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Trends in the prevalence of thrombocytopenia among individuals infected with hepatitis C Virus in the United States, 1999-2008

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Title:
Trends in the prevalence of thrombocytopenia among individuals infected with hepatitis C Virus in the United States, 1999-2008
Series Title:
BMC Research Notes
Creator:
Kauf, Teresa L.
Nelson, David R.
Schelfhout, Jonathan
Delaney, Joseph A. C.
Wang, Peter Feng
Publisher:
BioMed Central
Publication Date:
Language:
English

Subjects

Subjects / Keywords:
Thrombocytopenia
Hepatitis C
Platelets
NHANES

Notes

Abstract:
Background: Thrombocytopenia is associated with the natural history of hepatitis C virus (HCV) infection and antiviral therapy. Recent, national estimates of the clinical burden of thrombocytopenia among HCV-infected individuals in the United States are unavailable. Bi-yearly data from the 1999-2000 to 2007-2008 National Health and Nutrition Examination Surveys (NHANES) were used to examine the prevalence of thrombocytopenia among HCV-infected individuals in the United States. Results: Among 467 HCV-infected individuals in the survey (weighted population = 3,597,039), mean weighted age was 46.7 years (standard deviation = 15.5) and 61.7% were male. Overall, 7.6% met the study definition of TCP at the 150 × 109/L threshold; 4.5%, 2.0%, and 0.8% had platelet counts below 125, 100, and 75 × 109/L, respectively. The 2-year weighted prevalences of thrombocytopenia (150 × 109/L threshold) from 1999-2008 were 4.9%, 8.6%, 6.5%, 4.1%, and 12.9%. The unadjusted biannual time trend (odds ratio) was 1.16 (95% confidence interval = 0.82- 1.64). In the two adjusted models, the odds by time ranged from 1.24-1.40, depending on whether the model included demographic or laboratory variables or both, but did not reach statistical significance. Age was positively and significantly related to thrombocytopenia status. Conclusions: As the HCV-infected population ages, the prevalence of thrombocytopenia is expected to rise. This study provides limited evidence of such an effect at the national level.

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University of Florida
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University of Florida
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All rights reserved by the source institution.
Resource Identifier:
10.1186/1756-0500-5-142 ( DOI )

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dochead Research article
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title
p Trends in the prevalence of thrombocytopenia among individuals iInfected with hepatitis C Virus in the United States, 1999-2008
aug
au id A1 ca yes ce snm Kaufmi Lfnm Teresainsr iid I1 email kauf@cop.ufl.edu
A2 NelsonRDavidI2 nelsodr@ufl.edu
A3 SchelfhoutJonathanschelfho@ufl.edu
A4 DelaneyACJosephjdelaney@cop.ufl.edu
A5 Wangmnm FengPeterI3 wangdelano@yahoo.com
insg
ins Department of Pharmaceutical Outcomes and Policy, College of Pharmacy, University of Florida, Gainesville, Florida, USA
Department Division of Gastroenterology, Hepatology & Nutrition and Clinical and Translational Science Institute, College of Medicine, University of Florida, Gainesville, Florida, USA
Global Health Economics and Outcomes Research, Bristol-Myers Squibb Company, New York, New York, USA
source BMC Research Notes
issn 1756-0500
pubdate 2012
volume 5
issue 1
fpage 142
url http://www.biomedcentral.com/1756-0500/5/142
xrefbib pubidlist pubid idtype doi 10.1186/1756-0500-5-142pmpid 22414142
history rec date day 29month 11year 2011acc 1332012pub 1332012
cpyrt 2012collab Kauf et al; licensee BioMed Central Ltd.note This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
kwdg
kwd Thrombocytopenia
Hepatitis C
Platelets
NHANES
abs
sec
st
Abstract
Background
Thrombocytopenia is associated with the natural history of hepatitis C virus (HCV) infection and anti-viral therapy. Recent, national estimates of the clinical burden of thrombocytopenia among HCV-infected individuals in the United States are unavailable. Bi-yearly data from the 1999-2000 to 2007-2008 National Health and Nutrition Examination Surveys (NHANES) were used to examine the prevalence of thrombocytopenia among HCV-infected individuals in the United States.
Results
Among 467 HCV-infected individuals in the survey (weighted population = 3,597,039), mean weighted age was 46.7 years (standard deviation = 15.5) and 61.7% were male. Overall, 7.6% met the study definition of TCP at the 150 × 10sup 9/L threshold; 4.5%, 2.0%, and 0.8% had platelet counts below 125, 100, and 75 × 109/L, respectively. The 2-year weighted prevalences of thrombocytopenia (150 × 109/L threshold) from 1999-2008 were 4.9%, 8.6%, 6.5%, 4.1%, and 12.9%. The unadjusted biannual time trend (odds ratio) was 1.16 (95% confidence interval = 0.82-1.64). In the two adjusted models, the odds by time ranged from 1.24-1.40, depending on whether the model included demographic or laboratory variables or both, but did not reach statistical significance. Age was positively and significantly related to thrombocytopenia status.
Conclusions
As the HCV-infected population ages, the prevalence of thrombocytopenia is expected to rise. This study provides limited evidence of such an effect at the national level.
bdy
Background
Thrombocytopenia, which may be defined generally as a platelet count below 150 × 109/L, is a common complication of chronic hepatitis C virus (HCV) infection, particularly among those with advanced liver disease, and those receiving antiviral treatment for HCV abbrgrp
abbr bid B1 1
B2 2
B3 3
B4 4
. Estimates of the prevalence of thrombocytopenia in liver disease vary widely, depending on the population and the platelet threshold used
B5 5
B6 6
. Among studies of chronic liver disease patients where thrombocytopenia was defined as a platelet count less than 150 × 109/L, prevalence estimates range from 16-45%
6
. In clinical trials of interferon-based therapy, more than one third of patients experienced a decrease in platelet counts, with counts falling below 50 × 109/L observed in 4-8% of patients
B7 7
B8 8
. Thrombocytopenia while on antiviral therapy may lead to dose reductions, interruption, or discontinuations of interferon, potentially jeopardizing the chances of achieving sustained virologic response (SVR). In cases of portal hypertension and severe thrombocytopenia, HCV patients may be unable to initiate antiviral treatment due to low platelets.
An understanding of trends in the prevalence of HCV and its complications facilitates public health planning and treatment efforts. Although the current incidence of HCV infection is low, the aging of individuals infected with HCV over the past several decades suggests that the burden of liver disease in the United States (US) will continue to increase, with a peak in cirrhosis cases in the year 2020 preceding peaks in liver cancer in the following decade
B9 9
. As that happens, the prevalence of thrombocytopenia within the HCV-infected population also is likely to increase. However, recent projections of HCV and liver disease burden in the US have not considered the prevalence of thrombocytopenia
9
B10 10
B11 11
B12 12
. Similarly, available estimates of the future cost of HCV which are based on past treatment patterns may not reflect adequately the additional cost associated with an increased prevalence of thrombocytopenia.
The most recent examination of thrombocytopenia at the national level was conducted using the National Health and Nutrition Examination Survey (NHANES) III
B13 13
. In that study, 13% of individuals with positive HCV antibody had platelet counts below 175 × 109/L. While NHANES III spans the period 1988-1994, it is not possible to determine trends across that time period due to the nature of data collection during that survey phase. Newer administrations of NHANES, however, do permit an examination of trends in the US over consecutive, two-year periods. The objective of this study was to document national trends over the past decade in the prevalence of thrombocytopenia among individuals infected with HCV, with the goal of informing efforts to model the prevalence of complications associated with chronic HCV infection.
Results
Across the 10-year study period, 467 NHANES participants were identified as having confirmed HCV infection; platelet counts were available for 465 (99.6%). The raw HCV frequency translates to an estimated prevalence in the United States of 3,597,039 individuals (1.48% prevalence), including both diagnosed and undiagnosed cases of infection. Weighted summary characteristics for HCV-infected participants are shown in Table tblr tid T1 1. Mean weighted age was 46.7 years and 61.7% were male. Table 1 also summarizes HCV-infected individuals with and without thrombocytopenia (defined as platelet count below 150 × 109/L). Compared to those with normal platelet counts, individuals with low platelet tended to be older (55.3 vs 46.0 years) and have higher ALT (81.5 vs 50.0), AST (84.6 vs 44.2), and iron (138.9 vs 106.9) levels, respectively (p < 0.05 for all comparisons). Questionnaire items tend to have a large number of missing values, and a limited number of participants were eligible for certain examinations, such as fasting glucose and fasting insulin; these items should be interpreted with caution.
tbl Table 1caption Confirmed HCV infection study sample characteristicstblbdy cols 5
r
c left
b Characteristic
Confirmed HCV-Infected
Raw Frequency (n = 467)
cspan 3
Confirmed HCV-Infected
Weighted Mean (SD) or Proportion
All HCV Patients
Thrombocytopenia Population1
(n = 43)
Non-Thrombocytopenia Population1
(n = 422)
hr
Age at screening (yrs), mean (SD)
467
46.7 (15.5)
55.3 (22.5)
46.0 (12.7)
Male gender, %
293
61.7
73.4
61.2
Weight (kg), mean (SD)
451
78.2 (22.5)
78.0 (23.3)
78.3 (22.6)
Race/ethnicity, %
467
indent 1
White
190
65.7
21.6
20.0
Black/African-American
160
20.1
56.3
66.4
Hispanic
103
10.9
19.3
10.3
Other
14
3.3
2.9
3.3
Annual Household income, %
433
Below $20,000
185
36.3
39.5
35.6
$20,000 $74,999
204
50.1
47.1
50.7
Above $75,000
44
13.6
13.4
13.7
Ever used marijuana or hashish, %1
124
87.4
100.0
88.0
Times received health care over past 12 months, %
467
43
422
None
83
16.5
13.0
16.9
1-3 times
162
35.6
39.7
34.9
More than 4 times
222
47.9
47.3
48.3
Alcohol use (drinks/day over past year), mean (SD)
270
4.4 (3.7)
4.1 (2.9)
4.4 (3.7)
Albumin (g/dL), mean (SD)
456
4.2 (0.4)
3.7 (1.01)
4.2 (0.4)
ALT (u/L), mean (SD)
456
52.2 (60.9)
81.5 (93.6)
50.0 (56.5)
AST (u/L), mean (SD)
456
47.2 (49.7)
84.6 (46.7)
44.2 (48.5)
Blood urea nitrogen (mg/dL), mean (SD)
456
12.1 (6.4)
13.9 (11.1)
12.0 (5.3)
Total calcium (mg/dL), mean (SD)
456
9.4 (0.5)
9.1 (0.7)
9.5 (0.5)
Creatinine (mg/dL), mean (SD)
346
0.9 (0.3)
1.0 (0.6)
0.9 (0.3)
Iron (ug/dL), mean (SD)
456
108.9 (58.0)
138.9 (61.7)
106.9 (57.2)
Bilirubin (umol/L), mean (SD)
456
13.1 (7.6)
19.3 (13.1)
12.6 (6.9)
Total protein (g/dL), mean (SD)
456
7.4 (0.8)
7.3 (0.9)
7.4 (0.9)
Globulin (g/dL), mean (SD)
456
3.3 (0.8)
3.6 (0.7)
3.2 (0.8)
Hemoglobin (g/dL), mean (SD)
465
14.9 (2.1)
14.5 (2.2)
14.9 (2.1)
Fasting glucose (mg/dL), mean (SD)2
91
107.7 (38.9)
105.6 (21.2)
108.0 (42.8)
Fasting insulin (uU/mL), mean (SD)2
86
13.3 (12.3)
26.4 (33.9)
11.5 (12.7)
White blood cell count (1000 cells/uL), mean (SD)
465
7.3 (3.2)
5.4 (2.3)
7.4 (3.2)
Platelet count
465
257.6 (87.7)
112.0 (31.2)
269.5 (76.0)
Thrombocytopenia, %
465
< 150 × 109/L
43
7.6
100
0
< 125 × 109/L
25
4.5
59.4
0
< 100 × 109/L
12
2.0
26.7
0
< 75 × 109/L
7
0.8
10.7
0
tblfn
HCV = hepatitis C virus; SD = standard deviation; ALT = alanine aminotransferase; AST = asparate aminotransferase
NOTES:
1. Defined as platelet count < 150 × 109/L
2. Among participants 20 years of age and older for survey years 2005-2006 and 2007-2008
3. Among participants 12 years of age and older who attended a morning examination session for survey years 2005-2006 and 2007-2008
Figure figr fid F1 1 shows the 2-year point estimates and 95% confidence intervals for the prevalence of thrombocytopenia at the 150 × 109/L threshold from 1999-2008 for participants with and without confirmed HCV infection. Trends for lower thresholds were unstable due to very small sample sizes and are not shown. Among HCV-infected individuals, the prevalence of thrombocytopenia at the 150 × 109/L threshold increased from 4.9% in 1999-2000 to 12.9% in 2007-2008, but first increased then decreased from 2001-2006, although none of the periods showed a statistically significant change from other periods. Trends in thrombocytopenia prevalence among non-HCV-infected individuals followed a similar pattern, although at much lower levels. The rise in thrombocytopenia prevalence of 8 percentage points among those with confirmed HCV infection represented a 164.0% increase but did not reach statistical significance. In contrast, thrombocytopenia prevalence among non-HCV-infected individuals was relatively stable during the same time period, increasing by less than 9%, from 1.4% to 1.6%.
fig Figure 1Prevalence of platelet counts below 150 × 109/L among individuals with confirmed HCV infection and all NHANES participants, 1999-2008text
Prevalence of platelet counts below 150 × 109/L among individuals with confirmed HCV infection and all NHANES participants, 1999-2008. Note: Error bars represent 95% confidence interval for the proportion of HCV patients with TCP. HCV = hepatitis C virus; NHANES = National Health and Nutrition Examination Survey; TCP = thrombocytopenia.
graphic file 1756-0500-5-142-1 hint_layout double
Platelet counts among patients with HCV were significantly correlated with several laboratory measures (data not shown but available from the authors by request). Those not correlated with platelets included protein, fasting glucose, and fasting insulin, although the ability to detect relationships to the fasting variables was hampered by limited data availability. ALT and AST were significantly correlated with bilirubin, protein, hemoglobin, iron, and globulin. Of these, iron, protein, and globulin were excluded from further analysis because they showed particularly strong correlations with ALT and AST.
Results for the three time-trend regression models are shown in Table T2 2. The univariate, biannual time trend (odds ratio) for platelets less than 150 × 109/L was 1.16 (95% CI = 0.82-1.64). The point estimate, which did not reach statistical significance, can be interpreted as a bi-yearly increase in thrombocytopenia prevalence of 16%. In adjusted models, the odds by time increased to 1.24-1.40, depending on whether the model included demographic or laboratory variables or both, but failed to reach statistical significance. Age was positively associated with an increase in the odds of thrombocytopenia in both adjusted models. None of the laboratory measures was significantly related to thrombocytopenia status, although the coefficients were of the expected sign. The presence of thrombocytopenia was not associated with ALT or AST level.
Table 2Adjusted time-trend regression results4
HCV-Confirmed Patients (n = 467)
Variable
Model 1
n = 465
OR (95% CI)
Model 2
n = 449
OR (95% CI)
Model 3
n = 440
OR (95% CI)
Time
1.16 (0.82-1.64)
1.24 (0.84-1.84)
1.40 (0.88-2.22)
Age (years)
1.05 (1.02-1.08)
1.02 (1.02-1.12)
Male gender
2.87 (0.97-8.51)
1.45 (0.30-6.94)
Weight (kg)
0.99 (0.96-1.02)
0.99 (0.95-1.04)
Race/ethnicity (vs White)
Black/African-American
1.26 (0.47-3.37)
0.50 (0.10-2.52)
Hispanic
1.19 (0.38-3.72)
0.94 (0.27-3.30)
Other
1.18 (0.13-11.06)
1.09 (0.17-7.00)
Albumin
0.28 (0.04-2.21)
ALT
1.01 (0.99-1.03)
AST
1.01 (0.99-1.03)
Blood urea nitrogen
0.92 (0.84-1.01)
Total calcium
0.18 (0.02-2.23)
Bilirubin
1.05 (0.99-1.13)
Hemoglobin
1.07 (0.73-1.56)
White blood cell count
0.59 (0.73-1.56)
Model c-statistic
0.48
0.74
0.89
HCV = hepatitis C virus; OR = odds ratio; CI = confidence interval; ALT = alanine aminotransferase; AST = asparate aminotransferase
Discussion
This study is the first to report trends in the prevalence of thrombocytopenia across a national sample of individuals infected with HCV. For the most recent time period available, 2007-2008, the prevalence of platelets below 150 × 109/L among HCV patients reached nearly 13%. Further, the prevalence over time among the non-HCV-infected US population remained fairly stable. While there was a dip in thrombocytopenia prevalence for survey years 2005-2006, the presence of a similar dip among the weighted population of all NHANES participants suggests that the decrease could be a function of laboratory processing or some other systematic change during that survey round.
A prior study utilizing NHANES III data for the years 1988-1994 found similar thrombocytopenia prevalence among HCV-infected individuals. In that study, however, a higher platelet threshold of 175 × 109/L-the bottom 5% of platelet counts across all participants-was used
13
. If platelet counts remained stable, then the prevalence estimates from the current study, at a lower threshold, should have been lower than in 1988-1994. We also found age to be positively and significantly related to thrombocytopenia status. Taken together, these two studies suggest that the prevalence of thrombocytopenia among individuals infected with HCV likely increased-perhaps substantially-over the past two decades. However, the spike in thrombocytopenia prevalence among HCV-infected individuals observed in 2007-2008 could be an outlier. Additional years of data will be needed to delineate a clear trend.
Several previous studies have examined platelet counts among HCV patient populations. Louie et al (2011) performed a systematic review of those studies conducted in populations of 50 or more confirmed HCV-infected patients. Among the 9 studies which used a platelet threshold of 150 × 109/L to define thrombocytopenia, reported prevalence ranged from 16.0% to 41.0%
6
. The much higher proportions reported in these studies compared to the current analysis may be explained, in part, by the inclusion in the present study of individuals with undiagnosed HCV infection. Davis et al (2010) estimates that approximately 70% of individuals infected with HCV are unaware of their serostatus
9
. Among the 167 NHANES participants from 1999-2008 with confirmed HCV infection who responded to a follow-up telephone survey, 48.9% reported that they were previously unaware of their serostatus. It is likely that a large proportion of those patients have yet to exhibit symptoms of liver disease, and one would expect a lower prevalence of thrombocytopenia among such patients.
The use of NHANES presents both advantages and disadvantages for the examination of thrombocytopenia among individuals infected with HCV. The primary advantage of NHANES lies in its sampling strategy, which allows for the examination of a nationally representative population of individuals. Additionally, NHANES has been conducted on a biennial basis since 1999, allowing for the examination of disease trends over the past decade. The present study examines two conditions of which patients may be unaware. HCV infection may remain asymptomatic for several decades, such that many individuals infected with HCV are unaware of their status
9
. Similarly, thrombocytopenia is a laboratory abnormality that may not appear as a specific diagnosis in administrative data and patients may or may not identify it as a (known) medical condition. Claims data or self-reported surveys thus would be inadequate to examine the prevalence of thrombocytopenia within the HCV-infected population.
NHANES does present some limitations. Since HCV is relatively uncommon among the general population, sample sizes within each 2-year survey period are small, limiting the ability to detect changes over time, particularly for lower platelet counts which may be more relevant to clinical practice. The small sample also contributes to the volatility in the estimates; a difference of just one or two cases could have a large impact on the prevalence estimates. Further, some high-risk groups such as the homeless and incarcerated individuals are not represented. Because those groups have not been adequately studied, it is not known whether the risk of thrombocytopenia with such risk groups is higher or lower than among the overall HCV patient population. Finally, NHANES is a cross-sectional survey with limited information about patients' medical histories, including duration of HCV infection, liver disease status, treatment history, and mode of transmission. Because NHANES lacks this information, it is not possible to model the relationship between chronic liver disease and thrombocytopenia. In particular, duration of HCV infection is an unobserved latent variable that may be explaining part of the variation in thrombocytopenia rates.
Davis et al (2010) predict that the prevalence of cirrhosis will peak in 2020
9
. Previous investigators have suggested that the future burden of liver disease is likely to be reduced only through improvements in the effectiveness of antiviral therapy and increases in the numbers of patients receiving therapy
9
10
11
12
B14 14
B15 15
. The latter goal could be positively affected through the use of emerging treatments which may safely improve platelet counts among HCV-infected patients
5
B16 16
. One study has shown that treatment for low platelets can improve the ability of some patients to initiate antiviral treatment
B17 17
, but further study is needed to see whether the use of such therapies will help patients initiate, maintain, and complete antiviral treatment. Moreover, non-peginterferon-based treatment strategies for chronic HCV infection, several of which are under investigation, may enable more patients to initiate and complete anti-viral therapy and have a higher likelihood of SVR
B18 18
.
Conclusions
Thrombocytopenia increases health costs
5
B19 19
and may interfere with the ability of some patients to initiate or tolerate antiviral therapy
1
2
17
. If the burden of HCV is to be reduced, the clinical impact of thrombocytopenia in HCV-related liver disease must be addressed. A substantial proportion of HCV patients have low platelet counts, and the prevalence of low platelets among individuals with chronic liver disease is likely to increase through the coming decade. Future efforts to estimate the human and economic consequences of HCV infection should consider the role of thrombocytopenia as both a clinical manifestation of disease and a possible barrier to treatment.
Methods
Data and patients
Multiple years of NHANES data were used to examine changes in the prevalence of thrombocytopenia among HCV patients in the US from 1999-2008
B20 20
. NHANES consists of an interview and comprehensive medical examination of a nationally representative sample of about 5,000 persons each year. The interview component includes demographic, socioeconomic, dietary, and health-related questions. The examination component consists of medical, dental, and physiological measurements, as well as laboratory tests administered by highly trained medical personnel. NHANES study participants aged 6 years and older were eligible for hepatitis C antibody testing, which was repeated in duplicate for positive samples.
All participants with available information on hepatitis C testing and evidence of confirmed infection (positive Chiron RIBA 3.0 Strip Immunoblot Assay) were eligible for inclusion in the current study
20
. NHANES participants also received a complete blood count with differential in whole blood, which included platelet count and mean platelet volume, and a standard biochemistry profile. Included in the latter were alanine aminotransferase (ALT) and asparate aminotransferase (AST). Self-reported information about prescription drug use during the past 30 days and medical conditions were included in the questionnaire portion of the survey.
Study measures
The primary measure of interest for the study was thrombocytopenia. Thrombocytopenia was defined as platelet count below 150 × 109/L, although other thresholds were examined. Laboratory and examination variables used to assess the likelihood of thrombocytopenia included ALT, AST, iron, fasting glucose, fasting insulin, albumin, creatinine, bilirubin, total protein, hemoglobin, white blood cell count, and weight. Questionnaire variables included alcohol use, marijuana use, health care utilization over the past 12 months, and prior diagnosis of liver cancer. Demographic variables included age, gender, race/ethnicity, and income.
Statistical analysis
Summary statistics for the variables noted above were calculated for all confirmed HCV-infected NHANES participants. The proportion of confirmed HCV-infected participants meeting a threshold criterion for thrombocytopenia was calculated for each 2-year survey period and compared using Fisher's exact test. The proportion of all NHANES participants with low platelets in each period was provided as a comparison.
Trends over time were analyzed via a series of logistic regression models to account for non-linear relationships between variables. The dependent variable in each model was a dichotomous marker of thrombocytopenia (yes/no) for each subject. The initial model considered only time, with each 2-year survey timeframe considered as one period. Subsequent models included time plus demographic variables (Model 2) and time plus demographic variables plus laboratory measures (Model 3). Pearson correlation coefficients between laboratory measures were calculated. Measures not significantly correlated with platelet counts were excluded from the regression analysis to arrive at a more parsimonious model. Similarly, laboratory measures which were significantly and strongly correlated with ALT and AST were excluded to avoid problems with multi-colinearity and improve model fit. Strong correlations were defined as correlation coefficients with absolute values exceeding 0.20. Questionnaire items with low response rates were not included due to missing data. Odds ratios and 95% confidence intervals were reported for each model.
Summary statistics, prevalence estimates, and regression analyses were weighted to represent the US population using survey weights provided by the National Center for Health Statistics. All analyses were conducted using SAS version 9.2, with 2-sided tests of hypothesis. P-values of 0.05 or lower were considered statistically significant. The study was approved by the University of Florida Institutional Review Board. All authors read and approved the final manuscript.
Abbreviations
HCV: hepatitis C virus; SVR: sustained virologic response; US: United States; NHANES: National Health and Nutrition Examination Survey; ALT: alanine aminotransferase; AST: asparate aminotransferase.
Competing interests
TLK has received funding from the study sponsor, GlaxoSmithKline, Inc, for this and other studies. DRN has served as a consultant for GlaxoSmithKline, Inc. PFW was a full-time employee of GlaxoSmithKline, Inc. at the time of the study. JACD and JS have no conflicts to disclose.
Authors' contributions
This study was conceived by TLK and DRN and executed by TLK, JS, and JACD. PFW provided important background information and served as a consultant regarding data analysis and interpretation. TLK drafted the manuscript, and all authors provided important intellectual contributions to the content. Full responsibility for all results and conclusions lies with the corresponding author.
bm
ack
Acknowledgements
The authors would like to thank Dr. Babette Brumback for her assistance regarding the use of NHANES survey weights.
refgrp Diagnosis, management, and treatment of hepatitis C: an updateGhanyMGStraderDBThomasDLetal Hepatology2009491335lpage 137410.1002/hep.22759link fulltext 19330875Diagnosis, management, and treatment of hepatitis CStraderDBWrightTThomasDLHepatology2004391147117110.1002/hep.2011915057920Strong association of hepatitis C virus (HCV) infection and thrombocytopenia: Implications from a survey of a community with hyperendemic HCV infectionWangCSYaoWJWangSTClin Infect Dis20043979079610.1086/42338415472809Management and treatment of hepatitis C viral infection: recommendations from the Department of Veterans Affairs Hepatitis C Resource Center program and the National Hepatitis C Program officeYeeHSCurrieSLDarlingJMAm J Gastroenterol20061012360237810.1111/j.1572-0241.2006.00754.x17032203Thrombocytopenia associated with chronic liver diseaseAfdhalNMcHutchisonJBrownRJ Hepatol2008481000100710.1016/j.jhep.2008.03.00918433919Prevalence of thrombocytopenia among patients with chronic hepatitis C: A systematic reviewLouieKSMicallefJMPimentaJMJ Viral Hepat2011181721824223Pegasys (peginterferon alfa-2a) product informationcnm Hoffman-La Roche Inchttp://www.gene.com/gene/products/information/pegasys/pdf/pi.pdfPegIntron (Peginterferon alfa-2b) product informationSchering Corporationhttp://www.spfiles.com/pipeg-intron.pdfAging of hepatitis C virus (HCV)-infected persons in the United States: A multiple cohort model of HCV prevalence and disease progressionDavisGLAlterMJEl-SeragHGastroenterology201013851352110.1053/j.gastro.2009.09.06719861128Projecting future complications of chronic hepatitis C in the United StatesDavisGLAlbrightJECookSFLiver Transpl2003933133810.1053/jlts.2003.5007312682882The healthcare burden imposed by liver disease in aging Baby BoomersDavisGLRobertsWLCurr Gastroenterol Rep2010121610.1007/s11894-009-0087-220425478Estimating future hepatitis C morbidity, mortality, and costs in the United StatesWongJBMcQuillanGMMcHutchisonJGAm J Public Health20009015621569pmcid 144636811029989Peripheral blood count abnormalities among patients with hepatitis C in the United StatesStreiffMBMehtaSThomasDLHepatology20023594795210.1053/jhep.2002.3248611915043Trends in health care resource use for hepatitis C virus infection in the United StatesGrantWCJhaveriRRMcHutchisonJGHepatology2005421406141310.1002/hep.2094116317670Prevalence and challenges of liver diseases in patients with chronic hepatitis C virus infectionJacobsonIMDavisGLEl-SeragHClin Gastroenterol Hepatol2010892493310.1016/j.cgh.2010.06.03220713178Thrombocytopenia in chronic liver diseasePoordadFAliment Pharmacol Ther200726Suppl 151117958514Eltrombopag for thrombocytopenia in patients with cirrhosis associated with hepatitis CMcHutchisonJGDusheikoGShiffmanMLN Engl J Med20073572227223610.1056/NEJMoa07325518046027New hepatitis C therapies in clinical developmentVermehrenJSarrazinCEur J Med Res20111630331410.1186/2047-783X-16-7-30321813371A pharmacoeconomic analysis of thrombocytopenia in chronic liver diseaseBrownRSsuf JrAliment Pharmacol Ther200726Suppl 1414817958518National Health and Nutrition Examination SurveyCenters for Disease Control and Preventionhttp://www.cdc.gov/nchs/nhanes.htm



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RESEARCHARTICLE OpenAccessTrendsintheprevalenceofthrombocytopenia amongindividualsinfectedwithhepatitisCVirus intheUnitedStates,1999-2008TeresaLKauf1*,DavidRNelson2,JonathanSchelfhout1,JosephACDelaney1andPeterFengWang3AbstractBackground: ThrombocytopeniaisassociatedwiththenaturalhistoryofhepatitisCvirus(HCV)infectionandantiviraltherapy.Recent,nationalestimatesoftheclinicalburdenofthrombocytopeniaamongHCV-infected individualsintheUnitedStatesareunavailable.Bi-yearlydatafromthe1999-2000to2007-2008NationalHealth andNutritionExaminationSurveys(NHANES)wereusedtoexaminetheprevalenceofthrombocytopeniaamong HCV-infectedindividualsintheUnitedStates. Results: Among467HCV-infectedindividualsinthesurvey(weightedpopulation=3,597,039),meanweightedage was46.7years(standarddeviation=15.5)and61.7%weremale.Overall,7.6%metthestudydefinitionofTCPat the150109/Lthreshold;4.5%,2.0%,and0.8%hadplateletcountsbelow125,100,and75109/L,respectively. The2-yearweightedprevalencesofthrombocytopenia(150109/Lthreshold)from1999-2008were4.9%,8.6%, 6.5%,4.1%,and12.9%.Theunadjustedbiannualtimetrend(oddsratio)was1.16(95%confidenceinterval=0.821.64).Inthetwoadjustedmodels,theoddsbytimerangedfrom1.24-1.40,dependingonwhetherthemodel includeddemographicorlaboratoryvariablesorboth,butdidnotreachstatisticalsignificance.Agewaspositively andsignificantlyrelatedtothrombocytopeniastatus. Conclusions: AstheHCV-infectedpopulationages,theprevalenceofthrombocytopeniaisexpectedtorise.This studyprovideslimitedevidenceofsuchaneffectatthenationallevel. Keywords: Thrombocytopenia,HepatitisC,Platelets,NHANESBackgroundThrombocytopenia,whichmaybedefinedgenerallyasa plateletcountbelow150109/L,isacommoncomplicationofchronichepatitisCvirus(HCV)infection,particularlyamongthosewithadvancedliverdisease,andthose receivingantiviraltreatmentforHCV[1-4].Estimatesof theprevalenceofthrombocytopeniainliverdiseasevary widely,dependingonthepopulationandtheplatelet thresholdused[5,6].Amongstudiesofchronicliverdisease patientswherethrombocytopeniawasdefinedasaplatelet countlessthan150109/L,prevalenceestimatesrange from16-45%[6].Inclinicaltrialsofinterferon-basedtherapy,morethanonethirdofpatientsexperienceda decreaseinplateletcounts,withcountsfallingbelow50 109/Lobservedin4-8%ofpatients[7,8].Thrombocytopeniawhileonantiviraltherapymayleadtodosereductions, interruption,ordiscontinuationsofinterferon,potentially jeopardizingthechancesofachievingsustainedvirologic response(SVR).Incasesofportalhypertensionandsevere thrombocytopenia,HCVpatientsmaybeunabletoinitiate antiviraltreatmentduetolowplatelets. AnunderstandingoftrendsintheprevalenceofHCV anditscomplicationsfacilitatespublichealthplanningand treatmentefforts.AlthoughthecurrentincidenceofHCV infectionislow,theagingofindividualsinfectedwith HCVoverthepastseveraldecadessuggeststhattheburdenofliverdiseaseintheUnitedStates(US)willcontinue toincrease,withapeakincirrhosiscasesintheyear2020 precedingpeaksinlivercancerinthefollowingdecade[9]. Asthathappens,theprevalenceofthrombocytopenia *Correspondence:kauf@cop.ufl.edu Contributedequally1DepartmentofPharmaceuticalOutcomesandPolicy,CollegeofPharmacy, UniversityofFlorida,Gainesville,Florida,USA FulllistofauthorinformationisavailableattheendofthearticleKauf etal BMCResearchNotes 2012, 5 :142 http://www.biomedcentral.com/1756-0500/5/142 2012Kaufetal;licenseeBioMedCentralLtd.ThisisanopenaccessarticledistributedunderthetermsoftheCreativeCommons AttributionLicense(http://creativecommons.org/licenses/by/2.0),whichpermitsunrestricteduse,distribution,andreproductionin anymedium,providedtheoriginalworkisproperlycited.

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withintheHCV-infectedpopulationalsoislikelyto increase.However,recentprojectionsofHCVandliver diseaseburdenintheUShavenotconsideredtheprevalenceofthrombocytopenia[9-12].Similarly,availableestimatesofthefuturecostofHCVwhicharebasedonpast treatmentpatternsmaynotreflectadequatelytheadditionalcostassociatedwithanincreasedprevalenceof thrombocytopenia. Themostrecentexaminationofthrombocytopeniaat thenationallevelwasconductedusingtheNational HealthandNutritionExaminationSurvey(NHANES) III[13].Inthatstudy,13%ofindividualswithpositive HCVantibodyhadplateletcountsbelow175109/L. WhileNHANESIIIspanstheperiod1988-1994,itis notpossibletodeterminetrendsacrossthattimeperiod duetothenatureofdatacollectionduringthatsurvey phase.NeweradministrationsofNHANES,however,do permitanexaminationoftrendsintheUSoverconsecutive,two-yearperiods.Theobjectiveofthisstudywas todocumentnationaltrendsoverthepastdecadeinthe prevalenceofthrombocytopeniaamongindividuals infectedwithHCV,withthegoalofinformingeffortsto modeltheprevalenceofcomplicationsassociatedwith chronicHCVinfection.ResultsAcrossthe10-yearstudyperiod,467NHANESparticipantswereidentifiedashavingconfirmedHCVinfection; plateletcountswereavailablefor465(99.6%).Theraw HCVfrequencytranslatesto anestimatedprevalencein theUnitedStatesof3,597,039individuals(1.48%prevalence),includingbothdiagnosedandundiagnosedcasesof infection.WeightedsummarycharacteristicsforHCVinfectedparticipantsareshowninTable1.Meanweighted agewas46.7yearsand61.7%weremale.Table1alsosummarizesHCV-infectedindividualswithandwithout thrombocytopenia(definedasplateletcountbelow150 109/L).Comparedtothosewithnormalplateletcounts, individualswithlowplatelettendedtobeolder(55.3vs 46.0years)andhavehigherALT(81.5vs50.0),AST(84.6 vs44.2),andiron(138.9vs106.9)levels,respectively(p< 0.05forallcomparisons).Questionnaireitemstendto havealargenumberofmissingvalues,andalimitednumberofparticipantswereeligibleforcertainexaminations, suchasfastingglucoseandf astinginsulin;theseitems shouldbeinterpretedwithcaution. Figure1showsthe2-yearpointestimatesand95%confidenceintervalsfortheprevalenceofthrombocytopenia atthe150109/Lthresholdfrom1999-2008forparticipantswithandwithoutconfirmedHCVinfection.Trends forlowerthresholdswereunstableduetoverysmall samplesizesandarenotshown.AmongHCV-infected individuals,theprevalenceofthrombocytopeniaatthe 150109/Lthresholdincreasedfrom4.9%in1999-2000 to12.9%in2007-2008,butfirstincreasedthendecreased from2001-2006,althoughnoneoftheperiodsshoweda statisticallysignificantchangefromotherperiods.Trends inthrombocytopeniaprevalenceamongnon-HCVinfectedindividualsfollowedasimilarpattern,although atmuchlowerlevels.Theriseinthrombocytopenia prevalenceof8percentagepointsamongthosewithconfirmedHCVinfectionrepresenteda164.0%increasebut didnotreachstatisticalsignificance.Incontrast,thrombocytopeniaprevalenceamongnon-HCV-infectedindividualswasrelativelystable duringthesametimeperiod, increasingbylessthan9%,from1.4%to1.6%. PlateletcountsamongpatientswithHCVweresignificantlycorrelatedwithseverallaboratorymeasures(data notshownbutavailablefromtheauthorsbyrequest). Thosenotcorrelatedwithplateletsincludedprotein,fastingglucose,andfastinginsulin,althoughtheabilityto detectrelationshipstothefastingvariableswashampered bylimiteddataavailability.ALTandASTweresignificantlycorrelatedwithbilirubin,protein,hemoglobin,iron, andglobulin.Ofthese,iron,protein,andglobulinwere excludedfromfurtheranalysisbecausetheyshowedparticularlystrongcorrelationswithALTandAST. Resultsforthethreetime-trendregressionmodelsare showninTable2.Theunivariate,biannualtimetrend (oddsratio)forplateletslessthan150109/Lwas1.16 (95%CI=0.82-1.64).Thepointestimate,whichdidnot reachstatisticalsignificance,canbeinterpretedasabiyearlyincreaseinthrombocytopeniaprevalenceof16%. Inadjustedmodels,theod dsbytimeincreasedto1.241.40,dependingonwhetherthemodelincludeddemographicorlaboratoryvariablesorboth,butfailedto reachstatisticalsignificance.Agewaspositivelyassociatedwithanincreaseintheoddsofthrombocytopenia inbothadjustedmodels.Noneofthelaboratory measureswassignificantlyrelatedtothrombocytopenia status,althoughthecoefficientswereoftheexpected sign.ThepresenceofthrombocytopeniawasnotassociatedwithALTorASTlevel.DiscussionThisstudyisthefirsttoreporttrendsintheprevalence ofthrombocytopeniaacrossanationalsampleofindividualsinfectedwithHCV.Forthemostrecenttimeperiodavailable,2007-2008,th eprevalenceofplatelets below150109/LamongHCVpatientsreachednearly 13%.Further,theprevalenceovertimeamongthenonHCV-infectedUSpopulationremainedfairlystable. Whiletherewasadipinthrombocytopeniaprevalence forsurveyyears2005-2006,thepresenceofasimilardip amongtheweightedpopulationofallNHANESparticipantssuggeststhatthedecreasecouldbeafunctionof laboratoryprocessingorsomeothersystematicchange duringthatsurveyround.Kauf etal BMCResearchNotes 2012, 5 :142 http://www.biomedcentral.com/1756-0500/5/142 Page2of7

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Table1ConfirmedHCVinfectionstudysamplecharacteristicsCharacteristic Confirmed HCV-Infected RawFrequency (n=467) ConfirmedHCV-Infected WeightedMean(SD)orProportion AllHCV Patients Thrombocytopenia Population1(n=43) Non-Thrombocytopenia Population1(n=422) Ageatscreening(yrs),mean(SD)46746.7(15.5)55.3(22.5)46.0(12.7) Malegender,% 293 61.7 73.4 61.2 Weight(kg),mean(SD) 451 78.2(22.5)78.0(23.3) 78.3(22.6) Race/ethnicity,% 467 White 190 65.7 21.6 20.0 Black/African-American 160 20.1 56.3 66.4 Hispanic 103 10.9 19.3 10.3 Other 14 3.3 2.9 3.3 AnnualHouseholdincome,% 433 Below$20,000 185 36.3 39.5 35.6 $20,000-$74,999 204 50.1 47.1 50.7 Above$75,000 44 13.6 13.4 13.7 Everusedmarijuanaorhashish,%1124 87.4 100.0 88.0 Timesreceivedhealthcareoverpast12 months,% 467 43 422 None 83 16.5 13.0 16.9 1-3times 162 35.6 39.7 34.9 Morethan4times 222 47.9 47.3 48.3 Alcoholuse(drinks/dayoverpastyear), mean(SD) 270 4.4(3.7)4.1(2.9) 4.4(3.7) Albumin(g/dL),mean(SD) 456 4.2(0.4)3.7(1.01) 4.2(0.4) ALT(u/L),mean(SD) 456 52.2(60.9)81.5(93.6) 50.0(56.5) AST(u/L),mean(SD) 456 47.2(49.7)84.6(46.7) 44.2(48.5) Bloodureanitrogen(mg/dL),mean(SD)456 12.1(6.4)13.9(11.1) 12.0(5.3) Totalcalcium(mg/dL),mean(SD)456 9.4(0.5)9.1(0.7) 9.5(0.5) Creatinine(mg/dL),mean(SD) 346 0.9(0.3)1.0(0.6) 0.9(0.3) Iron(ug/dL),mean(SD) 456 108.9(58.0)138.9(61.7) 106.9(57.2) Bilirubin(umol/L),mean(SD) 456 13.1(7.6)19.3(13.1) 12.6(6.9) Totalprotein(g/dL),mean(SD) 456 7.4(0.8)7.3(0.9) 7.4(0.9) Globulin(g/dL),mean(SD) 456 3.3(0.8)3.6(0.7) 3.2(0.8) Hemoglobin(g/dL),mean(SD) 465 14.9(2.1)14.5(2.2) 14.9(2.1) Fastingglucose(mg/dL),mean(SD)291 107.7(38.9)105.6(21.2) 108.0(42.8) Fastinginsulin(uU/mL),mean(SD)286 13.3(12.3)26.4(33.9) 11.5(12.7) Whitebloodcellcount(1000cells/uL), mean(SD) 465 7.3(3.2)5.4(2.3) 7.4(3.2) Plateletcount 465 257.6(87.7)112.0(31.2) 269.5(76.0) Thrombocytopenia,% 465 <150109/L 43 7.6 100 0 <125109/L 25 4.5 59.4 0 <100109/L 12 2.0 26.7 0 <7509/L 7 0.8 10.7 0HCV=hepatitisCvirus;SD=standarddeviation;ALT=alanineaminotransferase;AST=asparateaminotransferase NOTES: 1.Definedasplateletcount<150109/L 2.Amongparticipants20yearsofageandolderforsurveyyears2005-2006and2007-2008 3.Amongparticipants12yearsofageandolderwhoattendedamorningexaminationsessionforsurveyyears2005-2006and2007-2008Kauf etal BMCResearchNotes 2012, 5 :142 http://www.biomedcentral.com/1756-0500/5/142 Page3of7

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ApriorstudyutilizingNHANESIIIdatafortheyears 1988-1994foundsimilarthrombocytopeniaprevalence amongHCV-infectedindividuals.Inthatstudy,however,a higherplateletthresholdof175109/L-thebottom5%of plateletcountsacrossallparticipants-wasused[13].Ifplateletcountsremainedstable,thentheprevalenceestimates fromthecurrentstudy,atalowerthreshold,shouldhave beenlowerthanin1988-1994.Wealsofoundagetobe positivelyandsignificantlyr elatedtothrombocytopenia status.Takentogether,thesetwostudiessuggestthatthe prevalenceofthrombocyt openiaamongindividuals infectedwithHCVlikelyincreased-perhapssubstantiallyoverthepasttwodecades.However,thespikeinthrombocytopeniaprevalenceamongHCV-infectedindividuals observedin2007-2008couldbeanoutlier.Additional yearsofdatawillbeneededtodelineateacleartrend. Severalpreviousstudieshaveexaminedplateletcounts amongHCVpatientpopulations.Louieetal(2011)performedasystematicreviewofthosestudiesconductedin populationsof50ormorec onfirmedHCV-infected patients.Amongthe9studieswhichusedaplatelet thresholdof150109/Ltodefinethrombocytopenia, reportedprevalencerangedfrom16.0%to41.0%[6].The muchhigherproportionsreportedinthesestudiescomparedtothecurrentanalysismaybeexplained,inpart,by theinclusioninthepresent studyofindividualswith undiagnosedHCVinfection.Davisetal(2010)estimates thatapproximately70%ofindividualsinfectedwithHCV areunawareoftheirserostatus[9].Amongthe167 NHANESparticipantsfrom1999-2008withconfirmed HCVinfectionwhorespondedtoafollow-uptelephone survey,48.9%reportedthattheywerepreviouslyunaware oftheirserostatus.Itislikelythatalargeproportionof thosepatientshaveyettoexhibitsymptomsofliverdisease,andonewouldexpectalowerprevalenceofthrombocytopeniaamongsuchpatients. TheuseofNHANESpresentsbothadvantagesanddisadvantagesfortheexaminationofthrombocytopenia amongindividualsinfectedwithHCV.TheprimaryadvantageofNHANESliesinitssamplingstrategy,whichallows fortheexaminationofanationallyrepresentativepopulationofindividuals.Additionally,NHANEShasbeenconductedonabiennialbasissince1999,allowingforthe examinationofdiseasetrendsoverthepastdecade.The presentstudyexaminestwoconditionsofwhichpatients maybeunaware.HCVinfectionmayremainasymptomaticforseveraldecades,suchthatmanyindividuals infectedwithHCVareunawareoftheirstatus[9].Similarly,thrombocytopeniaisalaboratoryabnormalitythat maynotappearasaspecificdiagnosisinadministrative dataandpatientsmayormaynotidentifyitasa(known) medicalcondition.Claimsdataorself-reportedsurveys thuswouldbeinadequatetoexaminetheprevalenceof thrombocytopeniawithintheHCV-infectedpopulation. NHANESdoespresentsomelimitations.SinceHCVis relativelyuncommonamon gthegeneralpopulation, Figure1 Prevalenceofplateletcountsbelow150109/LamongindividualswithconfirmedHCVinfectionandallNHANES participants,1999-2008 .Note:Errorbarsrepresent95%confidenceintervalfortheproportionofHCVpatientswithTCP.HCV=hepatitisC virus;NHANES=NationalHealthandNutritionExaminationSurvey;TCP=thrombocytopenia. Kauf etal BMCResearchNotes 2012, 5 :142 http://www.biomedcentral.com/1756-0500/5/142 Page4of7

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samplesizeswithineach2-yearsurveyperiodaresmall, limitingtheabilitytodetectchangesovertime,particularlyforlowerplateletcountswhichmaybemorerelevanttoclinicalpractice.Thesmallsamplealso contributestothevolatilityintheestimates;adifference ofjustoneortwocasescouldhavealargeimpacton theprevalenceestimates.Further,somehigh-riskgroups suchasthehomelessandincarceratedindividualsare notrepresented.Becausethosegroupshavenotbeen adequatelystudied,itisnotknownwhethertheriskof thrombocytopeniawithsu chriskgroupsishigheror lowerthanamongtheoverallHCVpatientpopulation. Finally,NHANESisacross-sectionalsurveywithlimited informationaboutpatients medicalhistories,including durationofHCVinfection, liverdiseasestatus,treatmenthistory,andmodeoftransmission.Because NHANESlacksthisinformation,itisnotpossibleto modeltherelationshipbetweenchronicliverdisease andthrombocytopenia.Inparticular,durationofHCV infectionisanunobservedlatentvariablethatmaybe explainingpartofthevariationinthrombocytopenia rates. Davisetal(2010)predictthattheprevalenceofcirrhosiswillpeakin2020[9].Previousinvestigatorshavesuggestedthatthefutureburdenofliverdiseaseislikelyto bereducedonlythroughimprovementsintheeffectivenessofantiviraltherapyandincreasesinthenumbersof patientsreceivingtherapy[9 -12,14,15].Thelattergoal couldbepositivelyaffected throughtheuseofemerging treatmentswhichmaysafelyimproveplateletcounts amongHCV-infectedpatients[5,16].Onestudyhas shownthattreatmentforlowplateletscanimprovethe abilityofsomepatientstoinitiateantiviraltreatment [17],butfurtherstudyisneededtoseewhethertheuse ofsuchtherapieswillhelppatientsinitiate,maintain,and completeantiviraltreatment.Moreover,non-peginterferon-basedtreatmentstrategiesforchronicHCVinfection,severalofwhichareunderinvestigation,mayenable morepatientstoinitiateandcompleteanti-viraltherapy andhaveahigherlikelihoodofSVR[18].ConclusionsThrombocytopeniaincreaseshealthcosts[5,19]andmay interferewiththeabilityofsomepatientstoinitiateortolerateantiviraltherapy[1,2,17].IftheburdenofHCVisto bereduced,theclinicalimpactofthrombocytopeniain HCV-relatedliverdiseasemustbeaddressed.Asubstantial proportionofHCVpatientshavelowplateletcounts,and theprevalenceoflowplateletsamongindividualswith chronicliverdiseaseislikelytoincreasethroughthecomingdecade.FutureeffortstoestimatethehumanandeconomicconsequencesofHCVinfectionshouldconsider theroleofthrombocytopeniaasbothaclinicalmanifestationofdiseaseandapossiblebarriertotreatment.MethodsDataandpatientsMultipleyearsofNHANESdatawereusedtoexamine changesintheprevalenceofthrombocytopeniaamong HCVpatientsintheUSfrom1999-2008[20].NHANES Table2Adjustedtime-trendregressionresultsHCV-ConfirmedPatients(n=467) Variable Model1 n=465 OR(95%CI) Model2 n=449 OR(95%CI) Model3 n=440 OR(95%CI) Time 1.16(0.82-1.64) 1.24(0.84-1.84) 1.40(0.88-2.22) Age(years) 1.05(1.02-1.08) 1.02(1.02-1.12) Malegender 2.87(0.97-8.51) 1.45(0.30-6.94) Weight(kg) 0.99(0.96-1.02) 0.99(0.95-1.04) Race/ethnicity(vsWhite) Black/African-American 1.26(0.47-3.37) 0.50(0.10-2.52) Hispanic 1.19(0.38-3.72) 0.94(0.27-3.30) Other 1.18(0.13-11.06) 1.09(0.17-7.00) Albumin 0.28(0.04-2.21) ALT 1.01(0.99-1.03) AST 1.01(0.99-1.03) Bloodureanitrogen 0.92(0.84-1.01) Totalcalcium 0.18(0.02-2.23) Bilirubin 1.05(0.99-1.13) Hemoglobin 1.07(0.73-1.56) Whitebloodcellcount 0.59(0.73-1.56) Modelc-statistic 0.48 0.74 0.89HCV=hepatitisCvirus;OR=oddsratio;CI=confidenceinterval;ALT=alanineaminotransferase;AST=asparateaminotransferaseKauf etal BMCResearchNotes 2012, 5 :142 http://www.biomedcentral.com/1756-0500/5/142 Page5of7

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consistsofaninterviewandcomprehensivemedical examinationofanationallyrepresentativesampleof about5,000personseachyear.Theinterviewcomponentincludesdemographic,socioeconomic,dietary,and health-relatedquestions.Theexaminationcomponent consistsofmedical,dental,andphysiologicalmeasurements,aswellaslaboratorytestsadministeredbyhighly trainedmedicalpersonnel.NHANESstudyparticipants aged6yearsandolderwereeligibleforhepatitisCantibodytesting,whichwasrepeatedinduplicateforpositivesamples. AllparticipantswithavailableinformationonhepatitisC testingandevidenceofconfirmedinfection(positive ChironRIBA3.0StripImmuno blotAssay)wereeligible forinclusioninthecurrentstudy[20].NHANESparticipantsalsoreceivedacompletebloodcountwithdifferentialinwholeblood,whichincludedplateletcountand meanplateletvolume,andastandardbiochemistryprofile. Includedinthelatterwerealanineaminotransferase (ALT)andasparateaminotransferase(AST).Self-reported informationaboutprescriptiondruguseduringthepast 30daysandmedicalconditionswereincludedinthequestionnaireportionofthesurvey.StudymeasuresTheprimarymeasureofinterestforthestudywasthrombocytopenia.Thrombocytopeniawasdefinedasplatelet countbelow150109/L,althoughotherthresholdswere examined.Laboratoryandexaminationvariablesusedto assessthelikelihoodofthrombocytopeniaincludedALT, AST,iron,fastingglucose,fastinginsulin,albumin,creatinine,bilirubin,totalprotein,hemoglobin,whitebloodcell count,andweight.Questionnairevariablesincludedalcoholuse,marijuanause,healthcareutilizationoverthepast 12months,andpriordiagnosisoflivercancer.Demographicvariablesincludedage,gender,race/ethnicity,and income.StatisticalanalysisSummarystatisticsforthevariablesnotedabovewere calculatedforallconfirmedHCV-infectedNHANES participants.TheproportionofconfirmedHCV-infected participantsmeetingathresholdcriterionforthrombocytopeniawascalculatedforeach2-yearsurveyperiod andcomparedusingFisher sexacttest.Theproportion ofallNHANESparticipantswithlowplateletsineach periodwasprovidedasacomparison. Trendsovertimewereanalyzedviaaseriesoflogistic regressionmodelstoaccountfornon-linearrelationships betweenvariables.Thedependentvariableineachmodel wasadichotomousmarkerofthrombocytopenia(yes/no) foreachsubject.Theinitialmodelconsideredonlytime, witheach2-yearsurveytimeframeconsideredasoneperiod.Subsequentmodelsincludedtimeplusdemographic variables(Model2)andtimeplusdemographicvariables pluslaboratorymeasures(Model3).Pearsoncorrelation coefficientsbetweenlaboratorymeasureswerecalculated. Measuresnotsignificantlycorrelatedwithplateletcounts wereexcludedfromtheregressionanalysistoarriveata moreparsimoniousmodel.Similarly,laboratorymeasures whichweresignificantlyandstronglycorrelatedwithALT andASTwereexcludedtoavoidproblemswithmulticolinearityandimprovemod elfit.Strongcorrelations weredefinedascorrelationcoefficientswithabsolute valuesexceeding0.20.Questionnaireitemswithlow responserateswerenotincludedduetomissingdata. Oddsratiosand95%confidenceintervalswerereported foreachmodel. Summarystatistics,prevalenceestimates,andregressionanalyseswereweightedtorepresenttheUSpopulationusingsurveyweightsprovidedbytheNational CenterforHealthStatistics.Allanalyseswereconducted usingSASversion9.2,with2-sidedtestsofhypothesis. P-valuesof0.05orlowerwereconsideredstatistically significant.ThestudywasapprovedbytheUniversityof FloridaInstitutionalReviewBoard.Allauthorsreadand approvedthefinalmanuscript.Abbreviations HCV:hepatitisCvirus;SVR:sustainedvirologicresponse;US:UnitedStates; NHANES:NationalHealthandNutritionExaminationSurvey;ALT:alanine aminotransferase;AST:asparateaminotransferase. Acknowledgements TheauthorswouldliketothankDr.BabetteBrumbackforherassistance regardingtheuseofNHANESsurveyweights. Authordetails1DepartmentofPharmaceuticalOutcomesandPolicy,CollegeofPharmacy, UniversityofFlorida,Gainesville,Florida,USA.2DepartmentDivisionof Gastroenterology,Hepatology&NutritionandClinicalandTranslational ScienceInstitute,CollegeofMedicine,UniversityofFlorida,Gainesville, Florida,USA.3GlobalHealthEconomicsandOutcomesResearch,BristolMyersSquibbCompany,NewYork,NewYork,USA. Authors contributions ThisstudywasconceivedbyTLKandDRNandexecutedbyTLK,JS,and JACD.PFWprovidedimportantbackgroundinformationandservedasa consultantregardingdataanalysisandinterpretation.TLKdraftedthe manuscript,andallauthorsprovidedimportantintellectualcontributionsto thecontent.Fullresponsibilityforallresultsandconclusionslieswiththe correspondingauthor. Competinginterests TLKhasreceivedfundingfromthestudysponsor,GlaxoSmithKline,Inc,for thisandotherstudies.DRNhasservedasaconsultantforGlaxoSmithKline, Inc.PFWwasafull-timeemployeeofGlaxoSmithKline,Inc.atthetimeof thestudy.JACDandJShavenoconflictstodisclose. Received:29November2011Accepted:13March2012 Published:13March2012 References1.GhanyMG,StraderDB,ThomasDL, etal : Diagnosis,management,and treatmentofhepatitisC:anupdate. Hepatology 2009, 49 :1335-1374.Kauf etal BMCResearchNotes 2012, 5 :142 http://www.biomedcentral.com/1756-0500/5/142 Page6of7

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2.StraderDB,WrightT,ThomasDL, etal : Diagnosis,management,and treatmentofhepatitisC. Hepatology 2004, 39 :1147-1171. 3.WangCS,YaoWJ,WangST, etal : StrongassociationofhepatitisCvirus (HCV)infectionandthrombocytopenia:Implicationsfromasurveyofa communitywithhyperendemicHCVinfection. ClinInfectDis 2004, 39 :790-796. 4.YeeHS,CurrieSL,DarlingJM, etal : Managementandtreatmentof hepatitisCviralinfection:recommendationsfromtheDepartmentof VeteransAffairsHepatitisCResourceCenterprogramandtheNational HepatitisCProgramoffice. AmJGastroenterol 2006, 101 :2360-2378. 5.AfdhalN,McHutchisonJ,BrownR, etal : Thrombocytopeniaassociated withchronicliverdisease. JHepatol 2008, 48 :1000-1007. 6.LouieKS,MicallefJM,PimentaJM, etal : Prevalenceofthrombocytopenia amongpatientswithchronichepatitisC:Asystematicreview. JViral Hepat 2011, 18 :1-7. 7.Hoffman-LaRocheInc: Pegasys(peginterferonalfa-2a)product information.[http://www.gene.com/gene/products/information/pegasys/ pdf/pi.pdf]. 8.ScheringCorporation: PegIntron(Peginterferonalfa-2b)product information.[http://www.spfiles.com/pipeg-intron.pdf]. 9.DavisGL,AlterMJ,El-SeragH, etal : AgingofhepatitisCvirus(HCV)infectedpersonsintheUnitedStates:AmultiplecohortmodelofHCV prevalenceanddiseaseprogression. Gastroenterology 2010, 138 :513-521. 10.DavisGL,AlbrightJE,CookSF: Projectingfuturecomplicationsofchronic hepatitisCintheUnitedStates. LiverTranspl 2003, 9 :331-338. 11.DavisGL,RobertsWL: Thehealthcareburdenimposedbyliverdiseasein agingBabyBoomers. CurrGastroenterolRep 2010, 12 :1-6. 12.WongJB,McQuillanGM,McHutchisonJG, etal : Estimatingfuturehepatitis Cmorbidity,mortality,andcostsintheUnitedStates. AmJPublicHealth 2000, 90 :1562-1569. 13.StreiffMB,MehtaS,ThomasDL: Peripheralbloodcountabnormalities amongpatientswithhepatitisCintheUnitedStates. Hepatology 2002, 35 :947-952. 14.GrantWC,JhaveriRR,McHutchisonJG, etal : Trendsinhealthcare resourceuseforhepatitisCvirusinfectionintheUnitedStates. Hepatology 2005, 42 :1406-1413. 15.JacobsonIM,DavisGL,El-SeragH, etal : Prevalenceandchallengesofliver diseasesinpatientswithchronichepatitisCvirusinfection. Clin GastroenterolHepatol 2010, 8 :924-933. 16.PoordadF: Thrombocytopeniainchronicliverdisease. AlimentPharmacol Ther 2007, 26(Suppl1):5-11. 17.McHutchisonJG,DusheikoG,ShiffmanML: Eltrombopagfor thrombocytopeniainpatientswithcirrhosisassociatedwithhepatitisC. NEnglJMed 2007, 357 :2227-2236. 18.VermehrenJ,SarrazinC: NewhepatitisCtherapiesinclinical development. EurJMedRes 2011, 16 :303-314. 19.BrownRSJr: Apharmacoeconomicanalysisofthrombocytopeniain chronicliverdisease. AlimentPharmacolTher 2007, 26(Suppl1):41-48. 20.CentersforDiseaseControlandPrevention: NationalHealthandNutrition ExaminationSurvey. [http://www.cdc.gov/nchs/nhanes.htm].doi:10.1186/1756-0500-5-142 Citethisarticleas: Kauf etal .: Trendsintheprevalenceof thrombocytopeniaamongindividualsinfectedwithhepatitisCVirusin theUnitedStates,1999-2008. BMCResearchNotes 2012 5 :142. Submit your next manuscript to BioMed Central and take full advantage of: Convenient online submission Thorough peer review No space constraints or color gure charges Immediate publication on acceptance Inclusion in PubMed, CAS, Scopus and Google Scholar Research which is freely available for redistribution Submit your manuscript at www.biomedcentral.com/submit Kauf etal BMCResearchNotes 2012, 5 :142 http://www.biomedcentral.com/1756-0500/5/142 Page7of7


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Abstract
Background
Thrombocytopenia is associated with the natural history of hepatitis C virus (HCV) infection and anti-viral therapy. Recent, national estimates of the clinical burden of thrombocytopenia among HCV-infected individuals in the United States are unavailable. Bi-yearly data from the 1999-2000 to 2007-2008 National Health and Nutrition Examination Surveys (NHANES) were used to examine the prevalence of thrombocytopenia among HCV-infected individuals in the United States.
Results
Among 467 HCV-infected individuals in the survey (weighted population = 3,597,039), mean weighted age was 46.7 years (standard deviation = 15.5) and 61.7% were male. Overall, 7.6% met the study definition of TCP at the 150 × 109/L threshold; 4.5%, 2.0%, and 0.8% had platelet counts below 125, 100, and 75 × 109/L, respectively. The 2-year weighted prevalences of thrombocytopenia (150 × 109/L threshold) from 1999-2008 were 4.9%, 8.6%, 6.5%, 4.1%, and 12.9%. The unadjusted biannual time trend (odds ratio) was 1.16 (95% confidence interval = 0.82-1.64). In the two adjusted models, the odds by time ranged from 1.24-1.40, depending on whether the model included demographic or laboratory variables or both, but did not reach statistical significance. Age was positively and significantly related to thrombocytopenia status.
Conclusions
As the HCV-infected population ages, the prevalence of thrombocytopenia is expected to rise. This study provides limited evidence of such an effect at the national level.
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Teresa L Kauf et al.; licensee BioMed Central Ltd.
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BMC Research Notes. 2012 Mar 13;5(1):142
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