Expert Insight Into: Renal Dysfunction in Asian American Patients with Chronic Hepatitis B Treated with an Oral Nucleotide Analogue

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Clinical Insights

Treatment of chronic hepatitis B with adefovir dipivoxil (ADV) can be associated with significant renal function deterioration.
Patients receiving ADV should be closely monitored using estimated glomerular filtration rate (eGFR), a more accurate measure of renal function than serum creatinine (sCr).
Older patients (>50 years) and those with baseline renal insufficiency, hypertension, and/or diabetes are at increased risk when treated with ADV.
These findings are from a small study with limitations in conclusions that can be drawn, since it is a non-randomized, retrospective trial, and it does not reflect all of the characteristics of the agent discussed.

PLEASE NOTE: The peer-reviewed journal article reviewed in this educational activity has been selected by faculty on the scientific merits of the new data and/or information being reported, which form the building blocks for a better understanding of the disease and its management. The evidence-based clinical findings provided in these articles are important in helping clinicians improve patient care and outcomes. Each article review is one part of a larger overall curriculum mosaic that provides a full and balanced perspective on this disease and its management. We suggest that you read all of the article reviews in this series.

The nucleotide analogue, adefovir dipivoxil (ADV), has been a popular choice for long-term therapy in patients with chronic hepatitis B (CHB) because of its efficacy in suppressing hepatitis B virus replication in both treatment-naïve and lamivudine-resistant patients, reduced risk of development of resistance, and generally favorable toxicity profile. The primary drawback associated with ADV is dose-related nephrotoxicity. At the current dosage of 10 mg, 3% to 16% of patients experienced an increase in serum creatinine (sCr) of ≥0.5 mg/dL in clinical trials ranging from 30 months to 5 years. However, since levels of creatinine clearance as measured by a specific sCr may vary depending on patient characteristics such as weight, age, and race, results of these studies may underestimate the incidence of clinically significant renal impairment. In addition, patients in these trials were carefully selected and may not be representative of the CHB patient population seen in general practice. This limitation may be especially important in applying trial results to Asian American patients who typically have a smaller body mass than individuals of other ethnic groups and in whom smaller changes in sCr may reflect a greater degree of renal function impairment than that seen in other groups.

Estimated glomerular filtration rate (eGFR), which takes into account Cr level, weight, age, and sex, is a more accurate measure of renal function than sCr. In an effort to better understand the effect of ADV on renal function in Asian American patients treated in a community setting, a retrospective cohort study was conducted in 290 Asian Americans with CHB: 145 consecutive patients who received ADV 10 mg daily and 145 randomly selected ADV-unexposed patients who received entecavir (ETV) 0.5 mg or 1.0 mg daily. Patient eGFRs were calculated using the Cockcroft-Gault formula and classified as unimpaired (≥80 mL/min), mildly impaired (50 mL/min to <80 mL/min), moderately impaired (30 mL/min to <50 mL/min), and severely impaired (<30 mL/min). Patients were treated in two community-based clinics in the San Francisco Bay area.

All patients had baseline eGFR ≥50 mL/min and the two groups were matched in terms of age (+10 years), sex, and baseline eGFR classification. The two groups were similar across baseline variables with the following exceptions: a greater number of patients in the ETV group (43.5%) than in the ADV group (29%) were HBeAg-positive, and baseline HBV DNA levels were significantly higher in the ETV group (6.1 log₁₀ IU/ML) than in the ADV group (5.0 log₁₀ IU/mL) (P = .0001). Baseline sCr (0.99 mg/dL and 0.97 mg/dL) and eGFR (85.0 mL/min and 85.4 mL/min) were similar in the ADV and ETC groups. Treatment discontinuation was decided by the treating physician and most discontinued patients were switched to an alternative anti-HBV agent.

Significantly greater renal function impairment was observed with ADV than ETV. The number of patients experiencing mild, moderate, and severe decreases in eGFR from baseline was significantly greater in the ADV group than in the ETV group, as was the number of patients with an increase in eGFR severity classification (Table 1). Similar results in these two variables were found when the MDRD formula, an alternative calculation of eGFR, was used. Treatment was discontinued due to renal impairment in 10 patients in the ADV arm, compared with none in the ETV arm, with eGFR returning to baseline levels in all 10 discontinued patients at an average of 9 months after stopping ADV. Although the ETV patients had a shorter duration of treatment than the ADV patients (18 months vs 30 months), the incidence density of renal dysfunction was still significantly higher in the ADV group than in the ETV group (5 vs 1.36 patients per 100 patient-years, P = .02).

Table 1. Effect of Treatment on Renal Function

	Treatment Group
Renal Function	ADV	ETV	P Value
Decrease in eGFR from baseline Mild (10% - 20%) Moderate (20% - 30%) Severe (>30%)	30% 15% 7%	16% 6% 1%	.0001
Increased severity classification Baseline unimpaired Elevated to mild Elevated to moderate Baseline mildly impaired Elevated to moderate	22.7% 1% 24.2%	15.2% 0% 4.5%	.005 .005
Treatment discontinued due to renal impairment	6.9%	0%	.004
Incidence density of renal dysfunction (cases per 100 patient-years)	5.0	1.36	.02

As shown by multivariate analysis, treatment with ADV 10 mg was a predictor for both a significant decrease (≥20%) in eGFR (HR 2.30, p=.018) and the development of moderate renal dysfunction (HR 3.94, p=.030) (Table 2). Other predictors of a ≥20% decrease in eGFR were age >50 years, male sex, and mild baseline renal impairment.

Table 2. Predictors of Reduced Renal Function on Multivariate Analysis

	HR	P Value
Incremental eGFR decrease >20%^a ADV 10 mg treatment Age >50 years Mild baseline renal impairment Male sex	2.30 3.02 0.43 0.46	.018 <.004 .021 .014
Development of moderate renal impairment and/or treatment discontinuation due to renal impairment ADV 10 mg treatment	3.94	.030

^a Adjusted for hypertension and/or diabetes mellitus

Therefore, although all CHB patients receiving ADV should be carefully monitored for signs of renal function deterioration, special attention should be paid to older males, those with hypertension and/or diabetes, and patients with mild baseline renal impairment. In addition, for the most accurate assessment, monitoring should be done using eGFR rather than sCr.

Reference

Ha NB, Ha NB, Garcia RT, et al. Renal dysfunction in chronic hepatitis B patients treated with adefovir dipivoxil. Hepatology. 2009;50:727-734.

Privacy Policy

Expert Insight Into:
Renal Dysfunction in Asian American Patients with Chronic Hepatitis B Treated with an Oral Nucleotide Analogue

Based on the Article:

Renal Dysfunction in Chronic Hepatitis B Patients Treated with Adefovir Dipivoxil

Medical Writer: Karen Gravelle, PhD
Expert Faculty: Steven-Huy B. Han, MD, AGAF

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Privacy Policy

Expert Insight Into: Renal Dysfunction in Asian American Patients with Chronic Hepatitis B Treated with an Oral Nucleotide Analogue

Based on the Article: Renal Dysfunction in Chronic Hepatitis B Patients Treated with Adefovir Dipivoxil

Medical Writer: Karen Gravelle, PhD Expert Faculty: Steven-Huy B. Han, MD, AGAF

Available for CME/CE:

Physicians

Nurses

Pharmacists

Estimated time for completion of this activity:

Target Audience

Activity Goal

Learning Objective (s)

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CE Information: Nurses

CE Information: Pharmacists

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Physicians

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Pharmacists

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Target Audience

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CE Information: Nurses

CE Information: Pharmacists

CME/CE Instructions

Expert Insight Into:
Renal Dysfunction in Asian American Patients with Chronic Hepatitis B Treated with an Oral Nucleotide Analogue

Based on the Article:

Renal Dysfunction in Chronic Hepatitis B Patients Treated with Adefovir Dipivoxil

Medical Writer: Karen Gravelle, PhD
Expert Faculty: Steven-Huy B. Han, MD, AGAF