SEROPREVALENCE AND RISK FACTORS OF HCV IN DIALYSIS

DlcLE TIP DERGlsi (JOURNAL OF MEDICAL SCHOOL) C:27 S:3-4
2000
SEROPREVALENCE AND RISK FACTORS OF HCV IN
DIALYSIS PATIENTS
Mehmet Emin YILMAZ, MD., Assoc. Prof.
ismail H. KARA, MD., Assist. Prof.
Suzan DOZEN, MD., Resident.4
2
1
Yasin SARI, MD., Resident.
3
Yasemin Usul, MD., Resident.5
Bunyamin I~IKOGLU, MD., Prof.
6
ABSTRACT
Nowadays, increased seroprevalence of hepatitis C virus (HCV) in hemodialysis
(HO) patients is an important problem. In this study, it was aimed to investigate the
seroprevalence and risk factors leads to spread of HCV in HO and continuous
ambulatory peritoneal dialysis (CAPO) patients. 67 HO and 35 CAPO patients were
.enrolled in the study, 44 (43.1%) of them were female and 58 (56.9%) were male. Any
risk factor for HCV infection was questioned. Third generation EL/SA reagent was used
in the study. In our HO Center, all precautions have been taken for the prevention of
spreading of HCV. Rooms and dialysis machines of HCV patients were separated from
others. Mean age of cases was 41.6%15.3(range 19-75)year. All cases except two had
blood transfusion and all cases had at least one surgical intervention (central venous
catheter and/or arterio-venous shunting operation). Eight (7.8%) cases had dental
interventions including conservative .tooth treatment or tooth extractions. There was not
relation between low socioeconomic status, duration time of dialysis and higher
prevalence of HCV in dialysis patients (p>O.05).In general, anti HCV seropositivity in our
center was 41% and these cases were generally asymptomatic, but had elevated liver
enzyme levels and slightly decreased albumin levels and at least all cases had one risk
factor. Seroconversion ratelyear of our anti HCV (-) patients were O.148lpatients year in
HO patients and O.OO2/patientsyear in CAPO patients, respectively. The seroconversion
ratelyear and prevalence of HCV is higher in HO patients than CAPO patients. It should
be necessary to take additional measures to universal precautions for the prevention of
spreading of HCV such as separation of dialysis machines, education of nurses and to
change gloves regularly when moving from patient to patient, etc.
Key
Words:Hemodialysis, Hepatitis C, Risk factors, Blood Transfusion.
INTRODUCTION
Approximately 4 million persons in the United States and probably more
than 100 million persons worldwide are infected with hepatitis C virus (HCV).
The virus has the unique ability to cause persistent infection in susceptible
hosts after parenteral or percutaneous transmission, and its underlying
mechanisms are not well understood. Hepatitis C virus, which before its
identification was labeled "non A, non B hepatitis" is a linear, single-stranded,
(1,3.4.5.6) Department
(2) Department
01 Nelrology.
01 Family Medicine,
Dlcte University, School 01 Medicine,
Diyarbaklr,
TURKEY.
116
positive-sense. 9500 nucleotide RNA virus. the genome of which is similar in
organization to that of flaviviruses and pestiviruses; HCV constitutes its own
genus in the family Flaviviridae. The HCV genome contains a single large open
reading frame (gene) that codes for a virus polyprotein of approximately 3000
amino acids (1-3).
The 5' end of the genome consists of an untranslated region adjacent to
the genes for structural proteins. the nucleocapsid core protein and two
envelope glycoproteins, E1 and E2/NS1. Nucleotide sequencing has identified
at least six distinct genotypes, as well as subtypes within genotypes. of HCV.
The genotypic diversity of HCV results from its high mutation rate. There is no
specific treatment for HCV and however there are new hopeful studies for that
(2,4.5).
Essentially, it is determined that genotype 1. 2 and 3 are seen very
often in all over the world, genotype 1b is the main genotype in Japan, Eastern
and Southern Europe and Southeast Asia. It is suggested that the treatment
and prognosis of that illness changes according to the type of genotypes.
. Especially in the patients with HCV genotype 1b. there is no correlation
between the amount of viral load and response to interferon treatment. Type 1
is seen more often after blood transfusion and in sporadic hepatitis (6).
Initial studies reported on HCV antibody prevalence in hemodialysis (HO)
patients ranging from 2 to 60%. A number of risk factors account for the
increased risk of HCV infection in hemodialysis patients. These include blood
transfusions, immune defects relating to viremia and extracorporal
hemocirculation that is repeated (7).
We aimed to determine the risk factors that are important for spreading of
HCV and HCV seroprevalence in HD and CAPO patients in our HO center.
SUBJECTS AND METHODS
PATIENTS AND STUDY DESIGN
67 HO [38 Male (M), 29 Female (F)) and 35 CAPO [20 M. 15 F] patients
undergoing dialysis program in HD center, Medical Faculty of Oicle University
were evaluated according to prospective cohort study from January 1999 to
December 1999. Our new renal dialysis center started its function since 1998.
The rooms of HO patients, dialysis machines and personnel were divided in
three sections such as HBV, HCV and normal groups. Any risk factor for HCV
infection (blood or blood products transfusion, low socioeconomic status,
surgical interventions, intrafamilial transmission and hospitalization) was
questioned. The ethical committee of the university hospital approved the
protocol of the study. All patients and controls gave written informed consent to
the study.
Blood sampling
The collection of blood samples of controls was performed in early
morning. In patients undergoing HO, blood samples were drawn just before the
start of HO and immediately after its end from the arterial line. Freshly drawn
blood (15 ml) samples obtained and immediately centrifuged at 200 9 (20 min at
=
117
24°C). Then, centrifuged samples were investigated by Third generation ELlSA
reagent (Equipar, Sri. -Italy) and Tecan-Minilyser (Austria) apparatus. The
results were supported immunoComb 11HCV test (indirect solid phase enzyme
immunoassay-EIA, Organics-Israel). Cut-off value: After finding mean values of
both two positive controls and two negative controls, the results were divided by
three. Cut off: positive control+negative control/3.
Hemodialysis
The patients received 5 hour and three times per week HO with a PS
hollow fiber disposable dialyser (Fresenius Medical Care, Germany) and
dialysers were never reused. HO was carried out using Braun-Oialog and
Fresenius-4008S (Germany) dialysis machines and bicarbonate as dialysate.
All patients were receiving heparin (Iow molecule weight heparin). Machines
were heat disinfected between treatments and chemically every month.
Screening of anti-HCV antibodies and monitoring of alanine aminotransferase
(ALT) and albumin levels were part of HD center routine. Blood samples are
collected every 2 weeks from anti-HCV negative patients and every 4 weeks
. from
anti-HCV positive ones. Medical records were kept constantly for all
. patients,
and these records included data such as symptoms of hepatitis,
history of liver enzyme abnormalities, medication history, past medical history,
history of transfusions, dialysis schedule, bleeding episodes, and demographic
and risk factors.
Statistical
Analysis
Statistical analyses were made in SPSS 7.5 PC program. Results were
expressed as means:tSO. Two different groups were compared by independent
t test. The one-way ANOVA and post hoc Bonferroni tests were used to
compare independent-unpaired parametric samples of different groups,
chi-square test were used to compare categorical samples and the Spearman
correlation tests were used to determine the correlations. Values of p<O.05
were considered statistically significant.
RESULTS
In table 1, age, duration of hemodialysis and laboratory data of patients in
HO and CAPO group were reported, and in table 2 all of them were compared
according to type of hepatitis. 44 of patients were female and 58 were male.
Mean age of patients was 41.6:t15.3. HCV patients (40.8:t15.9) were younger
than HBV (49.4:t16.0) and normal (44.6:t14.8) groups, but there was statistically
no difference between them (p>O.05).
There was difference in ALT (p=O.03) and AST (p=O.01) levels between
these groups. There was statistically significant difference in ALT levels
between normal and HCV (+) groups (p=O.03)and that of AST levels between
normal and HbsAg (+) groups (p=O.01). However, duration of hemodialysis,
albumin concentrations and ages of HCV patients weren't statistically different
from other groups (p>O.05). All of the patients had at least one risk factor. All
patients except two had blood transfusion, all patients had at least one surgical
intervention (central venous catheter and/or arterio-venous shunting operation).
118
Only eight (%7.8) patients had dental interventions including conservative tooth
treatment or tooth extractions. All patients had a social guarantee. However, the
socioeconomic status of patients those were insured by social guarantees and
by government were lower than that of Western societies. There was no relation
between low socioeconomic status, time of dialysis duration and prevalence of
HCV in dialysis patients (p>O.05). In general, anti HCV seropositivity in our
center was 41% and these patients were generally asymptomatic, but had
elevated liver enzyme levels and decreased albumin levels (Rgure 1 and 2).
Table 1. Sociodemographic and laboratory data of patients in HD and
CAPD groups.
GROUPS
HD (n=67)
CAPD (n=35)
44.6:t:16.4
4O.3:t:13.8
>0.05
Dunation time of Dialysis (Month)
15.9:t:9.0
43.8:t:34.9
<0.0001
Albumin (aIL)
3.4:t:O.6
3.0:t:0.6
<0.05
ALT (lUll)
58:t63
42:1:73
0<05
Age (Year)
31:t:44
AST (lUll)
p
<0.05
Table 2. Sociodemographic and laboratory data of patients according to
type of hepatitis.
GROUPS
NORMAL
11=69
Age (Year)
44.6:t:14.8
Dunat. time of Dialy. (Mnh) 28.3:t23.9
HCV
0=39
HBV
HCV+HBV
n=11
0=3
4O.8:t:15.9
49.4:t:16.0
33.7:t:7.6
23.1 :t27.3
28.2:t28.3
16.3:t6.7
Albumin (9IL)
3.3:t:O.8
3.3:t:O.5
3.0:t:O.5
ALT (lUll)
21:t:11
69:t:82
68:t65
51:t:38
AST (lUll)
18:t:11
4O:t:42
61:t:52
29:t:15
3.0:t:O.6
::-
119
300
200
..
Ii ~
T
~ 'ro1
..
~
. .
oJ
.
I!IIAlT
-100
8AST
NORMAl
HCV
HBV
HCV+HBV
HEPATEST
Figure 1a. Liver enzymes levels in patients undergoing HD.
400
300
20C
g?
Z
:J
100
=r:: -
~
LE;::
I!BAlT
-100
NORMAl
HCV
HBV
.AST
HEPATEST
Figure 1b. Liver enzymes levels in patients treated by CAPD.
120
HEMODIAL YSIS
HCV+HBV
3/4%
HBV
7/10%
NORMAL
29 / 43%
HCV
28/ 42%
Figure 2a. HCV and HBV Percents in patients undergoing HO.
CAPD
HBV
4/11%
HCV
NORMAL
11/31 %
20 / 57%
Figure 2b. HCV and HBV Percents in patients treated by CAPD.
121
In HD group, in 28 of 67 cases HCV, in three of them HCV + HBV, and in
seven HBV was positive. In CAPD group, in 11 cases HCV and in four cases
HBV was positive. In HD group 28 cases and in CAPD group 20 cases had
negative hepatitis marker. Seroconversion rate/year of our anti HCV (-) patients
were 0.148/patients year in hemodialysis patients and 0.002/patients year in
CAPD patients, respectively.
DISCUSSION
In patients with hepatitis C, an episodic pattern of aminotransferase
elevation is common. A specific serologic diagnosis of hepatitis C can be mode
by demonstrating the presence in serum of anti HCV. Because nonspecificity
can confound immunoassays for anti-HCV, a supplementary recombinant
immunoblot assay (RIBA) should be done, especially in persons with tow prior
probability of infection, to establish the specific viral proteins to which anti-HCV
is directed. Assays for HCV RNA are the most sensitive tests for HCV infection
(8,9).
Elevation of ALT with anti-HCV seropositivity for at least 6 months are the
.laboratory features enough to define chronic hepatitis C. Chronic hepatitis
follows acute hepatitis C in 50 to 70 percent of patients. Many patients of
hepatitis C are identified in asymptomatic patients who have no history of acute
hepatitis, eq., those discovered while attempting to donate blood or as a result
of routine laboratory screening tests. Among symptomatic persons with
anti-HCV, even when aminotransferase levels are normal, between a third and
a half have been reported to have chronic hepatitis on liver biopsy, although
mild in most patients. In these asymptomatic persons with normal
aminotransferase levels, the presence of detectable circulating HCV RNA
appears to distinguish those with chronic hepatitis on biopsy from those with
normal liver histology (10,11).
Among the patients with chronic hepatitis B, HCV seroprevalence was
reported ranging from 10 to 20% in the Southern Europe and USA (11,12). HCV
co-infection in patients with inactive chronic hepatitis B increases to 30-35%
levels especially in the Mediterranean Countries (13). In our country, dual
infection ratio was found 9% in a study that HCV co-infection was investigated
among patients with chronic HBV infection (14).
HCV infection is investigated in two different groups according to the
routes of transmission.
A-Parenteral: Occupational, Transfusion of blood and blood products,
Nosocomial, Hemodialysis patients, Intravenous drug users,
B-Non-Parenteral:
Perinatal transmission, Sexuel transmission,
Intrafamilial transmission. Routine screening of blood donors for anti-HCV
reduced the frequency of transfusion-associated HCV infection. After the
introduction of first generation anti-HCV immunoassays, the infection risk of
transfusion-associated hepatitis reduced 80% in countries such as Japan, USA,
and Spain that HCV genotype 1 is predominant. The introduction of
second-generation
of HCV assays has reduced the frequency of
transfusion-associated hepatitis C to almost imperceptible levels. Rarely, when
122
donor is at window period during the blood transfusion, it can be transmitted
(15,16). Solvent detergent treatment in screening of plasma for anti-HCV is the
most effective method and is used commonly. Thus, transmission of HCV by
immune globulins preparations and coagulation factor concentrates are
eliminated by this way (17). The mechanism of HCV transmission as a hospital
infection isn't well known. During surgical interventions, it should be necessary
to take additional measures for the prevention of transmission of HCV (18).
Although it is reported that HCV is the most common cause of post-transfusion
or sporadic non A-non B hepatitis in USA, in 40% of the patients there was no
risk factor for parenteral transmission (19).
Similarly, also in our country, only 44% of patients whose anti-HCV was
positive had a transfusion story (20). Since 1989, the prevalence of HCV
infection in different risk groups and blood donors was investigated by using
specific tests for HCV. First prevalence study of HCV infection was made in
volunteer blood donors (21). Anti-HCV prevalence in volunteer blood donors is
lower than 2% in Northern Europe and larger part of USA, 0.5-0.8% in Australia
and other parts of USA, 1-1.5% in the Southern Europe and Japan, 5% in
Chine, higher than 10% in the Northern Africa (22-24). In our country, the
'prevalence of anti-HCV in blood donors is about 1% (25,26).
The seroprevalence of anti-HCV in intravenous drug users is high in all
over the world (57-86%) and there is a significant parallelism between the
seropositivity and duration of drug using (27,28). The importance of sexual
transmission in the epidemiology of HCV infection is not clear. It ranges from 0
to 27% (29). The hospitalization story is an epidemiological risk in patients with
HCV infection (30). Transmission from a patient to another one can be seen. It
is reported that this type of transmission can cause outbreak of HCV infection in
hematologyand pediatric oncology clinics (31).
The risk of HCV infection is increased in organ transplant recipients and
in hemodialysis patients (7,27,32-37). The HCV prevalence changes from
country to country. In our country, according to European Dialysis and
Transplant Association (EDTA) data, HCV prevalence was 17.7% in 1993.
However, according to Turkish Nephrology Associations' (TNA) data, HCV
seroprevalence was reported as 38% in 1996, it increased to 52.6% in 1997
and finally to 63.2% in 1998 (32,33).
In these studies, the relationship between HCV seropositivity and blood
transfusion and duration of hemodialysis were demonstrated. Previous HD story
is an important risk factor for HCV seropositivity of CAPD patients. Some of
these studies were tests that made by using first generation ELlSA and had
significant risk of false negativism (34-36). A number of factors account for the
risk of HCV infection in hemodialysis patients. These include blood transfusions
and duration of hemodialysis. Moreover, the presence of anti-HCV has been
often documented in non-transfused hemodialysis patients suggesting
nosocomial transmission of HCV. Seroconversion rate/year of 129 anti-HCV (-)
patients undergoing HD was reported as 0.15/year (9,37).
The patients that are enrolled in our study had a hospitalization story at
least one time. At the beginning of 1999 (first six months), when there was 16
123
patients in HCV room, liver enzymes of 16 patients that undergoing dialysis in
normal room began to increase. All these patients had blood transfusions
or/and surgical intervention during 1999. In 11 of these patients anti-HCV
antibody became detectable in 6-12th months. On the other hand, in CAPD
group, only one anti-HCV seropositivity was demonstrated. In only one case,
intrafamilial transmission was identified. Only eight (7.8%) patients had dental
interventions including conservative tooth treatment or tooth extractions.
It is reported that in France anti-HCV seroprevalence was 23.6% in renal
transplant recipients (35). When 27 patients were followed prospectively, it was
seen that ten (37%) patients were seropositive during the transplantation and
other patients became seropositive in following days, in 11 (41%) patients
antibodies become detectable after 95 months and in 6 (22.2%) patients who
were seropositive at the beginnings, antibodies became undetectable after 111
months (35).
Hemodialysis patients are at high risk of infection by hepatitis C virus
and this is also an important problem that is met in our country's hemodialysis
. units. It is suggested the separation of the hemodialysis machines and rooms of
anti-HCV positive patients, couldn't prevent the outbreak of HCV infection in a
HD Unit. However, in a recent study of Katsoulidou and his colleagues (37),
molecular and epidemiological analysis suggested that horizontal nosocomial
patient to patient transmission was the most likely explanation for the virus
spread within the HD Unit and other recognized rates had less importance.
In our country, there are many studies that HCV seroprevalence in HD
units was investigated (38). In the study of Ozdemir et al. (39) anti-HCV
seropositivity was found in 145 (34.7%) patients by using 2nd generation ELlSA
reagent. YOcel et al. (40) found anti-HCV seropositivity in 33 (32.6%) of 101
patients by using 2nd generation ELlSA reagent in Bursa Hospital HD Unit.
Olmez et al. (41) found anti-HCV seropositivity in 36 (24.6%) patients, HbsAg
seropositivity in 20 (%13) patients and anti-HCV plus HbsAg seropositivity in six
(%4.1) patients in Dicle University HD Center by using 2nd generation ELlSA
reagent (In 1996, dialysis machines, rooms and personnel weren't yet
separated).
Nowadays, in our center, the rooms, dialysis machines and personnel of
HD patients are separated according to HCV, HBV and HCV plus HBV and
normal patients groups. When 67 HD and 35 CAPD patients that are
undergoing dialysis program at presently in our HD center as from 1999, are
evaluated by using 3rd generation ELlSA reagent, it is seen that anti-HCV
seropositivity is 41%. In general, these patients were generally asymptomatic.
but had elevated liver enzyme levels and decreased albumin levels. In our
study, total 102 patients were enrolled. In 39 of them, anti-HCV seropositivity
and in 11 of them, HbsAg seropositivity was demonstrated.
CONCLUSION
In conclusion, our observation that seroconversion rate/year of our
anti-HCV patients were 0.148/patients years in HD patients and 0.002/patients
years in CAPD patients, respectively. The seroconversion rate/year and
124
prevalence of HCV is higher in HO patients than CAPO patients. In HO patients,
it should be necessary to take additional measures to universal precautions for
the prevention of outbreak of HCV such as separation of dialysis machines,
education of nurses and changing gloves regularly when moving from patients
to patient, etc.
OZET
DivALiz HASTALARINDA HEPATiT C SEROPREVALANSI VE RisK
FAKTORLERi
Hemodiyaliz hastalannda hepatit C virOsO (HCV) seroprevelansmm
yOksekligi anemli bir problemdir. Bundan dolaYI HCV'nin bula~ma yollan da
gOnOmOzdeanem kazanml~tlr. Bu ~all~mada, Oicle Universitesi Hemodiyaliz
Merkezinde, hemodiyaliz (HO) ve sOrekli ayaktan periton diyalizi (SAPO)
hastalarmda HC seroprevelansl ve virOsOnyaYllmasml saglayan risk faktarleri
ara~tlnldl.
Qah~maya 67 HO ve 35 SAPO hastasl ahndl. Hastalann 44 ( % 43.1)'i
kadm, 58 (% 56.9)'u erkekti. Hastalar, HCV infeksiyonu i<;in risk saYllan
herhangi bir faktare sahip olma (kan veya kan OrOnleritransfOzyonu, dO~Ok
sosyoekonomik statO, cerrahi mOdahale ve hastahanede yatma) aylsmdan
sorgulandl. Qah~mada 3. ku~ak ELisA kiti kullanlldl. Merkezimizde HCV
yaYllmasln1engelleyici tOm anlemler almml~tlr. HCV'li hastalarm oda ve diyaliz
makinalan digerlerinden aynlml~tlr.
Olgulann ortalama ya~141.6:t:15.3 (19-75) Ylldlr. Olgulann ikisi dl~mda
hepsine kan transfOzyonu ve tOmOneen az bir cerrahi giri~im (santral venaz
katater ve/veyaarteriyo-venaz ~ant operasyonu) yapJlml~tlr. Yalnlz sekiz olgu
/%7.8) difl <;ekimiveya konservatif difl tedavisi garmO~tOr.Oiyaliz hasatalannda
dOflOksosyo ekonomik statOve diyaliz sOresiile HCV seropozitifligi % 41'dir ve
bu olgulann tOmO genelde asemptomatik olmakla birlikte, karaciger enzim
seviyelerinde yOkselme, albumin seviyelerinde yOkselme, albumin seviyesinde
ise hafifye dOflme bulunuyordu ve hastalann hepsi en az bir risk faktarOne
sahipti. Anti-HCV(-) hastalanmlzda Yllllk serokonversiyon oranl, HO
hastalannda O.148/hasta Ylh iken; SAPO hastalannda bu oran O.OO2/hasta
Yllldlr.
HO merkezimizde, HO hastalarmda HCV prevalansl ve Yllllk
serokonversiyon oranl SAPO hastalarmdan daha yOksektir. HO hastalannda,
HCV yaYlhmlnl anlemek iyin, diyaliz makinalannln aYlrlml, hemflire egitimi ve
bir hastadan ba~ka bir hastaya geyildiginde eldiven degi~tirilmesi vb. genel
anlemlerin allnmasl gerekli olabilir.
Anahtar Kelimeler:
TransfOzyonu.
Hemodiyaliz, Hepatit C, Risk Faktarleri, Kan
125
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