory symptoms (cough, sore throat, nasal symptoms), and one of the following constitutional symptoms (headache, myalgia, sweats and or chills or fatigue)
* Positive rapid diagnostic test for influenza A
* Who have giving written informed consent prior to enrollment
* Patient examined before the inclusion
* Primary care follow up

Exclusion Criteria:

* Influenza Vaccination in the 12 months prior the beginning of the study
* Asthma, Chronic bronchitis
* Woman with a positive urine pregnancy test
* Active breast feeding
* Woman without contraception
* Clearance of creatinine\< 30 ml/min Chronic renal disease
* History of depression, psychiatric disorders, epilepsy
* Patients receiving cortocosteroids, immunosuppressants or antipsychotic antiemetic drugs
* Known oseltamivir or zanamivir hypersensibility
* Non member of the social security or CMU