Could the human papillomavirus vaccine prevent recurrence of ano-genital warts?: a systematic review and meta-analysis

Abstract

Human papillomavirus (HPV) is the most prevalent sexually transmitted infection worldwide and ano-genital warts (AGWs) are highly infectious. This virus is transmitted through sexual, anal, or oral contact as well as skin-to-skin contacts. Treatment for this condition has significant morbidity and it can be frustrating in certain cases. The HPV vaccination has been demonstrated as a promising strategy of secondary prevention in HPV-related diseases such as head and neck cancers, cervical diseases, and recurrent respiratory papillomatosis. Regarding AGWs, it is unclear whether vaccination can provide analogous clinical benefit. The aim of this work is to systematically review the literature regarding HPV vaccination for secondary disease prevention after treatment of AGWs. From October to December 2018, a systematic search for clinical trials was conducted in five databases: PubMed, MEDLINE, EMBASE, Cochrane, and clinicaltrials.gov using a combination of the following descriptors: ‘gardasil’ OR ‘cervarix’ OR ‘nine-valent’ OR ‘9-valent’ OR ‘vaccine’ AND ‘recurrence’ OR ‘relapse’ AND ‘hpv’ OR ‘papillomavirus’ AND ‘warts’ OR ‘condyloma.’ Data were synthetized and entered in the Review Manager software (RevMan 5.3.5) to perform the meta-analysis. The search yielded 824 potentially relevant studies. Two studies fulfilled the eligibility criteria involving 656 participants. The meta-analysis estimated the rate of recurrence of AGWs was similar between the vaccine group and the control group. The overall effect estimate was 1.02 (0.75–1.38). This is the first meta-analysis exploring the effect of HPV vaccine in preventing the relapse of AGWs. These results suggest that HPV vaccination does not provide secondary benefit in patients with previous AGWs. However, these results cannot be generalized due to the scarce number of RCTs currently available in the literature. The outcomes from future randomized controlled trials (RCTs) are warranted to further clarify the precise effect of the vaccine.

Keywords

Human papillomavirus vaccine secondary prevention condylomas ano-genital warts

Introduction

Human papillomavirus (HPV) is the most prevalent sexually transmitted infection worldwide and ano-genital warts (AGWs) are highly infectious. This virus is transmitted through sexual, anal, or oral contact as well as skin-to-skin contacts.¹ Based on a systematic review, global incidence of AGWs ranges from 160 to 289 cases per 100,000 person-years.² Most AGWs are asymptomatic and self-cleared in a period of two years.³ In rare cases, AGWs can be associated with malignant lesions, namely Buschke–Lowenstein tumors. Treatment for this condition has significant morbidity and it can be frustrating in certain cases. There exist several available approaches such as antimitotics (podofilox), immune enhancers (imiquimod), protein coagulators (trichloroacetic acid), cryotherapy, and surgical removal; however, the main limitation of these therapies is that it is unclear whether they reduce future HPV transmission or infectivity.⁴ In fact, AGWs often recur after initial remission and require repeated treatments.^5–7 This causes psychosocial distress to patients and patients’ parents.⁸,⁹

AGWs result from persistent infection with low-risk HPV types. HPV types 6 and 11 account for almost 100% of AGWs, but 20–50% represents co-infections with low- and high-risk HPV types.¹⁰

Currently, there exist three vaccines approved by the FDA: the bivalent vaccine which protects against HPV type 16 and 18; the tetravalent vaccine, which protects against HPV type 6, 11, 16, and 18; and the 9-valent vaccine which exerts protection against HPV type 6, 11, 16, 18, 31, 33, 45, 52, and 58. The high efficacy of these vaccines is thought to be based on the induction of neutralizing antibodies that bind to virions and protect human cells.¹¹

The Advisory Committee on Immunization Practices recommends the immunization prior to sexual debut because the immunologic response is higher. The vaccination schedule in this population depends on age at initial vaccination: ages from 9 to 14 years require a two-dose series at 0, 6–12 months (minimum interval of five months), while in ages equal to or older than 15 years a three-dose series at 0, 1–2 months, and 6 months is given.¹²

Effectively, the implementation of HPV vaccines on these vaccination programs has produced a wide benefit for public health and the incidences of HPV infections, AGWs, and HPV-related precancer cervical lesions have dramatically decreased.^13–18 Furthermore, previous vaccination among women who underwent treatment for HPV-related cervical disease significantly decreased the incidence of subsequent HPV-related disease, including high grade disease.⁴,¹⁹ A similar effect was observed in a non-randomized study of men who have sex with men treated for high grade anal intraepithelial neoplasia.²⁰ As with subjects at ages equal to or older than 15 years, the suggested vaccination program for subjects with previous HPV infections is a three-dose series at 0, 1–2 months, and 6 months.⁴,¹⁹,²⁰ Therefore, the HPV vaccine-induced protection seems to apply not just to the general population of adolescent and young adult women, but to older women and men who have been previously exposed to HPV-related disease at the time of vaccination.

Regarding AGWs, it is unclear whether vaccination can provide analogous clinical benefit. Given the burden of this sexually transmitted infection and its high rate of recurrence, we designed a systematic review and meta-analysis with the aim to assess whether a new approach with the HPV vaccine provides a positive response in preventing relapse in patients with previous AGWs.

Material and method

Literature search

The protocol for this review was defined a priori and registered online in the PROSPERO international prospective register of systematic reviews (https://www.crd.york.ac.uk). The register ID was PROSPERO CRD42019133812. From October to December 2018, we carried out a wide and comprehensive search of literature from five databases: PubMed, MEDLINE, EMBASE, Cochrane, and clinicaltrials.gov using a combination of the following descriptors: ‘gardasil’ OR ‘cervarix’ OR ‘nine-valent’ OR ‘9-valent’ OR ‘vaccine’ AND ‘recurrence’ OR ‘relapse’ AND ‘hpv’ OR ‘papillomavirus’ AND ‘warts’ OR ‘condyloma.’ The Preferred Reporting Items for Systemic Reviews and Meta-analyses recommendations were followed for the preparation of this report.²¹

Only RCTs in English language involving patients diagnosed with AGWs were included. Exclusion criteria included research aimed to evaluate the prophylactic effect of the vaccine against warts and other HPV-related diseases (i.e. primary prevention) and research on subjects with already developed cervical intraepithelial disease as well as oral and respiratory tract papillomatosis and anal intraepithelial neoplasia. Institutional review board approval was not required for this review.

Outcomes

The primary outcomes of the analysis were as follows: (1) Proportion of patients achieving a complete clinical clearance of AGWs and (2) proportion of patients showing recurrence of the AGWs after vaccination.

Search strategy

The search strategy was conducted from 1990 until December 2018. Titles and abstracts of all retrieved articles were screened. Then, when potential eligibility for the review was detected, the full text was screened and data were extracted. The flowchart of the search is shown in Figure 1.

Figure 1.

Flow diagram of the eligibility proceeding in the systematic review and meta-analysis.

Data analysis and synthesis

Data were synthetized and entered in the Review Manager software (RevMan 5.3.5) to perform the meta-analysis. To evaluate the efficacy of the vaccine in the recurrence of AGWs, dichotomous data in the vaccine and control groups were extracted from each study and inserted into a contingency table with subsequent determination of the relative risk to obtain a summarized overall estimation. We examined heterogeneity across studies using I² and χ² statistics. I² values less than 50% represent low heterogeneity, between 50 and 75% substantial heterogeneity, and more than 75% high heterogeneity. The p value associated with the Chi square statistics represents the statistical significance of heterogeneity.²² When a significant heterogeneity existed across the included studies (I²> 50%), a random-effects model was used for the analysis, otherwise, the fixed-effects model was used. In addition, we used the Egger funnel plot to assess possible publication bias.

Results

Our search yielded 828 potentially relevant studies. After screening the title and abstract, 105 records underwent full-text review. After the full-text review, 11 records were assessed for eligibility criteria. The removal of duplicated and excluded records yielded two RCTs involving 656 participants to be included in the meta-analysis.²³,²⁴ The complete flowchart of the systematic search is depicted in Figure 1.

One of these RCTs was conducted in Turkey in 171 heterosexual men with a mean age of 34.05 ± 7.61 who were vaccinated with the 4-valent vaccine at 0, 2, and 6 months and followed up for 12 months.²³ The other RCT was an international, multicenter research including 485 women aged between 15 and 26 years who received the same vaccine with the same schedule and followed up for 42 months.²⁴

In the Turkish study, 91 out of 171 men (53%) were vaccinated. In this cohort, AGW recurrence was observed in 45 subjects (49.45%), while in the unvaccinated cohort of 80 men, the AGW was observed in 35 subjects (43.75%). The per-protocol analysis did not find significant difference in both groups either in the uni- or multi-variant analyses.

In the multicenter study, 134 out of 485 women (28%) were vaccinated. In this cohort, AGW recurrence was observed in ten subjects (7.5%), while in the unvaccinated cohort of 351 women, the AGW was observed in 33 subjects (9.4%). The intention-to-treat analysis revealed non-statistical differences between vaccinated and unvaccinated women.

The meta-analysis merging these two studies estimated the rate of AGW recurrence was similar between the vaccine group and the control group. The overall effect estimate was 1.02 (0.75–1.38 with 95% confidence interval). Results of the meta-analysis as well as the forest and funnel plots are presented in Figure 2.

Figure 2.

Forest and funnel plots of meta-analysis about the impact of human papillomavirus vaccine in the recurrence of ano-genital warts.

Discussion

The current vaccination strategy targeting non-sexually active (HPV-naïve) individuals is intuitively advantageous. However, many subjects who are beyond sexual debut and have already been exposed to HPV are likely to benefit from vaccination. Apart from the well-documented prophylactic effects of HPV virus-like particle vaccines in sexually naïve subjects, whether HPV vaccination provides a benefit in individuals with already active clinical AGWs is less understood.

The former concept of ‘therapeutic’ vaccines directed toward stimulating T-cell responses against HPV has been explored previously with apparently some level of clearance in AGWs,^25–28 although other authors obtained opposite outcomes.²⁹ This new concept of vaccine as a secondary prevention measure in AGWs is a relatively novel concept.

The rationale of using vaccination as a secondary prevention measure is that the natural immune response can be boosted by vaccinating HPV-infected persons. These high antibody levels following the vaccination would prevent new sites of epithelial HPV infection, whether from local dissemination of existing infected areas or from new HPV exposure.³⁰ This latter effect would include HPV types beyond those covered by the vaccine based on the emerging evidence of cross-protection to other viral strains.³¹ This alleged cross-reactivity between HPV types covered and not covered by the vaccines may be based on the homology and similar structure of the T-helper cells (CD4 receptor), which are conserved due to a cross-linking function within the L1 virus-like particle.³²

In other HPV-related diseases such as head and neck cancers,³³ cervical diseases,^4,19,34 and recurrent respiratory papillomatosis,³⁵ the vaccination has been demonstrated as a promising and seemingly safe strategy of secondary prevention.

Remarkably, these studies failed to evaluate whether this reported potential positive response comes from (1) a therapeutic effect on residual infection directly or through reduced ability of residual virus to infect new human cells (i.e. ‘secondary’ effect) or (2) benefit of vaccination on de novo primary lesions caused by a new HPV infection after treatment (i.e. prophylactic effect).³⁶

Our results suggest that HPV vaccination does not provide secondary benefit in patients with previous AGWs since the recurrence rates were similar between the vaccinated and the control groups. This finding is consistent with a retrospective study by Swedish and Goldstone,³⁷ who evaluated the effectiveness of the quadrivalent HPV vaccine in 103 subjects with previously treated AGWs and 203 subjects without history of AGWs. The median follow-up period was 981 days. No difference in the rate of recurrence was observed after vaccination. Additionally, in another small case series of six immunocompetent patients who received the quadrivalent HPV vaccine at the time of intervention, all patients experienced recurrence with persistence of initial HPV type DNA.³⁸

Apart from trials exploring the effects of the HPV vaccine in patients with clinically-active AGWs, other studies have investigated its efficacy in subpopulations of individuals with HPV DNA positivity and/or seropositivity, i.e. individuals who have been previously exposed to HPV at the time of vaccination, but they have not developed clinically-active AGWs. The outcomes are inconsistent: the FUTURE II Study Group found the quadrivalent HPV vaccine is effective in preventing AGWs related to HPV-6, -11, -16, and -18 in women who were either seropositive or PCR positive for at least one of the HPV vaccine types at enrollment.³⁹ On the contrary, Giuliano et al.⁴⁰ observed that within the overall study population involving 4065 patients, in a subgroup of 1087 boys and men with HPV DNA positivity or seropositivity, the vaccination did not appear to be associated with a decreased occurrence of AGWs.

The strongest evidence of secondary prevention of HPV vaccination so far is for precancer cervical diseases, but even for this condition the literature is not fully consistent: In one trial conducted in 1711 women with prevalent HPV-related cervical infection and 311 women with recurrent infections after undergoing surgical treatment, these two cohorts were randomized to receive HPV or hepatitis A vaccine. Authors concluded after a median follow-up of 56.7 months that there was no evidence of vaccine efficacy: neither on the fate of a present infection nor protection against new infections after treatment.³⁶

This approach of a vaccine for secondary prevention in AGWs is a pristine concept, which explains why few RCTs were yielded in this systematic review. Apart from the two RCTs included in the meta-analysis, the PATRICIA Randomized Trial accounting for 8863 women with cervical intraepithelial neoplasia and 8870 controls was not finally included because clinical data on the presence of AGWs were not systematically collected as this was not the primary outcome of the trial. Since women were not specifically screened, diagnosed, or treated for the presence of AGWs, efficacy against this clinical disease cannot be evaluated.⁴¹

Strengths of this meta-analysis include the inclusion of RCTs exclusively, and as result the possibility of bias is dramatically reduced. In addition, publication bias is unlikely as shown by the funnel plot. Besides, the follow-up period of these RCTs is over 12 months. Median time to develop AGWs after incident infection with HPV 6 or 11 is 6–10 months (range up to 18 months) in men; women may have even a shorter time (median time 2.9 months).⁴² Therefore, the likelihood of missing any possible incident AGWs in those studies is low.

The results of this meta-analysis should be interpreted with caution because it has certain limitations: First, the meta-analysis was conducted with the two identified available RCTs. Despite reviewing thoroughly five of the most relevant and important databases, the novelty of the issue precluded additional trials. Second, the trials in this meta-analysis had different target populations: Coskuner et al.²³ included heterosexual men, while Joura et al.²⁴ performed the intervention in women. Though we have to assume the natural history of HPV is the same in individuals who are HIV-negative regardless of the gender or reported sexual behavior, the optimal case scenario of comparison should include the same target population.

Finally, more clinical trials are warranted to define the exact role of vaccine in the treatment and relapse of AGWs, and their outcomes will certainly shed more light on this issue. In our systematic review, we identified three RCTs in the database clinicaltrials.gov which are being currently conducted to evaluate the effectiveness of HPV vaccine as a secondary prevention measure in AGWs. Two out of these three RCTs are at the recruitment stage and are about to yield some outcomes in the near future,⁴³,⁴⁴ the other one has completed recruitment and the protocol has been recently published,⁴⁵ unlike their results which are yet to be released.

Conclusion

This is the first meta-analysis exploring the effect of HPV vaccine in preventing the relapse of AGWs. The results show there is insufficient evidence to support the vaccination of patients with previous infection since it has not demonstrated an impact in the course of recurrent AGWs. However, these results cannot be generalized due to the scarce number of RCTs currently available in the literature. The fact that the HPV vaccination has showed a positive secondary prevention in other HPV-related diseases has contributed to the development of clinical trials currently investigating its effect on preventing the recurrence of AGWs. The outcomes from these RCTs are awaited to further clarify the precise effect of the vaccine.

What is already known about this subject

HPV is the most prevalent sexually transmitted infection worldwide and ano-genital warts are highly infectious.

The HPV vaccination has been demonstrated as a promising strategy of secondary prevention in HPV-related diseases such as head and neck cancers, cervical diseases, and recurrent respiratory papillomatosis.

What this study adds

This is the first meta-analysis exploring the effect of HPV vaccine in preventing the relapse of ano-genital warts. The results suggest that HPV vaccination does not provide secondary benefit in patients with previous ano-genital warts.

Impact on clinical practice

These results raise new questions about the utility of vaccine in secondary prevention of ano-genital warts, so that further research is warranted to further clarify the precise effect of the vaccine.

Footnotes

Declaration of conflicting interests

The author declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The author disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This work was supported by grants from Qatar National Research Fund, Qatar foundation, and MRC fund from Hamad Medical Corporation, Qatar (to MS).

ORCID iD

Husein Husein-ElAhmed

References

Yanofsky

Patel

Goldenberg

Genital warts: a comprehensive review. J Clin Aesthet Dermatol 2012; 5: 25–36.

Patel

Wagner

Singhal

, et al. Systematic review of the incidence and prevalence of genital warts. BMC Infect Dis 2013; 13: 39.

Hariri

Dunne

Saraiya

, et al. Human papillomavirus. In: Roush SW, Baldy LM and Kirkconnell Hall MA (eds.) Manual for the surveillance of vaccine-preventable diseases. Atlanta, GA: Centers for Disease Control and Prevention, 2011.

Kang

Choi

Kim

SM.

Is vaccination with quadrivalent HPV vaccine after loop electrosurgical excision procedure effective in preventing recurrence in patients with high-grade cervical intraepithelial neoplasia (CIN2-3)?

Gynecol Oncol 2013; 130: 264–268.

Wiley

Douglas

Beutner

, et al. External genital warts: diagnosis, treatment, and prevention. Clin Infect Dis 2002; 35: S210–S224.

Centers for Disease Control and Prevention. Sexually transmitted diseases treatment guidelines. MMWR 2006; 55: 62–67.

von Krogh

Lacey

Gross

, et al. European guideline for the management of anogenital warts. Int J STD AIDS 2001; 12: 40–47.

Pirotta

Ung

Stein

, et al. The psychosocial burden of HPV-related disease and screening interventions. Sex Transm Infect 2009; 85: 508–513.

Palefsky

JM.

HPV infection in men. Dis Markers 2007; 23: 261–272.

10.

Lacey

Lowndes

Shah

KV.

Burden and management of non-cancerous HPV-related conditions: HPV-6/11 disease. Vaccine 2006; 24: S3/35–41.

11.

Schiller

Lowy

DR.

Understanding and learning from the success of prophylactic human papillomavirus vaccines. Nat Rev Microbiol 2012; 10: 681–692.

12.

https://www.cdc.gov/vaccines/schedules/hcp/imz/child-adolescent.html#note-hpv (accessed November 2018).

13.

Arbyn

Simoens

, et al. Prophylactic vaccination against human papillomaviruses to prevent cervical cancer and its precursors. Cochrane Database Syst Rev 2018; 5: CD009069.

14.

Dillner

Kjaer

Wheeler

, et al. Four year efficacy of prophylactic human papillomavirus quadrivalent vaccine against low grade cervical, vulvar, and vaginal intraepithelial neoplasia and anogenital warts: randomised controlled trial. BMJ 2010; 341: c3493.

15.

Steben

Tan Thompson

Rodier

, et al. A review of the impact and effectiveness of the quadrivalent human papillomavirus vaccine: 10 years of clinical experience in Canada. J Obstet Gynaecol Can 2018; 40: 1635–1645.

16.

Patel

Brotherton

Pillsbury

, et al. The impact of 10 years of human papillomavirus (HPV) vaccination in Australia: what additional disease burden will a nonavalent vaccine prevent? Euro Surveill 2018; 23: 1700737.

17.

Zeybek

Lin

Kuo

, et al. The impact of varying numbers of quadrivalent human papillomavirus vaccine doses on anogenital warts in the United States: a database study. J Low Genit Tract Dis 2018; 22: 189–194.

18.

Wangu

Katherine

Impact of HPV vaccination on anogenital warts and respiratory papillomatosis. Hum Vaccin Immunother 2016; 12: 1357–1362.

19.

Garland

Paavonen

Jaisamrarn

, et al. Prior human papillomavirus-16/18 AS04-adjuvanted vaccination prevents recurrent high-grade cervical intraepithelial neoplasia after definitive surgical therapy: Posthoc analysis from a randomized controlled trial. Int J Cancer 2016; 139: 2812–2826.

20.

Swedish

Factor

Goldstone

SE.

Prevention of recurrent high-grade anal neoplasia with quadrivalent human papillomavirus vaccination of men who have sex with men: a nonconcurrent cohort study. Clin Infect Dis 2012; 54: 891–898.

21.

Moher

Liberati

Tetzlaff

, et al. Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. Int J Surg 2010; 8: 336–341.

22.

Higgins

Green

(eds) Cochrane handbook for systematic reviews of interventions, version 5.1.0. The Cochrane Collaboration, www.cochrane-handbook.org (2011, accessed 28 May 2014).

23.

Coskuner

Ozkan

Karakose

, et al. Impact of the quadrivalent HPV vaccine on disease recurrence in men exposed to HPV infection: a randomized study. J Sex Med 2014; 11: 2785–2791.

24.

Joura

Garland

Paavonen

, et al. Effect of the human papillomavirus (HPV) quadrivalent vaccine in a subgroup of women with cervical and vulvar disease: retrospective pooled analysis of trial data. BMJ 2012; 344: e1401.

25.

Stern

Immune control of human papillomavirus (HPV) associated anogenital disease and potential for vaccination. J Clin Virol 2005; 32: S72–S81.

26.

Trimble

Frazer

IH.

Development of therapeutic HPV vaccines. Lancet Oncol 2009; 10: 975–980.

27.

Hung

Monie

, et al. Therapeutic human papillomavirus vaccines: current clinical trials and future directions. Exp Opin Biol Ther 2008; 8: 421–439.

28.

Jardine

Pang

, et al. A randomized trial of immunotherapy for persistent genital warts. Hum Vaccin Immunother 2012; 8: 623–629.

29.

Vandepapeliere

Barrasso

Meijer

, et al. Randomized controlled trial of an adjuvanted human papillomavirus (HPV) type 6 L2E7 vaccine: infection of external anogenital warts with multiple HPV types and failure of therapeutic vaccination. J Infect Dis 2005; 192: 2099–2107.

30.

Szarewski

Poppe

Skinner

, et al. Efficacy of the human papillomavirus (HPV)-16/18 AS04-adjuvanted vaccine in women aged 15–25 years with and without serological evidence of previous exposure to HPV-16/18. Int J Cancer 2012; 131: 106–116.

31.

Malagon

Drolet

Boily

, et al. Cross-protective efficacy of two human papillomavirus vaccines: a systematic review and meta-analysis. Lancet Infect Dis 2012; 12: 781–789.

32.

Hepburn

Schwarz

Perlitz

, et al. Long term ex vivo monitoring of memory CD4 T helper cell responses in women immunized with Gardasil® or Cervarix®. In: Presented at EUROGIN, Lisbon, 2011. Abstract SS 19-6.

33.

Schneider

Grønhøj

Hahn

, et al. Therapeutic human papillomavirus vaccines in head and neck cancer: a systematic review of current clinical trials. Vaccine 2018; 36: 6594–6605.

34.

Pieralli

Bianchi

Auzzi

, et al. Indication of prophylactic vaccines as a tool for secondary prevention in HPV-linked disease. Arch Gynecol Obstet 2018; 298: 1205–1210.

35.

Yiu

Fayson

Smith

, et al. Implementation of routine HPV vaccination in the management of recurrent respiratory papillomatosis. Ann Otol Rhinol Laryngol 2019; 128: 309–315.

36.

Hildesheim

Gonzalez

Kreimer

, et al. Impact of human papillomavirus (HPV) 16 and 18 vaccination on prevalent infections and rates of cervical lesions after excisional treatment. Am J Obstet Gynecol 2016; 215: 212.e1–212.e15.

37.

Swedish

Goldstone

SE.

Prevention of anal condyloma with quadrivalent human papillomavirus vaccination of older men who have sex with men. PLoS One 2014; 9: e93393.

38.

Kreuter

Wieland

Lack of efficacy in treating condyloma acuminata and preventing recurrences with the recombinant quadrivalent human papillomavirus vaccine in a case series of immunocompetent patients. J Am Acad Dermatol 2013; 68: 179–180.

39.

FUTURE II Study Group. Prophylactic efficacy of a quadrivalent human papillomavirus (HPV) vaccine in women with virological evidence of HPV infection. J Infect Dis 2007; 196: 1438–1446.

40.

Giuliano

Palefsky

Goldstone

, et al. Efficacy of quadrivalent HPV vaccine against HPV infection and disease in males. N Engl J Med 2011; 364: 401–411.

41.

Szarewski

Skinner

Garland

, et al. Efficacy of the HPV-16/18 AS04-adjuvanted vaccine against low-risk HPV types (PATRICIA randomized trial): an unexpected observation. J Infect Dis 2013; 208: 1391–1396.

42.

Park

Introcaso

Dunne

EF.

Human papillomavirus and genital warts: a review of the evidence for the 2015 centers for disease control and prevention sexually transmitted diseases treatment guidelines. Clin Infect Dis 2015; 61: S849–S855. :

43.

Fouere S and Chosidow O. https://clinicaltrials.gov/ct2/show/NCT03296397?id=NCT02750202+OR+NCT03296397+OR+NCT00941889&rank=1&load=cart (accessed November 2018).

44.

Dreyer GG and Visser C. https://clinicaltrials.gov/ct2/show/NCT02750202?id=NCT02750202+OR+NCT03296397+OR+NCT00941889&rank=2&load=cart (accessed November 2018).

45.

Murray

Meadows

Doré

, et al. Human papillomavirus infection: protocol for a randomised controlled trial of imiquimod cream (5%) versus podophyllotoxin cream (0.15%), in combination with quadrivalent human papillomavirus or control vaccination in the treatment and prevention of recurrence of anogenital warts (HIPvac trial). BMC Med Res Methodol 2018; 18: 125.