|Year : 2017 | Volume
| Issue : 2 | Page : 35-41
Long-term outcomes of hepatitis C virus infected renal allograft recipients
Narayan Prasad1, Praveen Kumar Etta1, Akhilesh Jaiswal1, Raj Kumar Sharma1, Dharmendra Bhadauria1, Vivek Saraswat2, Anupama Kaul1, Gaurav Pandey2, Sameer Mahindra2, Amit Gupta1
1 Department of Nephrology and Renal Transplantation, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, Uttar Pradesh, India
2 Department of Gastroenterology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, Uttar Pradesh, India
|Date of Web Publication||12-Sep-2017|
Department of Nephrology and Renal Transplantation, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow - 226 014, Uttar Pradesh
Source of Support: None, Conflict of Interest: None
Background and Aim: This study aims to study the long-term outcomes of hepatitis C virus (HCV)-infected renal allograft recipients, which is still debatable. Materials and Methods: In this study (study period - January 2003 to December 2013), we studied long-term outcomes of 106 living donor renal allograft recipients - 53 HCV-infected (33 genotype 3 and 20 genotype 1) and 53 age- and gender-matched HCV-noninfected patients. Results: Thirty-nine (73.6%) patients detected HCV positive during dialysis, while 14 (26.4%) before the start of dialysis. Forty (75.5%) patients were positive for both anti-HCV and HCV RNA, while 13 (24.5%) were HCV RNA positive and anti-HCV negative. Twelve and nine patients died among HCV positive and negative groups, respectively. Major cause of death was sepsis in both groups. Hepatic failure contributed to mortality in four HCV-positive patients, two of them also had graft failure. Patient and death noncensored graft survival rates at 1, 5, and 10 years of follow-up in HCV-positive group were 100% and 100%; 79.8% and 70.8%; 58.9% and 37.8%; respectively; and in HCV-negative group were 100% and 100%; 95.9% and 91.8%; 58.9% and 27.4%; respectively. Conclusions: The long-term survival of HCV-positive renal transplant recipients was not inferior to that of HCV-negative recipients.
Keywords: Graft survival, hepatitis C virus, patient survival, renal transplantation, viral replication
|How to cite this article:|
Prasad N, Etta PK, Jaiswal A, Sharma RK, Bhadauria D, Saraswat V, Kaul A, Pandey G, Mahindra S, Gupta A. Long-term outcomes of hepatitis C virus infected renal allograft recipients. Indian J Transplant 2017;11:35-41
|How to cite this URL:|
Prasad N, Etta PK, Jaiswal A, Sharma RK, Bhadauria D, Saraswat V, Kaul A, Pandey G, Mahindra S, Gupta A. Long-term outcomes of hepatitis C virus infected renal allograft recipients. Indian J Transplant [serial online] 2017 [cited 2017 Nov 24];11:35-41. Available from: http://www.ijtonline.in/text.asp?2017/11/2/35/214383
| Introduction|| |
Globally, more than 185 million people are affected with chronic hepatitis C virus (HCV) infection, which accounts for approximately 2.8% of the general population. Chronic HCV infection, most common cause of chronic liver disease in chronic kidney disease (CKD) patients, detrimentally affects the quality of life, posttransplant graft survival, and increases the mortality of maintenance hemodialysis (MHD) patients. The incidence and prevalence of HCV infection in patients on MHD is higher than that of the general population and varies across the globe depending on the local practice of blood screening with nucleic acid amplification testing (NAT) or antibody detection and moreover on isolation practices of HCV-infected MHD patients. Dialysis outcomes and practice patterns study reported mean prevalence of chronic HCV infection 13.5% (range: 2.6% in the UK to 22.9% in Spain) among adult MHD patients from developed countries  and varying prevalence of 1.5% to 50% has been reported from different countries of Asia-Pacific region.,,,, Moreover, there is geographical and ethnicity variation in treatment responsiveness to antiviral agents. HCV genotype is one of the important factors which determines treatment responsiveness, varies not only across different geographical regions around the world but also in different regions within the countries like genotype 3 is more common in North India while genotype 1 in South India. Asians are more likely to have favorable CC-genotype IL28B gene polymorphism than Europeans and Africans. There is a paucity of data on treatment response and posttransplant patient and graft outcomes on long-term follow-up from Asian region.
Moreover, with availability of newer direct-acting antiviral agents (DAAs) which target HCV-encoded proteins and are associated with high sustained viral response (SVR) rates, lesser side effects, fewer drug interactions; the management of HCV infection is likely to change in future in CKD and posttransplant period. Sofosbuvir cannot be used in end-stage renal disease (ESRD) patients on dialysis as per manufacturers' instruction and CKD patients who have GFR of <30 ml/min, and the posttransplant experience is also limited at present. However, the standard of care in HCV-infected ESRD patients was interferon (IFN)-based regimen during dialysis and achievement of SVR before transplant. It is not an uncommon practice that many patients opt to go for renal transplantation with RVR and early viral response (EVR) without awaiting SVR; however, the long-term outcome data on such patients are lacking. The literature evidences of patient and graft outcomes of HCV-infected patients are conflicting with some evidences showing inferior survival while others showing at least similar survival. We retrospectively studied the short- and long-term outcomes of HCV-infected ESRD patients and compared with HCV noninfected patients who underwent renal transplantation during the same period at our institute.
| Materials and Methods|| |
In this retrospective designed study (study period - January 2003 to December 2013), we included a total of 106 living donor renal allograft recipients - 53 consecutive HCV-positive and 53 age- and gender-matched HCV-negative patients, who received renal allograft at similar time points. None of these patients were treated with DAAs at any point of time in past. All recruited patients were from our tertiary care institute which is located in the northern region of India. Third-generation ELISA and quantitative HCV RNA by real-time polymerase chain reaction (PCR) were performed in all patients. Viral load was measured by a quantitative HCV RNA assay (lower limit of detection of 15 log IU/mL, Cobas Amplicor HCV, Roche). Anti-HCV-positive patients were considered HCV infected only if they were positive for HCV RNA on quantification. Patients who received deceased donor allograft and coinfected with hepatitis B or HIV were excluded from the study. Patients with evidences of cirrhosis and portal hypertension on ultrasonography (USG) of hepatobiliary system and Doppler of portal vessels, elastometry (Fibroscan, Echosens, France) with cutoff values >12.5kPa, and patients with varices on upper gastrointestinal endoscopy were excluded from the study. Liver biopsy was not performed in any patient.
The demographic profiles and clinical characteristics of the patients, patient and graft survival, hepatic dysfunction, renal allograft function, rejection episodes, and causes of death in these patients were retrieved and compared between HCV-infected and noninfected patients. All patients were followed either till death or graft failure of the patients or the end of the study period. The study was conducted as per guidelines of Declaration of Helsinki and the study was approved from Ethics Committee of the Institute.
All HCV-infected patients were treated with standard IFN with or without ribavirin therapy and advised to complete recommended duration of therapy till SVR; however, this was not compulsory. Only the patients who did not show EVR with conventional IFN were treated with Peg-IFN. Those patients who had achieved EVR and having normal liver enzymes (alanine aminotransferase [ALT] and aspartate aminotransferase [AST]) and were not willing to continue antiviral therapy due to logistics and cost of therapy, were allowed for transplantation without waiting for the end of treatment response (ETR) and SVR. Quantitative HCV RNA analysis was performed before initiation of therapy, at 4 weeks, 12 weeks, and at the end of treatment, and at least 6 months after completion of therapy in cases of waiting to SVR, where applicable. In posttransplant period, AST/ALT levels and HCV NAT was performed at 3 months, 6 months, and then every year till end of the study. The relapse of HCV was defined by reappearance of HCV RNA on quantification. The following definitions were used for the study purpose.
- EVR: At least 2 log fall in the HCV viral titer at 12 weeks after initiation of therapy
- ETR: Undetectable HCV RNA at the end of therapy, i.e., 24 weeks for genotype 2 and 3; 48 weeks for genotype 1 and 4
- SVR: Undetectable HCV RNA at least 24 weeks after completion of therapy
- No response: <2 log reduction from baseline HCV RNA at 12 weeks or more after initiation of therapy.
All patients in both groups were treated with similar maintenance immunosuppressive regimen - prednisolone, mycophenolate mofetil (MMF), cyclosporine A (CsA), or tacrolimus. All patients were started with calcineurin inhibitors and MMF 2 days before renal transplantation, and induction therapy with IL-2 receptor antagonist (basiliximab or daclizumab) or ATG was given depending on immunological risk.
Quantitative data are expressed as mean and standard deviation or median and range as appropriate and categorical variables as frequencies and percentages. The differences in mean values between the groups were compared using the Student's t-test. The percentage of categorical variables between the two groups were compared using nonparametric Mann–Whitney U-test, χ2 test, or Fisher's exact probability test as appropriate. Kaplan–Meier survival analysis was used to compare the cumulative patient and graft survival, and log-rank test was used to assess the significance of difference between the groups. The deaths of the patients were considered as events in cases of patient survival analysis. Death-censored graft survival was calculated with events as irreversible graft failure, and death with a functioning graft was censored. In the event of death with a functioning graft, the follow-up period was censored at the date of death. Graft survival noncensored for death was calculated from the date of transplantation to the date of irreversible graft failure with events considering graft failure. Here, death with functioning graft was treated as graft failure. All data are analyzed using SPSS statistical software, version 16.0 (SPSS Inc., Chicago, IL, USA). P < 0.05 was considered statistically significant.
| Results|| |
The demographics and clinical characteristics of the patients in both HCV positive and negative groups are shown in [Table 1]. Patients in both groups were similar in terms of age, gender, native kidney diseases, modality of dialysis before transplantation, HLA mismatches, cold and warm ischemia time, induction therapy, and duration of follow-up. Greater number of patients received CsA in HCV-positive group as compared to HCV-negative group although not significant statistically. HCV-positive patients received longer duration of hemodialysis compared to HCV-negative patients [Table 1].
|Table 1: Demographic and clinical characteristics of hepatitis C virus positive and negative patients|
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Treatment, side effects, and response to therapy
The HCV- and treatment-related details are shown in [Table 2]. Thirty-nine (73.6%) patients became HCV positive during dialysis, while 14 (26.4%) were positive before the start of dialysis. Forty (75.5%) patients were positive for both anti-HCV and HCV RNA, while 13 (24.5%) were HCV RNA positive and anti-HCV negative. Most common genotype was genotype 3 in 33 (62.2%) patients followed by genotype 1 in 20 (37.7%) of patients. Cytopenias were the most common side effects followed by gastrointestinal side effects, which led to treatment interruption in four patients. Both patients who developed central nervous system-related side effects were receiving Peg-IFN. Six patients developed secondary infections, including tuberculosis in two. Majority patients were treated with conventional IFN alone (86.8%), 3 (5.7%) with conventional IFN plus ribavirin, three with peg-IFN alone, and one with peg-IFN plus ribavirin.
|Table 2: Diagnostic and therapeutic details of hepatitis C virus infection|
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Thirty-two patients had undergone renal transplantation after EVR, 15 after ETR, and only four after SVR. All the four patients who waited for SVR had also been treated with peg IFN, including the one in combination with ribavirin. Two patients did not respond to conventional IFN and ribavirin combination and opted to undergo renal transplant in HCV RNA positive state; however, their ALT/AST level was normal.
In posttransplant period, 19/32 (59.3%) patients who had been transplanted after EVR, 7/15 (46.6%) after ETR, and 2/4 (50%) after SVR experienced relapses [Table 3]. All relapses were associated with increased AST/ALT level. The ALT/AST levels at different time points at 1 year, 5 years, and end of follow-up are shown in [Table 4].
|Table 3: Patient's hepatitis C virus status at the time of transplantation and frequencies of hepatitis C virus relapse after transplantation|
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Acute rejection episodes were similar in both HCV positive and negative groups. New onset diabetes after transplantation (NODAT) was significantly high in HCV-positive patients (39.6%) as compared to that of negative patients (18.9%), P = 0.02. Significant proteinuria (more than 500 mg/day) was noted in 15 patients among HCV-positive group and seven in HCV-negative group (28.3% vs. 13.2%, P = 0.05) [Table 4]. Renal allograft biopsy was performed in 11 HCV-positive patients either for graft dysfunction or proteinuria. Two patients who showed membranoproliferative changes and one predominantly mesangial proliferation without IgA deposits may have HCV-associated glomerulopathy. All three of them had viral replication.
Patient and graft survival analysis
During follow-up, 12 (22.6%) patients in HCV-positive patients and nine (17%) in HCV-negative patients were died. Sepsis was the most common cause of death in both groups of patients; hepatic failure contributed to death of four patients in HCV-positive group.
Actuarial patient survival rates at 1, 5, and 10 years of follow-up in HCV-positive group were 100%, 79.8%, and 58.9% and in HCV-negative group were 100%, 95.9%, and 58.9%, respectively [Figure 1]. Although separation of curves was wide at 5 years, the difference was not significant (P = 0.06). Actuarial graft survival rates (death noncensored) at 1, 5, and 10 years were 100%, 70.8%, and 37.8% in HCV-positive group and 100%, 91.8%, and 27.4% in HCV-negative group, respectively [Figure 2]. When graft survival rates were censored for patient death with functioning allograft, actuarial graft survival at 1, 5, and 10 years were 100%, 79.5%, and 42.5% in HCV-positive group and 100%, 95.8%, and 39.8% in HCV-negative group, respectively [Figure 3]. Even though there was a trend for greater patient and graft survival rates among HCV-negative group especially at 5 years of follow-up, overall, there were no significant differences in patient and graft survivals among the groups at last follow-up.
|Figure 1: Kaplan–Meier survival analysis showing patient survival in hepatitis C virus infected and noninfected patients.|
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|Figure 2: Kaplan–Meier survival analysis showing death noncensored graft survival in hepatitis C virus infected and noninfected patients.|
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|Figure 3: Kaplan–Meier survival analysis showing death censored graft survival in hepatitis C virus infected and noninfected patients.|
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| Discussion|| |
In this study, we observed that overall patient survival of HCV-positive patients at 10 years is not significantly different from that of HCV-negative patients after transplantation; however, there was a wide separation of survival curves at 5 years with 95.9% surviving in HCV-negative group and only 79.8% in HCV-positive group. This observation indicates that majority of deaths in HCV-infected patients occurred within 5 years of transplant. The major causes of deaths in these HCV-positive patients were sepsis and hepatic failure. Anti-HCV positive status is associated with increased risk of mortality; however, it is not a contraindication to transplantation as survival rates of these patients are better after transplantation as compared to patients continuing on dialysis.,, Ridruejo et al. also showed reduced graft and patient survival of anti-HCV positive compared with anti-HCV negative status in a retrospective study. Meta-analysis by Fabrizi et al. concluded that HCV-positive patients pose a greater risk of graft failure and death compared to HCV-negative patients. In a systematic review of 18 observational studies by Rostami et al., the hazard ratio in HCV-infected recipients was 1.69 times and 1.56 times greater than that of HCV-negative recipients for mortality and graft loss, respectively. In contrast, Uyar et al. in their study concluded that graft and patient survivals were not influenced by HBV or HCV infection. Arango et al. also showed similar overall graft and patient survival at the end of 5 years in HCV positive and negative renal allograft recipients.
Similar to our study, Legendre et al. in deceased donor transplantation  and Agarwal et al. in living donor transplantation also found that liver failure and sepsis are two major causes of death in these patients. Agarwal et al. showed similar survival in HCV positive and negative patients on follow-up till 28 months, and sepsis was the cause of death in 65% of their patients; however, in both studies, HCV RNA status was uncertain. Few anti-HCV-negative patients may be positive for HCV NAT. In our study, we observed 13 patients were diagnosed based on PCR only as they were negative for third-generation ELISA. Occult HCV infection is burning issue presently; in whom, anti-HCV and HCV RNA both are negative, but they are positive on testing mononuclear cells and hepatocytes.
We have also observed that the incidence of NODAT was significantly greater in HCV-positive patients as compared to that of the negative patients; similar observation has been seen in many other studies including a meta-analysis. Potential mechanisms for the diabetogenic effect of HCV infection include insulin resistance, decreased hepatic glucose uptake and glycogenesis, and direct cytopathic effect of the virus on pancreatic cells and recently recognized interaction between tacrolimus and HCV infection.
The association of viral infections such as CMV with rejection has been debated, and association of HCV with rejection remains controversial with one study showing higher frequency of acute rejection  while another  did not, similar to our study. Treatment of HCV with IFN alpha is associated with increased risk of acute rejection in posttransplant period. Besides rejection and transplant-related chronic allograft failure, HCV may also be associated with various other renal diseases such as mixed cryoglobulinemia, membranoproliferative glomerulonephritis (MPGN), membranous nephropathy, and rarely polyarteritis nodosa. Kidney Disease: Improving Global Outcomes (KDIGO) guidelines suggest that HCV-infected kidney transplant recipients should be tested at least every 3–6 months for proteinuria. In our cohort of HCV-positive patients, we observed greater degree of proteinuria and proportion of nephrotic syndrome than HCV-negative patients and at least two patients have MPGN and one had mesangioproliferative GN, which may be attributed to HCV infection.
The treatment of these patients before transplant is concerned as rate of spontaneous remission is rare, and disease may progress faster in posttransplant. Factors such as genotype 3, more common in our cohort and in accordance with distribution in general non-CKD, HCV patients in India, and favorable IL-28B polymorphism, although not studied in our patients, but reportedly more common in Asians and Indians, are good prognostic factors in these patients. Liver biopsy was not performed in any of our patients; however, every patient was meticulously tested by USG, Doppler, and transient elastography (TE) for indirect evidences of chronicity. There are conflicting suggestions from different guidelines in this regard. KDIGO suggested that HCV-infected kidney transplant candidates should undergo a liver biopsy before transplantation. However, American Association for the Study of Liver Disease suggests for liver biopsy for patients with genotypes 1 and 4 only, not for genotypes 2 and 3. In a recent study, there was good correlation of TE with histology on liver biopsy in predicting significant hepatic fibrosis and cirrhosis in patients with ESRD infected with HCV. However, the final evidence in this regard is yet to come.
The treatment of HCV before transplant remains conflicting, as relapse of viral replication has been observed in every group of patients irrespective of EVR, ETR, and SVR. It is possible that occult infection with viruses in mononuclear cells and hepatocytes may be responsible factor. With availability of newer DAAs, the scenario may change as these drugs (especially Sofosbuvir) are not recommended with GFR of <30 ml/min with present evidences;, however, they can be used once the renal function becomes normal after renal transplantation. However, the evidences in this support are still lacking. Data in liver transplant recipients showed that DAAs are safe and effective and have been reported to salvage liver transplant patients with HCV-related fibrosing cholestasis. The recent availability of other DDAs such as daclatasvir or ledipasvir in India and treating these patients after relapse in posttransplant period may improve the outcome of these patients in future.
The ideal immunosuppression in HCV-infected patients in posttransplant period is debatable as immunosuppression may be detrimental for liver function and HCV replication. Evidences suggest that CsA and MMF may have protective effects and inhibit HCV replication in renal transplant patients with HCV infection. In cultured hepatocytes, cyclosporin, but not tacrolimus, prevents HCV replication. In our patients, 58.4% of patients were treated with CSA-based regimen while 39.6% with tacrolimus and there was no much difference in terms of viral activation in two groups. Shah et al. have shown no difference in the patients' outcomes on patient special induction protocol with convention immunosuppression regimen and showed no difference in outcomes. However, such protocol needs to be validated in larger and randomized study.
Strengths and Limitations of the study
The major strength of the study is that all patients recruited in the study have HCV RNA titer and genotypes available since beginning unlike other studies where all anti-HCV patients were recruited irrespective of HCV RNA status. All HCV-infected patients received at least 12 weeks of antiviral therapy before renal transplantation. The limitations are unavailability of liver biopsy and histology report and small sample size of HCV-positive patients; however, long duration of follow-up is major strength. Even in the era of DDAs, the study carries the importance because the long-term outcome is not available with DDAs at present and the present data of pre-DDAs era will provide historical outcome values to compare with the outcomes on DDAs in future.
| Conclusions|| |
The patient and graft survival of HCV-infected patients are not inferior to HCV-negative patients. Sepsis and liver failure are major causes of deaths in HCV-positive patients. NODAT and proteinuria are more frequently observed in HCV-infected patients. Virus may replicate in few transplant patients despite SVR after IFN therapy. About one-quarter of HCV-infected patients were anti-HCV negative and diagnosed only after HCV RNA on NAT. HCV infection is not a contraindication for transplantation.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
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[Figure 1], [Figure 2], [Figure 3]
[Table 1], [Table 2], [Table 3], [Table 4]