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Incidence and Patterns of Hepatitis C Virus Seroconversion in aCohort of Hemodialysis Patients
Vana Sypsa, MSc, Mina Psichogiou, MD, PhD, Antigoni Katsoulidou, PhD,Gregory Skoutelis, PhD, Spiridon Moutafis, MD, Valsamakis Hadjiconstantinou, MD, PhD,
John Kakavas, PhD, Viktoria Kalapothaki, MD, PhD, John Boletis, MD,and Angelos Hatzakis, MD, PhD,
for the Multicentre Haemodialysis Cohort Study on Viral Hepatitis
Background: The aim of this multicenter hemodialysis (HD) cohort study is to prospectively investigate thencidence of hepatitis C virus (HCV) infection in Greece from 1993 to 1995 and delineate early virological anderological events associated with HCV seroconversion in the HD setting. Methods: Sequential serum samplesollected weekly from 562 patients were tested biochemically and serologically by means of a second- (EIA-2) andhird-generation enzyme immunoassay (EIA-3). All patients with positive antibody to HCV test results (anti-HCV�)nd sequential samples from seroconverting patients were tested for HCV RNA. Results: Anti-HCV prevalence attudy entry was 29% (163 of 562 patients), and viremia was detectable in 110 of 163 anti-HCV� patients (67.5%). HCVncidence was 6.2 cases/100 person-years. Seroconversions could not be attributed to transfusions after studyntry (only 1 patient had been administered transfusion), and HD unit was associated with increased hazard foreroconversion (P � 0.002), even after adjusting for potential differences among their patients. According toaplan-Meier estimation, the median interval by which the HCV RNA assay detected HCV infection earlier thannti-HCV testing was 246 and 154 days for EIA-2 and EIA-3, respectively. Detectable HCV RNA and at least 2onsecutive abnormal alanine aminotransferase levels in the preseroconversion period were observed in 29 of 3097%) and 14 of 32 patients (44%), respectively. Reductions in HCV RNA levels immediately after seroconversionere transient or did not occur. Conclusion: On the grounds of apparent nosocomial transmission, the wideindow period of HCV infection in HD patients emphasizes the need for strict adherence to specific infection-ontrol measures in this setting. Am J Kidney Dis 45:334-343.2004 by the National Kidney Foundation, Inc.
NDEX WORDS: Hepatitis C virus (HCV); HCV RNA; hemodialysis (HD); seroconversion patterns; window period;
osocomial transmission.cHc1r1B7Hfiay3wpEewfo
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EPATITIS C VIRUS (HCV) infection re-mains a major problem for hemodialysis
HD) patients despite recent improvement in the
From Athens University Medical School; Athinaiki Hospi-al; Kyanous Stavros Hospital; A. Fleming Hospital;ippokration General Hospital; and Laiko General Hospi-
al, Athens, Greece.Received May 18, 2004; accepted in revised form Septem-
er 29, 2004.Originally published online as doi:10.1053/j.ajkd.2004.09.021
n December 17, 2004.For the Multicentre Haemodialysis Cohort Study on Viral
epatitis. Investigators and institutions: A. Hatzakis, A.atsoulidou, M. Psichogiou, and E. Vaindirli (Athens Univer-
ity Medical School, Athens); J. Boletis and D. StamatiadisLaiko General Hospital, Athens); J. Kakavas and M. Kou-ousiou (Hippokration General Hospital, Athens); S.
outafis, K. Ifandi, and I. Thanou (Kyanous Stavros Clinic,thens); G. Skoutelis, K. Triandafilou, and M. Matzaropou-
ou (Athinaiki Clinic, Athens); and V. Hadjiconstantinou, D.rvanitis, and E. Logothetis (A. Fleming Hospital, Athens).Address reprint requests to Angelos Hatzakis, MD, PhD,
ssociate Professor, Department of Hygiene and Epidemiol-gy, Athens University Medical School, 75 Mikras Asias St,R-115 27 Athens, Greece. E-mail: [email protected]© 2004 by the National Kidney Foundation, Inc.0272-6386/04/4502-0013$30.00/0
bdoi:10.1053/j.ajkd.2004.09.021
American Journal of Kid34
ontrol of HCV transmission. The prevalence ofCV infection in these patients varies geographi-
ally and from year to year. Studies in the late980s to early 1990s reported prevalence estimatesanging from 14% to 30% in western Europe1-4;0% to 22% in the United States5-7; 17% to 45% inrazil, Japan, and Taiwan8-10; and greater than0% in Venezuela.11 Studies of the incidence ofCV in HD patients during the same period identi-ed rates of less than 1/100 person-years in Italynd the United States7,12,13; 1 to 3/100 person-ears in Belgium, France, and Japan1,4,10; and 15 to8/100 person-years in Brazil, Venezuela, and Tai-an.8,9,11 Studies in the late 1990s reported lowerrevalence estimates for the countries of westernurope, ranging from 3% to 16%,14-17 with thexception of Italy, where a high prevalence of 30%as reported.18 High prevalence estimates ranging
rom 31% to 75% also were observed in countriesf eastern Europe.17,19
Duration of HD therapy, previous kidney trans-lantation, and blood transfusion were consideredhe main risk factors for HCV infection in HDatients.1,2,5,14,15,20 The independent association
etween duration of HD therapy and HCV infec-ney Diseases, Vol 45, No 2 (February), 2005: pp 334-343
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HEPATITIS C VIRUS INFECTION IN HEMODIALYSIS 335
ion,5,9,20,21 lack of previous transfusions in serocon-erting patients,1,3,13,15,21 clustering of seroconver-ions in particular HD units,15,16,22-24 and greaterCV prevalence in patients undergoing HD com-ared with those undergoing peritoneal dialysis6,8
trongly suggest that nosocomial transmission ishe most potent risk factor within HD units. Severalechanisms have been proposed to be responsible
or the nosocomial transmission of HCV, but datare controversial.17
The present study aims to prospectively inves-igate the incidence and risk factors for newlycquired HCV infections and assess the earlyirological and serological events associated withCV seroconversion in the HD setting.
METHODS
D Units and PatientsFive HD units in Athens, Greece, participated in theulticentre HD Cohort Study on Viral Hepatitis. From
ebruary 1993 to May 1995, all patients on HD therapy inhese units entered the study. For purposes of analysis, onlyhose followed up for at least 1 month were considered. As aesult, 562 patients constituted our study sample.
None of these units isolated patients with antibodies toCV. However, when an outbreak occurred in 1 of thesenits (unit 5), all anti-HCV–positive (anti-HCV�) patientsere moved to 1 dialysis shift (by December 1993).
ata CollectionA baseline and a follow-up questionnaire were filled out
or every HD patient, with information on demographicharacteristics, cause of end-stage renal failure, history ofenal transplantation and transfusion, number of blood unitsransfused, history of elevated alanine aminotransferaseALT) levels (1 to 7 times the upper limit of normal),umber of times ALT levels were found to be elevated,istory of acute hepatitis (ALT �8 times the upper limit oformal), hepatomegaly, and splenomegaly.
lood Sample Collection: HCV Serological andirological TestsSerum samples were collected weekly for anti-HCV–
egative (anti-HCV�) patients and monthly for anti-HCV�
atients. Samples were tested for ALT level, and multipleerum aliquots from each bleed were frozen at �70°C. Onceach month, anti-HCV� patients were tested for anti-HCV byeans of second-generation enzyme immunoassay (EIA-2;bbott Laboratory, Wiesbaden, Germany). Samples from sero-
onverting patients were collected weekly for the first 2 monthsfter seroconversion. Later, representative samples from 189atients and most samples from anti-HCV–seroconverting pa-ients were tested by means of both EIA-2 and a third-eneration enzyme immunoassay (EIA-3; Ortho HCV 3.0 Testystem, Ortho Diagnostics System, Raritan, NJ), and all anti-
CV� samples were confirmed by means of a third-generation bmmunoblot assay (HCV 3.0 SIA; Chiron Corp, Emeryville,A).All initial samples from anti-HCV� patients and sequential
amples from seroconverting patients were tested for qualita-ive HCV RNA (Amplicor Hepatitis C Virus Test; Rocheiagnostic Systems, Branchburg, NJ). In seroconversion pan-
ls, HCV RNA load was determined longitudinally using theobas HCV-Monitor assay (Cobas Amplicor HCV Monitorest; Roche Molecular Systems Inc). HCV genotype was testedy means of INNOLiPA HCV (Innogenetics, NV, Zwijndrecht,elgium).
tatistical MethodsRelationships between HCV serostatus at baseline and
uestionnaire-derived variables were examined by means ofhi-square test, t-test, or Wilcoxon’s rank-sum test, as appro-riate. Multiple logistic regression was used to determineisk factors associated with HCV serostatus at baseline.
The Cox proportional hazards model was used to determineisk factors independently associated with increased hazard foreroconversion after study entry. The cumulative probability oferoconversion after the initiation of dialysis therapy was esti-ated by means of Kaplan-Meier.For evaluation of the window period, a Kaplan-Meier esti-ate was obtained. To account for HCV RNA positivity of
ome patients at study entry, an estimate of median number ofays that an HCV RNA–reactive result preceded anti-HCVetection was obtained as follows: seroconversion day wasonsidered time 0, and the Kaplan-Meier estimate of the prob-bility that a patient had his or her last HCV RNA–reactiveample after any time, looking backward from the seroconver-ion day, was calculated. Consequently, an HCV RNA–reactiveesult was defined to be an event if it was followed by aonreactive sample (looking backward from seroconversionay), whereas patients who were HCV RNA reactive at studyntry were considered censored. Similarly, a Kaplan-Meierstimate was obtained for evaluation of the time between therst abnormal ALT value and seroconversion.
RESULTS
aseline Characteristics
Patient baseline characteristics are listed in Table. Mean patient age at study entry was 57.2 � 14.3SD) years, and median time on dialysis therapyas 31.4 months (25th to 75th percentiles, 7.8 to2.6 months).
econd- and Third-Generation Enzymemmunoassay Results
Of 562 baseline samples, 189 randomly selectedamples were tested by means of both EIA-2 andIA-3. Seventy-nine samples were positive by bothIA-2 and EIA-3, and 101 patients had negative
esults on both assays. Nine patients had discordantesults; those for 8 patients were negative by EIA-2nd positive by EIA-3, and for 1 patient, positive
y EIA-2 and negative by EIA-3.
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nti-HCV, HCV RNA, and HCV Genotypeistribution at Study Entry
Anti-HCV was detected by means of EIA-2 in63 of 562 baseline specimens (29.0%; 95% confi-ence interval, 25.3 to 32.9). Anti-HCV prevalenceanged from 12.0% to 49.1% in the 5 HD units.IA-2 detected 90.8% of cases positive by EIA-3.ased on this, we would expect an anti-HCVrevalence by EIA-3 of 31.9%.
HCV RNA was detected in 110 of 163 anti-CV–seropositive patients (67.5%). HCV geno-
ype evaluation was attempted in all anti-HCV�/CV RNA� baseline specimens. HCV genotype
Table 1. Characteristics of 562 HD Patientsat Study Entry
ge (y) 57.2 � 14.3exM 324 (57.7)F 238 (42.3)ause of end-stage renal diseaseChronic glomerulonephritis 171 (30.4)Polycystic kidney disease 59 (10.5)Diabetic nephropathy 51 (9.1)Nephroangiosclerosis 29 (5.2)Pyelonephritis 28 (5.0)Nephrolithiasis 15 (2.7)Other 48 (8.5)Unknown 161 (28.6)uration of HD (mo) 31.4 (7.8–72.6)istory of renal transplantation 47 (10.1)istory of transfusion 264 (58.1)istory of acute hepatitis 24 (5.4)istory of elevated ALT level 83 (18.6)epatomegaly 36 (8.4)plenomegaly 15 (3.5)
NOTE. Values expressed as mean � SD, number (per-ent), or median (25th to 75th percentiles).
ould not be identified in 20 specimens (18.2%).CV-1 was the dominant genotype (n � 45;0.9%), followed by HCV-3 (n � 22; 20.0%),CV-4 (n � 20; 18.2%), and HCV-2 (n � 3;.7%). HCV genotype distribution at baseline byD unit is shown in Fig 1.ElevatedALT levels at study entry were detected
n only 22 of 104 anti-HCV� patients (21.2%) and4 of 399 anti-HCV� patients (6.0%).
isk Factors for Anti-HCV Positivity at Studyntry (Cross-Sectional Analysis)
Multivariate logistic regression analysis wassed to determine independent risk factors fornti-HCV positivity. Duration of dialysis therapy,D unit, history of transplantation, and historyf elevated ALT level proved to be the mostmportant prognostic factors for HCV infection.djusted odds ratios for patients who were onD therapy for 21 to 40 and longer than 40onths compared with those who were on HD
herapy for 20 months or less were 2.3 (P �.096) and 24.3 (P � 0.001), respectively. Pa-ients who had experienced ALT level elevationad a 7.4 times greater risk for being anti-HCV�
ompared with those who had not (P � 0.001).imilarly, patients with a history of transplanta-
ion had a 3.5 times greater risk for being anti-CV� relative to those without such a history
P � 0.011). Adjusted odds ratios for patientsttending different HD units compared with unitwere 18.6 for unit 2 (P � 0.001), 2.7 for unit 3
P � 0.206), 5.9 for unit 4 (P � 0.026), and 69.2or unit 5 (P � 0.001). There was no associationetween anti-HCV serostatus and having beendministered a transfusion or the number of
Fig 1. Distribution of HCVgenotypes at baseline andamong seroconvertors (SC)
during the follow-up periodby HD unit.
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HEPATITIS C VIRUS INFECTION IN HEMODIALYSIS 337
lood units administered during a patient’s life-ime (data not shown). No association was foundetween anti-HCV status and age, sex, or causef end-stage renal disease.
CV Incidence
Three hundred ninety-nine anti-HCV� pa-ients were followed up for a mean of 16.2 � 7.0SD) months (range, 2.0 to 27.4 months). Duringollow-up, 32 seroconversions to anti-HCV posi-ivity were observed. Hepatitis C incidence was.2 cases/100 person-years and ranged from 2.1o 12.1 cases/100 person-years in different HDnits. Incidence rates were 5.8 and 2.1 cases/100erson-years in the 2 units with a low prevalencef anti-HCV positivity (12.0% and 14.8%, respec-ively) and 3.9, 12.1, and 3.1 cases/100 person-ears in units with a high anti-HCV positivityrevalence (29.9%, 36.3%, and 49.1%, respec-ively; Table 2).
aplan-Meier Estimate of the Cumulativerobability of Seroconversion After HDherapy Initiation
Using information on the initiation of HDherapy for the 399 anti-HCV� patients anderoconversion dates for the 32 patients whoecame anti-HCV� during the follow-up period,t was possible to estimate the cumulative prob-bility of seroconversion at any time after HDherapy initiation (Fig 2). Ten percent of patientsre estimated to seroconvert during the first 5ears, and 20% are expected to seroconvert dur-ng the first 12 years after HD therapy initiation.sing data from units 1 to 4, during the first 10ears, 10% of patients are estimated to serocon-ert. However, when only data from unit 5 areonsidered, 10% of patients are estimated to
Table 2. Prevalence and Incidence
Unit N
Prevalence at Study Entry
Anti-HCV�
(%)95% Confidence
Interval
50 12.0 4.5-24.357 49.1 35.6-62.7
142 14.8 9.4-21.787 29.9 20.5-40.6
226 36.3 30.0-42.9verall 562 29.0 25.3-32.9
eroconvert during the first 2 years. t
CV Genotype Distributionmong Seroconvertors
HCV genotype was identified in 30 of 32eroconvertors. HCV-4 was the dominant sub-ype, detected in 11 patients (36.7%), followedy HCV-1 in 10 patients (33.3%) and HCV-3 in 9atients (30.0%). HCV genotype distributionmong seroconvertors by HD unit is shown inig 1. All seroconversions occurring in unit 1 (4f 4 patients) and 30% of those occurring in unit(6 of 20 patients) were genotype 4.
eroconversion Patterns by EIA-2 and EIA-3esults, ALT Levels, Anti-HCV Status, and HCVNA
In 30 of 32 seroconvertors, all collected serialamples were tested by means of both EIA-2 andIA-3. This allowed us to evaluate the quantita-
ive differential performance of the 2 assays. In7 patients (56.7%), reactivity was observed onhe same sample by means of EIA-2 and EIA-3.nterestingly, detection by EIA-2 was soonerhan by EIA-3 in 2 patients (6.7%; 7 and 9 days).
V Infection Overall and by HD Unit
Incidence
otal Persone at Risk (y) Seroconversions
Incidence rate(/100 person-years)
68.7 4 5.832.4 1 3.1
144.5 3 2.1104.0 4 3.9165.7 20 12.1515.2 32 6.2
of HC
TTim
Fig 2. Cumulative probability of seroconversion af-er initiation of HD therapy.
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n the remaining 11 patients (36.7%), detectiony EIA-3 was sooner than by EIA-2 by a medianf 92 days (25th to 75th percentiles, 63 to 133ays).Seroconversion patterns for representative pa-
ients are shown in Fig 3. We defined ALT levellevation as the occurrence of 2 consecutiveeasurements greater than 45 IU/L. In 6 of 32
eroconvertors (18.8%), there was no ALT levellevation throughout the follow-up period (be-ore and after anti-HCV seroconversion). Only4 of 26 patients (53.8%) had ALT level eleva-ion during preseroconversion (EIA-2) follow-p, and in 8 more patients, ALT level elevationoincided with EIA-2 seroconversion. Medianime from the first 2 consecutive abnormal ALTalues (�45 IU/L) until EIA-2 seroconversionas estimated to be 70 days (25th to 75th percen-
iles, 36 to 210 days), and until EIA-3 seroconver-ion, 49 days (25th to 75th percentiles, 27 to 119ays). Seroconversion occurred in the majorityf patients concomitantly with or after the appear-nce of maximum ALT values (Fig 3; patients08, 447, 371, 373, 347, and 408). However,ome patients presented a minor ALT level eleva-ion pattern (Fig 3; patients 344 and 399).
Patterns of HCV RNA levels among serocon-ertors were evaluated in 29 patients. Two pa-ients were excluded because they had an insuffi-ient number of samples for serial evaluation.etectable HCV RNA levels in the preserocon-ersion period were observed in 29 of 30 HDatients (97%). One patient always tested HCVNA� (in 18 consecutive samples obtained in 8onths). We estimated the number of days thatCV RNA preceded anti-HCV appearance in
eroconverting patients. Seventeen of 29 patientsere HCV RNA reactive at study entry. For theseatients, the true number of days that HCV RNAreceded anti-HCV appearance is higher than thebserved number of days. To account for this, aaplan-Meier estimate of median days that HCVNA preceded anti-HCV was obtained. Medianumbers of days that the HCV-RNA assay de-ected HCV infection earlier than anti-HCV test-ng was calculated to be 246 (25th to 75thercentiles, 91 to 350) and 154 (25th to 75thercentiles, 77 to 217) for EIA-2 and EIA-3,espectively (P � 0.063; Fig 4). Reductions inCV RNA levels after anti-HCV seroconversion
ere transient or were not observed. 0isk Factors for Anti-HCV (Prospectivenalysis)
A Cox proportional hazards model was used todentify risk factors independently associatedith an increased hazard for seroconversion
Table 3). HD unit and history of elevated ALTevel were associated with an increased hazardor seroconversion. Patients from unit 5 had a 9.5imes greater hazard for seroconversion relativeo patients from other HD units (P � 0.002).atients with a history of elevated ALT levelsad a 12 times greater hazard for seroconversionelative to those who did not have such a historyP � 0.001). Information on whether patientsere administered blood transfusions in the inter-al between study entry and seroconversionhowed that only 1 patient had been adminis-ered a blood transfusion (twice) in this period.
DISCUSSION
This multicenter prospective study conductedn the mid-1990s of a large cohort of patientsollowed up with serial samples clearly indicateshat factors other than blood transfusion prevails risk factors for HCV infection in HD units,nd new cases of HCV infection are still emerg-ng despite the reduction in number of transfu-ions and use of HCV-screened blood. Becausef the frequent collection of serum samples, thistudy represents a unique setting to assess HCVNA patterns in the anti-HCV preseroconver-
ion and postseroconversion periods.The study documents a high prevalence of
nti-HCV positivity of 29% in Greek HD pa-ients, which falls into the range of prevalencestimates reported by other studies in Europe inhe early 1990s.1-4 Prevalence varied markedlyn HD units, ranging from 12% to 49%. As alsobserved in other European countries,25,26 impor-ant changes occurred since that time in Greeceegarding HCV infection in the HD setting. Ac-ording to a postal survey performed in 2003 in19 HD units in Greece, the mean prevalence ofnti-HCV in HD patients was 7.4% (range, 0% to1.7%; Psichogiou M, Boletis J, Sobolos K,atrou C, Katerelos P, Panagiolopoulos T, June004, unpublished data). HCV prevalence in theeneral population of Greece is estimated to be
.5% to 1.0%.27
HEPATITIS C VIRUS INFECTION IN HEMODIALYSIS 339
Fig 3. Seroconversion patterns in representative HD patients.
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HCV RNA was detected in 67.5% of anti-CV� patients, which is in agreement with other
tudies.11,20 Other investigators identified areater concordance between anti-HCV and theresence of HCV RNA.7,28 Recently, Furusyo etl29 showed that HCV RNA levels are signifi-antly lower in HD patients compared with non-remic subjects, and that this is related to the HDrocedures.Multiple logistic regression identified HD unit,
uration of HD therapy, and history of transplan-ation as risk factors for anti-HCV positivity attudy entry. History of elevated ALT levels alsoas found to be a prognostic factor for anti-HCVositivity. The finding that duration of HD therapy
Fig 4. Kaplan-Meier estimate of the probability thatpatient has his or her first HCV RNA� result at any
ime before EIA-2 or EIA-3 seroconversion (windoweriod).
Table 3. Estimates From a Cox Proportional HazarMultivar
Relativ
ge (years)�60/�60
exF/Mause of end-stage renal diseaseOther/glomerulonephritisUnknown/glomerulonephritisuration of dialysis (mo)21-40/�20�40/�20istory of transfusion (yes/no)istory of renal transplantation (yes/no)istory of acute hepatitis (yes/no)istory of elevated ALT level (yes/no) 1D unit
Unit 5/unit 1–4 9.5nd HD units are risk factors for anti-HCVositivity has been reported by several othertudies and suggests that nosocomial transmis-ion occurs in the HD setting.5,7,14,15,20 It isoteworthy that there was no association be-ween anti-HCV serostatus and previous transfu-ions; since the implementation of screeninglood products for anti-HCV, the residual risk forcquiring HCV infection from transfusion is neg-igible.5,9,15,18,20
HCV incidence (6.2 cases/100 person-years)as greater than that reported by studies per-
ormed in other European countries, the Unitedtates, and Japan, where reported rates rangedrom 0 to 3.7 cases/100 person-years.1,4,12,13,15,21
ther studies in South America and Taiwan iden-ified greater incidence rates.8,9,11 We also esti-
ated that 10% of Greek HD patients are ex-ected to seroconvert during the first 5 yearsfter HD therapy initiation.
We evaluated the distribution of HCV geno-ypes at baseline and among seroconvertors (Fig). It is evident that multiple outbreaks haveccurred in units 3, 4, and 5 because seroconver-ors have been infected by more than 1 genotypen each of these units.
Evaluation of serial samples obtained from sero-onvertors by means of both EIA-2 and EIA-3howed that 36.7% of patients were detected earliery means of EIA-3. A similar result (33%) waseported in another study of patients undergoing
del for the Relative Hazard for Seroconversion bynalysis
rd 95% Confidence Interval P
(0.3-1.5) 0.286
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(0.3-2.6) 0.712(0.5-5.3) 0.497
(0.2-2.2) 0.565(0.4-3.7) 0.825(0.3-2.1) 0.648(0.5-12.4) 0.239(0.1-5.0) 0.849(3.1-45.8) �0.001
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HEPATITIS C VIRUS INFECTION IN HEMODIALYSIS 341
D.30 However, that study reported a much shorternterval between EIA-2 and EIA-3 seroconversionmean, 17 days; range, 7 to 30 days) than thatstimated from our data (median, 92 days).Accord-ng to Tobler et al,31 such differences may bexplained by a number of reasons, such as charac-eristics of the panels (number and timing of thepecimens) or whether calculation included or ex-luded all available panels. Couroucé et al,30 forxample, excluded from their analysis 2 patientshose first available specimens were already HCVIA 3.0 positive. In these patients, EIA 2.0 reactedand 3 months after the beginning of follow-up.oncerning the number and timing of specimens inur study, careful examination of data showed thatatients with a large difference between EIA-2 andIA-3 results had several samples that repeatedly
ested EIA-2� after the documented EIA-3 serocon-ersion.
Seroconvertors showed variable patterns ofLT levels and HCV RNA. Only 14 of 32 of
hose who seroconverted (44%) had ALT levelsreater than the upper limit of normal duringreseroconversion follow-up, and in 8 of 32atients (25%), ALT level elevation coincidedith seroconversion. This estimate is lower than
hat reported by another study of dialysis patients83%).32 This may be explained because weefined ALT level elevation as the occurrence ofconsecutive measurements greater than 45 IU/L.
n patients who had an abnormal ALT levelattern preseroconversion, median time from therst abnormal ALT value until seroconversionas 70 days for EIA-2 and 49 days for EIA-3.ur study corroborates others that showed ALT
evel is not a sensitive marker of HCV infectionn HD patients.32
Detectable HCV RNA was observed in 29 of0 seroconverting individuals (97%). Medianime to the appearance of anti-HCV by means ofIA-2 or EIA-3 compared with first HCV RNAetection was extremely prolonged (246 days forIA-2, 154 days for EIA-3). The window perioduring which specific antibodies are not detect-ble, but the virus is present, may last up to 3onths in immunocompetent33 patients and as
ong as 6 to 12 months in immunodeficientatients.34 Many investigators emphasized thexistence of anti-HCV�/HCV RNA� pa-
ients.11,13,16,28 sSeroconversions could not be attributed toransfusions after study entry because only 1atient was administered blood transfusions. In-erestingly, HD unit was associated with in-reased hazard for seroconversion, even afterdjusting for differences among their patientselated to duration of dialysis therapy and historyf transfusion, renal transplantation, and acuteepatitis. Consequently, nosocomial practiceseem to be the predominant mechanism of HCVransmission in the HD setting. Molecular biol-gy techniques would be necessary to providetrong evidence on this point. Katsoulidou et al35
nvestigated an outbreak in 1 of the participatingnits and found that seroconverting patients andprevalent case clustered together. Their results
oint to horizontal nosocomial patient-to-patientransmission. In several other studies, moleculariology techniques provided strong evidence ofosocomial transmission, emphasizing the impor-ance of infection-control procedures in HDnits.22-24 Several investigators stressed that thepread of HCV is related mainly to nonstrictbservance of universal precautionary mea-ures,1,5,19,24,35-38 and adherence to these mea-ures results in a decrease in incidence of newnfections.36,37 The Centers for Disease Controlnd Prevention provided guidelines for infectionontrol strategies that are unique to the HDnvironment, being more stringent than generalrecautions, because of the increased potentialor contamination with blood in this setting.37
he Centers for Disease Control and Preventionoes not recommend isolation of HCV-infectedD patients in separate rooms or the use ofedicated HD equipment.37
In conclusion, in view of data suggesting in-reased mortality in HD patients39 and shorterurvival in renal transplant recipients because ofCV infection,40 it is essential to protect patients
rom contracting HCV during time spent on HDherapy. The prolonged viremia of HCV preced-ng seroconversion emphasizes that infection-ontrol procedures specific for the HD environ-ent should be strictly implemented.
REFERENCES
1. Jadoul M, Cornu C, Van Ypersele De Strihou C, andhe UCL Collaborative Group: Incidence and risk factors forepatitis C seroconversion in haemodialysis: A prospective
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