Skip to main content
MyDeficiencies

Entecavir

nucleoside analogue, hepatitis B polymerase inhibitor

Also sold as Baraclude.

Analyze another medication Medication directory

Findings for this medication

Research about this medication, graded for how strongly each finding can be attributed to it. Nothing here describes your own levels.

Entecavir has almost no classical depletion machinery. It is not a substrate, inhibitor or inducer of cytochrome P450 enzymes, is only minimally conjugated (glucuronide and sulfate), is about 13% protein bound, and 62 to 73% leaves in urine unchanged, with renal clearance of 360 to 471 mL/min, above glomerular filtration, so the label infers net tubular secretion [1]. No vitamin, mineral, carnitine, phosphate or hemoglobin statement appears in the Baraclude sections read. The one nutrient-related label instruction runs from food to the drug: a high-fat or light meal lowers Cmax by 44 to 46% and AUC by 18 to 20%, so it is taken on an empty stomach, at least 2 hours after and 2 hours before a meal [1]. That is a timing interaction, filed yellow (Hard Rule 4), not a depletion.

nucleoside analogue, hepatitis B polymerase inhibitor · ATC J05AF10 (WHO ATC/DDD Index [2]) · also sold as Baraclude · reviewed 2026-10-09. This describes research about the medication. It does not say anything about your own levels or health.

How to read the evidence grades

These colours describe how strongly a finding can be attributed to the medication in the research. They are not a severity score and they say nothing about your own health.

Grades describe how strongly a finding can be attributed to Entecavir in the research — not how common it is, how serious it would be, and not anything about you personally.

Red — Severe
Two or more independent Tier A sources, this drug in the cohort, the nutrient directly measured, consistent direction, clinically meaningful magnitude, a named mechanism, no substantial contradicting Tier A evidence.
Orange — Moderate
At least one Tier A source with this drug in the cohort showing a real but bounded deficit: an exposure window, a subgroup, low frequency, or a functional rather than circulating deficit.
Yellow — Low
Mechanistic plausibility only (Tier B), or class extrapolation (Tier C) with no drug-specific human status data; also used for context flags and interactions running the other direction.
Not graded — disclosed evidence gap
Nothing has been measured here, so this finding cannot be graded. That does not establish either safety or harm, and it is not the same as a White result.Source definition: Not gradeable under the rules above because nothing has been measured. Published as a documented gap, never as reassurance that there is no effect.

What the research found

Phosphate (serum; renal handling): conflicting cross-sectional data; entecavir least phosphate-lowering of the compared agents

Yellow — Low

Evidence: low

Direction: depletion of serum phosphate through renal handling (a disturbance of a measured serum value, not a dietary shortfall). Near-orange candidate held at yellow because the two Tier A cross-sectional studies disagree and the positive one could not be read for counts.

Full detail, limits and 9 references

What the grade means here: Mechanistic plausibility only (Tier B), or class extrapolation (Tier C) with no drug-specific human status data; also used for context flags and interactions running the other direction. Yellow, low

Limits on what this shows

  • Key null findings: Saeedi: entecavir mean phosphate above controls and 1 of 17 low [8]; Tonon 2018 [14] (cirrhosis, tenofovir n = 48 versus entecavir n = 22): no difference in calcium, phosphate, vitamin D, PTH or creatinine; MENTE: bone-turnover markers unchanged [9]; network analysis ranks entecavir lowest for phosphorus lowering [12]; Yang 2022 shows a tenofovir versus entecavir phosphorus gap only at 12 months [11]; the Italian single-arm cohort found 1% below 2.3 mg/dL [34].
  • At-risk subgroups: Long-term users with renal impairment (accumulation; label dose reduction below CrCl 50) [1]; the single Fanconi case was an older man after prolonged exposure [10].

Regulatory status

No phosphate, hypophosphatemia or bone statement in the Baraclude clinical-trial sections read. Section 12.3: renal clearance 360 to 471 mL/min exceeds glomerular filtration, so the label infers net tubular secretion; section 7: drugs that compete for active tubular secretion may raise entecavir levels; no significant interaction with lamivudine, adefovir dipivoxil or tenofovir disoproxil [1].

Population evidence

Rodriguez-Novoa 2016 (MENTE) [9]: multicenter cross-sectional, 280 patients with chronic hepatitis B (entecavir n = 89, tenofovir disoproxil n = 69, untreated controls n = 122). The proportion with serum phosphate below 2.5 mg/dL was higher in both the entecavir and tenofovir groups than in controls; counts were not in the abstract and the article is closed access (a repair pass re-checked the abstract on an institutional portal and an OpenAlex works lookup, which lists the article as closed with no repository copy; the counts and any P-value for the phosphate comparison remain unretrievable). Altered retinol-binding protein/creatinine (a tubular marker) was 25% with tenofovir versus 7% in the entecavir and control groups (P < 0.001); tenofovir was independently associated (OR 4.4, 1.4 to 14, P = 0.013); tubular differences did not track bone-turnover markers. Saeedi 2017 [8]: cross-sectional, 125 patients (controls 36, tenofovir 36, entecavir 17, lamivudine 36), treatment at least 1 year. Mean serum phosphate (mmol/L): controls 0.98, tenofovir 0.97, entecavir 1.04, lamivudine 0.95. Hypophosphatemia: controls 3 of 36 (8%), tenofovir 5 of 36 (14%), lamivudine 4 of 36 (11%), entecavir 1 of 17 (5.9%, my calculation). FGF23 elevated in 4 tenofovir patients (11.1%) and 1 control, in none on entecavir or lamivudine. No P-values were reported for group comparisons; the authors state hypophosphatemia did not differ significantly among groups and the study was underpowered. Full text (SciELO PDF) read via summarizer. Pooled analyses (entecavir as the reference arm) : Liu 2023 network meta-analysis [12]: probability of lowering blood phosphorus tenofovir disoproxil 90.6%, tenofovir alafenamide 49.8%, entecavir 9.7%; serum creatinine rise smaller with entecavir than with tenofovir disoproxil (SMD minus 0.61, 95% CI minus 1.06 to minus 0.15). Yang 2022 meta-analysis [11] (16 studies, 7,251 participants: 3,184 tenofovir disoproxil and 4,067 entecavir; 8 studies reported serum phosphorus; journal full-text page read via a summarizer): mean difference in serum phosphorus, tenofovir minus entecavir, minus 0.12 (95% CI minus 0.22 to minus 0.03, P = 0.01, I2 41%) at 12 months, minus 0.47 (minus 1.70 to 0.75, P = 0.45, I2 99%) at 18 to 24 months and 0.02 (minus 0.14 to 0.17, P = 0.83, I2 0%) beyond 24 months; units were not stated in the retrieved text. This is a head-to-head contrast with tenofovir, so it does not give entecavir versus non-use; eGFR SMD minus 0.07 (minus 0.12 to minus 0.01) at 12 months and minus 0.11 (minus 0.17 to minus 0.05) at 18 to 24 months. A literature review of 21 studies [29] found eGFR tended to fall with tenofovir and rise with entecavir over time (abstract; no phosphate data). Single-arm entecavir cohort : Italian multicenter cohort [34] (418 treatment-naive patients on entecavir 0.5 mg, median 30 months; conference abstract): blood phosphorus fell below 2.3 mg/dL in 1%, with no comparator and no baseline phosphate. Huang 2021 [15]: renal threshold phosphate concentration was similar between tenofovir and entecavir groups (abstract; no values). Case and pharmacovigilance : Fujii 2019 [10]: 73-year-old man after about 5 years of entecavir with Fanconi syndrome (hypophosphatemia, hypokalemia, hyperchloremic acidosis, aminoaciduria, hypouricemia), recovered after a switch to tenofovir alafenamide (Tier B case report). FAERS [7]: hypophosphatemia 9 reports, ROR 8.3 (4.32 to 15.97) for entecavir, versus ROR 7.88 (270 reports) for tenofovir disoproxil; reporting-based, subject to notoriety and indication bias.

Mechanism

Plausible and named but unconfirmed: entecavir is a substrate of renal tubular uptake and efflux transporters (human OCT2, MATE1, MATE2-K, and OCTN1/2 in vitro) [22], so proximal tubular exposure is plausible. No study measured intracellular entecavir or tubular injury directly.

Competing explanations

Chronic hepatitis B, cirrhosis and the indication itself can lower phosphate; both MENTE and Saeedi used untreated hepatitis B controls, which partly addresses this, but both are cross-sectional (Hard Rule 6). A 2025 cohort of 4,335 Korean hepatitis B patients on antivirals found hypophosphatemia in 1.7% with lower eGFR, but the abstract names no drug and is not used as evidence for entecavir [32].

Counter-evidence held on record

Counter-evidence on record Saeedi [8] contradicts MENTE [9] in direction for entecavir; the meta-analyses place entecavir at the benign end [11][12]. Grade would rise to orange if the MENTE counts (entecavir versus controls) show a statistically significant excess of phosphate below 2.5 mg/dL, or if a second cohort measures phosphate against a non-tenofovir comparator. Repair-pass search for that second source (WebSearch on entecavir hypophosphatemia and phosphorus cohorts; OpenAlex and journal full-text lookups) found none: the MENTE counts remain closed, Saeedi contradicts, Yang 2022 and Liu 2023 are tenofovir-versus-entecavir contrasts, Park 2025 names no drug, and the Italian single-arm cohort is unfavorable to an effect. Orange is therefore not supported. Framing caution Serum phosphate is a lab value affected by kidney handling, not a dietary deficiency; the signal does not imply that anyone on entecavir should take phosphate, calcium or vitamin D supplements. Tenofovir disoproxil tubulopathy data do not transfer to entecavir.

Carnitine: transporter plausibility in vitro and a class signal from a different nucleotide analogue; entecavir carnitine not measured

Yellow — Low

Evidence: low

Direction: possible depletion, theoretical. No study measured carnitine in an entecavir-treated patient. CLASS EXTRAPOLATION: the supporting trial lowered carnitine on besifovir, not entecavir.

Full detail, limits and 1 references

What the grade means here: Mechanistic plausibility only (Tier B), or class extrapolation (Tier C) with no drug-specific human status data; also used for context flags and interactions running the other direction. Yellow, low

Limits on what this shows

  • Key null findings: PubMed "entecavir carnitine" returned seven records; none measured carnitine in entecavir users.
  • At-risk subgroups: None established.

Regulatory status

No carnitine statement in the Baraclude text read, including the patient counseling section read in an earlier pass of this review [1].

Population evidence

CLASS EXTRAPOLATION, cohort test: entecavir was in the trial but carnitine was not measured in its arm. Lai 2014 [23], 48-week randomized trial in chronic hepatitis B (besifovir 90 mg n = 36, 150 mg n = 39, entecavir 0.5 mg n = 39): besifovir-treated patients had lowered serum L-carnitine (94.1%, and carnitine was supplemented); carnitine was not tested in the entecavir arm. Tier C for entecavir. Tier B transporter data : Yang 2016 [22], in vitro: entecavir is a substrate of human MATE1, MATE2-K, OCT2 and the OCTN family (OCTN1/2), with efflux transporters MRP2 and MDR1; 50 micromolar entecavir reduced probe accumulation. OCTN2 is the main sodium-coupled carnitine uptake transporter [31] (reference page, Tier D pointer only); the possibility of competition with carnitine uptake is my inference and no study tested it. Nutrient-to-treatment direction : Jun 2013 (GOAL) [24]: 130 randomized, treatment-naive patients with raised ALT received entecavir with or without a carnitine and vitamin complex; ALT normalization at 3 months 58.9% versus 95.2% (P < 0.0001) and at 12 months 85.7% versus 100% (P = 0.0019); HBV DNA suppression did not differ; no carnitine level was reported. Manufacturer-sponsored; this tests carnitine as an add-on therapy and is not evidence of depletion.

Mechanism

Transporter competition is theoretical and untested; no depletion pathway has been demonstrated.

Counter-evidence held on record

Counter-evidence on record Besifovir is structurally a different (nucleotide, carnitine-conjugated) molecule, and the loss of carnitine reported there does not establish a similar effect for entecavir. Framing caution The add-on trial [24] must not be read as advice to take carnitine. Lactic acidosis is a label-warned toxicity, not proof of carnitine deficiency.

Vitamin D and bone: entecavir groups show no consistent bone or vitamin D change; low vitamin D tracks hepatitis B itself

Yellow — Low

Evidence: low

Direction: neutral for entecavir. Bone density and fracture-type outcomes are outcome entries, not vitamin D or calcium deficiencies (Hard Rule 2).

Full detail, limits and 6 references

What the grade means here: Mechanistic plausibility only (Tier B), or class extrapolation (Tier C) with no drug-specific human status data; also used for context flags and interactions running the other direction. Yellow, low

Limits on what this shows

  • Key null findings: Entecavir groups did not differ from baseline or from comparators for BMD [13][14]; vitamin D, PTH and calcium unchanged in [14]. Repair pass: the Tonon, Kahraman, Huang and Ning records were re-read through OpenAlex or the publisher page and none gives numeric 25-hydroxyvitamin D values for an entecavir group (Tonon states no difference without values; Huang does not mention vitamin D). Searches for entecavir with 25(OH)D surfaced studies of lamivudine [35] and tenofovir cohorts that do not include entecavir, so no second entecavir-specific vitamin D source exists to firm this entry.
  • At-risk subgroups: Older and female patients had higher low-bone-mass odds even on entecavir [16], consistent with background risk.

Regulatory status

No bone, vitamin D or osteomalacia statement in the Baraclude text read [1].

Population evidence

Kahraman 2022 [13] prospective, 58 patients (tenofovir n = 40, entecavir n = 18; mean follow-up 33 and 31 months): entecavir arm, no significant change in lumbar spine BMD or total hip T-score; tenofovir L3 BMD changed (P = 0.033). Tonon 2018 [14] cirrhosis, tenofovir n = 48 versus entecavir n = 22: no difference in calcium, phosphate, vitamin D, PTH or creatinine, or in DXA T-scores. Huang 2021 [15] retrospective, 258 patients on therapy for 3 years or more (tenofovir disoproxil 135, entecavir 123), DXA every 48 weeks: tenofovir had greater BMD loss and more osteopenia at weeks 48 and 96 and was the only predictor of BMD loss at week 144 (abstract via PubMed single record; no effect sizes retrieved). Yang 2022 [11]: osteopenia/osteoporosis RR 1.29 (0.93 to 1.77) for tenofovir versus entecavir. Ning 2021 [16]: 211 patients on long-term entecavir monotherapy, no comparator; low bone mass ratios per year of medication use 1.387 and 1.276 at two measured sites (the record does not label the ratio type or name the sites, and CIs were not retrievable), but per decade of age 2.225 and 1.66 and female sex 3.048 and 2.496 were larger. Dessordi 2021 [17]: 81 patients (three groups of 27); lumbar osteopenia 7.4% (no drug), 15% (tenofovir), 3.7% (lamivudine or entecavir pooled; entecavir not separated). Vitamin D values : Saeedi [8]: only 1 entecavir patient in the 13-patient vitamin D subset (38 nmol/L); no group inference. A Scientific Reports cohort [28] (128 treatment-naive hepatitis B patients versus 128 healthy controls; nucleoside/nucleotide analogue unnamed): mean 25(OH)D3 16.88 +/- 6.40 versus 20.16 +/- 5.50 ng/mL (P < 0.001) before treatment, rising to 20.16 ng/mL after 5 to 6 years of suppression; entecavir not named, so this is disease context, not a drug effect.

Mechanism

None named for entecavir; the bone signal in these studies is attributed to tenofovir disoproxil.

Counter-evidence held on record

Counter-evidence on record Confounding by indication: hepatitis B and cirrhosis themselves lower vitamin D [28]. Active-comparator designs ([11][13][14][15]) test tenofovir against entecavir, not entecavir against non-use. Framing caution Low BMD is not vitamin D deficiency. No vitamin D, calcium or phosphate supplement is indicated by these data.

Food and meals: a high-fat or light meal lowers entecavir peak and total exposure; take on an empty stomach

Yellow — Low

Evidence: low

Direction: food affects the drug, not the drug affecting a nutrient (Hard Rule 4). Filed as a timing interaction with the label separation interval, not as a depletion.

Full detail and limits

What the grade means here: Mechanistic plausibility only (Tier B), or class extrapolation (Tier C) with no drug-specific human status data; also used for context flags and interactions running the other direction. Yellow, low

Limits on what this shows

  • Key null findings: No mineral, vitamin or antacid chelation interaction was found in the label sections read or in consumer drug pages opened (WebMD, 1mg, Wikipedia) [1][30].
  • At-risk subgroups: None specific.

Regulatory status

Section 2.1: "BARACLUDE should be administered on an empty stomach (at least 2 hours after a meal and 2 hours before the next meal)." Section 12.3: a 0.5 mg dose with a standardized high-fat meal (945 kcal) or a light meal delayed absorption, with Cmax down 44 to 46% and AUC down 18 to 20% [1]. Consumer drug pages repeat the same instruction [30].

Population evidence

Label-level pharmacokinetic study only; the label reports no clinical-efficacy consequence in the text read. Peak concentrations are reached in 0.5 to 1.5 hours; the terminal half-life is about 128 to 149 hours; steady state is reached in 6 to 10 days [1].

Mechanism

Delayed and reduced absorption with food; mineral and antacid interactions are not described in the label text read.

Counter-evidence held on record

Counter-evidence on record None. The interval comes from the label, not a mineral or vitamin study. Framing caution Follow the prescriber and label instruction on timing. This entry is about the timing of meals, not a nutrient shortfall and not a reason to change what is eaten.

Zinc: no entecavir-specific or usable class evidence

Not graded — disclosed evidence gap

See study details

No source measured zinc in entecavir-treated patients.

Full detail and limits

What the grade means here: Nothing has been measured here, so this finding cannot be graded. That does not establish either safety or harm, and it is not the same as a White result. Ungraded

Limits on what this shows

  • Why no grade: Dual condition met. The only zinc value found is the liver zinc rise in [25] (unnamed antivirals).

Channels tried

Same PubMed and WebSearch queries as Copper; no entecavir-and-zinc record located. Repair pass: WebSearch for entecavir with zinc supplementation or serum zinc returned a registered zinc sulphate fibrosis trial in antiviral-treated hepatitis B (listing only, not opened) and zinc-in-hepatitis papers without entecavir data; serum zinc studies opened name no antiviral [36].

Gap type

Genuine gap.

Vitamin B12 and folate: no entecavir-specific or class evidence

Not graded — disclosed evidence gap

See study details

No source measured vitamin B12, folate or homocysteine in entecavir-treated patients.

Full detail and limits

What the grade means here: Nothing has been measured here, so this finding cannot be graded. That does not establish either safety or harm, and it is not the same as a White result. Ungraded

Limits on what this shows

  • Why no grade: Dual condition met. The label has no macrocytic anemia, neuropathy or B-vitamin term; no circulating claim was located (WebMD, 1mg and drugs.com pages opened list no nutrient effects) [1][30].

Channels tried

PubMed listings for entecavir with B12, folate, homocysteine and cobalamin: 4 records, all irrelevant (hepatitis B-related hemolytic anemia case, reactivation cases). WebSearch "entecavir vitamin B12 OR folate OR homocysteine OR carnitine": results were the besifovir and carnitine-complex trials already used under Carnitine, with no B12 or folate measure. WebMD and 1mg pages opened. Repair pass: a further WebSearch (entecavir with vitamin B12, folate, homocysteine) returned an entecavir interferon-gamma study (no nutrient measure) and a 2005 Turkish thesis of B12 and folic acid in hepatitis B with no drug [36].

Gap type

Genuine gap.

The five body-system areas

Each finding is counted once, in a single area. Where a study is mentioned in a second area it is context only.

Mitochondrial Burden

Each finding below is counted once, in this area only.

Mitochondrial burden (drug toxicity pathway): lactic acidosis confined to decompensated cirrhosis with MELD 20 or higher, and a transient fall in blood-cell mtDNA at years 2 to 3

Orange — Moderate

Evidence: moderate

Direction: drug toxicity pathway (excess mitochondrial burden), not a nutrient deficiency. Entecavir triphosphate is a weak polymerase gamma inhibitor, yet humans on entecavir show lactic acidosis in advanced liver failure and a measurable, reversible fall in peripheral blood mononuclear cell (PBMC) mitochondrial DNA.

Full detail, limits and 3 references

What the grade means here: At least one Tier A source with this drug in the cohort showing a real but bounded deficit: an exposure window, a subgroup, low frequency, or a functional rather than circulating deficit. Orange, moderate

Limits on what this shows

  • Key null findings: Mazzucco 2008 [6] (Tier B, HepG2 cells, 15 days, entecavir up to 100 times Cmax): no change in proliferation, lactate production, mtDNA or cytochrome c oxidase II and IV; entecavir triphosphate was not recognized by polymerase gamma up to 300 micromolar. Lampertico 2016 [26] (review abstract): registration studies showed no clinically significant lactic acidosis with entecavir; real-world cases were few and all in decompensated cirrhosis. Kayaaslan 2017 [27]: entecavir has been used safely in decompensated cirrhosis in other studies. Duan [5] found mtDNA recovered by year 4 and the authors reported no clinical toxicity.
  • At-risk subgroups: Decompensated cirrhosis, especially MELD 20 or higher [3]; female sex, obesity, prolonged exposure (label) [1]; renal impairment with accumulation (label dose reduction below CrCl 50 mL/min) [1].

Regulatory status

Baraclude boxed warning: "Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of nucleoside analogue inhibitors alone or in combination with antiretrovirals." Section 5.3: a majority of cases in women; obesity and prolonged nucleoside exposure may be risk factors; patients with decompensated liver disease may be at higher risk. Postmarketing: lactic acidosis listed under metabolism. In the decompensated-liver trial (study 048), "blood bicarbonate decreased" occurred in 2% of entecavir-treated subjects. Lactate does not appear in the clinical-trial laboratory table (Table 4) [1].

Population evidence

Lange 2009 [3] (entecavir as the studied exposure): 16 patients with cirrhosis and chronic hepatitis B on entecavir; 5 of 16 developed lactic acidosis (lactate 26 to 200 mg/dL, pH 7.02 to 7.40, base excess minus 5 to minus 18 mmol/L), 4 to 240 days after starting. All 5 had MELD of 20 or higher; the 11 without it all had MELD below 18. MELD and its components (bilirubin, INR, creatinine) correlated with lactic acidosis (P < 0.005); Child-Pugh did not. One patient died; the others recovered after entecavir was stopped or interrupted. Abstract read via PubMed single record, summarizer-read. Zhou 2012 [4] (chronic hepatitis B, entecavir monotherapy 2 years n = 17, 3 years n = 17, versus 18 not on antivirals): PBMC mtDNA relative quantity 0.5 +/- 0.3 at 3 years versus 1.4 +/- 1.2 in controls (P = 0.009) and 0.4 +/- 0.2 at 2 years (P = 0.004 versus controls); no clinical signs of mitochondrial toxicity. English abstract of a Chinese-language article. Duan 2015 [5] (34 treatment-naive patients on entecavir monotherapy, no control group): mtDNA content fell at years 2 and 3 and returned to roughly baseline by year 4; mtDNA4977 deletion rate was 32.4% at baseline, 79.4% at year 2, 70.6% at year 3 and 8.8% at year 4 (P < 0.01). The abstract and results text disagree on some mtDNA means, so only the pattern is relied on. Pharmacovigilance [7]: in FAERS (4,820 entecavir primary-suspect reports, 2004 to 2024), lactic acidosis 46 reports, reporting odds ratio (ROR) 10.06 (95% CI 7.53 to 13.44); metabolic acidosis 11 reports, ROR 2.36 (1.30 to 4.26). A disproportionality signal, not an incidence.

Mechanism

Named. Label section 12.4: entecavir triphosphate is a weak inhibitor of cellular DNA polymerases alpha, beta and delta and of mitochondrial DNA polymerase gamma, Ki 18 to above 160 micromolar [1]. Reduced mtDNA content in PBMCs [4][5] is consistent with, but does not prove, polymerase gamma interference; the lactic acidosis cases cluster in severe hepatic dysfunction [3], where reduced lactate clearance is an alternative contributor.

Why orange, not red

Two human cohorts with entecavir as the exposure show the surrogate moving [4][5], and a case series shows the clinical event [3], but (a) none measured a nutrient, (b) the mtDNA studies are small, from one research group (Duan is last author of [4] and first author of [5]), and one has no control arm, (c) the effect reverses by year 4 [5], and (d) Tier B data show no in vitro effect [6]. Red also needs a nutrient directly measured; this is a toxicity entry (Hard Rule 2).

Counter-evidence held on record

Counter-evidence on record Weak in vitro polymerase gamma affinity [1][6]; no lactate listing in the label trial laboratory table [1]; reversal by year 4 [5]; confounding by severe liver failure for the lactic acidosis cases [3]. Framing caution This is a drug-toxicity entry. It does not mean a vitamin, carnitine or coenzyme Q10 shortfall, and nothing here supports adding a supplement. Anyone with symptoms of lactic acidosis (label) needs prescriber review, not self-treatment.

Oxidative Stress

Each finding below is counted once, in this area only.

Oxidative stress: lower lipid-peroxidation product and lower total antioxidant capacity after 3 years of entecavir; malondialdehyde unchanged

Yellow — Low

Evidence: low

Direction: mixed. One small human cohort shows a lower oxidative lipid product (F2-isoprostanes) and lower total antioxidant capacity (TAOC) in entecavir users than in untreated hepatitis B patients, with no difference in malondialdehyde (MDA).

Full detail and limits

What the grade means here: Mechanistic plausibility only (Tier B), or class extrapolation (Tier C) with no drug-specific human status data; also used for context flags and interactions running the other direction. Yellow, low

Limits on what this shows

  • Key null findings: MDA unchanged [4]. A PubMed listing for entecavir with oxidative stress returned seven records, none with a human redox measurement apart from [4].
  • At-risk subgroups: None identified.

Regulatory status

No oxidative-stress statement in the Baraclude sections read [1].

Population evidence

Zhou 2012 [4]: entecavir 2 years n = 17, 3 years n = 17, versus untreated n = 18. F2-isoprostanes (ng/mL): 3 years 1.2 +/- 0.5 versus controls 3.6 +/- 2.9 (P = 0.002); 2 years 2.4 +/- 1.3. TAOC (IU/mL): 3 years 2.6 +/- 1.2 versus controls 5.0 +/- 3.0 (P = 0.005); 2 years 3.2 +/- 1.6. MDA: no difference among groups (P = 0.749). English abstract of a Chinese-language article, read via PubMed single record (summarizer).

Mechanism

Not named. The authors suggest mitochondrial damage may be offset by mechanisms not yet identified [4]; lower F2-isoprostanes may simply reflect lower hepatic inflammation after viral suppression, which this design cannot separate (Hard Rule 6).

Counter-evidence held on record

Counter-evidence on record Lower F2-isoprostanes points to less oxidative injury, the opposite of a harmful signal; lower TAOC points the other way. One group of 52 patients, no baseline values for the same individuals, no replication. Framing caution A lower antioxidant-capacity reading in this abstract is not evidence of an antioxidant vitamin shortfall, and does not support antioxidant supplements.

Copper and Iron Balance

Copper and iron are assessed separately. Nothing here is counted twice.

Copper: no entecavir-specific or usable class evidence

Not graded — disclosed evidence gap

See study details

No source measured copper in entecavir-treated patients.

Full detail, limits and 1 references

What the grade means here: Nothing has been measured here, so this finding cannot be graded. That does not establish either safety or harm, and it is not the same as a White result. Ungraded

Limits on what this shows

  • Why no grade: Dual condition met: no Tier B or C evidence for entecavir and no circulating claim. The one trace-element study found for treated hepatitis B (Sahin 2019 [25]: liver tissue copper median 2.82 to 5.31 micrograms/g at 6 months, P = 0.002; zinc 48.05 to 74.9, P = 0.035; iron associated with histologic and fibrosis change) names no antiviral in its abstract or on the Springer page read, so it cannot pass the cohort test for entecavir or even be placed as a class source; it describes liver recovery in treated hepatitis B.

Channels tried

PubMed listing "entecavir (zinc OR copper OR ferritin OR iron)": 7 records, none relevant (water treatment, in silico). WebSearch (copper, zinc, ferritin with entecavir): one trace-element link was an entecavir-concentration paper (Med Sci Monit 2019) whose abstract mentions no trace elements; a serum copper and zinc in hepatitis B abstract (no drug) was not opened. Springer page for [25] opened (abstract only). Baraclude label: no copper term.

Repair pass

Further WebSearch phrasings (entecavir with serum copper, ceruloplasmin, zinc supplementation, trace elements in treated hepatitis B) and openings of the Acta Med Iran, Ankara and Istanbul (Sahin) records: none names entecavir or reports a treated-versus-untreated copper comparison [25][36]. Wilson disease results were unrelated to entecavir.

Gap type

Genuine gap, with a tooling caveat: the full text of [25] (drug regimens, sample size) was not accessible.

Iron: no entecavir-specific or usable class evidence

Not graded — disclosed evidence gap

See study details

No source measured serum iron, ferritin or iron stores in entecavir-treated patients.

Full detail, limits and 1 references

What the grade means here: Nothing has been measured here, so this finding cannot be graded. That does not establish either safety or harm, and it is not the same as a White result. Ungraded

Limits on what this shows

  • Why no grade: Dual condition met. The Sahin 2019 liver iron association [25] has unnamed antivirals and is a histology-response correlation, not a drug effect. Anemia is an outcome and is not filed as iron deficiency (Hard Rule 2); the label lists no hemoglobin abnormality [1].

Channels tried

Same PubMed and WebSearch queries as Copper; PubMed "entecavir hemoglobin" (8 records; only [21], an animal study, relevant). No ferritin, transferrin saturation or iron-absorption study with entecavir found.

Repair pass

WebSearch for entecavir with serum ferritin, iron overload and hepcidin; opened a hepcidin and iron-marker study (hepatitis C versus untreated hepatitis B, entecavir not mentioned), a ferritin and PEG-interferon study (nucleos(t)ide analogue unspecified) and a hemochromatosis case (lamivudine, adefovir, tenofovir) [36]. A hepatitis B iron overload case report titled as resolving after nucleoside analogue treatment (PMC8723841) could not be read (bot check), so its drug is unconfirmed and it is not used; it would in any case be a disease-direction finding.

Gap type

Genuine gap, with a tooling caveat for the one unread case report.

Gut Microbiome Risk

Each finding below is counted once, in this area only.

Gut microbiome risk: entecavir-treated human and mouse data show movement toward healthy composition, not disruption

Yellow — Low

Evidence: low

Direction: reverse or neutral. No source found shows entecavir damaging the gut microbiota; disease-linked dysbiosis in hepatitis B appears to improve with treatment, but treatment and disease recovery cannot be separated.

Full detail, limits and 2 references

What the grade means here: Mechanistic plausibility only (Tier B), or class extrapolation (Tier C) with no drug-specific human status data; also used for context flags and interactions running the other direction. Yellow, low

Limits on what this shows

  • Key null findings: Zeng 2021 [33] (Sci Rep, baseline fecal 16S before tenofovir or entecavir, 37 seroconverters versus 41 non-seroconverters) measures baseline predictors, not a drug effect, and is not used. PubMed listing "entecavir gut microbiota" returned six records after a long wait; nothing else usable.
  • At-risk subgroups: None identified.

Regulatory status

No microbiome, diarrhea-dysbiosis or Clostridioides difficile statement in the Baraclude sections read [1].

Population evidence

Human, entecavir in the cohort : Infect Dis Ther 2021 [19], 60 patients with chronic hepatitis B randomized to entecavir 0.5 mg alone (n = 30) or entecavir plus Clostridium butyricum (n = 30), plus 30 healthy controls; 16S rDNA after 8 weeks. Median Shannon index: healthy controls 4.886, entecavir alone 4.819, hepatitis B before treatment 4.710, entecavir plus C. butyricum 4.614. Entecavir-alone versus entecavir plus C. butyricum differed slightly (ANOSIM R = 0.073, P = 0.04); no concurrent untreated hepatitis B arm. Abstract read via a Springer page (summarizer). Mouse, entecavir as the exposure (Tier B) : Li 2020 [18], rAAV8-HBV persistent infection model with 16S of cecal contents: alpha diversity fell in infected mice and was significantly restored after 4 weeks of entecavir; Akkermansia fell with infection and returned to control level with entecavir; Blautia and Clostridium sensu stricto decreased with infection (restoration not stated). Abstract via PubMed single record; no dose or group size in the abstract. CLASS EXTRAPOLATION (Tier C) : Shen 2023 [20], 64 patients with HBV-related chronic liver disease and 17 healthy controls: antiviral treatment was a main contributing factor to composition, and depletion of Eubacterium hallii was restored with 5 years of antiviral treatment. Entecavir is not named in the abstract, so entecavir is not confirmed in that cohort; capped at yellow.

Mechanism

Not applicable as a harm pathway: entecavir has no antibacterial activity in any source read, and 62 to 73% is absorbed and excreted in urine unchanged [1], leaving little intraluminal drug. Improvement more likely tracks reduced hepatic inflammation.

Counter-evidence held on record

Counter-evidence on record Human arm [19] lacks an untreated hepatitis B comparator and followed 8 weeks; the mouse model [18] is an HBV vector model. The two together support no more than a reverse-direction yellow. Framing caution Nothing here supports a probiotic or fiber prescription for entecavir users; an improving microbiome in hepatitis B is a disease-treatment association.

Oxygen and ATP Output

Oxygen delivery and ATP production are assessed separately. Nothing here is counted twice.

Oxygen delivery/utilization: no human hemoglobin signal found; one cell and mouse study shows higher hemoglobin

Yellow — Low

Evidence: low

Direction: reverse and non-human. The label lists no anemia or hemoglobin finding; the only drug-specific hemoglobin data are from cells and transgenic mice, not people.

Full detail, limits and 1 references

What the grade means here: Mechanistic plausibility only (Tier B), or class extrapolation (Tier C) with no drug-specific human status data; also used for context flags and interactions running the other direction. Yellow, low

Limits on what this shows

  • Key null findings: Label laboratory tables show no hemoglobin signal [1]. PubMed "entecavir hemoglobin" returned eight records; only [21] was relevant. Searches for entecavir with anemia, hemolysis or methemoglobin surfaced a thrombocytopenia case report (title only, not opened) and no red-cell finding.
  • At-risk subgroups: None identified.

Regulatory status

No hemoglobin, anemia or hemolysis term in Baraclude Table 4 (grade 3 to 4 laboratory abnormalities versus lamivudine: platelets below 50,000/mm3 under 1% in both arms) or the adverse reaction lists read [1].

Population evidence

No human hemoglobin or hematocrit study with entecavir as the exposure was located. Ullah 2026 [21] (Tier B): in K562 cells and in beta-YAC transgenic mice given oral entecavir (dose-dependent, 6 days a week for 4 weeks), total hemoglobin, gamma-globin mRNA and fetal hemoglobin rose; docking suggested NFKB, PTGS2, HDAC2 and HIF1A as targets. No numbers were available in the abstract (via OpenAlex, summarizer).

Mechanism

Hypothesis-generating only (gamma-globin induction in a mouse model). No human oxygen-carrying consequence is claimed.

Counter-evidence held on record

Counter-evidence on record The direction (hemoglobin up in mice) contradicts any depletion claim. Anemia in hepatitis B or cirrhosis is a disease outcome and not an iron or oxygen-delivery entry (Hard Rule 2). Framing caution Not a statement that entecavir improves or impairs oxygen delivery in people.

ATP production: no direct measurement; mtDNA and lactate surrogates point both ways

Yellow — Low

Evidence: low

Direction: unresolved. ATP synthesis or mitochondrial respiration was not measured in any entecavir study located; surrogate readouts are the mtDNA and lactate findings already graded under Mitochondrial burden.

Full detail, limits and 1 references

What the grade means here: Mechanistic plausibility only (Tier B), or class extrapolation (Tier C) with no drug-specific human status data; also used for context flags and interactions running the other direction. Yellow, low

Limits on what this shows

  • Key null findings: Mazzucco 2008 in vitro null [6]. PubMed searches for entecavir with ATP, respiration, mitochondria and mitochondrial (47 records combined) returned no ATP, oxygen-consumption or membrane-potential measurement.
  • At-risk subgroups: See Mitochondrial burden.

Regulatory status

No ATP or energy-metabolism statement; lactic acidosis warning only [1].

Population evidence

Surrogates only, shared with Mitochondrial burden: lower PBMC mtDNA at years 2 to 3 [4][5] and lactic acidosis in advanced liver failure [3]. In HepG2 cells at up to 100 times Cmax, entecavir did not change lactate production, mtDNA or cytochrome c oxidase subunits II and IV [6] (Tier B).

Mechanism

Possible via polymerase gamma inhibition (weak, Ki 18 to above 160 micromolar) [1]; not demonstrated for ATP output.

Counter-evidence held on record

Counter-evidence on record The same studies are counted once in the Overlap map and are not independent confirmation of an energy deficit. Framing caution Do not read this as low cellular energy; no such measurement exists for entecavir.

Claims checked and not supported

These circulate online for this medication. They are listed here only so they can be answered, never as findings, and they are not graded.

A claim with no supporting evidence is not necessarily disproven. Where evidence actually argues against a claim, that is stated below.

  • Lactic acidosis as a carnitine, B vitamin or coenzyme Q10 deficiency

    Where it comes from: Nutrient-deficiency framing of the label lactic acidosis warning. Consumer origin not traced; WebMD, 1mg and drugs.com pages opened state the warning without any nutrient link [30].

    Why it fails: The label treats lactic acidosis as a drug toxicity with an instruction to stop treatment; the case series ties it to MELD 20 or higher, not to a nutrient [1][3]. No nutrient was measured in any entecavir lactic acidosis report. Hard Rule 2.

  • Entecavir is a strong mitochondrial polymerase gamma poison like stavudine or didanosine

    Where it comes from: Applying the older-nucleoside mitochondrial toxicity profile to the whole class. Consumer origin not traced.

    Why it fails: Label Ki for polymerase gamma 18 to above 160 micromolar (weak) [1]; entecavir triphosphate was not recognized by polymerase gamma up to 300 micromolar and HepG2 cells showed no lactate, mtDNA or cytochrome oxidase change at 100 times Cmax [6]. The only human signals are the bounded ones graded orange [3][4][5].

  • Entecavir causes tenofovir-type kidney tubule and bone loss

    Where it comes from: Reading the tenofovir disoproxil tubulopathy and bone warnings across to all hepatitis B nucleoside analogues. Consumer origin not traced.

    Why it fails: As stated (equivalence with tenofovir), it fails: tubular marker abnormalities were 7% on entecavir versus 25% on tenofovir (same as controls) [9]; entecavir bone density did not change in two cohorts [13][14]; network analysis ranks entecavir lowest for phosphate lowering [12]. A narrower phosphate signal remains yellow.

  • Carnitine or antioxidant supplements are needed to protect against entecavir mitochondrial toxicity

    Where it comes from: Inferring a protective need from the carnitine add-on trial and from mitochondrial warnings. Consumer origin not traced.

    Why it fails: The add-on trial measured ALT normalization, not carnitine levels or mitochondrial toxicity [24]; carnitine was not measured in entecavir patients in any source; the one antioxidant-capacity marker was lower, not higher, with entecavir [4]. Unsupported at every tier for this purpose; no dosing statement is made.

How the body handles this medication

Metabolism and enzymes
Not a substrate, inhibitor or inducer of CYP450 enzymes; minor glucuronide and sulfate conjugates. Plasma protein binding about 13%; volume of distribution above total body water.[1] Baraclude label sec 12.3, summarizer-read
Elimination
Urinary recovery of unchanged drug at steady state 62 to 73%; renal clearance 360 to 471 mL/min, independent of dose; "both glomerular filtration and net tubular secretion." Terminal half-life 128 to 149 hours. Dose reduction at CrCl below 50 mL/min (0.25 mg daily or 0.5 mg every 48 hours at 30 to below 50).[1] sec 2.4, 12.3
Absorption and transporters
Tmax 0.5 to 1.5 hours; steady state at 6 to 10 days of once-daily dosing. In vitro, entecavir is a substrate of human MATE1, MATE2-K, OCT2 and OCTN1/2, and of MRP2 and MDR1 (mouse Oat1/3, Oct2, Octn1/2 and Mrp2 modulators changed secretion).[1] sec 12.3; [22] Yang 2016, Tier B
Food interaction
A high-fat (945 kcal) or light meal: Cmax down 44 to 46%, AUC down 18 to 20%. Label instruction: empty stomach, at least 2 hours after a meal and 2 hours before the next meal.[1] sec 2.1, 12.3
Drug interactions
Drugs that reduce renal function or compete for active tubular secretion may raise entecavir concentrations; no significant interaction with lamivudine, adefovir dipivoxil or tenofovir disoproxil.[1] sec 7
Mitochondrial statements in the label
Boxed warning and sec 5.3: lactic acidosis and severe hepatomegaly with steatosis with nucleoside analogues; majority women; obesity and prolonged exposure may be risk factors; decompensated liver disease may be higher risk. Sec 12.4: entecavir triphosphate is a weak inhibitor of DNA polymerases alpha, beta, delta and mitochondrial polymerase gamma, Ki 18 to above 160 micromolar. Label revised 11/2019.[1] Boxed warning, sec 5.3, 12.4

What the research says is worth watching

General information from the medication label and the studies above. It is not personal medical advice, and any change belongs with your prescriber.

  • Safety / boxed warning

    Hepatitis B flares and HIV co-infection

    Boxed warning headings: severe acute exacerbations of hepatitis B in patients who have discontinued anti-hepatitis B therapy; patients co-infected with HIV and HBV; lactic acidosis and hepatomegaly [1]. Not a nutrient issue. Do not stop without prescriber direction.

  • Safety / lactic acidosis

    Decompensated liver disease

    Label: patients with decompensated liver disease may be at higher risk; female sex, obesity and prolonged exposure are possible risk factors [1]. In the Frankfurt series all five lactic acidosis cases had MELD of 20 or higher, and onset ranged from 4 to 240 days [3]. Symptoms and lactate or bicarbonate checks are a clinical decision, not a nutrient one.

  • Labs / kidney

    Creatinine, eGFR and phosphate

    Dose adjustment below CrCl 50 mL/min [1]. A review recommends monitoring eGFR and serum phosphorus in hepatitis B nucleoside analogue therapy, with renal impairment mainly a tenofovir concern [26]. A low phosphate with an unexplained low potassium or acidosis in a long-term user warrants clinician review (one Fanconi case) [10].

  • Timing

    Empty stomach

    At least 2 hours after a meal and 2 hours before the next meal [1]. Meals lower Cmax by 44 to 46% and AUC by 18 to 20%. The label states no separate interval for vitamins, minerals or antacids.

  • Bone

    Bone health context

    Entecavir groups showed no consistent BMD change versus baseline [13][14]; age and female sex were stronger predictors of low bone mass than years of entecavir use [16]. Decisions about DXA or vitamin D testing follow ordinary clinical risk, not this drug alone.

  • At-risk groups

    Who to watch

    Decompensated cirrhosis (MELD 20 or higher), renal impairment, long-term exposure and women or obese patients per the label [1][3]. Drugs that compete for tubular secretion can raise entecavir levels [1]. Pregnancy and pediatric nutrient considerations were not evaluated; no graded nutrient entry interacts with them.

Overlap map, to prevent double counting

Entries that rest on the same underlying source or mechanism (Hard Rule 9).

  • Mitochondrial burden

    Shares evidence with: ATP production; Oxidative stress

    Note: Zhou 2012 [4] (PBMC mtDNA, F2-isoprostanes, TAOC) and Duan 2015 [5] (mtDNA) feed Mitochondrial burden and the surrogate readout for ATP production; [4] also feeds Oxidative stress. Duan is last author of [4] and first author of [5], so they are not fully independent research groups. Count once as the mtDNA line.

  • Mitochondrial burden

    Shares evidence with: ATP production; Carnitine

    Note: Label lactic acidosis warning, Lange 2009 [3], FAERS [7] and Mazzucco 2008 [6] support mitochondrial toxicity and the lactate surrogate under ATP; the carnitine entry cites lactic acidosis only as context, not as evidence of a carnitine shortfall.

  • Phosphate

    Shares evidence with: Vitamin D and bone

    Note: Saeedi [8], MENTE [9], Tonon [14] and the Yang and Liu meta-analyses [11][12] appear in both. The phosphate lab value and the bone-density outcome are different measurements from the same head-to-head studies.

  • Gut microbiome risk

    Shares evidence with: Oxygen delivery/utilization

    Note: No shared source; listed to confirm independence. Oxygen delivery rests on Ullah 2026 [21] and the label only; ATP production and Oxygen delivery are separate entries.

  • Copper; Iron; Zinc

    Shares evidence with: (none usable)

    Note: The single trace-element source [25] names no antiviral and supports none of the three entries; it is not counted as evidence in any of them.

All references used above
  1. BARACLUDE (entecavir) tablet, film coated; oral solution, DailyMed label. — Regulatory label (Tier A). Revised 11/2019. Boxed warning, sections 2, 5, 6, 7, 12.3 and 12.4 read via a summarizing fetch tool (first 100,000 of 109,661 characters in the final pass; the patient counseling section was read in an earlier pass of this review, also summarizer).Summarizer-read: quoted phrases are from the tool's output.
  2. WHO Collaborating Centre for Drug Statistics Methodology. ATC/DDD Index: J05AF10 entecavir. — Reference index. DDD 0.5 mg, oral. Class J05AF (nucleoside and nucleotide reverse transcriptase inhibitors).
  3. Lange CM, Bojunga J, Hofmann WP, et al. Severe lactic acidosis during treatment of chronic hepatitis B with entecavir in patients with impaired liver function. Hepatology 2009;50(6):2001-6. PMID 19937695. DOI 10.1002/hep.23346. — Case series (Tier A), 16 patients with cirrhosis, 5 with lactic acidosis, all MELD of 20 or higher. Abstract read via PubMed single record.Abstract only, summarizer-read.
  4. Zhou L, Liu XY, Zhao CY, Duan ZP. Entecavir treatment causes injury to the mitochondrial DNA of peripheral blood mononuclear cells. Zhonghua Gan Zang Bing Za Zhi 2012;20(10):751-4. PMID 23207335. DOI 10.3760/cma.j.issn.1007-3418.2012.10.009. — Cross-sectional, 52 patients (entecavir 2 years n = 17, 3 years n = 17, untreated n = 18). English abstract read via PubMed single record and OpenAlex.Abstract only, summarizer-read.
  5. Duan Z, et al. Changes in mitochondrial toxicity in peripheral blood mononuclear cells during four-year administration of entecavir monotherapy in Chinese patients with chronic hepatitis B. Med Sci Monit 2015;21:2058-63. PMID 26176539. DOI 10.12659/MSM.892937. — Prospective repeated-measures, 34 patients, no control group. Abstract read via the journal page and OpenAlex.Abstract only; the abstract and results text disagree on some mtDNA means. Summarizer-read.
  6. Mazzucco et al. In vitro mitochondrial toxicity and polymerase gamma study of entecavir in HepG2 cells (article title not transcribed). Antimicrob Agents Chemother 2008;52(2):598-605. PMID 18056280. DOI 10.1128/aac.01122-07. — In vitro HepG2 study (Tier B), manufacturer-affiliated authors.Abstract only, summarizer-read.
  7. Zhu et al. FAERS disproportionality analysis, entecavir and tenofovir (Q1 2004 to Q3 2024; article title not transcribed). Int J Clin Pharm 2025. PMID 40828435. DOI 10.1007/s11096-025-01969-1. — Pharmacovigilance; 4,820 entecavir primary-suspect reports. Lactic acidosis 46 reports, ROR 10.06 (7.53 to 13.44); metabolic acidosis 11, ROR 2.36 (1.30 to 4.26); hypophosphatemia 9, ROR 8.3 (4.32 to 15.97). Reporting-based, not incidence.Abstract only via a Springer page, summarizer-read.
  8. Saeedi et al. Lamivudine, entecavir, or tenofovir treatment of hepatitis B infection: effects on calcium, phosphate, FGF23 and indicators of bone metabolism. Ann Hepatol 2017;16(2). PMID 28233741. DOI 10.5604/16652681.1231577. — Cross-sectional, 125 patients (controls 36, tenofovir 36, entecavir 17, lamivudine 36). Full text read via a summarizer; the abstract and results disagree on the vitamin D insufficiency fraction (67% vs 77%).Summarizer-read; group P-values not reported by the authors; no ETV-specific inferential test.
  9. Rodriguez-Novoa et al. Altered Underlying Renal Tubular Function in Patients With Chronic Hepatitis B Receiving Nucleos(t)ide Analogs in a Real-World Setting (MENTE). J Clin Gastroenterol 2016;50(9):779-89. PMID 27332746. DOI 10.1097/MCG.0000000000000569. — Cross-sectional, 280 patients (entecavir 89, tenofovir 69, controls 122). Abstract read via PubMed single record and an institutional repository.Closed access: full text and phosphate counts not retrieved (re-checked in a repair pass via an institutional portal and an OpenAlex works lookup, which lists no open copy).
  10. Fujii et al. Case report of Fanconi syndrome during long-term entecavir, recovered after switch to tenofovir alafenamide (article title not transcribed). CEN Case Rep 2019. PMID 31154657. DOI 10.1007/s13730-019-00404-5. — Case report (Tier B), 73-year-old man after about 5 years of entecavir. Springer page read via summarizer.Abstract summarizer-read.
  11. Yang et al. Meta-analysis of tenofovir disoproxil versus entecavir, 16 studies (article title not transcribed). Int J Infect Dis 2022. PMID 36122671. DOI 10.1016/j.ijid.2022.09.021. — Meta-analysis. eGFR SMD minus 0.07 (minus 0.12 to minus 0.01) at 12 months and minus 0.11 (minus 0.17 to minus 0.05) at 18 to 24 months; osteopenia/osteoporosis RR 1.29 (0.93 to 1.77). Abstract read in an earlier pass via OpenAlex.Repair pass: the journal full-text page (https://www.ijidonline.com/article/S1201-9712(22)00519-7/fulltext) was read via a summarizer and gave the phosphorus mean differences cited above (8 studies; 12 months MD minus 0.12, 95% CI minus 0.22 to minus 0.03). Summarizer-read.
  12. Liu et al. Network meta-analysis of entecavir, tenofovir disoproxil and tenofovir alafenamide (article title not transcribed). BMC Gastroenterol 2023. PMID 37950196. DOI 10.1186/s12876-023-03027-4. — Network meta-analysis. Probability of lowering phosphorus: TDF 90.6%, TAF 49.8%, ETV 9.7%; creatinine, ETV vs TDF SMD minus 0.61 (minus 1.06 to minus 0.15). Abstract via PubMed single record.Abstract only; study and patient counts not stated in the record. Summarizer-read.
  13. Kahraman et al. Effects of long-term tenofovir and entecavir treatment on bone mineral density in patients with chronic hepatitis B. Turk J Gastroenterol 2022. PMID 35040786. DOI 10.5152/tjg.2020.18024. — Prospective, 58 patients (tenofovir 40, entecavir 18). Abstract read via the journal page.Abstract only; laboratory values not in the abstract. Summarizer-read.
  14. Tonon et al. Cirrhosis cohort, tenofovir versus entecavir, bone and mineral markers (article title not transcribed). Eur J Gastroenterol Hepatol 2018. PMID 29309397. DOI 10.1097/MEG.0000000000001051. — Cross-sectional, cirrhosis, tenofovir 48 vs entecavir 22; no difference in calcium, phosphate, vitamin D, PTH, creatinine or DXA T-scores.Abstract only, earlier pass, summarizer-read.
  15. Huang et al. Retrospective BMD and renal comparison, tenofovir disoproxil versus entecavir (article title not transcribed). Hepatol Int 2021. PMID 33907949. DOI 10.1007/s12072-021-10148-z. — Retrospective, 258 patients (tenofovir 135, entecavir 123), DXA every 48 weeks, propensity-balanced. Abstract via PubMed single record.Abstract only; no effect sizes. Summarizer-read.
  16. Ning et al. Analysis of bone mineral density and its influencing factors in 211 patients with chronic hepatitis B treated with long-term entecavir monotherapy (title as shown in the OpenAlex record). Zhonghua Gan Zang Bing Za Zhi 2021;29(3):234-239. PMID 33902190. — Cross-sectional, 211 patients on entecavir; low-bone-mass odds ratios per year of use 1.387 and 1.276 (CIs not retrieved).Abstract only; re-read via OpenAlex in a repair pass. Ratio type and CIs not retrievable.
  17. Dessordi et al. Bone and vitamin D study in chronic hepatitis B, three medication groups (article title not transcribed). Sci Rep 2021. PMID 33986322. DOI 10.1038/s41598-021-89486-9. — Cross-sectional, 81 patients in three groups of 27; lamivudine and entecavir pooled.Abstract only; entecavir not separated; not used as entecavir-specific evidence.
  18. Li et al. Entecavir and gut microbiota in an HBV mouse model (article title not transcribed). Int J Antimicrob Agents 2020. PMID 32360229. DOI 10.1016/j.ijantimicag.2020.106000. — Mouse rAAV8-HBV model (Tier B), 16S of cecal contents. Abstract read via PubMed single record.Abstract only; no dose or group sizes.
  19. Effect of additional Clostridium butyricum on the intestinal flora of chronic hepatitis B patients treated with entecavir. Infect Dis Ther 2021;10:1519-30. DOI 10.1007/s40121-021-00463-1. — Randomized, 60 patients plus 30 healthy controls, 16S after 8 weeks. Springer page read via summarizer.Abstract only, summarizer-read.
  20. Shen et al. Gut microbiota in HBV-related chronic liver disease and antiviral treatment (article title not transcribed). Gut Microbes 2023. PMID 36519342. DOI 10.1080/19490976.2022.2155018. — Cohort, 64 patients plus 17 healthy controls. Antiviral treatment named generically.CLASS EXTRAPOLATION: entecavir not named in the abstract; cohort test not passed. Abstract only.
  21. Ullah et al. Entecavir, K562 cells and beta-YAC transgenic mice, hemoglobin outcomes (article title not transcribed). Biomed Pharmacother 2026;203:119901. PMID 42697041. DOI 10.1016/j.biopha.2026.119901. — Cell and mouse study (Tier B). Abstract via OpenAlex.Abstract only; no numbers.
  22. Yang et al. Entecavir transporter study (hMATE1, hMATE2-K, hOCT2, hOCTNs; article title not transcribed). Antimicrob Agents Chemother 2016. PMID 27503646. DOI 10.1128/AAC.00986-16. — In vitro (Tier B). Abstract only.Abstract summarizer-read.
  23. Lai et al. Besifovir versus entecavir, 48-week randomized trial (article title not transcribed). Gut 2014;63(6):996-1004. PMID 23979965. DOI 10.1136/gutjnl-2013-305138. — Randomized (besifovir 90 mg n = 36, 150 mg n = 39, entecavir 0.5 mg n = 39). Carnitine tested for besifovir only.CLASS EXTRAPOLATION for carnitine. Abstract only.
  24. Jun et al. Efficacy and safety of entecavir plus carnitine complex (Godex) versus entecavir (GOAL study; title as listed on the repository page). Clin Mol Hepatol 2013;19(2):165-72. PMID 23837141. DOI 10.3350/cmh.2013.19.2.165. — Randomized open-label, 130 patients (119 completed); manufacturer-sponsored. Abstract read via an institutional repository.Abstract only; carnitine levels not reported. Nutrient-to-outcome direction, not depletion evidence.
  25. Sahin et al. Liver trace elements and histology in antiviral-treated HBV patients (article title not transcribed). Biol Trace Elem Res 2019;188(2):245-50. PMID 29926391. DOI 10.1007/s12011-018-1414-y. — Liver tissue copper 2.82 to 5.31 micrograms/g (P = 0.002), zinc 48.05 to 74.9 (P = 0.035) at 6 months. Title paraphrased.Antivirals not named; fails the cohort test. Abstract only.
  26. Lampertico et al. Review of nucleos(t)ide analogue safety in chronic hepatitis B (article title not transcribed). Aliment Pharmacol Ther 2016. PMID 27198929. DOI 10.1111/apt.13659. — Review abstract; no clinically significant lactic acidosis with entecavir or tenofovir in registration studies; recommends monitoring eGFR and serum phosphorus.Narrative review; abstract only.
  27. Kayaaslan et al. Review of adverse effects of oral antiviral therapy in chronic hepatitis B (article title not transcribed). World J Hepatol 2017;9(5):227. PMID 28261380. DOI 10.4254/wjh.v9.i5.227. — Narrative review (Tier C); entecavir lactic acidosis in decompensated disease discussed.Abstract only.
  28. Sustained suppression of viral replication in improving vitamin D serum concentrations in patients with chronic hepatitis B. Sci Rep 2015;5:15441. — Observational, 128 treatment-naive patients and 128 healthy controls; nucleoside analogues unnamed. Springer page read via summarizer.Entecavir not named; disease context only.
  29. Yang et al. Literature review of renal and bone safety, tenofovir and entecavir (article title not transcribed). Ther Clin Risk Manag 2017;13:1273-85. PMID 29033575. DOI 10.2147/TCRM.S143286. — Literature review of 21 studies; eGFR tended to fall with tenofovir and rise with entecavir over time.Abstract only; not relied on for any grade.
  30. Consumer drug pages: WebMD entecavir side effects, 1mg Entehep, drugs.com entecavir food interactions, Wikipedia Entecavir. — Tier D. Opened to audit circulating claims: none names a vitamin, mineral or phosphate effect; all repeat the empty-stomach instruction and the lactic acidosis warning. drugs.com and Wikipedia were read in an earlier pass.Tier D: supports no claim at any level. An antidote-research page for entecavir returned a fetch error and was not read.
  31. Wikipedia: SLC22A5 (OCTN2). — Reference page used only to identify OCTN2 as the sodium-coupled carnitine uptake transporter. Tier D pointer.Summarizer-read; supports no grade by itself.
  32. Park et al. Clinical consequence of hypophosphatemia during antiviral therapy for chronic hepatitis B. Kidney Res Clin Pract 2025;44(1):123-31. — Cohort of 4,335 adults; hypophosphatemia 1.7%; lower eGFR. Institutional repository abstract.Abstract names no antiviral: entecavir not confirmed in the cohort; not used as evidence.
  33. Zeng et al. Baseline fecal 16S in hepatitis B before antiviral therapy and seroconversion (article title not transcribed). Sci Rep 2021. PMID 33547384. DOI 10.1038/s41598-021-82939-1. — Cohort of 37 seroconverters and 41 non-seroconverters; antiviral (tenofovir or entecavir) not specified.Baseline predictors, not a drug effect; not used as evidence. Listing and abstract only.
  34. Italian multicenter cohort of long-term entecavir monotherapy in treatment-naive chronic hepatitis B, 18 liver units (AASLD 2010 poster abstract, as reported by NATAP). — Single-arm (Tier A observational, entecavir is the exposure), 418 patients on entecavir 0.5 mg, median 30 months; blood phosphorus below 2.3 mg/dL in 1%; creatinine rise above 0.3 mg/dL in 3%. Conference abstract, not peer-reviewed full text.Abstract only, summarizer-read; no comparator or baseline phosphate; garbled creatinine range in the source.
  35. Lamivudine treatment and serum 25(OH)D3 in chronic hepatitis B (Infect Disord Drug Targets, Bentham; title not transcribed). — 80 subjects (50 treatment-naive patients, 30 controls); 25(OH)D3 21.6 +/- 5.8 ng/mL before and 31.1 +/- 7.3 ng/mL after at least 6 months of lamivudine; controls 33.4 +/- 5. Lamivudine only.Entecavir not in the cohort: not used as evidence for entecavir. Abstract only.
  36. Excluded leads opened in the repair pass for copper, iron, zinc and B12/folate (none includes an entecavir-specific nutrient measurement). — Serum copper, zinc and selenium in 60 chronic hepatitis B patients, Acta Med Iran 2011 (no antiviral named). Serum copper and zinc in carriers, chronic active hepatitis B and controls, Ankara (n = 46, 25, 34; no differences; treatment not stated). Hepcidin, serum iron, transferrin saturation and ferritin in hepatitis C versus hepatitis B, Hepat Mon 2014 (entecavir not mentioned). Serum ferritin and PEG-interferon response, Front Cell Infect Microbiol 2025 (102 patients; the nucleos(t)ide analogue is unspecified). Secondary hemochromatosis case with hepatitis B, Open Med 2023 (lamivudine, adefovir, tenofovir; not entecavir). Vitamin B12 and folic acid in 29 hepatitis B patients versus 30 controls, Turkish thesis 2005 (no drug). Entecavir versus untreated hepatitis B and interferon-gamma, Hepat Mon 2023 (193 versus 107 patients; no nutrient measured).Cohort test failed for entecavir in every item; disease-context or no-drug sources, supports no grade. Abstract or page summaries only. Not opened: PMC8723841 (hepatitis B iron overload case, behind a bot check; antiviral not confirmed).