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Bone and Kidney Problems Uncommon Among Hepatitis B Patients on Long-term Antiviral Therapy

Long-term hepatitis B treatment using nucleoside/nucleotide antivirals appears safe over a follow-up period of 5 years, according to a large study from Hong Kong published in the September edition of Hepatology. Researchers saw no significant rise in the likelihood of kidney-related adverse events, and while nucleotide analogs were associated with an increased occurrence of hip fractures, the risk remained very low.


Antiviral therapy using nucleoside/nucleotide analogs such as lamivudine (Epivir), entecavir (Baraclude), adefovir (Hepsera), or tenofovir (Viread) is the mainstay of chronic hepatitis B treatment. While these antiviral drugs can effectively suppress hepatitis B virus (HBV) replication during treatment, they usually do not lead to a cure -- as indicated by HBsAg loss and HBs antibody seroconversion -- necessitating long-term therapy.

The nucleoside/nucleotide analogs commonly used for hepatitis B treatment are considered generally safe and well-tolerated. However, the nucleotides adefovir and tenofovir are associated with kidney toxicity (in fact, adefovir was never approved for HIV treatment for this reason). Used as a treatment for HIV, tenofovir can cause or worsen kidney impairment in susceptible individuals and often causes a small amount of bone loss after starting therapy. Long-term side effects have not been as extensively studied in people using it for hepatitis B.

Grace Lai-Hung Wong from the Chinese University of Hong Kong evaluated the risk of kidney and bone side effects in patients who received nucleoside/nucleotide analogs as hepatitis B treatment.

This cohort study used data from Hospital Authority, the major provider of medical services in Hong Kong, looking at more than 53,000 patients diagnosed with HBV infection between 2000 and 2012.

The primary events of interest were incident (new) kidney failure, renal replacement therapy or kidney dialysis, and incident fractures of the hip, vertebra, and all sites.

Among the 53,500 total hepatitis B patients, 7046 had been treated with nucleoside/nucleotide analogswhile 46,454 remained untreated. Those who were event-free for 3 years were included in the analysis.


  • After a median follow-up period of 4.9 years, adverse events occurred with the following frequencies in treated and untreated patients:

           o   Chronic kidney failure: 1.4% vs 0.6%;

           o   Renal replacement therapy: 0.7% vs 0.2%;

           o   All fractures: 1.3% vs 0.7%;

           o   Hip fractures: 0.2% vs 0.1%;

           o   Vertebra fractures: 0.2% vs 0.1%.

  • While adverse events occurred more often among treated people, nucleoside/nucleotide analog therapy was not associated with a significant increase in the risk of any of these events after propensity score weighting (hazard ratio [HR] 0.79 to 1.31; p= 0.225-0.887).
  • Looking only at nucleotide analogs (not nucleoside analogs), exposure was associated with a significantly increased risk of hip fractures (HR 5.69; 95% confidence interval 1.98-16.39; p=0.001), but not other events (HR 0.58-1.44; p=0.202-0.823).

"[Nucleoside/nucleotide analog]treatment does not increase the risk of renal and bone events in general," the study authors concluded. "Nucleotide analogs may increase the risk of hip fracture, but the overall event rate is low."

These findings provide reassuring evidence that the likelihood of serious kidney and bone side effects while using long-term antiviral therapy for hepatitis B is low. However, they suggest that ongoing kidney function and bone density monitoring is advisable during adefovir or tenofovir treatment, and that people with pre-existing kidney or bone problems should be treated cautiously or avoid these drugs.



GLH Wong, YK Tse, VWS Wong, et al. Long-term safety of oral nucleos(t)ide analogs for patients with chronic hepatitis B: A cohort study of 53,500 subjects. Hepatology 62(3):684-693. September 2015.

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