Human papillomavirus (HPV) vaccination in women with conisation

- Rationale Cervical cancer is the fourth most common cancer affecting women worldwide, caused by persistent infection with oncogenic human papillomavirus (HPV) types. While HPV infections usually resolve spontaneously, persistent infections with high‐risk HPV types can progress to premalignant glandular or — mostly — squamous intraepithelial lesions, usually classified in cervical intraepithelial neoplasia (CIN). Women with CIN 2 and CIN 3 (i.e. high‐grade CIN) typically undergo cervical conisation to remove precancerous cervical lesions. While conisation is effective, there is a risk of recurrence and progression to invasive cervical cancer. Additionally, women who have undergone conisation are at higher risk of HPV‐associated anogenital precancerous lesions and cancers in other locations. HPV vaccination is an important measure to prevent HPV‐related cancer. It is unclear to what extent HPV vaccination offers protection to women with conisation. Of note, the term 'with conisation' is interchangeably used for all time points of HPV vaccination relative to the conisation procedure for the purpose of this review. Objectives To investigate the benefits and harms of HPV vaccination (given shortly before, at, or after conisation) in comparison to no HPV vaccination in women with conisation. Search methods We searched CENTRAL, MEDLINE, Embase, and Clarivate Web of Science (May 2023). We also searched ClinicalTrials.gov to identify ongoing studies. Eligibility criteria We included randomised controlled trials (RCTs) and non‐randomised studies of interventions (NRSI) if they compared an HPV vaccine (nonavalent, quadrivalent, or bivalent) with no HPV vaccine, placebo, or other vaccines not directed against HPV in women of any age with conisation for treating precancerous lesions following HPV infection. Outcomes Critical outcomes: CIN 2+ (irrespective of HPV type and related to HPV 16/18), CIN 3+ (irrespective of HPV type and related to HPV 16/18), incident invasive cervical cancer (irrespective of HPV type and related to HPV 16/18), persistent HPV infection (irrespective of HPV type and related to HPV 16/18) and incident HPV infection (irrespective of HPV type and related to HPV 16/18). Risk of bias We evaluated RCTs using the Cochrane RoB 2 tool and NRSI using the 'Risk of Bias in Non‐randomised Studies of Interventions' tool (ROBINS‐I). Synthesis methods Two review authors independently screened, extracted data, and assessed risk of bias. We used random‐effects meta‐analyses for our primary analyses. We rated the certainty of evidence using the GRADE approach. Included studies The search identified 13 studies (2 RCTs, 11 NRSI), with 21,453 women with conisation. Studies were conducted in Europe (10), China (1), South Korea (1), and Iran (1), and published between 2013 and 2023. The length of follow‐up after conisation was up to 36 months in RCTs and up to greater than 60 months in NRSI. Eight studies included women older than 25 years. The remaining studies included women across different age groups (range 17 to greater than 50 years). In 10 studies, the treatment for cervical lesions included loop electrosurgical excision procedures or large loop excision of the transformation zone as the conisation procedure. The spectrum of precancerous lesions (in terms of baseline characteristics) varied widely between women. Seven studies used the quadrivalent HPV vaccine, one used the nonavalent HPV vaccine, four used various HPV vaccine types, and one did not specify the HPV vaccine type. All studies compared the HPV vaccine with no intervention. Synthesis of results Critical outcomes HPV vaccination compared to no HPV vaccination in women with conisation may reduce the risk of CIN 2+ (evidence from RCTs: risk ratio (RR) 0.40, 95% confidence interval (CI) 0.26 to 0.63; 2 RCTs, 420 women; evidence from NRSI: hazard ratio (HR) 0.49, 95% CI 0.27 to 0.89; 5 NRSI, 19,059 women; odds ratio (OR) 0.23, 95% CI 0.05 to 0.97; 3 NRSI, 928 women; RR 0.24, 95% CI 0.13 to 0.46; 3 NRSI, 1027 women; low‐certainty evidence). There were similar results for CIN 2+ (related to HPV 16/18) (evidence from NRSI: RR 0.38, 95% CI 0.21 to 0.68; 7 NRSI, 2970 women; low‐certainty evidence). Effects on CIN 3+ varied between studies. One study suggested similar effects to CIN 2+ favouring HPV vaccination (evidence from NRSI: OR 0.20, 95% CI 0.10 to 0.60; 1 NRSI, 285 women; low‐certainty evidence), while the remaining evidence was very uncertain (evidence from NRSI: RR 0.53, 95% CI 0.15 to 1.90; 2 NRSI, 17,472 women; very low‐certainty evidence). The evidence on CIN 2+ (related to HPV 16/18) based on RCT evidence was very uncertain. The evidence on CIN 3+ (related to HPV 16/18), incident invasive cervical cancer (irrespective of HPV type), and persistent HPV infections (irrespective of HPV type and related to HPV 16/18) was very uncertain. Adverse events One RCT reported minor local reactions (redness and rash: 127/138 (92%) women; headache: 11/138 (8%) women) and severe allergies (2/158 (1%) women). Authors' conclusions HPV vaccination given around the time of conisation in comparison to no HPV vaccination in women with conisation may reduce the risk of CIN 2+ and CIN 2+ (related to HPV 16/18; evidence based on NRSI). Effects on CIN 3+ (irrespective of HPV type) varied, with one NRSI suggesting similar effects to CIN 2+, while the remaining evidence was very uncertain. The evidence on other outcomes was predominantly very uncertain or inconclusive. Overall, the existing evidence for HPV vaccination in women with conisation is largely based on NRSI with serious or critical risk of bias and low‐ to very low‐certainty evidence. Evidence from RCTs is limited (i.e. only two RCTs are available). Additional RCTs with a placebo intervention in the control group to evaluate the efficacy and safety of HPV vaccination (particularly with the nonavalent vaccine) as an adjuvant to conisation would provide more robust evidence. Future RCTs should also aim to assess how effects of vaccination around the time of conisation vary according to whether a previous HPV vaccine for primary prevention was received, timing of HPV vaccination related to conisation, and different age groups. Funding EU4Health Programme. Registration PROSPERO (CRD42023428998) Plain language summary How effective are human papillomavirus vaccines for women who had or undergo a surgical procedure to remove abnormal cells in the cervix, and do they have any unwanted effects? Key messages Human papillomavirus (HPV) vaccination in comparison to no HPV vaccination in women with conisation (removal of a cone of tissue that contains abnormal cells, also known as cone biopsy) may reduce the risk of precancerous cervical cell changes (primarily CIN 2+). Due to limitations in data, we are not sure whether HPV vaccination (given shortly before, at, or after conisation) in comparison to no HPV vaccination in women with conisation affects cervical cancer risk or persistent HPV infection. Further high‐quality studies are needed to assess the effectiveness and unwanted effects of HPV vaccination in women with conisation. These trials should also consider specific groups, such as women who had received HPV vaccination before and different age groups. What is human papillomavirus and how is it treated? Cervical cancer (cancer in the neck of the womb) is the fourth most common cancer affecting women worldwide. It is caused by persistent infection with specific types of human papillomavirus (HPV). While HPV infections are common and usually resolve without any problems, persistent HPV infections can progress to abnormal cell changes in the cervix (that is, precancerous conditions), called cervical intraepithelial neoplasia (CIN). These precancerous conditions can be classified as low‐grade lesions (called CIN 1) and high‐grade lesions (called CIN 2 and CIN 3). While low‐grade lesions usually reduce spontaneously without treatment, high‐grade lesions have a higher chance of progressing to cervical cancer. CIN 3 corresponds to carcinoma in situ (abnormal cells confined to where they first occurred), and adenocarcinoma in situ (abnormal cells that have moved to glands); it is well accepted that these immediately precede cervical cancer. There are more than 200 types of HPV, and over 40 of them infect the genital area. Seven in 10 cervical cancers are caused by HPV types 16 and 18. Women diagnosed with CIN 2 and CIN 3 are usually considered for cervical conisation (also known as cone biopsy), a surgical procedure to remove abnormal cells to prevent progression to cervical cancer. In Europe, there are three approved HPV vaccines: a bivalent (which protects against two HPV types), quadrivalent (which protects against four HPV types), and nonavalent (which protects against nine HPV types) vaccine. HPV vaccination is used to prevent cervical cancer, but its effectiveness for women with conisation remains uncertain. Of note, we use the term 'with conisation' interchangeably to refer to whenever the HPV vaccination was given around the time of the conisation procedure, that is, before, at, or, after the procedure. What did we want to find out? We wanted to find out how effective HPV vaccination is for women who had or undergo conisation to remove precancerous cervical lesions, and if it has any unwanted effects. What did we do? We searched for studies that examined the effects of HPV vaccination in women of any age with conisation to treat precancerous cervical cell changes caused by HPV. We summarised the results, assessed their reliability, and rated our confidence in the evidence. What did we find? We found 13 studies that included 21,453 women with conisation. The studies varied in design and quality. Most studies were conducted in Europe (10 studies) and used the quadrivalent (seven studies) or nonavalent (one study) HPV vaccine. Some studies monitored women for more than 60 months. Main results HPV vaccination in comparison to no HPV vaccination in women with conisation may reduce the risk of precancerous lesions. However, results have to be interpreted with caution. We are not sure whether HPV vaccination in comparison to no HPV vaccination in women with conisation has an effect on cervical cancer and persistent HPV infection. There were no data for new HPV infections, adenocarcinoma in situ, and quality of life, and the remaining evidence was mostly inconclusive. Unwanted effects included minor reactions (redness and rash: 92 in every 100 women; headache: 8 in every 100 women) and severe allergies (1 in every 100 women). What are the limitations of the evidence? The evidence was mainly from studies that had potential problems with how they were conducted. Only two studies were designed to produce more robust evidence. The studies did not provide enough information to know whether a previous HPV vaccination means that another vaccination and its timing in relation to the conisation procedure gives different results. We also need to know more about the effects on different age groups. How up to date is this evidence? The evidence is current to May 2023.