|Year : 2018 | Volume
| Issue : 5 | Page : 1092-1099
|The long-term impact of hepatitis C infection in kidney transplantation in the pre-direct acting antiviral era
Radhika Chemmangattu Radhakrishnan1, Basu Gopal2, Uday G Zachariah3, Priya Abraham4, Anjali Mohapatra5, Anna T Valson5, Suceena Alexander5, Shibu Jacob5, Kakde Shailesh Tulsidas5, Vinoi G David5, Santosh Varughese5
1 Department of Pediatric Nephrology, Government Medical College, Thiruvananthapuram, Kerala, India
2 Central Northern Adelaide Renal and Transplant Service, Royal Adelaide Hospital, Adelaide, Australia
3 Department of Hepatology, Christian Medical College, Vellore, India
4 Department of Clinical Virology, Christian Medical College, Vellore, India
5 Department of Nephrology, Christian Medical College, Vellore, India
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|Date of Submission||30-Sep-2017|
|Date of Acceptance||26-Nov-2017|
|Date of Web Publication||26-Oct-2018|
| Abstract|| |
Hepatitis C virus (HCV) infection in kidney transplantation is an important issue with effects on patient and graft survival. The current standard of care involves using oral Direct Acting Antiviral drugs. Till recently, pre-transplant treatment with interferon was the only option for treatment. We studied 677 consecutive kidney transplant recipients with HCV infection. 5.2% patients had evidence of HCV infection. 2.0% were newly detected to have HCV infection after transplant (de novo HCV group). Nearly 28.6% had negative antibody tests but positive Nucleic Acid Test at the time of diagnosis. Eighty-five percent of pre-transplant HCV-positive patients were treated with interferon-based regimens. Early virologic response was seen in 66.6%. End of treatment response was achieved by 94.1%. Sustained virologic response was seen in 81.2%. Overall, patient and graft survival were not different between HCV and control groups (log-rank P = 0.154). Comparing HCV and control groups, there was a tendency toward increased fungal (11.4% vs. 5.6%, P = 0.144) and CMV infections (25.7% vs. 17.1%, P = 0.191) in the HCV group, though it did not reach statistical significance. Eighty-percent of the interferon-treated patients suffered side effects. On comparing, the pre-transplant HCV-positive group (85% treated) with the de novo HCV group (none treated), the de novo group had significantly reduced patient survival (P = 0.020) and NODAT (35.7 vs 4.8%, P = 0.028), and a tendency toward higher CMV infections (35.7% vs 19%, P = 0.432). In addition, death and hepatic complications (decompensated liver disease, fibrosing cholestatic hepatitis) occurred only in de novo HCV group. These results highlight the need for continued post-transplant treatment of HCV positive patients. The newer anti-HCV drugs are expected to fulfill this felt-need in kidney transplantation but long-term results are awaited. This study can serve as a benchmark for future studies to compare the long-term effect of Direct Acting Antiviral drugs.
|How to cite this article:|
Radhakrishnan RC, Gopal B, Zachariah UG, Abraham P, Mohapatra A, Valson AT, Alexander S, Jacob S, Tulsidas KS, David VG, Varughese S. The long-term impact of hepatitis C infection in kidney transplantation in the pre-direct acting antiviral era. Saudi J Kidney Dis Transpl 2018;29:1092-9
|How to cite this URL:|
Radhakrishnan RC, Gopal B, Zachariah UG, Abraham P, Mohapatra A, Valson AT, Alexander S, Jacob S, Tulsidas KS, David VG, Varughese S. The long-term impact of hepatitis C infection in kidney transplantation in the pre-direct acting antiviral era. Saudi J Kidney Dis Transpl [serial online] 2018 [cited 2018 Nov 15];29:1092-9. Available from: http://www.sjkdt.org/text.asp?2018/29/5/1092/243964
| Introduction|| |
Hepatitis C is an important co-morbid infection in Kidney Transplant Recipients (KTRs). In developed countries, the prevalence of hepatitis C virus (HCV) infection in KTRs varies from 1.8% to 8%.,, Despite a relatively lower patient and graft survival, kidney transplantation remains the therapy of choice for patients with end-stage renal disease (ESRD) and HCV infection. Lack of safe and effective therapy after kidney transplantation was a problem till the recent discovery of Direct Acting Antiviral (DAA) drugs. There is limited data from India on HCV infection in KTRs. Hence, we studied the prevalence, clinical profile, treatment, and outcome of HCV infection in KTRs in India in the pre-DAA era to identify potential areas where DAA use could have a great impact.
| Subjects and Methods|| |
We studied consecutive KTRs from January 2005 to December 2013 at Department of Nephrology, Christian Medical College (CMC), Vellore. All prospective kidney transplant candidates underwent testing: HBsAg and anti HCV antibody were tested by ELISA (Abbott Architect, US), HBV DNA PCR and HCV RNA PCR by Quantitative RT PCR (Abbott M2000SP/M2000RT, US) and liver function tests. Transaminitis was defined as AST/ALT values >2 times of the upper limit of normal (ULN). In the pre-transplant period, ULN was taken as 18 IU/L for AST and 16 IU/L for ALT. In the post-transplant period, ULN was taken as 40 IU/L for AST and 35 IU/L for ALT. Early and sustained virologic responses and end of treatment response were defined according to standard definitions.
HCV infection was defined as a positive anti-HCV Antibody and/or HCV RNA PCR positivity. HCV/HBV positive patients were further evaluated by liver biopsy. Controls were defined as patients with no evidence of HCV or hepatitis B virus (HBV) infection. KTRs with HCV infection detected in the pre-transplant period were grouped under the pre-transplant HCV group and those with newly detected HCV infection after transplant were considered as de novo HCV group.
| Statistical Analysis|| |
Statistical analysis was done using Statistical Package for the Social Sciences (SPSS) software version 15.0 (SPSS Inc., Chicago, IL, USA). Chi-square test and Fischer’s test were used for comparison of nonpaired categorical data. Mann–Whitney test was used to compare medians of two independent samples. Graft and patient survivals were analyzed using Kaplan–Meier analysis.
| Results|| |
A total of 677 KTRs underwent kidney transplantation from January 2005 to December 2013. Their mean age was 35.9 ± 12.1 years and had male:female ratio of 3.3:1 and mean duration of post-transplant follow-up of 46.2 months. 605 (89.3%) and 72 (10.7%) were live and deceased donor transplants, respectively. Native kidney disease was unknown in 389 (57.4%), diabetic nephropathy in 97 (14.3%) and Ig A nephropathy in 34 (5%). Predominant immunosuppressive agents used were Mycophenolate (MPA) in 560 (82.7%), Tacrolimus in 517 (76.4%), Cyclosporine in 157 (23.2%) and Azathioprine in 121 (17.3%).
Thirty-five (5.2%) patients had evidence of HCV infection including two patients who had both HBV and HCV co-infection (HCV group). The baseline characteristics of HCV group is summarized in [Table 1]. Twenty-one patients (3.1%) had HCV infection detected in the pretransplant period (Pretransplant HCV group). 14 patients (2.0%) were newly detected to have HCV infection after transplant (de novo HCV group) [Figure 1]. Six hundred and nine patients who had no evidence of HBV or HCV infection were considered as the control group. Comparison of baseline characteristics between control and HCV groups is summarized in [Table 1]. The HCV group had male preponderance compared to controls (M:F 10.7:1 vs 3.2:1, P =0.038).
|Table 1: Comparison of baseline characteristics and outcomes between control and HCV groups.|
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|Figure 1: Overview of HCV infection in kidney transplant recipients.|
KTR: Kidney transplant recipients, HCV: Hepatitis C virus, Tx: Transplant, PCR: Polymerase chain reaction test.
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The pre-transplant hepatitis C virus group
2.8% of KTRs were detected to have HCV infection before transplant. In 71.4% cases (14 patients), there was concordance between HCV RNA PCR and Anti-HCV antibody positivity. However, 28.6% were negative for anti-HCV but had viremia detected by HCV PCR at the time of diagnosis [Figure 1]. On the other hand, only one patient tested positive for anti-HCV antibody but negative by HCV PCR. This patient was considered to either have a false positive antibody result or to have cleared the infection and was not treated.
Genotyping of HCV was done in eight patients. Genotype 1 was the predominant type (5 patients, 62.5%) followed by genotype 3 (3 patients, 37.5%). In one patient, genotype could not be identified due to low viral counts. Median RNA copies were 15200 IU/mL (range: 64.0 – 11×106 IU/mL).
Pre-transplant hepatitis C virus treatment
Of the 20 HCV RNA PCR-positive patients detected pre-transplant, 17 (85%) were treated. The rest could not be treated either due to non-willingness or economic reasons. Eight patients (47%) were treated with peg-Interferon 2α, six (35.2%) patients with standard interferon, two patients (11.8%) with combination of interferon 2α and ribavirin, and one patient (5.8%) with pegylated-Interferon 2β. Median treatment duration was 4.8 months (range: 0.85–18.3 months). Thus, 58.8% of patients received interferon with or without ribavirin. The main adverse event noted during the treatment was anemia and flu-like symptoms (80%).
Early virologic response was seen in six out of nine tested patients (66.6%). End of treatment response, defined as HCV PCR negativity at the end of treatment before the transplant was achieved by 16 patients (94.1%). Sustained virologic response defined as HCV PCR negativity for up to six months after stopping therapy was seen in 13 out of 16 tested patients (81.2%).
De novo hepatitis C virus group
In the post-transplant period, 14 (2%) patients were newly detected to have HCV infection. There was no significant identifiable risk factor for de novo seroconversion like exposure to hemodialysis versus peritoneal dialysis, duration of hemodialysis, blood transfusion history, or episodes of rejection [Table 2]. Absence of induction use was found to be associated with de novo seroconversion.
Post-transplant outcomes were compared between: (1) HCV group and controls, (2) pretransplant HCV treated and untreated groups, and (3) pre-transplant HCV and de novo HCV groups. Overall, patient and graft survival were not different between HCV and control groups (log-rank P = 0.154) [Figure 2]. There was no HCV-associated glomerulonephritis in any of the patients.
|Figure 2: Comparison of patient survival and death adjusted graft survival between HCV and control groups and patient survival between Pre-transplant HCV and de novo HCV groups.|
HCV: Hepatitis C virus, HBV: Hepatitis B virus.
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The incidence of NODAT was not increased in HCV group (17.1% vs. 22.5%, P = 0.595). HCV group was predominantly on cyclosporine rather than tacrolimus-based immunosuppression, as is our institution protocol (65.7% vs. 18.7%, P<0.001).
Comparing HCV and control groups, there was a tendency toward increased fungal (11.4% vs. 5.6%, P = 0.144) and CMV disease (25.7% vs. 17.1%, P = 0.191) in the HCV group, though it did not reach statistical significance. Especially, the patients who did not receive anti HCV Therapy before kidney transplantation had significantly increased fungal infections compared to those who were treated (67.0% vs. 0%, P = 0.016). The untreated group also had a trend toward higher proportion of CMV disease (33.3% vs. 17.6%, P = 0.509) and lesser rejections (0% vs. 29.4%, P = 0.539).
Outcomes in pre-transplant hepatitis C virus versus de novo hepatitis C virus groups
On comparing the pre-transplant HCV positive group (85% treated) with the de novo HCV group (none treated), the de novo group had significantly reduced patient survival (P = 0.020) and NODAT (35.7 vs. 4.8%, P = 0.028), and a tendency toward higher CMV disease (35.7% vs. 19%, P = 0.432) [Figure 2] and [Table 3]. In addition, death and hepatic complications (decompensated liver disease, fibrosing cholestatic hepatitis) occurred only in de novo HCV group. Of this, two patients developed and died of hepatic complications (1 each with fibrosing cholestatic hepatitis and decompensated liver disease). There was a higher rate of acute rejection episodes in the pre-transplant group (28.6% vs 14.3%), thought not statistically significant.
|Table 3: Comparison of outcomes between pre-transplant and de novo HCV groups.|
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| Discussion|| |
In this study, 5.2 % of our KTRs had evidence of HCV infection. Importantly, in the pre-transplant period, 28.6% of patients had negative antibody results but were HCV RNA PCR positive. El-Sherif et al also reported high anti-HCV false-negative rate of 17.9% among Egyptian patients on regular hemodialysis. This highlights the need for routine nucleic acid test testing ideally in all dialysis patients if not, at least in those planning for kidney transplantation.
The earlier standard of care in treating HCV infected ESRD patients was to provide antiviral therapy with interferon before kidney transplantation, while patients are on dialysis, thus prolonging their waiting period for transplantation. This was because the interferonbased treatment increased the risk of rejections and hence could not be used in posttransplant period except in life-threatening situations. It was adviced to stop interferon therapy at least four weeks before kidney transplantation, though its effect on the immune system could last longer. Even though we had an excellent end of treatment response of 94%, sustained virological response (SVR) was observed only in 81.2%. However, an SVR rate of 81% is still considerably higher than reported in literature., This may be because most of our patients were identified to have HCV infection early in the course of their illness with limited liver involvement by histology (all biopsied patients had no or mild periportal fibrosis).
In spite of this, 13% of patients who attained end of treatment response and underwent transplantation had recurrence of viremia in the post-transplant period. In addition, 80% of the patients who received interferon developed anemia and flu-like symptoms. Patients who received interferon therapy pre-transplant had a trend toward higher rates of acute rejection episodes compared to those untreated as well as those who developed HCV de novo post-transplant, possibly related to interferon exposure. Thus, treatment with interferon-based regimens is limited by efficacy, side effects, and increased risk of rejections. This highlights the need for safe and effective anti-HCV therapy in this group of patients.
There is a trend toward increase in co-infections, namely CMV disease and fungal infections in KTRs with HCV infection, owing to the immunomodulatory effects of HCV. This association was stronger among those with pre-transplant HCV infection who were not treated. The reported association of HCV with co-infections is variable. Some studies have shown that HCV is associated with bloodstream, pulmonary and central nervous system infections, but a recent meta-analysis by Fabrizi et al did not show any such association. Torres et al reported HCV as an independent risk factor for Mycobacterium tuberculosis infection after renal transplantation, but we did not find an increase in tuberculosis infection in HCV group. However, in a previous study from our centre by John et al, chronic liver disease per se has been found to be a risk factor for tuberculosis. Control of HCV infection post-kidney transplant could potentially reduce the risk of co-morbid infections.
A reduced patient survival has been well documented among KTRs with HCV infections in two large meta-analyses with respective hazard ratios: 1.69 [95% confidence interval (CI) 1.33–1.97] and 1.79 [95% CI 1.57–2.03]., In our patients, de novo post-transplant HCV infection, which is largely untreated, was strongly associated with more deaths and reduced patient survival. The major cause of death in de novo HCV group was liver failure and co-infections. Liver complications in the form of fibrosing cholestatic hepatitis and decompensated chronic liver disease occurred only in the de novo group, none of whom received antiviral therapy. Effective antiviral therapy in the post-transplant setting could effectively reduce these complications and improve patient survival.
Graft survival was also shown to be significantly reduced with HCV infections in two independent meta-analysis by Fabrizi et al and Rostami et al [respective hazard ratios 1.56 (95% CI 1.22–2.004) and 1.56 (95% CI 1.35–1.80) for graft loss]., However, we did not find decrease in graft survival in HCV group compared to controls or even in de novo positive group. This may be because none of our patients had HCV associated glomerulonephritis or significantly increased rejections compared to control group.
The absence of induction use was found to be associated with de novo seroconversion. We hypothesize that it could be due to lesser rejections and hence lesser cumulative immunosuppressive drug exposure associated with induction agent use, but this requires further validation. The fact that no other risk factor was found for de novo seroconversion highlights the importance of regular post-transplant screening of KTRs.
There was no increased incidence in NODAT in overall HCV positive group compared to controls as a result of our policy of using cyclosporine (CsA)-based immunosuppression. This is consistent with current evidence that tacrolimus increases the risk for NODAT in HCV infected recipients more than CSA., However, de novo post-transplant HCV group had significantly higher NODAT than pre-transplant HCV group. This is important because NODAT is a complication that can affect survival in HCV infected patients. Treatment of HCV and achieving SVR prior to transplant has been shown to reduce NODAT incidence. Thus, post-transplant treatment of HCV with DAA could potentially reduce NODAT.
| Conclusion|| |
HCV infection in KTRs reduces patient survival and is associated with CMV and fungal co-infections. Outcomes are better when HCV is treated in the pre-transplant period. In view of high false negative rate of anti-HCV antibody testing, we suggest that all prospective transplant candidates should be screened by NAT for early identification and treatment in the pre-transplant period. Interferon-based HCV treatment is limited by side effects, loss of viral remission, increased risk of rejections and inability to be used in the post-transplant period. KTRs need to be regularly monitored for post-transplant HCV seroconversion, which is associated with poor survival and increased co-infections and liver complications. This is because of lack of safe therapy in the post-transplant period earlier. With newer, safer, oral DAA drugs in the market, this scenario has changed. This study can serve as a benchmark for future studies to compare the long-term effect of DAA drugs.
Conflict of interest: None declared.
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Dr. Radhika Chemmangattu Radhakrishnan
Department of Pediatric Nephrology, Government Medical College, Thiruvananthapuram, Kerala
[Figure 1], [Figure 2]
[Table 1], [Table 2], [Table 3]
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