Virologist specialising in HPV-based screening shares insights on HPV45 and its link to cervical cancers

Human Papillomavirus (HPV) is thought to be the most common sexually transmitted infection in the world.

Whilst this virus does not always cause symptoms and can go undetected, HPV is known to cause most cases of cervical cancer as well as being associated with several other cancers. The Australian National Cervical Screening Program (NCSP) offers regular Primary HPV-based cervical screening tests to people with a cervix aged 25 and above, to catch the HPV infection before it leads to more serious complications.

The last two decades have brought us breakthrough vaccines for HPV: Gardasil was initially developed by Australian researcher Professor Ian Frazer and was approved by the FDA in 2006. This quadrivalent HPV vaccine offered protection against the two HPV types most commonly linked to cervical cancer: HPV 16 and 18, as well as two other HPV types associated with genital warts, 6 and 11.

And more recently in 2014, an evolution of the Gardasil vaccine called Gardasil 9 was FDA approved. This newer vaccine can protect patients against infections with HPV6, 11, 16, 18, 31, 33, 45, 52, and 58. Gardasil 9 replaced the quadrivalent Gardasil vaccine in the Australian HPV vaccination program in 2018.

A particular type of HPV that is of interest to the scientific community is HPV45. Studies show that this strain affects less than 1.8%[1] of the population with a cervix in Australia. Australians who haven’t been vaccinated for HPV at all, or were vaccinated before Gardasil 9 was introduced, will not be immunised against HPV45.

The Australian Centre for the Prevention of Cervical Cancer (ACPCC) oversees the Australian HPV Reference Laboratory and is based in Melbourne, Australia. ACPCC was involved in a study which investigated HPV types associated with Australian cervical cancers between 2005 to 2015, and the findings were published in 2017 in the International Journal of Cancer. The research found that HPV45, whilst less well-known than its counterparts HPV16 and 18, was linked to over 5% of all cervical cancers[2].

Associate Professor Dave Hawkes is the Director of Molecular Microbiology at ACPCC. He explains why it is important to test for HPV45.

“The available data from studies of cervical cancers in Australia show that HPV45 is certainly the worst of the rest after you take out HPV16 and 18.

“In Australia, it's a requirement that you test for HPV45 [as part of the NCSP]. All eight different HPV assays that have been used in the Australian NCSP test for the presence of HPV45. Only three of these assays give an individual result for the presence of HPV45”

HPV45 can be detected using the Abbott Alinity m with an assay that detects 14 types of HPV. In Australia, if an HPV45 is detected in a patient, a liquid-based cytology test will also be undertaken. If the cytology doesn’t show a high-grade lesion the patient will be asked to come back for a cervical screening test one year later.

If the patient again tests positive for HPV (other than types 16 and 18) but has negative cytology results they will again be asked to test in twelve months. If this third test is HPV positive and was taken at least nine months after their previous test, the patient will be referred for colposcopy.

It is worth noting that some groups who have been identified as being at higher risk (e.g., those over 50 years of age) only have to have one repeat non-16/18 HPV positive result before being sent for colposcopic investigation for cell changes in the cervix.

For more details take a look at the latest National Cervical Screening Program's Clinical Guidelines pathway for women at intermediate risk.

A/Prof Hawkes said: “A test must have a certain sensitivity for cervical disease, not necessarily cancer, but pre-cancer because with cervical screening, we don't want to detect cancer. The idea is we detect pre-cancers and treat them.

What we liked about the Alinity m is that it was the first high-volume machine to actually give us extended genotyping beyond HPV16/18.”

HPV-based cervical screening is hoped to improve the sensitivity of screening for a range of cervical pre-cancers according to A/Prof Hawkes,

What we do know is that when our Pap smear-based screening program was introduced in 1991, within 10 years, the number of cervical cancers was halved but there was no significant effects on the prevalence of adenocarcinomas.

So cervical screening for HPV is predicted to give more sensitivity for pre-cancerous lesions before they develop into adenocarcinomas.

HPV45, 16 and 18 tend to be the ones associated with adenocarcinoma, with one study showing >94% of adenocarcinomas were associated with one of these three HPV types[3]. . So that's one of the reasons why the presence of HPV45 is asked about specifically by specialists.”

A/Prof Hawkes praised Australia’s vaccination program against HPV, but highlighted the gaps that still need addressing:

“Australia's a bit unique. We really are at the cutting edge because not only do we have a really comprehensive vaccination program, but we also had the first gender-neutral vaccination program which was introduced in 2013.

The most recent available data shows that around 79% of females got their first dose of Gardasil9 in their first year of high school. So that's great, but that's still 20% missing, so HPV45 is still something that could be circulating.

And there's certainly inequity. We don't understand the screening rates of our Aboriginal and Torres Strait Islander people or even our culturally and linguistically diverse communities because this information is not captured on many pathology request forms.

What we do know is that Aboriginal and Torres Strait Islander peoples are twice as likely to have cervical cancer and four times[4] as likely to die of this disease.”

In the future, higher levels of vaccination among people of all genders will reduce the number of infections with HPV types associated with causing cervical cancers, offering better protection to the Australian population. Coupled with a good level of participation in the National Cervical Screening Program this stands Australia in good stead to eliminate cervical cancer within the next 15 years.

[1] Garland SM, Brotherton JML et al, BMC Medicine, 2011 9:104.

[2] Brotherton JML et al, International Journal of Cancer,