Primary cervical HPV screening, and efficacy of 9-valent vaccine

Primary HPV cervical cancer screening (ie only testing for cancer-associated HPV types) is superior to cytology screening as shown in many prior studies, but now found in Australia, a country with very high rates of HPV vaccination (see http://journals.plos.org/plosmedicine/article?id=10.1371/journal.pmed.1002388​ ​). 

Details:

--by 2014, women <34 yo were eligible for HPV vaccination, with 3-dose vaccination rates being 50-77%

--this Compass trial was an open-label randomized trial of 5-yearly HPV screening versus 2.5-yearly liquid-based cytology (LBC) screening, with 3 options:

    ​--LBC screening: image-read LBC screening with HPV triage of low-grade cytology. Colposcopy if HPV positive or HSIL. routine screen in 2.5 years if negative initial screen

    --HPV+LBC screening: HPV screening along with partial genotyping, with women positive for HPV 16/18 referred to colposcopy, and those women with other oncogenic HPV types getting LBC. referral for colposcopy if LBC found high-grade squamous intraepithelial lesion. routine screen in 5 years if HPV negative, though 1 year if LBC with ASCUS/LSIL

    ​--HPV+DS screening: HPV screening, with women positive for 16/18 referred to colposcopy; and with dual-stained cytology triage for other oncogenic types, referred to colposcopy if P16/Ki67 positive. routine screen in 5 years if HPV negative

--5006 women were recruited from 2013-2014, divided pretty evenly into these 3 groups

--22% were of age group eligible for vaccine

--main outcomes: colposcopy referral and detected CIN2+ rates at baseline screening, on intention-to-treat basis, after follow-up of the subgroup of triage-negative women in each arm referred to 12 months of surveillance, and after a further 6 months of follow-up for histological outcomes

Results:

--LBC group: 0.1% had high-grade SIL and 6.6% low-grade (66.7% of the low-grade were HPV negative). overall referral for colposcopy 2.7%, CIN2+ in 0.1%

--HPV+LBC group: 1.3% were HPV 16/18 positive, 5.5% had other high risk HPV. overall referral for colposcopy 3.8%, CIN2+ in 1.0%

--HPV+DS group: 1.1% were HPV 16/18 positive, and 6.0% had other high risk HPV. overall referral for colposcopy 3.9%, CIN2+ in 1.2%

--overall:

    --p=0.09 for difference in referrals in LBC vs all HPV-screened women​

    --p=0.003 for difference in CIN2+ detection rate

--specifically looking at the different age groups
    --those HPV-vaccine eligible had CIN2+ at around 2.8% in the HPV screening groups vs 0.5% LBC

    --those HPV-vaccine ineligible (age>33) had CIN2+ at around 0.7% in the HPV screening groups vs 0.0% LBC

--no adverse events likely associated with the screening tests

Commentary:

--so, primary HPV screening was found to have increased detection of high-grade pre-cancerous lesions overall, vs cytology screening

--HPV screening had consistently higher detection rates for high-grade precancerous lesions (CIN2+), which was true in the younger aged group as well (the group offered HPV vaccinations), who had CIN2+ at around 2.8% in the HPV screening groups vs 0.5% with cytology

--several prior studies have found that cervical cancer screening just assessing HPV (and not LBC) was a reasonable, high-yeild alternative.  This study extends those findings by looking at the Australian cohort, one with a very high incidence of prior HPV vaccination rates.​

--study limitations include lack of specific data on those who had HPV vaccination (ie, was the efficacy of HPV screening really in the group who got the vaccine?, though the % of vaccine recipients was quite high), and lack of long-term followup on disease detection in screen-negative women (study is ongoing). also, this was a population of previously well-screened individuals and does not necessarily reflect the results in a high-risk but poorly screened group of women

so, this study further supports primary HPV screening, which has been adopted in several European countries, given studies finding increased sensitivity of HPV vs cytology screening, and long-term follow-up showing that the rates for the development of CIN3 and invasive cervical cancer to be significantly and substantially lower in those getting HPV vs cytology screening. This Compass trial will continue and should have more detailed data over time.  It supplements the literature by showing that primary HPV screening seems to do well in younger women who have been eligible for HPV vaccination, though we need to wait for further data which shows a real decrease in development of more advanced precancerous and cancerous lesions, as well as granular data showing that the benefit was evident in women who had actually received the vaccine…

see http://gmodestmedblogs.blogspot.com/2015/01/primary-hpv-testing-for-cervical-cancer.html has a review of several studies supporting primary HPV screening, as well as the interim primary HPV testing guidelines by an array of Ob/gyn associations (including Am Coll of Ob/Gyn), and the FDA document supporting primary HPV screening (see https://www.fda.gov/newsevents/newsroom/pressannouncements/ucm510251.htm )​

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as a marginally related item, there was a recent article in Lancet finding 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 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 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​