Review article: nucleos(t)ide analogues in patients with chronic hepatitis B virus infection and chronic kidney disease

Authors

  • C. Pipili,

    1. Department of Nephrology, Laiki Merimna, Athens, Greece
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  • E. Cholongitas,

    1. 4th Department of Internal Medicine, Medical School of Aristotle University, Hippokration General Hospital, Thessaloniki, Greece
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  • G. Papatheodoridis

    Corresponding author
    1. Department of Gastroenterology, Athens University Medical School, Laiko General Hospital of Athens, Athens, Greece
    • Correspondence to: Dr G. Papatheodoridis, Department of Gastroenterology, Athens University Medical School, Laiko General Hospital, 17 Agiou Thoma street, 11527 Athens, Greece.

      E-mail: gepapath@med.uoa.gr

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  • This uncommissioned review article was subject to full peer-review.

Summary

Background

The treatment of chronic hepatitis B (CHB) in patients with chronic kidney disease (CKD) is based on nucleoside (lamivudine, telbivudine, entecavir) or nucleotide (adefovir, tenofovir) analogues (NAs), but it may be complex and the information is scarce. Entecavir and tenofovir represent the currently recommended first-line NAs for NA-naive CHB patients, while tenofovir is the NA of choice for CHB patients with resistance to nucleosides.

Aim

To review the efficacy and safety of NAs in adult CHB patients with CKD and to provide reasonable recommendations for their optimal management.

Methods

Literature search in PubMed/Medline and manual search of relevant articles, reviews and book chapters.

Results

NAs are cleared by kidneys and their dosage should be adjusted in patients with creatinine clearance <50 mL/min. There are concerns about nephrotoxic potential of the nucleotides, particularly adefovir, while improvements of creatinine clearance have been reported under telbivudine. Most existing data in CHB patients with CKD are for lamivudine and, less frequently, for other NAs, mostly entecavir. Besides CHB, NA should be used in case of immunosuppressive therapy in any HBsAg-positive patient with CKD including renal transplant (RT) recipients and in anti-HBs-positive recipients of kidney grafts from HBsAg-positive donors.

Conclusions

Chronic hepatitis B patients with chronic kidney disease receiving nucleoside analogues should be followed carefully for treatment efficacy and renal safety. Despite the absence of strong data, entecavir and telbivudine seem to be the preferred options for nucleoside analogue-naive CHB patients with chronic kidney disease, depending on viraemia and severity of renal dysfunction. More studies are certainly needed in this setting.

Introduction

Chronic hepatitis B virus (HBV) infection is a rare cause of secondary glomerulopathies, has a pivotal influence on patients undergoing haemodialysis (HD) and brings complex issues in candidates for renal transplantation (RT). Over the last 15 years, the development of effective, well-tolerated and relatively safe oral anti-viral agents [nucleos(t)ide analogues (NAs)] has offered the opportunity for successful management of chronic HBV infection in several patient subgroups, including those with chronic kidney disease (CKD).[1-3] Currently, there are five oral agents that have been licensed for the treatment of chronic HBV infection: three nucleoside (lamivudine, telbivudine, entecavir) and two nucleotide (adefovir dipivoxil, tenofovir disoproxil fumarate) analogues.[1, 3, 4] Before the era of oral anti-HBV agents, the poor tolerance, the potential adverse events including the risk of acute rejection in renal transplant recipients and the relatively low efficacy and tolerability limited dramatically the use of the only available therapeutic option, interferon-alpha, in this setting.

To date, the information about the use of NAs in patients with CKD is scarce, as such patients were not included in the phase II or III randomised trials. Thus, several clinical questions about the optimal management of these patients remain unanswered. This paper provides an overview for the treatment strategies with NAs in all types of renal disease associated with HBV infection.

Search strategy

A literature search was conducted through PubMed/Medline using the search terms ‘nucleos(t)ide analogues’ and ‘chronic kidney disease’, ‘renal transplantation’ or ‘hemodialysis’ and ‘chronic hepatitis B’. In addition, a manual search of all relevant review articles, of the retrieved original studies and of chapters in renal pathology and renal transplantation, was performed. Only papers published in English were included, while there was no restriction for the year of publication.

Nucleos(t)ide analogues

Nucleos(t)ide analogues target the reverse transcriptase of HBV and achieve inhibition of HBV replication that leads to aminotransferases (AST and ALT) normalisation and improvements in liver histological lesions and long-term outcomes of patients with CHB.[1, 3-5] Their main advantages, compared with interferon-alpha, are the high anti-viral potency and high on-therapy efficacy, the better safety and tolerability profile and the oral administration.[1-4] On the other hand, the main limitations of NAs include the need for long-term, perhaps indefinite, therapy, particularly in HBeAg-negative patients, the risk of viral resistance and the unknown long-term safety.[1-4]

Lamivudine was the first NA approved for treatment of chronic HBV infection and probably remains the most widely used NA worldwide, due to its low cost. One year of lamivudine monotherapy achieves virological remission in 36–44% of HBeAg-positive and 72–75% of HBeAg-negative chronic hepatitis B (CHB) patients.[6-10] However, long-term lamivudine monotherapy results in progressively accumulating rates of viral resistance due to YMDD mutations (10–25% at year-1, 65–80% at year-5) followed by virological and biochemical breakthroughs and clinical worsening of liver disease, including severe exacerbations, decompensation and liver failure.[1, 3, 11, 12] Because of the high cumulative probability of viral resistance, lamivudine monotherapy is not currently considered to be an optimal first-line therapy for CHB.[1, 3]

Adefovir was the second NA approved for the treatment of chronic HBV infection. It has moderate anti-viral potency, achieving virological remission at the end of the first year in 13–21% of HBeAg-positive and 51–63% of HBeAg-negative CHB patients.[13-15] Adefovir is active against lamivudine-resistant strains and therefore was the commonest option for the treatment of patients who developed lamivudine resistance until a few years ago.[1, 3, 4, 16, 17] However, its lower anti-viral potency in both NA-naive and NA-experienced patients, the moderate risk of resistance during long-term therapy in naive patients (29% at year-5) and its higher cost resulted in its replacement by the newer, more effective and cheaper nucleotide analogue, tenofovir, in all countries with tenofovir availability.[3, 15, 18]

Telbivudine is a potent anti-viral agent, achieving 1-year virological remission rates in 60% of HBeAg-positive and 88% of HBeAg-negative CHB patients.[8] It may also select for mutations in the YMDD motif, but at a lower rate compared with lamivudine.[1, 3, 4] Two years of telbivudine therapy achieve virological remission in 54% of HBeAg-positive and 79% of HBeAg-negative CHB patients, while 1-year and 2-year resistance rates under telbivudine have been reported to be 4.4% and 21.6% of HBeAg-positive and 2.7% and 8.6% of HBeAg-negative CHB patients respectively.[19] The rates of resistance to telbivudine are relatively low in patients with low baseline viraemia (<2 × 108 IU/mL for HBeAg-positive and <2x106 IU/mL for HBeAg-negative patients), who achieve undetectable HBV DNA at 6 months of therapy.[19, 20] In addition, telbivudine was recently reported to maintain satisfactory virological remission rates at 4 years of therapy in both HBeAg-positive and HBeAg-negative CHB patients without genotypic resistance at 2 years (88% in those with undetectable HBV DNA at 6 months of therapy).[21]

Entecavir and tenofovir are potent anti-viral agents with a minimal, or even no, risk of resistance and therefore they usually represent the currently recommended first-line NAs for the therapy of NA-naive patients with CHB.[1, 3] They achieve 1-year virological remission rates of 67–76% in HBeAg-positive and 90-93% of HBeAg-negative CHB patients.[6, 9, 15] As resistance develops only occasionally in NA-naive patients under long-term entecavir or tenofovir monotherapy (approximately 1.5% at 6 years of entecavir, 0% at 6 years of tenofovir), prolongation of monotherapy with either entecavir or tenofovir results in accumulating and maintained virological remission rates, which exceed 95% after the first 3 years of such monotherapy.[22-26] In contrast to NA-naive patients, only tenofovir is a quite effective option for patients with lamivudine or telbivudine resistance, while the use of entecavir (even at a higher daily dose: 1.0 mg instead of 0.5 mg used in NA-naive patients) in patients with lamivudine resistance is associated with high rates of resistance to entecavir, exceeding 50% at 5 years.[1, 3, 27] Thus, entecavir is a less attractive therapeutic option for the long-term treatment of patients with known lamivudine-resistant strains.[1, 3, 4]

Nucleos(t)ide analogues and renal function

Nucleos(t)ide analogues are cleared by the kidneys and therefore their dosage has to be adjusted in all patients with impaired renal function (creatinine clearance <50 mL/min).[3] The recommended NA dosages according to the patients' renal function are shown in Table 1. Thus, creatinine clearance should be estimated in all patients starting NA therapy.

Table 1. Dosage adjustments of nucleos(t)ide analogues according to creatinine clearance (CrCl) based on the approved special product characteristics (SPCs)
CrCl (mL/min)LamivudineCrCl (mL/min)Adefovir dipivoxil
≥50100 mg daily≥5010 mg daily
30–49100 mg loading dose – 50 mg daily20–4910 mg every 2nd day
15–29100 mg loading dose – 25 mg daily10–1910 mg every 3rd day
5–1435 mg loading dose – 15 mg daily<10, no HD
5<35 mg loading dose – 10 mg dailyHDa10 mg once weekly
CrCl (mL/min)Entecavir
NA-naive patientsWith lamivudine resistanceb
≥500.5 mg daily1.0 mg daily
30–490.25 mg daily or 0.5 mg every 2nd day0.5 mg daily
10–290.15 mg daily or 0.5 mg every 3rd day0.3 mg daily or 0.5 mg every 2nd day
<10 or HDa0.05 mg daily or 0.5 mg every 5th to 7th day0.1 mg daily or 0.5 mg every 3rd day
CrCl (mL/min)TelbivudineCrCl (mL/min)Tenofovir DF
  1. HD, haemodialysis; DF, disoproxil fumarate.

  2. a

    In patients undergoing HD, all agents should be given once weekly after an HD session.

  3. b

    In patients with prior lamivudine resistance, entecavir should be given 2 h before or 2 h after food.

≥50600 mg daily≥50300 mg daily
30–49400 mg daily or 600 mg every 2nd day30–49300 mg every 2nd day
<30, no HD200 mg daily or 600 mg every 3rd day10–29300 mg every 3rd to 4th day
HDa200 mg/24 h ή 600 mg/96 h<10, no HD
  HDa300 mg once weekly

During long-term therapy, minimal rates of creatinine clearance decline have been reported with all NAs, except for telbivudine.[3, 28, 29] In particular, in a large (n = 655) subset of CHB patients of the phase III telbivudine trial who were evaluated for long-term telbivudine safety, the estimated glomerular filtration rate (eGFR) (MDRD formula) increased by 14.9 mL/min/1.73 m2 or by 16.6% from baseline to year-4 (P < 0.0001).[21] The improvement in renal function was more evident in the telbivudine-treated patients with mildly reduced baseline eGFR (60–90 mL/min/1.73 m2), with 74% (165/223) of them shifting to >90 mL/min/1.73 m2 after 4 years of treatment. In another randomised trial in NA-naive patients with HBV decompensated cirrhosis, eGFR had a steady decline in 114 patients treated with lamivudine for up to 2 years and a steady improvement in 114 patients treated with telbivudine mainly in the second year of treatment (P ≤ 0.01 after week 60).[30] Finally, no significant change in eGFR was recently reported in 45 NA-naive HBeAg-positive CHB patients who received telbivudine and tenofovir combination from week 24 to 52 due to residual viraemia after 24 weeks of telbivudine monotherapy,[31] while eGFR was reported to improve in 19 lamivudine-experienced patients who received telbivudine and tenofovir combination for 2 years in contrast to 19 similar patients who received lamivudine and tenofovir combination for 2 years (change of mean eGFR: +18.6 vs. −12.8 mL/min).[32] Similar data for improvement of creatinine clearance in several patient subgroups under telbivudine therapy regardless of virological response have been repeatedly reported in several international liver meetings over the last 2–3 years. The mechanism of this potential renal-protective effect of telbivudine, which is excreted in urine unchanged, has not been clarified yet.

Based mainly on pre-clinical data and data from HIV-infected patients, the nephrotoxic potential is considered to be higher for nucleotide analogues, particularly adefovir.[33-35] However, the clinical data are not straightforward. Renal adverse events including creatinine clearance decline and proximal tubular dysfunction resulting in hypophosphataemia, osteomalacia have been reported in several cohorts of CHB patients treated with adefovir at the licensed (10 mg) or, more frequently, at higher than the licensed daily dosage (30 mg)[14, 36-38] as well as in small cohorts (n = 9) of CHB patients treated with tenofovir.[38] In addition, tenofovir-containing anti-HIV regimens have been associated with an increased risk of similar renal adverse events, including occasionally even Fanconi syndrome.[38-43] On the other hand, an increased risk of such renal adverse events has not been confirmed in other CHB cohorts treated with adefovir for up to 5 years,[18, 44] whereas large 6-year phase III (n = 466) and 3-year real-life cohorts (n = 302) have reported very low rates(<2%) of renal adverse events.[26, 45] Moreover, there are studies questioning tenofovir nephrotoxicity even after 10 years of therapy in large cohorts of HIV-infected patients[46, 47] or even the nucleotide nephrotoxicity in liver transplant patients who represent a group of high risk for renal dysfunction over time.[48] Thus, there is currently no recommendation that tenofovir should not be used in patients with mild-to-moderate renal dysfunction,[1, 3] but some clinicians might still hesitate to use it in such cases.

In daily clinical practice, there are two main questions on the optimal use of NAs in relation to renal function: which is the optimal on-therapy monitoring and which NA should be preferred in patients with, or at, high risk for renal dysfunction. The recent clinical practice guidelines of the European Association for the Study of the Liver provide a weak, but reasonable, recommendation, which takes into account not only the type of NA but also the patient's baseline renal risk.[3] Chronic HBV patients are considered to be at high renal risk if they have one or more of the following factors: decompensated cirrhosis, creatinine clearance <60 mL/min, poorly controlled hypertension, proteinuria, uncontrolled diabetes, active glomerulonephritis, concomitant nephrotoxic drugs and solid organ transplantation. Renal monitoring during NA therapy is recommended for all patients at high renal risk regardless of NA (every month for the first 3 months, every 3 months until the end of the first year and every 6 months thereafter, in case of no worsening) as well as for patients at normal renal risk who are treated with a nucleotide analogue (adefovir or tenofovir) (every 3 months for the first year and every 6 months thereafter, in case of no worsening). Renal monitoring is based on serum creatinine and estimated creatinine clearance measurements for high renal risk patients under nucleoside analogues and on both serum creatinine (estimated creatinine clearance) and phosphate measurements for patients under nucleotide analogues due to reported risk of proximal tubular dysfunction.[3] Closer renal monitoring is required in patients who develop creatinine clearance <60 mL/min or in those with serum phosphate levels <2 mg/dL.

Similar to baseline, dosage modifications for all NAs are clearly required in patients with confirmed creatinine clearance decreasing to <50 mL/min (Table 1). In contrast, there no clear recommendations for the management of patients with hypophosphataemia under tenofovir, the currently used nucleotide analogue. Based on reasonable clinical judgement, other markers of proximal tubulopathy (serum glucose and potassium, urine glucose) must be checked in all patients who develop confirmed serum phosphate levels <2.0 mg/dL, while some experts recommend phosphate replacements and/or lower tenofovir dosage (one tablet every other day) in such cases.

The choice of the appropriate NA in CHB patients does not depend solely on the renal safety. In NA-naive patients with renal dysfunction at baseline (creatinine clearance <50–60 mL/min), entecavir may be preferred over tenofovir, but even telbivudine as a potentially renal-protective agent may be tried for 6 months in cases with low baseline viraemia (<108 or 10IU/mL for HBeAg-positive or HBeAg-negative patients) and continued if it achieves HBV DNA undetectability. Consideration should be also given to switching tenofovir to entecavir or even telbivudine in the few NA-naïve patients who may experience creatinine clearance decreased to <50 mL/min or severe hypophosphataemia (<1.0–1.5 mg/dL). It should be noted that there is no recommended tenofovir dose for nonhaemodialysed patients with creatinine clearance <10 mL/min. On the other hand, tenofovir represents practically the only effective choice for patients with resistance to lamivudine or any nucleoside analogue[3] and therefore it cannot be replaced in patients who develop renal dysfunction. Based on limited data, the addition of telbivudine might be tried in the latter patients with reduced creatinine clearance.

HBV-related glomerulopathies

Τhe incidence of glomerulopathies in HBsAg-positive patients is low. In particular, polyarteritis nodosa[49] or immune complex-mediated glomerulopathies including membranous/membranoproliferative/IgA glomerulonephritis[50, 51] and focal segmental glomerulosclerosis[52] may develop. The prevalence of HBV-related glomerulopathy is in parallel with the geographical pattern of HBV prevalence (high in Southeast Asia, low in North America and Western Europe) and its clinical presentation is mostly with nephrοtic or non-nephrotic proteinuria associated with microhaematuria.[50]

Given the small numbers of patients, there are no strong data for NA therapy in patients with HBV-related glomerulopathies. There have been only case reports and small cohort studies, which included mostly lamivudine[52-61] and, less frequently, entecavir.[59, 62-65] Telbivudine, which might have a theoretical advantage in this setting due to its potentially favourable effect on glomerular filtration,[21, 30-32] was also recently reported to be safe and effective for both liver and kidneys in 12 patients with HBV-associated glomerulonephritis.[66] One relevant meta-analysis[67] concluded that lamivudine was superior to interferon-alpha therapy in inducing virological remission and preserving renal function despite the emergence of resistance. In a most recent meta-analysis including 10 lamivudine and 2 entecavir studies,[68] the combined approach of NAs and low-dose steroids was found to achieve, more frequently, proteinuria remission compared with NAs alone or steroids alone (83% vs. 29% and 75% respectively).

Based on the above data, the combination of a NA and low-dose steroids seems to be the more effective approach for the management of patients with HBV-related glomerulopathies and therefore it is currently preferred by most clinicians. Interferon-alpha may be better avoided as it can worsen immune-mediated events. Regarding the choice of NA, the same principles as those for patients with reduced creatinine clearance should be applied. Thus, entecavir or telbivudine may be used in NA-naïve patients with HBV-related glomerulopathies, depending on the viraemia levels and the renal function impairment. It should be noted that NA therapy should be used even pre-emptively in all patients who will start steroids or any other immunosuppressive agent for their renal disease.[1, 3] Given than extrahepatic reservoir of HBV may be frequently detected in patients with HBV-related glomerulopathies,[64] NA therapy may better continue until HBsAg loss, as HBV relapses are often followed by relapses of proteinuria.[55, 60, 61] In patients with undetectable or low (<2000 IU/mL) HBV DNA levels at baseline who receive pre-emptive NA therapy, NA may be discontinued after 12 months after the cessation of any immunosuppressive agent.[3]

HBV infection in patients under haemodialysis

The prevalence of HBsAg positivity among patients undergoing HD has been reported to range between 0 and 7% in developed and between 0 and 20% in developing countries.[69, 70] The introduction of HBV immunisation in several endemic regions has significantly lowered that HBV incidence in this setting,[71] but end-stage renal patients often have poor responses to vaccination, even after intensified protocols and booster doses.[72, 73] Thus, additional preventive measures and behavioural modifications should be always recommended to minimise the risk of patient-to-patient HBV transmission.

Chronic HBV infection in HD-dependent patients has an asymptomatic, but often progressive, course.[74] Similar to all CHB patients,[1, 3] the therapeutic indications in HBsAg-positive patients undergoing HD are based on serum HBV DNA levels >2000 IU/mL, elevated ALT and at least moderate histological liver lesions by liver biopsy or, more recently, by non-invasive markers of fibrosis.[75] It should be noted, however, that the therapeutic indications are not so straightforward in this setting. ALT values should be interpreted with caution as they are often low in patients on HD, which stresses the importance of liver biopsy in such cases.[76] On the other hand, percutaneous liver biopsy may be often deferred due to an increased bleeding risk associated with clotting disorders, uraemia-associated platelet dysfunction and intradialysis anti-platelet and anticoagulant therapies, while transjugular liver biopsy that is associated with a lower complication rate[77] is available only in a few specialised centres. Transient elastography or other non-invasive markers of liver fibrosis have not been extensively evaluated in this group of patients.[78] Thus, based on reasonable clinical judgment, NA therapy can be started in patients undergoing HD with HBV DNA >2000 IU/mL regardless of ALT activity, particularly if they have at least moderate histological liver lesions at liver biopsy or at least moderate fibrosis estimated by a non-invasive marker.

All NAs need dose adjustments in patients undergoing HD, as their pharmacokinetics are significantly altered. Renal insufficiency results in reduced drug excretion and dialysis procedure to drug removal. NAs are dialysable in almost 50%, because they have low molecular weight and relative lack of protein binding. However, due to high volume of drug distribution (>100 L) and the intermittent nature of HD technique (thrice weekly), no additional dose following HD is required.[79-81] Thus, most NAs are given once weekly after a HD session (Table 1). Studies on lamivudine pharmacokinetics have shown that patients on peritoneal dialysis should receive the same reduced dosage with that used in patients on HD.[82]

There are very few clinical data on the use of NAs in patients undergoing HD. In particular, there are 5 reports with a total of 38 patients treated with lamivudine for 10–14 months (4–16 patients in each report),[83-87] 3 reports with a total of 7 patients treated with adefovir for 15–24 months (two case reports and one report with 5 patients),[88-90] one report with 7 patients treated with entecavir for 14 months[91] and one report with an HIV and HBV co-infected patient treated with tenofovir for 6 months.[92] Given that kidneys are seriously damaged in patients undergoing HD, renal safety may not affect the choice of NA in this subgroup of CHB patients. Thus, entecavir or tenofovir, the usual first-line options for NA-naive CHB patients,[1, 3] can be used at adapted dosages (one tablet weekly following a HD session). Tenofovir should be preferred in such patients with prior lamivudine resistance.[1, 3] In patients with some residual diuresis and low viraemia, telbivudine may be also tried.

HBV and renal transplantation

HBV-positive renal transplant candidates or recipients

Untreated HBsAg-positive RT recipients usually have a worse prognosis compared with HBsAg-negative RT recipients.[93-95] More than half (57%) of deaths among untreated HBsAg-positive RT recipients are attributed to liver-related complications, such as fulminant hepatitis, hepatocellular carcinoma and decompensated cirrhosis.[94, 96] The use of immunosuppressive therapy after RT has also been associated with a risk of rapidly progressing fibrosing cholestatic hepatitis, even in patients with mild or inactive liver disease before RT.[97]

Interferon-alpha should be avoided in RT recipients because of risk of rejection and low anti-viral potency.[3, 98] Although there are no large and well-designed studies for the efficacy of NAs in HBsAg-positive RT recipients, it is reasonably assumed and widely accepted that their use has substantially improved the clinical course of these patients. Therefore, treatment with a NA is recommended for all HBsAg-positive RT recipients. NA therapy should ideally start at CHB diagnosis in RT candidates with HBV DNA >2000 IU/mL or 2 weeks before RT in candidates with HBV DNA ≤2000 IU/mL and should continue for life as long as the patients remain under any immunosuppressive agent(s).[3, 78, 99] It should be noted that patients with compensated cirrhosis are precluded from RT, while patients with decompensated cirrhosis may only undergo combined liver and kidney transplantation.[100, 101]

The need for anti-HBV prophylaxis in HBsAg-negative, anti-HBc-positive RT recipients is rather questionable. As they are not at high risk of HBV reactivation, they can be just followed with regular HBV DNA monitoring, similar to other HBsAg-negative, anti-HBc-positive patients who require immunosuppressive agent(s).[3]

The choice of the NA for HBsAg-positive RT recipients is decided on an individual basis guided by the patient's viraemia levels and previous exposure to NA(s) and by the drug renal safety profile. Lamivudine has been used extensively in HBsAg-positive RT recipients, but its results have been similar to those in other CHB patients.[78, 102] In 5 small series with a total of 32 patients with lamivudine resistance,[88, 103-107] adefovir often given at a low dosage (2.5–10 mg daily) was reported to offer satisfactory virological responses, but to be associated with renal adverse events in some cases.[103, 104] Because of its potential nephrotoxicity and the current availability of tenofovir, adefovir is not considered to be a preferable treatment option for RT recipients.[78] Entecavir is an attractive option for RT recipients. Entecavir at a daily dose of up to 1 mg has been proved efficacious and well tolerated without causing allograft rejection or creatinine clearance declines in 4 reports including 76 patients followed up for a mean of 16–31 months.[91, 106, 108, 109] Telbivudine, with its potentially favourable effect on glomerular filtration,[21, 30-32] may also be an attractive option in HBsAg-positive RT recipients who have a high risk for renal dysfunction, particularly those with low viraemia who receive NA therapy pre-emptively. Finally, there are very limited data for the use of tenofovir in this setting showing satisfactory results, but in only 3 RT recipients followed up for 12 months.[110]

Based on the existing data and knowledge, entecavir, regardless of viraemia, and telbivudine, in cases with low viraemia, seem to be the preferred options for HBsAg-positive RT recipients. Tenofovir may be also used in NA-naive RT recipients with normal renal function, while it represents the agent of choice for any RT recipient with prior lamivudine or any nucleoside resistance. Given that RT recipients who always remain under close renal monitoring may develop renal impairment with time, vigilance for the need of dosage and/or NA therapy modifications is mandatory.

HBV-positive renal transplant donors

HBsAg-positive and/or anti-HBc-positive donors have been usually excluded from the RT process in most renal transplant centres, as there is a risk of HBV transmission, particularly from HBsAg-positive, but even from HBsAg-negative, anti-HBc-positive, kidney donors. However, the lack of adequate number of renal allografts and the prolonged waiting time have made several transplant centres reconsider their criteria and try RT with grafts from HBsAg-negative, anti-HBc-positive or even from HBsAg-positive donors to HBsAg-positive or negative recipients.

In one report, 1-year lamivudine prophylaxis was shown to be safe and effective in 45 HBsAg-negative RT recipients of kidney grafts from anti-HBc-positive donors, with no patient developing HBV viraemia or HBsAg seropositivity during 6–66 months after lamivudine discontinuation.[111] In a retrospective study without any anti-HBV prophylaxis, no active HBV infection was observed in 344 HBsAg-negative recipients of kidney grafts from 210 anti-HBc-positive donors without any difference in the 5-year patient and graft survival rates between anti-HBc-positive and negative recipients.[112] Similarly, the use of kidneys from anti-HBc-positive donors was not found to be associated with any risk of HBV transmission or to affect graft and patient survival in 28 HBsAg-negative, anti-HBc- and/or anti-HBs-positive recipients as well as in 8 HBV non-exposed (anti-HBc-negative) recipients who received pre-transplant prophylaxis with hepatitis B immunoglobulin.[113] In another study,[114] the safety and efficacy of RT from HBsAg-positive donors to 65 anti-HBs-positive recipients were also evaluated. Among them, 7 recipients of grafts from donors with detectable HBV DNA were treated with hepatitis B immunoglobulin (400 IU weekly) for 3 months and lamivudine for 6 months. Two recipients developed de novo HBV infection, but no recipient developed severe liver dysfunction or died during a mean follow-up of 39 months. The rates of liver injury and survival did not differ between these 65 RT recipients and 308 RT recipients of grafts from HBsAg-negative donors. Moreover, kidney grafts from HBsAg-positive, HBeAg/HBV DNA-negative donors were reported to carry no risk of HBV transmission and to offer excellent graft and patient survival over a mean of 42 months in 7 HBsAg-negative, anti-HBs-positive RT recipients who received lamivudine after RT.[115]

Thus, kidney grafts from HBsAg-negative, anti-HBc-positive donors seem to be safe to be used in any RT recipient regardless of HBV status, even without any anti-HBV prophylaxis. On the latter occasion, it may be reasonable to test for serum HBV DNA a few months after RT, particularly in anti-HBs-negative recipients. Finally, even kidney grafts from HBsAg-positive donors might be used in anti-HBs-positive recipients who may better receive post-RT prophylaxis with a NA (even lamivudine) alone or perhaps combined with a short course of hepatitis B immunoglobulin in case of donors with HBV viraemia.

Conclusions

Treatment options for renal patients with chronic HBV infection are complex and should be therefore based on a multidisciplinary approach according to the patient's overall clinical status. In particular, renal patients under anti-HBV therapy should be followed not only for the treatment efficacy against HBV but also with a thorough renal monitoring as well. NAs represent the first-line treatment options for CHB patients with any level of renal dysfunction and renal replacement therapy (Figure 1). Physicians should be aware of the necessary drug dose adjustments according to creatinine clearance as well as the potential nephrotoxicity and long-term drug efficacy. In general and despite the absence of strong data, entecavir, an agent without signs of nephrotoxicity, and telbivudine, an agent with promising data for even improvement in creatinine clearance, seem to be the preferred options for NA-naive patients with any renal dysfunction, depending on the HBV viraemia levels and the severity of renal dysfunction. Although there are no definite conclusions about the risk of tenofovir-associated nephrotoxicity, most clinicians are concerned and therefore avoid using this agent in this setting. However, tenofovir remains the agent of choice for patients with renal dysfunction and prior resistance to lamivudine or any nucleoside analogue. Whether a combination of tenofovir with telbivudine might be more beneficial for the renal function in the latter group remains to be confirmed. The current knowledge can be the basis for multicentre randomised controlled studies evaluating the therapeutic benefits and long-term renal safety to identify the optimal NA therapy for the several subgroups of patients with CKD.

Figure 1.

Proposed treatment algorithm for management of patients with chronic hepatitis B virus (HBV) infection and chronic kidney diseases. Close renal monitoring and potential drug dosage modifications according to creatinine clearance are required for all cases. *Treatment indications include two of the following criteria: HBV DNA >2000 IU/mL, elevated ALT and at least moderate histological liver lesions by liver biopsy or, more recently, by non-invasive markers of fibrosis. #Low viraemia is considered as HBV DNA levels <108 or <106 IU/mL for HBeAg-positive and HBeAg-negative patients respectively. Patients starting telbivudine monotherapy should be continued with such therapy only if they achieve undetectable HBV DNA at 24 weeks. NA, nucleos(t)ide analogue; HBIG, hepatitis B immunoglobulin.

Authorship

Guarantor of the article: George Papatheodoridis.

Author contributions: Chrysoula Pipili and Evangelos Cholongitas run the initial literature search. All authors made substantial contributions to the manuscript preparation, data presentation and discussion of the contents and conclusions. All authors approved the final version of the manuscript.

Acknowledgements

Declaration of personal interests: George Papatheodoridis has received research grants from Bristol-Meier Squibb, Gilead and Roche, and has served as an advisor/lecturer for Bristol-Meier Squibb, Gilead, Merck Sharp & Dohme, Novartis and Roche, as well as a member of data safety management board for Gilead.

Declaration of funding interests: None.

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