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CLINICAL OBSERVATIONS, INTERVENTIONS, AND THERAPEUTIC TRIALS
From the Division of Cancer Epidemiology and
Genetics, National Cancer Institute, Rockville, MD; Milton S. Hershey
Medical Center, Pennsylvania State University School of Medicine; Case
Western Reserve University School of Medicine, Cleveland, OH;
Hemophilia Center, Second Regional Blood Transfusion Center, Laikon
General Hospital, Athens, Greece; Hôpital Cantonal Universitaire,
Geneva, Switzerland; Comprehensive Hemophilia Center, University of
North Carolina, Chapel Hill; Department of Hematology, Children's
Hospital National Medical Center, Washington, DC; Division of Digestive
Diseases, University of Cincinnati Medical Center, OH; Mountain States
Regional Hemophilia and Thrombosis Program, University of Colorado,
Aurora; Research Triangle Institute, Rockville, MD; Section of
Hematology/Oncology, Tulane University Medical School, New Orleans, LA;
Lombardi Cancer Research Center, Georgetown University Hospital,
Washington, DC; Department of Hematology, Children's Hospital of
Philadelphia, PA; Hemophilia Treatment Center, New York Presbyterian
Hospital, NY; Hemophilia Center, Mount Sinai Medical Center, New York,
NY; and National Retrovirus Reference Center, Athens University School
of Medicine, Athens, Greece. Other collaborators and institutions of
the Multicenter Hemophilia Cohort Study are listed in the Appendix at
the end of this article.
Many persons with hemophilia were infected with hepatitis C
and B viruses (HCV, HBV) and HIV, but the consequences of these transfusion-acquired infections are poorly defined. We estimated the
risk of HCV-related end-stage liver disease (ESLD) and the associations
of age, HBV, and HIV with that risk. All 1816 HCV-seropositive hemophilic patients at 16 centers were followed for up to 16 years. Of
these, 624 were HIV Hepatitis C virus (HCV), a single-stranded RNA
virus of the Flaviviridae family, was discovered in 1989 and
subsequently shown to account for most cases of non-A, non-B
posttransfusion hepatitis.1,2 Approximately 80% of
patients with acute disease develop persistent HCV infection,
manifested as detectable viremia.3 With chronic hepatitis
C for 20 years, up to 20% develop cirrhosis.4,5 Once
cirrhosis is established, hepatocellular carcinoma develops at a rate
of 1% to 4% per year.6-8
Most persons with hemophilia acquired HCV infection from intravenous
infusions of contaminated clotting factor concentrates that were widely
available from the early 1970s to the mid 1980s.9-13 HCV
seroprevalence rates approach 100% among those who received frequent
infusions of plasma-derived factor VIII or factor IX concentrates.
Virally inactivated concentrates were phased in during the mid 1980s
and completely by 1987. Between 1978 and 1986, two thirds of the
HCV-infected patients in the United States were also infected with
HIV.10-12
Thus, the likelihood of liver disease is high among persons with
hemophilia. Liver biopsies, however, are not performed routinely, because of the risk of hemorrhage and the expense of prophylaxis with
large doses of clotting factors. More than 15 years ago, of 115 hemophiliacs who underwent liver biopsy for clinical indications, 18 (16%) were found to have cirrhosis and an additional 10 (9%) had
severe chronic active hepatitis.14 Now, supported by liver histology in nonhemophilic coinfected patients,15
hemophilic patients who are coinfected with HCV and HIV are developing
a clinical picture of end-stage liver disease (ESLD) manifested by
persistent ascites, bleeding esophageal varices, or hepatic encephalopathy.11,16-19 Because the natural history of
HCV/HIV coinfection is still uncertain, we sought to quantify the
effects of immunodeficiency, age, and hepatitis B virus (HBV) on ESLD among participants in the Multicenter Hemophilia Cohort Study (MHCS)
using data collected before the widespread use of highly active
antiretroviral therapy.
Study design and participants
Laboratory methods
Outcome measure ESLD was defined as persistent ascites (n = 97), bleeding esophageal varices (n = 33), hepatic encephalopathy (n = 33), or death (n = 85) excluding nonhepatic causes; 2 or more of these conditions were recorded for 118 of the 137 ESLD cases.Statistical methods The annual hazard rate and cumulative incidence of developing ESLD and of having a nonhepatic death were estimated with follow-up starting from the median MHCS HIV seroconversion date (May 29, 1982) or the participant's birth date, if later. For those with HIV, starting follow-up on May 29, 1982, versus on each individual's HIV seroconversion date (imputed by statistical modeling of HIV antibody results on stored sera, type and severity of coagulopathy, and geography21), yielded essentially identical results (data not presented).Smoothed annual cause-specific hazard rates were estimated using spline functions.22 The cumulative incidence rates of ESLD and nonhepatic death were estimated using competing risk survival methods.23 Cause-specific hazard rates measure the annual incidence of a condition (ESLD or nonhepatic death) among persons who are still susceptible. The units in this analysis are cases per 100 person years (py). By definition, anyone who is susceptible as of a given time did not have the condition of interest or the competing condition up to that time. In contrast, the cumulative incidence of a condition at a given year (year 16 of follow-up) is the probability that that condition has occurred at any time up to the given year despite the competing risk. Cumulative incidence measures the net impact of a specific condition in a specific population at risk for other conditions. Gray's method24 was used to test for heterogeneity in the cumulative incidence curves by HIV status, HBV status, age, and CD4+ and CD8+ lymphocyte counts closest to the start of follow-up. Proportional hazards modeling (PHREG procedure, SAS Institute, Cary, NC) was used to estimate the relative hazard (and 95% confidence interval [CI]) of ESLD by forced entry of age and other variables; late entry at the date of the CD4+ count (median of 5.5 years [IQR, 4.2-7.0 years] after HIV seroconversion) was used for models including this variable. Data were censored at the date of last follow-up (median July 10, 1994, IQR March 12, 1991-October 20, 1997) and no later than May 28, 1998 (16 years of follow-up).
Patient characteristics and viral prevalence Typical of the hemophilia population, most of the 2056 MHCS participants were male, white, and had hemophilia A with or without an inhibitor (anti-factor VIII antibody), especially those with HIV infection (Table 1). Overall, 1194 (58%) were seropositive for HCV and HIV ("coinfected"), 624 (30%) were seropositive for HCV but not HIV, 20 (1%) were seropositive for HIV but not HCV, and 218 (11%) were negative for both viruses. Of the 1194 HCV/HIV-coinfected participants, 104 (9%) had chronic HBV surface antigenemia, 987 (83%) had resolved HBV infection, and 91 (8%) were HBV-uninfected (Table 1). Of the 624 with HCV but not HIV, 31 (5%) had chronic HBV surface antigenemia, 389 (62%) had resolved HBV infection, and 196 (31%) were HBV-uninfected. Fewer of the HCV/HIV-coinfected participants had hemophilia B or mild coagulopathy (8% and 10%) than did the participants with HCV but not HIV (20% and 26%, respectively; Table 1).
Annual hazard and cumulative incidence of ESLD with HCV, by age and HIV and HBV status During a median follow-up of 12.1 years, 137 HCV+ participants developed ESLD, including 10 (1.6%) of the 624 HIV participants and 127 (10.6%) of the 1194 HIV-positive participants. The ESLD cases included 2 with
hepatocellular carcinoma (1 confirmed, 1 suspected). Median ages at the
starting date were 28 years (IQR 19-36 years) for the HIV+
ESLD cases and 40.5 years (IQR 29-51 years) for the HIV
ESLD cases, which were substantially older than their respective cohorts (median ages 21 and 18 years, respectively; Table 1). Two of
the HIV+ ESLD cases occurred prior to the starting date and
were excluded, leaving 1192 HIV+ participants for
prospective analysis. Seventeen participants (14 HIV+, 3 HIV) were treated with interferon- before ESLD, as
were 14 participants (13 HIV+) who did not develop ESLD. No
participant had received ribavirin. Among HIV+
participants, 91 (73%) had received zidovudine before ESLD, as had 661 (62%) of those who did not develop ESLD. Other nucleoside reverse
transcriptase inhibitors and cotrimoxazole were used less often, and use of these medications did not readily distinguish ESLD
risk from preferential treatment of patients at highest risk for AIDS
(data not presented).25
As shown in Figure 1, the annual hazard
of ESLD among the 1192 HIV+ participants increased over
time to a rate of 4 per 100 py. The cumulative incidence of ESLD at
year 16 in this group was 14.0% (95% CI, 11.6%-16.4%). The annual
hazard of ESLD among the 624 HIV
The annual hazard rate of ESLD was very high and increased over time
for the oldest participants, as shown in Figure
2A for the HIV+ participants.
The cumulative incidence was 23.3% (95% CI, 17.2%-29.5%) among the
HIV+ participants who enrolled after age 32, compared with
9.7% to 15.9% in the middle-age quintiles and 5% in the youngest
quintile (Ptrend < .0001). Among the
HIV
By proportional hazards modeling (Table
2), ESLD risk was greatly increased with
HIV coinfection (relative hazard 7.9 [95% CI, 4.2-15.2]) and older
age (relative hazard 1.6 [95% CI, 1.0-2.5] for ages 17 to 32;
relative hazard 5.0 [95% CI, 3.2-7.9] after age 32). Risk
increased with older age in both HIV
With HIV coinfection, the annual hazard of ESLD increased over time for
participants with chronic HBV surface antigenemia or with resolved HBV
infection but not for the HBV Markers of ESLD with HCV and HIV coinfection Participants whose CD4+ lymphocyte counts obtained closest to enrollment were 0.2 × 109/L to 0.499 × 109/L (200-499/µL) and more than 0.5 × 109/L (500 × 109/L) had overlapping ESLD hazard rates (data not shown). Combining these 2 groups, ESLD hazard rates increased steadily during follow-up, especially for those with CD4+ lymphocyte counts below 0.2 × 109/L (200/µL) (Figure 2C). Although hazard rates differed between these 2 CD4 count groups, they both had an ESLD cumulative incidence rate of 13% (P = .76). CD8+ lymphocyte count was not associated with the rate of ESLD (P = .60, data not presented).Multivariate proportional hazards modeling was used to determine the
independent relationships of age, HBV status, and baseline CD4+ lymphocyte count to ESLD risk among coinfected
participants. In the final model (Table
3), ESLD risk was increased 1.04-fold (95% CI, 1.03-1.06) per year of age, 8.1-fold (95% CI, 1.9-35.2) with
chronic HBV, 3.4-fold (95% CI, 0.8-14.0) with resolved HBV, and
2.1-fold (95% CI, 1.3-3.3) with fewer than 0.2 × 109/L
(200/µL) CD4+ lymphocytes. With the same variables but
changing the HBV referent group, ESLD risk was 2.4-fold (95% CI,
1.50-3.94) higher with chronic compared with resolved HBV.
Fifty-eight percent of our participants were HCV/HIV-coinfected, and an additional 30% were infected with HCV without HIV. We used competing risk survival methods to estimate the instantaneous rate and the cumulative incidence, which is the net effect, of ESLD and nonhepatic deaths. Primarily because of AIDS, the coinfected participants had a high risk of nonhepatic death. Cumulative incidence rates of nonhepatic death and ESLD were 45.0% and 14.0%, respectively, with coinfection; and they were 6.2% and 2.6%, respectively, without HIV. Irrespective of HIV status, the risk of ESLD increased markedly with older age. For those with coinfection and over age 32, 23.3% developed ESLD during 16 years of follow-up. It is unknown whether this will apply to current patients whose HIV infection is treated with highly active antiretroviral therapy, because most of our participants received no specific therapy or only zidovudine during the first 14 years of follow-up.26,27 With age adjustment, ESLD risk for the coinfected participants was increased significantly by 2.4-fold with a CD4+ lymphocyte count below 0.2 × 109/L (200/µL) and 8-fold with chronic HBV infection. Their risk was increased nonsignificantly by 3.4-fold with resolved HBV infection. Two cross-sectional studies found increased prevalence rates of
resolved or occult HBV infection with cirrhosis or hepatocellular carcinoma,28,29 supporting the concept that HBV's
contribution to the risk of ESLD may be underestimated, especially with
subsequent or concurrent HCV infection. Our estimate of the
contribution of HBV is imprecise, because we had so few
HBV Our study had several limitations. First, because our population is predominantly white and almost entirely male, we could not study differences by race or sex. Second, because we could not accurately estimate the date of HCV infection for each participant, we could not corroborate the finding of Telfer et al that older age and duration of HCV infection were independently associated with an increased risk of ESLD.16 Third, we had limited data (not presented) on alcohol use. Reported alcohol use was directly correlated with age. However, because it was substantially less than the 50 g per day reported to increase liver fibrosis,30 alcohol use is unlikely to account for most of our observed associations with ESLD. Fourth, although we found no consistent association of ESLD with any particular medication (data not presented), our study was poorly suited to assess medication complications.25 The hepatotoxic potential of medications commonly used in the care of people with HIV and HCV should be investigated further. And, fifth, because routine liver biopsy is seldom performed in patients with hemophilia because of the risk of hemorrhage, we could not estimate the prevalence of compensated cirrhosis or less severe liver pathologies, much less their incidence. The prevalence is certain to be high; 20 years ago, liver biopsy of 115 hemophilic patients revealed that one quarter of the population had cirrhosis or severe chronic active hepatitis.14 In the current study, during 16 years of follow-up of participants with HCV but not HIV, we observed a 3% cumulative incidence of ESLD, similar to that seen among Irish women and U.S. veterans31,32 but lower than the cirrhosis rate reported in biopsy studies.30 The extraordinary incidence of ESLD among our HCV/HIV-coinfected participants corroborates the mortality experience of hemophilic men in the United Kingdom.18,19 These findings point to a profound effect of impaired immunity on the development of HCV-related ESLD. The mechanisms that underlie this relationship are not clear. In studies performed elsewhere, detection of intrahepatic cytotoxic T lymphocytes (CTLs) has been associated with severe liver pathology but relatively low HCV viral load.33-35 The CD4+ and CD8+ lymphocytes that we could measure in peripheral blood may not accurately reflect those that home to the liver. In summary, in a prospective study that is highly representative of the hemophilia population in the United States,36 88% were infected with HCV and two thirds of these were coinfected with HIV. With 16 years of active follow-up, ESLD developed in 14.0% of the coinfected participants compared with 2.6% of those with only HCV. With coinfection, ESLD incidence was substantially increased with older age, chronic HBV, or a low CD4+ lymphocyte count. These observations suggest that HCV-related ESLD is a major cause of morbidity and mortality among people also infected with and untreated for HIV and HBV.
The authors thank Susan Wilson, Syliva Cohn, Myhanh Dotrang, and Dr Frances Yellin for computer programming; Virginia Lamprecht for central coordination and training; the coordinators at each hemophilia center; and especially the participants and their families for contributing to the MHCS.
Submitted July 18, 2001; accepted April 16, 2002.
Supported in part by National Cancer Institute contract NO1-CP-33002 with Research Triangle Institute.
The publication costs of this article were defrayed in part by page charge payment. Therefore, and solely to indicate this fact, this article is hereby marked "advertisement" in accordance with 18 U.S.C. section 1734.
Reprints: J. J. Goedert, 6120 Executive Blvd, MSC 7248, Rockville, MD 20892; e-mail: goedertj{at}mail.nih.gov.
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Collaborating investigators (and institutions) in the MHCS are J. J. Goedert, T. R. O'Brien, P. S. Rosenberg, C. S. Rabkin, E. A. Engels, M. H. Gail, S. J. O'Brien, M. Dean, M. Carrington, M. Smith, C. Winkler (National Cancer Institute, Rockville and Frederick, MD); M. Elaine Eyster (Division of Hematology and Oncology, Pennsylvania State University Medical Center, Hershey); B. Konkle (Cardeza Foundation Hemophilia Center, Philadelphia, PA); M. Manco-Johnson (Mountain States Regional Hemophilia and Thrombosis Program, University of Colorado, Aurora); D. DiMichele, M. W. Hilgartner (Hemophilia Treatment Center, New York Presbyterian Hospital, NY); Philip Blatt (Christiana Hospital, Newark, DE); L. M. Aledort, S. Seremetes (Hemophilia Center, Mount Sinai Medical Center, New York, NY); K. Hoots (Gulf States Hemophilia Center, University of Texas at Houston); A. L. Angiolillo, N. L. C. Luban (Hemophilia Center, Children's Hospital National Medical Center, Washington, DC); A. Cohen, C. S. Manno (Hemophilia Center, Children's Hospital of Philadelphia, PA); C. Leissinger (Tulane University Medical School, New Orleans, LA); G. C. White II (Comprehensive Hemophilia Center, University of North Carolina, Chapel Hill); M. M. Lederman, S. Purvis, J. Salkowitz (Case Western Reserve University School of Medicine, Cleveland, OH); C. M. Kessler (Georgetown University Medical Center, Washington, DC); A. Karafoulidou, T. Mandalaki (Hemophilia Center, Second Regional Blood Transfusion Center, Laikon General Hospital, Athens, Greece); A. Hatzakis, G. Touloumi (National Retrovirus Reference Center, Athens University Medical School, Greece); W. Schramm, F. Rommel (Medizinische Klinik Innerstadt der Maximilian, Universitaet Muenchen, Munich, Germany); P. de Moerloose (Haemostasis Unit, Hôpital Cantonal Universitaire, Geneva, Switzerland); S. Eichinger (University of Vienna Medical School, Austria); K. E. Sherman (University of Cincinnati Medical Center, OH); D. Waters (Scientific Applications International, Frederick, MD); and V. Lamprecht, B. L. Kroner (Research Triangle Institute, Rockville, MD).
© 2002 by The American Society of Hematology.
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H. Qin, N. J. Shire, E. D. Keenan, S. D. Rouster, M. E. Eyster, J. J. Goedert, M. J. Koziel, K. E. Sherman, and and the Multicenter Hemophilia Cohort Study Group HCV quasispecies evolution: association with progression to end-stage liver disease in hemophiliacs infected with HCV or HCV/HIV Blood, January 15, 2005; 105(2): 533 - 541. [Abstract] [Full Text] [PDF]
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S. Castellino, S. Lensing, C. Riely, S. N. Rai, R. Davila, R. T. Hayden, J. Fleckenstein, M. Levstik, S. Taylor, P. J. Dean, et al. The epidemiology of chronic hepatitis C infection in survivors of childhood cancer: an update of the St Jude Children's Research Hospital hepatitis C seropositive cohort Blood, April 1, 2004; 103(7): 2460 - 2466. [Abstract] [Full Text] [PDF]
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E. Santagostino, M. Colombo, M. Rivi, M. G. Rumi, A. Rocino, S. Linari, and P. M. Mannucci A 6-month versus a 12-month surveillance for hepatocellular carcinoma in 559 hemophiliacs infected with the hepatitis C virus Blood, July 1, 2003; 102(1): 78 - 82. [Abstract] [Full Text] [PDF]
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Abstract
Introduction
]).
