Chronic Hepatitis C in Chronic Hemodialysis Recipients - An Observational Study
Chronic Hepatitis C in Chronic Hemodialysis Recipients - An Observational Study
This is an observational study of cases of chronic hepatitis C and negative HCV controls in
 adults receiving chronic hemodialysis at the National Renal Health Center (NRHC) -EsSalud in
 Lima - Peru.The NRHC provides specialized health care, including hemodialysis, to people with
 advanced kidney disease from all the districts of Lima.

 Study population: By December 2017, there were 293 adults receiving chronic hemodialysis at
 the NRHC-EsSalud.

 All adult patients receiving chronic hemodialysis at the NRHC-EsSalud will be invited to
 participate.

 Primary objective: Characterize HCV disease in patients receiving chronic hemodialysis at the
 NRHC-EsSalud.

 Secondary objective: Identify factors associated with an increased risk of HCV infection.

 Inclusion criteria:

 Age > 18 years Receive chronic hemodialysis (for at least 6 consecutive months) at the NRHC.

 Exclusion criteria:

 • Inability to provide informed consent. To comply with the primary objective of the study,
 samples from volunteers with HCV serology confirmed in Roe Clinic Laboratory (cases) will be
 subjected to additional tests: HCV viral load followed by determination of the HCV genotype
 by using the Abbott m2000 real-time PCR system capable of identifying genotypes 1 (1a and
 1b), 2, 3, 4 , 5 and 6, using fluorescent probes of oligonucleotides specific for each
 genotype .

 In addition to these lab tests, volunteers will have a Fibroscan test performed at a local
 provider, with the Fibroscan Model 402 with E and XL probes.

 The information will be collected in a Case Report Form (CRF), which will be filled out by
 study staff. The source of clinical information will be primarily the clinical history of the
 NRHC - EsSalud. The source of information on the results of the auxiliary tests will be
 obtained from the results issued by Roe Clinic Laboratory and by the image center of the
 Delgado Clínic.

 Protection of Human Subjects:

 The protocol and informed consent will be reviewed and approved by the Ethics Committee of
 the NRHC. No study procedure will be carried out if the volunteer has not given his or her
 written consent. All reasonable precautions will be taken to protect the privacy of the
 volunteer's information, whose data will be identified only through a code. Researchers will
 keep the study folders in a locked cabinet in a safe place
Epidemiological Data

 It is estimated that chronic infection with the chronic hepatitis C virus (HCV) affects
 approximately 180 million people worldwide (1). It has surpassed HIV infection as the leading
 cause of death from viral infection in multiple countries including the United States (2).
 Complications of chronic HCV occur after several years and include cirrhosis, liver failure,
 need for liver transplantation, and hepatocellular carcinoma. Complications of cirrhosis
 include portal hypertension, spontaneous bacterial peritonitis, gastrointestinal bleeding,
 and hepatic encephalopathy, among others (3). There are also multiple extrahepatic
 manifestations of the disease such as uveitis, cryoglobulinemia, autoimmune thrombocytopenic
 purpura, membranoproliferative glomerulonephritis, Porphyria Cutaneous Tarda (PCT), among
 others (4). Consequently, HCV represents a major cause of health care expenses.

 In Peru, the prevalence of HCV in the general population is estimated at less than 1%. While
 people receiving multiple blood transfusions and health workers are known risk groups, the
 highest prevalence - 59% (5,6) - has been reported in people receiving chronic hemodialysis.

 Previously, patients with chronic kidney disease - stage 5 received blood transfusions for
 the treatment of anemia associated with this disease so it was considered an important risk
 factor, which has decreased with the use of erythropoietin (EPO). Currently, the most
 important risk factor in dialysis is nosocomial transmission related to the biosecurity
 practices used.

 New era in the treatment of HCV: The HCV treatment standard in Peru has been pegylated
 interferon +/- ribavirin, however, its use in patients on hemodialysis has been limited due
 to its low efficacy and unfavorable safety profile. There is a clear need for new HCV
 treatments that are effective and well tolerated.

 In recent years there has been a significant improvement in drugs and drug combinations for
 the treatment of HCV. The current treatments are oral interferon-free schedules, which
 combine 2 or more medications called direct acting agents (DAA). DAAs schemes are highly
 effective and well tolerated, with cure rates above 90% even in patients who have
 traditionally been difficult to treat. The metabolism of DAAs varies among the different
 classes, being that only a few have indication of use in people receiving hemodialysis (7).

 Preliminary local data: The Social Security of Peru (EsSalud) is the second largest public
 health system in the country, which has been treating most people who require chronic
 hemodialysis in Peru. The National Renal Health Center (NRHC) of the Social Security of Peru
 (EsSalud) provides specialized health care, including hemodialysis, to people with advanced
 kidney disease from all the districts of Lima. Currently they serve 293 people on chronic
 hemodialysis. Because the NRHC routinely performs the serology test for HCV, they have
 identified 124 patients (42.32% of all patients on hemodialysis at the NRHC) with positive
 serology for HCV and 12 additional patients (4% of patients in hemodialysis) who have mixed
 infection with HCV and with the hepatitis B virus (HBV). Those 136 patients with chronic
 hepatitis C will have already developed or will eventually develop the complications of the
 disease that will result in a high economic burden for EsSalud.

 Since Peru is entering the era of interferon-free HCV treatments, with regimens that are
 effective and safe in hemodialysis patients, there is the potential to implement
 interventions that reduce or even eradicate HCV infection from hemodialysis programs.

 Significance: The characterization of HCV disease in chronic hemodialysis patients in terms
 of genotype, viral load, and degree of liver fibrosis will be of key importance to understand
 the burden of disease and to define priorities and interventions. Additionally, understanding
 the risk factors associated with chronic HCV infection in this setting will inform decision
 makers so that they can optimize policies and procedures to keep hemodialysis programs free
 of this infection.

 METHODS:

 Study design:

 This is an observational study of cases of chronic hepatitis C and negative HCV controls in
 adults receiving chronic hemodialysis at the NRHC-EsSalud.

 Objectives of the study:

 -  Primary objective: Characterize HCV disease in patients receiving chronic hemodialysis
 at the NRHC-EsSalud.

 -  Secondary objective: Identify factors associated with an increased risk of HCV
 infection.

 Inclusion criteria:

 -  Age > 18 years

 -  Receive chronic hemodialysis (for at least 6 consecutive months) at the NRHC-EsSalud

 Exclusion criteria:

 • Inability to provide informed consent

 Procedures of the study:

 All adult patients receiving chronic hemodialysis at the NRHC-EsSalud will be invited to
 participate in the study. Before conducting any study procedure, volunteers will sign a
 consent form approved by the local ethics committee. For volunteers who have signed the
 informed consent will proceed to make the review of their clinical history will be invited to
 provide a blood sample for HCV serology to be held in the Roe Clinic Laboratory. Although
 patients in hemodialysis in the NRHC-EsSalud undergo periodic evaluation with HCV serology,
 performing the HCV serology in Roe Clinic Laboratory as a procedure of this study will
 provide a confirmation of the results with a standardized method (an automated test of
 third-generation electrochemical-luminescence, made with the Cobas® e 601 immunoassay
 analyzer from Roche Diagnostics).

 After determining the serology result for hepatitis C in each patient, proceed according to
 the following flow diagram:

 Chronic hemodialysis in adults: Informed consent

 HCV + :

 Main objective: Define HCV disease Clinical chart review HCV genotype HCV viral load
 Fibroscan

 HCV -:

 Secondary objective: Define HCV risk factors Clinical chart review Electronic data review

 To comply with the primary objective of the study, samples from volunteers with HCV serology
 confirmed in Roe Clinic Laboratory (cases) will be subjected to additional tests: HCV viral
 load followed by determination of the HCV genotype. The total blood volume to be obtained
 from each volunteer will not be greater than 16 ml.

 The viral load of HCV will be quantified by using the Abbott m2000 real-time Polymerase Chain
 Reaction (PCR) system. Samples from volunteers with positive serology for HCV and detectable
 viral load will be analyzed to determine the HCV genotype using the Abbott RealTime HCV
 Genotype II test, capable of identifying genotypes 1 (1a and 1b), 2, 3, 4 , 5 and 6, using
 fluorescent probes of oligonucleotides specific for each genotype.

 In addition to these lab tests, volunteers will have a Fibroscan test performed at a local
 provider, with the Fibroscan Model 402 with E and XL (extra large) probes.

 To comply with the secondary objective, both cases and controls (volunteers with negative
 serology for HCV in Roe Clinic Laboratory) will be invited. A predefined format will be
 applied to collect information on cases and controls including: date of birth, sex, time
 since the first hemodialysis, date of the first positive local serology, frequency of
 dialysis, time since the first hemodialysis at the NRHC-EsSalud , number of centers where
 hemodialysis was attended, history of surgery (yes / no, and type of surgery) before the
 diagnosis of HCV, history of blood transfusions or by-products (yes / no, and number) before
 diagnosis of HCV, type of venous access for hemodialysis (AV / catheter fistula), use of
 dedicated hemodialysis machines (yes / no), use of individual filters (yes / no),
 comorbidities (such as diabetes mellitus, HIV infection, and other conditions of
 immunosuppression), history of transplantation, number and type of sexual partners, and
 history of intravenous drug use.

 The study is expected to be completed within six months of its local approval.

 Statistical considerations:

 Study population: By December 2017, there were 293 adults receiving chronic hemodialysis at
 the NRHC-EsSalud. Given that the patients of this center are tested for HCV serology every
 six months, it is known that 124 (42.3%) patients have HCV infection and 12 additional
 patients have co-infection with HBV and HCV, giving a total of 136 infected with HCV (general
 prevalence of 46.41%). The remaining 157 patients have negative serology for HCV. These
 numbers may vary when the serology confirmation results are known (done as a procedure in
 this study).

 All adult patients receiving chronic hemodialysis at the NRHC-EsSalud will be invited to
 participate, therefore an estimate of sample size does not correspond.

 The collected data will be analyzed with Statistical Package for the Social Sciences (SPSS).
 Descriptive statistics will be applied, including medians and means ± Standard Deviation
 (SD). Proportions will be used for the categorical variables. Unpaired T-test will be used to
 compare medians of time in dialysis and age. Poisson regression (bivariate) will be used to
 evaluate associations of variables with HCV infection. Multivariate Poisson regression
 analysis will be used to model the associations between the explanatory variables detected as
 significant in the univariate analysis. The level of statistical significance for the
 univariate analysis will be 0.10 and for the multivariate it will be 0.05.

 Collection and Data Management:

 The information will be collected in a Case Report Form (CRF), which will be filled out by
 study staff. The source of clinical information will be primarily the clinical history of the
 NRHC-EsSalud. The source of information on the results of the auxiliary tests will be
 obtained from the results issued by Roe Clinic Laboratory and by the image center of the
 Delgado Clinic.

 Protection of Human Subjects:

 The protocol and informed consent will be reviewed and approved by the Ethics Committee at
 the NRHC. No study procedure will be carried out if the volunteer has not given his or her
 written consent. All reasonable precautions will be taken to protect the privacy of the
 volunteer's information, whose data will be identified only through a code. Researchers will
 keep the study folders in a locked cabinet in a safe place.
Inclusion Criteria:

 -  Age: > 18 years

 -  Receive chronic hemodialysis (for at least 6 consecutive months) at the NRHC. EsSalud

 Exclusion Criteria:

 -  Inability to provide informed consent