Their use is essential against pluriserotipic viruses or against
latent infections : anyway in acute viroses replication usually
preceed symptoms and antimicrobials can't prevent infection. They
can interfere with ...
[WTO regulations allow for drug patents to be violated in the event of medical emergencies, providing the patent holder is compensated at a later dateref]
|zanamivir / GG167 /
4-guanidino-Neu5Ac2en (Relenza®; source : GlaxoSmithKline (complete
information, revised on June 2004)), manufactured from
a readily available starting material, N-acetyl-neuraminic-acid
(NANA), approved in 1999. The lactose dose (80 mg per dose)
is insufficient to cause symptoms in lactase-deficient
||guanidino group => a dry powder that is
self-administered via oral inhalation by using a plastic
device (DiskHaler®) included in the
package with the medication. Investigational
formulations include nebulised mist, nasal spray,
After inhalation of 10 mg :
|not approved by FDA, but meta-analyses of clinical trials have shown that it is highly effective for postexposure prophylaxis or early treatment in compliant patients with no underlying pulmonary diseaseref1, ref2||for persons aged > 5-7 years (depending on the country)
: 2 inhalations (one 5-mg blister per inhalation for a total
dose of 10 mg) twice daily (approximately 12 hours apart)
for 5 days : take
2 doses on the first day of treatment whenever possible if there are at least 2 hours
between doses. No dose adjustment for patients with either mild to moderate or severe impairment in renal function
|while there were reports of bronchospasm post-release,
trials specifically targeting patients with mild-to-moderate asthma or COPD showed that zanamivir was an effbctive treatment and had a similar safety profile to the inhaled lactose placeboref. There were no adverse eff-ect on pulmonary function, however, the pack insert reports that it is not recommended for treatment for patients with underlying airway disease unless used with caution under conditions of appropriate monitoring and supportive care (including the availability of short-acting inhaled bronchodilators) due to reports of >20% decline in FEV1. Oropharyngeal or facial edema have also been reported; no increased incidence of other side effects
|2-3 days of symptom relief in high-risk patients, those
presenting with severe influenza-related
symptoms or those who had symptoms for <30 hours.
Older patients, aged >50 years, presenting with severe symptoms
derived up to 7 days of benefit, as in this group, untreated patients
experienced up to 11.5 days of symptoms; reduced nasal pro-inflammatory cytokine levelsref;
no definitive evidence is available regarding the safety or efficacy of zanamivir for persons with underlying respiratory or cardiac disease or for persons with complications of acute influenza. Anyway studies with nebulized and intravenous preparations suggest that zanamivir has good safety and efficacy, even in patients with underlying respiratory diseaseref1, ref2, ref3
E119G (>100 fold reduction in NA sensitivity; isolated in the strain NWS:G70C, a reassortant containing the HA of A:NWS:33 and NA of A:Tern:Australia:G70C:75
833:80 (A:Turkey:Minn, H4N2)ref1, ref2 (Gubareva, L.V., Bethell, R.C., Penn, C.R., Webster, R.G., 1996. In vitro characterization of 4-guanidino-Neu5Ac2en -resistant mutants of influenza A virus. In:
Brown, L.E., Hampson, A.W., Webster, R.G. (Eds.), Options for the control of Influenza III, Elsevier, Amsterdam, pp. 753–760.), the B:HK:Lee strain, a reassortant with the HA of B:HK:8:73 and NA of B:Lee:40ref, and B:Beijing:1:87 (B:Beijing)ref
|only Germany and India are storing zanamivir up in large quantities, although other European countries and the USA have some stocks. Shorter shelf-life than oseltamivir|
|oseltamivir phosphate /
GS4104 (Tamiflu®; developed from a rare
natural compound, shikimic acid, and patented by Gilead Sciences,
South San Francisco, until 2016, described in 1997ref;
in 1996 Roche
Holding AG acquired the worldwide rights to develop
and market the drug : Tamiflu was FDA approved in 1999 and
launched in North America (US and Canada) and Switzerland
during 1999/2000. In all key European markets, it was
launched by 2002/2003. Chugai
Co., Ltd. distributes it in Japan; complete
information, revised on June 2004. Available in
blister packages of 10 capsules (enough for a 5-day bid
course per person) (cost US$34-60, but up to US$190 on some
or in glass bottles containing 25 ml of suspension after
constitution equivalent to 300 mg oseltamivir base. Seasonal
flu prevention requires at least six weeks of treatment --
that is 84 pills or about $1,600 of Tamiflu based on current
the original developer, still receives a royalty from
Roche equaling about 10% of sales.
|bulky hydrophobic group => orally administered
ethyl ester prodrug (absolute bioavailability = 80%; 30-73%
in rodents, ferrets, dogs, and marmosets) converted by liver
and gut carboxyesterases to the active metabolite oseltamivir
carboxylate / GS4071 / Ro 64-0802 / 4-guanidino-2,4-
dideoxy-2,3-dehydro- N-acetylneuraminic acid
(4-guanidino-Neu5Ac2en). Oseltamivir activation by
HCE1 is inhibited by 90% by clopidogrelref.
Oseltamivir carboxylate detectable in plasma within 30
minutes and reaches maximal concentrations after 3 to 4
hours (350 ng/ml)
||initially in patients > 13 years of age, but for all
ages since 21 Dec 2005ref
: 75 mg capsules once dailyfor at least 7 days.
Therapy should begin within 2 days of exposure. Safety and
efficacy have been demonstrated for up to 6 weeks, but the
duration of protection last for as long as dosing is
In healthy unvaccinated adults (aged 13 to 65 years), oseltamivir 75 mg once daily taken for 42 days during a community outbreak reduced the incidence of laboratory confirmed clinical influenza from 4.8% for the placebo group to 1.2% (>70% protective efficacy) and from 4.4% to 0.4% (92% protective efficacy) in vaccinated (80%) high-risk (14% had COPD, and 43% had cardiac disorders) elderly residents of skilled nursing homes. In a study of post-exposure prophylaxis in household contacts (aged 13 years) of an index case, oseltamivir 75 mg once daily administered within 2 days of onset of symptoms in the index case and continued for 7 days
reduced the incidence of laboratory confirmed clinical influenza from 12% in the placebo group to 1% for the oseltamivir group. Index cases did not receive oseltamivir in the studyref
|for people aged >= 1 year recommended treatment dosages
for children vary by the weight of the child:
The treatment dosage for persons aged >13 years is 75 mg capsules bid for 5 days. It needs to be initiated within 2 days of symptom onset achieves and maintains plasma concentrations above the antiviral IC50 for laboratory strains of influenza A and B for 12 hours after a single 75 mg dose, but the relationship between the in vitro antiviral activity in cell culture and the inhibition of influenza virus replication in humans has not been establishedref.
A liquid formulation of oseltamivir (2 mg/kg twice daily
for 5 days) is effectiveref.
from potential traffic injuryref. Tatsuo Kurokawa (2nd L), the health ministry official in charge of pharmaceutical matters, announces at a predawn news conference in Tokyo on March 21 2007 that the government has recommended against the use of Tamiflu among teenagers. After taking Tamiflu, 2 12-year-old boys apparently jumped off the 2nd floor of their houses and broke their legs in February and March. In February, a 14-year-old boy fell to his death at his condominium in Miyagi after apparently taking the drug while a 14-year-old girl died in similar circumstances in Aichiref. Separately, the EMEA’s Committee for Medicinal Products for Human Use requested at its Nov. 14-17 meeting that Roche provide a “cumulative safety review of all available data on serious psychiatric disorders, including all case reports with a fatal outcome where Tamiflu was involved,” after 2 cases of alleged suicides in adolescents reported to the EMEA. In Japan, oseltamivir is often dispensed as a powder in Japan, and mixed at the pharmacy, possibly contributing to higher dosing. The length of dosing may also be different, with Japanese patients possibly stopping administration before the recommended period, contributing to recrudescenceref. Roche commissioned Ingenix to investigate the safety of Tamiflu in 63,000 children (1-12 years old) and concluded that there “was no indication of an increased risk of neuropsychiatric events for children aged 1-12 over that already posed by influenza illness alone. A case report was published about the 22-yo Cape Coral resident Lianne Espositoref. In Dec 2005 2 new cases in Japan. A man in his 50s was hospitalized due to a rash he developed 2 days after starting Tamiflu. He died 10 days from toxic epidermal necrosis, which produced fever and MOF. He had also been taking antibiotics, cold medicine and herbal medicine. A man in his 80s was hospitalized for fatigue on the 5th day on Tamiflu and died 3 weeks later from kidney failure. He had been taking 2 types of medicines to treat high blood pressure and stomach problemsref.
A single-dose of 1000 mg/kg of oseltamivir phosphate to 7-day-old rats causes 10-fold higher plasma levels and 1500-fold higher brain levels (3-fold for oseltamivir carboxylate) those found in adults because of blood-brain barrier immaturity, and results in deaths, while 2000 mg/kg do not cause effects in 14-day-old rats. No adverse effect occurred at 500 mg/kg/day administered to 7- and 21-day-old rats, at which exposure to prodrug is 800-fold that expected in a 1-year old child.
|reduces the median time to alleviation of all symptoms
by 30% (3 vs. 4.3 days) and the median time to become
afebrile by 38% (42.3 vs. 69.3 hours) compared with
placebo (earlier initiation of therapy associated with
faster resolution), reduces lower respiratory tract
complications resulting in antibiotic therapy, overall
antibiotic use, and hospitalization in both healthy
adolescents and adults (4.6% vs 10.3% with placebo, and
14.0% vs 19.1% with placebo, respectively) and "at-risk"
adults (12.2% vs. 18.5% with placebo, and 0.7% vs. 1.7% with
placebo, respectively) with a proven influenza illnessref,
and flu-related death rates (-60-90% in children). >103
infectious units/mL of virus were detected in some of the
patients who did not shed drug-resistant viruses, even after
5 days of treatmentref.
Anyways zeroing of median virus titers occurs in 60 hrs vs.
108 hrs for influenzavirus A and in 24 vs. 72 hrs or
influenzavirus B (Hayden F, et al. Efficacy of oral
oseltamivir in experimental human influenza B virus
infection. Poster presented at: 37th Annual Meeting of the
Infectious Diseases Society of America; November 18-21,
1999; Philadelphia, Pa.). The durations of virus shedding
from children treated with neuraminidase inhibitors were not
significantly shorter than those of untreated patientsref.
For later-stage intervention in severe influenza
illness, please contact WHOinfluenza @who.int for information on clinical trial protocols. In studies of naturally acquired and experimental influenza, oseltamivir did not impair normal humoral antibody response to infection. Initiation of therapy within the first 12 h after fever onset reduced the total median illness duration by 74.6 h (3.1 days; 41%) > intervention at 48 h. Intermediate interventions reduced the illness proportionately compared with 48 h. In addition, the earlier administration of oseltamivir further reduced the duration of fever, severity of symptoms and the times to return to baseline activity and health scoresref; reduced nasal pro-inflammatory cytokine levelsref. Effective and well tolerated in high-risk patients with chronic respiratory or cardiac diseasesref
|develops within day 4 in 8-12% of aged < 12 yrs, 1-4%
in aged > 12 yrs, but viruses that develop resistance
appear to be less virulent in laboratory animals and to
replicate less efficiently than parent strainsref.
Mutants detected in vitro by passage of virus in the
presence of increasing concentrations (underlined mutants
have been found also in clinical specimens : no drug-induced
HA variants have been recognised to date)
HAref1, ref2 :
NA [N2 numbering of aminoacid residues] :
(developed world: € 7.70 per 1 treatment course; developing world: € 7.00 per 1 treatment course) and Tamiflu caps purchased by governments for pandemic use are at a significant discount (developed world: € 15.00 (US$18) per 1 treatment course; developing world: € 12.00 (US$ 15) per 1 treatment course) compared to the seasonal price (seasonal ex-factory price
ranges between € 20 and € 51 in Europe)ref. 7 of the 13 sites involved in making Tamiflu are controlled by subcontractors : on Dec 9 Roche reached agreements with 2 US generic drugmakers (Teva Pharmaceuticals and Mylan Laboratories, Inc.), as well as 13 other drug producers. Roche donated the WHO's stockpile 125,000 packs in 2004 and, 3 million treatment courses in Aug 2005 (enough to delay spread in an affected nation according to models), and 2 million treatment courses in Jan 2006
USA : 5.5 million people (872, 386 pediatrics) treated since 2001, 2.3 million 10-dose courses stockpiled, enough to treat < 1% of Americans, with plans to acquire another 2 million courses by the end of 2005, and projects for 80 million courses to cover about 25% of the population, but Roche could provide only 13 million courses in 2006, followed by 70 million in 2007. On July 19, 2006, < 2 weeks before a federal deadline for states to announce their plans, at least 16 say they're undecided how much Tamiflu and Relenza they'll buy. 13 others — including California, the biggest state — say they plan to buy their full allotments. The federal government plans to buy 44 million antiviral treatment courses for the states this fiscal year and next, enough to cover 17% of their populations. It wants states to buy 31 million more courses, to reach 25%. Even at a discount — about $15 for Tamiflu, about 20% of the Internet retail rate — cost is a concern. Arizona plans to spend $1 million for 70,000 courses. The state's full allotment of 585,780 courses would cost about $8 million, draining funds needed to prepare hospitals. Colorado plans to buy 5,400 courses — not the 477,470 allotted to it. Arizona and Nebraska are trying to get local entities to pay for more anti-virals. So is Oklahoma, which now plans to buy 9% of its allotment but may increase it. Montana and North Dakota also don't plan to buy full allotments. Other states didn't respond. The Aug. 1 deadline will help drugmakers plan, but states can change orders through Dec. 31. Businesses cannot buy the drugs at the federal discountref.
Kuwait : 5 million dosesref; 10 million capsules, which are sufficient to treat about 40% of the
population of 3 millionref
Roche has no patents in :
Roche asked the European Medicines Agency, which regulates the use of drugs in Europe, to approve 2 smaller capsules - 30 mg and 45 mg - and planned a similar filing soon with the Food and Drug Administration in the USA. Roche has been granted an accelerated review and is optimistic that EMEA will complete their evaluation by mid 2007. The new capsules would be in addition to the 75 mg dosages already approved and will be easier to use than the liquid suspension already available for children. The capsules also will have a longer shelf life than the liquidref.
The anti-influenza drug oseltamivir is an ester prodrug activated by hepatic carboxylesterases. Plasma esterases also convert up to 31.8% of the parent compound to the active metabolite after 4 h ex vivo, with wide interindividual variation. This source of error is removed by adding the esterase inhibitor dichlorvos to blood collection tubesref.
Ferrets were protected from lethal infection with the A/Vietnam/1203/04 (H5N1) virus by oseltamivir 5 mg/kg/day given 4 h after virus inoculation, but higher daily doses (25 mg/kg) were required for treatment when initiated 24 h after virus inoculation. For the treatment of ferrets inoculated with the less pathogenic A/Turkey/15/06 (H5N1) virus, 10 mg/kg/day of oseltamivir was sufficient to reduce the lethargy of the animals, significantly inhibit inflammation in the upper respiratory tract, and block virus spread to the internal organs. Importantly, all ferrets that survived the initial infection were re-challenged with homologous virus after 21 days and were completely protected from infection. Direct sequencing of the NA or HA1 gene segments in viruses isolated from ferret after treatment showed no amino acid substitutions known to cause drug resistance in conserved residues. Thus, early oseltamivir treatment is crucial for protection against highly pathogenic H5N1 viruses and that higher dose may be needed for the treatment of more virulent virusesref.
An influenza B virus from an infant with no history of treatment or contact with neuraminidase inhibitors demonstrated a significant reduction in sensitivity to these drugs. A mixed viral population was isolated that contained a novel D197E amino acid substitution that was responsible for this reductionref
The impact of various NA mutations (E119A/G/V, H274Y, R292K and N294S) on the susceptibility profiles to different NAIs (oseltamivir, zanamivir and peramivir) was evaluated using recombinant NA proteins of influenza A/WSN/33 (H1N1) and A/Sydney/5/97-like (H3N2) viruses. In the Nl subtype, the E119V mutation conferred cross-resistance to oseltamivir, zanamivir and peramivir [1,727-2,144 and 5,050-fold increase in IC50 values compared with wild-type (WT)] whereas only oseltamivir-resistance (1,028-fold increase in IC50) was conferred by the same mutation in the N2 subtype. The N294S mutation conferred resistance to oseltamivir in both the NI and N2 subtypes (197- and 1,879-fold increase in IC50 values, respectively) whereas the H274Y mutation conferred resistance to oseltamivir (754-fold increase) and peramivir (260-fold increase) in the N1 subtype only. The virulence of reverse genetics-rescued A/WSN/33 viruses harbouring H274Y and N294S NA mutations was investigated in Balb/c mice. The WT and H274Y recombinants had identical LD50 values (103 PFUs) and generated similar viral lung titres, whereas a higher LD50 (10 PFUs) and a 1-log decrease in viral lung titres were obtained with the N294S mutant. This study shows that some NA mutations at framework residues may confer resistance to 1 or 3 NAIs depending on the viral subtype. It suggests that certain drug-resistant NA mutants may still be virulent although additional studies using clinical isolates are needed to confirm these resultsref.
|Hong Kong 1997 (10 out of 18 patients) : amantadine was used for most of the patients with severe infections. However, the majority of those patients were already at a critical stage of the disease when the drug was administered, and amantadine is known to be most effective when it is given at an early stage of disease (within 2 days of onset)ref||3 yrs-old male from ? (patient 1)||onset of illness on 10 May 1997; persistent MODS; no major illnesses||acyclovir started at late stage of disease||died 5 days after hospital admission|
|Hong Kong 1997 (10 out of 18 patients) : amantadine was used for most of the patients with severe infections. However, the majority of those patients were already at a critical stage of the disease (> 4 days after the onset of symptoms ) when the drug was administered, and amantadine is known to be most effective when it is given at an early stage of disease (within 2 days of onset)ref1 (Arabian numerals), ref2 (Roman numerals)||54 yrs-old male (patient 4)||onset of illness on 24 Nov 1997; fever (39°C) for 6 days, cough, vomiting, shortness of breath, bilateral pneumonia, persistent MODS; WBC 5.8, lymphopenia 0.3, AST 157, ALT 70, acute renal failure, ECG evidence of old myocardial infarct||amantadine started on hospital admission (6 days after the onset of illness) for 6 days||died 7 days after hospital admission with areas of hemorrhage, and fibrinous exudates in air spaces, and extensive acute tubular necrosis|
|5-years old female (patient 5 or VI)||onset of illness on 7 Dec 1997; fever (37.8°C) for 3 days, rhinorrhea, vomiting and diarrhea, epistaxis, WBC 8.4, lymphocytosis 6.05, atypical lymphocyte 0.34 x 103/mL, ALT 43, AST 91, fever, URTI symptoms; no major illnesses||amantadine started on hospital admission||recovered|
|24-yrs old female (patient 7)||onset of illness on 4 Dec 1997; fever (39°C) for 3 days, productive cough, rhinorrhea, sore throat, dizziness, headache, decreased appetite, right-upper abdominal pain, congested oropharynx, clinical and radiological signs of severe pneumonia, septic shock, ARDS, bilateral pleural effusion, requiring ventilatory support for 21 days, leukopenia 2.29, lymphopenia 0.28, PLT 161, aPTT 40.7, PT 12.4, AST 60||amantadine started on the third day after hospital admission||recovered|
|2 yrs-old male (patient 8)||onset of illness on 12 Dec 1997; fever (39°C) for 1 day, sore throat, rhinorrhea and cough; WBC 14.66, neutrophilia 9.31 x 103/ml; glucose-6-phosphate dehydrogenase deficiency||amantadine started on hospital admission||recovered|
|60-years old female (patient 12)||onset of illness on 16 Dec 1997; fever (39.7°C) for 2 days, no pulmonary symptoms or signs, progressive bilateral pneumonia, ARDS, renal failure, progressive MODS; WBC 5.4, lymphopenia 0.3, PLT 147, AST 62, ALT 52, malignant thymoma treated with radiotherapy 10 years ago||amantadine started on the 5th day after hospital admission||died 6 days after hospital admission|
|25-years old Filipino female (patient 13 or V)||onset of illness on 17 Dec 1997; fever (39.6°C) for 4 days, cough, sore throat, rhinorrhea, diarrhoea, headache, dizziness, clinical and radiological signs of left-lower-lobe consolidation, persistent MODS; leukopenia 2.4, lymphopenia 0.4, PLT 106, ALT 74, ARDS, bilateral massive hemorrhagic pleural effusion, no major illnesses||amantadine started on the third day after hospital admission||died 24 days after hospital admission (1 month after the onset of illness) of acute respiratory distress syndrome and multiple organ failure showing features of reactive hemophagocytic syndrome, central lobular necrosis, fatty changes, and extramedullary hematopoiesis in the liver and prominent acute tubular necrosis, congestion, and swelling in the kidneys|
|19-yrs-old female (patient 16 or IX)||onset of illness on 14 Dec 1997, fever (39°C) for 3 days, productive cough, vomiting, clinical and radiological signs or left-lower-lobe pneumonia, progressive bilateral pneumonia/ARDS requiring steroid therapy and ventilatory support for 20 days, pleural effusions requiring tube thoracotomy drainage, WBC 4.0, lymphopenia 0.6, PLT 106; no major illnesses||amantadine started on the third day after hospital admission||recovered|
|Hong Kong 1997 (1 out of 18 patients)ref||13-yrs-old female from ? (patient 3 or III)||onset of illness on 20 Nov 1997; fever (39.8°C) for 4 days, rhinorrhea, cough, headache, clnical and radiological signs of patchy right-lower-lobe consolidation. Haemoptysis due to pulmonary hemorrhage; ARDS; gastrointestinal bleeding, renal failure, haemophagocytosis, leukopenia 2.54; lymphopenia 0.18, platelet 31, PT 12.8, aPTT 38.5, urea 30.6, creatinine 222; persistent MODS; no major illnesses in medical history||amantadine and intravenous ribavirin (1 g every 8 h) started on the seventh day after hospital admission||died 25 days after hospital admission|
|Vietnam 2004 (2 out of 10 patients) : relatively low doses not associated with obvious effectivenessref||10 yrs-old male from Bac Nihn (patient 3)||student; family members are farmers who kept chickens, which died unexpectedly 5 days before onset of illness; parents and older sibling healthy||cough, dyspnea, fever 39°C, ABP 105/80 mmHg, RR = 64 bpm, crackles, HGB 12.4 g/dl, WBC 2800/ml, lymphocytes 860/ml, neutrophils 1900/ml, platelets 135,000/ml, O2 saturation during receipt of 40% O2 86%, PCR for H5N1 performed on day 9 of illness||800 mg 3 times a day||died day 14|
|8 yrs-old female from Ha Tay (patient 4)||cough, dyspnea, fever 38.5°C, ABP 80/40 mmHg, RR = 60 bpm, bleeding gums, HGB 12.3 g/dl, WBC 1900/ml, lymphocytes 250/ml, neutrophils 780/ml, platelets 91,000/ml, ALT 265 U/l, AST 1,217 U/l, creatinine 27 mmol/l, O2 saturation during receipt of 40% O2 50%, PCR for H5N1 performed on day 6 of illness||400 mg 3 times a day||died day 7|
|China 2005ref||a 9-yrs-old boy from Hunan||brother of a 12-years old girl who fell ill on Oct 8 died of ARDS, DIC, and MODS on Oct 17 but tested negative for H5-specific antibodies in both microneutralisation and haemagglutination-inhibition assays against the A/Hunan-Xiangtan-he/12/2005 virus, which was isolated from the only live chicken remaining in the household||developed fever and cough on Oct 10||amantadine, ribavirin, corticosteroids, and broad spectrum antibiotics since Oct 17||discharged on Nov 12. At his final follow-up on Dec 9, 2005, he remained asymptomatic|
|Hong Kong, 2003ref||33-year old man from Hong Kong||father of a family of 5 who visited Fujian province, mainland China, from Jan 26, to Feb 9, 2003. The 7-year-old daughter developed high fever and respiratory symptoms 2 days after arriving there and died of a pneumonia-like illness 7 days after the onset of symptoms. The exact cause of death could not be ascertained since the girl was buried in mainland China. The family returned to Hong Kong on Feb 9, 2003||admitted on Feb 11, 2003, with a 4-day history of fever, malaise, sore throat, cough with blood-stained sputum, and bone pain. He had a lymphocyte count of 0.6×109/L and radiological evidence of right lower-lobe consolidation.||despite treatment with intravenous cefotaxime and oral clarithromycin, clinical and radiological signs showed that the patient was deteriorating. 2 days after admission (day 6 of illness), oral oseltamivir (75 mg twice daily) was added and continued for 4 days||the patient was electively intubated because of progressive respiratory distress, but his condition worsened and he died 6 days after admission exhibiting virus in the lungs|
|Thailand 2004 (8 patients; 10 out of 17 patients ?) : 7 of 10 patients given oseltamivir died a mean of 11 days after the onset of symptoms (range, 5 to 22 days), as compared with 5 of 7 untreated patients. Oseltamivir was used in conventional doses (75 mg orally, twice daily for 5 to 10 days with a weight-based dose reduction in children) in the majority of recipients. Treatment tended to have been started earlier in those who survived (a median of 4.5 days from onset compared with 9 days for those who died), and both survivors who were treated received the complete 5-day course of drug, whereas 2 of 5 patients who died received the complete 5-day courseref1, ref2||2 yrs-old male from Supanburi (patient 1)||raised chickens in backyard. Chickens died unexpectedly 5 days before illness onset. Frequently played with chickens and had direct contact with carcasses.||fever, cough, sore throat, dyspnea, diarrhea, HCT 30%, WBC 4,200/ml, lymphocytes 2,646/ml, platelets 214,000/ml, peak ALT 57 U/l, peak AST 129 U/l||days 5 to 10 + corticosteroids||survived (discharged from hospital on Feb10 2004)|
|31 yrs-old male from Nakornratchasima (patient 3)||raised chickens in backyard. Three days before onset, chickens started to die. The last patient died on the date he became sick. He buried all carcasses||fever, cough, sore throat, myalgia, dyspnea, diarrhea, HCT 38%, WBC 4,660/ml, lymphocytes 513/ml, platelets 171,000/ml, peak ALT 74 U/l, peak AST 41 U/l, peak BUN 10.7 mg/dl, peak creatinine 1.07 mg/dl||days 4 to 9 + corticosteroids||survived|
|5 yrs-old male from Khonkaen (patient 5)||Raised fighting cocks that died 4 days before onset. Reported direct contact with carcasses. Ate chicken with suspected H5N1 influenza||fever, rhinorrhea, cough, sore throat, dyspnea, diarrhea, abdominal pain, HCT 39%, WBC 5,600/ml, lymphocytes 2,296/ml, platelets 94,000/ml, peak ALT 47 U/l, peak AST 70 U/l, peak BUN 12 mg/dl, peak creatinine 0.7 mg/dl||days 9 to 13||dead on day 13|
|6 years-old male from Kanchanaburi (patient 6)||No poultry in family. Helped slaughter one ill chicken 2 days before onset||fever, rhinorrhea, cough for 5 days, dyspnea on day 6, HCT 32%, WBC 1,200/ml, lymphocytes 624/ml, platelets 89,000/ml, CXR patchy infiltrates in right lower lobe, ARDS, respiratory failure on day 8, hepatitis, peak ALT 150 U/l, peak AST 790 U/l, peak BUN 12 mg/dl, peak creatinine 0.7 mg/dl, proteinuria >= 3||days 18 to 20 + corticosteroids||dead on day 20|
|6 yrs-old male from Kanchanaburi (patient 8, initials N.C.)||Chickens in backyard died unexpectedly. Grandfather slaughtered ill chickens. No direct contact with chickens but played near slaughtering area||since 24 Jan 2004 fever, cough, sore throat, myalgia, dyspnea, diarrhea, vomiting, HCT 40%, WBC 4,900 (2,900 ?ref)/ml, lymphocytes 1,763 (696 ?ref)/ml, platelets 111,000/ml, ARDS, respiratory failure on day 5, cardiac failure, renal failure, inotropic support, peak ALT 50 U/l, peak AST 280 U/l, peak BUN 22 (50 ?ref) mg/dl, peak creatinine 1.1 (4.6 ?ref) mg/dl||days 5 to 8 + corticosteroids||dead on day 8 (2 Feb 2004)|
|7 yrs-old male from Supanburi (patient 9)||No poultry in family. Frequently played on ground near a chicken farm that reported unexpected poultry deaths||since 3 Jan 2004 fever, cough, sore throat, dyspnea on day 6, HCT 41%, WBC 4,100/ml, lymphocytes 1,435/ml, platelets 304,000/ml, ARDS (CXR bilateral interstitial infiltrates), respiratory failure on day 10, cardiac failure, pneumothorax, gastrointestinal bleeding, inotropic support, peak ALT 52 U/l, peak AST 120 U/l, peak BUN 10 mg/dl, peak creatinine 0.7 mg/dl||days 22 to 27ref (18 to 22 ?ref) + corticosteroids||dead on day 29 (2 Feb 2004)|
|13 yrs-old male from Chaiyapoum (patient 10)||Helped raise chickens in back yard. Eight days before onset, chickens died unexpectedly and patient assisted with slaughtering||fever, cough, sore throat, dyspnea, vomiting, HCT 37%, WBC 2,000/ml, lymphocytes 580/ml, platelets 150,000/ml, ARDS, inotropic support, peak ALT 47 U/l, peak AST 34 U/l, peak BUN 132 mg/dl, peak creatinine 8.1 mg/dl||days 6 to 11 + corticosteroids||dead on day 16|
|32-year-old female from Kamphaeng Phetref||buried dead chickens on Aug 30, provided bedside care in hospital for her 11-year-old niece for 12 or 13 hours on Sep 7, and attended her funeral on Sep 9 (which died as a suspected case (cremated) part of a cluster involving also her mother - embalmed)||onset of fever, myalgia, and chills on Sep 16. An upper respiratory infection was diagnosed at a clinic on Sep 19, but she had progressive difficulty breathing and was admitted to the district hospital on Sep 23 with a temperature of 39.7°C, WBC 5,400, lymphocyte 1,296, platelet 230,000, and left-lower-lobe consolidation||oseltamivir started on hospital admission||recovered (discharged on Oct 7)|
|Vietnam 2004 (5 out of 10 patients) : 1 of 5 recipients of oseltamivir recovered, as compared with 1 of 5 untreated patientsref : one of the 2 surviving patients did not start oseltamivir therapy until the 12th day of illness. At that point, she was still antigen-positive and PCR-positive for the virus.||8 yrs-old female from Ho Chi Minh City (patient 5)||student; patient bought duckling as pet and cared for it in her house for 5 days; duck has diarrhea and died, patient buried it, dug it up a day later and reburied it; both patient and brother handled duck; patient also ate barely cooked eggs (Vietnamese delicacy) 2 days before onset of illness; neighbors kept 40 chickens, but no illness reported in these birds; fevere developed in patient 3 days after she bought duck; no other poultry or animals at home; no other houselhold members or relatives sick||cough, dyspnea, sputum, diarrhea, fever 38.5°C, ABP 104/64 mmHg, RR = 40 bpm, crackles, HGB 11.3 g/dl, WBC 1,200/ml, lymphocytes 300/ml, neutrophils 700/ml, platelets 117,000/ml, CD4:CD8 ratio 0.71, ALT 354 U/l, AST 320 U/l, creatinine 34 mmol/l, O2 saturation during receipt of 40% O2 95%, PCR for H5N1 performed on day 12 of illness||35 mg twice daily for ? days||recovered|
|16 yrs-old female from Soc Trang (patient 7)||student, extensive exposure, including handling of 10 dead or dying chickens in patient's homestead; father of patient prepared dead chickens for eating (removed feathers, washed, cut meat) 3 days before onset of illness; no other household members or relatives sick; no other poultry or animals at home||cough, dyspnea, sputum, diarrhea, fever 40°C, ABP 110/60 mmHg, RR = 60 bpm, crackles, HGB 11.9 g/dl, WBC 3,000/ml, lymphocytes 500/ml, neutrophils 2,500/ml, platelets 70,000/ml, CD4:CD8 ratio 0.62, ALT 47 U/l, AST 20 U/l, creatinine 71 mmol/l, glucose 19 mmol/l, O2 saturation during receipt of 40% O2 67%, PCR for H5N1 performed on day 5 of illness, influenza antigens negative||75 mg twice daily for up to 5 days.||died on day 14 (3 Feb 2004)|
|18 yrs-old male from Lam Dong (patient 8)||farmer, direct handling of 50 chickens, including dead chickens, at home (which was also a restaurant); patient and father prepared chickens for eating; no other household members or relatives sick; no other poultry or animals at home||cough, dyspnea, sputum, diarrhea, fever 38.5°C, ABP 100/60 mmHg, RR = 60 bpm, crackles, HGB 14.7 g/dl, WBC 1700/ml, lymphocytes 500/ml, neutrophils 1100/ml, platelets 69,000/ml, CD4:CD8 ratio : 0.75, serum creatine 89 mmol/l, glucose 13.5 mmol/l, O2 saturation during receipt of 40% O2 81%, PCR for H5N1 performed on day 6 of illness, influenza antigens positive||75 mg twice daily for up to 5 days||died on day 9|
|24 yrs-old male from Lam Dong (patient 9)||farmer, direct handling of chickens in patient's homestead 3 days before onset of ilness; he prepared dead chickens for eating; noone else in family sick||cough, dyspnea, sputum, diarrhea, fever 39.5°C, ABP 110/60 mmHg, RR = 50 bpm, crackles, HGB 15.8 g/dl, WBC 1900/ml, lymphocytes 800/ml, neutrophils 1100/ml, platelets 62,000/ml, CD4:CD8 ratio : 0.59, creatinine 0.43 mmol/l, glucose 11.7 mmol/l, O2 saturation during receipt of 40% O2 80%, PCR for H5N1 performed on day 5 of illness, influenza antigens negative||75 mg twice daily for up to 5 days||died day 6|
|23 yrs-old male from Lam Dong (patient 10)||direct handling of sick ducks and chickens in patient's home; many sick poultry in the district; no other illness in family||cough, dyspnea, sputum, diarrhea, fever 38.7°C, ABP 120/80 mmHg, RR = 28 bpm, crackles, HGB 17.6 g/dl, WBC 2100/ml, lymphocytes 700/ml, neutrophils 1300/ml, platelets 62,000/ml, ALT 89 U/l, AST 110 U/l, creatinine 121 mmol/l, glucose 11.7 mmol/l, O2 saturation during receipt of 40% O2 90%, PCR for H5N1 performed on day 7 of illness, influenza antigens negative||75 mg twice daily for up to 5 days||recovered|
|Ho Chi Minh City 2005 (10 out of 10 patients)||NA|
|Thailand 2005||a 6-year-old boyref1, ref2 from Bangrakam district, Phitsanulok province||patient’s family and neighbors raised chickens in the back yard and let them feed freely in the yard and surrounding areas. Chickens in the village started to die in late Dec with diarrhea and hypersecretion, more than in previous years. All of the chickens in the relative’s farm were sick and died or were culled. 4 of the 5 chickens in the patient’s house also died during that time. The patient had helped cull the sick chickens and carried one of them from the farm back home on Dec 28 : the patient’s family did not eat any sick chickens; some neighbors had symptoms of the common cold||intermittent URT symptoms since late Dec 2003,
mild until Jan 9, 2004, when he developed a distinct
spike of fever and shortness of breath. On Jan 12
increased tachypnea, WBC 1200 cells/mm3
neutrophils, 52% lymphocytes, 2% eosinophils, 2%
monocytes), PLT 89,000 cells/mm3. CXR on day 4 of illness revealed
right lower lobe opacification => admission to hospital, fever 40°C, ABP 90/60 mmHg, HR = 120 bpm, RR = 48 bpm, SO2 = 85%, AST 790, ALT 150, proteinuria and hematuria
|Daily ceftriaxone intramuscular injections since Jan 10 to 12 . Oseltamivir + methylprednisolone 2 mg/kg/day started on day 15 (imported from abroad) until death and with filgrastim from day 5 to day 10 of illness||died on day 17 as a result of respiratory failure (significant insults from barotraumas, including pneumothorax and pneumomediastinum after treatment with a high frequency ventilator with 100% oxygen on day 10 of illness); particles consistent with influenza virus were detected in the lungs and spleen with electron microscopy and were confirmed with reverse transcription-PCR assays, despite 3 days of oseltamivir therapy.|
|a 7-year-old boy (Ronnarit Benpad) in Panuamthuan (Phanom Thuan) district of Kanchanaburi province (150 km (94 miles) west of Bangkok), which had reported fresh outbreaks of the deadly avian influenza strain in poultry around 100 km (60 miles) west of the capital, Bangkok, son of a 48-year-old male farmer named Bang-orn Benpad who developed symptoms on 13 Oct 2005, was hospitalized on 17 Oct 2005, and died on Wed 19 Oct 2005ref.||had assisted his father with defeathering of the diseased birds||developed respiratory symptoms on 16 Oct 2005 and tested positive on Oct 21||treated with oseltamivir early in his illness, recovered his appetite and his fever resolved||recovered|
|Vietnam 2005||a 5-year-old boy from Nakhon Nayokref||touched some chickens raised by a relative, 4 out of 10 died||fell ill with high fever, stomach pain and vomiting around Nov 25. 2 days after that he was taken to 2 private clinics, and finally moved on day 10 to HRH Princess Maha Chakri Sirindhorn Medical Centre in Nakhon Nayok's Ongkharak district||oseltamivir started on hospital admission (day 10)||died on day 12 (Dec 7, 2005)|
Consideration of use of neuraminidase inhibitors such as oseltamivir and zanamivir in IgA nephropathyref.
Influenza virus with resistance to antiviral drugs emerges with increased frequency in immunocompromised patients and can limit the benefit of M2 and neuraminidase (NA) inhibitors. 3 cases of influenza have been documented in severely immunocompromised patients from whom virus variants with molecular markers of resistance to anti-influenza drugs were recovered. Virus variants recovered from 2 patients had mutations in the M2, NA (with a previously recognized Glu119Val NA substitution), and hemagglutinin genes. The novel Asp198Asn NA mutation was described in an influenza B virus and its decreased susceptibility to both oseltamivir and zanamivirref.
Oseltamivir 5 mg/kg oseltamivir for 5 days (equivalent to the approved human treatment dose of 75 mg twice daily) 4 hours after inoculation prevented viral replication in the upper respiratory tract and effectively treated all infected ferrets, with no deaths. All ferrets in the control group died. Resistance mutations of the H5N1 avian influenza virus were not detectedref.
TaqMan probes could clearly discriminate wild type H274 from the mutant 274Y variant. The sensitivity of this assay was as low as 10 copies/ml and allowed the detection of the mutation in a mixture of wild type and mutantref
Zanamivir protects mice against lethal challenge with
A/HK/156/97 (H5N1) influenza virusref
and protects chickens from A/chick/Victoria/1/85 (H7N7),
highly pathogenic virusref,
but fails to protect chickens from other highly virulent
viruses of the NA subtypes N1, N2, N3,
N7, and N8ref1,
There have been recent reports of enhanced potency of multivalent
zanamivir by Sankyo in Japanref1,
and Biota in Australiaref,
where a single dose of drug may be sufficient for
protection. Zanamivir dimers 8 and 13 are highly potent
neuraminidase inhibitors which, along with dimer 3, are
being investigated as potential second generation inhaled
therapies both for the treatment of influenza and for
prophylactic use. Dimer 3 shows NA inhibitory activity
against N1 viruses including the recent highly
Viruses resistant to zanamivir have been generated in
vitro, but no resistant virus has yet been isolated
from a zanamivir-treated immunocompetent patient. In
contrast most resistant viruses isolated from
oseltamivir-treated patients correspond to those selected in
vitro. However, despite mutations being in conserved
residues in the neuraminidase (NA) they do not confer
resistance in all NA subtypes. Reverse genetics and the
recombinant baculovirus expression system were used for
investigating reasons for the lack of isolation of
zanamivir-resistant H3N2 viruses and
for further exploring subtype-specific oseltamivir
resistance. H3N2 viruses generated by
reverse genetics with H274Y, R292K E119V and E119D mutations
were rescued. Those with E119G, E119A or R152K mutations
could only be rescued in the presence of exogenous NA and
after passage in the absence of exogenous NA only isolates
that had reverted to the wild-type NA or, surprisingly,
E119G/A to E119V NA were isolated. Mutations conferring
zanamivir resistance significantly affected enzyme activity,
virus replication or NA thermal stability. E119V viruses
were stable and grew to similar titres as wild-type virus,
consistent with their isolation from oseltamivir-treated
patients. Mutations conferring oseltamivir resistance in N1
(H274Y) and B (R152K) NAs also conferred resistance in
recombinant G70C N9 NA expressed in insect cells. These data
suggest that zanamivir-resistant H3N2
viruses may not readily arise in vivo due to their
poor viability. The G70C N9 NA may also provide a useful
model for understanding the structural basis of
subtype-specific drug resistanceref.
An influenza A/H3N2 variant with NA mutations E59G, E119V, and I222V was first detected after 38 days of oseltamivir treatment. In an NA inhibition assay, this variant was 274 times more resistant to oseltamivir than the original isolate but was susceptible to zanamivir. The I222V substitution enhanced the level of oseltamivir resistance that was primarily conferred by the E119V mutation in recombinant NA proteins. Remarkably, the E119V mutation persisted for 8 months after cessation of oseltamivir. Amantadine therapy led to rapid emergence of the M2 mutation S31N, which is known to confer amantadine resistance. The patient shed the virus intermittently while receiving nebulized zanamivir therapy despite the absence of a resistance phenotype, which could be the result of nonoptimal drug delivery and impaired host immunityref.
Other treatments may have to be considered in patients with rapid disease progression. Intravenous ribavirin was tried in one case without success. The use of immune serum from convalescent patients may be another option worth consideration since neutralising monoclonal antibodies have been effective in treating established influenza A virus infection in mice with severe combined immunodeficiencyref. The efficacy of convalescent immune serum in human beings remains speculative, but combination therapy with immuneglobulin with high neutralising antibody titre and aerosolised ribavirin has resulted in improved outcome in adult bone-marrow-transplant recipients with respiratory syncytial virus diseaseref
Recombinant viruses possessing the 1918 NA or both the 1918 HA and 1918 NA were inhibited effectively in both tissue culture and mice by zanamivir and oseltamivir. A recombinant virus possessing the 1918 M segment was inhibited effectively both in tissue culture and in vivo by amantadine and rimantadineref.
4 household-based, randomized clinical trials, two each of zanamivir and oseltamivir, were designed primarily to estimate the effect of postexposure prophylaxis on preventing influenza illness in household contacts. However, the effect of influenza antivirals on infectiousness as well as on the ability of the virus to cause disease--the pathogenicity--have important public health consequences. The authors show how such studies can provide estimates of pathogenicity, antiviral efficacy for pathogenicity, and the antiviral effect on infectiousness. Analysis of the four studies confirmed the high prophylactic efficacy against illness of both zanamivir (75%, 95% confidence interval (CI): 54, 86) and oseltamivir (81%, 95% CI: 35, 94). The effect on reducing infectiousness was 19% (95% CI: -160, 75) for zanamivir and 80% (95% CI: 43, 93) for oseltamivir. Pathogenicity in controls ranged from 44% (95% CI: 33, 55) to 66% (95% CI: 48, 72). Efficacy in reducing pathogenicity for zanamivir was 52% (95% CI: 19, 72) and 56% (95% CI: 14, 77) in the two studies; for oseltamivir, it was 56% (95% CI: 10, 73) and 79% (95% CI: 45, 92). Studies of influenza antivirals in transmission units would be improved if randomization schemes were used that allow estimation of the antiviral effect on infectiousness from individual studiesref.
NAIs reduce NO production in influenza virus-infected and IFN-g-activated RAW 264.7 macrophagesref
2 mechanisms of resistance have been recognised :
|Subscribe to Pandemic influenza antivirals|
|Browse Archives at groups.google.com|
Desensitization therapyref1, ref2, ref3.
During the lytic form of infection, 2 virally encoded kinases, the HHV-4 / EBVthymidine kinase (EBV-TK) and the BGLF4 gene product, which phosphorylate the prodrug GCV and convert it into its active cytotoxic form, are expressed. Phosphorylated GCV inhibits not only the virally encoded DNA polymerase but also the cellular DNA polymerase, leading to premature termination of the nascent DNA and cell deathref1, ref2, ref3. In addition, phosphorylated GCV can be transferred to adjacent cells, thus inducing "bystander" killingref. Lytic EBV infection also confers sensitivity to the cytotoxic effects of zidovudine (AZT), possibly by inducing AZT phosphorylationref1, ref2, ref3, ref4.
Side effects : myelosuppression, urticaria
Side effects : Fanconi syndromeref