Won-Young Kim, Sung-Cheol Yun, Min-ju Kimaac.asm.org/content/early/2011/10/03/AAC.05529-11.full.pdfWon-Young Kim, Sung-Cheol Yun, Min-ju Kim (University of Ulsan College of Medicine);

1

Triple combination antiviral drug for pandemic H1N1 in critically ill patients on 1

mechanical ventilation 2

Running title: Triple Therapy in Critically Ill H1N1 Infection 3

4

†Won-Young Kim1*, †Gee Young Suh2, Jin Won Huh1, Sung-Han Kim3, Min-ju Kim4, 5

Yun Seong Kim5, Hye-Ryoun Kim6, Yon Ju Ryu7, Min Soo Han8, Young Gwan Ko9, Gyu 6

Rak Chon10, Kwan Ho Lee11, Sang-Ho Choi3, and Sang-Bum Hong1*; for the Korean 7

Society of Critical Care Medicine (KSCCM) H1N1 Collaborative‡ 8

1Department of Pulmonary and Critical Care Medicine, 3Department of Infectious Diseases, 9

and 4Department of Clinical Epidemiology and Biostatistics, Asan Medical Center, 10

University of Ulsan College of Medicine, Seoul; 2Division of Pulmonary and Critical Care 11

Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul; 12

5Pusan National University School of Medicine, Pusan; 6Korea Cancer Center Hospital, 13

Seoul; 7Ewha Womans University School of Medicine, Seoul; 8Eulji University School of 14

Medicine, Daejon; 9School of Medicine, Kyung Hee University, Seoul; 10Konkuk University 15

School of Medicine, Cheungju; 11College of Medicine, Yeungnam University, Daegu, 16

Republic of Korea 17

† Dr. Won-Young Kim and Dr. Gee Young Suh contributed to this paper equally. 18

19

‡ Korean Society of Critical Care Medicine (KSCCM) H1N1 Collaborative 20

Gee Young Suh, Kyeongman Jeon (Sungkyunkwan University School of Medicine); Shin Ok 21

Koh, Moo Suk Park (Yonsei University College of Medicine); Won-Il Choi (Keimyung 22

University School of Medicine); Younsuck Koh, Chae-Man Lim, Sang-Bum Hong, Eun 23

Young Choi, Sung-Han Kim, Jaemin Lim, Jong-Joon Ahn, Jin Won Huh, Sang-Ho Choi, 24

Copyright © 2011, American Society for Microbiology and/or the Listed Authors/Institutions. All Rights Reserved.Antimicrob. Agents Chemother. doi:10.1128/AAC.05529-11 AAC Accepts, published online ahead of print on 3 October 2011

on May 17, 2018 by guest

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Won-Young Kim, Sung-Cheol Yun, Min-ju Kim (University of Ulsan College of Medicine); 25

Hyun-Kyung Lee (College of Medicine, Inje University); Seok Chan Kim (The Catholic 26

University of Korea College of Medicine); Sang Hyun Kwak (Chonnam National University 27

Medical School); Young Joo Lee (Ajou University School of Medicine); Heung-Bum Lee 28

(Chonbuk National University Medical School); Jae Yeol Kim (Chung Ang University 29

College of Medicine); Jae Hwa Cho (Inha University College of Medicine); Hye Sook Choi 30

(Dongguk University Gyeongju Hospital); Myung Goo Lee, Yong Bum Park (Hallym 31

University School of Medicine); Ho Cheol Kim (Gyongsang National University School of 32

Medicine); Yeon Sook Kim (Chungnam National University Hospital); Chang Young Lim 33

(CHA University College of medicine); Ki Uk Kim, Yun Seong Kim (Pusan National 34

University School of Medicine) Hye-Ryoun Kim (Korea Cancer Center Hospital); Yon Ju 35

Ryu (Ewha Womans University School of Medicine); Min Soo Han (Eulji University School 36

of Medicine); Young Gwan Ko (School of Medicine, Kyung Hee University); Sun-Jong Kim, 37

Gyu Rak Chon (Konkuk University School of Medicine); Kwan Ho Lee (College of 38

Medicine, Yeungnam University). 39

40

Corresponding author: Sang-Bum Hong, MD, Department of Pulmonary and Critical Care 41

Medicine, Asan Medical Center, University of Ulsan College of Medicine, 88, Olympic-ro 42

43-Gil, Songpa-gu, Seoul 138-736, Republic of Korea. E-mail: [email protected] 43

Tel: 82-2-3010-3893 Fax: 82-2-3010-6970 44

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ABSTRACT 49

Recent in vitro study showed that the three compounds of antiviral drugs with different 50

mechanisms of action (amantadine, ribavirin, and oseltamivir) could result in synergistic 51

antiviral activity. However, no clinical studies have evaluated the efficacy and safety of 52

combination antiviral therapy in patients with severe influenza illness. 245 adult patients who 53

were critically ill with confirmed pandemic influenza A/H1N1 2009 (pH1N1) infection and 54

were admitted to one of the intensive care units (ICUs) of 28 hospitals in Korea were 55

reviewed. Patients who required ventilator support and received either triple combination 56

antiviral drug (TCAD) therapy or oseltamivir monotherapy were analyzed. A total of 127 57

patients were included in our analysis. Among them, 24 patients received TCAD therapy and 58

103 patients received oseltamivir monotherapy. The 14-day mortality was 17% in the TCAD 59

group and 35% in the oseltamivir group (P = 0.08) and the 90-day mortality was 46% in the 60

TCAD group and 59% in the oseltamivir group (P = 0.23). None of the toxicities attributable 61

to antiviral drugs occurred in either group of our study, including hemolytic anemia and 62

hepatic toxicities related with the use of ribavirin. Logistic regression analysis indicated that 63

the odds ratio (OR) for the association of TCAD with 90-day mortality was 0.58 (95% CI 64

0.24-1.42, P = 0.24). Although this study was retrospective and did not provide virologic 65

outcomes, our results suggest that the treatment outcome of the triple combination of 66

amantadine, ribavirin, and oseltamivir was comparable to that of oseltamivir monotherapy. 67

68

Keywords: Pandemic A/H1N1 2009, triple combination antiviral drug, critically ill patients, 69

mechanical ventilation 70

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INTRODUCTION 73

Pandemic influenza A/H1N1 2009 (pH1N1) was a considerable public health concern 74

worldwide. Most infected people experienced mild and uncomplicated illnesses, but some 75

patients developed rapidly progressive pneumonia that lead to respiratory failure, shock, and 76

death (6, 22, 30). The Centers for Disease Control and Prevention (CDC) recommended that 77

all patients with severe pH1N1 illness be treated with oseltamivir or zanamivir as soon as 78

possible (9). Oseltamivir and zanamivir are neuraminidase inhibitors (NAIs), which interfere 79

with the release of progeny influenza virus from infected cells, thereby preventing new 80

rounds of infection (27). Oseltamivir is readily available in oral formulation, and zanamivir in 81

inhalation or intravenous form. Rimantadine and amantadine are closely related adamantanes 82

(also called M2 inhibitors), and they target the M2 protein of influenza A, which forms a 83

proton channel in the viral membrane that is essential for efficient viral replication (35). 84

Ribavirin is approved for the treatment of respiratory syncytial virus and in combination with 85

interferon or peginterferon for hepatitis C virus. In vitro inhibitory activity against both viral 86

RNA and DNA polymerase may implicate for a reduced potential of ribavirin for the drug 87

resistance of influenza viruses (26). Ribavirin is available in oral, aerosolized, and 88

intravenous formulations, although intravenous form is not currently approved in the United 89

States. 90

Previous studies on antiviral therapies in influenza virus were conducted primarily in 91

healthy outpatients with uncomplicated illnesses (12, 29). Limited data are available on 92

antiviral use in patients with severe influenza infection, and recommendations are mostly 93

based on expert opinions or observational studies (24, 42). Treatment can be complicated if 94

NAI-resistant viral strains are suspected (4, 40). Recent studies reported the emergence of 95

oseltamivir-resistant viruses after short-term drug therapy (16, 25). The prevalence of drug-96


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resistant strains could undermine clinical benefit of antiviral drugs when utilized as 97

monotherapy, especially for critically ill patients, when the development of antiviral 98

resistance is rapid. 99

The present limitations of monotherapy to treat severe influenza illness have renewed 100

interest in antiviral therapies that combine multiple drugs with different mechanisms of action 101

(15, 28, 32). Nguyen et al. evaluated the three compounds of antiviral drugs (amantadine, 102

ribavirin, and oseltamivir), so called a triple combination antiviral drug (TCAD) regimen, 103

using an in vitro infection model (28). They reported that TCAD had a strong effect on drug-104

resistant viruses, including pH1N1 strains. Such combination therapy might be clinically 105

useful in treatment of influenza viruses that are resistant to one or more antivirals. The CDC 106

reported that 1,143 of 1,148 (99.6%) seasonal H1N1 viruses isolated in the period 2008-2009 107

and 10 of 1,497 (0.6%) pH1N1 isolates tested in the United States were resistant to 108

oseltamivir (4). In Korea, from May 2009 through January 2010, a total of 740,835 patients 109

were reported with pH1N1 virus infection and 11 of 67 (16%) patients who were suspected of 110

having drug-resistant pH1N1 strains were identified as oseltamivir-resistant (31). To date, 111

rapid diagnostic tests to determine the susceptibility profile of influenza viruses are not 112

available. The availability of a broad-spectrum antiviral therapy that would be effective 113

regardless of the susceptibility against each antiviral drug would be of high clinical utility. 114

However, no clinical studies have demonstrated the efficacy and safety of TCAD for patients 115

with severe influenza illness. 116

In this study, we analyzed the efficacy and safety of TCAD for patients with pH1N1 117

infection whose illnesses were severe enough for admission to an ICU with ventilator support. 118

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MATERIALS AND METHODS 121

Patient selection 122

We initially reviewed the data of a cohort from the Korean Society of Critical Care 123

Medicine (KSCCM) H1N1 Collaborative. The cohort is composed of critically ill adult 124

patients who were at least 15 years old, had confirmed pH1N1 infection, and were admitted 125

to one of the ICUs of the 28 participating tertiary or referral hospitals of Korea from 126

September 2009 to February 2010. Pandemic influenza A/H1N1 2009 virus was confirmed 127

by a positive result from a probe-based reverse-transcriptase polymerase-chain-reaction test 128

from a nasopharyngeal swab or broncho-alveolar lavage (37). From this cohort, we included 129

in analysis patients who: (i) required ventilator support (invasive or noninvasive); (ii) 130

received either TCAD or oseltamivir monotherapy as initial antiviral treatment. 131

132

Antiviral treatment protocol 133

During 2009 pandemic, the KSCCM established the management protocol for new H1N1 134

influenza pneumonia with respiratory failure (21). The KSCCM also invited the study 135

investigators to participate in this study, and encouraged them to follow the protocol. With 136

respect to the use of antivirals, the protocol states that triple combination antiviral regimen 137

(oseltamivir 150 mg twice daily + amantadine 100 mg twice daily + ribavirin 300 mg three 138

times daily) may be considered in case of severe influenza illness. The drug dosage for 139

amantadine was based on data from product labels (www.drugs.com/pro/symmetrel.html), 140

and a reduction in dosage was recommended for patients with age ≥65 years or creatinine 141

clearance (CCr) <50 mL/min. The dosage for oral ribavirin was based on previously 142

published studies (5, 23), and the drug was used with caution in patients with CCr <50 143

mL/min. As for oseltamivir, we suggested doubling the dose (150 mg twice daily) when used 144


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in triple combination regimen to treat severe influenza illness. For patients with CCr <30 145

mL/min, a reduction in dosage was recommended. The antiviral drugs were administered via 146

a nasogastric (NG) or gastric tube when the patients were on ventilator support. 147

148

Study design 149

We performed a retrospective cohort analysis to compare the clinical outcomes of patients 150

given TCAD therapy or oseltamivir therapy. The primary outcome of this study was mortality. 151

To assess the safety of antiviral agents, we identified any possible adverse events related to 152

antiviral therapy and reviewed serum liver enzymes and creatinine at the time of ICU 153

admission (baseline) and at 3, 7, and 14 days after initiation of drugs. We also analyzed 154

factors associated with mortality, including TCAD treatment. This study was approved by the 155

local Institutional Review Board (IRB) of each hospital. Informed consent was not necessary 156

because this was not an interventional study (IRB of Asan Medical Center: 20110294). 157

158

Definitions 159

A nosocomial infection of pH1N1 was defined as one in which symptoms or signs 160

suggestive of influenza illness newly developed three days or more after hospital admission 161

and pH1N1 virus was confirmed as a causative agent. Cardiovascular disease included 162

hypertension, ischemic heart disease, arrhythmia, and congestive heart failure. An 163

immunosuppressive condition was diagnosed if there was an underlying disease that affected 164

the immune system (chronic liver disease, chronic renal disease, human immunodeficiency 165

virus infection, or malignancy) or if immunosuppressive therapy was being administered at 166

the time of infection. Acute respiratory distress syndrome (ARDS) was diagnosed by 167

consensus definition (3). Severity of illness was assessed by the Acute Physiology and 168


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Chronic Health Evaluation (APACHE) II score (20) and the Sequential Organ Failure 169

Assessment (SOFA) score (39) on the day of ICU admission. 170

171

Statistical analysis 172

Data are presented as the number ± standard deviation (SD) or (%) of patients unless 173

indicated otherwise. Student’s t-test or the Kruskall-Wallis test was used to compare 174

continuous data and the chi-square or Fisher’s exact test was used to compare categorical data 175

as appropriate. In order to identify factors associated with 90-day mortality, all prespecified 176

covariables, which are listed in Table 1 and Table 2 of the article, were included in the 177

multiple logistic regression analysis by using step-wise backward selection procedures with P 178

< 0.10. To prevent multicollinearity, variables with high correlation between each other were 179

strictly controlled. Model calibration was assessed with Hosmer-Lemeshow test (χ2 = 4.07, df 180

= 8, P = 0.85). All tests of significance were two-tailed and P value less than 0.05 were 181

considered significant. All analyses were performed with SPSS version 18.0K for Windows 182

(SPSS Inc, Chicago, IL, USA). 183

184

185

RESULTS 186

There were 245 patients in the initial cohort, and 127 of these patients were ultimately 187

included in our analysis. Considerable drop-out occurred largely due to patients being treated 188

with NAIs other than oseltamivir (n = 32). A total of 24 of the included patients received 189

TCAD and 103 received oseltamivir monotherapy (Figure 1). 190

Table 1 shows the baseline characteristics of the TCAD group and the oseltamivir group. 191

Patients given TCAD were older (mean age, 63.5 ± 18.9 years vs. 55.7 ± 17.7 years, P = 192


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0.046), but there was no difference in sex or body mass index. There were no differences 193

between the two groups in co-morbidities, immunosuppressive conditions, severity of illness, 194

and baseline values measured at ICU admission. The proportion of patients with shock and 195

ARDS were also similar between the two groups. Adjuvant corticosteroids were administered 196

to about half of the patients in each group. There were no differences between the groups in 197

mean time from onset of symptoms to antiviral drug administration. In the TCAD group, 198

higher doses of oseltamivir were administered (oseltamivir ≥300 mg/d, 63% vs. 33%, P = 199

0.01). The mean treatment duration was longer (11.1 ± 7.0 days vs. 6.2 ± 3.6 days, P < 0.001) 200

in the TCAD group, although in patients who survived (n = 55), there was no significant 201

difference (9.6 ± 5.4 days vs. 7.3 ± 3.1 days, P = 0.15). The mean doses of amantadine and 202

ribavirin in the TCAD group were less than the recommended doses of the KSCCM protocol. 203

Table 2 shows the clinical outcomes of the two groups. There were three cases (13%) of 204

community-acquired pneumonia in the TCAD group, and ten cases (10%) in the oseltamivir 205

group. During the course of illness, hospital-acquired pneumonia occurred and the proportion 206

of patients was similar between the two groups. Within 90 days from onset of symptoms, 11 207

patients (46%) died in the TCAD group and 61 (59%) in the oseltamivir group. The deaths 208

occurred within 14-day period in 36% (4/11) of the TCAD group and 59% (36/61) of the 209

oseltamivir group. There was a trend toward lower 14-day, 30-day, and 90-day mortality in 210

the TCAD group, but this was not statistically significant. In the TCAD group, all 11 patients 211

died due to aggravation of septic shock or pneumonia, and 50 patients (82%) in the 212

oseltamivir group. In the oseltamivir group, three patients died due to uncontrolled liver 213

failure, two due to intra-abdominal infection, two due to exacerbation of underlying disease, 214

and four due to undetermined cause. There were no differences between the two groups in 215

mean ventilator-free days. 216


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The results of additional analysis of the study group stratified by duration of ICU stay are 217

shown in Table 3. Most of the baseline characteristics were similar between the two groups, 218

but patients with ICU stay more than 7 days were more immunocompromised (34% vs. 52%, 219

P = 0.04) and had longer mean duration of symptom before antiviral administration (3.5 ± 3.1 220

days vs. 6.3 ± 5.1 days, P = 0.001). Secondary bacterial (hospital-acquired) pneumonia 221

occurred more in the group with longer ICU stay (31% vs. 69%, P < 0.001), however more 222

deaths occurred in patients with ICU stay less than or equal to 7 days (66% vs. 48%, P = 223

0.04). 224

Table 4 shows the safety measures related to antiviral agents. There were neither 225

hematologic (eg. hemolytic anemia) nor neurologic (eg. seizure) events in any of the 127 226

patients. In the TCAD group, the mean difference (post-treatment value – baseline value) for 227

aspartate transaminase (AST) was -12.8 ± 38.7 IU/L, for alanine transaminase (ALT) was -228

2.9 ± 21.3 IU/L, and for total bilirubin (TB) was -0.2 ± 3.0 mg/dL. In the oseltamivir group, 229

seven cases had severe liver enzyme elevation (Supplementary Table 1) and the mean 230

differences of AST and ALT were very high. There was no significant difference in the mean 231

difference of serum creatinine between the two groups. Three patients, all in oseltamivir 232

group, died due to uncontrolled liver failure, although the relationship between toxicity and 233

drug use was unclear. 234

Table 5 shows the results of our univariate and multivariate analysis of risk factors 235

associated with 90-day mortality. APACHE II score and mean arterial pressure were excluded 236

in further analysis due to multicollinearity with SOFA score and shock, respectively. 237

Multivariate analysis that adjusted for variables associated with 90-day mortality rate 238

indicated that increasing age, nosocomial infection of the virus, higher SOFA score, and 239

prone position were significantly associated with increased mortality. On the other hand, 240


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larger doses of oseltamivir, longer duration of antiviral therapy, and TCAD therapy were not 241

significantly associated with increased survival. 242

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244

DISCUSSION 245

The present results indicate that use of the TCAD regimen to treat pH1N1 illness with 246

ventilator support was well tolerated with no significant adverse drug reactions. Although the 247

use of TCAD was not associated with decreased mortality, its treatment outcome was 248

comparable to that of oseltamivir monotherapy. 249

The prevalence of the oseltamivir-resistant pH1N1 viruses were identified worldwide (4, 31). 250

The prevalence of drug-resistant strains is a concern to patients with severe influenza illness, 251

especially when the development of antiviral resistance occurs within few days of patients’ 252

exposure to antivirals (16, 25). Most cases of the oseltamivir-resistant pH1N1 virus have 253

been associated with the H275Y mutation in neuraminidase gene and they are susceptible to 254

zanamivir. However, zanamivir in inhalation form is not recommended for patients with 255

asthma or chronic obstructive pulmonary disease due to the possibility of bronchospasm (11). 256

More importantly, the use of a zanamivir disc inhaler is impossible for intubated patients 257

because the medication cannot be properly delivered to infection sites. Also, a nebulized 258

preparation is not recommended because it can clog the ventilator tube (18). Recent clinical 259

data of patients with oseltamivir-resistant pH1N1 infection have indicated that intravenous 260

zanamivir is effective (10, 19), but most of them are case reports of a single patient. Recently, 261

Hernandez et al. described 31 hospitalized patients who received peramivir, another 262

parenteral antiviral agent, and showed moderate efficacy and safety (14). However, most of 263

patients concomitantly received oseltamivir, no comparison group was available, and no 264


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virologic outcomes were provided. 265

Alternative drug regimen to treat severe influenza infection, such as combining agents with 266

different mechanisms of action, is possible. To date, two clinical studies evaluated 267

combination therapy, but have failed to prove its efficacy (8, 17). Several pre-clinical studies, 268

both in vitro and in vivo, support the effectiveness of combination therapy (15, 28, 32). In 269

double combinations, however, the additive or synergistic effects varied according to 270

combination type, dosage of drugs, and virus strain. For example, in the animal study by 271

Ilyushina and Smee et al., double combination of amantadine and other antivirals provided 272

greater protection against amantadine-sensitive strain than did monotherapy. In contrast, no 273

benefit was noted with combination therapy when the infecting virus was resistant to 274

amantadine (15, 32). Such combinations with amantadine would not be effective in patients 275

with pH1N1 virus because the World Health Organization confirmed that the pandemic virus 276

is resistant to the M2 inhibitors (41). In a recent in vitro study, Nguyen et al. tested the 277

activity of TCAD against six amantadine-resistant viruses, including three strains of pH1N1 278

virus, and two oseltamivir-resistant viruses (28). Surprisingly, they found that the TCAD was 279

highly synergistic against resistant viruses, and the synergism from a triple combination was 280

greater than that from any double combination. Amantadine, which is intrinsically resistant to 281

pH1N1 virus, had no activity as single agent. However, when it was added to ribavirin and 282

oseltamivir, amantadine significantly contributed to the synergism of the TCAD. This may 283

suggest that the TCAD regimen have a broad-spectrum antiviral activity for seasonal and 284

pandemic influenza viruses compared to double combination or monotherapy. Moreover, the 285

synergism of the triple combination occurred at concentrations that are achievable in plasma 286

for the recommended doses of each antiviral drug, implicating for the clinical use of TCAD 287

therapy. 288


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In addition to potential antiviral effect, oral combination antiviral drugs can be easily 289

administered via a NG tube without clogging the ventilator tube. The absorption of oral 290

agents in a patient with the decreased bowel movement associated with ventilator may be a 291

concern. However, several clinical studies indicated that enteric absorption of oseltamivir via 292

a NG tube in ventilated patients achieved plasma levels that were comparable to those in 293

ambulatory patients (1, 36). 294

TCAD appears to be an effective treatment modality for critically ill influenza patients, but 295

more data are needed before it can be recommended in a clinical setting. To date, our study is 296

the first clinical study in which the efficacy of triple antiviral combination therapy is 297

compared to single oseltamivir therapy in patients with severe influenza illness. However, our 298

statistical analysis of mortality appears to provide that TCAD was not superior to the standard 299

oseltamivir therapy against pH1N1 infection, in contrast with previous pre-clinical studies. 300

There are several possible explanations for this discrepancy. Many of our study patients were 301

severely diseased and had the poor conditions to be treated. As a result, the treatment 302

outcomes might have not been satisfactory despite the use of multiple antiviral drugs. 303

Insufficient antiviral dosage may also have been the problem. Ribavirin, although its use for 304

the treatment of influenza is investigational, showed a promising effect when used in high-305

dose or intravenous formulation (13, 34). In the recent observation by van der Vries et al., 306

pH1N1 virus titer significantly dropped when ribavirin was added to oseltamivir and 307

zanamivir in a dually NAI-resistant patient (38). In our study, the actual dose of ribavirin 308

administered was much less than the dose used in the previous studies or the dose 309

recommended by the KSCCM. The treatment outcomes might have been different for the 310

TCAD group if higher dose of ribavirin was administered. 311

Toxicity can be a significant problem when using three different drugs simultaneously. 312


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Oseltamivir is well-tolerated and safe at the recommended doses, with few side effects (7). 313

On the other hand, ribavirin has teratogenic properties and can cause hematologic, 314

gastrointestinal, and hepatic toxicities (www.drugs.com/pro/rebetol.html). An increased 315

incidence of seizures has been reported in patients given amantadine (2). During the study 316

period, none of the toxicities attributable to amantadine or ribavirin occurred. Hemolytic 317

anemia, the primary toxicity of ribavirin, usually occurs within 1 to 2 weeks of initiation of 318

therapy. In our case, the median (range) duration of ribavirin treatment was 7 (2-24) days, and 319

6 of 24 (25%) patients received ribavirin treatment for longer than 14 days. The mean dose of 320

ribavirin was less than 600 mg/d. In spite of relatively long treatment duration in some of our 321

study patients, there is a chance that serious anemia could have been avoided due to small 322

dosage of ribavirin administered. There were no remarkable elevation of serum liver enzymes 323

and creatinine in the TCAD group. On the other hand, seven patients in the oseltamivir group 324

experienced severe liver enzyme elevation. We believe that oseltamivir played at most a 325

minor role in elevation of liver enzymes, because oseltamivir is known to be adequately 326

metabolized in hepatically-impaired individuals (33) and most of these patients were in 327

uncontrolled sepsis with organ failure at the time of liver enzyme elevation. 328

The present study has several limitations. First, the study was retrospective and 329

underpowered. Also, relatively small sample size was used for the TCAD group compared to 330

the oseltamivir group. We could not adjust unmeasured confounders, and the matching 331

process to compensate the sample size difference between the two groups was not feasible; 332

hence, our results cannot be considered conclusive and must be assessed for consistency with 333

other studies. Second, we did not monitor the duration of viral shedding and emergence of 334

drug resistance. As a result, we could not clarify the relationship between antiviral effect and 335

clinical outcome or evaluate the efficacy of TCAD in association with viral resistance. Third, 336


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we did not measure the serum concentrations of the antiviral agents during treatment, and 337

hence could not establish their pharmacokinetic profiles. Fourth, antiviral dose, timing of 338

antiviral commencement, and duration of antiviral treatment were not standardized among 339

centers. The proportion of patients who received the double dose of oseltamivir and antiviral 340

duration varied between the two groups. However, in the regression analysis, the oseltamivir 341

dose and antiviral duration were not associated with increased or decreased survival. Last, 342

there is a possibility that secondary bacterial pneumonia, especially hospital-acquired, might 343

have significantly contributed to mortality. We performed additional analysis of the study 344

group stratified by duration of ICU stay. From the results, we assume that the bacterial 345

pneumonia by itself was less likely to be the major determinant of increased mortality. Also, 346

the presence of bacterial pneumonia was not associated with increased mortality in the 347

regression model. Further studies are needed to evaluate the efficacy and safety of TCAD in 348

severe influenza illness. However, as prospective clinical trials are not available in the near 349

future, we believe that this observational study can provide a certain aspect regarding to 350

selection of antiviral agents in severe influenza infection with mechanical ventilation and 351

possibly, a useful background for planning further clinical trials. 352

In conclusion, our comparison of TCAD therapy with oseltamivir monotherapy for patients 353

who were critically ill on mechanical ventilation with pH1N1 virus indicates that TCAD was 354

well tolerated and the treatment outcome was comparable to that of oseltamivir monotherapy. 355

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ACKNOWLEDGEMENTS 361

All the authors have no conflicts of interest to disclose and no funding source, and are 362

indebted to all who participated in this study. All the authors read and approved the final 363

manuscript. 364

We also thank Eun Mi Cho and Na Yeon Lee (clinical research nurses) for assistance in the 365

chart review. 366

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358:261-273. 538

539

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FIG. 1. Disposition of pH1N1-infected patients included in the analysis of the impact of 553

TCAD vs. oseltamivir monotherapy (NAIs, neuraminidase inhibitors; TCAD, triple 554

combination antiviral drug) 555

556

557

558

559

560

561

562

563

564

565

566

567

568

569

570

571

572

573

574

575

576


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TABLE 1. Baseline characteristics of TCAD group and oseltamivir groupa 577

Variables

TCAD

(n = 24)

Oseltamivir

(n = 103)

P

Age, years (mean ± SD) 63.5±18.9 55.7±17.7 0.046

Male sex 14 (58) 58 (56) 0.86

Body mass index, kg/m2 (mean ± SD) 22.5±4.3 23.3±4.9 0.39

Nosocomial H1N1 infection 4 (17) 16 (16) >0.99

Chronic coexisting conditions

Cardiovascular disease 9 (38) 54 (52) 0.19

COPD/Asthma 6 (25) 15 (15) 0.23

Diabetes 4 (17) 28 (27) 0.29

Chronic liver disease 2 (8) 5 (5) 0.62

Chronic renal disease 2 (8) 15 (15) 0.53

Cerebral vascular disease 3 (13) 18 (18) 0.76

Solid tumor 5 (21) 29 (28) 0.47

Hematologic malignancy 3 (13) 3 (3) 0.08

Pregnancy 0 1 (1) >0.99

No underlying diseases 3 (13) 13 (13) >0.99

Immunosuppressive conditions 11 (46) 45 (44) 0.85

Shock 10 (42) 50 (49) 0.54

ARDS 16 (67) 63 (61) 0.62

Severity of illness at ICU admission

APACHE II score (mean ± SD) 22.5±6.7 22.1±7.5 0.84

SOFA score (mean ± SD) 8.1±2.3 9.2±3.5 0.14


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Baseline values at ICU admission

(mean ± SD)

Temperature, °C 37.8±1.0 37.7±2.1 0.60

Heart rate, /min 120.1±26.5 127.8±32.0 0.28

PaO2/FiO2 145.9±80.9 129.3±68.6 0.53

Mean arterial pressure, mmHg 73.7±14.1 72.5±17.9 0.76

White cell count, /mm3 13791±10066 10655±7363 0.19

Hemoglobin, g/dL 11.2±2.0 11.7±2.9 0.56

Platelet count, /mm3 150100±113758 166770±118327 0.47

Total bilirubin, mg/dL 1.4±2.5 1.2±2.0 0.46

Creatinine, mg/dL 1.6±1.8 1.9±2.3 0.49

Antibiotic treatment 24 (100) 103 (100)

Steroid treatment 14 (58) 53 (52) 0.54

Time from symptom onset to ICU admission,

days (mean ± SD)

5.6±5.7 5.2±5.6 0.94

Time from symptom onset to antivirals, days

(mean ± SD)

4.7±5.4 5.0±4.3 0.14

Antiviral dose, mg/d (mean ± SD)

Oseltamivir 0.01

≤150 mg/d 9 (38) 68 (67)

≥300 mg/d 15 (63) 34 (33)

Amantadine 188.3±48.2 NA

Ribavirin 587.5±211.2 NA

Antiviral duration, days (mean ± SD) 11.1±7.0 6.2±3.6 <0.001


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TCAD, triple combination antiviral drug; ICU, intensive care unit; COPD, chronic 578

obstructive pulmonary disease; ARDS, acute respiratory distress syndrome; APACHE, Acute 579

Physiology and Chronic Health Evaluation; SOFA, Sequential Organ Failure Assessment; 580

PaO2, partial pressure of arterial oxygen; FiO2, fraction of inspired oxygen; NA, not 581

applicable 582

a Data are presented as the number ± SD or (%) of patients unless indicated otherwise. 583

584

585

586

587

588

589

590

591

592

593

594

595

596

597

598

599

600

601


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TABLE 2. Clinical outcomes of TCAD group and oseltamivir groupa 602

Variables

TCAD

(n = 24)

Oseltamivir

(n = 103)

P

Secondary bacterial pneumonia

Community-acquired 3 (13) 10 (10) 0.71

Hospital-acquired 13 (54) 51 (50) 0.82

Barotrauma 1 (4) 5 (5) >0.99

Renal replacement therapyb 2 (8) 21 (20) 0.24

Rescue therapy

Neuromuscular blocker 16 (70) 59 (58) 0.30

Nitric oxide 3 (13) 2 (2) 0.04

Prone position 3 (13) 12 (12) >0.99

Extracorporeal membrane oxygenator 0 5 (5) 0.58

Ventilator-free days (mean ± SD) 9.7±12.2 8.6±11.5 0.74

Time from symptom to death

14-day 4 (17) 36 (35) 0.08

30-day 8 (33) 51 (50) 0.15

90-day 11 (46) 61 (59) 0.23

Cause of death (n = 72) 0.36

Septic shock/Multi-organ failure 3 (27) 12 (20)

Pneumonia/ARDS 8 (73) 38 (62)

Othersc/Undetermined 0 11 (18)


b Patients who were dialyzed due to previous renal failure were excluded. 604


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c Other causes of deaths include aggravation of underlying conditions, bleeding, liver failure, 605

and infection other than pneumonia. 606

607

608

609

610

611

612

613

614

615

616

617

618

619

620

621

622

623

624

625

626

627

628


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TABLE 3. Baseline characteristics and clinical outcomes of ICU patients stratified by 629

duration of ICU staya 630

Variables

ICU stay ≤7 days

(n = 59)

ICU stay >7 days

(n = 67)

P

Age, years (mean ± SD) 57.0±20.3 57.4±16.2 0.74

Nosocomial H1N1 infection 8 (14) 12 (18) 0.51

Immunosuppressive conditions 20 (34) 35 (52) 0.04

Shock 31 (53) 29 (43) 0.30

ARDS 36 (61) 42 (63) 0.85

APACHE II score (mean ± SD) 22.1±7.6 22.1±7.1 0.98

SOFA score (mean ± SD) 9.4±3.6 8.6±3.0 0.17

Steroid treatment 28 (48) 39 (58) 0.23

Type of antivirals 0.31

TCAD 9 (15) 15 (22)

Oseltamivir monotherapy 50 (85) 52 (78)

Symptom to antivirals, days

(mean ± SD)

3.5±3.1 6.3±5.1 0.001

Oseltamivir dose ≥300 mg/d 22 (38) 26 (39) 0.92


Hospital-acquired 18 (31) 46 (69) <0.001

Death 39 (66) 32 (48) 0.04

Cause of death 0.61

Septic shock/MOF 10 (26) 5 (16)

Pneumonia/ARDS 23 (59) 22 (69)


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Othersb/Undetermined 6 (15) 5 (16)

MOF, multi-organ failure 631


b Other causes of deaths include aggravation of underlying conditions, bleeding, liver failure, 633

and infection other than pneumonia. 634

635

636

637

638

639

640

641

642

643

644

645

646

647

648

649

650

651

652

653


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TABLE 4. Safety assessments of antiviral agentsa 654

Variables TCAD Oseltamivir P

Δ (post-treatment – baseline)b

AST, IU/L -12.8±38.7 518.0±1993.0 0.03

ALT, IU/L -2.9±21.3 283.2±1116.9 0.08

TB, mg/dL -0.2±3.0 0.9±2.5 0.46

Creatinine, mg/dL -0.4±1.4 -0.3±1.5 0.55

Hemolytic anemia None None

Seizure None None

AST, aspartate transaminase; ALT, alanine transaminase; TB, total bilirubin 655

a Data are presented as the mean number ± SD unless indicated otherwise. 656

b The baseline values (at ICU admission) were subtracted from values measured after 657

initiation of drugs (day 3, 7, or 14) for each case. 658

659

660

661

662

663

664

665

666

667

668

669


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TABLE 5. Unadjusted (univariate) and adjusted (multivariate) logistic regression models of 670

factors associated with 90-day mortalitya 671

Variables

Unadjusted OR

(95% CI)

P

Adjusted OR

(95% CI)

P

Age 1.04 (1.01-1.06) 0.002 1.04 (1.01-1.07) 0.005

Body mass index 1.08 (0.98-1.18) 0.12

Nosocomial H1N1 infection 5.36 (1.48-19.36) 0.01 4.26 (1.01-18.03) 0.049

Chronic coexisting conditions

Diabetes 1.98 (0.85-4.63) 0.11

Hematologic malignancy 4.03 (0.46-35.53) 0.21

No underlying diseases 0.41 (0.14-1.21) 0.11

Immunosuppressive conditions 2.30 (1.11-4.76) 0.03

Shock 2.19 (1.07-4.49) 0.03

APACHE II scoreb 1.07 (1.02-1.13) 0.01

SOFA score 1.23 (1.09-1.38) <0.001 1.21 (1.05-1.40) 0.01

Mean arterial pressureb 0.99 (0.97-1.01) 0.19

Hemoglobin 0.74 (0.63-0.87) <0.001 0.83 (0.68-1.01) 0.06

Platelet count 0.997 (0.99-1.00) 0.08

Total bilirubin 1.27 (0.92-1.75) 0.15

Steroid treatment 1.68 (0.83-3.41) 0.15


Hospital-acquired 1.42 (0.70-2.87) 0.33

Renal replacement therapy 4.57 (1.46-14.36) 0.01 3.10 (0.84-11.51) 0.09

Nitric oxide 3.06 (0.33-28.19) 0.32


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Prone position 5.62 (1.21-26.08) 0.03 9.95 (1.89-52.33) 0.01

Oseltamivir dose ≥300 mg/d 0.60 (0.29-1.24) 0.17

Antiviral duration 0.94 (0.87-1.02) 0.13

TCAD 0.58 (0.24-1.42) 0.24

a The variables with P values less than 0.10 (in univariate analysis) were included in the 672

multivariate analysis by using step-wise backward selection procedures. 673

b The APACHE II score and mean arterial pressure were not considered for the multivariate 674

analysis to prevent multicollinearity. 675


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Won-Young Kim, Sung-Cheol Yun, Min-ju Kimaac.asm.org/content/early/2011/10/03/AAC.05529-11.full.pdfWon-Young Kim, Sung-Cheol Yun, Min-ju Kim (University of Ulsan College of Medicine);