Original Report: Patient-Oriented, Translational Research American
Journal of
Nephrology
Received: August 2, 2013 Accepted: September 16, 2013 Published online: October 29, 2013
Am J Nephrol 2013;38:405–412 DOI: 10.1159/000355615
Hepatitis C Infection Is Very Rarely Treated among Hemodialysis Patients David A. Goodkin a Brian Bieber a Brenda Gillespie b Bruce M. Robinson a Michel Jadoul c
c
Arbor Research Collaborative for Health, Ann Arbor, Mich., USA; b University of Michigan, Ann Arbor, Mich., USA; Cliniques Universitaires St-Luc, Université catholique de Louvain, Brussels, Belgium
Key Words Antiviral · Dialysis Outcomes and Practice Patterns Study · Hepatitis C · Interferon · Mortality · Ribavirin · Transplantation
Abstract Background: Hepatitis C virus (HCV) infection is associated with increased mortality among hemodialysis (HD) patients. Guidelines from Kidney Disease: Improving Global Outcomes recommend that infected HD patients awaiting renal transplantation be treated for HCV and that clinicians decide whether to treat other infected patients on a case-by-case basis. We evaluated the extent and outcome of HCV therapy among HD patients. Methods: The Dialysis Outcomes and Practice Patterns Study is an observational study; 49,762 HD patients in 12 nations enrolled between 1996 and 2011. We reviewed HCV status, use of interferon or ribavirin, and survival over a median 1.4 years per study phase. Results: 4,735 patients (9.5%) were HCV+. Only 48 (1.0%) of the 4,589 HCV+ patients with prescription data were receiving antiviral medication. Among the subset of 617 HCV+ patients also known to be on a waiting list for renal transplantation, only 3.7% were receiving treatment. After restricting to HCV+ patients with overlapping propensity for antiviral treatment, 4 (9.5%) of 42 treated patients and 638 (21.0%) of 3,037 untreated patients died. The hazard ratio for adjusted mortality comparing treated patients with untreated patients was 0.47
© 2013 S. Karger AG, Basel 0250–8095/13/0385–0405$38.00/0 E-Mail [email protected] www.karger.com/ajn
(95% CI, 0.17–1.26). Conclusions: HD patients with hepatitis C infection very rarely receive antiviral therapy. Increased intervention might prolong survival for some patients and in particular might improve the prospects for those awaiting renal transplantation. © 2013 S. Karger AG, Basel
Introduction
Hepatitis C viral (HCV) infection occurs more frequently among hemodialysis (HD) patients than in the general population, and infection is associated with markedly increased mortality. However, it is unclear from the medical literature how often HD patients with hepatitis C infection are treated with antiviral agents. Historically, these agents have included interferon, pegylated interferon, and ribavirin, with protease inhibitors just recently approved. Also, there is a paucity of data addressing survival of patients with HCV infection who are treated versus those who are untreated. The Dialysis Outcomes and Practice Patterns Study (DOPPS) is a large, prospective, observational study of HD patients in 12 countries that collects extensive data on enrollees, including hepatitis status and medications [1, 2]. The DOPPS is thus well suited to investigate antiviral treatment practices and survival among patients with hepatitis C, and those are the goals of the current analysis. David A. Goodkin, MD 3807 134th Avenue NE Bellevue, WA 98005 (USA) E-Mail davidagoodkin @ comcast.net
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a
Phase 2
Phase 1 1998
1999
2000
2001
2002
2003
Phase 3 2004
2005
2006
2007
Phase 4 2008
2009
2010
2011
Fig. 1. Phases of the DOPPS for Cox regression mortality modeling. Data collection did not begin until phase 2
in Australia, Belgium, Canada, New Zealand, and Sweden.
Patients and Data Collection Patients were enrolled randomly from a representative sample of dialysis facilities between 1996 and 2010 [1, 2]. Data from 49,762 HD patients in Australia, Belgium, Canada, France, Germany, Italy, Japan, New Zealand, Spain, Sweden, the UK, and the USA were analyzed. Phase 1 of the DOPPS collected data from 1996 to 2001; phase 2 from 2002 to 2004; phase 3 from 2005 to 2008, and phase 4 from 2009 to 2011 (fig. 1). Data collection in Australia, Belgium, Canada, New Zealand, and Sweden did not begin until phase 2. Demographic data, comorbid conditions, laboratory values, and medications were abstracted from patient records. Medication lists were ascertained at study entry and updated every 4 months, except in phase 2 when medication lists were updated every year. Transplant wait-list status was routinely collected in phases 2, 3, and 4, but was only queried for patients enrolled toward the end of phase 1 in Japan and the USA and was not queried during phase 1 in Europe. Definitions Patients were defined as positive for hepatitis C infection (HCV+) if they had a diagnosis of hepatitis C entered in their medical record or if they tested positive for hepatitis C antibody, at the time of study entry or during follow-up. All others were defined as HCV–. During phase 2, HCV status was ascertained at entry, but, thereafter, was not collected every 4 months, as was the case during the other study phases. Both pegylated and nonpegylated interferons were included in the single category ‘interferon.’ Data Analysis The percentage of HCV+ patients receiving antiviral therapy was first determined overall, and then among just the subset of HCV+ patients who were also on a waiting list for renal transplantation. Two sensitivity analyses were conducted to gauge the likelihood of ascertainment bias. First, the calculations above were repeated among only those patients who seroconverted from HCV– to HCV+ status after entry into the DOPPS. Second, treatment rates were examined across the 4 study phases. To account for case-mix differences between treated and untreated HCV+ patients when considering mortality risk, a propensity score approach was used. First, a logistic model predicting antiviral treatment was used to calculate each patient’s propensity score, which is the estimated probability of receiving antiviral treatment based on age, vintage, sex, country, phase, black race in the USA, 14 comorbid conditions (coronary artery disease, cancer, other cardiovascular disease, cerebrovascular disease, conges-
406
Am J Nephrol 2013;38:405–412 DOI: 10.1159/000355615
tive heart failure, diabetes mellitus, gastrointestinal bleeding, HIV/AIDS, hypertension, lung disease, neurologic disorder, psychological disorder, peripheral vascular disease, recurrent cellulitis), albumin, and hemoglobin levels. The subsequent analyses included only those untreated patients whose propensity scores were in the same range as the treated patients. Treated patients whose propensity scores exceeded the range of the untreated patient group were excluded. A Cox regression model predicting mortality, with time starting at the earliest of (a) DOPPS enrollment or (b) September 15, 1998 (for patients enrolled in the USonly portion of DOPPS 1, which started in 1996) was then fit. The association of antiviral treatment with time to death was adjusted for the propensity score, while accounting for facility clustering and stratifying by country. HCV+ patients were included in the risk set at the time of DOPPS enrollment for prevalent HCV, or left-truncated at the time of first diagnosis for those diagnosed after enrollment. Treatment was included as a time-dependent covariate, and some patients were followed across DOPPS phases. During each phase, the majority of patients were newly enrolled prevalent patients. The participating sites were not identical from phase to phase. No patients were treated in more than one phase. Patients in multiple DOPPS phases were removed from the risk set while unobserved between phases. Censoring events included transplant, dialysis modality change, transfer, and loss to follow-up.
Results
The patient population and exclusion criteria for each portion of the following analyses are shown in figure 2. HCV Prevalence The prevalence of HCV+ patients varied from 3.3 to 16.8% across nations, pooling the results from all 4 DOPPS study phases (see fig. 3). Out of 49,762 total patients enrolled, 4,735 (9.5%) were HCV+. The median duration of patient follow-up during each DOPPS phase was 1.4 years. Antiviral Medication Prescriptions Table 1 shows the number of HCV+ patients who were prescribed an interferon formulation or ribavirin during each phase (at baseline or at any time during follow-up), Goodkin/Bieber/Gillespie/Robinson/ Jadoul
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Methods
Figure 3, table 1
n = 49,762 (overall population) - 45,027 HCV– n = 4,735 (HCV+)
Table 2, all patients
Figure 4, table 2
- 216 US DOPPS 1 patients lacking follow-up after Sep. 15, 1998 (approximate start of international DOPPS 1) - 144 patients missing medications information - 227 patients missing comorbidity data - 74 patients with insufficient data for follow-up time
n = 4,074 (follow-up)
- 197 patients in countries without antiviral treatment - 798 patients with nonoverlapping propensity scores
n = 3,079 (propensity score)
n = 42 (treated)
n = 3,037 (untreated)
Fig. 2. Patient selection diagram.
16.0
16 14
12.9
12
10.5
10
8.6
8 6 4
16.8
3.3
4.6
4.7
4.7
4.7
4.8
5.9
2 0
UK CA SW GE AU NZ
HCV cases: 85
87
99
130
76
11
BE USA FR
SP
IT
JP
115 1,766 280 395 413 1,278
Country
Fig. 3. Prevalence of HCV infection in HD patients, by country. Overall prevalence 9.5% (4,735 of 49,767 patients). CA = Canada; SW = Sweden; GE = Germany; AU = Australia; NZ = New Zealand; BE = Belgium; FR = France; SP = Spain; IT = Italy; JP = Japan.
phase 2; 1.6% in phase 3, and 1.0% in phase 4. Among the HCV+ patients who were also known to be wait-listed for transplant, the following percentages were treated: 4.8% in phase 1; 2.3% in phase 2; 4.9% in phase 3, and 1.2% in phase 4. Am J Nephrol 2013;38:405–412 DOI: 10.1159/000355615
407
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Treatment of HCV in Hemodialysis
18 Prevalence of HCV (%)
by country. The interferon numbers include both pegylated and nonpegylated formulations. In total, 48 (1.0%) of 4,589 HCV+ patients with medication data submitted were prescribed antiviral treatment: 17 received both interferon and ribavirin, 27 received interferon alone, and 4 received ribavirin alone. Among the patients treated with interferon, 22 received a nonpegylated formulation and 22 received a pegylated formulation. Use of pegylated formulations increased from 0% during phase 1 to 70% during phase 4. Renal transplantation waiting list status was known for 2,800 of the HCV+ patients, and 624 (22.3%) of these were wait-listed. Among the 617 HCV+ wait-listed individuals for whom medication data were submitted, 23 (3.7%) received antiviral medication. The first sensitivity analysis found that 3 (0.4%) of the 847 patients who seroconverted from HCV– to HCV+ status after entry into the DOPPS were prescribed antiviral medication. Of the 129 patients who seroconverted after entry into the DOPPS and also were known to be on a transplantation waiting list, 2 (1.6%) were treated. The second sensitivity analysis found that the following percentages of HCV+ patients were treated during the respective phases of the study: 0.6% in phase 1; 0.7% in
Table 2. HCV patient characteristics, by antiviral treatment
Characteristic Country
Australia Belgium Canada France Germany Italy Japan New Zealand Spain Sweden UK USA All
phase 1
phase 2
phase 3
phase 4
Int
Rib
Int
Rib
Int
Rib
Int
Rib
– – – 4 0 1 0 – 0 – 0 7 12
– – – 0 0 0 0 – 0 – 0 3 3
0 0 0 0 1 2 0 0 2 1 0 0 6
0 0 0 0 1 0 0 0 0 1 1 0 3
0 0 1 3 3 2 1 0 3 1 0 2 16
0 0 0 1 2 2 0 0 2 1 0 1 9
0 0 0 0 1 0 1 0 2 2 0 4 10
0 0 0 0 2 0 0 0 0 2 0 2 6
Phase 1 = 1996–2001; phase 2 = 2002–2004; phase 3 = 2005– 2008; phase 4 includes data from 2009 to 2011. Interferon (Int) includes both pegylated and nonpegylated formulations. Of 21 patients receiving ribavirin (Rib), 4 received it as monotherapy and 17 also received interferon. 27 patients received interferon alone. We did not observe any patients treated in more than one phase. Australia, Belgium, Canada, New Zealand, and Sweden did not join the DOPPS until phase 2.
Mortality among Treated versus Untreated HCV+ Patients Among HCV+ patients with sufficient data for analysis (n = 4,074, fig. 2), prior to propensity score analyses 4 (9.3%) of the 43 treated patients and 914 (22.7%) of 4,031 untreated patients died (unadjusted hazard ratio, HR = 0.28, 95% CI, 0.11–0.73). The HCV+ patients treated with antiviral medications were younger, had a longer vintage, and had lower prevalence of coronary artery disease, cerebrovascular disease, congestive heart failure, diabetes mellitus, gastrointestinal bleeding, and peripheral vascular disease than the untreated patients (table 2). A propensity score was calculated (accounting for multiple demographic and comorbid factors as well as serum albumin and hemoglobin concentrations) to control for patient characteristics predictive of antiviral treatment that could potentially confound the relationship between treatment and mortality. Subsequent analyses were restricted to treated and untreated patients whose propensity for treatment was within the range of propensity scores for the other group. Among these patients, 4 (9.5%) 408
All patients
DOPPS Data Collection Phase
Am J Nephrol 2013;38:405–412 DOI: 10.1159/000355615
Age, years Vintage, years Male, % US black, % Wait-listed, % Comorbidities, % Coronary artery disease Cancer Cerebrovascular disease Congestive heart failure Other cardiovascular disease Diabetes Gastrointestinal bleed HIV/AIDS Hypertension Lung disease Neurologic disorder Psychiatric disorder Peripheral vascular disease Recurrent cellulitis Labs, g/dl Albumin Hemoglobin Country, % Australia Belgium Canada France Germany Italy Japan New Zealand Spain Sweden UK USA DOPPS phase, % 1 (1998–2001) 2 (2002–2004) 3 (2005–2008) 4 (2009–2011)
untreated (n = 4,031)
treated (n = 43)
59.4±13.8 7.4±8.1 62 15 21
48.9±11.1 10.1±9.1 61 12 64
36 10 34 14 28 34 7 2 75 8 10 20 21 6 3.7±0.5 10.8±1.7
23 9 30 2 21 19 2 5 86 7 7 16 7 0 3.7±0.3 11.0±2.0
2 3 2 7 3 10 31 0 10 2 2 29
0 0 2 16 16 12 5 0 19 9 2 19
44 20 22 14
23 16 37 23
of 42 treated patients and 638 (21%) of untreated patients died (unadjusted HR = 0.32, 95% CI, 0.13–0.82). Casemix difference between treated and untreated patients persisted in this restricted population (table 2) prompting several adjusted analyses. Figure 4 shows the KaplanMeier survival curves for HCV+ patients treated with antiviral medication and for untreated HCV+ patients; the Goodkin/Bieber/Gillespie/Robinson/ Jadoul
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Table 1. Numbers of HCV+ patients prescribed antiviral medication (interferon; ribavirin), by country and study phase
Table 3. Hepatitis C infection among hemodialysis patients is associated with markedly increased risk of mortality (case-mix adjusted)
Study
HR mortality
95% CI
Nation
DOPPS1 Pereira [5] Stehman-Breen [6] Nakayama [7] Espinosa [8] Johnson [9] Johnson [9]
1.22 1.41 1.97 1.57 1.62 1.37 1.29
1.11–1.33 1.01–1.97 1.16–3.33 1.23–2.00 1.05–2.49 1.15–1.62 1.05–1.58
International USA USA Japan Spain Japan Australia/ New Zealand
Discussion
100
Cumulative survival (%)
80 Antiviral treated 60 Untreated (adjusted)
40
Untreated (unadjusted) 20
0
2
4
6
8
10
12
14
Time since DOPPS enrollment (years)
Fig. 4. Survival of treated HCV+ patients, untreated HCV+ patients, and untreated HCV+ patients adjusted for treatment propensity. Adjusted curve is the expected survival if the propensity for treatment of the untreated patients had been equal to the mean propensity among the treated patients (see text for propensity score details). HR (95% CI) = 0.47 (0.17–1.26; treated vs. untreated), based on Cox regression adjusted for propensity for treatment, stratified by country, and accounting for facility clustering. Antiviral treatment was included as a time-dependent variable.
middle survival curve depicts survival among untreated patients, adjusted to match the average propensity for treatment among the treated patients. After adjusting for treatment propensity using Cox regression, the mortality HR for the treated patients compared with the untreated Treatment of HCV in Hemodialysis
Overall, 9.5% of the HD patients in the DOPPS were HCV+. Clearly, this is not a rare condition. The true number of patients who harbored HCV infection over the course of the DOPPS was likely even higher, as not all the dialysis facilities screened patients for HCV on a regular basis [3], especially before the 2001 recommendation by the Centers for Disease Control and Prevention that all HD patients should be screened [4]. The prevalence varied from 3.3 to 16.8% across countries. Multiple factors contribute to HCV+ prevalence among HD patients, including prevalence and ongoing transmission rates within the general population, seroconversion on HD, and survival on dialysis. The more years a patient dialyzes, the greater the chance of eventual exposure. Seroconversion rates of 1.1–3.6 per 100 patient-years persisted across the DOPPS countries from 1997 to 2001 [3]. As shown in table 3, multiple studies have found increased risk of death, adjusted for case mix, among HD patients positive for HCV antibody [5–9]. It is important to establish the optimal treatment for this potentially lethal condition. The first striking finding of our current study is that only 48 (1.0%) of 4,589 HCV+ patients in 12 countries were receiving antiviral medication. During the most recent phase of the study, in most countries the number of patients treated with interferon was 0 or 1 and the number treated with ribavirin was 0 or 1. It appears that hepatitis C essentially goes untreated among HD patients internationally. It is possible that nephrologists underestimate the extent of liver damage because serum aminotransferase concentrations frequently remain normal or are only mildly elevated among HD patients with HCV infection [10–12]. The levels are often discrepantly low compared with hepatic biopsy findings. There are several potential limitations to our analyses. One might hypothesize that some patients completed a 6- to 12-month standard course of interferon prior to study entry, in which case we would be underestimating the true frequency of treatment. We therefore examined only patients who seroconverted from HCV– to HCV+ status after entry into the DOPPS, who are exempt from that concern, and found that only 0.4% were treated. Only 1.6% of the seroconverters who were also on a transplant Am J Nephrol 2013;38:405–412 DOI: 10.1159/000355615
409
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HRs compare HCV+ patients vs. HCV– patients. 1 DOPPS phases 1–3 (1996–2008).
0
patients was 0.47 (95% CI, 0.17–1.26). Further adjusting this model for the variables used to calculate the propensity score did not substantially alter this association.
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Am J Nephrol 2013;38:405–412 DOI: 10.1159/000355615
Our data also shed light on the specific choice of antiviral agent(s) selected in the setting of HD. The 2008 Kidney Disease: Improving Global Outcomes (KDIGO) guidelines recommend standard, nonpegylated interferon for patients on HD [14], yet half of those receiving interferon in the DOPPS were prescribed pegylated interferon. A randomized trial comparing pegylated versus nonpegylated interferon, that was unavailable at the time the KDIGO hepatitis C guidelines were drafted, found the pegylated formulation to be safer, more effective, and more convenient [15]. In the most recent phase 4 of the DOPPS, 70% of patients prescribed interferon received the pegylated formulation. It should also be noted that 21 patients were prescribed ribavirin, and in 4 cases it was prescribed without interferon. Controversy exists regarding the prescription of ribavirin in the setting of advanced CKD. The manufacturer’s product information for ribavirin specifies that patients with creatinine clearance
Journal of
Nephrology
Received: August 2, 2013 Accepted: September 16, 2013 Published online: October 29, 2013
Am J Nephrol 2013;38:405–412 DOI: 10.1159/000355615
Hepatitis C Infection Is Very Rarely Treated among Hemodialysis Patients David A. Goodkin a Brian Bieber a Brenda Gillespie b Bruce M. Robinson a Michel Jadoul c
c
Arbor Research Collaborative for Health, Ann Arbor, Mich., USA; b University of Michigan, Ann Arbor, Mich., USA; Cliniques Universitaires St-Luc, Université catholique de Louvain, Brussels, Belgium
Key Words Antiviral · Dialysis Outcomes and Practice Patterns Study · Hepatitis C · Interferon · Mortality · Ribavirin · Transplantation
Abstract Background: Hepatitis C virus (HCV) infection is associated with increased mortality among hemodialysis (HD) patients. Guidelines from Kidney Disease: Improving Global Outcomes recommend that infected HD patients awaiting renal transplantation be treated for HCV and that clinicians decide whether to treat other infected patients on a case-by-case basis. We evaluated the extent and outcome of HCV therapy among HD patients. Methods: The Dialysis Outcomes and Practice Patterns Study is an observational study; 49,762 HD patients in 12 nations enrolled between 1996 and 2011. We reviewed HCV status, use of interferon or ribavirin, and survival over a median 1.4 years per study phase. Results: 4,735 patients (9.5%) were HCV+. Only 48 (1.0%) of the 4,589 HCV+ patients with prescription data were receiving antiviral medication. Among the subset of 617 HCV+ patients also known to be on a waiting list for renal transplantation, only 3.7% were receiving treatment. After restricting to HCV+ patients with overlapping propensity for antiviral treatment, 4 (9.5%) of 42 treated patients and 638 (21.0%) of 3,037 untreated patients died. The hazard ratio for adjusted mortality comparing treated patients with untreated patients was 0.47
© 2013 S. Karger AG, Basel 0250–8095/13/0385–0405$38.00/0 E-Mail [email protected] www.karger.com/ajn
(95% CI, 0.17–1.26). Conclusions: HD patients with hepatitis C infection very rarely receive antiviral therapy. Increased intervention might prolong survival for some patients and in particular might improve the prospects for those awaiting renal transplantation. © 2013 S. Karger AG, Basel
Introduction
Hepatitis C viral (HCV) infection occurs more frequently among hemodialysis (HD) patients than in the general population, and infection is associated with markedly increased mortality. However, it is unclear from the medical literature how often HD patients with hepatitis C infection are treated with antiviral agents. Historically, these agents have included interferon, pegylated interferon, and ribavirin, with protease inhibitors just recently approved. Also, there is a paucity of data addressing survival of patients with HCV infection who are treated versus those who are untreated. The Dialysis Outcomes and Practice Patterns Study (DOPPS) is a large, prospective, observational study of HD patients in 12 countries that collects extensive data on enrollees, including hepatitis status and medications [1, 2]. The DOPPS is thus well suited to investigate antiviral treatment practices and survival among patients with hepatitis C, and those are the goals of the current analysis. David A. Goodkin, MD 3807 134th Avenue NE Bellevue, WA 98005 (USA) E-Mail davidagoodkin @ comcast.net
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a
Phase 2
Phase 1 1998
1999
2000
2001
2002
2003
Phase 3 2004
2005
2006
2007
Phase 4 2008
2009
2010
2011
Fig. 1. Phases of the DOPPS for Cox regression mortality modeling. Data collection did not begin until phase 2
in Australia, Belgium, Canada, New Zealand, and Sweden.
Patients and Data Collection Patients were enrolled randomly from a representative sample of dialysis facilities between 1996 and 2010 [1, 2]. Data from 49,762 HD patients in Australia, Belgium, Canada, France, Germany, Italy, Japan, New Zealand, Spain, Sweden, the UK, and the USA were analyzed. Phase 1 of the DOPPS collected data from 1996 to 2001; phase 2 from 2002 to 2004; phase 3 from 2005 to 2008, and phase 4 from 2009 to 2011 (fig. 1). Data collection in Australia, Belgium, Canada, New Zealand, and Sweden did not begin until phase 2. Demographic data, comorbid conditions, laboratory values, and medications were abstracted from patient records. Medication lists were ascertained at study entry and updated every 4 months, except in phase 2 when medication lists were updated every year. Transplant wait-list status was routinely collected in phases 2, 3, and 4, but was only queried for patients enrolled toward the end of phase 1 in Japan and the USA and was not queried during phase 1 in Europe. Definitions Patients were defined as positive for hepatitis C infection (HCV+) if they had a diagnosis of hepatitis C entered in their medical record or if they tested positive for hepatitis C antibody, at the time of study entry or during follow-up. All others were defined as HCV–. During phase 2, HCV status was ascertained at entry, but, thereafter, was not collected every 4 months, as was the case during the other study phases. Both pegylated and nonpegylated interferons were included in the single category ‘interferon.’ Data Analysis The percentage of HCV+ patients receiving antiviral therapy was first determined overall, and then among just the subset of HCV+ patients who were also on a waiting list for renal transplantation. Two sensitivity analyses were conducted to gauge the likelihood of ascertainment bias. First, the calculations above were repeated among only those patients who seroconverted from HCV– to HCV+ status after entry into the DOPPS. Second, treatment rates were examined across the 4 study phases. To account for case-mix differences between treated and untreated HCV+ patients when considering mortality risk, a propensity score approach was used. First, a logistic model predicting antiviral treatment was used to calculate each patient’s propensity score, which is the estimated probability of receiving antiviral treatment based on age, vintage, sex, country, phase, black race in the USA, 14 comorbid conditions (coronary artery disease, cancer, other cardiovascular disease, cerebrovascular disease, conges-
406
Am J Nephrol 2013;38:405–412 DOI: 10.1159/000355615
tive heart failure, diabetes mellitus, gastrointestinal bleeding, HIV/AIDS, hypertension, lung disease, neurologic disorder, psychological disorder, peripheral vascular disease, recurrent cellulitis), albumin, and hemoglobin levels. The subsequent analyses included only those untreated patients whose propensity scores were in the same range as the treated patients. Treated patients whose propensity scores exceeded the range of the untreated patient group were excluded. A Cox regression model predicting mortality, with time starting at the earliest of (a) DOPPS enrollment or (b) September 15, 1998 (for patients enrolled in the USonly portion of DOPPS 1, which started in 1996) was then fit. The association of antiviral treatment with time to death was adjusted for the propensity score, while accounting for facility clustering and stratifying by country. HCV+ patients were included in the risk set at the time of DOPPS enrollment for prevalent HCV, or left-truncated at the time of first diagnosis for those diagnosed after enrollment. Treatment was included as a time-dependent covariate, and some patients were followed across DOPPS phases. During each phase, the majority of patients were newly enrolled prevalent patients. The participating sites were not identical from phase to phase. No patients were treated in more than one phase. Patients in multiple DOPPS phases were removed from the risk set while unobserved between phases. Censoring events included transplant, dialysis modality change, transfer, and loss to follow-up.
Results
The patient population and exclusion criteria for each portion of the following analyses are shown in figure 2. HCV Prevalence The prevalence of HCV+ patients varied from 3.3 to 16.8% across nations, pooling the results from all 4 DOPPS study phases (see fig. 3). Out of 49,762 total patients enrolled, 4,735 (9.5%) were HCV+. The median duration of patient follow-up during each DOPPS phase was 1.4 years. Antiviral Medication Prescriptions Table 1 shows the number of HCV+ patients who were prescribed an interferon formulation or ribavirin during each phase (at baseline or at any time during follow-up), Goodkin/Bieber/Gillespie/Robinson/ Jadoul
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Methods
Figure 3, table 1
n = 49,762 (overall population) - 45,027 HCV– n = 4,735 (HCV+)
Table 2, all patients
Figure 4, table 2
- 216 US DOPPS 1 patients lacking follow-up after Sep. 15, 1998 (approximate start of international DOPPS 1) - 144 patients missing medications information - 227 patients missing comorbidity data - 74 patients with insufficient data for follow-up time
n = 4,074 (follow-up)
- 197 patients in countries without antiviral treatment - 798 patients with nonoverlapping propensity scores
n = 3,079 (propensity score)
n = 42 (treated)
n = 3,037 (untreated)
Fig. 2. Patient selection diagram.
16.0
16 14
12.9
12
10.5
10
8.6
8 6 4
16.8
3.3
4.6
4.7
4.7
4.7
4.8
5.9
2 0
UK CA SW GE AU NZ
HCV cases: 85
87
99
130
76
11
BE USA FR
SP
IT
JP
115 1,766 280 395 413 1,278
Country
Fig. 3. Prevalence of HCV infection in HD patients, by country. Overall prevalence 9.5% (4,735 of 49,767 patients). CA = Canada; SW = Sweden; GE = Germany; AU = Australia; NZ = New Zealand; BE = Belgium; FR = France; SP = Spain; IT = Italy; JP = Japan.
phase 2; 1.6% in phase 3, and 1.0% in phase 4. Among the HCV+ patients who were also known to be wait-listed for transplant, the following percentages were treated: 4.8% in phase 1; 2.3% in phase 2; 4.9% in phase 3, and 1.2% in phase 4. Am J Nephrol 2013;38:405–412 DOI: 10.1159/000355615
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Treatment of HCV in Hemodialysis
18 Prevalence of HCV (%)
by country. The interferon numbers include both pegylated and nonpegylated formulations. In total, 48 (1.0%) of 4,589 HCV+ patients with medication data submitted were prescribed antiviral treatment: 17 received both interferon and ribavirin, 27 received interferon alone, and 4 received ribavirin alone. Among the patients treated with interferon, 22 received a nonpegylated formulation and 22 received a pegylated formulation. Use of pegylated formulations increased from 0% during phase 1 to 70% during phase 4. Renal transplantation waiting list status was known for 2,800 of the HCV+ patients, and 624 (22.3%) of these were wait-listed. Among the 617 HCV+ wait-listed individuals for whom medication data were submitted, 23 (3.7%) received antiviral medication. The first sensitivity analysis found that 3 (0.4%) of the 847 patients who seroconverted from HCV– to HCV+ status after entry into the DOPPS were prescribed antiviral medication. Of the 129 patients who seroconverted after entry into the DOPPS and also were known to be on a transplantation waiting list, 2 (1.6%) were treated. The second sensitivity analysis found that the following percentages of HCV+ patients were treated during the respective phases of the study: 0.6% in phase 1; 0.7% in
Table 2. HCV patient characteristics, by antiviral treatment
Characteristic Country
Australia Belgium Canada France Germany Italy Japan New Zealand Spain Sweden UK USA All
phase 1
phase 2
phase 3
phase 4
Int
Rib
Int
Rib
Int
Rib
Int
Rib
– – – 4 0 1 0 – 0 – 0 7 12
– – – 0 0 0 0 – 0 – 0 3 3
0 0 0 0 1 2 0 0 2 1 0 0 6
0 0 0 0 1 0 0 0 0 1 1 0 3
0 0 1 3 3 2 1 0 3 1 0 2 16
0 0 0 1 2 2 0 0 2 1 0 1 9
0 0 0 0 1 0 1 0 2 2 0 4 10
0 0 0 0 2 0 0 0 0 2 0 2 6
Phase 1 = 1996–2001; phase 2 = 2002–2004; phase 3 = 2005– 2008; phase 4 includes data from 2009 to 2011. Interferon (Int) includes both pegylated and nonpegylated formulations. Of 21 patients receiving ribavirin (Rib), 4 received it as monotherapy and 17 also received interferon. 27 patients received interferon alone. We did not observe any patients treated in more than one phase. Australia, Belgium, Canada, New Zealand, and Sweden did not join the DOPPS until phase 2.
Mortality among Treated versus Untreated HCV+ Patients Among HCV+ patients with sufficient data for analysis (n = 4,074, fig. 2), prior to propensity score analyses 4 (9.3%) of the 43 treated patients and 914 (22.7%) of 4,031 untreated patients died (unadjusted hazard ratio, HR = 0.28, 95% CI, 0.11–0.73). The HCV+ patients treated with antiviral medications were younger, had a longer vintage, and had lower prevalence of coronary artery disease, cerebrovascular disease, congestive heart failure, diabetes mellitus, gastrointestinal bleeding, and peripheral vascular disease than the untreated patients (table 2). A propensity score was calculated (accounting for multiple demographic and comorbid factors as well as serum albumin and hemoglobin concentrations) to control for patient characteristics predictive of antiviral treatment that could potentially confound the relationship between treatment and mortality. Subsequent analyses were restricted to treated and untreated patients whose propensity for treatment was within the range of propensity scores for the other group. Among these patients, 4 (9.5%) 408
All patients
DOPPS Data Collection Phase
Am J Nephrol 2013;38:405–412 DOI: 10.1159/000355615
Age, years Vintage, years Male, % US black, % Wait-listed, % Comorbidities, % Coronary artery disease Cancer Cerebrovascular disease Congestive heart failure Other cardiovascular disease Diabetes Gastrointestinal bleed HIV/AIDS Hypertension Lung disease Neurologic disorder Psychiatric disorder Peripheral vascular disease Recurrent cellulitis Labs, g/dl Albumin Hemoglobin Country, % Australia Belgium Canada France Germany Italy Japan New Zealand Spain Sweden UK USA DOPPS phase, % 1 (1998–2001) 2 (2002–2004) 3 (2005–2008) 4 (2009–2011)
untreated (n = 4,031)
treated (n = 43)
59.4±13.8 7.4±8.1 62 15 21
48.9±11.1 10.1±9.1 61 12 64
36 10 34 14 28 34 7 2 75 8 10 20 21 6 3.7±0.5 10.8±1.7
23 9 30 2 21 19 2 5 86 7 7 16 7 0 3.7±0.3 11.0±2.0
2 3 2 7 3 10 31 0 10 2 2 29
0 0 2 16 16 12 5 0 19 9 2 19
44 20 22 14
23 16 37 23
of 42 treated patients and 638 (21%) of untreated patients died (unadjusted HR = 0.32, 95% CI, 0.13–0.82). Casemix difference between treated and untreated patients persisted in this restricted population (table 2) prompting several adjusted analyses. Figure 4 shows the KaplanMeier survival curves for HCV+ patients treated with antiviral medication and for untreated HCV+ patients; the Goodkin/Bieber/Gillespie/Robinson/ Jadoul
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Table 1. Numbers of HCV+ patients prescribed antiviral medication (interferon; ribavirin), by country and study phase
Table 3. Hepatitis C infection among hemodialysis patients is associated with markedly increased risk of mortality (case-mix adjusted)
Study
HR mortality
95% CI
Nation
DOPPS1 Pereira [5] Stehman-Breen [6] Nakayama [7] Espinosa [8] Johnson [9] Johnson [9]
1.22 1.41 1.97 1.57 1.62 1.37 1.29
1.11–1.33 1.01–1.97 1.16–3.33 1.23–2.00 1.05–2.49 1.15–1.62 1.05–1.58
International USA USA Japan Spain Japan Australia/ New Zealand
Discussion
100
Cumulative survival (%)
80 Antiviral treated 60 Untreated (adjusted)
40
Untreated (unadjusted) 20
0
2
4
6
8
10
12
14
Time since DOPPS enrollment (years)
Fig. 4. Survival of treated HCV+ patients, untreated HCV+ patients, and untreated HCV+ patients adjusted for treatment propensity. Adjusted curve is the expected survival if the propensity for treatment of the untreated patients had been equal to the mean propensity among the treated patients (see text for propensity score details). HR (95% CI) = 0.47 (0.17–1.26; treated vs. untreated), based on Cox regression adjusted for propensity for treatment, stratified by country, and accounting for facility clustering. Antiviral treatment was included as a time-dependent variable.
middle survival curve depicts survival among untreated patients, adjusted to match the average propensity for treatment among the treated patients. After adjusting for treatment propensity using Cox regression, the mortality HR for the treated patients compared with the untreated Treatment of HCV in Hemodialysis
Overall, 9.5% of the HD patients in the DOPPS were HCV+. Clearly, this is not a rare condition. The true number of patients who harbored HCV infection over the course of the DOPPS was likely even higher, as not all the dialysis facilities screened patients for HCV on a regular basis [3], especially before the 2001 recommendation by the Centers for Disease Control and Prevention that all HD patients should be screened [4]. The prevalence varied from 3.3 to 16.8% across countries. Multiple factors contribute to HCV+ prevalence among HD patients, including prevalence and ongoing transmission rates within the general population, seroconversion on HD, and survival on dialysis. The more years a patient dialyzes, the greater the chance of eventual exposure. Seroconversion rates of 1.1–3.6 per 100 patient-years persisted across the DOPPS countries from 1997 to 2001 [3]. As shown in table 3, multiple studies have found increased risk of death, adjusted for case mix, among HD patients positive for HCV antibody [5–9]. It is important to establish the optimal treatment for this potentially lethal condition. The first striking finding of our current study is that only 48 (1.0%) of 4,589 HCV+ patients in 12 countries were receiving antiviral medication. During the most recent phase of the study, in most countries the number of patients treated with interferon was 0 or 1 and the number treated with ribavirin was 0 or 1. It appears that hepatitis C essentially goes untreated among HD patients internationally. It is possible that nephrologists underestimate the extent of liver damage because serum aminotransferase concentrations frequently remain normal or are only mildly elevated among HD patients with HCV infection [10–12]. The levels are often discrepantly low compared with hepatic biopsy findings. There are several potential limitations to our analyses. One might hypothesize that some patients completed a 6- to 12-month standard course of interferon prior to study entry, in which case we would be underestimating the true frequency of treatment. We therefore examined only patients who seroconverted from HCV– to HCV+ status after entry into the DOPPS, who are exempt from that concern, and found that only 0.4% were treated. Only 1.6% of the seroconverters who were also on a transplant Am J Nephrol 2013;38:405–412 DOI: 10.1159/000355615
409
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HRs compare HCV+ patients vs. HCV– patients. 1 DOPPS phases 1–3 (1996–2008).
0
patients was 0.47 (95% CI, 0.17–1.26). Further adjusting this model for the variables used to calculate the propensity score did not substantially alter this association.
410
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Our data also shed light on the specific choice of antiviral agent(s) selected in the setting of HD. The 2008 Kidney Disease: Improving Global Outcomes (KDIGO) guidelines recommend standard, nonpegylated interferon for patients on HD [14], yet half of those receiving interferon in the DOPPS were prescribed pegylated interferon. A randomized trial comparing pegylated versus nonpegylated interferon, that was unavailable at the time the KDIGO hepatitis C guidelines were drafted, found the pegylated formulation to be safer, more effective, and more convenient [15]. In the most recent phase 4 of the DOPPS, 70% of patients prescribed interferon received the pegylated formulation. It should also be noted that 21 patients were prescribed ribavirin, and in 4 cases it was prescribed without interferon. Controversy exists regarding the prescription of ribavirin in the setting of advanced CKD. The manufacturer’s product information for ribavirin specifies that patients with creatinine clearance
