Swabs in Screening for HPV (SWISH)

This multi-centred, order-randomised, controlled, cross-over clinical trial of self-versus clinician- collected swabs (SCS) and clinician-collected swabs (CCS), enrolling 700 participants across participating clinical trial recruitment sites in Australia. Participants will undertake SCS immediately followed by CCS, or vice versa, in an order-randomised manner with all participants completing both methods of collection. Both anal swabs will be tested for HRHPV, cytology, and methylation.

In the cervix, evidence suggests that a second swab taken on the same day may produce an inferior sample for cytology compared with the first swab. For this reason, studies comparing two swabs must control for the order of collection. In this trial, the order of the self-collected and clinician-collected anal swabs will be randomised. Randomisation will be stratified by clinical trial site.

Clinicians and participants will be unblinded to allow for swab collection; diagnostic and research laboratory staff, and research investigators who analyse the study outcomes will be blinded to both the order and method of collection for each swab.

Enrolment will continue until 700 participants have been randomised at a mixture of metropolitan and regional clinical trial sites. The study duration is 5 years.

Participants will be recruited via their regular HIV medical care at participating clinical trial sites.

Participants will be either gay or bisexual man (GBM) or trans women living with HIV aged 35 years or older, or all other people living with HIV aged 45 years or older. It is expected that most participants will be GBM, reflecting the Australian HIV epidemic but to ensure diversity, a minimum aggregate of 50 non- GBM living with HIV will be recruited per the inclusion criteria.

Participants who are HRHPV negative will exit the trial, unless they have been diagnosed with possible HSIL (pHSIL) or HSIL on cytology. Participants who are tested positive for HRHPV will be referred for high-resolution anoscopy (HRA). Participants who are tested negative for HRHPV but have pHSIL or HSIL diagnosed on cytology will be referred for high-resolution anoscopy (HRA).

During the HRA, the anoscopist will take small biopsies of any tissue suspected to have abnormal cells. The biopsy samples will undergo diagnostic histology.

Participants who are not diagnosed with high-grade squamous intraepithelial lesion (HSIL), will exit the trial. Participants who are diagnosed with HSIL but undergo treatment will exit the trial. Participants who are diagnosed with HSIL and do not receive treatment will have a 12-month Follow-up HRA then exit the trial.

• Self-collected anal swab (Other): Each participant will be order-randomised to undergo a self-collected or clinician-collected anal swab first, with the alternate swab collected immediately afterwards. Both swab will be collected on the same day at the Baseline Visit.

Primary outcomes

• Compare the sample validity of self-collected anal swabs with clinician-collected anal swabs, for HRHPV, in the eligible cohort. [At Baseline.]: To measure the percentage of self-collected anal swabs that are valid for HRHPV testing compared with clinician-collected anal swabs, as defined by internal control positivity.

Secondary outcomes

• To evaluate sample quality for cytology of self-collected ana swabs compared with clinician-collected anal swabs, in the eligible cohort. [At Baseline.]: To measure the proportion of self-collected anal swabs that have satisfactory sample quality for cytology, compared with the proportion of clinician-collected anal swabs that have satisfactory sample quality.
• To compare the HRHPV findings of self-collected anal swabs compared with clinician-collected anal swabs, in the eligible cohort. [At Baseline.]: To measure between self-collected and clinician-collected swabs, the level of agreement between HRHPV testing results.
• To compare the HRHPV findings of self-collected anal swabs compared with clinician-collected anal swabs, in the eligible cohort. [At Baseline.]: To measure between self-collected and clinician-collected swabs, prevalence of any HRHPV.
• To compare the HRHPV findings of self-collected anal swabs compared with clinician-collected anal swabs, in the eligible cohort. [At Baseline.]: To measure between self-collected and clinician-collected swabs, prevalence of HPV16.
• To compare the cytology findings of self-collected anal swabs compared with clinician-collected anal swabs, according to the modified Bethesda criteria in the eligible cohort. [At Baseline.]: To measure between self-collected and clinician-collected swabs according to modified Bethesda criteria, the level of agreement between cytology testing results.
• To compare the cytology findings of self-collected anal swabs compared with clinician-collected anal swabs, according to the modified Bethesda criteria in the eligible cohort. [At Baseline.]: To measure between self-collected and clinician-collected swabs according to modified Bethesda criteria, prevalence of any cytological abnormality.
• To compare the cytology findings of self-collected anal swabs compared with clinician-collected anal swabs, according to the modified Bethesda criteria in the eligible cohort. [At Baseline.]: To measure between self-collected and clinician-collected swabs according to modified Bethesda criteria, prevalence of cytological HSIL.

Other outcomes

• To evaluate participant perception of self-collected anal swabs as an alternative to clinician-collected anal swabs. [At Baseline.]: To measure distribution of participant responses on the acceptability and feasibility of self-collected anal swabs in future screening, measured via the Participant Reported Experience Measures instrument.
• To evaluate participant self-reported awareness of anal cancer, acceptability and willingness to complete self-collected swab for screening. [At Baseline.]: Interview data will be evaluated using standard qualitative analysis, including thematic analysis.
• To evaluate use of methylation testing, compared with anal cytology as a triage test for anal HSIL. [At Baseline.]: To compare sensitivity and specificity of methylation testing compared with anal cytology, for predicting histologically confirmed HSIL.
• To evaluate anal HSIL persistence at 12-month follow-up HRA, compared with Diagnostic HRA by Baseline anal swab methylation status. [From Baseline through to Month 15.]: To measure the proportion of participants diagnosed with HSIL at Diagnostic HRA who have persistent HSIL at 12-month follow-up HRA, stratified by Baseline anal swab methylation status.
• To evaluate long-term anal cancer outcomes, for participants that consent to data linkage. [From Baseline until 5 years after the completion of the initial trial.]: Evaluation of anal cancer diagnoses against HRHPV status, histological findings and methylation testing results.

Sex: All, ages: 35 Years to 75 Years

Inclusion Criteria:

1. Living with HIV.
2. Gay, bisexual or other man who has sex with men or trans woman aged at least 35 years, or all other people aged at least 45 years.
3. Able to commit to and undertake all study procedures.
4. Willing and able to provide informed consent, in any of the following languages:

i. English. ii. Alternatively, use of the accredited translation service usually utilised in the participant's healthcare appointments.

Exclusion Criteria:

1. Aged over 75 years of age at time of enrolment.
2. Previously undergone an HRA.
3. History of anal cancer and/or anal HSIL.
4. Medically directed treatment (including topical treatments) to the anal canal in the preceding two weeks, which in the opinion of the consenting investigator could impact swab viability.
5. Concurrent malignancy requiring systemic therapy, or medical conditions otherwise considered contraindicated to HRA by the delegated investigators.

• Dr Isobel Mary Poynten, MBBS, MPH, DCH PhD, Study chair, The Kirby Institute, University of New South Wales Sydney, Australia
• Scientia Prof Andrew Grulich, MBBS, PhD, FAFPHM, FAAHMS, Principal investigator, The Kirby Institute, University of New South Wales Sydney, Australia