Further evidence of the benefits associated with antiviral treatment in kidney allograft recipients with chronic hepatitis B virus infection
Authors: Jan Sperl, Sona Frankova, Julius Spicak, Ondrej Viklicky
Journal: Journal of Hepatology (2012)

Benefits associated with antiviral treatment in kidney allograft recipients with chronic hepatitis B virus infectionJournal of HepatologyVol. 57Issue 1PreviewHepatitis B virus (HBV) infection is more frequent in kidney recipients than in the general population with a higher rate of liver-related morbidity and mortality. We evaluated the benefit associated with HBV viral suppression by nucleos(t)ide analogues treatment in HBV-infected kidney recipients. Full-Text PDF Reply to: "Further evidence of the benefits associated with antiviral treatment in kidney allograft recipients with chronic hepatitis B virus infection"Journal of HepatologyVol. 58Issue 4PreviewWe read the interesting results of Sperl et al. [1], reporting the benefits associated with analogues treatment of HBV-infected kidney recipients (KR), which corroborate our previous findings [2]. A significant increase in graft and patient survival was observed in both our studies, by comparison with series where analogues were either not available [3,4] or less potent, with viral resistance concerns [5]. Full-Text PDF Open Access We read with interest about the recent study on the benefits associated with antiviral treatment in kidney allograft recipients with chronic hepatitis B virus (HBV) infection by Cosconea et al. [[1]Cosconea S. Fontaine H. Meritet J.F. Corouge M. Sogni P. Vallet-Pichard A. et al.Benefits associated with antiviral treatment in kidney allograft recipients with chronic hepatitis B virus infection.J Hepatol. 2012; 57: 55-60Abstract Full Text Full Text PDF PubMed Scopus (29) Google Scholar]. We highly appreciate the authors' results achieved with a specific group of patients with HBV. The authors acknowledged that there is still a lack of data on HBV kidney recipients' long-term survival. Therefore, we would like to present our results supporting the French group results. The immunosuppressive treatment in patients with chronic HBV infection leads to the loss of immune control of viraemia, hepatitis reactivation, fibrosis progression and hepatocellular carcinoma (HCC) occurrence [2Vigano M. Colombo M. Aroldi A. Lunghi G. Manenti E. Ponticelli C. et al.Long-term lamivudine monotherapy in renal-transplant recipients with hepatitis-B-related cirrhosis.Antivir Ther. 2005; 10: 709-713PubMed Google Scholar, 3Aroldi A. Lampertico P. Montagnino G. Passerini P. Villa M. Campise M.R. et al.Natural history of hepatitis B and C in renal allograft recipients.Transplantation. 2005; 79: 1132-1136Crossref PubMed Scopus (95) Google Scholar]. In 1999, Mathurin et al. precisely described the negative impact of HBV on the survival of untreated patients after kidney transplantation (RTx) [[4]Mathurin P. Mouquet C. Poynard T. Sylla C. Benalia H. Fretz C. et al.Impact of hepatitis B and C virus on kidney transplantation outcome.Hepatology. 1999; 29: 257-263Crossref PubMed Scopus (498) Google Scholar]. We retrospectively assessed 30 HBsAg-positive kidney allograft recipients who started antiviral treatment of HBV with nucleos(t)ide analogues (NUCs) between 1998 and 2007. The underlying renal disease was chronic glomerulonephritis in 17 patients, chronic interstitial nephritis in 7, polycystic kidney in 2, hypertensive nephropathy in 1 and unknown in 3 patients. Seven patients suffered from type 2 diabetes, 7 had BMI >30 and none reported the consumption of more than 20 g of alcohol per day. All the patients had negative serology for hepatitis C and HIV. All the patients received the standard immunosuppressive protocol used at the centre at the time of transplantation: two patients were on an azathioprine and prednisone regimen, 21 patients were on a cyclosporine regimen (together with prednisone and azathioprine or mycophenolate mofetil) and 7 patients were on immunosuppressive combination of tacrolimus, mycophenolate mofetil and prednisone. At the time of transplantation, all the patients were HBsAg positive with normal ALT values and normal synthetic liver function. The negative viraemia had to be documented only in the patients transplanted after 1999. The liver biopsies before RTx were performed by the referring centres and only patients with mild inflammatory activity and without cirrhosis were allowed. The antiviral treatment was started after RTx in all patients who presented hepatitis reactivation, as soon as the NUCs became available. All had detectable viraemia before treatment, 16 of them were HBeAg positive and 14 HBeAg negative. A subsequent liver biopsy was performed in 23/30 patients before treatment (2–6 weeks before starting NUCs), 16 had fibrosis F0–F2 and 7 F3–F4 according to the Metavir score. The treatment was initiated with lamivudine (LAM) monotherapy in 28 patients and adefovir (ADV) was added for the patients with reappearance of viraemia. If the LAM + ADV combination had not resulted in undetectable viraemia, then ADV was switched to tenofovir (TDF). Entecavir (ETV) was started in 2 patients and in 1 of them ETV was switched to TDF due to pregnancy. The antiviral doses were adjusted to kidney function. HBV DNA at the end of the follow-up (June 2012) was assessed using the Cobas Ampliprep/TaqMan method (lower limit of detection = 20 IU/ml). HCC screening was performed by ultrasound. The patients and kidney grafts survival was assessed using the Kaplan–Meier method. The average treatment duration was 108 months (30–156). Five patients died with no relation to the liver disease (1 myocardial infarction, 2 strokes, 1 sepsis and 1 skin tumour). Twenty-five patients are still living and continue treatment and 24 have undetectable viraemia. Eight patients remain on LAM monotherapy, 1 on ETV, 1 on TDF, 6 on LAM + ADV combination and 9 LAM + TDF. 9/16 HBeAg-positive patients achieved seroconversion. Viraemia reappeared on LAM monotherapy in 6/9 patients who achieved HBeAg seroconversion and ADV or TDF was added. In 9 patients, renal graft failure occurred due to chronic allograft nephropathy (2–12 years after NUCs treatment initiation, 4–20 years after RTx). No renal toxicities related to ADV/TDV were observed. Serum creatinine (225, 77–289 μmol/L, resp. 210, 73–261 μmol/L, p = 0.055, resp. p = 0,363) and serum phosphate levels (1.06, 0.90–1.42 mmol/L, resp. 1.08, 0–1.45 mmol/L, p = 0.530, resp. 0.674), after 1 and 3 years of therapy, did not differ significantly from the average values before starting ADV/TDF (168, 94–271 μmol/L, resp. 1.20, 0.83–2.62 mmol/L, Wilcoxon non-parametric test). On treatment, 2 patients underwent further RTx (1 with liver). 18/25 living patients have a well-functioning kidney allograft, with the average creatinine clearance of 48.6 ml/min at the end of the follow-up; and the 10-year graft survival in our cohort did not differ from the overall graft survival at our centre. One patient with cirrhosis at biopsy before treatment experienced liver decompensation, when LAM resistance emerged, and he underwent liver and kidney transplantation. At present, the function of both grafts is excellent after 5 years and he is being treated with LAM + TDF and hepatitis B immunoglobulin. Another patient with liver cirrhosis had also liver dysfunction after the emergence of LAM resistance. His liver function improved on LAM + ADV, but seven years later he presented with ascites and kidney graft failure, and he is currently awaiting liver and kidney transplant. None of our patients was diagnosed with HCC. The results, including 5- and 10-year patients and grafts survival, are summarised in Table 1 and Fig. 1.Table 1Comparison of characteristics and results of our group with the group studied by Cosconea et al.RTx, kidney transplantation; NUCs, nucleos(t)ide analogues. Open table in a new tab RTx, kidney transplantation; NUCs, nucleos(t)ide analogues. The patients and grafts survival in our cohort is substantially better than in the cohort described by Ahn et al. [[5]Ahn H.J. Kim M.S. Kim Y.S. Kim S.I. Huh K.H. Ju M.K. et al.Clinical outcome of renal transplantation in patients with positive pre-transplant hepatitis B surface antigen.J Med Virol. 2007; 79: 1655-1663Crossref PubMed Scopus (46) Google Scholar], but is slightly worse than in the Cosconea et al. cohort [[1]Cosconea S. Fontaine H. Meritet J.F. Corouge M. Sogni P. Vallet-Pichard A. et al.Benefits associated with antiviral treatment in kidney allograft recipients with chronic hepatitis B virus infection.J Hepatol. 2012; 57: 55-60Abstract Full Text Full Text PDF PubMed Scopus (29) Google Scholar]. Ahn et al. administered only LAM and ADV; after 5 years, they had only 58.3% patients with undetectable viraemia. In our cohort, 12 LAM + ADV patients who had detectable viraemia were switched to LAM + TDV. The excellent results by Cosconea et al. have been achieved thanks to early availability of the third generation antivirals. Our results could be influenced by delayed availability of the antivirals in the Czech Republic (LAM 1998, ADV 2005, ETV and TDF 2008). The statement is supported by the fact that liver decompensation occurred in 2 patients with flare-up due to LAM resistance in whom ADV was initiated more than 1 year after viraemia reappearance. Both patients were enlisted for combined liver and kidney transplantation according to our centre guidelines (liver dysfunction due to cirrhosis corresponding to Child-Pugh B class in a patient with creatinine clearance < 30 ml/min or on maintenance hemodialysis). The effect of antiviral therapy was significant despite the fact that in our historical cohort, the antiviral treatment was initiated with delay after RTx when HBV reactivated. Since 2008, all NUC-naïve, HBsAg positive patients with undetectable viraemia have received pre-emptive therapy with ETV from the day of transplant. Patients with pre-transplant detectable viraemia continue the treatment started on maintenance hemodialysis (ETV in NUC-naïve, TDF in LAM-experienced patients). The viraemia is regularly assessed every 3 months. HCC absence in our cohort can be explained by a lower rate of F3–F4 patients (7/30 vs. 15/42 or 23.3% vs. 33.3%) and by the small cohort size. We would like to emphasise the necessity of regular screening [[6]EASL-EORTC clinical practice guidelines: management of hepatocellular carcinoma. J Hepatol 2012; 56:908–943.Google Scholar]. We conclude that the results of our cohort substantiate the beneficial effect of antiviral treatment in HBsAg+ kidney graft recipients. The achievement of a long-term undetectable viraemia is the goal of the therapy, which should be initiated with third generation antivirals according to present guidelines [[7]European Association for the study of the L. EASL clinical practice guidelines: management of chronic hepatitis B virus infection. J Hepatol 2012; 57:167–185.Google Scholar]. All the authors declare that they do not have anything to disclose regarding funding or conflict of interests with respect to this manuscript.