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http://www.kidney-international.org & 2013 International Society of Nephrology

Treatment of hepatitis B in patients with chronic kidney disease

Chrysoula L. Pipili1, George V. Papatheodoridis2 and Evangelos C. Cholongitas3
1

Department of Nephrology, Aretaieion University Hospital, Athens, Greece; 22nd Department of Internal Medicine, Athens University Medical School, Hippokration General Hospital of Athens, Athens, Greece and 34th Department of Internal Medicine, Medical School of Aristotle University, Hippokration General Hospital of Thessaloniki, Thessaloniki, Greece

Although the prevalence of chronic hepatitis B virus (HBV) infection in patients with chronic kidney disease remains low in developed countries, clinicians should be aware of the rationale for treatment in this setting. This patient population presents particular features and various complicating conditions requiring special treatment strategies. Interferon, the standard treatment for HBV infection, has been poorly tolerated by patients with chronic kidney disease, has presented relatively low efficacy, and has posed renal transplant recipients under the risk of acute rejection. The advent of effective nucleos(t)ide analogs (NAs) has offered the opportunity to minimize the consequences of HBV infection in HBV-positive patients with chronic kidney disease. Combination with immunosuppressive agents might be considered in cases of rapid renal function deterioration and/or severe proteinuria. Among the newer NAs, entecavir may be preferred, because of its high potency, high genetic barrier to resistance, and favorable renal safety profile. However, entecavir presented low efficacy in case of lamivudine or telbivudine resistance, and thus tenofovir may be a better option in that setting. All HBsAg-positive candidates should be treated with NAs before renal transplantation in order to maintain undetectable HBV DNA, reduce liver fibrosis, and prevent hepatic decompensation after renal transplantation. This review summarizes updated issues related to treatment of chronic HBV infection in all categories of population with chronic kidney disease (those exhibiting HBV-associated glomerular disease, those treated with hemodialysis, as well as renal transplant candidates, donors, and recipients).
Kidney International (2013) 84, 880885; doi:10.1038/ki.2013.249; published online 19 June 2013 KEYWORDS: chronic kidney disease; hemodialysis; hepatitis B; transplantation

Chronic infection with hepatitis B virus (HBV) in patients with chronic kidney disease represents a distinct and challenging clinical entity. The special characteristics of this patient group (immunosuppressive effect of renal failure, polypharmacy, susceptibility for nosocomial transmission, immunosuppressive therapy after renal transplantation) and the related changes in clinical course of liver disease often have long-term implications on morbidity and mortality and affect the patients management.1 To date, the information about the use of antiviral therapy in patients with chronic kidney disease is scarce, as such patients were not included in the phase II or III randomized trials. Thus, several clinical questions about the optimal management of these patients remain unanswered. This review focuses on the current clinical knowledge for the treatment of chronic HBV patients with chronic kidney disease, including cases before end-stage renal disease, on maintenance hemodialysis, and in the renal transplantation setting.

GENERAL TREATMENT RECOMMENDATIONS

Correspondence: Evangelos C. Cholongitas, 4th Department of Internal Medicine, Medical School of Aristotle University, Hippokration General Hospital of Thessaloniki, 49, Konstantinopoleos Street, 54642, Thessaloniki, Greece. E-mail: cholongitas@yahoo.gr Received 20 January 2013; revised 17 April 2013; accepted 25 April 2013; published online 19 June 2013 880

Treatment options for renal patients with chronic HBV infection are complex, being dictated by the overall clinical picture and best conducted by multidisciplinary approach and thorough renal monitoring. Very limited datamostly case seriesare available to guide therapy in this patient setting. Antiviral treatment is indicated in hepatitis B surface antigen (HBsAg)positive patients with evidence of active liver disease based on aminotransferases and serum HBV DNA levels with or even without a liver biopsy. Serum HBV DNA levels of 200020,000 IU/ml have been proposed as the threshold to start treatment, whereas it remains to be investigated whether the upper limit of normal for aminotransferases needs to be adjusted downward among patients on hemodialysis.2 Although the ideal antiviral treatment would result in HBsAg seroconversion and HBV DNA clearance, the real goal in patients with chronic kidney disease is viral replication suppression (particularly in candidates for renal transplantation) and thus the prevention of viral complications (such as cirrhosis and hepatocellular carcinoma) and proteinuria remission with preservation of renal function.
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Table 1 | Characteristics of interferon and nucleos(t)ide analogs (NAs) in the treatment of chronic hepatitis B3,4
Interferon Antiviral target Antiviral potency On-therapy efficacy Off-therapy efficacy Administration Duration of treatment Side effects during administration Long-term safety Viral resistance Increase cytotoxic T lymphocytes and natural killer cell immune response to viral proteins Moderate Low High Subcutaneous Once to three times weekly Finite (up to a 48-week course) Moderategreat Known None NAs HBV reverse transcriptase inhibitorsachieve inhibition of HBV replication High High Low Oral Daily (up to once a week based on GFR) Unpredictable (long term) Limited Unknown Risk of resistance on prolonged therapy (very high for lamivudine, unknown for newer NAs)

Abbreviations: GFR, glomerular filtration rate; HBV, hepatitis B virus.

Table 2 | Dosage adjustment of nucleos(t)ide analogs and interferon according to serum creatinine clearance (CrCl)11
CrCl (ml/min) X50 3049 1529 514 o5 Lamivudine 100 mg/day 100 mg first dose, then 50 mg/day 35 mg first dose, then 25 mg/day 35 mg first dose, then 15 mg/day 35 mg first dose, then 10 mg/day Telbivudine 600 mg/day 600 mg/day 2 600 mg/day 3 600 mg/day 3 600 mg/day 4 Adefovir 10 mg/day 10 mg/day 2 10 mg/day 3 10 mg/day 3b 10 mg/week following HDc Entecavira 0.5 mg/day 0.25 mg/day 0.15 mg/day 0.05 mg/dayb 0.5 mg/week following HDc Tenofovir 245 mg/day 245 mg/day 2 245 mg/day 23 245 mg/ weekb 245 mg/week following HDc Pegylated interferon a-2a 180 mg SQ/week 135 mg SQ/week

Abbreviations: HD, hemodialysis; SQ, subcutaneous. a ve patients. Recommendations only for nucleos(t)ide analogna b Recommendation only for CrCl X10 ml/min. c Only for patients on HD.

Antiviral treatment options include interferon-a (IFN-a; standard and pegylated IFN-a) and nucleos(t)ide analogs (NAs) classified into nucleosides (lamivudine, telbivudine, and entecavir) and nucleotides (adefovir dipivoxil, tenofovir disoproxil fumarate)3,4 (Table 1). Although no controlled trials have investigated the role of IFN in patients with chronic kidney disease, a series of cases report the poor tolerance, the risk of acute rejection in renal transplant recipients, and the relatively low efficacy of IFN-a. Over the past 12 years, the development of effective, well-tolerated, and relatively safe oral antiviral agents (NAs) has offered the opportunity for successful management of chronic HBV infection in several patient subgroups including those with chronic kidney disease.4,5 Lamivudine, the first available oral anti-HBV agent, has the longest record for HBV treatment on patients with HBV-associated renal disease1 receiving hemodialysis,6 and HBV-positive transplant recipients.7 Nevertheless, the very high long-term resistance rates and the proteinuria recurrence after its discontinuation1,6,8 make lamivudine a suboptimal first-line option, not recommended for patients who may need a lengthy therapeutic course.
HBV-ASSOCIATED RENAL DISEASE

Renal injury may occasionally occur in chronic HBV patients. It usually manifests as polyarteritis nodosa9 or immune complexmediated glomerulopathy, with virus-like particles
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being identified in various areas of the glomeruli. Although HBV-associated renal disease usually resolves uneventfully in children, it rarely reaches spontaneous remission in adults, with most of them (3050%) progressing to end-stage renal disease.10 Recently, KDIGO (Kidney Disease: Improving Global Outcomes) indicated that patients with HBV-associated renal disease should be treated according to standard clinical practice guidelines for HBV infection. Dosing of IFN or NAs should be adjusted to the degree of kidney function (Table 2), and nephrotoxicity of adefovir and tenofovir should be of concern.11 Moreover, the latest meta-analysis12 on treatment of HBV-associated glomerulonephritis concluded that the combined antiviral and immunosuppressant therapy is an effective regimen in this setting, without altering HBV replication or damaging liver and renal function. The choice of the antiviral agent is decided on an individual basis via a multidisciplinary approach guided by the patients age, baseline viremia levels, type of renal disease, risk of viral resistance, concomitant immunosuppressive therapy, and drug renal safety profile. Long-term NA therapy is generally recommended for all patients with chronic HBV infection regardless of the presence of renal disease. NA therapy may be discontinued in patients with HBeAgpositive chronic HBV infection who achieve stable HBeAg seroconversion and HBV DNA undetectability for at least
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12 months, as well as in patients with HBeAg-negative chronic HBV infection who achieve HBsAg loss. The optimal duration of antiviral therapy for HBV-associated nephropathy has not been determined. Some clinicians13 propose long-term antiviral treatment in order to avoid relapses after initial remission, whereas others14 suggest antiviral continuation only in patients with relapses or no remission. Telbivudine may have a theoretical advantage in this setting, as it has been recently reported to have a favorable effect on renal function,15 but there are no reports on the efficacy of this drug in patients with renal disease, particularly cases under immunosuppression. Entecavir has the advantage of the good long-term resistance profile in NA-naive patients1 and has been reported to be safe and effective in a few patients with HBV-related glomerular disease.12,16 The use of tenofovir and emtricitabine in a HIVHBV coinfected patient with membranous nephropathy was not encouraging.17 IFN (pegylated IFN-a was obviously superior to conventional IFN-a, based on data referring to general population18) is the preferable treatment option for young patients with HBV-associated renal disease. Young adults can better tolerate IFN, and thus restore the cell-mediated immunity depressed by uremia and obtain sustained viral remission in a shorter interval.19 However, one should keep in mind that IFN is contraindicated in patients with decompensated cirrhosis, autoimmune disease, and uncontrolled severe depression or psychosis.4 Antiviral monotherapy may be sufficient to treat HBVassociated nephropathy in patients who do not have severe or life-threatening disease. Two additional treatment strategies are applicable to patients with rapidly progressive glomerulonephritis and polyarteritis nodosa (Figure 1). A course of corticosteroids with or without cyclophosphamide or rituximabfor suppression of vasculitisand plasma exchange9for removal of circulating immune complexes may be gainful for ameliorating kidney function and disease manifestations. In case of immunosuppressive

administration, all HBsAg-positive patients should receive NA therapy even preemptively (if they do not fulfill the HBV treatment indications).4,10 Preemptive anti-HBV therapy must ideally start 2 weeks before and continue during and for at least 612 months after the completion of immunosuppressive therapy. Lamivudine can be a choice for such preemptive NA therapy in patients with low viremia (HBV DNA o2000 IU/ml) and short duration of immunosuppressive therapy (o612 months). In all other cases of preemptive therapy, a NA with a high genetic barrier and minimal risk of HBV resistance should be preferred.4
HBV INFECTION IN HEMODIALYSIS PATIENTS

TREATMENT OF HBV-ASSOCIATED RENAL DISEASE

Normal GFR, mild proteinuria (- 3.5 g/day)

Rapidly progressive glomerulonephritis

Polyarteritis nodosa

NA monotherapy

NA+corticosteroids cyclophosphamide or rituximab

NA corticosteroids plasma exchange

-Maintain BP <130/80 mm Hg -ACE inhibitor -Monitor

Patients -50 years old without cirrhosis, autoimmune disease, or psychosis

Peg IFN- monotherapy

Figure 1 | Proposed algorithm for the management of patients with hepatitis B virus (HBV)related nephropathy. ACE, angiotensin-converting enzyme; BP, blood pressure; GFR, glomerular filtration rate; NA, nucleos(t)ide analog; Peg IFN-a, pegylated interferon-a.
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The major effort against chronic HBV infection on patients receiving hemodialysis should be directed at prevention. The introduction of HBV immunization has significantly lowered the HBV incidence in several endemic regions, although these patients often have poor responses to vaccination, even after intensified protocols and booster doses.20 Additional hygiene-preventive measures and lifestyle modifications, such as avoiding alcohol use, quit smoking, and keeping normal body mass index, are also very important and should be always recommended in order to minimize patient-topatient HBV transmission, slow the progression of liver disease, and reduce the risk of HBV-related complications. For the management of patients undergoing hemodialysis, physicians should also take into account that these patients may often present with moderate or no elevations of serum aminotransferases owing to altered inflammatory response,20 lower serum HBV DNA levels due to its removal by hemodialysis,21 higher risk of occult HBV infection (detection of viral genome in liver tissue and, in some instances, in serum in HBsAg-negative patients),22 and a lot of comorbidities such as cardiovascular disease, diabetes mellitus, and anemia. All these parameters may affect the clinical and laboratory presentation and course of chronic HBV infection and the patients response to antiviral therapy. The optimal therapy for chronic HBV infection on hemodialysis may involve observation, IFN-a, or NAs. Among patients who are not candidates for renal transplantation, antiviral treatment should be reserved for those with active or fibrotic liver disease. A limited literature exists on IFN therapy on patients with chronic HBV infection receiving hemodialysis. The experience in this patient group comes mostly from treatment of hepatitis C. Although IFN-a administration was related to HBe seroconversion and improvement of liver biochemistry, the exacerbation of IFN side effects (mostly myelosuppression and malnutrition) hampers its use in clinical practice.23 Preliminary data on pegylated-IFNa-2a did not show really better tolerance.24 Limited data for newer NAs in hemodialysis patients present that they are a safe and a potent antiviral treatment (Table 2). There are three reports20 including five HBV patients undergoing hemodialysis who were treated with adefovir for 1230 months. Both liver and renal function improved in parallel with the serum HBV DNA clearance.20
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There are no data for telbivudine together with its safety in such patients. Long-term entecavir therapy seemed to be safe and effective in nine patients on maintenance hemodialysis.25 Given its high potency and high genetic barrier in NA-naive patients profile, entecavir is the most promising anti-HBV agent for patients undergoing hemodialysis and/or candidates for renal transplantation. As long-term entecavir therapy is not so effective in patients with lamivudine resistance, tenofovir may be required in such cases,26 but with caution and dose adjustment for patients with estimated glomerular filtration rate o50 ml/min.4 Ultimately, for occult HBV carriers, active surveillance is suggested lest there be cirrhosis and hepatocellular carcinoma, as well as acceleration of chronic hepatitis C virus coinfection and interference in treatment response. In addition, effective vaccination to boost anti-HBsAg above 100 mIU/ml may modulate the infection,7 whereas the application of short-term NA during periods of intensified immunosuppression will possibly prevent infection reactivation.22
HBV INFECTION IN THE RENAL TRANSPLANTATION SETTING Candidates for renal transplantation

HBsAg-positive patients with end-stage renal disease can be candidates for solitary renal transplantation only if they do not have cirrhosis. HBsAg-positive patients with cirrhosis and end-stage renal disease are at risk for hepatic decompensation after isolated renal transplantation, and therefore they require simultaneous liver and kidney transplantation.27 According to the current guidelines, all HBsAg-positive candidates for solid-organ transplantation should be treated with NAs before renal transplantation in order to maintain undetectable HBV DNA, reduce liver fibrosis, and prevent hepatic decompensation after renal transplantation.4 In clinical practice, the optimal timing for treatment initiation in HBsAg-positive candidates for renal transplantation is often individualized, taking into account the recipients clinical status, dialysis-related complications, and most importantly the expected waiting time on hemodialysis.
HBV-positive renal transplant recipients

IFN-a therapy is contraindicated in transplant recipients owing to the increased risk of acute rejection and low antiviral potency.7 In 2009, KDIGO recommended prophylaxis with entecavir, tenofovir, or lamivudine for HBsAg-positive transplant recipients.7 The application of NAs prompted a new era in renal transplantation of HBV-positive transplant recipients. Before their use, HBsAg positivity was an independent and significant risk factor for mortality and graft loss. The effective NA therapy permitted a striking increase in patient (8189%) and graft survival (86%) at 10 years,2830 through the inhibition of viral replication, the retardation of liver disease progression, and the lower incidence of hepatocellular carcinoma (the cancer risk is not minimized, and hence annual screening is recommended).
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The preemptive use of NA therapy is recommended to all HBsAg-positive patients shortly before or at the time of renal transplantation regardless of the baseline histological severity and serum HBV DNA level,7 because the immunosuppressive therapy after renal transplantation has been associated with a risk of rapidly progressing fibrosing cholestatic hepatitis even in patients with mild or inactive liver disease before renal transplantation.31 Salvage NA therapy after post-renal transplantation HBV exacerbation can be used, but it is a less effective approach compared with preemptive NA therapy and confers excessive risk to patients.32 Treatment with a NA should usually continue for as long as immunosuppressive therapy lasts33 or at least for 24 months.7 The need for HBV therapy in HBsAg-negative, anti-HBc-positive transplant recipients is rather questionable. As they are not at high risk of HBV reactivation, they can just be followed up with HBV DNA monitoring, similar to other anti-HBc-positive patients who require immunosuppressives.4 In non-renal patients including those who undergo liver transplantation, monotherapy with a NA with high genetic barrier (entecavir or tenofovir) is currently recommended.4 Although there are very limited data in transplant recipients, entecavir is often considered as a preferable first-line option in this setting because of the theoretical lower risk of nephrotoxicity compared with tenofovir.7 Data for entecavir25, 30, 34, 35 have included a total of 80 NA-naive or lamivudine- or adefovir-resistant HBV transplant recipients with satisfactory results. Entecavir given at a daily dose of 1 mg for a maximum of 33 months25 was found to be effective, well tolerated, and without deterioration of renal function, microalbuminuria, or allograft rejection. Data for tenofovir have been reported for only three HBV transplant recipients. Tenofovir given at a dose of 245 mg adapted according to renal function was found to be effective, well tolerated, and safe without changes in serum creatinine levels after 12 months of therapy.36 There are no data for telbivudine therapy in transplant recipients, although the drug deserves to be evaluated in this setting, because of its potentially favorable renal profile. Ultimately, long-term, add-on therapy with adefovir has been reported in 11 lamivudine-resistant HBV-positive transplant recipients. This therapy proved efficacious and safe only with timely adaptation of adefovir dose.37
HBV-positive renal transplant donors

Kidneys from HBsAg-positive, but even from HBsAgnegative, anti-HBc-positive donors are not promoted for renal transplantation, because they have the potential to transmit HBV to recipients. Nevertheless, the fundamental need for donor pool expansion urged some transplant centers to use kidneys from anti-HBc-positive or even HBsAgpositive donors to HBsAg-positive or -negative transplant recipients. Indeed, there are reports for safe and effective lamivudine prophylaxis in HBsAg-negative transplant recipients of kidney grafts from anti-HBc-positive donors38 and for lamivudine combined with immunoglobulin in
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NUCLEOS(T)IDE ANALOGS FOR HEPATITIS B VIRUS INFECTION IN PATIENTS WITH KIDNEY DISEASES

REFERENCES
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2.
HBV-related renal disease HBV in RT Newer NA* (+steroids if renal dysfunction and/or severe proteinuria) HBsAg (+) recipient Anti-HBc (+) recipient Newer NA HBV in hemodialysis patients

3.

4.
HBsAg(+) or anti-HBc (+) donor in HBsAg () (preferably anti-HBs (+)) recipient

5.

Preemptively newer NA

Monitor HBV DNA or lamivudine**

Lamivudine ( HBIG)

6.

Figure 2 | Proposed algorithm for the management of patients with hepatitis B virus (HBV) infection and kidney diseases. *Newer NA is entecavir, tenofovir, and telbivudine. Among the newer NAs, entecavir may be preferred for most NA-naive patients because of its high potency, high genetic barrier to resistance, and favorable renal safety profile; tenofovir may be preferred in cases with prior lamivudine or telbivudine resistance due to the low efficacy of entecavir in this setting; telbivudine warrants further evaluation because of its potentially beneficial effect on renal function. **Lamivudine is only applicable in cases of short treatment duration. HBIG, hepatitis B immunoglobulin; HBsAg, hepatitis B surface antigen; NA, nucleos(t)ide analog; RT, renal transplantation.

7.

8.

9.

10.

11.

anti-HBs-positive recipients having received grafts from HBsAg-positive donors (with or without detectable HBV DNA).39
CONCLUSIONS

12.

13. 14.

The primary effort for HBV eradication and thus reduction of HBV-associated kidney disease is based on the global HBV immunization and the appropriate screening programs. NAs with high genetic barrier to HBV resistance are the best options for HBV-positive patients with chronic kidney disease in order to minimize the consequences of HBV infection. Combination with immunosuppressive agents might be considered in cases of rapid renal function deterioration and/or severe proteinuria. Entecavir is the most promising anti-HBV agent for patients undergoing hemodialysis and/or candidates for renal transplantation. As long-term entecavir therapy is not so effective in patients with lamivudine resistance, tenofovir may be required in such cases. Telbivudine needs to be evaluated further in this setting because of its potentially beneficial effect on renal function. All HBsAg-positive candidates should be treated with NAs before renal transplantation in order to maintain undetectable HBV DNA, reduce liver fibrosis, and prevent hepatic decompensation after renal transplantation (Figure 2). Ultimately, large, probably multicenter, controlled studies are required to evaluate the therapeutic benefits, the long-term safety, and the optimal regimen of NAs for the different groups of chronic HBV patients with chronic kidney disease.
DISCLOSURE

15.

16.

17.

18.

19.

20. 21.

22.

23.

24.

25.

26.

All the authors declared no competing interests.

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33.

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39.

Tse KC, Yap DY, Tang CS et al. Response to adefovir or entecavir in renal allograft recipients with hepatitic flare due to lamivudine-resistant hepatitis B. Clin Transplant 2010; 24: 207212. Huskey J, Wiseman AC. Chronic viral hepatitis in kidney transplantation. Nat Rev Nephrol 2011; 7: 156165. Daude M, Rostaing L, Saune K et al. Tenofovir therapy in hepatitis B viruspositive solid-organ transplant recipients. Transplantation 2011; 91: 916920. Lampertico P, Vigano M, Facchetti F et al. Long-term add-on therapy with adefovir in lamivudine-resistant kidney graft recipients with chronic hepatitis B. Nephrol Dial Transplant 2011; 26: 20372041. Akalin E, Ames S, Sehgal V et al. Safety of using hepatitis B virus core antibody or surface antigen-positive donors in kidney or pancreas transplantation. Clin Transplant 2005; 19: 364366. Jiang H, Wu J, Zhang X et al. Kidney transplantation from hepatitis B surface antigen positive donors into hepatitis B surface antibody positive recipients: a prospective nonrandomized controlled study from a single center. Am J Transplant 2009; 9: 18531858.

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