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).