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Hepatitis C virus treatment and survival in patients with
hepatitis C and human immunodeficiency virus co-infection
and baseline anaemia
S. Erqou,1,2,* A. Mohanty,1,* K. A. McGinnis,2 G. Vanasse,3 M. S. Freiberg,1 K. E. Sherman4
and A. A. Butt1,5 1School of Medicine, University of Pittsburgh, Pittsburgh, PA, USA; 2Veterans Administration (VA) Pittsburgh
Healthcare System, Pittsburgh, PA, USA; 3Harvard Medical School, Brigham and Women’s Hospital, Boston, MA, USA; 4University of Cincinnati
School of Medicine, Cincinnati, OH, USA; and 5Sheikh Khalifa Medical City, Abu Dhabi, UAE2
Received September 2012; accepted for publication March 2013
SUMMARY. The impact of pretreatment anaemia on sur-
vival in individuals with hepatitis C virus (HCV) and
human immunodeficiency virus (HIV) co-infection is not
known. Moreover, HCV treatment is offered less frequently
to individuals with anaemia, due to haematological side
effects of the treatment regimen. This study aimed to deter-
mine the effect of HCV treatment on survival among HCV/
HIV co-infected individuals with pretreatment anaemia. A
retrospective cohort study using the Electronically
Retrieved Cohort of HCV-Infected Veterans. Individuals
with HCV/HIV co-infection were included in current analy-
ses. Participants were considered treated if they were pre-
scribed �4 weeks of HCV treatment. All-cause mortality
data were obtained using record linkage. Survival analyses
were performed using Cox proportional hazard models.
Among 5000 HCV/HIV co-infected individuals, 1671
(33.4%) had pretreatment anaemia. In a follow-up period
of up to 7 years (19 500 person-years), individuals with
anaemia had significantly higher mortality rate compared
with those without anaemia [144.2 (95% CI: 134.5–
154.7) vs 47.5 (44.0–51.2) per 1000 person-years, respec-
tively]. Among individuals with anaemia, HCV treatment
was associated with significantly lower mortality rate
[66.6 (44.3–100.2) vs 149.6 (139.2–160.5) per 1000 per-
son-years, for treated vs untreated, respectively]. Treatment
remained associated with substantial survival benefit after
taking into account the effect of multiple comorbidities
(hazards ratio: 0.34, 95% CI: 0.21–0.62). These data sug-
gest that HCV/HIV co-infected individuals with pretreat-
ment anaemia have significantly higher mortality
compared with those without anaemia. HCV treatment is
associated with substantial survival benefit in this group.
Additional studies are needed to determine strategies to
improve HCV treatment rates among this group.
Keywords: anemia, HCV, HIV, survival, treatment.
INTRODUCTION
Chronic hepatitis C virus (HCV) infection is the leading
cause of cirrhosis of liver, end-stage liver disease, hepato-
cellular carcinoma and liver transplantation [1–3]. World-
wide, approximately 170 million people are infected with
HCV. Approximately 5–10% of HCV-infected persons are
co-infected with human immunodeficiency virus (HIV) [4–6].
Liver disease progression and mortality rates are higher
among individuals with HIV co-infection, compared with
those with HCV monoinfeciton [4,7].
Treatment for chronic HCV infection is associated with
substantial reduction in mortality, especially among those
who achieve sustained virological response [8,9]. This bene-
fit has been shown to extend to individuals with HCV/HIV
co-infection [4]. Until recently, the standard of treatment
involved administration of pegylated interferon alfa and
ribavirin for 24–48 weeks, depending on HCV genotype
[10]. Even with recent approval of directly acting antiviral
agents against HCV, pegylated interferon alfa and ribavirin
remain the backbone of the treatment regimen. As ribavirin
and interferon cause dose-dependent haemolysis and bone
Abbreviations: CAD, coronary artery disease; CHF, congestive heart
failure; CKD, chronic kidney disease; COPD, chronic obstructive pul-
monary disease; DLD, decompensated liver disease; DVT, deep-vein
thrombosis; ERCHIVES, Electronically Retrieved Cohort of HCV-
Infected Veterans; HCV, hepatitis C virus; HIV, human immunodefi-
ciency virus; ICD-9, International Classification of Diseases, Ninth
Revision; MI, myocardial infarction; PE, pulmonary embolism; PVD,
peripheral vascular disease; VA, Veterans Administration4 .
Correspondence: Adeel A. Butt, MD, MS, FACP, FIDSA, School of
Medicine, University of Pittsburgh, 3601 Fifth Avenue, Suite 3A,
Pittsburgh, PA 15213, USA.
E-mail: [email protected]
*Denotes joint first authors.
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© 2013 Blackwell Publishing Ltd
Journal of Viral Hepatitis, 2013 doi:10.1111/jvh.12107
J V H 1 2 1 0 7 B Dispatch: 6.4.13 Journal: JVH CE: Nivedha
Journal Name Manuscript No. Author Received: No. of pages: 7 PE: Priya M
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marrow suppression, respectively, the utility of this regimen
is limited by therapy associated anaemia [11].
Therapy associated anaemia in HCV has been studied
widely. Low pretreatment haemoglobin has been identified
as a factor associated with worsening of anaemia on treat-
ment [12–14]. Providers may be less likely to offer the
treatment to anaemic individuals to prevent further exacer-
bation of anaemia and related complications. It has been
shown that HCV-infected individuals with pretreatment
anaemia are less likely to receive treatment for HCV; in
fact, pretreatment anaemia is among the strongest predic-
tors of nontreatment [15]. Pretreatment anaemia is also
associated with treatment noncompletion for HCV infection
[16]. Most studies on anaemia in HCV have focused on
HCV mono-infected individuals and have not specifically
addressed the issue of pretreatment anaemia. Understand-
ing the impact of HCV treatment on survival among HCV/
HIV co-infected individuals with anaemia is important for
making appropriate risk–benefit assessment of HCV treat-
ment in this group of patients.
This study aimed to determine the impact of HCV treat-
ment on survival among HCV/HIV co-infected individuals
with pretreatment anaemia.
PATIENT AND METHODS
The Electronically Retrieved Cohort of Hepatitis C-Infected
Veterans (ERCHIVES) was used for this study. ERCHIVES is
a retrospective cohort of HCV-infected individuals and HCV
uninfected controls; and its earlier its iterations have been
described in previous publications [8,15–18]. The current
cohort was assembled and merged from 2001 to 2008
through linkage of records from several sources of the Vet-
erans Health Administration Healthcare System (VA).
Demographic and clinical data were retrieved from the
Department of Veterans Affairs National Patient Care Data-
base, pharmacy data from the Pharmacy Benefits Manage-
ment Database, laboratory data from the Decision Support
System and the Corporate Data Warehouse, and mortality
data from the Beneficiary Identification Records Locator
Subsystem. HCV-infected individuals were identified by a
positive HCV antibody at baseline. Corresponding HCV
uninfected controls were identified by a negative HCV anti-
body test performed in the same year as a positive antibody
test for the cases and were matched by age (5-year blocks),
race, sex and geographical location. HIV-infected individu-
als were identified by positive HIV antibody test in the
same year as the HCV antibody test. For the current study,
we included only subjects with concomitant HCV and HIV
infection.
Baseline demographic and comorbidity variables includ-
ing smoking, alcohol abuse, drug abuse, hypertension, dia-
betes, chronic kidney disease (CKD), decompensated liver
disease, chronic obstructive pulmonary disease (COPD),
cancer, coronary artery disease (CAD), peripheral vascular
disease and stroke were defined as described previously
[15–20]. Laboratory data retrieved included haemoglobin,
white cell count, total cholesterol, low-density and high-den-
sity lipoprotein cholesterol, triglycerides, alanine and aspar-
tate aminotransferase, and HCV and HIV antibody test. The
presence of anaemia and other co-morbidities were identified
at baseline (within 12 months prior to and 6 months after
entry to cohort). Anaemia was defined as haemoglobin level
less than 13 g/dL for men and 12 g/dL for women. Anae-
mia was further classified into mild (10–12 g/dL for women
and 10–13 g/dL for men), moderate (8.5–9.9 g/dL) and
severe (less than 8.5 g/dL).
Data on use of interferon alfa, pegylated interferon alfa
and ribavirin in various combinations were obtained from
the Pharmacy Benefits Management Database. Dates of
starting treatment and cumulative durations of prescription
were obtained. Patients with interferon doses higher than
those routinely used for HCV treatment were excluded.
Patients on treatment for HCV often undergo reduction in
ribavirin and interferon dosing due to anaemia. Our study
did not analyse change in dosage of these medications, but
concentrated on duration of cumulative therapy up to major
treatment decision points (12 weeks for early virological
response, 24 weeks which is the recommended duration
of treatment for genotypes 2 and 3, and 48 weeks which is
recommended duration of treatment for genotypes 1 and 4)
[10].
All-cause mortality data were obtained from VA Benefi-
ciary Identification Records Locator System. Subjects were
followed up until death or the last observation date in the
cohort. Individuals with no follow-up visits after baseline
visit were excluded from analyses.
Baseline characteristics of anaemic HCV/HIV co-infected
individuals were compared with those without anaemia
using t-test for continuous variables and chi-squared test
for categorical variables. The correlates of pretreatment
anaemia were further assessed using univariate and multi-
variate logistic regression models. The multivariate model
was built through backward selection with inclusion of all
variables from the univariate model with P-values less
than 0.001. Survival analyses were used to determine the
associations of pretreatment anaemia and HCV treatment
with mortality. Kaplan–Meir plots were used to visually
compare survivor function by anaemia and treatment sta-
tus. Log-rank test was used to determine the statistical sig-
nificance of differences between survivor curves. Hazard
ratios were estimated using Cox proportional hazard mod-
els. The assumptions of the proportionality of hazards were
evaluated using Schoenfeld residuals. Adjustments for
potential confounders were made by including covariates
in multivariable models progressively adjusted for four
groups of potential confounders. Model 1 was adjusted for
socio-demographic and biochemical factors including age,
sex, race, smoking, alcohol, drug abuse, baseline choles-
terol, triglycerides and high-density lipoprotein; Model 2
© 2013 Blackwell Publishing Ltd
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was adjusted for preceding plus baseline comorbidities,
namely diabetes, hypertension, decompensated liver dis-
ease, chronic kidney disease, COPD, cancer, coronary
artery disease, peripheral vascular disease and stroke.
Model 3 was adjusted for preceding plus incident comor-
bidities, namely diabetes, myocardial infarction, incident
congestive heart failure, peripheral vascular disease, stroke
and cirrhosis. Model 4 was adjusted for preceding plus HIV
viral load and CD4 count. All analyses were performed
using Stata (College Station, TX, USA), version 9.
Role of funding source
The sponsors of this study did not have any role in the
study design; in the collection, analysis, and interpretation
of data; in the writing of the report; and in the decision to
submit the article for publication.
RESULTS
Data were available for 5000 HCV/HIV co-infected Veter-
ans, of whom 1671 (33.4%) had pretreatment anaemia.
The baseline characteristics of the participants are shown
in Table 1. The mean age of HCV/HIV co-infected individu-
als with anaemia was 50 years; 98% were male, 26% were
white, 60% were African American, and 8% were His-
panic. As compared with individuals without anaemia,
those with anaemia were more likely to be African Ameri-
can (70% vs 55%), have hypertension (38% vs 29%), dia-
betes (18% vs 12%), CKD (39% vs 12%), decompensated
liver disease (43% vs 17%), COPD (10% vs 7%), CAD (7%
vs 3%) and cancer (12% vs 8%). In addition, they were
more likely to have lower CD4 counts (256 vs 401/lL)
and higher HIV viral loads (93 9 103 vs 57 9 103 copies/
mL). The correlates of anaemia among HCV/HIV co-
infected individuals are shown in Table S1. Age (OR, 2.10;
95% CI: 1.46–3.03, per 5 year increment), African Ameri-
can race (OR, 2.11; 95% CI: 1.79–2.50), CKD (3.34;
2.80–4.00), decompensated liver disease (2.56; 2.18–3.01)
and cancer (1.64; 1.29–2.09) were strongly associated
with pretreatment anaemia in the multivariate model.
Hepatitis C virus treatment was initiated in 84 (5.0%)
participants with anaemia and in 333 (10.0%) without
anaemia. HCV/HIV co-infected individuals with anaemia
were 52% less likely to be treated compared with those
with no anaemia (OR, 0.48; 95% CI: 0.37–0.61). Among
individuals with pretreatment anaemia, those who did not
receive treatment, compared with those who received treat-
ment, were more likely to be African American (71% vs
46%), abuse drug (43% vs 30%), have CKD (40% vs 25%),
CAD (7% vs 1%) and higher HIV viral load (mean viral
load: 95 9 103 vs 47 9 103 copies/mL). (Table 2) In addi-
tion, those who did not receive treatment tended to have
lower CD4 counts (253 vs 310/lL), but this was not statis-
tically significant (P-value = 0.4). (Table 2)
In a follow-up period of up to 7 years (19 520 person-
years of follow-up), individuals with pretreatment anaemia
had significantly higher mortality compared with those
with no anaemia [144.2 (95% CI: 134.5–154.7) vs 47.5
(44.0–51.2) per 1000 person-years, respectively]. (Table 3,
Fig. 1) Among individuals with pretreatment anaemia,
those initiated on HCV treatment had a mortality rate of
66.6 (95% CI, 44.3–100.2) per 1000 person-years, com-
pared with a mortality rate of 149.5 (139.2–160.5) per
1000 person-years for those who did not receive treat-
ment. (Table 3, Fig. 2)
Table 1 Baseline characteristics of HIV/HCV co-infected
individuals included in current analyses
Variable
Anaemia
(N available =
1671)
No anaemia
(N available =
3329)
Mean (SD)
or N (%)
Mean (SD) or
N (%)
Haemoglobin (g/dL) 11 (1) 15 (1)
Age (years) 52 (7) 50 (7)
Male 1638 (98%) 3263 (98%)
White 308 (18%) 1014 (30%)
Black 1163 (70%) 1837 (55%)
Hispanic 123 (7%) 292 (9%)
Smoking 344 (21%) 675 (20%)
Alcohol abuse 475 (28%) 905 (27%)
Drug abuse 704 (42%) 1250 (38%)
Hypertension 640 (38%) 954 (29%)
Diabetes 299 (18%) 401 (12%)
CKD 659 (39%) 396 (12%)
DLD* 602 (43%) 452 (17%)
COPD 173 (10%) 217 (7%)
History of cancer 207 (12%) 250 (8%)
CAD 120 (7%) 86 (3%)
PVD 50 (3%) 45 (1%)
Stroke 37 (2%) 30 (1%)
Total cholesterol
(mg/dL)*152 (42) 172 (41)
Log-triglycerides
(log-mg/dL)*4.90 (0.56) 4.98 (0.59)
HDL-cholesterol
(mg/dL)*40 (16) 42 (15)
CKD, chronic kidney diseases; DLD, decompensated liver
disease; COPD, chronic obstructive pulmonary disease; CAD,
coronary artery disease; PVD, peripheral vascular disease.
P-value<0.001 for all variables, except for sex = 0.985,
smoking = 0.797, alcohol = 0.355, drug = 0.002.
*For DLD, available number was 1412 for individuals who
received treatment and 2665 for those who did not receive
treatment; similarly, available number was 1355 and 2901
for total cholesterol, 1322 and 2776 for log-triglycerides,
and 1158 and 2550 for HDL-cholesterol, for individual with
and without pretreatment anaemia, respectively.
© 2013 Blackwell Publishing Ltd
Treatment and survival in patients with HCV and HIV 13
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Table 4 shows hazard ratios for the association of treat-
ment with the risk of mortality among HCV-infected indi-
viduals with and without pretreatment anaemia. The
unadjusted hazard ratio for the association of HCV treat-
ment with mortality among HCV-infected individuals with
pretreatment anaemia was 0.41 (95% CI, 0.29–0.58). The
association was minimally altered after adjustment for
multiple covariates, including baseline demographic and
biochemical factors, baseline and incident comorbidites
(HR, 0.36; 95%CI, 0.21–0.62). Further adjustment for HIV
viral load and CD4 count a yielded similar result, but was
less informative due to limitation in sample size (HR, 0.59;
95% CI, 0.29, 1.21). The relative risk reduction in mortal-
ity was comparable for individuals without pretreatment
anaemia (adjusted HR, 0.34; 0.22–0.54). The number
needed to treat (NNT) to avert one death was 10 for indi-
viduals with pretreatment anaemia. By contrast, the NNT
for individuals without pretreatment anaemia was 32.
DISCUSSION
Although anaemia has been shown to be a predictor of
mortality in various populations [21–23], the association
of pretreatment with mortality has not been studied in
HCV/HIV co-infected individuals. Pretreatment anaemia
has been shown to predict the occurrence of on-treatment
haematological abnormalities among HCV-infected individ-
uals [24]. Moreover, HCV-infected individuals with anae-
mia often may not receive treatment for HCV due to
considerations that treatment leads to exacerbation of
anaemia and related complications. Individuals with pre-
treatment anaemia may also require reduction in ribavirin
dosage leading to lower rates of sustained virological
response [25,26]. Consequently, HCV/HIV co-infected indi-
viduals with pretreatment anaemia likely have overall
poorer prognosis than those without pretreatment anaemia.
Understanding the association of pretreatment anaemia with
Table 2 Univariate and multivariate associations of
anaemia among HCV/HIV co-infected individuals
Variable
Univariate OR
(95% CI)
Multivariate OR
(95% CI)*
Age (per 5 year
increment)
3.57 (2.67–4.77) 2.10 (1.46–3.03)
Blacks
(vs Whites)
2.08 (1.79–2.42) 2.11 (1.79–2.50)
Hispanics
(vs Whites)
1.39 (1.07–1.78) 1.50 (1.12–1.91)
Drug abuse 1.21 (1.07–1.36) 1.24 (1.07–1.43)
Hypertension 1.55 (1.37–1.75) 0.80 (0.68–0.94)
Diabetes 1.59 (1.35–1.87) –
CKD 4.82 (4.18–5.57) 3.34 (2.80–4.00)
DLD 3.64 (3.14–4.21) 2.56 (2.18–3.01)
COPD 1.66 (1.34–2.04) –
Cancer 1.74 (1.43–2.12) 1.64 (1.29–2.09)
CAD 2.92 (2.20–3.87) 1.61(1.12–2.29)
PVD 2.25 (1.50–3.38) –
Stroke 2.49 (1.53–4.05) –
CKD, chronic kidney diseases; DLD, decompensated liver
disease; COPD, chronic obstructive pulmonary disease; CAD,
coronary artery disease; PVD, peripheral vascular disease.
*Multivariate model was built through backward selection,
including all the variables from the univariate model
(P-value for inclusion = 0.001). Variables that did not meet
the P-value threshold were dropped from model.
Table 3 Crude mortality rates among HCV/HIV co-infected individuals with and without anaemia by treatment status
Anaemia status Treatment status Person-years follow-up n dead Crude rate (95% CI) per 1000 person-years
Anaemia Not treated 5070 758 149.5 (139.2–160.5)
Treated 345 23 66.6 (44.3–100.2)
Combined 5415 781 144.2 (134.5–154.7)
No anaemia Not treated 12512 636 50.8 (47.0–54.9)
Treated 1587 34 21.4 (15.3–30.0)
Combined 14102 670 47.5 (44.0–51.2)
Overall Not treated 17585 1394 79.3 (75.2–83.5)
Treated 1932 57 29.5 (22.8–38.2)
Combined 19518 1451 74.3 (70.6–78.3)
0.00
0.25
0.50
0.75
1.00
0 2 4 6 8
Follow-up time (years)
No anemia
Anemia
Su
rviv
al p
rob
ab
ilit
y
P <0.001
Fig. 1 Survivor plots among HCV/HIV co-infected
individuals by anemia.
COLOR
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mortality and the role of HCV treatment among HCV/HIV
co-infected individuals is important in informing decision-
making in this group of patients.
The current study, involving 5000 HCV/HIV co-
infected individuals and nearly 20 000 person-years of
follow-up, has demonstrated that HCV treatment among
individuals with pretreatment anaemia is associated with
>60% reduction in mortality. Individuals with pretreat-
ment anaemia were nearly three-fold as likely to die as
those without pretreatment anaemia. Although the rela-
tive risk reduction in mortality with HCV treatment is
similar for HCV/HIV co-infected individuals with pretreat-
ment anaemia (adjusted HR ~ 0.35), the association trans-
lates into substantial absolute risk reduction in mortality
for individuals with pretreatment anaemia, as their abso-
lute risk of death is much higher than those without
pretreatment anaemia. The NNT to avert one death was
10 for individuals with pretreatment anaemia, that is,
one death was averted for every 10 individual with
HCV/HIV co-infection and pretreatment anaemia that
received HCV treatment of at least 4 weeks duration. By
contrast, the NNT for individuals without pretreatment
anaemia was 32.
In interpreting our findings, one must be cognizant of
the fact that the observed association may be confounded
if factors that are associated with mortality influence the
probability of treatment. In our study, the proportions of
various comorbidities including CKD, decompensated liver
disease and cancer were lower among individuals who
received HCV treatment, which may account for the lower
mortality rate in this group. However, the association
between HCV treatment and mortality was unaltered after
adjusting for baseline and incident comorbidities, strongly
suggesting an independent effect.
As would be expected, our study demonstrated a lower
rate of HCV treatment for HCV/HIV co-infected individuals
with anaemia. Individuals with anaemia were 50% less
likely to receive HCV treatment as those with no anaemia.
The substantial mortality benefit of HCV treatment in
HCV/HIV co-infected individuals with pretreatment anae-
mia that we report highlights the need to identify strategies
for improving HCV treatment rates in this group of popula-
tion. For instance, the use of erythropoiesis stimulating
agents (ESAs) has been reported to improve adherence to
HCV treatment, although it is unclear if ESAs improve sur-
vival in individuals with pretreatment anaemia [25–27].
Anaemia in HCV/HIV-infected individuals can be multifac-
torial including anaemia of chronic disease, nutritional
deficiency, etc. In addition, in those with cirrhosis, portal
hypertensive gastropathy and chronic blood loss can lead
to iron deficiency anaemia [28]. Investigating and treat-
ing anaemia in these individuals may improve clinical
outcomes.
The strengths of the current report include the large size,
involving 5000 HCV/HIV co-infected individuals of whom
1671 had pretreatment anaemia and 417 were initiated
on HCV treatment. Second, availability of a wide range of
covariates including demographic factors, baseline and
incident comorbidities enabled good control for confound-
ing effect. Third, use of mortality as an endpoint reduced
the likelihood of any random and systematic misclassifica-
tion. To our knowledge, this is the only study evaluating
the effect of HCV treatment on HCV/HIV co-infected indi-
viduals with pretreatment anaemia.
Study limitations include analysis of administrative data-
bases and that data were not collected for the specific pur-
pose of this study. Second, as we used all-cause mortality
(as compared to liver-related mortality), we were not able
to determine the proportion of deaths directly attributable
to HCV infection. Third, we did not have sufficient data
to analyse the appropriateness of treatment initiation,
Table 4 Effect of treatment on mortality among HCV/HIV
co-infected individuals with and without anaemia
Adjustment
Hazard ratios (95% CI)
No anaemia Anaemia
Crude 0.41 (0.29–0.58) 0.46 (0.30–0.70)
Model1 0.42 (0.30–0.60) 0.46 (0.31–0.70)
Model2 0.35 (0.22–0.55) 0.37 (0.21–0.62)
Model3 0.34 (0.22–0.54) 0.36 (0.21–0.62)
Model 1: adjusted for socio-demographic and biochemical
factors, includes age, sex, race, smoking, alcohol, drug
abuse, baseline cholesterol, triglycerides, HDL-c. Model 2:
model 1 plus baseline comorbidity includes baseline hyper-
tension, diabetes, decompensated liver disease, chronic kid-
ney disease, chronic obstructive pulmonary disease,
cancer, coronary artery disease, peripheral vascular disease
and stroke. Model 3: model 2 plus incident comorbidity,
includes incident diabetes, myocardial infarction, incident
congestive heart failure, peripheral vascular disease, stroke
and cirrhosis.
*Comparison is with untreated HCV-infected individuals.5
0.25
0.50
0.75
1.00
0 2 4 6 8
Follow-up time (years)
No anemia, Untreated
No anemia, Treated
Anemia, Treated
Anemia, Untreated
Su
rviv
or
pro
ba
bil
ity
P < 0.001
Fig. 2 Survivor plots among HCV/HIV co-infected
individuals by anemia and treatment status.
COLOR
© 2013 Blackwell Publishing Ltd
Treatment and survival in patients with HCV and HIV 15
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duration of therapy, effect of genotype and rate of sus-
tained virological response. Fourth, the predominantly
male population with high burden of comorbidities is likely
different from other HCV/HIV co-infected population.
Nonetheless, using data on a large number of HCV/HIV
co-infected individuals on whom several baseline and fol-
low-up variables were available, our study provides robust
evidence on pretreatment anaemia and HCV treatment in
this group of population.
In conclusion, our study demonstrated that HCV treat-
ment is associated with substantial survival benefit in
HCV/HIV co-infected individuals with pretreatment anae-
mia. The importance of these findings is heightened
because this group of patients has significantly higher mor-
tality and lower HCV treatment rates as compared to those
without anaemia. Further study is needed to find strategies
such as erythropoiesis stimulating agents and ribavirin
sparing regimens in optimizing HCV treatment to improve
HCV treatment rates among this group.
ACKNOWLEDGEMENT
This material is the result of work supported and with the
use of facilities at the VA Pittsburgh Healthcare System
and the central data repositories maintained by the VA
Information Resource Center, including the National
Patient Care Database, Decisions Support System Database
and Pharmacy Benefits Management Database.
The views expressed in this article are those of the
authors and do not necessarily reflect the position or policy
of the Department of Veterans Affairs.
Drs Butt and Erqou had full access to all the data in the
study and take final responsibility for the decision to sub-
mit for publication.
REFERENCES
1 El-Serag HB. Hepatocellular carci-
noma and hepatitis C in the United
States. Hepatology 2002; 36(5 Suppl
1): S74–S83.
2 Armstrong GL, Wasley A, Simard
EP, McQuillan GM, Kuhnert WL,
Alter MJ. The prevalence of hepatitis
C virus infection in the United
States, 1999 through 2002. Ann
Intern Med 2006; 144(10): 705–
714.
3 Rustgi VK. The epidemiology of hep-
atitis C infection in the United
States. J Gastroenterol 2007; 42(7):
513–521.
4 Soriano V, Sulkowski M, Bergin C
et al. Care of patients with chronic
hepatitis C and HIV co-infection:
recommendations from the HIV-
HCV International Panel. AIDS
2002; 16(6): 813–828.
5 Laguno M, Murillas J, Blanco JL
et al. Peginterferon alfa-2b plus riba-
virin compared with interferon alfa-
2b plus ribavirin for treatment of
HIV/HCV co-infected patients. AIDS
2004; 18(13): F27–F36.
6 Sulkowski MS, Thomas DL. Hepatitis
C in the HIV-infected person. Ann
Intern Med 2003; 138(3): 197–207.
7 Chung RT, Andersen J, Volberding P
et al. Peginterferon Alfa-2a plus
ribavirin versus interferon alfa-2a
plus ribavirin for chronic hepatitis C
in HIV-coinfected persons. N Engl J
Med 2004; 351(5): 451–459.
8 Butt AA, Wang X, Moore CG. Effect
of hepatitis C virus and its treatment
on survival. Hepatology 2009; 50(2):
387–392.
9 Backus LI, Boothroyd DB, Phillips
BR, Belperio P, Halloran J, Mole LA.
A sustained virologic response
reduces risk of all-cause mortality in
patients with hepatitis C. Clin Gas-
troenterol Hepatol 2011; 9(6): 509–
516.
10 Ghany MG, Strader DB, Thomas DL,
Seeff LB. Diagnosis, management,
and treatment of hepatitis C: an
update. Hepatology 2009; 49(4):
1335–1374.
11 Fried MW. Side effects of therapy of
hepatitis C and their management.
Hepatology 2002; 36(5 Suppl 1):
S237–S244.
12 Hiramatsu N, Kurosaki M, Sakam-
oto N et al. Pretreatment prediction
of anemia progression by pegylated
interferon alpha-2b plus ribavirin
combination therapy in chronic
hepatitis C infection: decision-tree
analysis. J Gastroenterol 2011; 46
(9): 1111–1119.
13 Takaki S, Tsubota A, Hosaka T
et al. Factors contributing to ribavi-
rin dose reduction due to anemia
during interferon alfa2b and ribavi-
rin combination therapy for chronic
hepatitis C. J Gastroenterol 2004; 39
(7): 668–673.
14 Nachnani JS, Rao GA, Bulchandani D,
Pandya PK, Alba LM. Predictors of
hematological abnormalities in
patients with chronic hepatitis C
treated with interferon and ribavi-
rin. Ann Hematol 2010; 89(2):
121–125.
15 Butt AA, Justice AC, Skanderson M,
Rigsby MO, Good CB, Kwoh CK.
Rate and predictors of treatment
prescription for hepatitis C. Gut
2007; 56(3): 385–389.
16 Butt AA, McGinnis KA, Skanderson M,
Justice AC. Hepatitis C treatment
completion rates in routine clinical
care. Liver Int 2010; 30(2): 240–250.
17 Butt AA, Khan UA, McGinnis KA,
Skanderson M, Kent KC. Co-morbid
medical and psychiatric illness and
substance abuse in HCV-infected
and uninfected veterans. J Viral
Hepat 2007; 14(12): 890–896.
18 Butt AA, Wang X, Fried LF. HCV
infection and the incidence of CKD.
Am J Kidney Dis 2011; 57(3): 396–
402.
19 Butt AA, McGinnis K, Rodriguez-
Barradas MC et al. HIV infection
and the risk of diabetes mellitus.
AIDS 2009; 23(10): 1227–1234.
20 Fultz SL, Skanderson M, Mole LA
et al. Development and verification
of a “virtual” cohort using the
National VA Health Information
System. Med Care 2006; 44(8 Suppl
2): S25–S30.
21 Robinson BM, Joffe MM, Berns JS,
Pisoni RL, Port FK, Feldman HI.
Anemia and mortality in hemodial-
ysis patients: accounting for mor-
bidity and treatment variables
updated over time. Kidney Int 2005;
68(5): 2323–2330.
© 2013 Blackwell Publishing Ltd
6 S. Erqou et al.
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
Page 7
22 Zakai NA, Katz R, Hirsch C et al. A
prospective study of anemia status,
hemoglobin concentration, and mor-
tality in an elderly cohort: the Cardio-
vascular Health Study. Arch Intern
Med 2005; 165(19): 2214–2220.
23 Groenveld HF, Januzzi JL, Damman
K et al. Anemia and mortality in
heart failure patients a systematic
review and meta-analysis. J Am Coll
Cardiol 2008; 52(10): 818–827.
24 Sievert W, Dore GJ, McCaughan
GW et al. Virological response is
associated with decline in hemoglo-
bin concentration during pegylated
interferon and ribavirin therapy in
hepatitis C virus genotype 1. Hepa-
tology 2011; 53(4): 1109–1117.
25 Sulkowski MS. Anemia in the treat-
ment of hepatitis C virus infection.
Clin Infect Dis 2003; 37(Suppl 4):
S315–S322.
26 Dieterich DT. Treatment of hepatitis
C and anemia in human immunodefi-
ciency virus-infected patients. J Infect
Dis 2002; 185(Suppl 2): S128–S137.
27 Sulkowski MS, Shiffman ML, Afdhal
NH et al. Hepatitis C virus treat-
ment-related anemia is associated
with higher sustained virologic
response rate. Gastroenterology
2010; 139(5): 1602–1611.
28 Gonzalez-Casas R, Jones EA, Moren-
o-Otero R. Spectrum of anemia
associated with chronic liver dis-
ease. World J Gastroenterol 2009; 15
(37): 4653–4658.
SUPPORTING INFORMATION
Additional Supporting Information
may be found in the online version of
this article:
Table S1: Univariate and multivari-
ate associations of anemia among
HCV/HIV co-infected individuals.
© 2013 Blackwell Publishing Ltd
Treatment and survival in patients with HCV and HIV 17
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Page 9
O n c e y o u h a v e A c r o b a t R e a d e r o p e n o n y o u r c o m p u t e r , c l i c k o n t h e C o m m e n t t a b a t t h e r i g h t o f t h e t o o l b a r :
S t r i k e s a l i n e t h r o u g h t e x t a n d o p e n s u p a t e x tb o x w h e r e r e p l a c e m e n t t e x t c a n b e e n t e r e d .‚ H i g h l i g h t a w o r d o r s e n t e n c e .‚ C l i c k o n t h e R e p l a c e ( I n s ) i c o n i n t h e A n n o t a t i o n ss e c t i o n .‚ T y p e t h e r e p l a c e m e n t t e x t i n t o t h e b l u e b o x t h a ta p p e a r s .
T h i s w i l l o p e n u p a p a n e l d o w n t h e r i g h t s i d e o f t h e d o c u m e n t . T h e m a j o r i t y o ft o o l s y o u w i l l u s e f o r a n n o t a t i n g y o u r p r o o f w i l l b e i n t h e A n n o t a t i o n s s e c t i o n ,p i c t u r e d o p p o s i t e . W e ’ v e p i c k e d o u t s o m e o f t h e s e t o o l s b e l o w :S t r i k e s a r e d l i n e t h r o u g h t e x t t h a t i s t o b ed e l e t e d .
‚ H i g h l i g h t a w o r d o r s e n t e n c e .‚ C l i c k o n t h e S t r i k e t h r o u g h ( D e l ) i c o n i n t h eA n n o t a t i o n s s e c t i o n .
H i g h l i g h t s t e x t i n y e l l o w a n d o p e n s u p a t e x tb o x w h e r e c o m m e n t s c a n b e e n t e r e d .‚ H i g h l i g h t t h e r e l e v a n t s e c t i o n o f t e x t .‚ C l i c k o n t h e A d d n o t e t o t e x t i c o n i n t h eA n n o t a t i o n s s e c t i o n .‚ T y p e i n s t r u c t i o n o n w h a t s h o u l d b e c h a n g e dr e g a r d i n g t h e t e x t i n t o t h e y e l l o w b o x t h a ta p p e a r s .
M a r k s a p o i n t i n t h e p r o o f w h e r e a c o m m e n tn e e d s t o b e h i g h l i g h t e d .‚ C l i c k o n t h e A d d s t i c k y n o t e i c o n i n t h eA n n o t a t i o n s s e c t i o n .‚ C l i c k a t t h e p o i n t i n t h e p r o o f w h e r e t h e c o m m e n ts h o u l d b e i n s e r t e d .‚ T y p e t h e c o m m e n t i n t o t h e y e l l o w b o x t h a ta p p e a r s .
Page 10
I n s e r t s a n i c o n l i n k i n g t o t h e a t t a c h e d f i l e i n t h ea p p r o p r i a t e p a c e i n t h e t e x t .‚ C l i c k o n t h e A t t a c h F i l e i c o n i n t h e A n n o t a t i o n ss e c t i o n .‚ C l i c k o n t h e p r o o f t o w h e r e y o u ’ d l i k e t h e a t t a c h e df i l e t o b e l i n k e d .‚ S e l e c t t h e f i l e t o b e a t t a c h e d f r o m y o u r c o m p u t e ro r n e t w o r k .‚ S e l e c t t h e c o l o u r a n d t y p e o f i c o n t h a t w i l l a p p e a ri n t h e p r o o f . C l i c k O K .
I n s e r t s a s e l e c t e d s t a m p o n t o a n a p p r o p r i a t ep l a c e i n t h e p r o o f .‚ C l i c k o n t h e A d d s t a m p i c o n i n t h e A n n o t a t i o n ss e c t i o n .‚ S e l e c t t h e s t a m p y o u w a n t t o u s e . ( T h e A p p r o v e ds t a m p i s u s u a l l y a v a i l a b l e d i r e c t l y i n t h e m e n u t h a ta p p e a r s ) .‚ C l i c k o n t h e p r o o f w h e r e y o u ’ d l i k e t h e s t a m p t oa p p e a r . ( W h e r e a p r o o f i s t o b e a p p r o v e d a s i t i s ,t h i s w o u l d n o r m a l l y b e o n t h e f i r s t p a g e ) .
A l l o w s s h a p e s , l i n e s a n d f r e e f o r m a n n o t a t i o n s t o b e d r a w n o n p r o o f s a n d f o rc o m m e n t t o b e m a d e o n t h e s e m a r k s . .‚ C l i c k o n o n e o f t h e s h a p e s i n t h e D r a w i n gM a r k u p s s e c t i o n .‚ C l i c k o n t h e p r o o f a t t h e r e l e v a n t p o i n t a n dd r a w t h e s e l e c t e d s h a p e w i t h t h e c u r s o r .‚
T o a d d a c o m m e n t t o t h e d r a w n s h a p e ,m o v e t h e c u r s o r o v e r t h e s h a p e u n t i l a na r r o w h e a d a p p e a r s .‚
D o u b l e c l i c k o n t h e s h a p e a n d t y p e a n yt e x t i n t h e r e d b o x t h a t a p p e a r s .
