Researchers looked at thousands of reports about two common hepatitis B medications—entecavir and tenofovir—to find side effects that weren’t well-known. They discovered that both drugs may cause problems with vitamins, minerals, and bone health more often than previously thought. Tenofovir was linked to vitamin D deficiency in over 1,100 cases, while entecavir was connected to dangerous acid buildup in the blood. The study suggests that doctors should monitor patients taking these medications more carefully and that the official drug information needs updating to warn about these risks.

The Quick Take

  • What they studied: Whether two popular hepatitis B medications (entecavir and tenofovir) cause problems with the body’s metabolism, vitamins, and minerals that doctors might not know about
  • Who participated: The study analyzed 81,272 reports of side effects from people taking these medications between 2004 and 2024, collected by the U.S. Food and Drug Administration (FDA)
  • Key finding: Tenofovir was linked to vitamin D deficiency in 1,149 cases (27.7 times more often than expected), and entecavir was connected to dangerous lactic acidosis in 46 cases (10 times more often than expected). Most of these risks aren’t mentioned on the current drug labels
  • What it means for you: If you take either of these medications for hepatitis B, talk to your doctor about getting regular blood tests to check your vitamin D, phosphorus, and acid levels. These findings suggest doctors should monitor patients more closely, though the medications remain important treatments for hepatitis B

The Research Details

Researchers examined a massive database of side effect reports submitted to the FDA from 2004 to 2024. They looked at 4,820 reports mentioning entecavir and 76,452 reports mentioning tenofovir as the main suspect drug causing problems. They used special statistical methods to identify which side effects happened more often than would be expected by chance alone.

They used three different mathematical approaches to confirm their findings: reporting odds ratio (ROR), proportional reporting ratio (PRR), and a Bayesian method (BCPNN). A side effect was only considered a real signal if it met all three statistical tests, making the findings more reliable.

This type of study is called pharmacovigilance, which means watching for drug safety problems in the real world after medications are already being used by patients. It’s different from clinical trials because it looks at actual reports from everyday use rather than controlled experiments.

This research approach is important because it can catch side effects that might not show up during the initial drug testing before a medication is approved. Doctors and patients need to know about these risks so they can monitor for problems and catch them early. The study found that many of these side effects aren’t currently listed on the official drug information, which means doctors and patients might not be watching for them.

The study’s strength comes from its large sample size (over 81,000 reports) and use of multiple statistical methods to confirm findings. However, reports in the FDA database are voluntary and may not represent all side effects that occur. Some people may not report problems, while others might report coincidences that aren’t actually caused by the drug. The study cannot prove that the drug definitely caused the side effect, only that there’s a connection worth investigating further.

What the Results Show

For entecavir, researchers found eight confirmed side effect signals. The most serious was lactic acidosis (dangerous acid buildup in the blood), which appeared in 46 reports and was 10 times more common than expected. Metabolic acidosis (another type of acid problem) appeared in 11 reports, and hypophosphatemia (low phosphorus levels) appeared in 9 reports and was 8.3 times more common than expected.

For tenofovir, researchers found 16 confirmed side effect signals. The most common was vitamin D deficiency, appearing in 1,149 reports and being 27.7 times more common than expected. Hypophosphatemia (low phosphorus) appeared in 270 reports, and fat redistribution (unusual fat buildup in the body) appeared in 30 reports but was 28.8 times more common than expected.

Mitochondrial toxicity (damage to the energy-producing parts of cells) was found with both drugs and appeared more often than expected. This is concerning because mitochondria are essential for cells to function properly.

Additional findings included dyslipidemia (abnormal cholesterol and fat levels) with tenofovir in 72 reports, and hyperlactacidemia (high lactic acid) with entecavir in 5 reports. The study also identified a signal for hypokalemic alkalosis (low potassium with high alkalinity) that wasn’t previously recognized. These secondary findings suggest the medications affect multiple body systems beyond what was previously documented.

While entecavir and tenofovir are known to be effective treatments for hepatitis B, this study reveals that many of their metabolic side effects are under-recognized and not adequately described in current drug labels. Previous research has noted some of these risks, but this comprehensive analysis shows they occur more frequently than previously thought. The findings suggest that current medical guidance may not emphasize monitoring for these problems enough.

The study relies on voluntary reports, so it may miss side effects that weren’t reported or overcount coincidences. The database doesn’t prove the drug caused the problem, only that reports mentioned both together. Some reports may be incomplete or inaccurate. The study cannot determine how often these side effects actually occur in all patients taking these drugs, only that they appear more frequently in reports than would be expected. Additionally, the study cannot identify which patients are at highest risk or why some people develop these problems while others don’t.

The Bottom Line

If you take entecavir or tenofovir for hepatitis B: (1) Ask your doctor about regular blood tests to monitor phosphorus, vitamin D, and lactic acid levels—this is a moderate-confidence recommendation based on the frequency of these problems in reports. (2) Discuss with your doctor whether you should take vitamin D supplements or eat more vitamin D-rich foods. (3) Report any unusual symptoms like muscle weakness, bone pain, or shortness of breath to your doctor immediately. (4) Don’t stop taking your medication without talking to your doctor, as these drugs are important for controlling hepatitis B.

This research is most important for people currently taking entecavir or tenofovir for chronic hepatitis B, their doctors, and healthcare providers who prescribe these medications. It’s also relevant for people considering these medications who want to understand potential risks. People with existing bone problems, vitamin D deficiency, or kidney issues should definitely discuss these findings with their doctor. This research is less relevant for people who don’t take these medications.

Vitamin D deficiency and phosphorus imbalances can develop gradually over months to years of taking these medications. Some problems like lactic acidosis can develop more quickly. Most benefits from monitoring would appear within 3-6 months if your doctor adjusts your treatment or adds supplements based on blood test results. However, you should have baseline blood tests done soon if you’re starting or already taking these medications.

Want to Apply This Research?

  • Track your blood test results for vitamin D, phosphorus, and lactic acid levels every 3-6 months. Record the date, the test name, the result, and the normal range. Note any symptoms like bone pain, muscle weakness, or unusual fatigue on the same dates to see if they correlate with test results.
  • Set a reminder to schedule blood work every 3-6 months if you take these medications. Log any symptoms you experience between appointments. Increase vitamin D intake through food (fatty fish, egg yolks, fortified milk) or supplements as recommended by your doctor. Take photos or notes of any unusual changes in body fat distribution to discuss with your doctor.
  • Create a health tracking log in the app that includes: (1) Medication doses and dates taken, (2) Blood test results with dates, (3) Symptoms experienced, (4) Vitamin D and calcium intake, (5) Doctor visit notes and recommendations. Review this log before each doctor’s appointment to identify patterns and discuss concerns. Set up alerts for when blood work is due.

This research analyzes reported side effects but does not prove these medications caused the problems. Entecavir and tenofovir remain important and effective treatments for chronic hepatitis B. Do not stop taking these medications without consulting your doctor. If you take either medication, discuss these findings with your healthcare provider to determine if additional monitoring or testing is appropriate for your situation. This information is for educational purposes and should not replace professional medical advice. Always consult with your doctor before making any changes to your medication or treatment plan.