Conventional therapy for genital herpesvirus and remission of HPV-related lesions: a case series
Infectious Agents and Cancer volume 18, Article number: 36 (2023)
This report covers the case of 7 women affected by pathologies related to genital Herpesvirus and Papillomavirus. They were referred to the gynaecology outpatient clinic for colposcopic examination, and received pharmacological antiviral treatment. The patients presented clinical signs of genital Herpesvirus infections in the cervix and vulva. Cervical lesions and condylomatosis, which are characteristic of Papillomavirus infections were also detected, and patients underwent cervical cancer screening. Patients received oral and topical treatment with Acyclovir or oral treatment with Valacyclovir. During weekly or biweekly gynaecological follow-up visits, patients showed different times of remission of genital Herpesvirus. During the antiviral treatments, the vulvar and cervical Papillomavirus lesions also showed complete resolution with restitutio ad integrum of the tissues, and no recurrence at follow-up visits. Herpesvirus and Papillomavirus infections are often associated in genital infections and, as sexual transmitted infections, share the same risk factors. In the cases presented, the observed remission of HPV-related pathologies during Acyclovir and Valaciclovir treatments may suggest that antivirals are also effective in the treatment of HPV lesions. The cases described could pave the way for further investigations and clinical studies.
The pathologies described in this report regard women who had been to the outpatient clinic of a specialist in obstetrics and gynaecology. Following colposcopic examination, patients showed clinical signs of genital herpesvirus type 2 (HHV-2) and Papillomavirus (HPV)-related lesions. The patients’ clinical data are summarised in Table 1, and the colposcopic images of the pathologies treated are shown in Fig. 1. Patient ID and age are reported in Table 1, in columns A and B. All patients had vulvar or cervical lesions caused by genital HHV-2 (column C), and underwent cervical cancer screening, including cytology by ThinPrep specimens, HPV testing and typing, and cervical biopsy in one case (ID 32). HPV-DNA test was performed only in case of cytology abnormalities. The HPV-related pathologies detected are listed in column D. Atypical squamous cells of undetermined significance (ASC-US) were observed in ID6 Pap-test, while low-grade squamous intraepithelial lesions (L-SIL) were observed in ID 17, 29 and 37 Pap-tests. Patient ID29’s HPV-DNA test was negative, while the other mentioned patients had HPV-DNA test positive for the high-risk (HR) HPV16. HR-HPV66 and low-risk (LR)-HPV42 genotypes were also detected in cervical specimens from patients ID6 and ID17, respectively. Patient ID32 showed a high-grade intraepithelial lesion which was found to be CIN2 on histological examination after biopsy (column D). Patients ID12 and ID25 showed no cell abnormalities or HPV infection in Pap smear of cervical cells. HPV-related genital condylomatosis was observed in all patients except ID37 (column E), and candidiasis was observed in patients ID6, ID17, ID25, ID29 and ID32 (column F). The colposcopy images of clinical signs (blisters) of HHV-2 in vulva (ID12, 17, 25, 32 and 37) or cervix (ID6, 25 and 29), the perineal and anal condylomatosis (ID32), the vulvar microcondylomatosis (ID6, 12, 17, 25 and 29), and the HPV-related cervical lesions (ID6, 17, 29, 32 and 37) are shown in Fig. 1.
Patients were treated with oral and topical standard doses of Acyclovir (ACV), or its derivate Valacyclovir (VCV), which has a higher oral bioavailability . ACV and VCV are the gold standard drugs for the treatment of HHV-1 and HHV-2 infections .
For each patient, systemic treatment with ACV or VCV, alone or in combination with topical treatment, was recommended for different periods in relation to the severity of the case and the patient’s health conditions, as deduced from the Summary of Product Characteristics (SPC) in force in Italy. A biweekly gynaecological visit, including a colposcopy examination when necessary, was scheduled as a follow-up of HPV-derived pathologies. Instead, patient ID32 with CIN2 diagnosis received a weekly visit in the first period of therapy. In Table 1, column G, the oral antiviral dosage is indicated for each patient. The topical administration of 5% ACV cream was suggested to the patients with HHV-2 vulvar lesions with the exception of the ID 12 patient who was affected by vulvodynia. In cases of candidiasis, the patients were treated topically with 1-week cycles of 1% Econazole nitrate (Pevaryl). The patients received instructions regarding daily personal hygiene (Additional file 1).
Observations at follow-up
The specialist offered to patients with multiple infections a gynaecological visit including a colposcopic examination, if necessary, every 1–2 weeks. Through these follow-ups, the specialist was able to balance the drug treatment period and observe disease improvements, including the remission of HPV-related cervical lesions and vulvar condylomatosis. During the antiviral treatment, the follow up gynaecological visits revealed not only the healing of the herpetic lesions, but also the remission of the cervical and vulvar HPV-related lesions.
In HHV-infected cells, for antivirals to function, they must be phosphorylated by viral thymidine kinase (HHV-TK) to inhibit DNA synthesis and viral replication by HHV-DNA polymerase, for which ACV has a high affinity . However, it has been shown that cellular thymidine kinase can replace viral kinases , and ACV also showed inhibitory activity against cellular DNA Polymerases [5, 6]. Importantly, an in vitro study showed that the ACV treatment of HPV18-transformed HeLa cell line induced growth arrest, cell proliferation inhibition, and reduced cell survival with the formation of micronuclei . Furthermore, the efficacy of ACV has also been demonstrated by intralesional administration in cutaneous warts [8, 9], as well as by postoperative therapy in Recurrent Respiratory Papillomatosis , both HPV-related pathologies. Two clinical trials on the efficacy of ACV against plantar warts are currently ongoing (NCT05429151; NCT05324904).
To our knowledge, these are the first clinical observations on the possible efficacy of ACV on HPV-related anogenital lesions. Genital HHV infections have increased enormously in recent years , and the possible efficacy of ACV also on HPV-related clinical manifestations could have an impact on the high epidemiological burden of anogenital HPVs in countries where HPV vaccination is not widespread [12, 13].
Availability of data and materials
Anonymous patient records are available for consultation upon specific request and in compliance with the laws in force in Italy.
Majewska A, Mlynarczyk-Bonikowska B. 40 years after the registration of acyclovir: Do we need new anti-herpetic drugs? Int J Mol Sci. 2022;23(7).
WHO. WHO Guidelines for the Treatment of Genital Herpes simplex virus. WHO Libr. 2016;8(4):207–11.
De Clercq E, Li G. Approved antiviral drugs over the past 50 years. Clin Microbiol Rev. 2016;29(3):695–747.
Chen S-H, Cook WJ, Grove KL, Coen DM. Human thymidine kinase can functionally replace herpes simplex virus type 1 thymidine kinase for viral replication in mouse sensory ganglia and reactivation from latency upon explant. J Virol. 1998;72(8):6710–5.
Clair St. MH, Furman PA, Lubbers CM, Elion GB. Inhibition of cellular α and virally induced deoxyribonucleic acid polymerases by the triphosphate of acyclovir. Antimicrob Agents Chemother. 1980;18(5):741–5.
Ilsley DD, Lee SH, Miller WH, Kuchta RD. Acyclic guanosine analogs inhibit DNA polymerases α, δ, and ε with very different potencies and have unique mechanisms of action. Biochemistry. 1995;34(8):2504–10.
Jagetia GC, Aruna R. Effect of various concentrations of acyclovir on cell survival and micronuclei induction on cultured HeLa cells. Mutat Res Genet Toxicol Environ Mutagen. 1999;446(2):155–65.
Elsayed A, Nassar A, Marei A, Hoseiny HAM, Alakad R. Intralesional acyclovir: a potential therapeutic option for cutaneous warts. J Cutan Med Surg. 2022;26(1):25–30.
Bagwell A, Loy A, McFarland MS, Tessmer-Neubauer A. Oral acyclovir in the treatment of verruca. J Drugs Dermatol. 2016;15(2):237–8.
Mitra S, Das A, Ghosh D, Sengupta A. Postoperative systemic acyclovir in juvenile-onset recurrent respiratory papillomatosis: the outcome. Ear Nose Throat J. 2019;98(1):28–31.
Looker KJ, Johnston C, Welton NJ, James C, Vickerman P, Turner KME, et al. The global and regional burden of genital ulcer disease due to herpes simplex virus: a natural history modelling study. BMJ Glob Heal. 2020;5(3):1–15.
Kombe Kombe AJ, Li B, Zahid A, Mengist HM, Bounda GA, Zhou Y, et al. Epidemiology and burden of human papillomavirus and related diseases, molecular pathogenesis, and vaccine evaluation. Front Public Health. 2021;8(January):1–19.
Spayne J, Hesketh T. Estimate of global human papillomavirus vaccination coverage: analysis of country-level indicators. BMJ Open. 2021;11(9).
The authors are grateful to Dr Guglielmina Davide for her support and encouragement, to Mr Roberto Giuseppetti and to Mr. Fabio Maria Fanali for computer artwork and patient archive management.
The authors, who are personnel of the Istituto Superiore di Sanità, are alone responsible for the views expressed in this article and they do not necessarily represent the decisions, policy, or views of Istituto Superiore di Sanità.
Ethics approval and consent to participate
The reported observations in this paper derived from MB’s clinical practice. Patients voluntarily visited MB's outpatient clinic for conventional gynaecological treatment and gave their consent to use their medical records for scientific purpose.
Consent for publication
The authors have no competing interests.
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
About this article
Cite this article
Balestrieri, M., Carnovale-Scalzo, C., Garbuglia, A.R. et al. Conventional therapy for genital herpesvirus and remission of HPV-related lesions: a case series. Infect Agents Cancer 18, 36 (2023). https://doi.org/10.1186/s13027-023-00511-0