HPV vaccination: dramatic decrease in cervical dysplasia

A large Scottish study found a huge decrease in cervical dysplasia at age 20 after immunization with the bivalent HPV vaccine at age 12 to 13, and there was evident population protection for those unvaccinated as well (see hpv vaccine 2-dose and dec CIN BMJ2019 in dropbox, or doi.org/10.1136/bmj.l1161).

Details:

-- retrospective population study from 1988-1996, involving 138,692 women who had a cervical screening test recorded at age 20

-- Scotland developed a national vaccination program against HPV in 2008 using the bivalent vaccine until 2012, an integrated system for cervical cancer screening that includes not just the cervical screening, but also immunization status. And this database is patient-specific

-- This was a school-based program targeting girls aged 12 and 13, supplemented with a three-year catch up program until age 18

-- vaccination rates in the routinely immunized cohort was 85%, for the catch-up program 65%; in the 1995 birth cohort there was a 90% vaccination rate at age 13. Prior studies by this research group found a virtual eradication of infection related to the really high-risk HPV types 16 and 18 and a significant reduction in cross-protective types as well

-- cervical cancer screening was available for those age 20 until 2016 (thereafter, screening began at age 25)

-- for the current study, three groups of women were identified:

    -- unvaccinated women born in 1988-90, age 18-20 in 2008

    -- women vaccinated during the catch-up program born in 1991-94, age 14-17 at vaccination

    -- women routinely vaccinated born in 1995-96, age 12-13 at vaccination

-- they attempted to analyze results by number of vaccination doses given, but very few women received only one or two doses, limiting statistical validity

-- they also assessed herd protection, the effect of large-scale vaccination on those unvaccinated, presumably related to changes in the reservoir of HPV overall because of the immunization program

Results:

-- cytologic outcomes:

    -- high-grade dysplasia or worse: decreased from a pre-immunization rate of 0.75% (0.63%-0.89%) for women born in 1988 to 0.06% (0.04%-0.11%) for those born in 1995-96, 92% reduction

    -- moderate-grade dysplasia: decreased from a pre-immunization rate of 1.18% (1.04%-1.36%) for women born in 1988 to 0.27% (0.21%-0.35%) for those born in 1995-96, 77% reduction

    -- but, no statistically significant difference between women vaccinated and not vaccinated

-- histologic outcomes:

    -- CIN grade 3 or worse: decreased from a pre-immunization rate of 0.59% (0.48%-0.71%) in women born in 1988 to 0.06% (0.04%-0.11%) in women born in 1995-96, an 89% reduction

    -- CIN grade 2 or worse: decreased from a pre-immunization rate of 1.44% (1.28%-1.63%) down to 0.17% (0.12%-0.24%), an 88% reduction

        -- no cases of CIN grade 2 or worse was found in the 54 unvaccinated women in this age group

        -- the decline in high-grade CIN was steeper in fully vaccinated women, but by the 1995-96 cohort high-grade CIN was not statistically significantly different between unvaccinated and vaccinated women, both being extremely low

    -- CIN grade 1: decreased from a pre-immunization rate of 0.69% (0.58%-0.63%) [these are their numbers, though clearly an error] and women born in 1988 to 0.15% (0.10%-0.21%) overall for women born in 1995-96), a 79% reduction

        -- as above, the trend here was the same for fully immunized and un-immunized women

-- for fully immunized women first vaccinated age 12-13, vaccine effectiveness versus those first vaccinated age 17:

    -- CIN grade 1: 78% (66%-86%), versus 41% (14%-59%)

    -- CIN grade 2: 89% (81%-94%), versus 56% (35%-70%)

    -- CIN grade 3 or worse: 86%(75%-92%), versus 45% (17%-64%)

-- herd protection for those unvaccinated in the 1995-96 cohort:

    -- CIN grade 1: 63% reduction (11%-85%)

    -- CIN grade 2: 67% reduction (19%-86%)

    -- CIN grade 3: 100% reduction (69%-100%)

    -- similar reductions for moderate and high-grade dysplasia, but not for borderline/ASCUS

Commentary:

-- the dramatic decreases in CIN 3 with HPV vaccination in this study is most significant, since this is considered the best predictor of invasive cervical cancer.

-- some limitations of this study include the fact that the time for cytologic screening changed from age 20 to 25 during the study, there was a shorter follow-up time for women born later, the number of biopsies done over time changed as they moved to a more conservative management protocol for women with CIN grade 1 at colposcopy, and there were significant differences in women attending cervical cancer screening at age 20 (screening was done in 51% of fully vaccinated women aged 20- 21, but only 23% of unvaccinated women)

-- the study found that for women offered routine in-school vaccination only 1.6% were not fully immunized versus 9.8% in the first full-year of catch-up vaccinations for older adolescents. Not so surprising, since many adolescents may not interact with primary care. And school is a required venue

-- it is important to add here that HPV vaccinations are as important in boys, given the increasing levels of oropharyngeal carcinoma, more often in males, and now surpassing the number of cases of cervical cancer in females (see http://gmodestmedblogs.blogspot.com/2017/10/oral-hpv-in-men-and-oropharyngeal-cancer.html)

-- the HPV vaccine is so beneficial overall that the FDA approved its use til age 45 (though this has not filtered down to guidelines yet): see http://gmodestmedblogs.blogspot.com/2018/10/vaccine-approved-to-age-45-tdap-best.html

-- and, in terms of the benefits of immunizing kids at a younger age, see http://gmodestmedblogs.blogspot.com/2016/11/2-dose-hpv-vaccine-for-girls-and-boys.html , which shows improved efficacy at a younger age, and the decrease need from 3 to 2 vaccinations [at our health center, we have a concerted effort to vaccinate boys and girls 9-10 years old, given both these issues and the fact that at this age kids come to the health center more regularly]

-- as a perspective note, cervical cancer is 4th most common cancer in women, with significant morbidity and mortality worldwide. but, there is significant worldwide discrepancy in HPV vaccination programs, with programs largely quite effective in developed countries, but the cost of vaccination is prohibitive in resource-limited countries.

-- a recent Lancet study in 18 countries on the efficacy of the 9-valent HPV vaccine found that in 14K women aged 16-26, randomized to either the old quadrivalent vs 9-valent HPV vaccine (which includes additional HPV types 31,33,45,52,58), there was a 97.4% decrease in high-grade cervical, vulvar, and vaginal disease related to these additional HPV types (0.5 cases/10K vs 19.0/10K person-yrs, and similar efficacy against the 4 worst actors in both vaccines (types 6,11,16,18), with vaccine efficacy extending for the duration of this 6-year trial (see hpv 9-valent efficacy lancet2017 in dropbox, or doi.org/10.1016/ S0140-6736(17)31821-4). This new vaccine should reduce the incidence of cervical cancers from 70% attributable to the HPV types in the old quadrivalent vaccine to 90% with the nine-valent one. There was also a 97.7% decrease in cervical biopsies for these 5 additional HPV types.

So, a pretty impressive study, given the quality of linked data at an individual patient level. A few clear outcomes:

-- HPV vaccination works well, as found in other studies

-- it works better when given to younger women, as found in other studies

-- an important ancillary issue is that with a certain individual vaccination level, there is profound broad community protection, a level achieved in this Scottish program

-- and, in-school vaccination programs are likely to be more effective than those associated with clinic visits. and, given the huge burden of primary care tasks needed to be done, if HPV is given in a clinical setting, best to have established automatic protocols to deliver the vaccine at an early age (perhaps easiest at ages 9-11, when there is  more interaction with healthcare settings, and a 2-dose vaccine is adequate, as noted above)

geoff

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