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APPLICATION OF ACYCLOVIR TO THE ORAL MUCOSA:
MECHANISMS, PRE-CLINICAL EVIDENCE AND
CLINICAL UTILITY
Sardorbek Erkinboyev,
MSc.
Department of Pediatric Dentistry, Andijan State Medical Institute,
ORCID: 0009-0001-3816-1913
Abstract
Topical and locally delivered acyclovir (ACV) remain first-line interventions for
herpes-related oral mucosal disease, yet their place alongside novel wound-healing
strategies has evolved over the past decade. We systematically reviewed in-vitro, in-
vivo and clinical studies published 1 January 2015 – 31 March 2025 in PubMed,
Scopus, Web of Science, eLIBRARY, CyberLeninka and RSCI. Twenty-four eligible
records (11 laboratory, 3 animal, 8 randomised controlled trials, 1 cohort and 1 network
meta-analysis) were critically appraised with RoB 2/ROBINS-I and synthesised with
GRADE methodology. ACV inhibits herpes-viral DNA polymerase after viral
thymidine-kinase-triggered phosphorylation, halting replication and secondarily
reducing inflammation. Nanocarriers (solid-lipid nanoparticles, nanofibres, muco-
adhesive films) increased transepithelial uptake 3- to 5-fold in vitro and restored tight-
junction protein expression. A rat HSV-1 oral-wound model showed accelerated re-
epithelialisation with topical ACV versus control. Five human RCTs demonstrated that
adjuncts (honey, clobetasol, photobiomodulation) shortened lesion healing by 1–3 days
compared with ACV monotherapy. Prophylactic oral ACV halved chemotherapy-
induced oral mucositis incidence in autologous stem-cell recipients. Low-level diode
laser out-performed 5 % ACV cream for pain and recovery time. Adverse effects were
limited to mild local irritation; systemic nephro-/neuro-toxicity was not observed with
topical use. Evidence certainty was
moderate
(downgraded for sample size and
heterogeneity). ACV remains the benchmark for HSV-related oral lesions, but efficacy
is enhanced by anti-inflammatory or bio-adhesive technologies. Future trials should
standardise endpoints and explore non-herpetic indications.
Keywords:
acyclovir • oral mucosa • herpes simplex • nanofibre patch • wound
healing • mucositis
Introduction
Herpes-simplex-virus (HSV) infections of the oral mucosa—primary herpetic
gingivostomatitis in children and recurrent herpes labialis in adults—cause pain,
impaired nutrition and psychosocial distress. Systemic ACV revolutionised
management in the 1980s; topical 5 % cream became standard for labial lesions but
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shows variable benefit intra-orally because of salivary wash-out. Over 2015–2025,
research has focused on
(i)
optimised carriers that prolong mucosal residence and
(II)
combination regimens that couple antiviral and wound-healing actions.
Pharmacological Mechanisms
ACV is converted by viral thymidine kinase into ACV-monophosphate and
subsequently to the active triphosphate that competitively inhibits HSV DNA
polymerase and terminates the growing DNA chain [9]. Figure 1 depicts this selective
activation, explaining ACV’s low host-cell
toxicity.
Figure 1.
Mechanistic schematic of ACV
uptake, phosphorylation and chain termination.
1.
Entry
of the acyclovir molecule.
2.
Step-wise phosphorylation
(ACV
→ ACV-MP → ACV-DP → ACV-TP) driven
first by viral thymidine kinase, then host
kinases.
3.
Competitive binding
of ACV-TP
to viral DNA polymerase.
4.
Chain termination
that halts viral
DNA synthesis, preventing replication and
allowing the mucosa to heal.
Pre-clinical Evidence
Pre-clinical investigations support the biological plausibility of topical acyclovir
on the oral mucosa. In human gingival fibroblast cultures, acyclovir encapsulated in
solid-lipid nanoparticles boosted intracellular drug uptake three-fold while remaining
non-cytotoxic at concentrations up to 50 µM, yielding a low risk-of-bias rating [8]. A
porcine buccal-mucosa study then demonstrated that a bio-enhanced, muco-adhesive
film doubled acyclovir’s trans-epithelial permeability compared with a plain film;
methodological limitations placed this experiment in the moderate risk-of-bias
category [12]. Finally, in a rat model of HSV-1-infected oral wounds, topical 5 %
acyclovir ointment dampened mucosal inflammation and shortened re-epithelialisation
by roughly two days, although the absence of randomisation and blinding led to a
moderate risk-of-bias judgement.
Overall, nanocarriers improve mucosal residence and cellular uptake, while viral
suppression drives secondary wound repair.
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Clinical Evidence
Randomised Controlled Trials
Table 1. Clinical studies of ACV on oral mucosa (2015–2025)
#
Study
Population
(n)
Intervention
Comparator
Primary
Outcome
Effect
1
Awad &
Hamad 2018
[1]
Children
HSGS (100)
Oral ACV +
honey
Oral ACV
Median
healing 3 vs
6 days
Low
2
Honarmand
2017 [4]
Recurrent
labial HSV
(60)
Diode laser
5 % ACV
cream
Healing 2.2
vs 3.4 days
Some
3
Golestannejad
2022 [3]
Labial HSV
(60)
ACV
nanofibre
patch
5 % ACV
cream
Pain ↓,
healing NS
Low
4
Mirzaei 2024
[2]
Labial HSV
(80)
ACV-
clobetasol
nanofibre
ACV cream
Healing 4.1
vs 6.3 days
Low
5
Hong 2023 [5]
AHSCT (29)
Oral ACV
prophylaxis
No
prophylaxis
CIOM 16
% vs 59 %
Low
Systematic Review & Meta-analysis
A 2023 network meta-analysis of 39 RCTs ranked oral valacyclovir + topical
clobetasol highest for time-to-healing; ACV monotherapy was mid-tier [6].
Heterogeneity precluded quantitative pooling of the five homogeneous ACV-only
trials; qualitative synthesis indicates a consistent 0.5–3-day reduction in lesion
duration.
Comparative Analysis with Alternative Agents
Among adjunctive or alternative interventions, low-level laser therapy stood out
for its rapid symptomatic control: in a 60-patient RCT it shaved about 1.2 days off the
total healing time and cut pain by roughly 1.1 days compared with acyclovir cream,
although its practicality is limited by the need for specialised equipment [4]. Adding
topical honey to the standard oral acyclovir regimen offered an even more impressive
clinical edge—children recovered almost three days sooner and required fewer
analgesics, a benefit achieved with an inexpensive and widely available agent [1].
Combining acyclovir with a potent topical corticosteroid (e.g., clobetasol) produced a
synergistic effect; participants in an 80-patient trial healed 2.2 days faster and showed
markedly less crusting than those on acyclovir alone [2]. Finally, reformulating
acyclovir into muco-adhesive nanofibre patches enhanced drug retention: across two
RCTs these patches delivered consistently better symptom relief—particularly for
burning and itching—though improvements in overall healing time were variable [2,
3].
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Safety Profile & Contra-indications
Across 634 trial participants, only transient burning or dryness were reported with
topical ACV. No systemic toxicity occurred. Contra-indications are limited to known
ACV or valacyclovir hypersensitivity [9].
Discussion
Evidence quality is moderate: well-conducted RCTs exist, but sample sizes
remain < 100 and endpoints vary. ACV’s antiviral action alone yields modest clinical
gains; combining anti-inflammatory (steroids, honey) or physical (laser) modalities
consistently augments outcomes. Nanotechnologies improve pharmacokinetics but
require cost-effectiveness studies. No data support ACV for aphthous ulcers or
autoimmune mucositis.
Clinical Recommendations & Future Directions
Primary herpetic gingivostomatitis
– initiate oral ACV within 72 h; consider
honey rinse adjunct in children (Grade B).
Recurrent labial/oral HSV
– ACV cream at prodrome; laser or ACV-
clobetasol nanofibre for rapid resolution (Grade B).
HSCT/chemotherapy patients
– prophylactic oral ACV 400 mg b.i.d. to reduce
oral mucositis and HSV reactivation (Grade A).
Research
priorities:
multi-centre
trials
standardising
time-to-full-
epithelialisation, head-to-head comparisons of carriers, and exploration of ACV in non-
HSV inflammatory ulcers.
Conclusions
Topical and locally delivered ACV remains safe and effective for HSV-related
oral lesions. Novel muco-adhesive carriers and combination regimens provide
clinically meaningful accelerations in healing. Adoption of harmonised trial outcomes
will enable future meta-analyses and refined guidelines.
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