Combination drug therapy as a strategy to improve the efficacy and safety of treatment of herpes simplex virus infections: potential risks and prospects

Cover Page

Cite item

Full Text

Abstract

Herpes simplex viruses (HSV) are extremely widespread pathogens that cause human infections of varying severity, from mild orofacial ulcerations of the skin and mucous membranes to life-threatening encephalitis and severe generalized forms of infection or recurrent herpetic corneal lesions leading to blindness. Standard treatment with acyclovir, penciclovir, or the corresponding prodrugs valacyclovir and famciclovir is usually sufficient to stop recurrent HSV infections. However, immunocompromised patients are of particular concern and often require long-term antiviral therapy. In such conditions, the risk of developing drug resistance, often cross-resistance increases significantly, since all basic antiherpetic drugs have a similar mechanism of action and affect the same drug target – viral DNA polymerase (DNA-pol). With the development of drug resistance, the effectiveness of treatment decreases, and it becomes necessary to switch to second-line drugs with severe side effects. Thus, it is necessary to develop new alternative treatment options. The creation of drugs aimed at a biotarget different from DNA-pol eliminates the risk of cross-resistance to acyclovir and related drugs, and their use in combination with traditional antiherpetic drugs can prevent or slow down the development of drug resistance in the virus. When combining drugs that affect the pathogen in different ways, it is important to maintain the therapeutic effect with the use of lower doses due to the synergistic nature of the interaction, which reduces the likelihood of developing unwanted side effects of drugs. The review presents current data on the state and possible prospects for the development of combination therapy for HSV infections, obtained as a result of searching the literature related to anti-herpetical therapy using the PubMed, Medline databases, RSCI, the international registry of clinical trials of the US National Institutes of Health.

About the authors

Valeriya L. Andronova

The N.F. Gamaleya Research Center of Epidemiology and Microbiology of the Russian Ministry of Health

Author for correspondence.
Email: andronova.vl@yandex.ru
ORCID iD: 0000-0002-2467-0282

PhD (Biol.), Head of Laboratory, Leading Researcher at the Laboratory of Molecular Pathogenesis of Chronic Viral Infections

Russian Federation, 123098, Moscow

Georgy A. Galegov

The N.F. Gamaleya Research Center of Epidemiology and Microbiology of the Russian Ministry of Health

Email: g.galegov@yandex.ru
ORCID iD: 0000-0001-6162-1650
SPIN-code: 4218-5350

D.Sci. (Biol.), Leading Researcher at the Laboratory of Molecular Pathogenesis of Chronic Viral Infections

Russian Federation, 123098, Moscow

References

  1. Menéndez-Arias L., Delgado R. Update and latest advances in antiretroviral therapy. Trends Pharmacol. Sci. 2022; 43(1): 16–29. https://doi.org/10.1016/j.tips.2021.10.004
  2. Sarrazin C. The importance of resistance to direct antiviral drugs in HCV infection in clinical practice. J. Hepatol. 2016; 64(2): 486–504. https://doi.org/10.1016/j.jhep.2015.09.011.
  3. Batool S., Chokkakula S., Song M.S. Influenza treatment: limitations of antiviral therapy and advantages of drug combination therapy. Microorganisms. 2023; 11(1): 183. https://doi.org/10.3390/microorganisms11010183.
  4. Yan D., Yan B. Viral target and metabolism-based rationale for combined use of recently authorized small molecule COVID-19 medicines: Molnupiravir, nirmatrelvir, and remdesivir. Fundam. Clin. Pharmacol. 2023; 37(4): 726–38. https://doi.org/10.1111/fcp.12889
  5. Sun W., He S., Martínez-Romero C., Kouznetsova J., Tawa G., Xu M., et al. Synergistic drug combination effectively blocks Ebola virus infection. Antiviral Res. 2017; 137: 165–72. https://doi.org/10.1016/j.antiviral.2016.11.017.
  6. Xu M., Lee E.M., Wen Z., Cheng Y., Huang W.K., Qian X., et al. Identification of small-molecule inhibitors of Zika virus infection and induced neural cell death via a drug repurposing screen. Nat. Med. 2016; 22(10): 1101–7. https://doi.org/10.1038/nm.4184
  7. Chou S., Ercolani R.J., Derakhchan K. Antiviral activity of maribavir in combination with other drugs active against human cytomegalovirus. Antivir. Res. 2018; 157: 128–33. https://doi.org/10.1016/j.antiviral.2018.07.013
  8. O’Brien M.S., Markovich K.C., Selleseth D., DeVita A.V., Sethna P., Gentry B.G. In vitro evaluation of current and novel antivirals in combination against human cytomegalovirus. Antiviral Res. 2018; 158: 255–63. https://doi.org/10.1016/j.antiviral.2018.08.015
  9. Wildum S., Zimmermann H., Lischka P. In vitro drug combination studies of Letermovir (AIC246, MK-8228) with approved anti-human cytomegalovirus (HCMV) and anti-HIV compounds in inhibition of HCMV and HIV replication. Antimicrob. Agents Chemother. 2015; 59(6): 3140–8. https://doi.org/10.1128/AAC.00114-15
  10. Tognarelli E.I., Palomino T.F., Corrales N., Bueno S.M., Kalergis A.M., González P.A. Herpes simplex virus evasion of early host antiviral responses. Front. Cell. Infect. Microbiol. 2019; 9: 127. https://doi.org/10.3389/fcimb.2019.00127
  11. van den Bogaart L., Lang B.M., Rossi S., Neofytos D., Walti L.N., Khanna N., et al. Central nervous system infections in solid organ transplant recipients: results from the Swiss transplant cohort study. J. Infect. 2022; 85(1): 1–7. https://doi.org/10.1016/j.jinf.2022.05.019
  12. Mancuso R., Sicurella M., Agostini S., Marconi P., Clerici M. Herpes simplex virus type 1 and Alzheimer’s disease: link and potential impact on treatment. Expert Rev. Anti Infect. Ther. 2019; 17(9): 715–31. https://doi.org/10.1080/14787210.2019.1656064
  13. Poole C.L., James S.H. Antiviral therapies for herpesviruses: current agents and new directions. Clin. Ther. 2018; 40(8): 1282–98. https://doi.org/10.1016/j.clinthera.2018.07.006
  14. Evans T.G., Bernstein D.I., Raborn G.W., Harmenberg J., Kowalski J., Spruance S.L. Double-blind, randomized, placebo-controlled study of topical 5% acyclovir-1% hydrocortisone cream (ME-609) for treatment of UV radiation-induced herpes labialis. Antimicrob. Agents Chemother. 2002; 46(6): 1870–4. https://doi.org/10.1128/aac.46.6.1870-1874.2002
  15. LeFlore S., Anderson P.L., Fletcher C.V. A risk-benefit evaluation of aciclovir for the treatment and prophylaxis of herpes simplex virus infections. Drug Saf. 2000; 23(2): 131–42. https://doi.org/10.2165/00002018-200023020-00004.
  16. Glasgow H.L., Zhu H., Xie H., Kenkel E.J., Lee C., Huang M.L., et al. Genotypic testing improves detection of antiviral resistance in human herpes simplex virus. J. Clin. Virol. 2023; 167: 105554. https://doi.org/10.1016/j.jcv.2023.105554
  17. Wang L.X., Takayama Ito M., Kinoshita-Yamaguchi H., Kakiuchi S., Suzutani T., Nakamichi K., et al. Characterization of DNA polymerase-associated acyclovir-resistant herpes simplex virus type 1: mutations, sensitivity to antiviral compounds, neurovirulence, and in-vivo sensitivity to treatment. Jpn J. Infect. Dis. 2013; 66(5): 404–10. https://doi.org/10.7883/yoken.66.404
  18. Duan R., de Vries R.D., Osterhaus A.D. Remeijer L., Verjans G.M. Acyclovir-resistant corneal HSV-1 isolates from patients with herpetic keratitis. J. Infect. Dis. 2008; 198(5): 659–63. https://doi.org/10.1086/590668.
  19. Frobert E., Burrel S., Ducastelle-Lepretre S., Billaud G., Ader F., Casalegno J.S., et al. Resistance of herpes simplex viruses to acyclovir: an update from a ten-year survey in France. Antiviral Res. 2014; 111: 36–41. https://doi.org/10.1016/j.antiviral.2014.08.013
  20. Ariza-Heredia E.J., Chemaly R.F., Shahani L.R., Jang Y., Champlin R.E., Mulanovich V.E. Delay of alternative antiviral therapy and poor outcomes of acyclovir-resistant herpes simplex virus infections in recipients of allogeneic stem cell transplant–a retrospective study. Transpl. Int. 2018; 31(6): 639–48. https://doi.org/10.1111/tri.13142
  21. Safrin S., Crumpacker C., Chatis P., Davis R., Hafner R., Rush J., et al. A controlled trial comparing foscarnet with vidarabine for acyclovir-resistant mucocutaneous herpes simplex in the acquired immunodeficiency syndrome. The AIDS Clinical Trials Group. N. Engl. J. Med. 1991; 325(8): 551–5. https://doi.org/10.1056/NEJM199108223250805
  22. Piret J., Boivin G. Antiviral drugs against herpesviruses. Adv. Exp. Med. Biol. 2021; 1322: 1–30. https://doi.org/10.1007/978-981-16-0267-2_1
  23. Anton-Vazquez V., Mehra V., Mbisa J.L., Bradshaw D., Basu T.N., Daly M.L., et al. Challenges of aciclovir-resistant HSV infection in allogeneic bone marrow transplant recipients. J. Clin. Virol. 2020; 128: 104421. https://doi.org/10.1016/j.jcv.2020.104421
  24. Schalkwijk H.H., Georgala A., Gillemot S., Temblador A., Topalis D., Wittnebel S., et al. A herpes simplex virus 1 DNA polymerase multidrug resistance mutation identified in a patient with immunodeficiency and confirmed by gene editing. J. Infect. Dis. 2023; 228(11): 1505–15. https://doi.org/10.1093/infdis/jiad184
  25. Khellaf L., Bouscarat F., Burrel S., Fidouh N., Hachon L., Bucau M., et al. Novel mutations in antiviral multiresistant HSV-2 genital lesion: A case report. J. Med. Virol. 2022; 94(12): 6122–6. https://doi.org/10.1002/jmv.28070
  26. Schalkwijk H.H., Gillemot S., Reynders M., Selleslag D., Andrei G., Snoeck R. Heterogeneity and viral replication fitness of HSV-1 clinical isolates with mutations in the thymidine kinase and DNA polymerase. J. Antimicrob. Chemother. 2022; 77(11): 3153–62. https://doi.org/10.1093/jac/dkac297
  27. Sutton D., Taylor J., Bacon T.H., Boydt M.R. Activity of penciclovir in combination with azido~hymidine, ganciclovir, acyclovir, foscarnet and human interferons against herpes simplex virus replication in cell culture. Antivir. Chem. Chemother. 1992; 3(2): 85-94. https://doi.org/10.1177/095632029200300203
  28. Gayretli Aydin Z.G., Tanir G., Genc Sel C., Tasci Yıldız Y., Aydin Teke T., Kaman A. Acyclovir Unresponsive Herpes Simplex Encephalitis in a child successfully treated with the addition of Foscarnet: Case report. Arch. Argent. Pediatr. 2019; 117(1): e47–51. https://doi.org/10.5546/aap.2019.eng.e47
  29. Sagnier S., Poli M., Debruxelles S., Renou P., Rouanet F., Sibon I. High-dose acyclovir combined with foscavir (foscarnet) in the management of severe herpes simplex virus meningoencephalitis. Rev. Neurol. (Paris). 2017; 173(4): 240–2. https://doi.org/10.1016/j.neurol.2017.03.006
  30. Bache M., Andrei G., Bindl L., Bofferding L., Bottu J., Géron C., et al. Antiviral drug-resistance typing reveals compartmentalization and dynamics of acyclovir-resistant Herpes Simplex Virus Type-2 (HSV-2) in a case of neonatal herpes. J. Pediatric Infect. Dis. Soc. 2014; 3(2): e24–7. https://doi.org/10.1093/jpids/pit045
  31. Yue Z., Shi J., Li H., Li H. Association between concomitant use of acyclovir or valacyclovir with NSAIDs and an increased risk of acute kidney injury: data mining of FDA adverse event reporting system. Biol. Pharm. Bull. 2018; 41(2): 158–62. https://doi.org/10.1248/bpb.b17-00547
  32. Heylen R., Miller R. Adverse effects and drug interactions of medications commonly used in the treatment of adult HIV positive patients. Genitourin. Med. 1996; 72(4): 237–46. https://doi.org/10.1136/sti.72.4.237
  33. Freitas V.R., Fraser-Smith E.B., Matthews T.R. Increased efficacy of ganciclovir in combination with foscarnet against cytomegalovirus and herpes simplex virus type 2 in vitro and in vivo. Antiviral Res. 1989; 12(4): 205–12. https://doi.org/10.1016/0166-3542(89)90030-2
  34. Tunkel A.R., Glaser C.A., Bloch K.C., Sejvar J.J., Marra C.M., Roos K.L., et al. The management of encephalitis: clinical practice guidelines by the infectious diseases society of America. Clin. Infect. Dis. 2008; 47(3): 303–27. https://doi.org/10.1086/589747.
  35. Mylonakis E., Kallas W.M., Fishman J.A. Combination antiviral therapy for ganciclovir-resistant cytomegalovirus infection in solid-organ transplant recipients. Clin. Infect. Dis. 2002; 34(10): 1337–41. https://doi.org/10.1086/340101
  36. Schinazi R.F., Nahmias A. Different in vitro effects of dual combinations of anti-herpes simplex virus compounds. Am. J. Med. 1982; 73(1A): 40–8. https://doi.org/10.1016/0002-9343(82)90061-4
  37. Topalis D., Gillemot S., Snoeck R., Andrei G. Distribution and effects of amino acid changes in drug-resistant α and β herpesviruses DNA polymerase. Nucleic Acids Res. 2016; 44(20): 9530–54. https://doi.org/10.1093/nar/gkw875
  38. Kakiuchi S., Nonoyama S., Wakamatsu H., Kogawa K., Wang L., Kinoshita-Yamaguchi H., et al. Neonatal herpes encephalitis caused by a virologically confirmed acyclovir-resistant herpes simplex virus 1 strain. J. Clin. Microbiol. 2013; 51(1): 356–9. https://doi.org/10.1128/jcm.02247-12
  39. Andronova V.L., Jasko M.V., Kukhanova M.K., Skoblov Yu.S., Deryabin P.G., Galegov G.A. Research of suppression of the herpes simplex virus reproduction with drug resistance by combination phosphite of acycloguanosine with some antiherpetic drugs. Voprosy virusologii. 2014; 59(6): 32–5. https://elibrary.ru/sxtdrj (in Russian)
  40. Pancheva S., Shishkov S., Ilieva D. Effect of combined acyclovir and ribavirin on experimental herpes simplex virus type 1 keratoconjunctivitis in rabbits. Acta Microbiol. Bulg. 1993; 29: 61–4.
  41. Neyts S.J., Andrei G., De Clercq E. The novel immunosuppressive agent mycophenolate mofetil markedly potentiates the antiherpesvirus activities of acyclovir, ganciclovir, and penciclovir in vitro and in vivo. Antimicrob. Agents Chemother. 1998; 42(2): 216–22. https://doi.org/10.1128/AAC.42.2.216
  42. Sergerie Y., Boivin G. Hydroxyurea enhances the activity of acyclovir and cidofovir against herpes simplex virus type 1 resistant strains harboring mutations in the thymidine kinase and/or the DNA polymerase genes. Antiviral Res. 2008; 77(1): 77–80. https://doi.org/10.1016/j.antiviral.2007.08.009
  43. Andronova V.L. Modern ethiotropic chemotherapy of herpesvirus infections: advances, new trends and perspectives. Alphaherpesviruses (Part II). Voprosy virusologii. 2018; 63(4): 149–59. https://doi.org/10.18821/0507-4088-2018-63-4-149-159 https://elibrary.ru/vlfuzb (in Russian)
  44. Lince K.C., De Mario V.K., Yang G.T., Tran R.T., Nguyen D.T., Sanderson J.N., et al. A systematic review of second-line treatments in antiviral resistant strains of HSV-1, HSV-2, and VZV. Cureus. 2023; 15(3): e35958. https://doi.org/10.7759/cureus.35958
  45. Kawashima M., Imafuku S., Fujio K., Komazaki H. Single-dose, patient-initiated amenamevir therapy for recurrent genital herpes: a phase 3, randomized, double-blind, placebo-controlled study. Open Forum Infect. Dis. 2022; 9(10): ofac494. https://doi.org/10.1093/ofid/ofac494
  46. Kawamura Y., Uchibori N., Arakawa T., Fujii T., Negishi S., Morikawa S., et al. Successful treatment of acyclovir-resistant herpes simplex virus infection with amenamevir in a patient who received umbilical cord blood transplantation for T-cell prolymphocytic leukemia. EJHaem. 2024; 5(3): 616–9. https://doi.org/10.1002/jha2.899
  47. Tayyar R., Ho D. Herpes simplex virus and varicella zoster virus infections in cancer patients. Viruses. 2023; 15(2): 439. https://doi.org/10.3390/v15020439.
  48. Wald A., Timmler B., Magaret A., Warren T., Tyring S., Johnston C., et al. Effect of pritelivir compared with valacyclovir on genital HSV-2 shedding in patients with frequent recurrences: a randomized clinical trial. JAMA. 2016; 316(23): 2495–503. https://doi.org/10.1001/jama.2016.18189
  49. Greeley Z.W., Giannasca N.J., Porter M.J., Margulies B.J. Acyclovir, cidofovir, and amenamevir have additive antiviral effects on herpes simplex virus type 1. Antiviral Res. 2020; 176: 104754. https://doi.org/10.1016/j.antiviral.2020.104754
  50. Chono K., Katsumata K., Suzuki H., Shiraki K. Synergistic activity of amenamevir (ASP2151) with nucleoside analogs against herpes simplex virus types 1 and 2 and varicella-zoster virus. Antiviral Res. 2013; 97(2): 154–60. https://doi.org/10.1016/j.antiviral.2012.12.006
  51. Schalkwijk H.H., Andrei G., Snoeck R. Combined use of pritelivir with acyclovir or foscarnet suppresses evolution of HSV-1 drug resistance. Virus Evol. 2024; 10(1): veae101. https://doi.org/10.1093/ve/veae101
  52. Quenelle D.C., Birkmann A., Goldner T., Pfaff T., Zimmermann H., Bonsmann S., et al. Efficacy of pritelivir and acyclovir in the treatment of herpes simplex virus infections in a mouse model of herpes simplex encephalitis. Antiviral Res. 2018; 149: 1–6. https://doi.org/10.1016/j.antiviral.2017.11.002
  53. Prichard M.N., Kern E.R., Hartline C.B., Lanier E.R., Quenelle D.C. CMX001 potentiates the efficacy of acyclovir in herpes simplex virus infections. Antimicrob. Agents Chemother. 2011; 55(10): 4728–34. https://doi.org/10.1128/AAC.00545-11
  54. Andronova V.L. Modern ethiotropic chemotherapy of human cytomegalovirus infection: clinical effectiveness, molecular mechanism of action, drug resistance, new trends and prospects. Part I. Voprosy virusologii. 2018; 63(5): 202–11. https://doi.org/10.18821/0507-4088-2018-63-5-202-211 https://elibrary.ru/lcidzi (in Russian)
  55. Marty F.M., Winston D.J., Chemaly R.F., Mullane K.M., Shore T.B., Papanicolaou G.A., et al. A randomized, double-blind, placebo-controlled phase 3 trial of oral Brincidofovir for cytomegalovirus prophylaxis in allogeneic hematopoietic cell transplantation. Biol. Blood Marrow Transplant. 2019; 25(2): 369–81. https://doi.org/10.1016/j.bbmt.2018.09.038
  56. Piret J., Boivin G. Antiviral resistance in herpes simplex virus and varicella-zoster virus infections: diagnosis and management. Curr. Opin. Infect. Dis. 2016; 29(6): 654–62. https://doi.org/10.1097/QCO.0000000000000288

Supplementary files

Supplementary Files
Action
1. JATS XML
Download
2. Supplementary
Download (375KB)
Indexing metadata

Copyright (c) 2025 Andronova V.L., Galegov G.A.

Creative Commons License
This work is licensed under a Creative Commons Attribution 4.0 International License.

Согласие на обработку персональных данных с помощью сервиса «Яндекс.Метрика»

1. Я (далее – «Пользователь» или «Субъект персональных данных»), осуществляя использование сайта https://journals.rcsi.science/ (далее – «Сайт»), подтверждая свою полную дееспособность даю согласие на обработку персональных данных с использованием средств автоматизации Оператору - федеральному государственному бюджетному учреждению «Российский центр научной информации» (РЦНИ), далее – «Оператор», расположенному по адресу: 119991, г. Москва, Ленинский просп., д.32А, со следующими условиями.

2. Категории обрабатываемых данных: файлы «cookies» (куки-файлы). Файлы «cookie» – это небольшой текстовый файл, который веб-сервер может хранить в браузере Пользователя. Данные файлы веб-сервер загружает на устройство Пользователя при посещении им Сайта. При каждом следующем посещении Пользователем Сайта «cookie» файлы отправляются на Сайт Оператора. Данные файлы позволяют Сайту распознавать устройство Пользователя. Содержимое такого файла может как относиться, так и не относиться к персональным данным, в зависимости от того, содержит ли такой файл персональные данные или содержит обезличенные технические данные.

3. Цель обработки персональных данных: анализ пользовательской активности с помощью сервиса «Яндекс.Метрика».

4. Категории субъектов персональных данных: все Пользователи Сайта, которые дали согласие на обработку файлов «cookie».

5. Способы обработки: сбор, запись, систематизация, накопление, хранение, уточнение (обновление, изменение), извлечение, использование, передача (доступ, предоставление), блокирование, удаление, уничтожение персональных данных.

6. Срок обработки и хранения: до получения от Субъекта персональных данных требования о прекращении обработки/отзыва согласия.

7. Способ отзыва: заявление об отзыве в письменном виде путём его направления на адрес электронной почты Оператора: info@rcsi.science или путем письменного обращения по юридическому адресу: 119991, г. Москва, Ленинский просп., д.32А

8. Субъект персональных данных вправе запретить своему оборудованию прием этих данных или ограничить прием этих данных. При отказе от получения таких данных или при ограничении приема данных некоторые функции Сайта могут работать некорректно. Субъект персональных данных обязуется сам настроить свое оборудование таким способом, чтобы оно обеспечивало адекватный его желаниям режим работы и уровень защиты данных файлов «cookie», Оператор не предоставляет технологических и правовых консультаций на темы подобного характера.

9. Порядок уничтожения персональных данных при достижении цели их обработки или при наступлении иных законных оснований определяется Оператором в соответствии с законодательством Российской Федерации.

10. Я согласен/согласна квалифицировать в качестве своей простой электронной подписи под настоящим Согласием и под Политикой обработки персональных данных выполнение мною следующего действия на сайте: https://journals.rcsi.science/ нажатие мною на интерфейсе с текстом: «Сайт использует сервис «Яндекс.Метрика» (который использует файлы «cookie») на элемент с текстом «Принять и продолжить».