- Email: [email protected]
Hepatitis C screening strategies in hemodialysis patients
Hepatitis C Screening Strategies in Hemodialysis Patients Sammy Saab, MD, Maria Brezina, BS, Gary Gitnick, MD, Paul Martin, MD, and Hal F. Yee, Jr, MD, PhD ● Hepatitis C virus (HCV) infection is common in patients undergoing chronic hemodialysis, with an estimated yearly incidence of 0.2% and prevalence between 8% and 10%. Although a screening strategy based on alanine aminotransferase (ALT) values is currently recommended, this strategy has not been evaluated for costeffectiveness compared with other potential screening strategies. A comparison therefore was made using a decision-analysis model of a simulated cohort of 5,000 hemodialysis patients followed up for 5 years. Using direct medical costs, three strategies were evaluated, including: (1) ALT values with confirmatory testing (biochemical), (2) serial enzyme-linked immunosorbent and strip immunoblot assay testing (serological), and (3) polymerase chain reaction (viral). Under baseline assumptions, the per-patient cost of screening hemodialysis patients for HCV was $378 for biochemical-based testing, $195 for serological-based testing, and $696 for viral-based testing. Our model was robust when varying the costs of testing, as well as the incidence and prevalence of HCV infection. Results of sensitivity analysis by varying costs, HCV incidence, and HCV prevalence indicated that serological-based screening was less costly than biochemical testing. Biochemical testing was in turn less costly than viral-based screening. Serological-based testing was also more effective in the diagnosis of de novo HCV infection, with a likelihood ratio of 85, in contrast to the likelihood ratio of 44 with biochemical-based testing using viral-based screening as the gold standard. A serological-based screening strategy is less costly and more effective than biochemical-based screening in the diagnosis of de novo HCV infection. Serological-based screening should be considered for HCV screening in hemodialysis populations. © 2001 by the National Kidney Foundation, Inc. INDEX WORDS: Hepatitis C virus (HCV); hemodialysis (HD); decision analysis.
Editorial, p. 186
H
EPATITIS C VIRUS (HCV) infection remains a significant public health concern in hemodialysis patients. Between 8% and 10% of patients on chronic hemodialysis therapy are infected with HCV, with an estimated incidence of 0.2% per year.1,2 HCV-infected patients are at increased risk for morbidity and mortality, posing as a reservoir of HCV to hemodialysis staff.3-6 The relative risk for death in HCV-infected hemodialysis patients compared with non–HCV-infected hemodialysis patients is greater than 1.4.4-6 In addition, HCV infection leads to decreased graft and patient survival in renal transplant recipients.7 In patients awaiting renal transplantation, significant histological liver disease has been found, even with normal serum alanine aminotransferase (ALT) levels.8 The Centers for Disease Control and Prevention currently recommends screening chronic hemodialysis patients for HCV infection by serial ALT level testing (ie, biochemical-based strategy).9 Patients identified by elevated ALT levels undergo additional serological testing. However, this strategy has several potential limitations. First, baseline ALT levels are significantly lower in hemodialysis patients than non-
uremic patients.10,11 As a result, using the current range for healthy adults as normal values may not be sensitive enough for the detection of HCV infection. ALT levels in HCV-infected hemodialysis patients typically are within the laboratory normal range despite hepatitis C viremia and histological disease.8,12 Although mean ALT levels are greater in hemodialysis patients who are viremic with HCV than in noninfected hemodialysis patients, values are still within the reference range.13 Second, nonspecific sporadic ALT From the Departments of Medicine and Physiology, Division of Digestive Diseases, University of California at Los Angeles; and the Liver Transplant Program, Cedars Sinai Medical Center, Los Angeles, CA. P.M. and H.F.Y. contributed equally as senior authors. Received August 10, 2000; accepted in revised form February 16, 2001. Supported in part by award no. DK 02450 from the National Institute of Diabetes and Digestive and Kidney Diseases (H.F.Y.); American Association for the Study of Liver Diseases/Schering Award (S.S.); and National Service Research Award no. DK07180-2 from the National Institutes of Health (S.S.). Address reprint requests to Sammy Saab, MD, Division of Digestive Diseases, 44-138 CHS (MC 168417), UCLA Medical Center, 10833 Le Conte Ave, Los Angeles, CA 90095. E-mail: [email protected] © 2001 by the National Kidney Foundation, Inc. 0272-6386/01/3801-0014$35.00/0 doi:10.1053/ajkd.2001.25199
American Journal of Kidney Diseases, Vol 38, No 1 (July), 2001: pp 91-97
91
92
level elevations are common in hemodialysis patients, reflecting other factors, including comorbidities and medications; therefore, unnecessary viral testing may be initiated.1,14 Last, the positive predictive value of an elevated ALT level for de novo HCV infection is less than 5%.1 Alternative strategies for screening hemodialysis patients for HCV infection include a serologicalbased strategy and a viral-based strategy. In the serological-based strategy, an enzyme-linked immunosorbent assay (ELISA) is used to screen hemodialysis patients for HCV infection. However, supplemental testing is needed to exclude false-positive results with strip immunoblot assay (SIA).15,16 In the viral-based strategy, polymerase chain reaction (PCR) for HCV is performed. To evaluate potential screening approaches, we compared three strategies (biochemical-, serological-, and viral-based screening) for HCV screening in hemodialysis patients in a decision analysis. We compared costs of the three strategies and the efficacy of making a diagnosis of
SAAB ET AL
HCV using the viral-based strategy as the gold standard (Fig 1). Our hypothesis is that serological-based screening is more effective than biochemical-based screening, and serological-based screening is the least costly among the three strategies. PATIENTS AND METHODS
Study Design A decision-cost analysis was performed using a simulation model of 5,000 hemodialysis patients who were followed up for 5 years.17-20 A period of 5 years was arbitrarily chosen because the natural history of patients infected with HCV is not well understood, although substantial liver disease is seen in patients referred for renal transplantation. MEDLINE was searched between the years 1992 and 2000 using different combinations of the following key words: hepatitis C, hemodialysis, and screening. Additional pertinent studies were identified through reference checks from initial studies. Three alternative strategies were considered (Fig 1). In the biochemical strategy, all hemodialysis patients were screened at entry with antibody to HCV (anti-HCV) serological tests. Baseline serological testing was performed in accordance with recommendations that patients on chronic
Fig 1. Screening strategies for HCV infection in hemodialysis patients. (A) In biochemical screening, all patients undergo baseline screening with serological tests. Those without hepatitis C then undergo monthly ALT testing. Patients with elevated ALT values then undergo serological testing. (B) In serological screening, hemodialysis patients undergo testing twice yearly. Patients with negative anti-HCV ELISA and SIA results undergo continued serological screening. (C) In viral screening, hemodialysis patients undergo testing twice yearly. Patients with a negative PCR for HCV undergo continued viral screening. †Serological testing occurs only during entry into the biochemical screening strategy and when ALT levels are elevated.
HEPATITIS C SCREENING STRATEGIES Table 1.
93
Probability and Cost Estimates
Variable
Infection probability Prevalence Incidence* Test characteristics† ALT Sensitivity Specificity SIA Sensitivity Specificity Costs ($) ALT Anti-HCV ELISA Anti-HCV SIA HCV RNA
Baseline Value
0.09 0.002
Varied Range
0.15-0.15 0.0005-0.005
0.83 0.90 0.93 0.84 6.31 20.30 58.30 74.20
1.58-15.78 5.08-50.75 14.58-145.75 18.55-185.50
NOTE. Serology tests include serial testing using ELISA and SIA. Viral tests include evaluation by PCR. *Six-month risk. †SIA is the gold standard for ALT, and PCR for SIA.
sensitivity and specificity of both a positive ELISA and SIA result for a serological diagnosis of de novo HCV infection were 0.93 and 0.84, respectively.21,34-36 These values for SIA and ELISA were determined using PCR testing as the gold standard (Table 1).
Costs Charges were obtained from our institution and converted to costs using an approximate cost-charge ratio of 0.53. The perspective of the decision analysis was that of the health care provider, and only direct costs were assumed. Sensitivity analyses were performed, varying costs by 0.25 to 2.5 of the baseline cost value. For simplicity, the costs of ELISA and SIA were varied by the same proportion (Table 1).
Efficacy The likelihood ratio is the odds that a diagnosis of de novo HCV infection is made in patients with HCV infection versus those without HCV infection. It is a measure of how a test increases the posttest probability of a diagnosis.37 In addition, likelihood ratio is a uniform term that incorporates sensitivity and the false-positive rate (1-specificity), and it has been shown to be stable for changes in prevalence.38
RESULTS hemodialysis therapy should be tested for HCV by means of an ELISA.9 Positive results were confirmed by SIA. Patients with indeterminate and negative SIA results were considered not infected with HCV.21,22 In our model, we assumed serological testing with a third-generation ELISA and SIA. ALT values were checked monthly (biochemical-based strategy); elevated values were confirmed by serological testing, with initial screening performed by ELISA and positive results confirmed by SIA. In the serological-based strategy, anti-HCV testing was performed twice yearly by ELISA, with positive results confirmed by SIA. As in the biochemical strategy, hemodialysis patients with indeterminate and negative SIA results were considered not infected with HCV. In the viral-based strategy, PCR testing (by reverse transcriptase) was performed twice yearly using a qualitative assay.
Probability of Infection The prevalence and incidence of HCV infection in hemodialysis patients detected by serological and PCR testing were obtained from a systematic review of the literature. The incidence of HCV infection was similar using serological and viral techniques.2,13,23-32 Rates from defined outbreaks were not used. For our model, we assumed a yearly HCV incidence of 0.2% and prevalence of 9% in the hemodialysis centers.1,2 The prevalence varied in a sensitivity analysis by 0.25 to 2.5 times the baseline prevalence of 9% (ie, 1.5% to 15%), and the incidence varied by 0.25 to 2.5 times the baseline incidence of 0.2% (ie, 0.05% to 0.5%; Table 1).
Using baseline biochemical ($6.31), serological (ELISA, $20.30; SIA, $58.30), and viral ($74.20) test costs, serological-based screening was the least costly screening strategy. The cost of screening per patient in our hypothetical hemodialysis cohort was $382 for biochemical-based screening, $195 for serological-based testing, and $696 for viral-based screening. Total costs for screening the hypothetical cohort for the 5 years were $1,908,524, $975,965, and $3,480,506 using the biochemical, serological, and viralbased strategies, respectively (Table 2). Our model proved robust when sensitivity analyses were performed by varying test costs, HCV incidence, and HCV prevalence (Figs 2 and 3). In a comparison of biochemical and viral Table 2.
Results Summary
Screening Strategy
Total Costs ($)
Cost per Patient Screened ($)
Screening Accuracy
Biochemical Serological Viral
1,908,524 979,965 3,480,506
379 195 696
Viral-based screening was defined as the gold standard in our decision-analysis model.33 The sensitivity and specificity of an elevated ALT value for a serological diagnosis of de novo HCV infection were 0.83 and 0.90, respectively.1 The
NOTE. Model simulation of 5,000 hemodialysis patients followed up for 5 years. *Gold standard.
Likelihood Ratio
44 85 *
94
Fig 2. Sensitivity analysis comparing different hepatitis C screening strategies in hemodialysis patients. Costs varied by 0.25 to 2.5 of baseline test costs (ALT, $6.31; ELISA, $20.30; SIA, $58.30; and PCR, $74.20).
strategies, two-way sensitivity analysis indicated that biochemical-based screening was consistently less costly than viral-based screening (Fig 2). Costs used in the sensitivity analysis were $1.58 to $15.77 for ALT testing and $18.55 to $185.50 for viral testing. The cost per patient screened using the ALT strategy was $122 to $901 compared with $174 to $1,740 using the viral strategy. Comparing biochemical and viral strategies, serological costs were held fixed at their baseline costs. In a two-way sensitivity analysis comparing the costs of screening hemodialysis patients for HCV using the serological strategy compared with the biochemical strategy, the serological strategy was consistently lower across all tested cost values (0.25 to 2.5 of baseline costs; Fig 2). When the cost of ALT testing was $1.58 (0.25 of baseline cost), the cost per patient screened was $95.43, and when the cost of ALT testing was increased to $15.77 (2.5 of baseline cost), the cost per patient was $954.26. Conversely, when the cost of serological testing was reduced to 0.25 of its baseline cost value (ELISA, $5.07; SIA, $15.58), the cost per patient screened was $48.75, and when serological testing was increased to 2.5 of its baseline value (ELISA, $50.75; SIA, $145.75), the cost per patient screened was $487.53. Two-way sensitivity analysis comparing serological and viral strategies suggested that serological testing was also consistently less expensive than PCR testing using baseline cost values (ELISA, $20.30; SIA, $58.30; PCR, $74.20; Fig 2). When the cost of PCR testing was $18.55 (0.25 of baseline cost), the cost per patient screened was $174. When the cost was increased
SAAB ET AL
to $185.50 (2.5 of baseline cost), the cost per patient screened was $1,740. Conversely, the cost per patient screened using the serologicalbased strategy was between $48.75 and $487.53 when the baseline costs of serological tests were varied between 0.25 and 2.5 of baseline costs (ELISA, $5.07; SIA, $14.58 and ELISA, $50.75; SIA, $145.75). Sensitivity analyses were performed by varying the incidence and prevalence of HCV infection. Between an HCV prevalence of 0.023 and 0.225, serological-based screening was less costly than biochemical and viral-based screening (Fig 3). Viral-based screening was the most costly strategy. Per-patient costs of screening were $200 for serological-based screening, $396 for biochemical-based screening, and $724 for viralbased screening for an HCV prevalence of 0.023. Per-patient costs of screening were less as the prevalence increased. At an HCV prevalence of 0.225, per-patient costs were $178 for serologicalbased screening, $323 for biochemical-based screening, and $590 for viral-based screening. Similarly, serological-based screening was the least costly strategy in the sensitivity analysis varying the HCV incidence. Varying the incidence had little effect on per-patient costs of HCV screening. At a yearly HCV incidence of 0.0005, per-patient costs of screening were $193 for the serological-based strategy, $372 for the biochemical-based strategy, and $681 for the viral-based strategy. At the upper limits of the sensitivity analysis (HCV incidence, 0.005), perpatient costs of screening were $193 for the
Fig 3. Sensitivity analysis comparing different hepatitis C screening strategies in hemodialysis patients. The prevalence of hepatitis C varied by 0.023 and 0.225.
HEPATITIS C SCREENING STRATEGIES
serological-based strategy, $370 for the biochemical-based strategy, and $676 for the viral-based strategy. In our model, biochemical-based screening would have misclassified 45 hemodialysis patients as having no evidence of HCV infection (false negative) and 93 patients as having infection (false positive). Serological-based screening would have misclassified 45 hemodialysis patients as not being HCV infected and 48 hemodialysis patients as being HCV infected. The costs per true HCV infection detected were $4,257 for biochemical-, $2,210 for serological-, and $6,922 for viral-based screening. Serological-based testing was more effective in the diagnosis of de novo HCV infection, with a likelihood ratio of 85 compared with 44 for biochemical-based testing. DISCUSSION
HCV infection has important implications. Infected patients must be identified to encourage alcohol abstinence and be advised of their potential for transmission. For instance, infected patients should not share toothbrushes, razors, and combs or hairbrushes with close contacts to avoid transmission.9 Hemodialysis patients continue to be at increased risk for HCV infection despite the implementation of universal precautions and decreased need for blood products with the use of erythropoietin.39 Because de novo infection is usually subclinical, effective screening should help identify newly infected patients.40 Our decision-analysis model comparing three strategies of HCV screening proved relatively robust when varying the tests’ cost, HCV prevalence, and HCV incidence (Figs 1 through 3). Serological-based screening was the preferred strategy based on lower costs and greater efficacy than biochemical-based screening (Table 2). Our results suggest that the biochemical strategy may have a diminished role in the diagnosis of HCV because it is less effective in predicting HCV infection than serological testing alone. In addition, biochemical screening is substantially more expensive than serological testing. The current standard for HCV surveillance in hemodialysis patients is ALT testing.9 ALT testing should screen for all currently recognized hepatotrophic viruses (hepatitis A, B, and C
95
viruses). However, hemodialysis patients are not believed to be at increased risk for hepatitis A infection relative to the general population, and patients are already routinely screened for hepatitis B infection by regular monitoring of hepatitis B surface antigen and antibody to hepatitis B surface antigen.1,2 Currently, the major role in the detection of viral hepatitis by biochemical screening is identifying patients with HCV infection. However, our results suggest that the efficacy of biochemical testing in the diagnosis of HCV infection is less than that of serologicalbased screening, and the costs of biochemical screening are substantially greater than those of serological-based screening. Viral-based testing is widely accepted as the gold standard in HCV detection in the hemodialysis population. Unlike serological testing, which detects anti-HCV, PCR testing is able to distinguish active from resolved infection. In our model, biochemical-based screening would have misclassified 45 hemodialysis patients as having no evidence of HCV infection and 93 patients as having infection. With serological-based screening, there would have been 45 false-negative and 48 false-positive results. However, there have been concerns that widespread use of PCR may be limited by availability, the need for meticulous specimen handling, and concerns regarding reproducibility.15,41 Many of these reservations have been addressed by the introduction of automated PCR assays, shown to be accurate and suitable for the diagnosis and monitoring of viral load in patients infected with HCV.42,43 There has been concern about intermittent HCV viremia in hemodialysis patients, which may decrease the sensitivity of PCR testing in the diagnosis of HCV infection.44 Recent evidence suggests that although HCV RNA decreases during dialysis, viral clearance does not occur.45 A potential limitation of our model is that patients with indeterminate SIA results were considered not to be HCV infected. However, the proportion of patients with indeterminate SIA results and evidence of hepatitis C viremia is low and unlikely to have changed the results.21,22 Courouce et al21 compared antibody and PCR assays for the diagnosis of HCV in a hemodialysis population and found that 3 of 57 patients with positive ELISA results had indeterminate
96
SAAB ET AL
SIA results. These 3 patients were not found to be viremic by PCR. This is in contrast to results of second-generation SIA tests in which a greater proportion of hemodialysis patients with indeterminate SIA results are viremic.22 Another potential limitation in our model is that on entry into the biochemical strategy, patients undergo baseline serological testing. As a result, costs incurred with entry serological testing will be included in the total costs of biochemical testing. Nevertheless, this strategy is likely the most common screening strategy in the United States and the one that most closely resembles recommendations of the Centers for Disease Control and Prevention. A third potential limitation is that an incremental cost-effectiveness ratio was not calculated. Because long-term consequences of HCV infection are unclear, the costs of misdiagnosis are unknown. Consequently, a likelihood ratio was used as the measure of effectiveness. This unifying term considers both the sensitivity and the positive rate. Because the serological strategy was associated with a greater likelihood ratio and substantially lower costs than biochemical screening, it is the most cost-effective strategy.17,18 Our results suggest that serological-based testing using a combination of ELISA and SIA testing in series was more effective than using ALT values for the diagnosis of HCV and less costly. With increasing automation of HCV serological testing, a compelling argument can be made for serological screening as the method of choice for HCV surveillance in chronic hemodialysis patients. ACKNOWLEDGMENT The authors thank David Ly for data collection.
REFERENCES 1. Saab S, Martin P, Brezina M, Gitnick G, Yee H Jr: Serum alanine aminotransferase in hepatitis C screening of patients on hemodialysis. Am J Kidney Dis 37:308-315, 2001 2. Tokars JI, Miller ER, Alter MJ, Arduino MJ: National surveillance of dialysis-associated diseases in the United States, 1997. Semin Dial 13:75-85, 2000 3. Mitsui T, Iwano K, Masuko K, Yamazaki C, Okamoto H, Tsuda F, Tanaka T, Mishiro S: Hepatitis C virus infection in medical personnel after needlestick accident. Hepatology 16:1109-1114, 1992 4. Stehman-Breen CO, Emerson S, Gretch D, Johnson RJ: Risk of death among chronic dialysis patients infected with hepatitis C virus. Am J Kidney Dis 32:629-634, 1998
5. Pereira BJ, Natov SN, Bouthot BA, Murthy BV, Ruthazer R, Schmid CH, Levey AS: Effects of hepatitis C infection and renal transplantation on survival in end-stage renal disease. The New England Organ Bank Hepatitis C Study Group. Kidney Int 53:1374-1381, 1998 6. Hanafusa T, Ichikawa Y, Kishikawa H, Kyo M, Fukunishi T, Kokado Y, Okuyama A, Shinji Y, Nagano S: Retrospective study on the impact of hepatitis C virus infection on kidney transplant patients over 20 years. Transplantation 66:471-476, 1998 7. Gentil MA, Rocha JL, Rodriguez-Algarra G, Pereira P, Lopez R, Bernal G, Munoz J, Naranjo M, Mateos J: Impaired kidney transplant survival in patients with antibodies to hepatitis C virus. Nephrol Dial Transplant 14:2455-2460, 1999 8. Martin P, Carter D, Fabrizi F, Dixit V, Conrad AJ, Artinian L, Peacock V, Han S, Wilkinson A, Lassman CR, Danovitch G: Histopathological features of hepatitis C in renal transplant candidates. Transplantation 69:1479-1484, 2000 9. Centers for Disease Control: Recommendation for prevention and control of hepatitis C virus (HCV) infection and HCV-related chronic disease. MMWR Morb Mortal Wkly Rep 47:1-38, 1998 10. Guh JY, Lai YH, Yang CY, Chen SC, Chuang WL, Hsu TC, Chen HC, Chang WY, Tsai JH: Impact of decreased serum transaminase levels on the evaluation of viral hepatitis in hemodialysis patients. Nephron 69:459-465, 1995 11. Yashuda K, Okuda K, Endo N, Ishiwatari Y, Ikeda R, Hayashi H, Yokozeki K, Kobayashi S, Irie Y: Hypoaminotransferasemia in patients undergoing long-term hemodialysis: Clinical and biochemical appraisal. Gastroenterology 109:1295-1300, 1995 12. Sterling RK, Sanyal AJ, Luketic VA, Stravitz RT, King AL, Post AB, Mills AS, Contos MJ, Shiffman ML: Chronic hepatitis C infection in patients with end-stage renal disease: Characterization of liver hepatology and viral load in patients awaiting renal transplantation. Am J Kidney Dis 94:3576-3582, 1999 13. Fabrizi F, Martin P, Dixit V, Brezina M, Cole MJ, Gerosa S, Vinson S, Mousa M, Gitnick G: Quantitative assessment of HCV load in chronic hemodialysis patients: A cross-sectional survey. Nephron 80:428-433, 1998 14. Mondelli MU, Smedile V, Piazza V, Villa G, Barbieri C, Gattarello G, Mancini F, Riamondo G: Abnormal alanine aminotransferase activity reflects exposure to hepatitis C virus in haemodialysis patients. Nephrol Dial Transplant 6:480-483, 1991 15. Gretch D: Use and interpretation of HCV diagnostic tests in the clinical setting. Clin Liver Dis 1:543-557, 1997 16. Youmossi Z, McHutchison J: Serological tests for HCV infection. Viral Hepatitis Rev 2:161-173, 1996 17. Provenzale D, Lipscomb J: Cost-effectiveness: Definitions and use in the gastroenterology literature. Am J Gastroenterol 91:1488-1493, 1996 18. Provenzale D, Lipscomb J: A reader’s guide to economic analysis in the GI literature. Am J Gastroenterol 91:2461-2470, 1996 19. Naimark D, Krahn MD, Naglie G, Redelmeier DA, Detsky AS: Primer on medical decision analysis: Part
HEPATITIS C SCREENING STRATEGIES
5—Working with Markov processes. Med Decis Making 17:152-159, 1997 20. Krahn MD, Naglie G, Naimark D, Redelmeier DA, Detsky AS: Primer on medical decision analysis: Part 4—Analyzing the model and interpreting the results. Med Decis Making 17:142-151, 1997 21. Courouce AM, Bouchardeau F, Chauveau P, Le Marrec N, Girault A, Zins B, Naret C, Poignet JL: Hepatitis C virus (HCV) infection in haemodialysed patients: HCVRNA and anti-HCV antibodies (third-generation assays). Nephrol Dial Transplant 10:234-239, 1995 22. al Meshari K, al Ahdal M, Alfurayh O, Ali A, De Vol E, Kessie G: New insights into hepatitis C virus infection of hemodialysis patients: The implications. Am J Kidney Dis 25:572-578, 1995 23. Seelig R, Renz M, Bottner C, Seelig HP: Hepatitis C virus infections in dialysis units: Prevalence of HCV-RNA and antibodies to HCV. Ann Med 28:45-52, 1994 24. Bukh J, Wantzin P, Krogsgaard K, Knudsen F, Purcell RH, Miller RH, Unit CDHS: High prevalence of hepatitis C virus (HCV) RNA in dialysis patients: Failure of commercially available antibody tests to identify a significant number of patients with HCV infection. J Infect Dis 168:13431348, 1993 25. Caramelo C, Bartolome J, Albalate M, de Sequera P, Navas S, Bermejillo T, Oliva H, Marriott E, Ortiz A, Ruiz Tunon C, Casado S, Carreno V: Undiagnosed hepatitis C virus infection in hemodialysis patients: Value of HCV RNA and liver enzyme levels. Kidney Int 50:2027-2031, 1996 26. Schneeberger PM, Keur I, Vliet WVD, Hoek KV, Boswijk H, Loon AMV, Dijk WCV, Kauffmann RH, Quint W, Doorn L-JV: Hepatitis C virus infections in dialysis centers in The Netherlands: A national survey by serological and molecular methods. J Clin Microbiol 36:1711-1715, 1998 27. Fabrizi F, Lunghi G, Guarnori I, Raffaele L, Crepaldi M, Pagano A, Locatelli F: Incidence of seroconversion for hepatitis C virus in chronic haemodialysis patients: A prospective study. Nephrol Dial Transplant 9:1611-1615, 1994 28. Chan TM, Lok AS, Cheng IK, Chan RT: Prevalence of hepatitis C virus infection in hemodialysis patients: A longitudinal study comparing the results of RNA and antibody assays. Hepatology 17:5-8, 1993 29. Fabrizi F, Lunghi G, Andrulli S, Pagliari B, Mangano S, Faranna P, Pagano A, Locatelli F: Influence of hepatitis C virus (HCV) viraemia upon serum aminotransferase activity in chronic dialysis patients. Nephrol Dial Transplant 12:13941398, 1997 30. Fabrizi F, Lunghi G, Raffaele L, Guarnori I, Bacchini G, Corti M, Pagano A, Erba G, Locatelli F: Serologic survey for control of hepatitis C in haemodialysis patients: Thirdgeneration assays and analysis of costs. Nephrol Dial Transplant 12:298-303, 1997 31. Fabrizi F, Martin P, Dixit V, Brezina M, Cole MJ, Gerosa S, Mousa M, Gitnick G: Acquisition of hepatitis C virus in hemodialysis patients: A prospective study by branched DNA signal amplification assay. Am J Kidney Dis 31:647-654, 1998
97
32. Fabrizi F, Martin P, Dixit V, Brezina M, Russell J, Conrad A, Schmid P, Gerosa S, Gitnick G: Detection of de novo hepatitis C virus infection by polymerase chain reaction in hemodialysis patients. Am J Nephrol 19:383-388, 1999 33. Schiff ER, de Medina M, Kahn RS: New perspectives in the diagnosis of hepatitis C. Semin Liver Dis 19:S3-S15, 1999 (suppl 1) 34. Medina MD, Hill M, Sullivan HO, Leclerq B, Pennell JP, Jeffers L, Reddy KR, Schiff ER, Perez GO: Detection of anti-hepatitis C virus antibodies in patients undergoing dialysis by utilizing a hepatitis C virus 3.0 assay: Correlation with hepatitis C virus RNA. J Lab Clin Med 132:73-75, 1998 35. Dalekos GN, Boumba DS, Katopodis K, Zervou E, Sferopoulos G, Elisaf M, Tsianos EV, Siamopoulos KC: Absence of HCV viraemia in anti-HCV-negative haemodialysis patients. Nephrol Dial Transplant 13:1804-1806, 1998 36. Al-Ahdal MN, Kessie G: Serological diagnosis of hepatitis C virus in patients with liver disease in Saudi Arabia. Evaluation of antibody determination by recombinant immunoblot assays in relation to RNA detection by polymerase chain reaction. Diagn Microbiol Infect Dis 27: 69-73, 1997 37. Fagan TJ: Nomogram for Bayes’ theorem. N Engl J Med 293:257, 1975 (letter) 38. Sackett DL, Haynes RB, Tugwell P: Clinical Epidemiology: A Basic Science for Clinical Medicine (ed 2). Boston, MA, Little, Brown, 1991 39. Simon N, Courouce AM, Lemarrec N, Trepo C, Ducamp S: A twelve year natural history of hepatitis C virus infection in hemodialyzed patients. Kidney Int 46:504-511, 1994 40. Medin C, Allander T, Roll M, Jacobson SH, Grillner L: Seroconversion to hepatitis C virus in dialysis patients: A retrospective and prospective study. Nephron 65:40-45, 1993 41. Zaaijer HL, Cuypers HT, Reesink HW, Winkel IN, Gerken G, Lelie PN: Reliability of polymerase chain reaction for detection of hepatitis C virus. Lancet 341:722-724, 1993 42. Martell M, Gomez J, Esteban JI, Sauleda S, Quer J, Cabot B, Esteban R, Guardia J: High-throughput real-time reverse transcription-PCR quantitation of hepatitis C virus RNA. J Clin Microbiol 37:327-332, 1999 43. Kawai S, Yokosuka O, Kanda T, Imazeki F, Maru Y, Saisho H: Quantification of hepatitis C virus by TaqMan PCR: Comparison with HCV Amplicor Monitor assay. J Med Virol 58:121-126, 1999 44. Galan F, Perez-Gracia MT, Lozano A, Benavides B, Fernandez-Ruiz E, Rodriguez-Iglesias MA: A 3-year follow-up of HCV-RNA viraemia in haemodialysis patients. Nephrol Dial Transplant 13:1211-1214, 1998 45. Furusyo N, Hayashi J, Ariyama I, Sawayama Y, Etoh Y, Shigematsu M, Kashiwagi S: Maintenance hemodialysis decreases serum hepatitis C virus (HCV) RNA levels in hemodialysis patients with chronic HCV infection. Am J Gastroenterol 95:490-496, 2000
Editorial, p. 186
H
EPATITIS C VIRUS (HCV) infection remains a significant public health concern in hemodialysis patients. Between 8% and 10% of patients on chronic hemodialysis therapy are infected with HCV, with an estimated incidence of 0.2% per year.1,2 HCV-infected patients are at increased risk for morbidity and mortality, posing as a reservoir of HCV to hemodialysis staff.3-6 The relative risk for death in HCV-infected hemodialysis patients compared with non–HCV-infected hemodialysis patients is greater than 1.4.4-6 In addition, HCV infection leads to decreased graft and patient survival in renal transplant recipients.7 In patients awaiting renal transplantation, significant histological liver disease has been found, even with normal serum alanine aminotransferase (ALT) levels.8 The Centers for Disease Control and Prevention currently recommends screening chronic hemodialysis patients for HCV infection by serial ALT level testing (ie, biochemical-based strategy).9 Patients identified by elevated ALT levels undergo additional serological testing. However, this strategy has several potential limitations. First, baseline ALT levels are significantly lower in hemodialysis patients than non-
uremic patients.10,11 As a result, using the current range for healthy adults as normal values may not be sensitive enough for the detection of HCV infection. ALT levels in HCV-infected hemodialysis patients typically are within the laboratory normal range despite hepatitis C viremia and histological disease.8,12 Although mean ALT levels are greater in hemodialysis patients who are viremic with HCV than in noninfected hemodialysis patients, values are still within the reference range.13 Second, nonspecific sporadic ALT From the Departments of Medicine and Physiology, Division of Digestive Diseases, University of California at Los Angeles; and the Liver Transplant Program, Cedars Sinai Medical Center, Los Angeles, CA. P.M. and H.F.Y. contributed equally as senior authors. Received August 10, 2000; accepted in revised form February 16, 2001. Supported in part by award no. DK 02450 from the National Institute of Diabetes and Digestive and Kidney Diseases (H.F.Y.); American Association for the Study of Liver Diseases/Schering Award (S.S.); and National Service Research Award no. DK07180-2 from the National Institutes of Health (S.S.). Address reprint requests to Sammy Saab, MD, Division of Digestive Diseases, 44-138 CHS (MC 168417), UCLA Medical Center, 10833 Le Conte Ave, Los Angeles, CA 90095. E-mail: [email protected] © 2001 by the National Kidney Foundation, Inc. 0272-6386/01/3801-0014$35.00/0 doi:10.1053/ajkd.2001.25199
American Journal of Kidney Diseases, Vol 38, No 1 (July), 2001: pp 91-97
91
92
level elevations are common in hemodialysis patients, reflecting other factors, including comorbidities and medications; therefore, unnecessary viral testing may be initiated.1,14 Last, the positive predictive value of an elevated ALT level for de novo HCV infection is less than 5%.1 Alternative strategies for screening hemodialysis patients for HCV infection include a serologicalbased strategy and a viral-based strategy. In the serological-based strategy, an enzyme-linked immunosorbent assay (ELISA) is used to screen hemodialysis patients for HCV infection. However, supplemental testing is needed to exclude false-positive results with strip immunoblot assay (SIA).15,16 In the viral-based strategy, polymerase chain reaction (PCR) for HCV is performed. To evaluate potential screening approaches, we compared three strategies (biochemical-, serological-, and viral-based screening) for HCV screening in hemodialysis patients in a decision analysis. We compared costs of the three strategies and the efficacy of making a diagnosis of
SAAB ET AL
HCV using the viral-based strategy as the gold standard (Fig 1). Our hypothesis is that serological-based screening is more effective than biochemical-based screening, and serological-based screening is the least costly among the three strategies. PATIENTS AND METHODS
Study Design A decision-cost analysis was performed using a simulation model of 5,000 hemodialysis patients who were followed up for 5 years.17-20 A period of 5 years was arbitrarily chosen because the natural history of patients infected with HCV is not well understood, although substantial liver disease is seen in patients referred for renal transplantation. MEDLINE was searched between the years 1992 and 2000 using different combinations of the following key words: hepatitis C, hemodialysis, and screening. Additional pertinent studies were identified through reference checks from initial studies. Three alternative strategies were considered (Fig 1). In the biochemical strategy, all hemodialysis patients were screened at entry with antibody to HCV (anti-HCV) serological tests. Baseline serological testing was performed in accordance with recommendations that patients on chronic
Fig 1. Screening strategies for HCV infection in hemodialysis patients. (A) In biochemical screening, all patients undergo baseline screening with serological tests. Those without hepatitis C then undergo monthly ALT testing. Patients with elevated ALT values then undergo serological testing. (B) In serological screening, hemodialysis patients undergo testing twice yearly. Patients with negative anti-HCV ELISA and SIA results undergo continued serological screening. (C) In viral screening, hemodialysis patients undergo testing twice yearly. Patients with a negative PCR for HCV undergo continued viral screening. †Serological testing occurs only during entry into the biochemical screening strategy and when ALT levels are elevated.
HEPATITIS C SCREENING STRATEGIES Table 1.
93
Probability and Cost Estimates
Variable
Infection probability Prevalence Incidence* Test characteristics† ALT Sensitivity Specificity SIA Sensitivity Specificity Costs ($) ALT Anti-HCV ELISA Anti-HCV SIA HCV RNA
Baseline Value
0.09 0.002
Varied Range
0.15-0.15 0.0005-0.005
0.83 0.90 0.93 0.84 6.31 20.30 58.30 74.20
1.58-15.78 5.08-50.75 14.58-145.75 18.55-185.50
NOTE. Serology tests include serial testing using ELISA and SIA. Viral tests include evaluation by PCR. *Six-month risk. †SIA is the gold standard for ALT, and PCR for SIA.
sensitivity and specificity of both a positive ELISA and SIA result for a serological diagnosis of de novo HCV infection were 0.93 and 0.84, respectively.21,34-36 These values for SIA and ELISA were determined using PCR testing as the gold standard (Table 1).
Costs Charges were obtained from our institution and converted to costs using an approximate cost-charge ratio of 0.53. The perspective of the decision analysis was that of the health care provider, and only direct costs were assumed. Sensitivity analyses were performed, varying costs by 0.25 to 2.5 of the baseline cost value. For simplicity, the costs of ELISA and SIA were varied by the same proportion (Table 1).
Efficacy The likelihood ratio is the odds that a diagnosis of de novo HCV infection is made in patients with HCV infection versus those without HCV infection. It is a measure of how a test increases the posttest probability of a diagnosis.37 In addition, likelihood ratio is a uniform term that incorporates sensitivity and the false-positive rate (1-specificity), and it has been shown to be stable for changes in prevalence.38
RESULTS hemodialysis therapy should be tested for HCV by means of an ELISA.9 Positive results were confirmed by SIA. Patients with indeterminate and negative SIA results were considered not infected with HCV.21,22 In our model, we assumed serological testing with a third-generation ELISA and SIA. ALT values were checked monthly (biochemical-based strategy); elevated values were confirmed by serological testing, with initial screening performed by ELISA and positive results confirmed by SIA. In the serological-based strategy, anti-HCV testing was performed twice yearly by ELISA, with positive results confirmed by SIA. As in the biochemical strategy, hemodialysis patients with indeterminate and negative SIA results were considered not infected with HCV. In the viral-based strategy, PCR testing (by reverse transcriptase) was performed twice yearly using a qualitative assay.
Probability of Infection The prevalence and incidence of HCV infection in hemodialysis patients detected by serological and PCR testing were obtained from a systematic review of the literature. The incidence of HCV infection was similar using serological and viral techniques.2,13,23-32 Rates from defined outbreaks were not used. For our model, we assumed a yearly HCV incidence of 0.2% and prevalence of 9% in the hemodialysis centers.1,2 The prevalence varied in a sensitivity analysis by 0.25 to 2.5 times the baseline prevalence of 9% (ie, 1.5% to 15%), and the incidence varied by 0.25 to 2.5 times the baseline incidence of 0.2% (ie, 0.05% to 0.5%; Table 1).
Using baseline biochemical ($6.31), serological (ELISA, $20.30; SIA, $58.30), and viral ($74.20) test costs, serological-based screening was the least costly screening strategy. The cost of screening per patient in our hypothetical hemodialysis cohort was $382 for biochemical-based screening, $195 for serological-based testing, and $696 for viral-based screening. Total costs for screening the hypothetical cohort for the 5 years were $1,908,524, $975,965, and $3,480,506 using the biochemical, serological, and viralbased strategies, respectively (Table 2). Our model proved robust when sensitivity analyses were performed by varying test costs, HCV incidence, and HCV prevalence (Figs 2 and 3). In a comparison of biochemical and viral Table 2.
Results Summary
Screening Strategy
Total Costs ($)
Cost per Patient Screened ($)
Screening Accuracy
Biochemical Serological Viral
1,908,524 979,965 3,480,506
379 195 696
Viral-based screening was defined as the gold standard in our decision-analysis model.33 The sensitivity and specificity of an elevated ALT value for a serological diagnosis of de novo HCV infection were 0.83 and 0.90, respectively.1 The
NOTE. Model simulation of 5,000 hemodialysis patients followed up for 5 years. *Gold standard.
Likelihood Ratio
44 85 *
94
Fig 2. Sensitivity analysis comparing different hepatitis C screening strategies in hemodialysis patients. Costs varied by 0.25 to 2.5 of baseline test costs (ALT, $6.31; ELISA, $20.30; SIA, $58.30; and PCR, $74.20).
strategies, two-way sensitivity analysis indicated that biochemical-based screening was consistently less costly than viral-based screening (Fig 2). Costs used in the sensitivity analysis were $1.58 to $15.77 for ALT testing and $18.55 to $185.50 for viral testing. The cost per patient screened using the ALT strategy was $122 to $901 compared with $174 to $1,740 using the viral strategy. Comparing biochemical and viral strategies, serological costs were held fixed at their baseline costs. In a two-way sensitivity analysis comparing the costs of screening hemodialysis patients for HCV using the serological strategy compared with the biochemical strategy, the serological strategy was consistently lower across all tested cost values (0.25 to 2.5 of baseline costs; Fig 2). When the cost of ALT testing was $1.58 (0.25 of baseline cost), the cost per patient screened was $95.43, and when the cost of ALT testing was increased to $15.77 (2.5 of baseline cost), the cost per patient was $954.26. Conversely, when the cost of serological testing was reduced to 0.25 of its baseline cost value (ELISA, $5.07; SIA, $15.58), the cost per patient screened was $48.75, and when serological testing was increased to 2.5 of its baseline value (ELISA, $50.75; SIA, $145.75), the cost per patient screened was $487.53. Two-way sensitivity analysis comparing serological and viral strategies suggested that serological testing was also consistently less expensive than PCR testing using baseline cost values (ELISA, $20.30; SIA, $58.30; PCR, $74.20; Fig 2). When the cost of PCR testing was $18.55 (0.25 of baseline cost), the cost per patient screened was $174. When the cost was increased
SAAB ET AL
to $185.50 (2.5 of baseline cost), the cost per patient screened was $1,740. Conversely, the cost per patient screened using the serologicalbased strategy was between $48.75 and $487.53 when the baseline costs of serological tests were varied between 0.25 and 2.5 of baseline costs (ELISA, $5.07; SIA, $14.58 and ELISA, $50.75; SIA, $145.75). Sensitivity analyses were performed by varying the incidence and prevalence of HCV infection. Between an HCV prevalence of 0.023 and 0.225, serological-based screening was less costly than biochemical and viral-based screening (Fig 3). Viral-based screening was the most costly strategy. Per-patient costs of screening were $200 for serological-based screening, $396 for biochemical-based screening, and $724 for viralbased screening for an HCV prevalence of 0.023. Per-patient costs of screening were less as the prevalence increased. At an HCV prevalence of 0.225, per-patient costs were $178 for serologicalbased screening, $323 for biochemical-based screening, and $590 for viral-based screening. Similarly, serological-based screening was the least costly strategy in the sensitivity analysis varying the HCV incidence. Varying the incidence had little effect on per-patient costs of HCV screening. At a yearly HCV incidence of 0.0005, per-patient costs of screening were $193 for the serological-based strategy, $372 for the biochemical-based strategy, and $681 for the viral-based strategy. At the upper limits of the sensitivity analysis (HCV incidence, 0.005), perpatient costs of screening were $193 for the
Fig 3. Sensitivity analysis comparing different hepatitis C screening strategies in hemodialysis patients. The prevalence of hepatitis C varied by 0.023 and 0.225.
HEPATITIS C SCREENING STRATEGIES
serological-based strategy, $370 for the biochemical-based strategy, and $676 for the viral-based strategy. In our model, biochemical-based screening would have misclassified 45 hemodialysis patients as having no evidence of HCV infection (false negative) and 93 patients as having infection (false positive). Serological-based screening would have misclassified 45 hemodialysis patients as not being HCV infected and 48 hemodialysis patients as being HCV infected. The costs per true HCV infection detected were $4,257 for biochemical-, $2,210 for serological-, and $6,922 for viral-based screening. Serological-based testing was more effective in the diagnosis of de novo HCV infection, with a likelihood ratio of 85 compared with 44 for biochemical-based testing. DISCUSSION
HCV infection has important implications. Infected patients must be identified to encourage alcohol abstinence and be advised of their potential for transmission. For instance, infected patients should not share toothbrushes, razors, and combs or hairbrushes with close contacts to avoid transmission.9 Hemodialysis patients continue to be at increased risk for HCV infection despite the implementation of universal precautions and decreased need for blood products with the use of erythropoietin.39 Because de novo infection is usually subclinical, effective screening should help identify newly infected patients.40 Our decision-analysis model comparing three strategies of HCV screening proved relatively robust when varying the tests’ cost, HCV prevalence, and HCV incidence (Figs 1 through 3). Serological-based screening was the preferred strategy based on lower costs and greater efficacy than biochemical-based screening (Table 2). Our results suggest that the biochemical strategy may have a diminished role in the diagnosis of HCV because it is less effective in predicting HCV infection than serological testing alone. In addition, biochemical screening is substantially more expensive than serological testing. The current standard for HCV surveillance in hemodialysis patients is ALT testing.9 ALT testing should screen for all currently recognized hepatotrophic viruses (hepatitis A, B, and C
95
viruses). However, hemodialysis patients are not believed to be at increased risk for hepatitis A infection relative to the general population, and patients are already routinely screened for hepatitis B infection by regular monitoring of hepatitis B surface antigen and antibody to hepatitis B surface antigen.1,2 Currently, the major role in the detection of viral hepatitis by biochemical screening is identifying patients with HCV infection. However, our results suggest that the efficacy of biochemical testing in the diagnosis of HCV infection is less than that of serologicalbased screening, and the costs of biochemical screening are substantially greater than those of serological-based screening. Viral-based testing is widely accepted as the gold standard in HCV detection in the hemodialysis population. Unlike serological testing, which detects anti-HCV, PCR testing is able to distinguish active from resolved infection. In our model, biochemical-based screening would have misclassified 45 hemodialysis patients as having no evidence of HCV infection and 93 patients as having infection. With serological-based screening, there would have been 45 false-negative and 48 false-positive results. However, there have been concerns that widespread use of PCR may be limited by availability, the need for meticulous specimen handling, and concerns regarding reproducibility.15,41 Many of these reservations have been addressed by the introduction of automated PCR assays, shown to be accurate and suitable for the diagnosis and monitoring of viral load in patients infected with HCV.42,43 There has been concern about intermittent HCV viremia in hemodialysis patients, which may decrease the sensitivity of PCR testing in the diagnosis of HCV infection.44 Recent evidence suggests that although HCV RNA decreases during dialysis, viral clearance does not occur.45 A potential limitation of our model is that patients with indeterminate SIA results were considered not to be HCV infected. However, the proportion of patients with indeterminate SIA results and evidence of hepatitis C viremia is low and unlikely to have changed the results.21,22 Courouce et al21 compared antibody and PCR assays for the diagnosis of HCV in a hemodialysis population and found that 3 of 57 patients with positive ELISA results had indeterminate
96
SAAB ET AL
SIA results. These 3 patients were not found to be viremic by PCR. This is in contrast to results of second-generation SIA tests in which a greater proportion of hemodialysis patients with indeterminate SIA results are viremic.22 Another potential limitation in our model is that on entry into the biochemical strategy, patients undergo baseline serological testing. As a result, costs incurred with entry serological testing will be included in the total costs of biochemical testing. Nevertheless, this strategy is likely the most common screening strategy in the United States and the one that most closely resembles recommendations of the Centers for Disease Control and Prevention. A third potential limitation is that an incremental cost-effectiveness ratio was not calculated. Because long-term consequences of HCV infection are unclear, the costs of misdiagnosis are unknown. Consequently, a likelihood ratio was used as the measure of effectiveness. This unifying term considers both the sensitivity and the positive rate. Because the serological strategy was associated with a greater likelihood ratio and substantially lower costs than biochemical screening, it is the most cost-effective strategy.17,18 Our results suggest that serological-based testing using a combination of ELISA and SIA testing in series was more effective than using ALT values for the diagnosis of HCV and less costly. With increasing automation of HCV serological testing, a compelling argument can be made for serological screening as the method of choice for HCV surveillance in chronic hemodialysis patients. ACKNOWLEDGMENT The authors thank David Ly for data collection.
REFERENCES 1. Saab S, Martin P, Brezina M, Gitnick G, Yee H Jr: Serum alanine aminotransferase in hepatitis C screening of patients on hemodialysis. Am J Kidney Dis 37:308-315, 2001 2. Tokars JI, Miller ER, Alter MJ, Arduino MJ: National surveillance of dialysis-associated diseases in the United States, 1997. Semin Dial 13:75-85, 2000 3. Mitsui T, Iwano K, Masuko K, Yamazaki C, Okamoto H, Tsuda F, Tanaka T, Mishiro S: Hepatitis C virus infection in medical personnel after needlestick accident. Hepatology 16:1109-1114, 1992 4. Stehman-Breen CO, Emerson S, Gretch D, Johnson RJ: Risk of death among chronic dialysis patients infected with hepatitis C virus. Am J Kidney Dis 32:629-634, 1998
5. Pereira BJ, Natov SN, Bouthot BA, Murthy BV, Ruthazer R, Schmid CH, Levey AS: Effects of hepatitis C infection and renal transplantation on survival in end-stage renal disease. The New England Organ Bank Hepatitis C Study Group. Kidney Int 53:1374-1381, 1998 6. Hanafusa T, Ichikawa Y, Kishikawa H, Kyo M, Fukunishi T, Kokado Y, Okuyama A, Shinji Y, Nagano S: Retrospective study on the impact of hepatitis C virus infection on kidney transplant patients over 20 years. Transplantation 66:471-476, 1998 7. Gentil MA, Rocha JL, Rodriguez-Algarra G, Pereira P, Lopez R, Bernal G, Munoz J, Naranjo M, Mateos J: Impaired kidney transplant survival in patients with antibodies to hepatitis C virus. Nephrol Dial Transplant 14:2455-2460, 1999 8. Martin P, Carter D, Fabrizi F, Dixit V, Conrad AJ, Artinian L, Peacock V, Han S, Wilkinson A, Lassman CR, Danovitch G: Histopathological features of hepatitis C in renal transplant candidates. Transplantation 69:1479-1484, 2000 9. Centers for Disease Control: Recommendation for prevention and control of hepatitis C virus (HCV) infection and HCV-related chronic disease. MMWR Morb Mortal Wkly Rep 47:1-38, 1998 10. Guh JY, Lai YH, Yang CY, Chen SC, Chuang WL, Hsu TC, Chen HC, Chang WY, Tsai JH: Impact of decreased serum transaminase levels on the evaluation of viral hepatitis in hemodialysis patients. Nephron 69:459-465, 1995 11. Yashuda K, Okuda K, Endo N, Ishiwatari Y, Ikeda R, Hayashi H, Yokozeki K, Kobayashi S, Irie Y: Hypoaminotransferasemia in patients undergoing long-term hemodialysis: Clinical and biochemical appraisal. Gastroenterology 109:1295-1300, 1995 12. Sterling RK, Sanyal AJ, Luketic VA, Stravitz RT, King AL, Post AB, Mills AS, Contos MJ, Shiffman ML: Chronic hepatitis C infection in patients with end-stage renal disease: Characterization of liver hepatology and viral load in patients awaiting renal transplantation. Am J Kidney Dis 94:3576-3582, 1999 13. Fabrizi F, Martin P, Dixit V, Brezina M, Cole MJ, Gerosa S, Vinson S, Mousa M, Gitnick G: Quantitative assessment of HCV load in chronic hemodialysis patients: A cross-sectional survey. Nephron 80:428-433, 1998 14. Mondelli MU, Smedile V, Piazza V, Villa G, Barbieri C, Gattarello G, Mancini F, Riamondo G: Abnormal alanine aminotransferase activity reflects exposure to hepatitis C virus in haemodialysis patients. Nephrol Dial Transplant 6:480-483, 1991 15. Gretch D: Use and interpretation of HCV diagnostic tests in the clinical setting. Clin Liver Dis 1:543-557, 1997 16. Youmossi Z, McHutchison J: Serological tests for HCV infection. Viral Hepatitis Rev 2:161-173, 1996 17. Provenzale D, Lipscomb J: Cost-effectiveness: Definitions and use in the gastroenterology literature. Am J Gastroenterol 91:1488-1493, 1996 18. Provenzale D, Lipscomb J: A reader’s guide to economic analysis in the GI literature. Am J Gastroenterol 91:2461-2470, 1996 19. Naimark D, Krahn MD, Naglie G, Redelmeier DA, Detsky AS: Primer on medical decision analysis: Part
HEPATITIS C SCREENING STRATEGIES
5—Working with Markov processes. Med Decis Making 17:152-159, 1997 20. Krahn MD, Naglie G, Naimark D, Redelmeier DA, Detsky AS: Primer on medical decision analysis: Part 4—Analyzing the model and interpreting the results. Med Decis Making 17:142-151, 1997 21. Courouce AM, Bouchardeau F, Chauveau P, Le Marrec N, Girault A, Zins B, Naret C, Poignet JL: Hepatitis C virus (HCV) infection in haemodialysed patients: HCVRNA and anti-HCV antibodies (third-generation assays). Nephrol Dial Transplant 10:234-239, 1995 22. al Meshari K, al Ahdal M, Alfurayh O, Ali A, De Vol E, Kessie G: New insights into hepatitis C virus infection of hemodialysis patients: The implications. Am J Kidney Dis 25:572-578, 1995 23. Seelig R, Renz M, Bottner C, Seelig HP: Hepatitis C virus infections in dialysis units: Prevalence of HCV-RNA and antibodies to HCV. Ann Med 28:45-52, 1994 24. Bukh J, Wantzin P, Krogsgaard K, Knudsen F, Purcell RH, Miller RH, Unit CDHS: High prevalence of hepatitis C virus (HCV) RNA in dialysis patients: Failure of commercially available antibody tests to identify a significant number of patients with HCV infection. J Infect Dis 168:13431348, 1993 25. Caramelo C, Bartolome J, Albalate M, de Sequera P, Navas S, Bermejillo T, Oliva H, Marriott E, Ortiz A, Ruiz Tunon C, Casado S, Carreno V: Undiagnosed hepatitis C virus infection in hemodialysis patients: Value of HCV RNA and liver enzyme levels. Kidney Int 50:2027-2031, 1996 26. Schneeberger PM, Keur I, Vliet WVD, Hoek KV, Boswijk H, Loon AMV, Dijk WCV, Kauffmann RH, Quint W, Doorn L-JV: Hepatitis C virus infections in dialysis centers in The Netherlands: A national survey by serological and molecular methods. J Clin Microbiol 36:1711-1715, 1998 27. Fabrizi F, Lunghi G, Guarnori I, Raffaele L, Crepaldi M, Pagano A, Locatelli F: Incidence of seroconversion for hepatitis C virus in chronic haemodialysis patients: A prospective study. Nephrol Dial Transplant 9:1611-1615, 1994 28. Chan TM, Lok AS, Cheng IK, Chan RT: Prevalence of hepatitis C virus infection in hemodialysis patients: A longitudinal study comparing the results of RNA and antibody assays. Hepatology 17:5-8, 1993 29. Fabrizi F, Lunghi G, Andrulli S, Pagliari B, Mangano S, Faranna P, Pagano A, Locatelli F: Influence of hepatitis C virus (HCV) viraemia upon serum aminotransferase activity in chronic dialysis patients. Nephrol Dial Transplant 12:13941398, 1997 30. Fabrizi F, Lunghi G, Raffaele L, Guarnori I, Bacchini G, Corti M, Pagano A, Erba G, Locatelli F: Serologic survey for control of hepatitis C in haemodialysis patients: Thirdgeneration assays and analysis of costs. Nephrol Dial Transplant 12:298-303, 1997 31. Fabrizi F, Martin P, Dixit V, Brezina M, Cole MJ, Gerosa S, Mousa M, Gitnick G: Acquisition of hepatitis C virus in hemodialysis patients: A prospective study by branched DNA signal amplification assay. Am J Kidney Dis 31:647-654, 1998
97
32. Fabrizi F, Martin P, Dixit V, Brezina M, Russell J, Conrad A, Schmid P, Gerosa S, Gitnick G: Detection of de novo hepatitis C virus infection by polymerase chain reaction in hemodialysis patients. Am J Nephrol 19:383-388, 1999 33. Schiff ER, de Medina M, Kahn RS: New perspectives in the diagnosis of hepatitis C. Semin Liver Dis 19:S3-S15, 1999 (suppl 1) 34. Medina MD, Hill M, Sullivan HO, Leclerq B, Pennell JP, Jeffers L, Reddy KR, Schiff ER, Perez GO: Detection of anti-hepatitis C virus antibodies in patients undergoing dialysis by utilizing a hepatitis C virus 3.0 assay: Correlation with hepatitis C virus RNA. J Lab Clin Med 132:73-75, 1998 35. Dalekos GN, Boumba DS, Katopodis K, Zervou E, Sferopoulos G, Elisaf M, Tsianos EV, Siamopoulos KC: Absence of HCV viraemia in anti-HCV-negative haemodialysis patients. Nephrol Dial Transplant 13:1804-1806, 1998 36. Al-Ahdal MN, Kessie G: Serological diagnosis of hepatitis C virus in patients with liver disease in Saudi Arabia. Evaluation of antibody determination by recombinant immunoblot assays in relation to RNA detection by polymerase chain reaction. Diagn Microbiol Infect Dis 27: 69-73, 1997 37. Fagan TJ: Nomogram for Bayes’ theorem. N Engl J Med 293:257, 1975 (letter) 38. Sackett DL, Haynes RB, Tugwell P: Clinical Epidemiology: A Basic Science for Clinical Medicine (ed 2). Boston, MA, Little, Brown, 1991 39. Simon N, Courouce AM, Lemarrec N, Trepo C, Ducamp S: A twelve year natural history of hepatitis C virus infection in hemodialyzed patients. Kidney Int 46:504-511, 1994 40. Medin C, Allander T, Roll M, Jacobson SH, Grillner L: Seroconversion to hepatitis C virus in dialysis patients: A retrospective and prospective study. Nephron 65:40-45, 1993 41. Zaaijer HL, Cuypers HT, Reesink HW, Winkel IN, Gerken G, Lelie PN: Reliability of polymerase chain reaction for detection of hepatitis C virus. Lancet 341:722-724, 1993 42. Martell M, Gomez J, Esteban JI, Sauleda S, Quer J, Cabot B, Esteban R, Guardia J: High-throughput real-time reverse transcription-PCR quantitation of hepatitis C virus RNA. J Clin Microbiol 37:327-332, 1999 43. Kawai S, Yokosuka O, Kanda T, Imazeki F, Maru Y, Saisho H: Quantification of hepatitis C virus by TaqMan PCR: Comparison with HCV Amplicor Monitor assay. J Med Virol 58:121-126, 1999 44. Galan F, Perez-Gracia MT, Lozano A, Benavides B, Fernandez-Ruiz E, Rodriguez-Iglesias MA: A 3-year follow-up of HCV-RNA viraemia in haemodialysis patients. Nephrol Dial Transplant 13:1211-1214, 1998 45. Furusyo N, Hayashi J, Ariyama I, Sawayama Y, Etoh Y, Shigematsu M, Kashiwagi S: Maintenance hemodialysis decreases serum hepatitis C virus (HCV) RNA levels in hemodialysis patients with chronic HCV infection. Am J Gastroenterol 95:490-496, 2000