Lamivudine

Regulatory status

Epivir label: lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, with nucleoside analogues including lamivudine; postmarketing lactic acidosis, steatosis, rhabdomyolysis and body-fat redistribution [1]. Epivir-HBV label: creatine kinase at least 7 times baseline in 9% on lamivudine versus 5% on placebo (safety population 332 vs 200 in the adverse-reaction table); postmarketing rhabdomyolysis and lactic acidosis [2]. A polymerase gamma statement was not found in the Epivir text read [1].

Population evidence

Monnin 2020 [5] (lamivudine as the studied exposure): breastfed HIV-exposed uninfected African infants given lamivudine or lopinavir/ritonavir prophylaxis; median blood mtDNA copy number fell 41.7% (IQR 12.1 to 64.4) from day 7 to week 50 in the prophylaxis group; depletion (a fall of 50% or more) versus a South African unexposed reference group: lamivudine PR 1.54 (95% CI 1.00 to 2.37, p = 0.05), lopinavir/ritonavir PR 1.75 (1.15 to 2.68); no difference between the two regimens. Group sizes were not in the abstract, and deletions were unexpectedly frequent before randomisation. A follow-up of 17 infants with depletion at week 50 found only one still depleted at year 6, no lamivudine versus lopinavir/ritonavir difference and no association with growth, clinical or neurodevelopmental outcomes [6] (listing snippet only). Divi 2004 [9] (zidovudine plus lamivudine, Combivir): in utero exposure, n = 10 exposed versus 9 unexposed infants; moderate to severe mitochondrial damage on electron microscopy in umbilical cords of 6 of 9 exposed versus 0 of 7 unexposed (P = 0.011); mtDNA depleted in cord (P = 0.006) and cord blood (P = 0.003); no clinical symptoms. Lamivudine not isolated. Mallon 2005 [8]: 20 HIV-negative adults randomized to zidovudine/lamivudine or stavudine/lamivudine for 6 weeks; adipose and monocyte mitochondrial RNA transcription fell without significant mtDNA depletion; no p-values in the abstract; lamivudine in both arms. Xu 2014 [10] (Tier B case series): 6 hepatitis B patients with lamivudine or telbivudine associated myopathy or neuropathy; electron microscopy showed vacuolised mitochondria with simplified cristae and mtDNA was reduced in affected muscle; recovery after stopping or switching to entecavir; lamivudine not separated from telbivudine. Note 2003 [7] (mice, Tier B): lamivudine alone for 2 weeks moderately decreased liver mtDNA only (no significant change in muscle, heart, brain or white fat); blood lactate unchanged even at supratherapeutic doses; ketone bodies did not rise with lamivudine.

Mechanism

Present, weak. Kakuda 2000 [11] ranks polymerase gamma inhibition zalcitabine > didanosine > stavudine > lamivudine > zidovudine > abacavir (review abstract, Tier B pharmacology reference). Mallon [8] found reduced mitochondrial transcription without mtDNA loss, which the authors read as a mechanism other than polymerase gamma inhibition.

Cohort test

Lamivudine alone was the exposure in [5] (against a reference group, with lopinavir/ritonavir as the other arm) and in [7] (mice); in [8], [9] and [10] it was given with zidovudine, stavudine or telbivudine, so those results cannot be assigned to lamivudine.

Why yellow

Hard Rule 2 and the protocol rule on toxicity: mitochondrial DNA copy number and lactic acidosis are drug-toxicity surrogates, not nutrient measures. Even as a toxicity signal the only lamivudine-isolating human result has a confidence interval touching 1.00, reversed by year 6, and has no clinical correlate [5][6].

Counter-evidence held on record

Counter-evidence on record Mallon: no significant mtDNA depletion in either lamivudine-containing arm [8]. Note: lactate unchanged in mice, mtDNA unchanged in four of five tissues [7]. A review chapter in the NIDDK LiverTox series does not list lamivudine among agents linked to mitochondrial liver injury (listing snippet only) [38]. In a serial PBMC study, zidovudine plus lamivudine plus didanosine depleted mtDNA while none of seven patients on stavudine plus lamivudine plus indinavir changed significantly (listing snippet only) [39]. A case-report letter titled "Lamivudine-induced muscle mitochondrial toxicity" exists but only the title and indexing were seen [40]. Framing caution for the consumer surface A drug-safety signal for clinicians (the label asks for suspension if lactic acidosis or marked hepatotoxicity is suspected), not a deficiency of anything in the diet, and not a prompt to take mitochondrial supplements.

Regulatory status

No oxidative stress statement in the label text read [1][2].

Population evidence

Iorjiim 2022 [23] (Drosophila, lamivudine tested alone): LD50 47.07 mg per 10 g diet; dose-dependent loss of survival, longevity and climbing; acetylcholinesterase, glutathione S-transferase, superoxide dismutase, catalase, total thiols and malondialdehyde significantly altered (P < 0.05), direction per marker not given in the abstract. Balogun 2022 [26] (pregnant mice; lamivudine only in combinations): zidovudine/lamivudine raised placental malondialdehyde and lowered MnSOD and PGC-1 alpha mRNA versus tenofovir/emtricitabine; abacavir/lamivudine was a separate arm without a stated oxidative result in the abstract. Mohan 2023 [24] (HepG2 cells, 120 h; lamivudine, tenofovir disoproxil, dolutegravir alone and combined): combinations raised malondialdehyde (p = 0.0066) and activated Nrf2, SOD2 and catalase; lamivudine-alone values not reported in the abstract. Rat hepatotoxicity study, 2015 [28] (listing snippet only): hepatic GST, GGT, SOD and malondialdehyde elevated at 20 mg/kg. Hepatitis B patients [27] (Mikrobiyol Bul 2009, listing snippet only; n = 19 acute, 17 chronic, 24 carriers, 21 controls): malondialdehyde higher in all patient groups; after 6 months of interferon-alpha plus lamivudine, malondialdehyde fell and CuZn-SOD and glutathione peroxidase rose (p < 0.05).

Mechanism

Plausible, linked to the mitochondrial toxicity pathway in the same cell and animal systems (see Overlap map). Not demonstrated in people at therapeutic doses.

Cohort test

Lamivudine was the studied drug in [23] and [28]; in [24], [26] and [27] it was part of a combination, so effects cannot be assigned to it alone.

Why yellow

Tier B only; the fly study used toxicity-range doses (LD50 47.07 mg per 10 g diet) and the rat study doses of 20 to 500 mg/kg, and human-equivalent exposure was not compared in the abstracts; the one human study confounds lamivudine with interferon and viral suppression. No glutathione, vitamin C or E, selenium or other antioxidant nutrient was measured in a lamivudine cohort.

Counter-evidence held on record

Counter-evidence on record Opii 2007 (gerbil brain synaptosomes and mitochondria, in vitro) used lamivudine as a comparator for zalcitabine; lamivudine did not show the protein oxidation increase seen with zalcitabine at 40 nM, with no numbers given [25]. In hepatitis B patients, malondialdehyde fell on interferon plus lamivudine [27]. Framing caution for the consumer surface Not evidence that lamivudine lowers antioxidant nutrients, and not a reason to take antioxidant supplements.

Regulatory status

No iron statement in the label text read (the Epivir text read mentioned only black iron oxide, a tablet colorant) [1][2].

Population evidence

Ohkoshi 2008 [21] (prospective, lamivudine alone for 12 months, 30 Japanese chronic hepatitis B patients; abstract plus Springer page read through a summarizing tool): serum ferritin decreased at 6 months in the group; in the 23 patients without YMDD mutants ferritin kept falling (P < 0.01 at 12 months) while it rose with ALT and HBV DNA in the 7 with mutants; unsaturated iron-binding capacity rose (P < 0.05) and serum iron did not change significantly in non-mutant patients; one cirrhotic patient with hepatic hemosiderosis had baseline ferritin 291.7 ng/mL and improved iron stores. No control group; means and baseline values were in tables not reproduced in the page text.

Mechanism

Not a drug effect on iron handling. Ferritin tracks hepatic inflammation and ALT, which fall with HBV suppression.

Cohort test

Lamivudine was the only drug in [21]; the exposure is confounded with viral suppression, and the mutant versus non-mutant split is a response comparison, not a lamivudine versus non-lamivudine comparison.

Why yellow

Iron markers were measured directly in a lamivudine-only cohort (Tier A in design) but the finding is a reverse-direction, disease-response signal without a control (Hard Rule 6). No iron absorption, ferritin or hepcidin study with HIV patients on lamivudine was found.

Counter-evidence held on record

Counter-evidence on record Ferritin rose in patients whose virus escaped lamivudine, consistent with an inflammation-driven marker rather than a drug effect [21]. Hemoglobin rows in the label are not iron measures [1]. Framing caution for the consumer surface Do not read as iron deficiency or iron overload from lamivudine. No iron supplement is suggested.

Regulatory status

No copper statement in the label text read [1][2].

Population evidence

Sahin 2019 [22] (hepatitis B liver biopsies before treatment and at 6 months, ICP-MS, 11 trace elements; abstract via the PubMed record): liver copper median 2.82 to 5.31 microgram per gram (p = 0.002), liver zinc 48.05 to 74.9 (p = 0.035); copper, zinc and iron associated with histological activity; sample size and control group not stated; "antiviral-treated" patients, with lamivudine, telbivudine, tenofovir and entecavir appearing only among the index terms. No serum copper, ceruloplasmin or urinary copper measurement in a lamivudine cohort was found.

Mechanism

Absent for a drug-copper interaction; the authors link the rise to improved inflammation.

Cohort test

CLASS EXTRAPOLATION and unverified: lamivudine is listed in the index terms but not in the abstract text, and the drugs are pooled; cohort test not met for lamivudine. Tier C, capped at yellow.

Why yellow

A copper (and zinc) measurement exists in antiviral-treated hepatitis B, but it shows a rise tied to disease improvement and cannot be attributed to lamivudine. Kept separate from Iron per Hard Rule 7.

Counter-evidence held on record

Framing caution for the consumer surface Not a finding of copper or zinc depletion or excess from lamivudine, and not a reason to take either.

Regulatory status

No microbiome statement in the label text read [1][2].

Population evidence

Catala-Moll 2026 [29] (randomized open-label trial NCT02337322, 88 antiretroviral-naive adults with advanced HIV, median CD4 34, lamivudine/abacavir plus dolutegravir or ritonavir-boosted darunavir, 2 years; abstract via PubMed record): dolutegravir increased microbial richness and diversity and moved the microbiota toward that of people without HIV, darunavir/ritonavir did not; lamivudine/abacavir was the shared backbone, not the variable tested, and no numeric values were in the abstract. Yanamadala 2025 [30] and Muthumula 2025 [31] (rats, perinatal abacavir/dolutegravir/lamivudine, two dose levels): dose- and sex-dependent changes in diversity, Firmicutes, Actinobacteria, Lactobacillus, Bifidobacterium and Akkermansia; no change in short-chain fatty acids or IgA; sample sizes and numeric doses not in the abstracts. Infant cohort [33] (272 Nigerian infants, 18 months; listing snippet only): breast-milk antiretroviral drugs, including lamivudine, were associated with lower relative Bifidobacterium longum in infants; no number in the abstract.

Mechanism

Absent as a named mechanism for lamivudine; the studies report associations or combination effects.

Cohort test

Lamivudine in the cohort in all four, but only as part of a regimen. [29] contrasts the third drug, not lamivudine. Rat studies are Tier B and use combination dosing.

Why yellow

Plausible, not isolated, no diversity loss attributable to lamivudine and no clinical outcome. Confounding by HIV, advanced immunodeficiency and the partner drugs is presumed.

Counter-evidence held on record

Counter-evidence on record A Kenyan breast-milk microbiome analysis (n = 24 no antiretroviral vs n = 25 on zidovudine, nevirapine and lamivudine) found no significant difference in diversity or composition with antiretrovirals, though antibiotics did affect it; it studied milk, not gut [32] (listing snippet only). In [29] richness rose on one regimen with the same lamivudine backbone, so the backbone does not by itself reduce diversity. Framing caution for the consumer surface No specific bacteria or health outcome is attributed to lamivudine. Not a prompt to take a probiotic.

Regulatory status

Epivir label postmarketing: "Anemia (including pure red cell aplasia and severe anemias progressing on therapy)" [1]; Epivir-HBV label lists the same entry plus thrombocytopenia [2]. Laboratory tables: hemoglobin below 8.0 g/dL in 2.9% vs 1.8% (24-week trials, comparator zidovudine as returned by the summarizer) [1]; in the clinical endpoint trial (CAESAR, lamivudine plus current therapy vs placebo plus current therapy) hemoglobin below 8.0 g/dL in 2.2% vs 3.4% and neutrophils below 750/mm3 in 15% vs 13% [1]. Neutropenia 7.2% on lamivudine plus zidovudine vs 5.4% on zidovudine in 24-week trials [1]. Epivir-HBV placebo-controlled hepatitis B trials: platelets below 50,000/mm3 in 4% vs 3%; no hemoglobin or neutrophil rows in the tables read [2].

Population evidence

Majluf-Cruz 2000 [12] (Tier B case series, abstract read through the PubMed record): 5 men, median age 32, with AIDS, anemia with normal white cells and platelets, corrected reticulocytes below 1% and under 5% marrow erythroid progenitors; hemoglobin fell from above 11.8 to a mean of 5.2 g/dL (range 4.3 to 6.1) and recovered to 12.8 g/dL (11.3 to 13.8) seven weeks after withdrawal; erythroid progenitors 1.84% to 25.6%. Concomitant drugs including zidovudine, onset time and rechallenge were not reported in the abstract. Case report, Intern Med 2014 [13] (listing snippet only): pure red cell aplasia attributed to lamivudine without zidovudine in an HIV patient, with normalization after withdrawal. Duguma 2021 [14] (cross-sectional, 308 HIV-positive adults in Goba, Ethiopia; abstract via PubMed record): after treatment initiation, zidovudine, lamivudine and nevirapine were listed among predictors of anemia together with stage IV disease, female sex and intestinal parasites; no odds ratios in the abstract, and the regimens are not separable.

Mechanism

Present for the rare event (immune-mediated or toxic suppression of erythroid progenitors, supported by positive dechallenge in the case series). Absent for any generalized oxygen-carriage effect. Methemoglobin and hemolysis were searched without finding lamivudine data.

Cohort test

Lamivudine was in every source above, but in the label trials usually with zidovudine in both arms and in [12] and [14] with unreported or multiple concomitant drugs. The zidovudine-related anemia and neutropenia in combination products belongs to zidovudine and is not borrowed here.

Why yellow

Hard Rule 2: anemia and aplasia are clinical outcomes and a drug toxicity, not iron deficiency and not an oxygen-delivery nutrient deficit. Label Tier A data show no excess severe anemia against the comparator, and the aplasia evidence is case-level.

Counter-evidence held on record

Counter-evidence on record CAESAR hemoglobin below 8.0 g/dL: 2.2% on lamivudine vs 3.4% on placebo [1]. Hematologic rates in the label trials are confounded by zidovudine background therapy and advanced HIV. Framing caution for the consumer surface Unexplained severe anemia on lamivudine is a prescriber matter (stop-and-evaluate), not a signal to take iron, B12 or folate.

Regulatory status

No ATP or energy statement in the label text read [1][2].

Population evidence

Mohan 2023 [24] (HepG2, 120 h, n not stated): combination treatments lowered ATP production (p = 0.0017) and raised malondialdehyde; SIRT3 and UCP2 were suppressed for all treatments; lamivudine-alone ATP values not reported in the abstract. Kakuda 2000 [11] notes impaired adenylate kinase and the ADP/ATP translocator in vitro for nucleoside analogues as a class. Note 2003 [7]: mouse blood lactate unchanged.

Mechanism

Plausible through the mitochondrial pathway; ATP output itself was not shown to fall in any person taking lamivudine.

Cohort test

Lamivudine was in the cell cultures only as a member of combinations with tenofovir disoproxil and dolutegravir; Tier B.

Why yellow

Tier B mechanistic only; shares its source with Oxidative stress and Mitochondrial burden. Kept as its own entry per the protocol.

Counter-evidence held on record

Framing caution for the consumer surface A reduction in ATP in cultured liver cells is not a measured energy deficit in people.