Nephrotoxicity caused by oral antiviral agents in patients with chronic hepatitis B treated in a hospital for tropical diseases in Thailand

More than 350 million people are estimated to have chronic hepatitis B virus (HBV) infection. Patients may be asymptomatic, but can develop severe hepatic impairment. Approximately 15–40 % of chronic HBV cases progress to cirrhosis, end-stage liver failure or hepatocellular carcinoma [1].

Currently, five oral nucleoside or nucleotide analogs are approved for the treatment of chronic hepatitis B (CHB) by the United States Food and Drug Administration: lamivudine (LAM), entecavir (ETV), telbivudine (LdT), adefovir (ADV) and tenofovir (TDF). Currently, all of these antiviral drugs are approved by the Thai FDA for the treatment of CHB. Nucleoside and nucleotide analogs target HBV DNA polymerase protein, a multifunctional protein essential for viral replication [2].

LAM is a nucleoside analog and was the first oral agent approved for the treatment of CHB [3]. Although LAM resistance has emerged, LAM appears not to impair renal function [4]. ETV has potent antiviral activity with low rates of drug resistance, but the establishment of LAM resistance diminishes its efficacy because genotypic resistance to ETV develops more frequently in prior LAM-treated patients [5]. In clinical trials, ETV had a similar safety and tolerability profile to LAM [6], with only minor adverse events reported and no evidence of mitochondrial or other serious renal side effects in patients treated for up to 5 years. LdT is an L-nucleoside with potent activity against HBV, but its role in the treatment of CHB as monotherapy is limited by cross-resistance with LAM [3]. Generally LdT is well tolerated, and its safety profile appeared to be similar to LAM in registration trials.

Resistance to LAM is an increasing problem in the treatment of CHB [2]. Given the potential for cross-resistance to LdT and ETV in patients refractory to LAM, treatment with nucleotide analogs is preferred. Treatment with oral antiviral agents might require life-long administration. Clinical trials of ADV and TDF also concluded that they have an acceptable safety profile, but following their widespread use in clinical practice there have been reports that the long-term use of nucleotide analogs may impair renal function [2].

In one large randomized clinical trial, ADV exhibited dose-dependent nephrotoxicity [7]; however, no significant rise in serum creatinine concentration was observed in patients taking ADV compared with placebo in three other randomized controlled trials [8–10]. Ultimately ADV was given regulatory approval at a daily dose of 10 mg. Nucleotide analog-related nephrotoxicity has been reported in subsequent cohort studies, with a prevalence of 3.0–9.9 % for ADV monotherapy or ADV-LAM combination therapy [4, 11–13].

According to updated guidelines, TDF can also be used as a first-line treatment option for CHB [3]. A trial comparing TDF with ADV found that a 300 mg daily dose of TDF had superior antiviral efficacy and a good safety profile, with no adverse renal events reported during the 48-week follow-up period [14]. The nephrotoxicity of TDF was already observed for the treatment of human immunodeficiency virus (HIV), but in HIV other antiviral drugs might also contribute to renal dysfunction. One recent retrospective study found that 5.6 % of patients with CHB had evidence of nephrotoxicity after 2 years of treatment with TDF [15]. In a recently published 7-year safety and efficacy study of TDF in CHB, 3.6 % of patients had developed nephrotoxicity [16].

Renal toxicity may also be manifested by proximal tubular cell toxicity without a rise in serum creatinine concentration, including a Fanconi-like syndrome characterized by proteinuria, normoglycemic glycosuria and hyperphosphaturia [17, 18]. Several cases of this syndrome have been reported in patients taking nucleotide analogs for CHB [19, 20]. Differences in the age, body weight, baseline renal function, prevalence of hypertension, diabetes mellitus and cirrhosis in previous clinical trials and cohorts may also account for the differences in renal dysfunction reported after treatment with nucleotide analogs [11, 13, 19]. Importantly, renal dysfunction caused by nucleotide analogs appears to be reversible, and if renal impairment is detected promptly any further deterioration can be avoided with the correct intervention.

This study examined the long-term renal safety of currently approved nucleoside and nucleotide analogs, and determined the risk factors for renal dysfunction in patients with CHB treated in a hospital for tropical diseases in Thailand.

We undertook a retrospective observational study of patients with CHB who regularly attended the hepatology outpatient clinic at the Hospital for Tropical Diseases, Bangkok, Thailand between 2006 and 2014. Patient information was anonymized and de-identified prior to analysis.

We included all patients diagnosed with CHB on the basis of a positive test for serum HBV surface antigen (HBsAg) for more than 6 months who had been treated with any oral antiviral agent. We excluded patients who had hepatitis C virus or HIV co-infection, patients with advanced kidney disease (such as those requiring dialysis or renal transplant recipients) and patients treated with other drugs that have impacts on renal function.

In our study, 10.3 % of patients in the NTA group developed nephrotoxicity on the basis of a change in serum creatinine concentration (≥0.5 mg/dl above baseline) over 8 years. In contrast, none of the patients treated with NSA developed nephrotoxicity. However, many large-scale clinical trials concluded that there was no association between ADV (an NTA) therapy and elevated serum creatinine concentration after 48 weeks of treatment [7]. Similarly Lim and colleagues reported no significant nephrotoxicity after 48 weeks of treatment with ADV [10]. Two other clinical studies also did not report an increased incidence of renal dysfunction in patients treated with ADV compared with those who received placebo [4, 8].

The safety profile of TDF, another NTA, has mostly been established in patients with HIV infection, as TDF is one of the main components of anti-retroviral therapy. There are few safety data from the mono-infected CHB population. Tenofovir is reportedly nephrotoxic in some patients with HIV, but some of the other antiviral drugs used to treat HIV infection might also cause renal side effects. In a clinical trial of TDF in CHB, an increase in serum creatinine concentration of ≥0.5 mg/dl was observed in less than 1 % of participants after 36 months follow-up [22].

Our result supports that of Hartono and colleagues, who found that 9.9 % of those receiving ADV monotherapy developed nephrotoxicity after 7 years of treatment, although in contrast with our findings, they also reported that increasing age was a risk factor for nephrotoxicity [11]. Lampertico et al. reported a relatively lower incidence of nephrotoxicity of 7 % in patients treated with LAM + ADV for 45.5 months [12] and Marcellin et al. reported an incidence of 8 % after 5 years of ADV monotherapy [23]. Therefore, the risk of nephrotoxicity appears to increase with treatment duration.

The cumulative proportion of renal dysfunction in patients treated with nucleotide analogs in our study was 33.5 % at year 6, almost identical to the findings of another recent study conducted in an Asian population which was 33.8 % at year 6 [11, 13, 19]. We found that the proportion of patients exhibiting renal dysfunction increased to 47.6 % after 8 years. The development of oral antiviral-related renal dysfunction can occur as early as 4 months and up to 8 years or greater of treatment. The risk of renal dysfunction appears to be associated with treatment duration.

The incongruity between the incidence of nephrotoxicity reported by clinical trials and later observational studies could be explained by the short observation period, and strict inclusion and exclusion criteria, of randomized studies. In routine clinical practice, patients with risk factors that might contribute to renal dysfunction still require treatment, but these patients might have been excluded from clinical trials. Our findings support those of post-marketing surveillance and longer-term clinical observational studies, which reported nucleotide analogs are nephrotoxic [11, 12, 16]. The incidence of nephrotoxicity in our study was higher than in other studies, which may be a consequence of differences in the baseline characteristics of the study populations. Different outcome measures, definitions of renal impairment and measurement techniques make it difficult to perform direct comparisons between studies. Furthermore, our study was retrospective and there was no standardized patient management protocol.

Only one patient in our cohort had been treated with TDF. This patient developed ARSC after 4 months of TDF monotherapy, but already had a history of hypertension, diabetes mellitus, and cirrhosis before treatment. In this case we were unable to draw any conclusions about the cause of renal dysfunction. Nevertheless, two studies have reported that increasing age, low body weight, hypertension, diabetes and baseline serum creatinine concentration are predictors of renal dysfunction in patients with CHB or HIV taking ADV or TDF [24, 25].

Fanconi syndrome is increasingly recognized as a complication of long-term treatment with nucleotide analogs. It is characterized by normoglycemic glucosuria, proteinuria and phosphaturia [18]. In our study, urinalysis results were not included in the selection criteria, as they were not routinely or regularly undertaken in patients with CHB at the time our study was conducted. Thus, signs of renal tubular toxicity—including proteinuria or glycosuria—might have been overlooked.

In summary, we found that the long-term exposure to nucleotide analogs, especially ADV, increased the risk of nephrotoxicity in CHB patients. The incidence of nephrotoxicity was 10.3 % after 8 years of treatment, which was higher than previous reports (3.0–9.9 %) from studies conducted over 3–7 years.

The early detection of nephrotoxicity is critical, as it is reversible and thus further deterioration of renal function can be avoided. We recommend that individuals with CHB who are taking nucleotide analogs have their renal function monitored at least every 6 months (Fig. 4), especially those with abnormal baseline results, based on the risk of deterioration of renal function and recommendations from the literature [26].

There is no unified standard for the evaluation of renal side effects in long-term nucleotide analog treatment, which may explain the inconsistent results in the literature. Therefore, well-designed, standardized long-term clinical studies are still required to determine the true incidence of renal dysfunction and establish the risk factors in patients with CHB treated with these drugs.