Year : 2013 | Volume
: 24 | Issue : 6 | Page : 1195--1198
Pre-emptive treatment of Hepatitis B infection by lamivudine in two tunisian renal transplant recipients
Kais Harzallah, Wafa Haddad, Mondher Haloues, Imene El Kossai, Nabil Ben Romdhane, Hatem Ben Abdallah, Riadh Bouali, Mohamed Nabil Abdelli, Jalel Hmida, Jamel Manaa
Unity of Organ Transplantation, Military Hospital of Tunis, Tunis, Tunisia
Unity of Organ Transplantation, Military Hospital of Tunis, Tunis 1002
Infection with hepatitis B virus has a major implication for transplant recipients due to the risk of reactivation under immunosuppression, progression to chronic liver disease, development of liver cirrhosis and hepatocellular carcinoma. We report two cases of renal transplantation patients who were hepatitis B surface antigen positive before transplantation and were treated by Lamivudine.
|How to cite this article:|
Harzallah K, Haddad W, Haloues M, El Kossai I, Romdhane NB, Abdallah HB, Bouali R, Abdelli MN, Hmida J, Manaa J. Pre-emptive treatment of Hepatitis B infection by lamivudine in two tunisian renal transplant recipients.Saudi J Kidney Dis Transpl 2013;24:1195-1198
|How to cite this URL:|
Harzallah K, Haddad W, Haloues M, El Kossai I, Romdhane NB, Abdallah HB, Bouali R, Abdelli MN, Hmida J, Manaa J. Pre-emptive treatment of Hepatitis B infection by lamivudine in two tunisian renal transplant recipients. Saudi J Kidney Dis Transpl [serial online] 2013 [cited 2020 Feb 19 ];24:1195-1198
Available from: http://www.sjkdt.org/text.asp?2013/24/6/1195/121281
Hepatitis B virus (HBV) infection is an important cause of morbidity and mortality after kidney transplantation. The number of chronic HBV carriers exceeds 300 million worldwide, and up to 14% of renal allograft recipients in endemic areas are hepatitis B surface antigen (H-BsAg) positive.  Progressive liver disease affects more than 80% of the HBsAg-positive renal transplant recipients and accounts for 37-57% of the associated mortality. Life-threatening exacerbation of liver disease can develop in previously healthy HBV carriers. An optimal monitoring and treatment regimen for HBsAg-positive renal allograft recipients has not been defined. 
Lamivudine is a synthetic nucleoside analog with proven efficacy in suppressing HBV DNA levels and ameliorating aminotransferase and histologic abnormalities in non-immuno-suppressed patients with chronic hepatitis B. Unlike interferon, Lamivudine does not have an immunomodulatory effect and therefore can be safely used in renal transplant patients.  Short-term studies have shown virological and biochemical efficacy of Lamivudine in small series of renal transplant recipients. 
It is not clearly known whether patient survival can be improved by Lamivudine therapy in renal allograft recipients. Although early treatment seems mandatory in view of the time lag for clinical improvement following viral suppression, both the appropriate starting time and the optimal duration of treatment have not been established. At present, Lamivudine is often administered prophylactically at the time of kidney transplantation and continued indefinitely in view of the high rate of relapse after discontinuation. The emergence of Lamivudine-resistant HBV variants with prolonged treatment is an escalating problem. 
We report the results of a pre-emptive treatment by Lamivudine in two renal transplant recipients.
A 30-year-old man who was on regular follow-up for corticosteroid resistant nephrotic syndrome due to focal segmental glomerulusclerosis developed end-stage renal disease in 1996. An infection with HBV was diagnosed in 2005 and treated with peg interferon for 12 months with sustained viral response. He received a kidney from an HbsAg-negative living related donor in 2008. Induction treatment was based on thymoglobulin at a dose of 1.25 mg/kg/day for 5 days. Maintenance therapy was with Tacrolimus at a dose of 0.1 mg/kg/day, with trough levels between 10 and 15 ng/mL during the first 2 months post-transplantation and then between 5 and 10 ng/mL; mycophenolate mofetil at 2 g/day and corticosteroids decreased rapidly to 10 mg/day on the 6 th day after transplantation and maintained at this dose. Lamivudine (100 mg/day) was prescribed immediately after the transplantation with regular monitoring of renal and hepatic functions and HBV DNA - polymerase chain reaction (PCR). Viral load remained negative until the patient stopped Lamivudine for 1 month because of economic problems, leading to reactivation of the HBV (H-BV DNA - PCR at 207,000 copies/m). By resuming the treatment, the viral load became rapidly undetectable (771 copies/mL after 15 days and 200 copies/mL after 3 months) and has remained so on follow-up for the last 2 years.
A 42-year-old woman with occult hepatitis B (HbsAg-, Ac anti Hbs-, Ac antiHbc+, DNA virus B+) received a renal allograft from a negative HbsAg living unrelated donor in 2007 after 13 years of hemodialysis for end-stage renal disease secondary to a chronic interstitial nephritis. Induction treatment was with thymoglobulin, with the same dose as that of Case 1. Maintenance therapy was based on Cyclosporin at a dose of 5 mg/kg/day, with trough levels between 200 and 300 ng/mL during the first 2 months post-transplantation and then between 100 and 200 ng/mL; mycophenolate mofetil 2 g/day and corticosteroids dose was decreased as per our protocol to 10 mg/day on the 6 th day after transplantation and was maintained at this dose. She was treated with Lamivudine for the viral infection, started 1 month before transplantation and continued indefinitely after that, with an efficient suppression of virus replication till 3 years after transplantation. The treatment of viral infection was well tolerated, no one developed resistance to Lamivudine and no renal function impairment was noted.
Treatment of chronic hepatitis B patients among renal transplant recipients is an important issue at places where this infection is still seen, such as in Tunisia. Interferon, one of the standard therapies of HBV infection, cannot be used in this setting because of the low efficacy and a high risk of acute allograft rejection.  Thus, Lamivudine has been commonly used to treat HBV in these patients.
HBV DNA - PCR clearance and enzyme normalization were seen in our patients. However, enzyme normalization is difficult to interpret in these patients as they are immunosuppressed and they may not show enzyme elevation in spite of having disease activity on histology. 
Practically, in renal transplanted patients, we have to depend on virological response for assessing therapy rather than on response to ALT normalization.  In fact, hepatocyte damage in the course of chronic hepatitis B is mainly immune mediated, in addition to a less-significant role of direct HBV hepatotoxicity. Immunosuppression in kidney transplanted patients could diminish specific anti-HBV responses, which could alter immune-mediated cytopathic effects.  This could result in the reduction of hepatic inflammation and low ALT activity. On the other hand, immunosuppression could facilitate HBV replication. 
Large HBV viral load could cause different disorders such as accumulation of immune complexes in the glomeruli, further indicating the necessity of antiviral therapy in these patients.  Treatment of patients with chronic HBV infection seemed to be necessary when the number of HBV copies exceeded 10 5 /mL, independent of ALT activity. 
There have been several studies on the role of Lamivudine in renal transplant patients, and HBV DNA - PCR normalization was between 54% and 100% of cases treated by Lamivudine 50-100 mg/day. Enzyme normalization was noted in 53-100% of patients in these studies. 
Ben-Ari et al  described a significant decrease of HBV viral load in kidney transplanted chronic hepatitis B patients after Lamivudine treatment. Moreover, they observed elimination of hepatitis B envelope antigen in three of six treated patients.
Some studies have evaluated Lamivudine resistance in a similar patient population and found Lamivudine resistance in 10-50% of patients with a variable duration of therapy.  None of our patients developed resistance despite the indefinite duration of treatment with a follow-up of 3 years in one case and 2 years in the other.
In a recent Indian study,  22.8% patients had acute rejection of the graft although the group has not been compared statistically with HBV-negative patients due to gross disparity in the number of cases. During a single year of evaluation, one cannot expect notable changes in patients and graft survival in these patients due to HBV infection. No impairment of graft function was noted in our patients. Like our cases, Yap et al reported that treatment of HBsAg+ renal transplant recipients with nucleoside/nucleotide analogues confers long-term survival benefit.  For Zubkin, the efficacy of antiviral HBV therapy was limited by the duration of Lamivudine treatment: In four of five patients with a virological response, viremia relapsed several weeks after the medication had been stopped. 
Therapy of HBV infection is changing with time and with scientific advancement and availability of newer drugs like entecavir and tenofovir, which have become first-line therapy in naïve HBV-infected patients; we are likely to use these drugs in renal transplant patients also. 
In conclusion, treatment with Lamivudine in renal transplant patients is well tolerated and safe. The effectiveness of Lamivudine therapy in these patients is comparable to that in patients with normal renal function. Till the other drugs against HBV infections are studied in these patients, in view of low cost, reasonable response and good tolerability, Lamivudine may be used in these patients.
|1||Chan TM, Fang GX, Tang CS, Cheng IK, Lai KN, Ho SK. Preemptive lamivudine therapy based on HBV DNA level in HBsAg-positive kidney allograft recipients. Hepatology 2002; 36:1246-52.|
|2||Zubkin M, Balakirev E, Chervinko V, et al. Treatment of chronic hepatitis B with Lamivudine in renal transplant recipients. Int J Artif Organs 2007;30:308-14.|
|3||Tsai MC, Chen YT, Chien YS, Chen TC, Hu TH. Hepatitis B virus infection and renal transplantation. World J Gastroenterol 2010; 16:3878-87.|
|4||Agarwal SK, Tiwari SC. Efficacy and tolera-bility of Lamivudine in hepatitis B infected renal transplant recipients: A single center study. Indian J Nephrol 2009;19:91-5.|
|5||Lapinski TW, Flisiak R, Jaroszewicz J. Efficiency and safety of lamivudine therapy in patients with chronic HBV infection, dialysis or after kidney transplantation. World J Gastroenterol 2005;11:400-2.|
|6||Zhang CP, Tian ZB, Liu XS, Zhao QX, Wu J, Liang YX. Effects of Zhaoyangwan on chronic hepatitis B and posthepatic cirrhosis. World J Gastroenterol 2004;10:295-8.|
|7||Okamoto M, Omori Y, Kadotani Y, et al. Renal transplantation in HBeAG and HBV DNA-positive recipient: A case report. Transplant Proc 2003;35:286.|
|8||Lok AS, McMahon BJ. Chronic hepatitis B. Hepatology 2001;34:1225-41.|
|9||Ben-Ari Z, Broida E, Kittai Y, Chagnac A, TurKaspa R. An open-label study of lamivudine for chronic hepatitis B in six patients with chronic renal failure before and after kidney transplantation. Am J Gastroenterol 2000;95: 3579-83.|
|10||Park SK, Yang WS, Lee YS, et al. Outcome of renal transplantation in hepatitis B surface antigen positive after introduction of lamivudine. Nephrol Dial Transplant 2001;16: 2222-8.|
|11||Yap DY, Tang CS, Yung S, Choy BY, Yuen MF, Chan TM. Long-term outcome of renal transplant recipients with chronic hepatitis B infection-impact of antiviral treatments. Transplantation 2010;90:325-30. |
|12||Shamliyan TA, MacDonald R, Shaukat A, et al. Antiviarl therapy for adults with chronic hepatitis B: A systematic review for national institutes of health consensus development conference. Ann Intern Med 2009;159:111-24.|