Treatment of Severe 2009 Pandemic Novel H1N1 Infection. Many Questions, Few Answers.
Special Feature
By Stan Deresinski, MD, FACP, Clinical Professor of Medicine, Stanford, Associate Chief of Infectious Diseases, Santa Clara Valley Medical Center, is Editor for Infectious Disease Alert.
During the week ending October 31, 2009, 7.4% of all deaths in the United States reported to the CDC were due to pneumonia and influenza and > 99% of all subtyped influenza A viruses were 2009 influenza A H1N1 viruses.1 While the treatment of mild influenza virus infection is relatively settled, many questions remain with regard to the management of patients with severe infection.
Antiviral Therapy
All isolates of the 2009 pandemic H1N1 influenza virus to date are resistant to the adamantanes, amantadine and rimantadine, but remain susceptible to zanamivir and are only rarely resistant to oseltamivir. Zanamivir is only commercially available for administration by inhalation with the device provided and may not be administered by nebulization, while oseltamivir is only available for enteral administration. Thus, zanamivir cannot be administered to very young children or to patients undergoing mechanical ventilations and is not recommended for individuals with underlying airways disease, while oseltamivir cannot be administered to patients unable to take oral medications, except via a nasoenteric tube.2 Two antiviral preparations suitable for parenteral administration, an intravenous form of zanamivir and peramivir, are under investigation and may be accessed for use under treatment IND. Zanamivir has the potential advantage over peramivir of retaining activity against oseltamivir-resistant virus but the investigational IV formulation has been difficult to access, while the latter is more readily available. Additional agents, such as DAS181, a novel sialidase fusion protein that enzymatically removes sialic acids on the surface of respiratory epithelium, T-705 (an inhibitor of RNA polymerase), and antibody-based therapies are in earlier stages of investigation.
Oseltamivir
The usually recommended (and U.S. FDA-approved) adult dose of oseltamivir for adults is 75 mg twic daily by mouth, but total daily doses approaching 1,000 mg have been reported to be tolerated in healthy volunteers. The IC50 of five isolates of novel H1N1 (A/California/04/2009) ranged from 0.28 nM to 1.41 nM, while those of zanamivir were 0.31 nM to 1.34 nM (0.09 ng/mL-0.37 ng/mL) and those of peramivir were 0.11nM to 1.98 nM (0.03 ng/ml-0.55 ng/mL).3 The mean steady state trough concentration of oseltamivir with a dose of 75 mg twice daily is approximately 200 ng/mL, while it is approximately 300 ng/mL after 150 mg twice daily dosing in healthy volunteers and patients with mild influenza.2 The bioavailability of oseltamivir administered by nasogastric tube has been addressed in three mechanically ventilated Vietnamese patients with H5N1 infection in whom administration of 150 mg twice-daily was associated with drug exposure in excess of that reported in normal volunteers who received the drug orally.2 All three were receiving continuous venovenous hemofiltration; the associated ultrafiltration rate of the drug approximates the glomerular filtration rate. Of note is that one of the three was pregnant and likely had, as a result, a large volume of distribution. Published studies of oseltamivir pharmacokinetics in pregnancy, however, appear to be otherwise totally lacking.
Thus, the available data indicate that the serum concentrations of oseltamivir after oral administration are well in excess of the IC50 for pandemic H1N1. Nonetheless, although the kinetics would suggest it may be unnecessary, limited experimental evidence in mice and ferrets suggests that more intense drug administration may be beneficial, and it has been suggested that severely ill patients receive 150 mg oseltamivir twice daily, rather than the usual lower dose, and that it be administered for 10 instead of five days.3 Studies in Thai volunteers found a 205% increase in oseltamivir area under the curve with a doubling of the administered dose without reduction in rapid conversion from the prodrug to the active carboxylate.4 Administration of probenecid significantly reduces clearance of osel-tamivir.4 Although the available data is minimal, it is possible that higher doses may be associated with improved penetration at sites of infection. While there appear to be no published studies examining the penetration of oseltamivir into pulmonary tissue or epithelial lung fluid, the median concentration in saliva in healthy volunteers was only 4.7%.4 It should be noted, however, that there are no studies demonstrating improved outcome with "high-dose" oseltamivir. In fact, in one study, 150 mg twice-daily regimens were associated with only a statistically nonsignificant reduction in the duration of symptoms of approximately two hours.5 Whether this is true for more severely ill patients has not been determined.
Oseltamivir is administered as the phosphate, which is rapidly converted to the active form by hepatic carboxylesterases. Despite this, no dosage adjustment is required in patients with mild or moderate hepatic impairment (Child-Pugh score ≤ 9); there is no published data in patients with severe hepatic impairment.
Since almost all of the active metabolite is renally excreted, dose adjustments are recommended in the presence of renal insufficiency, a subject that has recently been reviewed here.6 Assuming that the appropriate dose in an adult with normal renal function is 75 mg twice daily, the dose should be reduced to 75 mg once daily if the glomerular filtration rate (GFR) is 10-30 mL/min. No data are available at lower GFRs, and the product insert contains no recommendations in that circumstance. Others, however, have recommended 30 mg every 10 days in the absence of dialysis. Administration of oseltamivir 30 mg after alternating hemodialysis sessions or 30 mg once a week after a peritoneal dialysis session appear to represent safe and potentially effective regimens for ESRD patients.6 In patients undergoing continuous arteriovenous or venovenous hemofiltration, 75 mg once daily may be considered.
Zanamivir
There appears to be very limited published information on the use of higher than recommended doses of inhaled zanamivir, < 20% of which is absorbed into the systemic circulation.7 In a single trial, administration of 10 mg four times daily demonstrated a trend toward improved outcome relative to the standard twice-daily regime, but the differences did not achieve statistical significance.8 The still-investigational formulation of zanamivir suitable for intravenous administation9 is said to be available from GlaxoSmithKline, but some colleagues have had difficulty accessing it.
Peramivir
Peramivir is a neuraminidase inhibitor with a spectrum of activity similar to that of oseltamivir which is undergoing investigation as a parenteral formulation. The U.S. FDA has authorized the use of peramivir under an Emergency Use Authorization.10 Its use is authorized for hospitalized adult patients for whom therapy with an IV agent is clinically appropriate, based upon one or more of the following reasons:
- lack of response to oseltamivir or inhaled zanamivir;
- drug delivery by inhalation or by the enteral route is not expected to be dependable or is not feasible;
- the clinician deems intravenous therapy is appropriate due to other circumstances.
The use of peramivir is appropriate in hospitalized pediatric patients for either of the first two reasons above, but not the third.
Antiviral Combinations
The use of antivirals in combination is under study. The triple combination of oseltamivir, amantadine, and ribavirin was synergistic against several influenza strains in vitro, although pandemic H1N1 was not tested.11 This combination is being studied in comparison to oseltamivir monotherapy in randomized clinical trials in immunocompromised patients.12
Adjunctive Immunomodulation
The progression of pulmonary disease in some patients with severe influenza virus infection despite receipt of antiviral therapy may be due to an overexuberant inflammatory response, an observation that has led to suggestions for the use of adjunctive corticosteroid therapy, as has been recommended in the management of patients with adult respiratory distress syndrome (ARDS). A recent guideline has recommended consideration of administration of moderate-dose glucocorticosteroid (1 mg/kg/day methylprednisolone as a continuous infusion) to adults with early severe ARDS (partial pressure of arterial oxygen/fraction of inspired oxygen [PaO2/FIO2] of < 200) and before day 14 in patients with unresolving ARDS.13 There are, however, no clinical trial data to support this approach in patients with severe influenza or other viral pneumonias. Systematic reviews of studies in patients with SARS found no evidence of benefit.14 Dexamethasone administration to mice with acute respiratory distress due to experimental H5N1 virus infection was not beneficial.15 Corticosteroid administration is associated with prolonged shedding of seasonal influenza.16 A retrospective review of 67 patients with H1N1 infection, in Ho Chi Minh City, found that corticosteroid administration was associated with an increased risk of death even when controlling for neutropenia on admission, a surrogate for disease severity.17
Other adjunctive immunomodulatory therapies, such as macrolides and statins, have also been considered. Two retrospective cohort studies of hospitalized patients have examined the association of statin therapy with outcomes. An evaluation of 415 patients, 84 of whom were receiving statin therapy, found that statin use was independently associated with a reduced length of hospital stay.18 In a second study, 26% of 3,921 patients with laboratory-confirmed influenza infections, administration of statins during hospitalization was independently associated with improved survival (adjusted OR = 0.34; 95% CI 0.16 to 0.70).19
The administration of erythromycin to mice experimentally infected with influenza A/Kumamoto/Y5/67 (H2N2) was associated with reduced local inflammation and improved survival,20 and administration of clarithromycin to patients with influenza was similarly associated with reduced inflammatory markers.21
Treatment of Bacterial Superinfection
Patients with influenza are at increased risk of bacterial pulmonary superinfection, most often due to Streptococcus pneumoniae or Staphylococcus aureus.22 Early recognition and institution of appropriate antibiotic therapy is critical to outcome. Experiments utilizing a murine model of influenza with S. pneumoniae superinfection found that administration of clindamycin or azithromycin was associated with improved survival when compared to β-lactam therapy.23 Evidence suggested that this was related to a reduced inflammatory response as evidenced by lower concentrations of inflammatory cells and proinflammatory cytokines, as well as less severe histopathologic changes in the lungs.
Extracorporeal Membrane Oxygenation (ECMO)
In addition to these pharmacological considerations, some evidence suggests the possibility that the use of extracorporeal membrane oxygenation in patients with influenza and respiratory failure may be associated with improved survival.24 The strength of the evidence is, however, severely limited by the non-randomized nature of the study.
Many Questions, Few Answers
The treatment of severe pandemic H1N1infection presents many choices, but little in the way of firm data with regard to many important therapeutic issues. The challenges presented to the clinician provide strong evidence of the need for federal support of a national clinical trials organization capable of moving quickly to implement appropriate investigations of therapeutic approaches to this and other infectious diseases. The following is a list of only some of the questions that urgently require answers:
- What is the appropriate dose of oseltamivir, including in special populations such as late pregnancy and massive obesity, as well as in patients with severe immuno compromise?
- What is the role of combination antiviral therapy, such as a regimen of oseltamivir, zanamivir, and ribavirin?
- What is the role of adjunctive corticosteroid therapy in patients with severe infection? What is the role of other immunomodulators, such as statins and macrolide antibiotics?
- Does ECMO have benefit in patients with severe influenza requiring mechanical ventilation?
The answers to these questions can only be addressed in multicenter clinical trials.
References
- http://www.cdc.gov/flu/weekly/index.htm#EIPNVSNCDC. Update: drug susceptibility of swine-origin influenza A (H1N1) viruses, April 2009. MMWR Morb Mortal Wkly Rep. 2009;58:433-435.
- Taylor WR, et al. Oseltamivir is adequately absorbed following nasogastric administration to adult patients with severe H5N1 influenza. PLoS One. 2008;3:e3410.
- CDC. Updated Interim Recommendations for the Use of Antiviral Medications in the Treatment and Prevention of Influenza for the 2009-2010 Season October 16, 2009 4:00 PM ET
- Wattanagoon Y, et al. Pharmacokinetics of high-dose oseltamivir in healthy volunteers. Antimicrob Agents Chemother. 2009;53:945-952.
- Treanor JJ, et al. Efficacy and safety of the oral neuraminidase inhibitor oseltamivir in treating acute influenza: a randomized controlled trial. JAMA. 2000;283:1016-1024.
- Hsu O, et al. Alternative dosing of oseltamivir for specific patient populations: Critically ill and renally impaired. Infect Dis Alert. October 2009;29:7-9.
- Cass LM, et al. Pharmacokinetics of zanamivir after intravenous, oral, inhaled or intranasal administration to healthy volunteers. Clin Pharmacokinet. 1999;36 Suppl 1:1-11.
- Monto AS, et al. Efficacy and safety of the neuraminidase inhibitor zanamivir in the treatment of influenza A and B virus infections. J Infect Dis. 1999;180:254-261.
- Kidd IM, et al. H1N1 pneumonitis treated with intravenous zanamivir. Lancet. 2009;374:1036.
- CDC. Antiviral Treatment Options, including Intravenous Peramivir, for Treatment of Influenza in Hospitalized Patients for the 2009-2010 Season. October 26, 2009 5:00 PM ET http://www.cdc.gov/h1n1flu/EUA/peramivir_recommendations.htm
- Nguyen JT, et al. Triple combination of oseltamivir, amantadine, and ribavirin displays synergistic activity against multiple influenza virus strains in vitro. Antimicrob Agents Chemother. 2009;53:4115-4126.
- http://clinicaltrials.gov
- Marik PE, et al. American College of Critical Care Medicine. Recommendations for the diagnosis and management of corticosteroid insufficiency in critically ill adult patients: consensus statements from an international task force by the American College of Critical Care Medicine. Crit Care Med. 2008;36:1937-1949.
- Stockman LJ, et al. SARS: Systematic review of treatment effects. PLoS Med. 2006;3:e343.
- Xu T, et al. Effect of dexamethasone on acute respiratory distress syndrome induced by the H5N1 virus in mice. Eur Respir J. 2009;33:852-60.
- Lee N, et al. Viral loads and duration of viral shedding in adult patients hospitalized with influenza. J Infect Dis. 2009;200:492-500.
- Liem NT, et al. Clinical features of human influenza A (H5N1) infection in Vietnam: 2004-2006. Clin Infect Dis. 2009;48:1639-1646.
- Hagan JE, Lawrence SJ. Statin therapy and outcomes in hospitalized patients with influenza A: a retrospective cohort study. 47th Annual Meeting of the IDSA, Oct 29-Nov 1, 2009, Philadelphia PA, Abstract 628.
- Thomas A, et al. Role of statins in preventing death among patients hospitalized with lab-confirmed influenza infections. 47th Annual Meeting of the IDSA, Oct 29-Nov 1, 2009, Philadelphia PA, Abstract 706.
- Sato K, et al. Therapeutic effect of erythromycin on influenza virus-induced lung injury in mice. Am J Respir Crit Care Med. 1998;157:853-857.
- Sato K. Low-dose and long-term therapy of clarithromycin could regulate the inflammation in human influenza virus infection. 47th Annual Meeting of the IDSA, Oct 29-Nov 1, 2009, Philadelphia PA, Abstract 625.
- CDC. Bacterial coinfections in lung tissue specimens from fatal cases of 2009 pandemic influenza A (H1N1) — United States, May-August 2009. MMWR. 2009;58:1071-1074.
- Karlström Ä, et al. Treatment with protein synthesis inhibitors improves outcomes of secondary bacterial pneumonia after influenza. J Infect Dis. 2009;199:311-319.
- The Australia and New Zealand Extracorporeal Membrane Oxygenation (ANZ ECMO) Influenza Investigators. Extracorporeal Membrane Oxygenation for 2009 Influenza A (H1N1) Acute Respiratory Distress Syndrome. JAMA. 2009;302:1888-1895.
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