HPV vaccine in the treatment of usual type vulval and vaginal intraepithelial neoplasia: a systematic review

Vulval/Vaginal Intraepithelial Neoplasia (VIN/VaIN) can precede the development of invasive cancer by a variable period. Usual-type VIN (uVIN) is commonly associated with carcinogenic subtypes of human papillomavirus (most commonly HPV 16) [1]. The HPV attribution for different anogenital lesions varies between studies, however, is found in approximately 76–87% of VIN, 30–40% of vulvar cancer [1], 96% of VaIN and 63–74% of vaginal cancer [2, 3].

The incidence of VIN is thought to be around 1–2/100,000 [4]. Although spontaneous regression has been reported (approx. 1.2%), VIN is considered a premalignant condition (as is VaIN), with a suggested progression rate to cancer of 3–16% [5]. Although primarily seen in older women (over 70 years old), 15% are diagnosed in women under the age of 50. Although presentation of VIN may be asymptomatic, symptoms often include pruritis, burning, and pain which can be distressing [6]. In addition, lesions may be multifocal affecting large areas of the vulva, pigmented or white or present as areas of erythema. Lesions may also be flat, raised or ulcerated [5].

Vaginal Intraepithelial neoplasia is an uncommon (incidence around 0.1/100,000 women in the US) usually asymptomatic disease [7], often associated with other intraepithelial neoplasias. Progression to invasive vaginal cancer has been reported as approximately 2% [8].

The current treatments for VaIN are either surgical (excision or CO₂ ablation) or medical (Imiquimod, 5FU or vaginal oestrogens) [9]. Most treatment regimens for VIN also consist of ablation or excision, medical therapy with Imiquimod has been shown to be effective [10] and is commonly used by dermatologists and genitourinary medicine (GUM) specialists. Its use can be limited by intolerable side effects such as erythema and vulval pain. Recurrence rates after treatment, regardless of modality are as high as 30–50%, implying that current treatment options are inadequate and not effective in the long term [11]. A review of practice at our unit showed poor response rate to all treatment modalities with rate of progression to invasive disease at 16%. Almost 15% of patients attend for 10 years or more, undergoing multiple biopsies and/or surgical treatments, in addition to being on long term Imiquimod treatment. These women participate in multiple hospital visits which is a burden to them and increases healthcare services costs. These findings from our own practice prompted this systematic review.

Women with natural antibodies to HPV have less frequent recurrence of VIN than those who are antibody negative (22.9% vs 52%) [12]. Three vaccines are available for the primary prevention of HPV infection. A bivalent vaccine (Cervarix® [GSK]) targets high risk HPV types 16 and 18, whilst a quadrivalent vaccine (Gardasil®) targets the same HR HPV types (16 and 18) and two HPV types that commonly cause genital warts (6, 11). A newer recombinant 9-valent vaccine prepared from the purified virus-like particles (VLP) of the major capsid (L1) protein of the 9 HPV subtypes - 6, 11, 16, 18, 31, 33, 45, 52, 58, is now available (Gardasil® 9 [MSD UK]). These are widely used for the prevention of premalignant genital lesions, and premalignant anal lesions, in females and males. These appear to be most effective at preventing CIN in women who are known to be HRHPV negative, but there is moderate to high quality evidence that they reduce high grade CIN for women whose HPV status is not known [13‐15]. This may be because prophylactic vaccination has been shown to augment the response to HPV in women who were previously seropositive [16]. This is consistent with studies that indicate that vaccination may have a therapeutic effect in other HPV-associated conditions such as recurrent respiratory papillomatosis (RRP), a benign neoplasm of the larynx among children, caused by HPV 6 and 11 [17].

Prophylactic vaccines act by inducing neutralising antibodies to the viral L1 capsid proteins. It is thought that treatment of already established HPV infection requires activation of T-cells capable of killing virus infected cells, rather than producing antibodies against the virus itself, so therapeutic vaccines (in development), target viral genome E6 and E7 oncoproteins (necessary for initiation and maintenance of transformation to cancer) [18].

Different types of therapeutic vaccines have been tested in other HPV driven diseases. These include;

The currently licensed HPV vaccines have an established role in the primary prevention of HPV infection generally in younger populations. The role of the HPV vaccine in secondary prevention and treatment has not yet been fully established. Women with VIN may have symptoms which are recurrent and difficult to treat. Clinicians who treat these patients (dermatologists, GUM specialists and gynaecologists) look for ways to improve the effectiveness of current treatment.

We performed a review of the literature regarding the role of any HPV vaccination for secondary prevention, in the treatment of women with HPV-related VIN and VaIN.

We conducted a systematic search of the literature with the strategy to review best available evidence. We searched for systematic reviews, and randomized controlled trials. If these were not available, we would include controlled non-random studies, and uncontrolled studies. We looked into the use of any form of HPV vaccine in the treatment of women with a histologically confirmed diagnosis of HPV related VIN and/or VaIN, versus control/standard treatment. These vaccines included the commercially available licensed vaccines prepared from the VLPs of the L1 protein of common HPV types, or the experimental vaccines against the HPV oncoproteins E6/E7. Our search also included vaccines as adjuvant to usual care. We excluded studies of other lower genital tract disease (pre-invasive or invasive), vulval/vaginal carcinoma and those studies concerning prophylactic use of vaccines.

We excluded studies whose participants were pregnant, immunocompromised, or had a history of allergy to vaccine products. In the included studies, patients with VIN or VaIN were given any form of HPV vaccination.

The outcome measures we wished to evaluate were lesion response to vaccination, symptom improvement, immune response, and HPV clearance. A Core Outcome Set protocol was not used as this is not currently available but is in development for vulva.

Database searches included Ovid Medline, Embase, Web of Science, The Cochrane Library and Clinicaltrials.​gov. Search terms included HPV vaccine OR Human Papilloma Virus vaccine OR Papilloma virus vaccines OR HPV Vaccin* AND therapeutic vaccine* AND VIN OR VAIN OR Vulval intraepithelial neoplasia OR Vaginal intraepithelial neoplasia, published in English with no defined date limit. Database searches were carried out with the aid of a UCL librarian in March 2018. Additional papers were identified via the reference lists of included studies (Additional file 1).

Our search strategy is detailed in the Prisma flow diagram in Additional file 2: Figure S1. Two independent reviewers identified 93 articles after excluding studies with titles unrelated to the subject matter. A further 86 articles were excluded at this stage: 55 were review articles i.e. not primary research or not addressing the review question. Seventeen studies were excluded as they reported on experimental HPV vaccine development - identifying the right dose for effect or analyzing the types of immune response to HPV vaccination. Four studies were concerned with HPV vaccine as prevention not as treatment and three studies were concerned with effect of experimental HPV vaccine in non-human subjects. In a search of clinicaltrials.​org we found 4 potential studies – two were active trials but not yet recruiting, with results expected in late 2018 – one involved CIN only and the other, a study from China which had completed, but no results had been reported at the time of writing. Two studies were concerned with other forms of anogenital pre-cancer and 1 study was concerned with trial of Imiquimod only.

There were no RCTs, systematic reviews or controlled studies identified. Seven studies that included 129 women, met our inclusion criteria, the included studies were all uncontrolled case series published between 2000 and 2017 (Table 1).

This study is the first systematic review of the use of any HPV vaccination in the treatment of HPV related vulval and vaginal disorders. This review has highlighted that no high-quality studies using commercially available vaccines have addressed this research question - available vaccines are designed for prevention. Studies that have been carried out are small, case series without control groups, rather than randomized controlled trials. They have used experimental therapeutic vaccines rather than the available vaccines. The study designs are of low methodological quality and a high risk of bias. Systematic reviews of randomized control trials indicate that available HPV vaccines are safe and effective for prevention. Effectiveness seems to decrease with age and exposure to HPV. The role of these vaccines as adjuvant to treatment has not been studied. The efficacy and safety of the experimental vaccines is yet to be established and it is likely to be a number of years before therapeutic vaccines become available for clinical use. Overall the evidence to answer the clinical questions of the role of HPV vaccination in the treatment of VIN/VAIN is of very low-quality.

Women with VIN/VaIN are living with chronic conditions, requiring prolonged and often repeated treatments which can have intolerable side effects, and yet high relapse rates. More effective treatments are needed that will reduce symptoms, reduce progression and reduce the rate of relapse. Having been introduced almost a decade ago as part of the childhood vaccination program, we should begin to see a reduction in the incidence of VIN/VAIN and other anogenital pre-cancers. In the meantime, for patients who have not been vaccinated, newer treatments with fewer side effects and morbidity are warranted. The evidence for the use of HPV vaccination in VIN/VaIN is of low quality and insufficient to guide practice. All of the vaccines used in these non-randomized studies were experimental and we did not find any research evaluating the use of commercially available vaccine as an adjuvant to usual treatment of VAIN/VIN. We aim to deliver such a study following on from this review. More studies are needed to investigate clinically important patient outcomes (symptoms, non-progression and recurrence rates) with the use of HPV vaccine in a therapeutic setting. It would be prudent to also investigate its use in secondary prevention of cancer, which would need to be assessed through further longitudinal studies.