In this study we clinically validate if host cell DNA methylation markers can predict (non-)regression of HGAIN, thus determining the need of immediate treatment versus active surveillance and the safety of withholding treatment. This could prevent…
ID
Source
Brief title
Condition
- Anal and rectal conditions NEC
- Viral infectious disorders
- Skin neoplasms malignant and unspecified
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
• The primary endpoint is the regression / non-regression dichotomy of each
individual HGAIN lesion at baseline.
• The primary endpoint is based on the histological outcome of the 24-months
follow-up anal biopsies from each individual HGAIN lesion.
• The histological outcome is based on the LGAIN/HGAIN dichotomy according to
the LAST criteria.
• To follow-up each individual HGAIN lesion, its location is recorded along 8
segments (octants) along the circular transformation zone in the anal canal.
• Regression is defined as any biopsy-proven LGAIN, or no AIN lesion in the
octant of an individual HGAIN lesion previously seen at baseline, or in one of
the adjacent octants.
• If no clinical lesion is visible upon HRA at 24 months, a biopsy is obtained
at random form the octant where the individual HGAIN lesion was previously seen
at baseline.
• HGAIN non-regression is defined as any biopsy-proven HGAIN lesion or anal
cancer in the octant of an individual HGAIN lesion previously seen at baseline,
or in one of the adjacent octants.
For the substudy, endpoints are:
1. To determine the frequency and phenotype of CXCR3+ TRMs in AIN lesions of
HIV-positive and HIV-negative individuals.
2. To identify HIV-specific altered immune pathways associated with CXCR3
expression, tumor progression, and/or aberrant immune responses to HPV at the
single-cell level.
3. To validate the presence and functional relevance of cTRMs in HPV by
characterizing their clone sequence and phenotype in pre-cancerous lesions.
4. To identify hot-spots of intensive HPV antiviral defense and cell-cell
interaction in the pre-cancerous lesion at the sub-compartmental level using
imaging and transcriptomic approaches.
Secondary outcome
Secondary endpoints are:
• The histological outcome of each individual HGAIN lesion at the 6-, 12-, and
18-month follow-up visits.
• The clinical outcome of each individual HGAIN lesion at the 6-, 12-, 18-, and
24-month follow-up visits, defined as a change in the size measured by the
number of octants of the anal surface affected
• Overall HGAIN disease: the clinical outcome of all HGAIN lesions combined at
the 6-, 12, 18-, and 24-month follow-up visits, defined as a change in the size
of any HGAIN lesion, measured by the number of octants of the anal surface
affected, including incident HGAIN lesions during, and in between follow-up
visits.
• Overall HGAIN disease: the histological outcome of all HGAIN lesions combined
at the 6-, 12-, 18, and 24-month follow-up visits.
• HRQoL of the study population compared to the control population at baseline,
the 6- and the 24-month follow-up visit.
For the substudy, endpoints are:
1. To determine the frequency and phenotype of CXCR3+ TRMs in AIN lesions of
HIV-positive and HIV-negative individuals.
2. To identify HIV-specific altered immune pathways associated with CXCR3
expression, tumor progression, and/or aberrant immune responses to HPV at the
single-cell level.
3. To validate the presence and functional relevance of cTRMs in HPV by
characterizing their clone sequence and phenotype in pre-cancerous lesions.
4. To identify hot-spots of intensive HPV antiviral defense and cell-cell
interaction in the pre-cancerous lesion at the sub-compartmental level using
imaging and transcriptomic approaches.
Background summary
Human Papillomavirus (HPV)-induced anal cancer precursors, high-grade anal
intraepithelial neoplasia (HGAIN), are known to have a high spontaneous
regression rate. Current histopathological assessment is unable to distinguish
between HGAIN likely to regress and HGAIN likely to persist or progress to
cancer. To prevent anal cancer, currently all HGAIN is treated by
electrocautery, which leads to substantial overtreatment.
Study objective
In this study we clinically validate if host cell DNA methylation markers can
predict (non-)regression of HGAIN, thus determining the need of immediate
treatment versus active surveillance and the safety of withholding treatment.
This could prevent overtreatment and the associated anal and psycho-sexual
morbidity, improving anal cancer screening efficacy and quality of life of HIV+
MSM.
Furthermore, in a subset of patients we aim to understand the role of CXCR3+
tissue resident effector memory T cells (TRMs) in HGAIN and identify new
immunological pathways that could lead eventually to new therapeutic
approaches, and prognostic markers in HIV+ patients affected by AIN.
Study design
We initiate a multicentre active monitoring cohort study in Amsterdam, the
Netherlands, in which HGAIN lesion will not be treated during a 24-months
follow-up. Participants will be monitored by six-monthly High-Resolution
Anoscopy (HRA) with biopsies and anal swabs for cytology. Baseline samples will
be tested with host cell DNA methylation markers (ASCL1, SST, ZNF582) and
possibly other biomarkers (HPV genotyping, HPV-E4, p16INK4A, Ki-67 and
PD-1/PD-L1). Participants of both the study group and the HRQoL control group
will be asked to fill in the validate A-HRSI questionnaire to measure the
health-related quality of life (HRQoL).
In a subset of patients (further referred to as substudy), a cross-sectional
analysis on HGAIN biopsies will be performed. During their regular treatment
visit, participants will undergo two additional biopsies after local
anaesthesia and before electrocoagulation. Besides, participants will undergo a
phlebotomy.
Study burden and risks
Participating patients will be withheld of treatments for anal cancer
prevention. The associated risk is acceptable because treatment for HGAIN for
anal cancer prevention is not yet evidence-based. Efficacy of treatment is
suboptimal and patients experience considerable side-effects. Currently, we
already offer patients the possibility to choose for active monitoring or
treatment. Furthermore, since the study follow-up will be two years, the risk
of cancer development will be particularly low, and patients at very high risk
for cancer (i.e. patients with more than 50% of anal canal affected, patients
with clinical suspicion for cancer and with abnormalities on DARE plus MRI)
will not be included at the start. Participants will be closely monitored
during the trial and excluded for treatment when clinical suspicion for cancer
arises.
Substudy participants indicated for electrocautorization of HGAIN lesions will
receive two additional biopsies prior to the treatment procedure. Since
participants will undergo the biopsies after local anaesthesia and before the
electrocoagulation treatment, the additional discomfort, blood loss, and pain
from the experimental biopsies will be neglible. In addition, two times 10 ml
of peripheral blood will be collected via phlebotomy. This substudy will allow
us to closely scrutinize immunological mechanisms such as the activation of
CXCR3+ in HGAIN lesions in HIV+ patients, potentially finding leads for new
biomarkers and therapeutics.
Meibergdreef 9
Amsterdam 1105AZ
NL
Meibergdreef 9
Amsterdam 1105AZ
NL
Listed location countries
Age
Inclusion criteria
Study group (N=200) - HIV+ patients of at least 18 years of age that are
cisgender men, transgender men or transgender women and who have sex with men
(further referred to as HIV+ MSM); - histopathological confirmed HGAIN (>=1
lesion); - satisfactory HRA at baseline, i.e. visualisation of entire
transformation zone with biopsies of all lesions; Substudy HIV-positive group
(N=20): - >18 years of age - Compliance to ART, undetectable viral load since
at least 1 year - A low nadir CD4 cell count (<200 cell/µl) -
Histopathologically confirmed HGAIN (>=1 lesion); - Satisfactory HRA at
baseline, i.e. visualisation of entire transformation zone with biopsies of all
lesions; Substudy HIV-negative group (N=20) - >18 years of age -
Histopathologically confirmed HGAIN (>=1 lesion); - Satisfactory HRA at
baseline, i.e. visualisation of entire transformation zone with biopsies of all
lesions;
Exclusion criteria
Study group: - HGAIN covering more than 50% of the circumference of the anal
canal (progression to cancer of these patients is estimated as high and
therefore withholding treatment would be unethical); - clinical suspicion for
anal cancer, defined as palpable abnormalities at DARE and suspicion of
invasion at MRI; - histopathological diagnosis of anal cancer; - history of
anal cancer; - previous HPV vaccination (including participants of the
VACCAIN-T and VACCAIN-P trial); - concomitant cancer; - insufficient Dutch or
English language skills. Substudy group (N=40): - Clinical suspicion for anal
cancer, defined as palpable abnormalities at DARE and suspicion of invasion at
MRI; - Histopathological diagnosis of anal cancer; - History of anal cancer; -
Previous HPV vaccination (including participants of the VACCAIN-T and VACCAIN-P
trial); - Known active chronic infection such as hepatitis B or C - Diabetes
mellitus - Insufficient Dutch or English language skills. - Presence of any
diseases affecting the anal mucosa (fistulas, rhagades, eczema). - Signs of
current STI.
Design
Recruitment
Kamer G4-214
Postbus 22660
1100 DD Amsterdam
020 566 7389
mecamc@amsterdamumc.nl
Kamer G4-214
Postbus 22660
1100 DD Amsterdam
020 566 7389
mecamc@amsterdamumc.nl
Kamer G4-214
Postbus 22660
1100 DD Amsterdam
020 566 7389
mecamc@amsterdamumc.nl
Followed up by the following (possibly more current) registration
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In other registers
| Register | ID |
|---|---|
| CCMO | NL76718.018.21 |
| Other | NL9664 |