Valacyclovir

Direction

Possible mitochondrial toxicity (a burden), not a nutrient deficiency; no supplementation implication.

Regulatory status

The label sections on carcinogenesis and mutagenesis read (summarized) contain no mitochondrial or DNA polymerase gamma statement; DNA polymerase is discussed only in the microbiology section [1].

Population evidence

No human study with valacyclovir or acyclovir measuring mtDNA, respiration or mitochondrial enzymes was found. A human infant cohort of valganciclovir (not valacyclovir) found "No evidence of mitochondrial toxicity" (Arch Dis Child 2022) [16]; valganciclovir is a different drug, so by the Hard Rule 6 cohort test it is excluded as evidence for valacyclovir.

Related-drug mechanistic data (acyclovir)

J Biol Chem 2007 in vitro kinetics of acyclovir triphosphate on human mitochondrial DNA polymerase gamma versus the HSV-1 polymerase: "moderate inhibition of mitochondrial DNA replication defining a toxicity index of 380"; "Mitochondrial toxicity is relatively low because acyclovir is activated only in infected cells" [16]. Toxicol In Vitro 2022, NCI-H1975 human lung cancer cells exposed to acyclovir: "a reduction of mitochondrial membrane potential, altered mitochondrial size and shape, and mtDNA damage were found"; concentration and effect sizes not in the record read [16]. TDP1 study (Nucleic Acids Res 2013): AZT and ddC depleted mtDNA, acyclovir reported for nuclear DNA effects only [16].

Cohort test

Valacyclovir was not in any mitochondrial study (searched "valacyclovir mitochondrial": three records, none a mitochondrial function outcome) [17]. Acyclovir-only studies are RELATED-DRUG (active metabolite) data and, for valacyclovir, CLASS EXTRAPOLATION: Tier B/C, capped at yellow. The acyclovir enzyme and cell-line work uses acyclovir triphosphate or acyclovir directly, so valacyclovir exposure of cells (which must first be hydrolyzed) was not tested.

Mechanism

Named: chain-terminating nucleoside analogue triphosphate acting on mitochondrial DNA polymerase gamma, with selective activation by viral thymidine kinase limiting exposure in uninfected cells [16].

Counter-evidence held on record

Counter-evidence and confounding The same enzyme paper reports low expected toxicity because acyclovir is phosphorylated mainly in infected cells. The cancer-cell line is not a model of normal tissue exposure. The valganciclovir infant data, though not valacyclovir, found no mitochondrial toxicity for a related antiviral. Framing caution for the consumer surface Not a vitamin or mineral finding. This is a theoretical drug-toxicity signal from the active metabolite in laboratory systems; there is no human evidence of mitochondrial harm from valacyclovir in the records read.

Direction

Mixed: possible increase in oxidative stress (acyclovir, healthy rats) and possible reduction (valacyclovir and acyclovir in disease models). Neither is a nutrient deficiency.

Regulatory status

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

Population evidence

No human study found. Animal (Tier B or related-drug): male Wistar rats, n = 28, acyclovir 10, 20 and 40 mg/kg orally for 28 days: brain catalase, superoxide dismutase and glutathione reduced and malondialdehyde increased, "particularly at 20 and 40 mg/kg" (Metab Brain Dis 2025); male Wistar rats, n = 18, acyclovir 10 and 40 mg/kg for 21 days: at 40 mg/kg serum malondialdehyde rose while testicular and serum SOD, GPx and CAT fell (JBRA Assist Reprod 2025; the title says "upregulating oxidative enzymes", which conflicts with the abstract) [19]. Valacyclovir: streptozotocin Alzheimer rat model, 100 and 150 mg/kg for 21 days, "significantly (p < 0.001) reduced" inflammatory and oxidative stress markers, no markers named and sample size not stated (Mol Neurobiol 2026) [18]. Acyclovir in diabetic mice reportedly reduced oxidative stress (Life Sci 2022) [19]; acyclovir 50, 150 and 450 mg/kg reversed streptozotocin-induced catalase, SOD, glutathione and malondialdehyde changes in rats (Endocr Metab Immune Disord Drug Targets 2024) [18].

Mechanism

Not named for valacyclovir. The acyclovir healthy-rat studies are framed as neurotoxic and testicular toxicity with redox changes, and the disease-model studies report lower markers alongside lower inflammation; no pathway is established in the abstracts read.

Cohort test

One valacyclovir animal abstract (Tier B). The acyclovir studies are RELATED-DRUG data (active metabolite) and are not human cohorts. No numeric values were in the abstracts read. Dose conversion to human exposure was not assessed.

Counter-evidence held on record

Counter-evidence and confounding The two directions come from different species-disease contexts (healthy toxicity studies versus streptozotocin disease models), and none reports human exposure-equivalent dosing. No antioxidant-nutrient level was measured in any of them. Framing caution for the consumer surface There is no evidence that valacyclovir depletes antioxidant vitamins or that antioxidant supplements are needed with it. The animal findings do not support a supplement recommendation in either direction.

Limits on what this shows

• Why no grade: Dual condition met on what was accessible: no Tier B or C evidence supports a yellow grade (synthetic complexes are not exposure-status data), and no circulating consumer claim was found to rebut as white. A disclosed gap, not a finding of safety; re-check when web search returns.

What was searched

Label text read: no copper statement [1]. PubMed "valacyclovir copper": 1 record, a synthetic copper(II) complex of valacyclovir binding calf thymus DNA (DNA Cell Biol 2012), which is coordination chemistry and not a copper-status finding [24]. PubMed "acyclovir copper": 20 results, 10 read: copper-acyclovir complexes (in vitro antiviral activity, crystallography), copper oxide nanoparticles as antivirals, electrodes and materials; the one human record (aqueous humor copper in CMV retinitis, n = 11 versus 24 controls) did not involve acyclovir [25]. Drugs.com food-interaction page (Tier D) and Wikipedia (Tier D) name no mineral effect [4][5].

Channel outcomes

Two PubMed phrasings worked. A combined "valacyclovir iron OR copper OR zinc OR ferritin" query was parsed loosely and returned 10 unrelated records, so it was discarded [30]. Web search (consumer-claim tracing) was unavailable because the shared budget was exhausted, so absence of a circulating claim rests on two Tier D pages. Repair pass (2026-10-08): "acyclovir ceruloplasmin" returned 1 record (PMID 16180713, Japanese encephalitis case, ceruloplasmin "unremarkable" on admission before acyclovir was started, no value, no copper), which is not an exposure-status measurement [38]. Web search remained unavailable. Mixed result: genuine gap on the channels that opened, plus tooling-limited consumer tracing.

Limits on what this shows

• Why no grade: Dual condition met on what was accessible: no Tier B or C source supports a yellow grade and no circulating claim was found. A disclosed gap, not a finding of safety.

What was searched

Label text read: no iron statement, and the iron-chelating-type interactions in section 12.3 (cimetidine, probenecid, antacids) were not extracted [1]. PubMed "valacyclovir iron" and "valacyclovir iron deficiency anemia": both returned HTTP 404, consistent with zero hits but unverified [27]. PubMed "acyclovir iron": 30 results, 10 read; none measured iron, ferritin or hemoglobin in acyclovir or valacyclovir users (a monkeypox case with hemoglobin 10.8 g/dL, iron 22 ug/dL and ferritin 2362 ng/mL had acyclovir only as incidental treatment; a transplant iron-loss cohort indexed ganciclovir, not acyclovir) [26]. Hemoglobin findings are covered in the Oxygen delivery/utilization entry and are not iron findings.

Channel outcomes

Two of three PubMed phrasings returned 404 pages and one returned a usable listing; the rest of the 30 results (20 records) were not read. Repair pass (2026-10-08): "valaciclovir iron" was rate-limited (HTTP 429; the fetch tool asked that the page not be retried, so it was not); "valacyclovir ferritin" opened and returned 1 record (PMID 38799982, a kidney-transplant HLH case with ferritin 67,600 ug/L attributed to HLH activity, acyclovir then valacyclovir given for HSV-2, no serum iron, not a drug effect on iron stores) [14][35]. Web search remained unavailable. Mixed result: probable genuine gap, with tooling limits on completeness.

Direction

Disturbance of the gut microbial community (a risk entry). Not a nutrient deficiency; implies no supplementation.

Regulatory status

The label text read does not mention the microbiome or C. difficile; gastrointestinal effects including diarrhea appear in the postmarketing list [1].

Population evidence

No human 16S or metagenomic study of valacyclovir or acyclovir was found. A pilot of 21 autologous stem-cell transplant patients (48 fecal swabs) measured acyclovir concentrations (76 samples); valacyclovir was not analysed and the abstract reports no microbiome result (Ann Hematol 2023) [20][21]. Case report (Tier B): 73-year-old man with lumbar herpes zoster on valaciclovir 1 g three times daily, stool positive for C. difficile, 3 to 4 stools per day rising to 7 to 13 within about six days, improved after metronidazole 500 mg three times daily for 10 days (Pharm World Sci 2004) [22].

Related-drug and mechanistic data

Mouse 16S study (PLoS One 2020, "Herpes simplex virus infection, Acyclovir and IVIG treatment all independently cause gut dysbiosis"): "ACV reduced Bacteroidetes levels in male but not female mice" and decreased Akkermansia muciniphila; no diversity or C. difficile data; sample size not stated [21]. In vitro (Res Microbiol 2017): valacyclovir is one of five hPepT1-transported drugs that are also substrates of the E. coli oligopeptide transporter YdgR, with transport shown and no effect on composition measured [20].

Cohort test

Valacyclovir was in the E. coli transport study (in vitro Tier B) and the C. difficile case (Tier B); the mouse study is acyclovir only (RELATED-DRUG, CLASS EXTRAPOLATION). The transplant pilot is a human cohort in which valacyclovir was recorded but not analysed, so it contributes nothing to the grade.

Mechanism

Plausible and partly named: valacyclovir is absorbed by a peptide transporter that gut bacteria also express; no antibacterial mechanism is described in the label text read (it is an antiviral) [1]. The mouse effect is unexplained.

Counter-evidence held on record

Counter-evidence and confounding The mouse study confounds acyclovir with HSV infection and IVIG; sex-specific effects were not replicated in females. The C. difficile case is one patient, in an older adult with other exposures unlisted in the record read. Framing caution for the consumer surface Persistent watery diarrhea on any antibacterial or antiviral warrants clinical evaluation. Nothing here supports adding a probiotic or a vitamin.

Limits on what this shows

• Null and contradicting findings: Randomized trial of valacyclovir for suppression of recurrent genital herpes in HIV-infected subjects (n = 293): "There were no episodes of thrombotic microangiopathy" [8]. The immunocompetent label tables above show hemoglobin and platelet abnormalities at placebo-like rates. The sickle-cell phase I trial found no hemoglobin change and "No clinically significant adverse effects occurred" [13]. Albion Street Centre database overview (J Acquir Immune Defic Syndr Hum Retrovirol 1998, PMID 9586650): the database was used to examine the reported valacyclovir and TTP/HUS-like association, and the abstract states that patients with terminal-stage AIDS showed the syndrome independently of their therapy, probably from multiorgan failure; no counts or incidence are given in the abstract read (Tier B or C, descriptive, not a controlled comparison) [31][33].
• At-risk subgroups: Advanced HIV-1 disease, allogeneic bone marrow and renal transplant recipients, and doses of 8 g/day (label). Elderly and renal-impairment patients are separately at risk for renal and CNS reactions [1].

Direction

Drug-toxicity outcome that lowers red-cell mass and platelets (microangiopathic hemolysis). It is not a nutrient deficiency, not iron or B12 deficiency, and nothing here supports supplementation. Hard Rule 2: anemia is not iron deficiency.

Regulatory status

Label 5.1 (summarized): "TTP/HUS, in some cases resulting in death, has occurred in patients with advanced HIV-1 disease and also in allogeneic bone marrow transplant and renal transplant recipients participating in clinical trials of VALTREX at doses of 8 grams per day." Treatment should stop immediately if signs, symptoms or laboratory abnormalities consistent with TTP/HUS appear. Postmarketing hematologic list: thrombocytopenia, aplastic anemia, leukocytoclastic vasculitis, TTP/HUS [1]. The label text read does not list hemolytic anemia.

Population evidence

ACTG 204 [10][9]: randomized double-blind trial, 1,227 CMV-seropositive adults with CD4 below 100/mm3; valaciclovir 8 g/day versus acyclovir 3.2 g/day or 0.8 g/day. Valaciclovir lowered confirmed CMV disease (11.7% versus 17.5%, a 33% risk reduction) but toxicity and discontinuation were more common and there was a trend toward earlier mortality (P =.06). The abstract gives no TMA, hemoglobin, platelet or LDH figures. The companion analysis by Bell and colleagues [9] is titled "Manifestations resembling thrombotic microangiopathy ... (ACTG 204)"; its PubMed record has no abstract and the OpenAlex abstract field holds only an abbreviations list (hemoglobin, LDH, HUS, TTP), so its counts were not retrieved. A news summary of the study states TMA signs "occurred significantly more often in valaciclovir users versus acyclovir users" [8] (secondary, not peer-reviewed). A review abstract says the risk of this syndrome appears higher in advanced HIV disease and gives no incidence [8][12]. Case: valacyclovir and TTP in an HIV-infected patient, Arch Intern Med 2000 (n = 1; PubMed record has no abstract) [8][34]. Repair pass: PubMed indexes the Bell 1997 record with publication types including Randomized Controlled Trial, Multicenter Study and Case Reports and MeSH terms Hemolytic-Uremic Syndrome, Purpura Thrombotic Thrombocytopenic and Valacyclovir, but carries no abstract, so the counts remain unretrieved [31][32]. A Cureus 2020 case report (PMID 32550073) describes TTP in an immunocompetent patient taking 1,000 mg/day with no other apparent trigger; hematologic values were not in the record read (single case, Tier B, read through a summarizing fetch tool) [33].

Direct measurement

Hemoglobin was measured as a routine laboratory abnormality in the label trials [1]: hemoglobin below 0.8 times the lower limit of normal in 0.8% (valacyclovir) versus 0% (placebo) in herpes zoster; 0.3% (1 g twice daily), 0.2% (500 mg twice daily) versus 0% (placebo) in genital herpes treatment; 0%, 0.8% versus 0.8% (placebo) in genital herpes suppression. Platelets below 100,000/mm3: 1.0% versus 1.2% in zoster. In HIV-1 suppression, decreased neutrophil counts 18% versus 10% and decreased platelet counts 3% versus 0% [1]. A phase I trial of valacyclovir as an anti-sickling agent (14 subjects, 11 in steady state for hemoglobin analysis) reported "the mean hemoglobin concentration was almost constant" [13].

Mechanism

Named in the label only by population and dose (advanced HIV, transplant, 8 g/day); the label text read gives no pathway. Hemolysis markers (LDH, haptoglobin) are not reported in any retrieved abstract.

Cohort test

Label, ACTG 204, the 293-person trial and the sickle-cell trial all had valacyclovir in the cohort (Tier A). The Italian spontaneous-report study (863 antiviral ADR reports versus 42,430 other reports; anemia reporting odds ratio 15.9, 95% CI 12.3 to 20.4; neutropenia 4.1, 2.9 to 5.8) names valacyclovir and acyclovir among implicated antivirals but gives no valacyclovir-specific count and is dominated by other antiviral classes [14]; it is CLASS EXTRAPOLATION (valacyclovir was in the report pool, no drug-level estimate), Tier C, and is not used to raise any grade.

Why orange, not red

One evidence line (label statement derived from trial experience, ACTG 204) rather than two independent Tier A sources; the TMA counts and hemoglobin values by arm were not retrievable; a second HIV trial (suppression regimen; dose not stated in the record read) saw no events; and immunocompetent hemoglobin data are flat. A repair-pass search for a second independent Tier A source found none: the additional records are one case report [33] and a database overview that attributes the syndrome in terminal AIDS to the disease rather than the drug [31]. The boundary is in the title: rare, advanced HIV or transplant, 8 g/day.

Counter-evidence held on record

Counter-evidence and confounding Confounding by indication is presumed (Hard Rule 6): advanced HIV disease and transplantation are the populations in which the TMA-like syndrome was observed, and the records read do not separate the contribution of the drug from the underlying disease or co-medication. ACTG 204 used an active acyclovir comparator, so it tests valaciclovir against acyclovir and not against non-use. TMA rates by arm were not seen. The Albion Street Centre abstract [31] supports the confounding concern directly. Framing caution for the consumer surface This is a rare drug-toxicity signal, not a nutrient deficiency. It does not mean iron, B12, folate or any supplement should be taken, and it is not a statement about people on usual doses. Pallor, dark urine, bruising, fever or confusion on valacyclovir warrant prompt clinical assessment (stopping is a prescriber decision).

Direction

Possible reduction of mitochondrial energy output (burden). Not a nutrient deficiency.

Regulatory status

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

Population evidence

No human data. The "acyclovir ATP" PubMed search returned 100 results (10 read): none reported an ATP, energy or oxygen-consumption effect of the drug; "ATP" hits were mostly ATP-binding cassette transporters. The one ATP statement, "ATP was significantly decreased at 12 h after infection" in infected Vero cells (Antiviral Res 2020), reflects virus infection and is qualitative [23]. Surrogate: reduced mitochondrial membrane potential with acyclovir in NCI-H1975 cells (Toxicol In Vitro 2022; same source as the Mitochondrial burden entry) [16].

Mechanism

Hypothetical: loss of membrane potential after mtDNA damage, if it occurred in normal tissue. Not shown.

Cohort test

Valacyclovir was not in any ATP or respiration study (searched "valacyclovir mitochondrial", "acyclovir ATP", "acyclovir ATP respiration"; the last returned HTTP 404, consistent with zero hits but unverified) [17][23]. The membrane-potential result is RELATED-DRUG (acyclovir) in vitro data: CLASS EXTRAPOLATION, capped at yellow.

Counter-evidence held on record

Counter-evidence and confounding The valganciclovir infant study found preserved complex IV activity, citrate synthase and mtDNA, but it is a different drug and is excluded by the cohort test. A cancer-cell line has altered mitochondria at baseline. Framing caution for the consumer surface There is no evidence that valacyclovir lowers energy production or causes "low energy" through ATP. Fatigue reported in the label HIV-1 suppression trial (8% versus 5% placebo) is a labeled adverse reaction and not an ATP finding [1].