MAJOR ARTICLE

Effectiveness of Antiviral Treatment in Human

Influenza A(H5N1) Infections: Analysis of a Global
Patient Registry

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Wiku Adisasmito,1 Paul K. S Chan,2 Nelson Lee,2 Ahmet Faik Oner,3 Viktor Gasimov,5 Faik Aghayev,6
Mukhtiar Zaman,7 Ebun Bamgboye,8 Nazim Dogan,4 Richard Coker,10 Kathryn Starzyk,9 Nancy A. Dreyer,9
and Stephen Toovey11
1
University of Indonesia, Depok, Indonesia; 2Faculty of Medicine, Chinese University of Hong Kong; 3Yuzuncu Yil University, Van, and 4Ataturk
University Medical School, Erzurum, Turkey; 5Azerbaijan Ministry of Health, and 6Research Institute of Lung Diseases, Baku, Azerbaijan; 7Khyber
Teaching Hospital, Peshawar, Pakistan; 8St Nicholas Hospital, Lagos, Nigeria; 9Outcome Sciences, Inc, Cambridge, Massachusetts; 10London School
of Hygiene and Tropical Medicine, and 11Royal Free and University College Medical School, Department of Infection and Immunity, Academic
Centre for Travel Medicine and Vaccines, London, United Kingdom

(See the editorial commentary by Couch and Davis, on pages 1149–1151.)

Background. Influenza A(H5N1) continues to cause infections and possesses pandemic potential.
Methods. Data sources were primarily clinical records, published case series, and governmental agency reports.
Cox proportional hazards regression was used to estimate the effect of treatment on survival, with adjustment
using propensity scores (a composite measure of baseline variables predicting use of treatment).
Results. In total, 308 cases were identified from 12 countries: 41 from Azerbaijan, Hong Kong SAR, Nigeria,
Pakistan, and Turkey (from clinical records); 175 from Egypt and Indonesia (from various sources); and 92 from
Bangladesh, Cambodia, China, Thailand, and Vietnam (from various publications). Overall crude survival was
43.5%; 60% of patients who received ⭓1 dose of oseltamivir alone (OS+) survived versus 24% of patients who
had no evidence of anti-influenza antiviral treatment (OS⫺) (P ! .001 ). Survival rates of OS+ groups were significantly
higher than those of OS⫺ groups; benefit persisted with oseltamivir treatment initiation ⭐6–8 days after symptom
onset. Multivariate modeling showed 49% mortality reduction from oseltamivir treatment.
Conclusions. H5N1 causes high mortality, especially when untreated. Oseltamivir significantly reduces mortality
when started up to 6–8 days after symptom onset and appears to benefit all age groups. Prompt diagnosis and
early therapeutic intervention should be considered for H5N1 disease.

Although the world was challenged in 2009 by a pan- with H5N1 virus continue to be reported and remain
demic caused by influenza A(H1N1), human infections a threat. The existence of an extensive avian reservoir
makes it likely that the H5N1 virus will continue to
pose a threat to human health. The high mortality rate
Received 17 January 2010; accepted 19 April 2010; electronically published 10
September 2010. associated with H5N1 (reported by the World Health
Potential conflicts of interest: W.A., M.Z., A.F.O., E.B., and N.D. received modest Organization [WHO] as 59% [1, 2]) and the novelty
support to facilitate data collection and review. R.C. receives funding from F.
Hoffmann-La Roche, the manufacturer of oseltamivir. P.K.S.C. and N.L. received
of the virus to humans give cause for concern that,
funding support from F. Hoffmann-La Roche for an investigator-initiated study. N.D. should the virus acquire increased capacity to transmit
is employed by Outcome Sciences, Inc, a private company that specializes in
patient registries and which received funding from F. Hoffmann-La Roche to create
from human to human, it might trigger a pandemic
and conduct the registry study. S.T. is a former employee and a paid consultant that exacts a very high human and economic cost.
to F. Hoffmann-La Roche and has been reimbursed by a number of influenza
vaccine manufacturers.
Currently, patients infected with H5N1 are treated
The registry is funded by a contract to Outcome Sciences, Inc, from F. Hoffmann- with supportive care, often at intensive care unit level,
La Roche. The sponsor provides scientific collaboration and has rights to nonbinding
and with specific antiviral drugs. There are 2 major
review of manuscripts but does not have the right to decide whether papers should
be submitted for publication, to choose authors, or have the final approval of the classes of antiviral drugs with anti-influenza activity in
wording of any manuscripts. clinical use: the neuraminidase inhibitors oseltamivir
Reprints or correspondence: Dr Nancy Dreyer, Outcome Sciences, 201 Broadway,
Cambridge, MA 02139 (ndreyer@outcome.com). and zanamivir and the adamantane M2 inhibitors ri-
The Journal of Infectious Diseases 2010; 202(8):1154–1160 mantidine and amantadine; ribavirin has also been used
 2010 by the Infectious Diseases Society of America. All rights reserved.
0022-1899/2010/20208-0003$15.00
occasionally [3]. Oseltamivir, which is orally adminis-
DOI: 10.1086/656316 tered and systemically bioavailable, has been the main-

1154 • JID 2010:202 (15 October) • Adisasmito et al

stay of antiviral treatment in H5N1 infections [4]; inhaled za- the field [6, 15–24]. Duplicate cases were eliminated by com-
manivir possesses minimal systemic bioavailability. Resistance paring all cases by age, sex, country of origin, and date of
to the M2 inhibitors is not infrequent and tends to emerge symptom onset (within 30 days).
rapidly during use [5]. Although there are reports of resistance Core data for all cases include the information available on
or reduced susceptibility by clinically isolated H5N1 viruses [6– demographics, dates of symptom onset and presentation for
9], a recent genotyping study predicted oseltamivir suscepti- treatment, characteristics of initial disease manifestation, in-
bility in 199% of circulating H5N1 strains [10], a finding point- fection outcome (survived or deceased), and the results of
ing to continued attention on oseltamivir’s clinical effectiveness. laboratory confirmation for influenza A(H5N1), if available.
To date, although most reports have demonstrated benefit Additional details, as available, were included for symptoms,
from intervention with oseltamivir, especially if given early dur- clinical presentation, all treatments used once a patient had
ing the course of illness, there have been reports that have sought medical attention, and other laboratory investigations.

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questioned treatment efficacy, the benefits of delayed treatment, Antiviral treatments were classified by whether they had anti-
and the optimum regimen [11, 12]. To better understand the influenza properties (AV+); acyclovir, an antiherpetic, and qing
course of H5N1 infection in humans and the effectiveness of kai ling, an antipyretic, were not considered to have anti-in-
various treatments, a pooled analysis of H5N1 cases was con- fluenza properties. Use of any antiviral was recorded if it had
ducted, drawn from a specially designed registry containing been documented in any record source. In some situations, it
individual case data from many countries [13]. To our knowl- was specifically noted that antivirals were not given, but because
edge, this is the first pooled, systematic analysis of multicountry this information was not systematically recorded or available,
data and the largest series of human cases of confirmed H5N1 the absence of documentation about antivirals, as well as notes
infection analyzed. confirming that no antivirals were given, were analyzed together
as “antiviral treatment not documented (AV⫺).” Because os-
METHODS eltamivir was the most commonly used antiviral, additional
analyses were performed comparing treatment with oseltamivir
Patients and procedures. Cases were drawn from an ongo-
only (OS+); this group included all patients who received ⭓1
ing, specially designed patient registry that allows for online
dose of oseltamivir. Treatment effectiveness was examined in
data entry of clinical presentation, all treatments, and all out-
the context of time to treatment from onset of symptoms and
comes, using a secure information platform (http://www
.avianfluregistry.org), and conforms to the most recent guid- from presentation for medical care.
ance for high-quality registries [14]. The registry protocol has Statistical analysis. Data were analyzed using 2 ⫻ 2 tables,
been reviewed and approved by ethical review committees with relative risks used to describe the risk of death in the
in study countries, as required, and in the US. Informed con- treated patients compared with the same risk in untreated pa-
sent was not required because data were obtained from rec- tients, with probability determined by use of a mid-P test [25].
ord review, without patient contact, and then made anony- Statistical significance was determined with a set at .05.
mous; all data are protected with strong security. A delayed cohort entry analysis was used to calculate survival
Patients with laboratory confirmation of infection with in- per day because deaths prior to presentation for medical at-
fluenza A(H5N1) who survived long enough to present for tention were not available for analysis [26]. Survival analyses
medical care were identified from 3 sources: (1) by in-country were performed using the Kaplan-Meier procedure for esti-
reporters, who helped abstract clinical data; (2) through clinical mating survival over time. Cox proportional hazards regression
records and reports from governmental health institutions at were performed for estimation of the hazard ratio of death
the national, regional, and district levels; and (3) from pub- associated with oseltamivir treatment among a subset of pa-
lished case series; some additional data elements were obtained tients with either oseltamivir treatment or no antiviral treat-
from ProMED. Published case reports were included only if ment recorded, from countries with both treated and untreated
age, sex, country, symptoms, exposure or viral testing, and patients. Because missing data are not a rarity in observational
outcome were reported for each case. Medline was searched by studies derived from existing records, we chose to impute miss-
PubMed for cases between 1997 and August 2009 using the ing dates for Cox proportional hazards analyses, blinded to
following medical subject heading search terms: influenza, hu- treatment status of patients. Patients reported as alive at last
man; influenza A virus, H5N1 subtype; influenza in birds/ep- contact were assumed to have lived ⭓30 days after presentation
idemiology; influenza in birds/transmission; case reports; treat- for medical care. Two of 150 patients reported as deceased did
ment outcome; and country (for any country where avian not have a recorded date of death; for these 2 patients the mean
influenza cases have been reported to WHO). Published reports time to death of 8 days was imputed. For 148 patients with
that provided additional information about cases already in the information about date of symptom onset but not date of
registry were used to supplement and verify data abstracted in presentation for treatment, the date of presentation for treat-

Antiviral Treatment of Influenza A(H5N1) • JID 2010:202 (15 October) • 1155

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Figure 1. Availability of data on medication and dates of presentation for medical care.

ment was imputed as 2 days after symptom onset for all pa- host2.com/Episheet.xls), and propensity score modeling, which
tients, on the basis of the overall mean observed time from was performed using STATA software (version 11.0; StataCorp).
symptom onset to presentation for treatment. For one patient
who survived !1 day, the survival time was estimated to be 0.5 RESULTS
days for analysis. No other missing data were imputed.
Stepwise logistic regression was used to estimate the pro- This report is based on 308 cases of human avian influenza
pensity score, or predicted probability of receiving treatment occurring from 1997 to 2009 from 12 countries in the Pan-
with oseltamivir. Probability of oseltamivir treatment was the demic/Avian Influenza Registry: Azerbaijan (7 cases), Bangla-
dependent variable, and factors including age, sex, country, desh (1 case), Cambodia (6 cases), China (20 cases), Egypt (82
cases), Hong Kong (18 cases), Indonesia (99 cases), Nigeria (1
exposure to poultry, exposure in the home or healthcare setting
case), Pakistan (4 cases), Thailand (12 cases), Turkey (11 cases),
to other H5N1 patients, history of respiratory or immunologic
and Vietnam (47 cases) [13]. All cases have laboratory confir-
disorders, pregnancy, time from symptom onset to first known
mation of H5N1 infection, 228 cases meet the WHO criteria
time of presentation for treatment, type of healthcare setting
for a confirmed case [27], 4 cases are known to have been
where patient presented for treatment, and symptoms at pre-
confirmed only by local laboratories, and WHO status for the
sentation were included as independent variables. A backward
other 111 lab-confirmed cases was not recorded. Forty-one
selection process was used, with a P value of .20 as the criterion
cases (13%) were abstracted from clinical records in Azerbai-
for retaining a variable in the model. Countries with no vari- jan, Hong Kong, Nigeria, Pakistan, Turkey; 175 cases (57%) in
ability in treatment (either 100% or 0% of patients treated) Egypt and Indonesia were obtained from governmental records,
were not included (Bangladesh, Cambodia, Hong Kong SAR, other clinical data, and from public Web sites [28, 29] com-
Nigeria, and Turkey). In total, 258 patients representing 7 coun- plemented by matching cases in ProMED [30]. And 92 cases
tries remained available for the propensity score analysis. The (30%) were obtained from detailed publications about cases in
estimated propensity score was used for statistical adjustment Bangladesh, Cambodia, China, Egypt, Thailand, Vietnam, and
in the Cox model. other regions in Indonesia [6, 7, 11, 18, 24, 31–40]. Figure 1
All statistical analyses were performed using SAS software, illustrates the availability of data on medication and dates of
version 9.2 (SAS Institute), except mid-P tests, which were presentation for medical care and highlights the 2 main analytic
performed using Episheet software (http://krothman.byethe- subgroups.

1156 • JID 2010:202 (15 October) • Adisasmito et al

 Overall, the median age of patients was 17 years (range, 1– difference for OS+ patients decreased to 21% for treatment
75 years); 46% were under 16 years; 39% were aged 16–34, initiated 3–5 or 6–8 days after symptom onset. No statistically
and 15% were aged ⭓35 years. Nearly half (45%) of patients significant benefit was seen when the first dose of oseltamivir
were male. The overall mortality rate was 56.5%. Analysis by was administered 18 days after symptom onset. Relative risks,
study period showed the lowest mortality in 2009 (27%), fol- risk differences, and confidence intervals for the survival benefit
lowed by 1997 (33%); mortality ranged from 48% to 78% of oseltamivir are presented in Table 1. The full set of AV⫺ and
during 2003–2008. Of 173 patients who were treated with os- OS+ patients are shown with the Kaplan-Meier survival curves
eltamivir or another antiviral with known anti-influenza prop- (Figure 3).
erties (AV+), 102 patients (59%) survived. Eighty-seven percent A propensity score model was developed as a summary mea-
(150/173) of those AV+ patients were treated only with osel- sure of factors associated with oseltamivir treatment, as de-
tamivir; 2 were also treated with ribavirin, and 1 also received scribed above in the section on statistical analysis. Variables

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rimantidine. retained in the final propensity score model included age, coun-
Of the 284 patients with known age and outcome who re- try (Vietnam), direct exposure to live poultry, indirect exposure
ceived either oseltamivir alone or no anti-influenza antiviral, to poultry, exposure to a case of avian influenza in the home,
the crude overall survival rate of patients who received at least a history of respiratory compromise, symptoms of unexplained
1 dose of oseltamivir alone (OS+) was 60% (90/150), whereas respiratory disease, rhinorrhea, sore throat, fatigue, and myalgia
survival among AV⫺ patients was 24% (32/134) (P ! .001). Fig- at onset, presentation at an emergency room for treatment, and
ure 2 shows survival rates by age and receipt of oseltamivir for presentation at a rural health center for treatment. The c statistic
3 age groups for these patients. For all age groups, a significantly for the final propensity score model was 0.85, indicating that
higher survival rate was observed for OS+ patients than AV⫺ the model is highly predictive of treatment with oseltamivir.
patients. For patients !16 years of age, 68% (49/72) of OS+ The estimated propensity score was then used as a covariate in
patients survived compared with 40% (23/58) of AV⫺ patients a multivariate analysis to adjust for potential confounding by
(P ! .001). For patients ⭓16 years but !35 years, 48% (28/58) factors associated with treatment.
of OS+ patients survived compared with 9% (5/55) of AV⫺ Results of a Cox regression analysis including only oselta-
patients (P ! .001). The comparison of survival rates of patients mivir treatment as an independent variable yielded a hazard
⭓35 years of age was 65% survival (13/20) for the OS+ patients ratio of death of 0.34 (95% confidence interval [CI], 0.25–
and 19% survival (4/21) for the AV⫺ patients (P ! .004). 0.48). Inclusion of the propensity score as a covariate changed
Survival by interval from symptom onset to first dose of the estimate to 0.51 (95% CI, 0.34–0.77). Additional covariates,
oseltamivir was analyzed by comparing the survival rate of OS+ including sex and the first known time of presentation for
patients with that of the AV⫺ patients: 221 patients had infor- treatment, to the Cox model including the propensity score,
mation available on symptom onset, survival, and oseltamivir did not change the adjusted hazard ratio estimate by 10% or
use. The survival rate of OS+ patients who received treatment more.
within 2 days of symptom onset was 83%, compared with 20% We examined the sensitivity of the findings to variations in
of AV⫺ patients who received no treatment in the interval, country-specific mortality and to secular trends. Comparing
giving a survival difference of 63% for OS+ patients. Survival the countries with high and low mortality rates, ⭓50 cases, and

Figure 2. Survival rates by age and receipt of oseltamivir for 3 age groups.

Antiviral Treatment of Influenza A(H5N1) • JID 2010:202 (15 October) • 1157

 Table 1. Relative Risk of Survival of Patients Treated with Oseltamivir, Compared with Patients Who Did Not Receive Antiviral
Treatment (N p 221)

Treatment initiation from Oseltamivir treatment, No antiviral treatment, Difference in

symptom onset, days survived/total (%) survived/total (%) survival, % Relative risk 95% CI P
0–2 15/18 (83) 19/95 (20) 63 4.17 2.65–6.55 !.001
3–5 15/31 (48) 32/117 (27) 21 1.77 1.11–2.83 .032
6–8 16/32 (50) 31/108 (29) 21 1.74 1.10–2.75 .031
9–11 3/8 (38) 30/70 (43) ⫺5 0.88 0.34–2.23 .797
⭓12 3/9 (33) 29/45 (64) ⫺31 0.52 0.20–1.34 .105
Any time 52/98 (53) 29/123 (24) 29 2.25 1.56–3.25 !.001

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NOTE. Relative risk of survival by interval from symptom onset and first dose of oseltamivir, compared with risk of survival of individuals who
presented for medical care during the interval, were alive in the interval, and did not receive any antiviral treatment during the interval. CI, confidence
interval.

sustained outbreaks lasting for 13 years, the relative risk of vived; one patient stopped oseltamivir at day 8 of therapy, due
survival from oseltamivir treatment within 6 days of symptom to severe headache and vomiting (the same patient mentioned
onset was 1.75 (95% CI, 1.13–2.72) in the country with low in the preceding paragraph).
mortality rate and 3.45 (95% CI, 1.2–10.1) in the country with
high mortality rate. DISCUSSION
Survival in patients who received oseltamivir for longer than
the standard 5-day duration of treatment usually given for sea- This study represents the largest multinational repository of
sonal influenza was available for 20 patients; other patients may data on cases of avian influenza. Cases were selected without
have been treated for 15 days but treatment start and stop dates regard to treatment and are likely to represent typical cases that
were not available in the records. The median duration was 7 present for medical attention, as is common practice with pa-
days (range, 6–26 days); 75% (15/20) of these patients survived. tient registries [14]. We observed that infection with H5N1
Two patients stopped oseltamivir therapy after 8 days: one pa- carries a high mortality rate (56.5%) and is lower in older age
tient on multiple medications exhibited hepatomegaly and had groups. Mortality reaches 76% in the absence of antiviral treat-
all medications withdrawn; a second patient had oseltamivir ment; receipt of oseltamivir reduces crude overall mortality to
withdrawn following a complaint of severe headache and vom- 40%. Multivariate modeling, which incorporated all statistically
iting. Both of these patients survived. significant measured treatment predictors, showed an overall
Fourteen patients received doses higher than those routinely benefit of a 49% reduction in mortality risk from treatment
used for the treatment of seasonal influenza: 50% (7/14) sur- with oseltamivir.

Figure 3. Kaplan-Meier survival curves showing receipt of oseltamivir compared with no antiviral treatment.

1158 • JID 2010:202 (15 October) • Adisasmito et al

 These data were abstracted from various sources, some data puzzle required to reduce mortality even further, once higher
were missing, and the data that were obtained reflect the various antiviral exposures have been fully explored, may be therapies
recording conventions of individual clinicians and institutions. directed at blunting detrimental inflammatory responses.
Because all subjects did not have detailed information on the Although this registry represents the largest global detailed
number of doses of oseltamivir received, patients who received patient data set on H5N1 cases, many questions remain un-
even a single dose of oseltamivir before death were classified answered. For example, it has been suggested that oseltamivir
as having been treated with oseltamivir. One can speculate that be used in combination with other antivirals, principally aman-
these were patients in extremis, and their inclusion may un- tadine, where resistance patterns make this a rational combi-
derstate the clinical utility of oseltamivir in patients who are nation, in that such combination therapy may promote efficacy
not immediately moribund. Sensitivity analyses were performed and retard emergence of transmissible resistant virus strains.
to examine the extent to which our findings were dependent The very small number of patients in this study who had re-

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on recorded source, country, and background mortality from ceived a combination that contained oseltamivir, 3 in all, un-
H5N1. The survival benefit from treatment with oseltamivir up fortunately precludes the drawing of any conclusions on the
to 6 days after symptom onset was evident in all record sources clinical efficacy of such combinations. Nonetheless, these reg-
and also was evident (P ⭐ .05 ) in countries with high and low istry data, by virtue of their numbers and scope, provide im-
survival rates from H5N1. portant information on treatment patterns and outcomes for
A clear benefit was evident from treatment with oseltamivir, a wide variety of patients treated under a variety of conditions
even when treatment was delayed, with maximum benefit ac- across the world.
cruing when therapy was administered within 2 days of onset These findings have important implications for clinical man-
of illness. The fact that 75% of patients die when they are not agement. These data show that humans infected with H5N1
treated with appropriate antivirals indicates that H5N1 is a face near certain death unless prescribed effective antiviral treat-
highly virulent virus, which in turn proffers suggestions as to ment, preferably within 2 days of symptom onset, although
both pathogenesis and additional lines of treatment to explore. benefit remains even with treatment initiation up to about 5–
Progressive infections associated with multiorgan dysfunc- 6 days after symptom onset, possibly a reflection of prolonged
tion and a high lethality suggest immune dysfunction [41]; viral replication in human H5N1 infection. Thus, there is still
indeed, previous work points strongly to cytokine dysregulation benefit from initiating treatment with oseltamivir in patients
playing a role in the pathogenesis of H5N1 mortality [42, 43]. who present relatively late in the course of their illness, and
clinicians should be mindful not to assume that all is lost in
This is compatible with the notion that early intervention with
such patients.
antivirals prevents viral load accumulating to a level that it
triggers an injurious and ongoing immune response, including
hypercytokinemia. Direct support for the role of cytokine dys- Acknowledgments
regulation comes from work showing that H5N1 infection in-
We thank Anna Layton and Priscilla Velentgas for their diligent work
duces high levels of proinflammatory cytokines, including in-
in data acquisition and analysis.
terferons, tumor necrosis factor a, interferon-g–induced pro-
tein 10, and interleukin 6, among others [42]. De Jong et al
[43] showed a correlation between H5N1 viral load and a num- References
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