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Expert Opinion on Investigational Drugs Volume 24, 2015 - Issue 12
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Reviews

An overview of early investigational drugs for the treatment of human papilloma virus infection and associated dysplasia

Lynne HampsonViral Oncology Laboratories, Research Floor, St Mary’s Hospital, University of Manchester, ManchesterM13 9WL, UK
,
Pierre Martin-HirschDepartment of Obstetrics and Gynaecology, Royal Preston Hospital, PrestonPR2 9HT, UK
&
Ian N HampsonViral Oncology Laboratories, Research Floor, St Mary’s Hospital, University of Manchester, ManchesterM13 9WL, UKCorrespondence[email protected]
Pages 1529-1537 | Published online: 12 Oct 2015

Bibliography

  • Bosch FX, Lorincz A, Munoz N, et al. The causal relation between human papillomavirus and cervical cancer. J Clin Pathol. 2002;55(4):244–265.
  • Zur Hausen H. Papillomavirus infections–a major cause of human cancers. Biochim Biophys Acta. 1996;1288(2):F55–78.
  • Walboomers JM, Jacobs MV, Manos MM, et al. Human papillomavirus is a necessary cause of invasive cervical cancer worldwide. J Pathol. 1999;189(1):12–19.
  • Parkin DM, Pisani P, Ferlay J. Estimates of the worldwide incidence of 25 major cancers in 1990. Int J Cancer J Int Du Cancer. 1999;80(6):827–841.
  • Temmerman M, Tyndall MW, Kidula N, et al. Risk factors for human papillomavirus and cervical precancerous lesions, and the role of concurrent HIV-1 infection. Int J Gynaecol Obstet. 1999;65(2):171–181.
  • Lindeque BG. Management of cervical premalignant lesions. Best Pract Res Clin Obstet Gynaecol. 2005;19(4):545–561.
  • Sankaranarayanan R, Nene BM, Shastri SS, et al. HPV screening for cervical cancer in rural India. N Engl J Med 2009;360(14):1385–1394
  • Martin-Hirsch PL, Paraskevaidis E, Kitchener H. Surgery for cervical intraepithelial neoplasia. Cochrane Database Syst Rev. 2000;2:CD001318.
  • Prendiville W, Cullimore J, Norman S. Large loop excision of the transformation zone (LLETZ). A new method of management for women with cervical intraepithelial neoplasia. Br J Obstet Gynaecol. 1989;96(9):1054–1060.
  • Founta C, Arbyn M, Valasoulis G, et al. Proportion of excision and cervical healing after large loop excision of the transformation zone for cervical intraepithelial neoplasia. BJOG. 2010;117(12):1468–1474.
  • Kyrgiou M, Koliopoulos G, Martin-Hirsch P, et al. Obstetric outcomes after conservative treatment for intraepithelial or early invasive cervical lesions: systematic review and meta-analysis. Lancet. 2006;367(9509):489–498
  • Sankaranarayanan R, Esmy PO, Rajkumar R, et al. Effect of visual screening on cervical cancer incidence and mortality in Tamil Nadu, India: a cluster-randomised trial. Lancet. 2007;370(9585):398–406
  • Wang JW, Roden RB. Virus-like particles for the prevention of human papillomavirus-associated malignancies. Expert Rev Vaccines. 2013;12(2):129–141.
  • Chatterjee A. The next generation of HPV vaccines: nonavalent vaccine V503 on the horizon. Expert Rev Vaccines. 2014;13(11):1279–1290.
  • Jeronimo J, Bansil P, Lim J, et al. A multicountry evaluation of care HPV testing, visual inspection with acetic acid, and Papanicolaou testing for the detection of cervical cancer. Int J Gynecol Cancer. 2014;24(3):576–585.

* Evaluation of the low-cost self-sampled careHPV test

* Comparison of pharmacotherapies used to treat of HPV-related disease in 2004

  • Ramirez-Fort MK, Au SC, Javed SA, et al. Management of cutaneous human papillomavirus infection: pharmacotherapies. Curr Probl Dermatol. 2014;45:175–185.
  • Tao XH, Guan Y, Shao D, et al. Efficacy and safety of photodynamic therapy for cervical intraepithelial neoplasia: a systemic review. Photodiagnosis Photodyn Ther. 2014;11(2):104–112

* A small study showing good efficacy of PDT for the treatment of CIN

  • Hillemanns P, Garcia F, Petry KU, et al. A randomized study of hexaminolevulinate photodynamic therapy in patients with cervical intraepithelial neoplasia 1/2. Am J Obstet Gynecol. 2015;212(4):465 e1–7.
  • Clamp PJ, Saunders MW. Systematic review of intralesional cidofovir dosing regimens in the treatment of recurrent respiratory papillomatosis. Int J Pediatr Otorhinolaryngol. 2013;77(3):323–328.
  • Snoeck R, Noel JC, Muller C, et al. Cidofovir, a new approach for the treatment of cervix intraepithelial neoplasia grade III (CIN III). J Med Virol. 2000;60(2):205–209.
  • Van Pachterbeke C, Bucella D, Rozenberg S, et al. Topical treatment of CIN 2+ by cidofovir: results of a phase II, double-blind, prospective, placebo-controlled study. Gynecol Oncol. 2009;115(1):69–74.

* Demonstrates 60% clearance of abnormal CIN lesions treated with cidofovir

  • De Schutter T, Andrei G, Topalis D, et al. Cidofovir selectivity is based on the different response of normal and cancer cells to DNA damage. BMC Med Genomics. 2013;6:18.

* Toxicity of cidofovir in HPV-positive cells depends on their reduced DNA repair capacity

  • McElhiney LFPR. Topical cidofovir for treatment of resistant viral infections. Int J Pharm Compd. 2006;10(5):324–328.
  • Soma MA, Albert DM. Cidofovir: to use or not to use? Curr Opin Otolaryngol Head Neck Surg. 2008;16(1):86–90.

* Describes perspectives on safety issues surrounding the off-licence use of cidofovir

  • Slade HB, Owens ML, Tomai MA, et al. Imiquimod 5% cream (Aldara). Expert Opin Investig Drugs. 1998;7(3):437–449.
  • Grillo-Ardila CF, Angel-Muller E, Salazar-Diaz LC, et al. Imiquimod for anogenital warts in non-immunocompromised adults. Cochrane Database Syst Rev. 2014;11(CD010389). doi:10.1002/14651858.CD010389.pub2.
  • Lin CT, Qiu JT, Wang CJ, et al. Topical imiquimod treatment for human papillomavirus infection in patients with and without cervical/vaginal intraepithelial neoplasia. Taiwan J Obstet Gynecol. 2012;51(4):533–538.
  • Chen FP. Efficacy of imiquimod 5% cream for persistent human papillomavirus in genital intraepithelial neoplasm. Taiwan J Obstet Gynecol. 2013;52(4):475–478.
  • Pachman DR, Barton DL, Clayton AC, et al. Randomized clinical trial of imiquimod: an adjunct to treating cervical dysplasia. Am J Obstet Gynecol. 2012;206(1):42 e1–7.

* Shows imiquimod has equivalent efficacy to surgery for the treatment of CIN but has worse side effects

  • Tristram A, Hurt CN, Madden T, et al. Activity, safety, and feasibility of cidofovir and imiquimod for treatment of vulval intraepithelial neoplasia (RT(3)VIN): a multicentre, open-label, randomised, phase 2 trial. Lancet Oncol. 2014;15(12):1361–1368.

* Illustrates the issue of patient non-complinace associated with side effects of imiquimod

  • Rahangdale L, Lippmann QK, Garcia K, et al. Topical 5-fluorouracil for treatment of cervical intraepithelial neoplasia 2: a randomized controlled trial. Am J Obstet Gynecol. 2013;210(4):314
  • Gamelin E, Boisdron-Celle M, Guerin-Meyer V, et al. Correlation between uracil and dihydrouracil plasma ratio, fluorouracil (5-FU) pharmacokinetic parameters, and tolerance in patients with advanced colorectal cancer: a potential interest for predicting 5-FU toxicity and determining optimal 5-FU dosage. J Clin Oncol. 1999;17(4):1105.
  • Chakalova G, Ganchev G. Local administration of interferon-alpha in cases of cervical intraepithelial neoplasia associated with human papillomavirus infection. J Buon. 2004;9(4):399–402.

* Only study reporting the use of direct intralesional injection of interferon-α as treatment for CIN

  • King M, Kumar P, Michel D, et al. In vivo sustained dermal delivery and pharmacokinetics of interferon alpha in biphasic vesicles after topical application. Eur J Pharm Biopharm. 2013;84(3):532–539.
  • Rosales R, Rosales C. Immune therapy for human papillomaviruses-related cancers. World J Clin Oncol. 2014;5(5):1002–1019.

** Very thorough review of the current status of immmune therapies for HPV-related disease

  • Corona Gutierrez CM, Tinoco A, Navarro T, et al. Therapeutic vaccination with MVA E2 can eliminate precancerous lesions (CIN 1, CIN 2, and CIN 3) associated with infection by oncogenic human papillomavirus. Hum Gene Ther. 2004;15(5):421–431.

* Shows the potential of vaccinia virus-based therapeutic vaccine MVA-2 for the treatment of CIN

  • Rosales R, Lopez-Contreras M, Rosales C, et al. Regression of human papillomavirus intraepithelial lesions is induced by MVA E2 therapeutic vaccine. Hum Gene Ther. 2014;25(12):1035–1049.

* Larger study confirming the activity of the MVA-2 against a variety of HPV-related pathologies

  • Verheust C, Goossens M, Pauwels K, et al. Biosafety aspects of modified vaccinia virus Ankara (MVA)-based vectors used for gene therapy or vaccination. Vaccine 2012;30(16):2623–2632
  • Bagarazzi ML, Yan J, Morrow MP, et al. Immunotherapy against HPV16/18 generates potent TH1 and cytotoxic cellular immune responses. Sci Transl Med. 2012;4(155):155ra38

* Shows early results on activity of the DNA-based therapeutic HPV vaccine VGX-3100

  • Kumar S, Jena L, Sahoo M, et al. In Silico docking to explicate interface between plant-originated inhibitors and E6 oncogenic protein of highly threatening human papillomavirus 18. Genomics Inform. 2015;13(2):60–67.
  • Palasap A, Limpaiboon T, Boonsiri P, et al. Cytotoxic effects of Phytophenolics from Caesalpinia mimosoides Lamk on cervical carcinoma cell lines through an apoptotic pathway. Asian Pac J Cancer Prev. 2014; 15(1): 449–454.
  • Mondal A, Chatterji U. Artemisinin represses telomerase subunits and induces apoptosis in HPV-39 infected human cervical cancer cells. J Cell Biochem. 2015;116(9):1968–1981.
  • Goodrich SK, Schlegel CR, Wang G, et al. Use of artemisinin and its derivatives to treat HPV-infected/transformed cells and cervical cancer: a review. Future Oncol. 2014;10(4):647–654.
  • Jansen FH, Adoubi I, DE Chodder T, et al. First study of oral Artenimol-R in advanced cervical cancer: clinical benefit, tolerability and tumor markers. Anticancer Res. 2011;31(12):4417–4422.
  • Munagala R, Kausar H, Munjal C, et al. Withaferin A induces p53-dependent apoptosis by repression of HPV oncogenes and upregulation of tumor suppressor proteins in human cervical cancer cells. Carcinogenesis. 2011;32(11):1697–1705.
  • Garcia-Zepeda SP, Garcia-Villa E, Diaz-Chavez J, et al. Resveratrol induces cell death in cervical cancer cells through apoptosis and autophagy. Eur J Cancer Prev. 2013;22(6):577–584.
  • Garcia FA, Cornelison T, Nuno T, et al. Results of a phase II randomized, double-blind, placebo-controlled trial of Polyphenon E in women with persistent high-risk HPV infection and low-grade cervical intraepithelial neoplasia. Gynecol Oncol. 2014;132(2):377–382.
  • Yim EK, Lee MJ, Lee KH, et al. Antiproliferative and antiviral mechanisms of ursolic acid and dexamethasone in cervical carcinoma cell lines. Int J Gynecol Cancer. 2006;16(6):2023–2031.
  • Saha SK, Khuda-Bukhsh AR. Berberine alters epigenetic modifications, disrupts microtubule network, and modulates HPV-18 E6-E7 oncoproteins by targeting p53 in cervical cancer cell HeLa: a mechanistic study including molecular docking. Eur J Pharmacol. 2014;744:132–146.
  • Lee HG, Yu KA, Oh WK, et al. Inhibitory effect of jaceosidin isolated from Artemisiaargyi on the function of E6 and E7 oncoproteins of HPV 16. J Ethnopharmacol. 2005;98(3):339–343
  • Basu P, Dutta S, Begum R, et al. Clearance of cervical human papillomavirus infection by topical application of curcumin and curcumin containing polyherbal cream: a phase II randomized controlled study. Asian Pac J Cancer Prev. 2013; 14(10): 5753–5759.

* Clinical trial of curcumin as a treatment for HPV infection suggests modest activity

* Illustrates the off-target effects of HIV protease inhibitors

  • Piccinini M, Mostert M, Rinaudo MT. Proteasomes as drug targets. Curr Drug Targets. 2003;4(8):657–671.
  • Piccinini M, Rinaudo MT, Anselmino A, et al. The HIV protease inhibitors nelfinavir and saquinavir, but not a variety of HIV reverse transcriptase inhibitors, adversely affect human proteasome function. Antivir Ther. 2005; 10(2): 215–223.

* Illustrates the off-target effects of HIV protease inhibitors

  • Banks L, Pim D, Thomas M. Viruses and the 26S proteasome: hacking into destruction. Trends Biochem Sci. 2003;28(8):452–459.
  • Hampson L, Kitchener HC, Hampson IN. Specific HIV protease inhibitors inhibit the ability of HPV16 E6 to degrade p53 and selectively kill E6-dependent cervical carcinoma cells in vitro. Antivir Ther. 2006;11(6):813–825.

** First preclinical report of the activity of HIV protease inhibitors against HPV

  • Kwara A, Delong A, Rezk N, et al. Antiretroviral drug concentrations and HIV RNA in the genital tract of HIV-infected women receiving long-term highly active antiretroviral therapy. Clin Infect Dis. 2008;46(5):719–725
  • Lahiri CD, Dugan KB, Xie X, et al. Oral lopinavir use and human papillomavirus infection in HIV-positive women. J Acquir Immune Defic Syndr. 2015;70(2):e63–e66.

* Provides evidence that the concentration of lopinavir produced by oral administration is insufficient for anti-HPV activity

  • Batman G, Oliver AW, Zehbe I, et al. Lopinavir up-regulates expression of the antiviral protein ribonuclease L in human papillomavirus-positive cervical carcinoma cells. Antivir Ther. 2011; 16(4): 515–525.

** Describes information on the mode of action of lopinavir against HPV and the concentration required for this effect in vitro

  • Bernstein WB, Dennis PA. Repositioning HIV protease inhibitors as cancer therapeutics. Curr Opin HIV AIDS. 2008;3(6):666–675.
  • Chow WA, Jiang C, Guan M. Anti-HIV drugs for cancer therapeutics: back to the future? Lancet Oncol. 2009;10(1):61–71.
  • Batman G, Hampson L, Hampson IN. Lessons from repurposing HIV drugs: a prospective novel strategy for drug design. Future Virol. 2011;6(9):1021–1023.
  • Bruning A, Gingelmaier A, Friese K, et al. New prospects for nelfinavir in non-HIV-related diseases. Curr Mol Pharmacol. 2010;3(2):91–97.
  • Hampson L, Oliver AW, Hampson IN. Using HIV drugs to target human papilloma virus. Expert Rev Anti Infect Ther. 2014;12(9):1021–1023.

* Speculates on prospective use and rationale underlying the off-target effects of HIV protease inhibitors against HPV

  • Shchukina VN, Loginova S, Borisevich SV, et al. Experience with empirical treatment of severe acute respiratory syndrome due to coronavirus, genotype IV. Antibiot Khimioter. 2011; 56(7–8): 42–46.

* Reports off-target activity of lopinavir against SARS virus

  • De Wilde AH, Jochmans D, Posthuma CC, et al. Screening of an FDA-approved compound library identifies four small-molecule inhibitors of Middle East respiratory syndrome coronavirus replication in cell culture. Antimicrob Agents Chemother. 2014;58(8):4875–4884.

* Identifies lopinavir as having activity against MERS virus in vitro

  • Chan JF, Lau SK, To KK, et al. Middle East respiratory syndrome coronavirus: another zoonotic betacoronavirus causing SARS-like disease. Clin Microbiol Rev. 2015;28(2):465–522.
  • Barillari G, Iovane A, Bacigalupo I, et al. Ritonavir or saquinavir impairs the invasion of cervical intraepithelial neoplasia cells via a reduction of MMP expression and activity. Aids. 2012;26(8):909–919
  • Lucci. A phase II single-arm intervention trial of nelfinavir in patients with grade 2/3 or 3 cervical intraepithelial neoplasia. 2013. Available from: https://clinicaltrials.gov/ct2/show/NCT01925378

** Clinical trial of oral nelfinavir as a treatment for CIN – not yet reported

** Proof-of-concept clinical trial of self-applied topical Kaletra (Lopimune) as a treatment for CIN2/3 – manuscript currently under revision

  • Sargent A, Bailey A, Almonte M, et al. Prevalence of type-specific HPV infection by age and grade of cervical cytology: data from the ARTISTIC trial. Br J Cancer. 2008;98(10):1704–1709
  • Pasley MV, Martinez M, Hermes A, et al. Safety and efficacy of lopinavir/ritonavir during pregnancy: a systematic review. AIDS Rev. 2013;15(1):38–48.

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