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 Previous Article | Table of Contents | Next Article 
Blood, Vol. 93 No. 11 (June 1), 1999:
pp. 3672-3677
Chronic Hepatitis C Virus Infections in Leukemia Survivors:
Prevalence, Viral Load, and Severity of Liver Disease
By
Ian M. Paul,
Jeffrey Sanders,
Francesca Ruggiero,
Thomas Andrews,
David Ungar, and
M. Elaine Eyster
From the Division of Hematology/Oncology, Department of Medicine and
the Departments of Pathology and Pediatrics, Pennsylvania State
University College of Medicine, Hershey, PA.
 |
ABSTRACT |
The natural history of chronic hepatitis C (HCV) infections in
long-term leukemia survivors has not been well characterized. We
studied the prevalence of HCV infections, measured HCV RNA levels, and
evaluated the severity of liver disease in patients with leukemia who
achieved long-term remissions after intensive chemotherapy or bone
marrow transplantation (BMT). HCV antibody tests were performed by the
enzyme-linked immunosorbent assay (ELISA) and positive tests confirmed
by the recombinant immunoblot assay (RIBA). HCV RNA levels were
measured by the branched DNA (bDNA) assay. Seventy-five leukemia
survivors with 25 or more blood donor exposures were identified. Nine
(12%) were anti-HCV positive. All were infected before 1992 when
second generation HCV screening tests were implemented. Mean HCV RNA
levels were 10.3 ×106 eq/mL versus 3.2 × 106 eq/mL (P = .056) in a control group of 20 anti-HCV positive immunocompetent individuals of comparable age who
were infected twice as long (17.8 ± 6.5 years v 9.0 ± 4.4 years in leukemia survivors, P = .001). Liver biopsies were
performed on six of the nine anti-HCV positive leukemia survivors. All
showed at least moderate portal inflammation and half had evidence of
bridging fibrosis. We conclude that viral loads in anti-HCV positive
leukemia survivors are markedly higher than in immunocompetent
controls. Our results suggest that long-term leukemia survivors with
chronic HCV may have more rapidly progressive liver disease than has
been previously recognized.
© 1999 by The American Society of Hematology.
| |
INTRODUCTION |
INDIVIDUALS WITH leukemia have an
increased risk of acquiring transfusion-associated hepatitis C virus
(HCV) infections.1,2 Adults with acute leukemia who have
achieved remission after chemotherapy have an anti-HCV prevalence
between 4.3% and 70%.3-7 Similarly, bone marrow
transplant (BMT) recipients have an anti-HCV prevalence between 3.3%
and 70%.8-14 A somewhat lower prevalence of 1% to 49%
has been found in studies restricted to children with
leukemia.15-20 The rate of infection has decreased
since implementation of blood donor screening for anti-HCV in 1990 and
second generation testing in 1992.3,13,14,18
Data are limited regarding the effects of immunosuppression on viral
load and severity of liver disease in long-term anti-HCV positive
leukemia survivors. However, numerous investigators have reported that
anti-HCV positive individuals who are coinfected with human
immunodeficiency virus (HIV) have significantly higher viral loads than
those who are anti-HIV negative.21-26
Some,21,22,27 but not others,23-26 have shown
that HCV RNA levels increase as the immune deficiency progresses.
Coinfection with HIV has also been shown to be associated with an
increased risk of cirrhosis and liver failure.28-34 Similar
findings have been reported in patients with primary
hypogammaglobulinemia.35,36 Conversely, long-term follow-up
of immunocompetent individuals has shown only a small increase in
deaths related to liver disease.37
The objectives of this study were (1) to determine the prevalence of
HCV infection and severity of liver disease in anti-HCV positive adults
and children with leukemia who achieved a complete remission after
intensive chemotherapy or allogeneic BMT and (2) to determine whether
HCV load differed in the study group compared with a control group of
immunocompetent anti-HCV positive hemophiliacs.
| |
MATERIALS AND METHODS |
Subjects.
The records of all patients with leukemia who were seen between 1973 and 1995 at the adult and pediatric hematology clinics at the Hershey
Medical Center and in the practices of five physician groups in the
Central Pennsylvania area were reviewed to identify those who had
achieved a complete remission after intensive chemotherapy or BMT.
Patients less than age 21 at the time of diagnosis were classified as
children. Seventy-five patients in active follow-up who met study
criteria were identified. They consisted of 46 adults and 29 children
with acute leukemia or chronic myelogenous leukemia (CML) who had
received 25 or more donor exposures to blood products. Four patients
were known to be anti-HCV positive at the initiation of the study.
After obtaining informed consent, medical records were reviewed and
histories were obtained to exclude other causes for hepatitis. Blood
was then drawn for HCV antibody testing and HCV RNA levels.
The control group consisted of 20 anti-HCV positive, anti-HIV negative,
otherwise healthy, randomly selected hemophilia patients with known
transfusion dates followed regularly at the hemophilia clinic at the
Hershey Medical Center and enrolled in a prospective cohort study on
HIV initiated in 1982. For these individuals, sera routinely collected
during the previous year and stored frozen at  70°C was
tested for HCV RNA.
Detection of HCV infection and quantitation of HCV RNA levels.
Sera were tested with the enzyme-linked immunosorbent assay (ELISA)
(Ortho Diagnostic System, Raritan, NJ) and positive tests were
confirmed by a second generation recombinant immunoblot assay test
(RIBA-2) (Chiron Corp, Emeryville, CA). Samples were considered positive if they reacted with two or more of the four test antigens. Serum HCV RNA levels were measured by the Quantiplex 1.0 bDNA assay
(Chiron Corp) on all who were anti-HCV positive except for one patient
from a community practice who had the quantitative polymerase chain
reaction (PCR)-based Monitor test (Roche Molecular Systems, Nutley, NJ)
performed by an outside laboratory. All who were below the cut off
(<3.5 × 105 eq/mL) were subsequently tested by the 2.0 assay (cut off 0.2 × 106 eq/mL). Those who were negative
by the bDNA assay as well as a subset of leukemia patients who were
anti-HCV negative were tested for HCV RNA by the more sensitive,
qualitative PCR assay as previously described.26 To obtain
a mean value of HCV RNA load for the control group, PCR positive
samples below the detectable limits of the bDNA assay of 0.2 × 106 eq/mL were assigned a value of 0.1 × 106 eq/mL (half the detectable limit) and PCR negative
samples were assigned a value of .001 × 106 eq/mL
(approaching the lowest level of 1,000 viral copies/mL detectable by PCR).
Estimation of duration of infection.
For the patients with acute leukemia, the date of infection was
estimated to be the initial exposure to blood products during the
induction phase of chemotherapy. For patients with CML undergoing allogeneic BMT, the date of transplant was assumed to be the date of
infection. For hemophilia patients, the midpoint between the maximum
duration of infection (the number of years since first transfusion) and
the minimum duration of infection (the number of years since first
exposure to unsterilized clotting factor concentrates) was used. The
minimum duration of infection for the hemophilia patients can be
accurately estimated because studies have shown a near 100% incidence
of infection with HCV after the first infusion of unsterilized clotting
factor concentrates obtained from large donor pools.38,39
For the five subjects who had received only single donor blood products
or only virally attenuated concentrates, the minimum duration of
infection was estimated from known duration of transaminase elevations.
Evaluation of liver histology.
Percutaneous liver biopsy specimens were evaluated blindly by a single
pathologist and scored using the Knodell total histology activity index
(HAl), which is a grading system for chronic hepatitis frequently used
in clinical studies.40
Statistical analysis.
Exact P values were calculated using the Pearson's
 2 test to determine the statistical significance of the
difference between the prevalence of detectable HCV RNA in the study
and control groups and prevalence of anti-HCV in (1) acute
lymphoblastic leukemia (ALL) versus acute myelogenous leukemia (AML);
(2) the two donor exposure groups; and (3) the three time periods
examined. To compare the HCV RNA values between the two groups, a
Wilcoxon rank sum test was used to determine the exact P value,
and a two sample t-test was used to compare the duration of
infection data.
| |
RESULTS |
Prevalence of HCV infection in the study cohort.
Nine (12.0%) of the 75 patients with leukemia who met the
study criteria were found to be anti-HCV positive by ELISA and
confirmed with the RIBA-2 assay (Table 1).
Six were males and three were females. Eight were treated for AML. One
of the eight received an allogeneic BMT. The ninth received an
allogeneic BMT for CML. None of the 27 subjects with ALL including four
allogeneic BMT recipients were anti-HCV positive compared with 8 of 37 (17.8%) with AML (P = .046). Of the 17 allogeneic BMT
recipients, 2 (11.8%) were anti-HCV positive. Three (10.3%) of 29 children were anti-HCV positive. All 3 were among the 8 children
treated for AML. None of 3 children treated with BMT were anti-HCV
positive. The rate of HCV infection was 3 of 44 (6.8%) among those
with 25 to 99 donor exposures compared with 6 of 31 (19.4%) among
those with 100 or more donor exposures (P = .15). Six (19.4%)
of 31 patients who were anti-HCV positive were transfused before June
1990, when first-generation anti-HCV testing was implemented. Three
(20.0%) of 15 patients transfused while first generation tests were in use tested positive. None of the 29 subjects studied after second generation testing was implemented in 1992 were positive for anti-HCV (P = .04).
Characteristics of the anti-HCV positive leukemia patients.
The nine anti-HCV positive patients had a mean age of 36.2 ± 15.4 (standard deviation [SD]) years with a range of 7 to 50 years at the time of evaluation and were estimated to be infected for a
mean of 9.0 ± 4.4 years with a range of 4 to 16 years
(Table 2). Seven (78%) had mild to
moderately elevated serum alanine transferases. All nine had normal
bilirubin determinations and normal serum albumin levels (data not
shown). None showed clinical evidence of liver disease. All had viral
loads above the level of detection by quantitative HCV RNA assays. The
mean HCV RNA level for the eight individuals tested by the bDNA assay
was 9.6 × 106 eq/mL (range, 0.28 to 40.5 × 106 eq/mL). The individual tested by quantitative PCR had a
level of 3.9 × 106 eq/mL, which is roughly equivalent
to a fourfold higher value of 15.6 × 106 eq/mL by the
bDNA test.41 When the adjusted value was included, the
overall mean for the nine patients was 10.3 × 106
eq/mL. None of the nine patients were receiving interferon- when the HCV RNA tests were performed. Four were treated
before the testing, but all had been off therapy for a minimum of
2 years. Six anti-HCV negative leukemia patients from the study
group were randomly selected to have HCV testing using PCR. All six
were HCV negative by PCR.
Liver histology in anti-HCV positive leukemia patients.
Six (67%) of nine anti-HCV positive patients had liver biopsies
performed after a mean of 9 years (range, 4 to 16 years) from the
estimated date of infection (Table 2). The mean Knodell score was 8.7 (range, 5 to 13). Two (33%) of the six showed moderate to marked
piecemeal necrosis. One (17%) showed moderate intralobular inflammation/necrosis. All six showed at least a moderate degree of
portal inflammation and half showed evidence of bridging fibrosis. One
showed severe fibrosis consistent with cirrhosis. The patient with the
highest Knodell score had the highest viral load, and two of the three
patients with scores of 10 or greater had viral loads greater than 10.0 × 106 eq/mL.
Characteristics of the anti-HCV positive patients with hemophilia.
The 20 hemophiliacs chosen at random for the control group had a mean
age of 30.7 ± 18.2 years with a range of 10 to 65 years. These
individuals had an estimated mean duration of infection of 17.8 ± 6.5 years with a range of 9 to 28 years. Twelve (60%) had mild to
moderately elevated transaminases. All had normal bilirubin and albumin
levels, and none showed clinical evidence of liver disease at the time
of study. One subsequently developed signs of portal hypertension with
splenomegaly and mild thrombocytopenia. Twelve (60%) including 10 with
elevated transaminases had detectable HCV RNA by the bDNA assay. The
mean level of viremia for those 12 patients was 5.3 × 106 eq/mL (range, 0.5 to 15.5 × 106
eq/mL). Eight hemophiliacs were HCV RNA negative by the bDNA assay. Six
of the eight were also negative when tested by the more sensitive
qualitative PCR assay. Overall, the mean HCV RNA level for the 20 controls was 3.2 × 106 eq/mL.
Comparison of HCV RNA levels in leukemia patients and hemophilia
controls.
Mean HCV RNA levels were 10.3 × 106 eq/mL in the
leukemia patients compared with 3.2 × 106 eq/mL in
the hemophilia controls (P = .056). HCV RNA levels were above
the detectable limit of 0.2 × 106 eq/mL in all nine
leukemia patients compared with only 12 of 20 hemophilia
controls (P = .067).
Furthermore, values above 20.0 × 106 eq/mL were found
only in the leukemia group. The estimated duration of infection was 9.0 ± 4.4 years in the leukemia group compared with 17.8 ± 6.5 years in the control group (P = .001). The mean age of the two
groups was comparable, although the range was broader for the controls.
| |
DISCUSSION |
The 12% prevalence of anti-HCV seropositivity in this group of
leukemia patients who achieved a complete remission after chemotherapy or BMT is in the range reported by others.3-7,15-20 The
10.3% prevalence in children and the 11.8% seropositivity rate among
allogeneic BMT recipients are also within the reported ranges, which
vary widely depending on the year of exposure, the number of
transfusions, and geographic considerations.8-20 No further
cases of anti-HCV positivity were found after second generation testing
of blood donors was used in 1992. These results are similar to previous reports3,14 and are consistent with the current estimated risk of HCV infection via transfusion of 1 in 103,000 donor exposures reported by Schreiber et al42 using the second generation
ELISA test to screen for anti-HCV.
Although 78% of our anti-HCV positive patients had elevated serum
alanine transferases, none showed clinical evidence of hepatic decompensation after a mean of 9 years from the estimated date of
infection. This relatively benign course in HCV positive leukemia survivors through the first decade of chronic infection is in agreement
with previous reports.16,20 Cesaro et al16
found little evidence of progression to liver failure in survivors of pediatric malignancies, of whom 63% had leukemia or lymphoma, after a
mean of 14 years. They observed HAI scores between 2 and 7, and
inactive cirrhosis and severe fibrosis in only 1 of 37 (2.7%) anti-HCV
positive patients. Locasciulli et al20 reported similar
findings in survivors of childhood leukemia 13 to 27 years (mean, 17 years) after chemotherapy withdrawal. The latter study did not include
any histologic data.
Two large studies by Kiyosawa et al43 and Tong
et al44 have focused on the pathologic evolution of
hepatitis C-related liver disease in transfusion recipients. These
studies showed progression to chronic hepatitis to cirrhosis to
hepatocellular carcinoma after a mean duration of HCV infection of
approximately 1, 2, and 3 decades, respectively. In another study, Yano
et al45 showed that those with severe inflammation or
fibrosis usually developed cirrhosis within 10 years. Our data show
that all six patients who were biopsied showed moderate to severe
hepatic inflammation and half had either severe fibrosis or cirrhosis
after a mean of less than one decade of infection. Although these
results must be interpreted with caution because of the small sample
size, this finding suggests that leukemia survivors with chronic HCV may have more rapidly progressive liver disease than has been previously recognized.
The pathogenesis of liver cell damage by HCV is not well understood.
However, evidence is emerging that both host cytotoxic T-lymphocyte
responses and direct viral injury play a role. Reports that patients
with high HCV RNA viral loads have more severe liver disease46-48 and that HCV runs a more aggressive course in
patients with immune deficiency lend support to the direct
hepatocellular toxic effect of the virus. However, HCV-specific CD8 and
CD4 lymphocyte responses have been shown in the liver of individuals
with HCV infection.49-53 Furthermore, in one study, those
with intrahepatic HCV-specific CD8 activity had lower levels of viremia
and more active liver disease than those without CD8
activity.52 This suggests that the level of CD8 response
might be responsible for much of the ongoing hepatocellular injury, and
that the balance between viral and host factors may be an important
determinant of hepatocellular injury. In patients with leukemia, the
disease process, chemotherapy, and BMT all affect cell-mediated and
humoral immunity, which may contribute to the pathogenesis of liver
disease. The immunocompromised status at the time of infection may also play a role, while chemotherapy-induced hepatotoxicity may accelerate the inflammatory and fibrotic hepatic changes.
Previous reports have paid much attention to the natural history of
hepatitis C, as well as the many factors associated with disease
progression including alcohol, male sex, older age at the time of
infection, and longer duration of infection. However, little attention
has been given to immunosuppression and its role in progression of
HCV-related liver disease. After a mean follow-up of 18 years after
transfusion-associated HCV infection, Seeff et al37 found
that there was no increase in overall mortality and only modest
increases in morbidity and deaths related to liver disease in the
infected group when compared with noninfected controls. After 20 years
of follow-up, approximately 10% of the infected group showed evidence
of cirrhosis.54 Conversely, numerous studies involving HIV
and HCV coinfected patients and two studies regarding patients with
primary hypogammaglobulinemia and HCV35,36 have clearly
shown more rapidly progressive HCV-related liver disease among those
with immunodeficiency.29-36 In addition, several studies have demonstrated increased HCV RNA levels among HIV positive patients
when compared with their immunocompetent, HIV negative controls.21-26 In one study, which examined serial samples,
HCV RNA levels increased as immune deficiency progressed over
time.21
We found that the HCV viral loads of leukemia survivors were markedly
higher than a control group of HIV negative, immunocompetent, HCV
positive patients of approximately the same age. This finding is more
significant when one considers that the control group was infected for
twice as long as the study group. These results suggest that the
previously immunocompromised status of the leukemia survivors may have
promoted more rapid viral replication or impaired host viral clearance.
While none of our leukemia survivors have shown evidence of hepatic
decompensation at a mean of 9 years after HCV infection, our results
suggest that they may be at increased risk for more rapid disease
progression. If so, a more aggressive approach regarding the use of
antiviral therapy in the population of leukemia survivors with chronic
HCV may be warranted.
| |
ACKNOWLEDGMENT |
We thank Mary Catherine Hess, RN, Drs James O. Ballard, Hamid
Al-Mondhiry, W. Christopher Ehmann, Barbara Miller, L. Eamonn Boyle,
Richard Dixon, David Prager, Michael Marrone, and Terrance Cescom for
assistance with patient enrollment and data collection; Sara Neagley,
RN, Elisabeth Crago, RN, and Linda Landis for assistance with data
collection; Allen Kunselman, MA, for help with biostatistics; and Linda
Nelson for assistance with preparing the manuscript.
| |
FOOTNOTES |
Submitted August 3, 1998; accepted January 29, 1999.
Supported in part by a medical student scholarship grant to I.P. from
the American Society of Hematology and by the Alice Livingston Trout
and Dorothy Rider Pool Trust Funds.
The publication costs of this
article were defrayed in part by
page charge payment. This article
must therefore be hereby marked
"advertisement"
in accordance with 18 U.S.C. section
1734 solely to indicate this fact.
Address reprint requests to M. Elaine Eyster, MD, Division of
Hematology/Oncology HO46, Department of Medicine, Pennsylvania State
University College of Medicine, PO Box 850, Hershey, PA 17033.
| |
REFERENCES |
1.
Hetherington ML, Buchanan GR:
Elevated serum transaminase values during therapy for acute lymphoblastic leukemia correlated with prior blood transfusions.
Cancer
62:1614, 1988[Medline]
[Order article via Infotrieve]
2.
Barrera JM, Bruguera M, Ercilla G, Sanchez-Tapias JM, Gil MP, Gil C, Costa J, Gelabert A, Rodes J, Castillo R:
Incidence of non-A non B hepatitis after screening blood donors for antibodies to hepatitis C virus and surrogate markers.
Ann Intern Med
115:596, 1991
3.
Lopez-Jiminez J, Cancelas JA, Garcia-Larana J, Sastre JL, Cervero C, Zamora C, Megido M, Hernandez-Jodra M, Lasa E, Perez-Oteyza J, Ramos P, Odriozola J, Navrro JL:
Posttransfusion hepatitis after induction chemotherapy in acute nonlymphoblastic leukemia: Implications for long-term management and outcome.
Transfusion
35:313, 1995[Medline]
[Order article via Infotrieve]
4.
Murphy MF, Waters AH, Grint PCA, Hardiman AE, Lister TA:
Hepatitis C infection in multitransfused patients with acute leukaemia.
Lancet
335:58, 1990[Medline]
[Order article via Infotrieve]
5.
Neilson JR, Harrison P, Skidmore SJ, King JA, Collingham KE, Milligan DW:
Chronic hepatitis C in long term survivors of haematological malignancy treated in a single center.
J Clin Pathol
49:230, 1996[Abstract/Free Full Text]
6.
Kolho E, Oksanen K, Honkanen E, Naukkarinen R, Krusius T:
Hepatitis C antibodies in dialysis patients and patients with leukemia.
J Med Virol
40:318, 1993[Medline]
[Order article via Infotrieve]
7.
Fujii Y, Kaku K, Tanaka M, Yosiaki M, Kaneko T, Matumoto N:
Hepatitis C virus infection in patients with leukemia.
Am J Hematol
46:278, 1994[Medline]
[Order article via Infotrieve]
8.
Ljundman P, Johansson N, Aschan J, Glaumann H, Lonnqvist B, Ringden O, Sparrelid E, Sonneborg A, Winiarski J, Gahrton G:
Long-term effects of hepatitis C virus infection in allogenic bone marrow transplant recipients.
Blood
86:1614, 1995[Abstract/Free Full Text]
9.
Jackson SR, Carter JM, Jackson TW, Green GJ, Hawkins TE, Romeril K:
Hepatitis C seroprevalence in bone marrow transplant recipients and hemophiliacs.
N Z Med J
107:10, 1994[Medline]
[Order article via Infotrieve]
10.
Fujii Y, Kaku K, Tanaka M, Kaneko T, Matumoto N, Shinohara K:
Hepatitis C virus infection and liver disease after allogenic bone marrow transplantation.
Bone Marrow Transplant
13:523, 1994[Medline]
[Order article via Infotrieve]
11.
Kolho E, Ruutu P, Ruutu T:
Hepatitis C infection in BMT patients.
Bone Marrow Transplant
11:119, 1993[Medline]
[Order article via Infotrieve]
12.
Locasciulli A, Bacigalupo A, Vanlint MT, Tagger A, Uderzo C, Portmann B, Shulman HM, Alberti A:
Hepatitis C virus infection in patients undergoing allogeneic bone marrow transplantation.
Transplantation
52:315, 1991[Medline]
[Order article via Infotrieve]
13.
Norol F, Roche B, Girardin MSM, Kuentz M, Desforges L, Cordonnier C, Duedari N, Vernant J:
Hepatitis C virus infection and allogeneic bone marrow transplantation.
Transplantation
57:393, 1994[Medline]
[Order article via Infotrieve]
14.
Tada K, Tajiri H, Kozaiwa K, Sawada A, Guo W, Okada S:
Role of screening for hepatitis C virus in children with malignant disease who undergo bone marrow transplantation.
Transfusion
37:641, 1997[Medline]
[Order article via Infotrieve]
15.
Myers B, Irving W, Hollingsworth R, Readett D, Lilleyman JS, Dolan G:
Hepatitis C virus infection in multi-transfused children with haematological malignancy.
Br J Haematol
91:480, 1995[Medline]
[Order article via Infotrieve]
16.
Cesaro S, Petris MG, Rossetti F, Cusinato R, Pipan C, Guido M, Masiero L, Botta GA, Meloni GA, Zanesco L:
Chronic hepatitis C virus infection after treatment for pediatric malignancy.
Blood
90:1315, 1997[Abstract/Free Full Text]
17.
Fink EM, Hocker-Schultz S, Mohr W, Puchhammer-Stockl E, Hoffmann H, Zoubek A, Pawlowsky J, Hocker P, Gardner H:
Association of hepatitis C infection with chronic liver disease in pediatric cancer patients.
Eur J Pediatr
152:490, 1993[Medline]
[Order article via Infotrieve]
18.
Arico M, Maggiore G, Silini E, Bono F, Vigano C, Cerino A, Mondelli MU:
Hepatitis C virus infection in children treated for acute lymphoblastic leukemia.
Blood
84:2919, 1994[Abstract/Free Full Text]
19.
Dibenedetto SP, Ragusa R, Sciacca A, Di Catuldo A, Miraglia V, D'Amico S, Lo Nigro L, Ippolito AM:
Incidence and morbidity of infection by hepatitis C virus in children with acute lymphoblastic leukaemia.
Eur J Pediatr
153:271, 1995
20.
Locasciulli A, Testa M, Pontisso P, Benvegnu L, Fraschini D, Corbetta A, Noventa F, Masera G, Alberti A:
Prevalence and natural history of hepatitis C infection in patients cured of childhood leukemia.
Blood
90:4628, 1997[Abstract/Free Full Text]
21.
Eyster ME, Fried M, Di Bisceglie A, Goedert JJ:
Increasing HCV RNA levels in hemophiliacs: Relationship to HIV infection and liver disease.
Blood
84:1020, 1994[Abstract/Free Full Text]
22.
Thomas DL, Shih JW, Alter HJ, Vlahov D, Cohn S, Hoover DR, Cheung L, Nelson KE:
Effect of human immunodeficiency virus on hepatitis C virus infection among injecting drug users.
J Infect Dis
174:690, 1996[Medline]
[Order article via Infotrieve]
23.
Sherman KE, O'Brien J, Gufierrez AG, Harrison S, Urdea M, Neuwald P, Wilber J:
Quantitative evaluation of hepatitis C virus RNA in patients with concurrent human immunodeficiency virus infections.
J Clin Microbiol
31:2679, 1993[Abstract/Free Full Text]
24.
Telfer PT, Brown D, Devereux H, Lee CA, DuSheiko GM:
HCV RNA levels and HIV infection: Evidence for a viral interaction in haemophilic patients.
Br J Haematol
88:397, 1994[Medline]
[Order article via Infotrieve]
25.
Picchio GR, Nakatsuno M, Boggiano C, Sabbe R, Corti M, Daruich J, Perez-Bianco R, Tezanos-Pinto M, Kokka R, Wilber J, Mosier D:
Hepatitis C (HCV) genotype and viral titer distribution among Argentinean hemophilic patients in the presence or absence of human immunodeficiency virus (HIV) co-infection.
J Med Virol
52:219, 1997[Medline]
[Order article via Infotrieve]
26.
Cribier B, Rey D, Schmitt C, Lang JM, Kirn A, Stoll-Keller F:
High hepatitis C viraemia and impaired antibody response in patients coinfected with HIV.
AIDS
9:1131, 1995[Medline]
[Order article via Infotrieve]
27.
Ghany MG, Leissinger C, Lagier R, Sanchez-Pescador R, Lok ASF:
Effect of human immunodeficiency virus infection on hepatitis C virus infection in hemophiliacs.
Dig Dis Sci
41:1265, 1996[Medline]
[Order article via Infotrieve]
28.
Soto B, Sanchez-Quijano A, Rodrigo L, del Olmo JA, Garcia-Bengoechea M, Hernandez-Quero J, Rey C, Abad MA, Rodriguez M, Sales Gilahert M, Gonzalez F, Miron P, Caruz A, Relimpio F, Torronteras R, Leal M, Lissen E:
Human immunodeficiency virus infection modifies the natural history of chronic parenterally-acquired hepatitis C with an unusually rapid progression to cirrhosis.
J Hepatol
26:1, 1997
29.
Eyster ME, Diamondstone LS, Lien JM, Ehmann WC, Quan S, Goedert JJ:
Natural history of hepatitis C virus infection in multitransfused hemophiliacs: Effect of coinfection with human immunodeficiency virus.
J Acquir Immune Defic Syndr
6:602, 1993
30.
Martin P, Di Bisceglie AM, Kassianides C, Lisker-Melman M, Hoofnagle JH:
Rapidly progressive non-A, non-B hepatitis in patients with human immunodeficiency virus infection.
Gastroenterology
97:1559, 1989[Medline]
[Order article via Infotrieve]
31.
Telfer P, Sabin C, Devereux H, Scott F, Dusheiko G, Lee C:
The progression of HCV-associated liver disease in a cohort of haemophilic patients.
Br J Haematol
87:555, 1994[Medline]
[Order article via Infotrieve]
32.
Hanley JP, Jarvis LM, Andrews J, Dennis R, Lee R, Simmonds P, Piris J, Hayes P, Ludlam CA:
Investigation of chronic hepatitis C infection in individuals with haemophilia: Assessment of invasive and non-invasive methods.
Br J Haematol
94:159, 1996[Medline]
[Order article via Infotrieve]
33.
Makris M, Preston FE, Rosendaal FR, Underwood JCE, Rice KM, Triger DR:
The natural history of chronic hepatitis C in haemophiliacs.
Br J Haematol
94:746, 1996[Medline]
[Order article via Infotrieve]
34.
Sanchez-Quijano A, Andreu J, Gavilan F, Luque F, Abad MA, Soto B, Munoz J, Aznar JM, Leal M, Lissen E:
Influence of human immunodeficiency virus type 1 infection on the natural course of chronic parenterally acquired hepatitis C.
Eur J Clin Microbiol Infect Dis
14:949, 1995[Medline]
[Order article via Infotrieve]
35.
Bjoro K, Froland SS, Yun Z, Samdal H, Haaland T:
Hepatitis C infection in patients with primary hypogammaglobulinemia after treatment with contaminated immune globulin.
N Engl J Med
331:1607, 1994[Abstract/Free Full Text]
36.
Rossi G, Tucci A, Cariani E, Ravagii A, Rossini A, Radaeli E:
Outbreak of hepatitis C virus infection in patients with hematologic disorders treated with intravenous immunoglobulins: Different prognosis according to the immune status.
Blood
90:1309, 1997[Abstract/Free Full Text]
37.
Seeff L, Buskell-Bales Z, Wright E, Durako SJ, Alter HJ, Iber FL, Hollinger B, Gitnick G, Knodell RG, Stevens CE, Hollingsworth CG:
Long term mortality after transfusion-associated non-A, non-B hepatitis.
N Engl J Med
327:1906, 1992[Abstract]
38.
Fletcher ML, Trowell JM, Craske J, Parier K, Rizza CR:
Non-A, non-B hepatitis after transfusion of factor VIII in infrequently treated patients.
Br Med J Clin Res Ed
287:1754, 1983
39.
Kernoff PB, Lee CA, Karayiannis P, Thomas HC:
High risk of non-A, non-B hepatitis after a first exposure to volunteer or commercial clotting factor concentrates: Effects of prophylactic immune serum globulin.
Br J Haematol
60:469, 1985[Medline]
[Order article via Infotrieve]
40.
Knodell RG, Ishak KG, Black WC, Chen TS, Craig R, Kaplowitz N, Kiernan TW, Wollman J:
Formulation and application of a numerical scoring system for assessing histological activity in asymptomatic chronic active hepatitis.
Hepatology
1:431, 1981[Medline]
[Order article via Infotrieve]
41.
Hawkins A, Davidson F, Simmonds P:
Comparison of plasma virus loads among individuals infected with hepatitis C virus (HCV) genotypes 1, 2, and 3 by quantiplex HCV RNA assay versions 1 and 2, roche monitor assay, and an in-house limiting dilution method.
J Clin Microbiol
35:187, 1997[Abstract]
42.
Schreiber GB, Busch MP, Kleinman SH, Korelitz JJ:
The risk of transfusion-transmitted viral infections.
N Engl J Med
334:1685, 1996[Abstract/Free Full Text]
43.
Kiyosawa K, Sodeyama T, Tanaka E, Gibo Y, Yoshizawa K, Nakano Y, Furuta S, Akahane Y, Nishioka K, Purcell RH, Alter HJ:
Interrelationship of blood transfusion, non-A, non-B hepatitis and hepatocellular carcinoma: Analysis by detection of antibody to hepatitis C virus.
Hepatology
12:671, 1990[Medline]
[Order article via Infotrieve]
44.
Tong MJ, El-Farra NS, Reikes AR, Co RL:
Clinical outcomes after transfusion-associated hepatitis C.
N Engl J Med
332:1463, 1995[Abstract/Free Full Text]
45.
Yano M, Kumada H, Kage M, Ikeda K, Shimamatsu K, Inoue O, Hashimoto E, Lelkowitch JH, Ludwig J, Okuda K:
The long term pathological evolution of chronic hepatitis C.
Hepatology
23:1334, 1996[Medline]
[Order article via Infotrieve]
46.
Gordon SC, Kodali VP, Silverman AL, Dmuchowski CR, Urdea MS, Chan CS, Wilber JC:
Levels of hepatitis C virus RNA and liver histology in chronic type C hepatitis.
Am J Gastroenterol
89:1458, 1994[Medline]
[Order article via Infotrieve]
47.
Gretch D, Corey L, Wilson J, dela Rosa C, Willson R, Carithers R, Busch M, Hart J, Sayers M, Han J:
Assessment of hepatitis C virus RNA levels by quantitative competitive RNA polymerase chain reaction: High-titer viremia correlates with advanced stage of disease.
J Infect Dis
169:1219, 1994[Medline]
[Order article via Infotrieve]
48.
Naito M, Hayashi N, Hagiwara H, Hiramatsu N, Kasahara A, Fusamoto H, Kamada T:
Serum hepatitis C virus RNA quantity and histological features of hepatitis C virus carriers with persistently normal ALT levels.
Hepatology
19:871, 1994[Medline]
[Order article via Infotrieve]
49.
Koziel MJ, Dudley D, Wong JT, Dienstag J, Houghton M, Ralston R, Walker BD:
Intrahepatic cytotoxic T lymphocytes specific for hepatitis C virus in persons with chronic hepatitis.
J Immunol
149:3339, 1992[Abstract]
50.
Minutello MA, Pileri P, Unutmaz D, Censini S, Kuo G, Houghton M, Brunetto M, Bonino F, Abrignani S:
Compartmentalization of T lymphocytes to the site of disease: Intrahepatic CD4+ T cells for the protein N54 of hepatitis C virus in patients with chronic hepatitis C.
J Exp Med
178:17, 1993[Abstract/Free Full Text]
51.
Hiroshi K, Kita H, Kojima M, Okamoto H, Monyama T, Kaneko T, Ishikawa T, Onishi S, Aikawa T, Tanaka N, Yazaki Y, Mitamura K, Imawari M:
Cytotoxic T lymphocyte response and viral load in hepatitis C virus infection.
Hepatology
25:705, 1997[Medline]
[Order article via Infotrieve]
52.
Nelson DR, Marousis CG, Davis GL, Rice CM, Wong J, Houghton M, Lau JY:
The role of hepatitis C virus-specific cytotoxic T lymphocytes in chronic hepatitis C.
J Immunol
158:1473, 1997[Abstract]
53.
Thiele DL:
Commentary: Liver injury associated with hepatitis C infection: Is it the virus or is it the host?
Hepatology
26:238, 1997[Medline]
[Order article via Infotrieve]
54.
Seeff LB, and the NHLBI Study Group:
Mortality and morbidity of transfusion associated non-A, non-B (NANB) and type C hepatitis: An NHLBI multi-center study.
Hepatology
20:204a, 1994 (abstr)
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