HPV Vaccination Close to Surgery May Reduce Recurrent Cervical Lesions

Vaccination for human papillomavirus (HPV) near the time of surgery for precancerous cervical lesions significantly reduced the rate of lesion recurrence, a meta-analysis showed.

Overall, vaccination reduced the risk of recurrent cervical intraepithelial neoplasia grade 2+ (CIN2+) by 57% as compared with surgery alone. An even larger risk reduction (74%) occurred when the analysis was limited to the two HPV strains that cause most cervical cancers.

Because of the low-to-moderate quality of data included in the analysis, the results do not prove vaccination will prevent recurrent cervical lesions, but are suggestive, particularly for CIN2+ associated with HPV16 or HPV18, reported Maria Kyrgiou, MD, of Imperial College London, and co-authors in The BMJ.

“Women who have been treated for high-grade CIN have a lifelong residual high risk of cervical cancer and other malignancies related to HPV infection,” the authors wrote. “New strategies to reduce the risk of these women might shorten and simplify screening programs and eliminate cervical cancer more rapidly. Large, appropriately powered randomized controlled trials are required to establish the effectiveness of adjuvant HPV vaccination at the time of local surgical treatment of CIN.”

The ongoing NOVEL trial should provide more insight into the effect of the nine-valent HPV vaccine on persistent, recurrent, and prevalent HPV infections, including cost effectiveness, they added.

Multiple large studies have shown that vaccination against HPV can prevent infection and diseases related to infection when administered to prepubertal boys and girls, but does not clear or reduce viral persistence in women with ongoing infection. The cost effectiveness of HPV vaccination declines substantially after age 26, the authors noted. However, women with CIN constitute a high-risk population who would benefit from adjuvant vaccination to reduce the risk of cervical cancer.

HPV vaccines are far more immunogenic as compared with infection. As such, antibodies induced by natural immunity wane over time, whereas vaccine-induced antibodies appear to provide protection against reinfection or reactivation in individuals who are seropositive from prior infection.

“The vaccine might have beneficial effects against new infections and reinfections from the same HPV subtype soon after treatment, although it is less likely that this effect promotes clearance of an existing infection in isolation,” the authors wrote. “Whether the vaccine can boost the effect of local surgical treatment and promote viral clearance is unclear.”

Observational studies on adjunctive use of the HPV vaccine have yielded inconsistent and conflicting data, they noted. Two randomized controlled trials suggested adjuvant vaccination reduced the risk of CIN recurrence, but both studies lacked statistical power.

In an effort to gain more insight into adjuvant use of the HPV vaccine, the investigators performed a systematic literature review and meta-analysis. The search included studies reporting HPV infection rates and HPV-related disease recurrence after local surgical excision in vaccinated individuals.

The review identified 22 studies, 18 of which reported data for nonvaccinated patients and were included in the meta-analysis (two randomized trials, 12 observational studies, and four post-hoc analyses). The observational studies and randomized trials had a median follow-up of 36 months, and the post-hoc analyses had a median follow-up of 27 months.

An analysis that included 19,909 study participants (3,472 vaccinated) yielded a hazard ratio of 0.43 for CIN2+ recurrence in patients who were vaccinated at the time of surgery versus those who were not (95% CI 0.30-0.60). Event rates were low in vaccinated (4.0%) and unvaccinated (5.6%) participants.

The effect estimates remained consistent in multiple sensitivity analyses. An analysis limited to CIN2+ associated with high-risk HPV strains (N=1,879) reduced the hazard ratio for recurrence to 0.26 (95% CI 0.16-0.43). Benefits were similar regardless of which HPV vaccine patients received.

A separate analysis of post-hoc studies of randomized trials (N=2,268) yielded a 55% reduction in the hazard ratio for recurrence. However, the value was associated with wide confidence intervals (95% CI 0.13-1.57).

A combined analysis of all studies, irrespective of design (N=22,177), produced a hazard ratio of 0.43 (95% CI 0.32-0.59). Yet another analysis showed a beneficial effect of vaccination whether patients received the vaccine before (HR 0.39) or after (HR 0.41) surgery.

Vaccination also reduced the risk of recurrent CIN3+ by 72%, but with wide confidence intervals (95% CI 0.01-6.37). Studies included in the analysis lacked evidence to determine whether vaccination reduced the risk of other HPV-related lesions or persistent/incident HPV infections.