Screening for Human Papillomavirus and Cervical Cancer in Young Women With Perinatally Acquired HIV
Conditions: HIV Infections, Human Papillomavirus Infection, Cervical Cancer
Sponsor: Imperial College London

SHiP Study Protocol 
 
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Study title: Screening for HPV and cervical cancer in young women with 
perinatally acquired HIV (SHiP study) 
 
Study type: An observational study to determine cervical cytological abnormalities and 
HPV prevalence amongst young women aged 18 or over with perinatally acquired HIV. 
 
Internal Reference / Short title:  
SHiP 
Protocol date and version number:   1.11.2019, Version 1.2 
Main sponsor:  
 
 
Imperial College London 
Funders:  
 
 
 
Imperial Health Charity 
 
Chief Investigator:  
 
 
Dr Tamara Elliott 
Specialist Registrar in HIV and GU medicine, Imperial College Healthcare NHS Trust 
Tamara.elliott04@ic.ac.uk 
 
Co-Principle Investigators: 
 
 
Prof Sarah Fidler 
Professor and consultant in HIV and GU medicine, Imperial College London 
 
Dr Caroline Foster 
Consultant in paediatric infectious diseases, Imperial College Healthcare NHS Trust 
 
 
Co-investigators: 
Dr Merle Henderson 
Specialist Registrar in HIV and GU medicine, Imperial College Healthcare NHS Trust 
 
Dr Deidre Lyons 
Consultant gynaecologist, Imperial College Healthcare NHS Trust 
 
Collaborators:  
 
 
 
 
Ms Miranda Cowen 
Colposcopy and Hysteroscopy nurse specialist, Imperial College Healthcare NHS Trust 
 
Dr Corrina Wright 
Consultant cytopathologist, North West London Pathology 
 
Dr Simon Beddows 
Principal scientist, Public Health England, Colindale  
 
 
 
 
 
 
 

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Sponsor 
Imperial College London is the main research Sponsor for this study. For further information 
regarding the sponsorship conditions, please contact the Head of Regulatory Compliance at: 
 
Joint Research Compliance Office (JRCO) 
Imperial College London & Imperial College Healthcare NHS Trust  
2nd Floor Medical School Building  
St Mary’s Hospital  
Praed Street  
London  
W2 1PG  
Tel: 020759 41862 
 
 

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TABLE OF CONTENTS 
1. 
TRIAL SUMMARY  
 
 
 
 
 
 
 
 
5 
2.  
STUDY BACKGROUND  
 
 
 
 
 
 
 
7 
3. 
STUDY OBJECTIVES 
 
 
 
 
 
 
 
 
9 
4. 
STUDY DESIGN 
 
 
 
 
 
 
 
 
9 
5.  
PARTICIPANT ENTRY  
 
 
 
 
 
 
 
10 
5.1 
Screening 
 
 
 
 
 
 
 
 
10 
5.2 
Inclusion criteria 
 
 
 
 
 
 
 
10 
5.3 
Exclusion criteria 
 
 
 
 
 
 
 
10 
5.4 
Withdrawal criteria 
 
 
 
 
 
 
 
10 
6.  
STUDY PLAN  
 
 
 
 
 
 
 
 
12 
 
6.1 
Visit summary  
 
 
 
 
 
 
 
12 
 
6.2 
Screening visit  
 
 
 
 
 
 
 
12 
 
6.3 
Visit 1  
 
 
 
 
 
 
 
 
13 
 
6.4 
Visit 2  
 
 
 
 
 
 
 
 
13 
 
6.5 
Visit 3  
 
 
 
 
 
 
 
 
13 
7.  
STUDY PROCEDURES   
 
 
 
 
 
 
 
15 
 
7.1  
Cervical sampling 
 
 
 
 
 
 
 
15 
 
7.2  
Venepuncture and urine 
 
 
 
 
 
 
15 
8.  
DEFINITION OF END OF STUDY  
 
 
 
 
 
 
16  
9. 
STATISTICAL ANALYSIS  
 
 
 
 
 
 
 
16 
10. 
DATA MANAGEMENT  
 
 
 
 
 
 
  
17  
10.1  Access to data  
 
 
 
 
 
 
 
17 
10.2 
Data recording and record keeping  
 
 
 
 
17 
11. 
QUALITY ASSURANCE PROCEDURES  
 
 
 
 
 
17 
12. 
ADVERSE EVENTS  
 
 
 
 
 
 
 
 
18 
 
12.1 
Definitions 
 
 
 
 
 
 
 
 
18 
 
12.2  Reporting 
 
 
 
 
 
 
 
 
18 
13. 
ETHICAL AND REGULATORY CONSIDERATIONS 
 
 
 
 
19 
14. 
DECLARATION OF HELSINKI   
 
 
 
 
 
 
19 
15. 
GOOD CLINICAL PRACTICE  
 
 
 
 
 
 
 
19 
16. 
REPORTING 
 
 
 
 
 
 
 
 
 
20 
17. 
PARTICIPANT CONFIDENTIALITY  
 
 
 
 
 
 
20 
18.  
EXPENSES AND BENEFITS 
 
 
 
 
 
 
 
20 
19. 
OTHER ETHICAL CONSIDERATIONS 
 
 
 
 
 
 
20 
20. 
FINANCE  
 
 
 
 
 
 
 
 
 
21 
21. 
INSURANCE 
 
 
 
 
 
 
 
 
 
21 
22. 
PUBLICATION POLICY  
 
 
 
 
 
 
 
21 
23. 
ADMINISTRATIVE MATTERS   
 
 
 
 
 
 
21  
 
23.1  Source data 
 
 
 
 
 
 
 
 
21 
 
23.2  Language 
 
 
 
 
 
 
 
 
21 
 
23.3  Electronic recording of data  
 
 
 
 
 
21 
 
23.4 
Study management structure  
 
 
 
 
 
21 
 
23.5 
Quality control and quality assurance 
 
 
 
 
21 
24. 
RESULTS DISSEMINATION 
 
 
 
 
 
 
 
22 
25. 
REFERENCES  
 
 
 
 
 
 
 
 
22  

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LIST OF ABBREVIATIONS 
HPV  
 
Human Papilloma Virus 
Hr-HPV 
High-risk Human Papilloma Virus 
ART  
 
Antiretroviral therapy  
HIV  
 
Human Immunodeficiency Virus  
PaHIV  
Perinatally acquired HIV 
WLWH  
Women living with HIV 
CIN  
 
Cervical Intraepithelial Neoplasia 
VIA 
 
Visual Inspection with Acetic acid 
BHIVA  
British HIV Association 
HYPNet 
HIV in Young People Network 
NSC 
 
National Screening Committee 
NHS  
 
National Health Service  
PHE 
 
Public Health England 
WHO  
World Health Organisation 
NHSCSP 
NHS Cervical Screening Programme 
PCR 
 
Polymerase Chain Reaction 
GCP  
 
Good Clinical Practice  
IEC  
 
Independent ethics committee  
IRB 
 
Institutional Review Board 
PI  
 
Primary investigator  
REC  
  
Research Ethics Committee 
 
 

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1. TRIAL SUMMARY 
Title: Screening for HPV and cervical cancer in young women with perinatally acquired HIV 
(SHiP study) 
Summary: This protocol describes an observational study of cervical cytology assessment, 
high risk human papilloma virus (hr-HPV) status, and HPV antibody titres amongst adult 
women living with perinatally acquired HIV infection (PaHIV).  Eligible consenting 
participants will have two samples taken; firstly, a cervical sample tested for cytology and 
Hr-HPV with the Cepheid GeneXpert HPV; secondly, Blood sampling, serum will be assessed 
for hr-HPV serology.  All women with PaHIV, vaccinated and unvaccinated for HPV, over the 
age of 18 years will be eligible and will be recruited into one of two cohorts: (1) sexually 
active women: full study, cervical and blood sampling (n=50) or (2) non-sexually active 
women, blood sampling only (n=30). Follow up for abnormal smear results or hr-HPV 
positivity will be arranged through standard NHS referral pathways for colposcopy. 
Rationale:  HIV increases the risk of HPV related cervical intraepithelial neoplasia (CIN) and 
cervical cancer, and it is hypothesized that women with perinatally acquired HIV may be 
more at risk from an earlier age than the general population, and than women living with 
HIV acquired in adulthood, although there is little data to support this. For this reason, the 
HIV in Young People Network (HYPNet) guidelines state that cervical screening should start 
when a young woman with PaHIV becomes sexually active, irrespective of age(1), but 
despite these recommendations this is not included in UK guidelines.  Currently cervical 
cytology is routinely available for all women with HIV yearly from the age of 25 to 65 in 
England, but younger women (<25 years) with PaHIV are not currently eligible for NHS 
cervical screening.  
We hypothesise that young women with PaHIV may benefit from cervical screening < 25 
years of age, due to an increased risk of cervical abnormalities as a consequence of lifelong 
impaired immune function and the potential for suboptimal responses to the HPV 
vaccination. A delay in screening until aged 25 may miss early detection of manageable pre-
cancers and cancer. 
Primary aim: To identify the prevalence of abnormal cervical cytology in a cohort of sexually 
active young women with PaHIV aged ³ 18 years 
 
Secondary aims: 
• To identify the prevalence of high-risk HPV by subtype in a cohort of sexually active 
women with PaHIV aged ³ 18 years 
• To identify the prevalence of CIN2+ in a cohort of sexually active women with PaHIV 
aged ³ 18 years 
• Explore the use of HPV testing as a primary screening tool compared with cervical 
cytology in this cohort 
• Characterisation of immunological and other correlates with high-risk HPV carriage, 
cervical abnormalities and CIN2+ 
• Investigate antibody titres to the HPV in vaccinated and unvaccinated women and 
compare this to the antibody responses to other vaccinations (e.g. hepatitis B) 

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• Explore the relationship between HPV-antibody titres and current immune function 
(CD4 count) and CD4 count at the time of vaccination 
• Explore the uptake and acceptability of cervical screening before the age of 25 in this 
cohort 
• Explore the cost-benefit of providing cervical screening before the age of 25 in this 
cohort 
 
Planned sample size: 80 
Sites:  
900 Clinic Imperial College Healthcare NHS Trust  
Team clinic, Mortimer Market Centre, Central and North West London NHS Foundation 
Trust 
Planned Study Period: Sept 2019 – Sept 2021 
 
 

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2. STUDY BACKGROUND 
Cervical cancer is caused by high-risk HPV subtypes, and the relationship between HIV and 
HPV is well recognised. In HIV uninfected women HPV 16 and HPV 18 are responsible for 
71% of cervical cancers(2). Women living with HIV are more likely to have persistent HPV 
infections, and are at greater risk of developing complications secondary to this, including 
cervical dyskaryosis, intraepithelial neoplasia (CIN) and cervical cancer(3–6).  It is due to 
these higher rates as well as the more rapid progression of disease that BHIVA recommends 
annual smear tests for HIV positive women aged 25-65 years(7), compared to 3-yearly for 
HIV non-infected women. BHIVA has no specific guidance for women with perinatally 
acquired HIV (PaHIV) under 25 years due to a paucity of data, but the HIV in Young People 
Network (HYPNet) state that cervical screening should start within a year of when a young 
woman with PaHIV becomes sexually active, ideally with baseline colposcopy(1). Due to 
limitations of national testing policies within the UK this is no longer achieved for those 
under 25.  
Although there are very little data on cervical screening in people with PaHIV, this 
population is known to be at an increased risk of all cause malignancy, with more than half 
being associated with chronic oncogenic viral infections(8). It is proposed that the 
pathogenesis of HPV related disease may be altered in those with PaHIV due to living with 
the HIV virus throughout childhood and sometimes having significant immunosuppression 
during this time. Moscicki et al. found that adolescents with primarily horizontally acquired 
HIV had a much higher rate of high grade squamous intraepithelial lesions (HSIL) at 22% 
compared with 5% in age- and risk-matched controls(9). In the same cohort, 77% of those 
with HIV were positive for HPV, and only 30% of these had normal cytology, compared to 
55% testing positive for HPV in the HIV-negative controls, of which 70% had normal 
cytology(10). Brogly et al. also found a higher prevalence (48%) of cervical abnormalities in 
those with PaHIV who had a smear test compared to that documented in aged matched 
HIV-negative adolescents(11). In a study looking at HPV infections in non-sexually active 
PaHIV, 30% of girls had anogenital HPV compared to 7% of HIV-exposed but uninfected girls, 
although the HIV uninfected girls were significantly younger in age. They suggest that HPV 
may be commonly acquired non-sexually in PaHIV, and that vaccine efficacy may be 
different in this group(12). Within our cohort of young adults with PaHIV (the 900 clinic) at 
Imperial College Healthcare NHS Trust, previous data showed 17% of young women had an 
abnormal first smear, with a median age of 19 years, and a median coitarche-first smear 
interval of 2 years. Overall the median age at coitarche was 16 years(13).  
In the NHS cervical screening programme, samples are not routinely tested for HPV unless 
there are borderline or low-grade changes. In 2016, the UK National Screening Committee 
(NSC) recommended that hr-HPV testing should replace cervical cytology as the primary 
cervical screening method. NHS England plans to achieve full rollout of this by the end of 
2019, and this is already being implemented in some pilot sites across England. Women 
living with HIV (WLWH) will continue to have annual screening using primary hr-HPV testing 
rather than cytology(15). Women who are positive for hr-HPV will also have cervical 
cytology sent to triage whether they should be referred for colposcopy or have repeat 
screening in one year(15). 

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Other international guidelines recommend primary cervical screening with hr-HPV(16), and 
management protocols differ slightly on the referral pathway to colposcopy, with some 
recommending partial genotyping and direct referral to colposcopy for women testing 
positive for the highest risk HPV (16 or 18)(17). In our cohort, there is little evidence to 
determine the best cervical screening algorithm, so for this reason we have elected to offer 
colposcopy to all women testing positive for hr-HPV as well as those with abnormal cervical 
cytology. 
The GeneXpert HPV Assay (Cepheid, Sunnydale, California, USA) is a clinically validated real-
time polymerase chain reaction (PCR) assay, which uses a single-use cartridge for the 
detection of 14 types of hr-HPV in 3 channels (HPV 16, HPV 18/45, and other hr-HPV 
31/33/35/52/58/51/59/39/56/66/68)(18). The NHS Cervical Screening Programme (NHSCSP) 
lists the Cepheid GeneXpert as acceptable for use within screening for HPV triage and test of 
cure(19). 
Part of the reason for this move to primary screening with HPV in the UK is due to the 
introduction of the national HPV immunisation programme in 2008. It is thought that the hr-
HPV testing is a more appropriate screening method in HPV vaccinated women, as the 
incidence of CIN should be lower(15). Since 2008, HPV vaccination has been offered to all 
girls aged 12-13 years (with a catch up programme for the first two years in girls aged up to 
18 years). Until 2012, girls were offered the bivalent vaccine (against HPV 16 and 18), and 
since then the quadrivalent vaccine has been offered (HPV 16, 18, 6 and 11)(20). Studies 
looking at immunogenicity of the HPV vaccine have showed overall good responses in 
people living with HIV, with better and more sustained responses in those with a higher CD4 
count and undetectable viral load(21–24), although data in people with PaHIV is sparse. A 
study by Giacomet et al. looked at HPV vaccine safety and response in HIV-infected and -
uninfected adolescents in Italy(21). They recruited 46 females and males with HIV aged 13-
27 years, and an equal number of age matched controls; the mean CD4 count in this group 
was 715 cells/ul and 95% had an undetectable viral load at baseline. At one month post 
vaccine, seroconversion rate was 85% in the HIV positive group compared to 91% in the 
control group. The mean titres measured using a HPV IgG ELISA kit were 5.8ug/ml less in the 
HIV positive group at 18 months post vaccine(21). In another study looking at vaccine 
response by Kahn et al. 99 women with HIV (none perinatally acquired) were recruited, 69 
into a non-antiretroviral therapy (ART) group, and 30 into an ART group(22). Overall mean 
CD4 count was 613 cells/ul, with 86% having a CD4 ³ 350 cells/ul. They found that 
geometric mean titres (GMT) were around twice as high in the ART group compared to non-
ART group, and this was statistically significant for HPV types 16 and 18. They found that 
GMT was also significantly lower in the non-ART group versus a historical comparison group. 
Seroconversion rates were 100% for all four HPV types in the ART group but were as low as 
92.3% for HPV 18 in the non-ART group and this dropped significantly by week 48 to 67.6%. 
Titres were also higher at week 28 and 48 in those with VL <400 copies/ml, but this was only 
significant for HPV 11(22). Lastly, in a study looking at HPV vaccine responses in children 
with HIV aged 7-12, seroconversion rates were 96% but immune titres to HPV 6 and 18 were 
30-60% lower than those achieved in historical controls(25). The clinical significance of this 
is unclear, and further studies are needed to assess the long-term efficacy of the HPV 
vaccination in young people living with HIV. 

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3. STUDY OBJECTIVES 
Primary objective: To identify the prevalence of abnormal cervical cytology in a cohort of 
sexually active young women with PaHIV aged ³ 18 years 
 
Secondary objectives: 
• To identify the prevalence of high-risk HPV by subtype in a cohort of sexually active 
women with PaHIV aged ³ 18 years 
• To identify the prevalence of CIN2+ in a cohort of sexually active women with PaHIV 
aged ³ 18 years 
• Explore the use of HPV testing as a primary screening tool compared with cervical 
cytology in this cohort 
• Characterisation of immunological and other correlates with high-risk HPV carriage, 
cervical abnormalities and CIN2+ 
• Investigate antibody titres to the HPV in vaccinated and unvaccinated women and 
compare this to responses to other vaccinations (e.g. hepatitis B) 
• Explore the relationship between HPV-antibody titres and current immune function 
(CD4 count) and CD4 count at the time of vaccination 
• Explore the uptake and acceptability of cervical screening before the age of 25 in this 
cohort 
• Explore the cost-benefit of providing cervical screening before the age of 25 in this 
cohort 
4. STUDY DESIGN 
This is an observational study of cervical cytology and hr-HPV carriage in young females 
attending a large tertiary referral centre providing HIV care for perinatally acquired HIV 
infection (n=80).  Recruitment will be over 18 months from the study start date or until the 
planned sample size is recruited. Consenting study participants will give consent to access 
HPV vaccination history from GP records with the dates and vaccines received.  
Eligible young women (≥ 18 years with PaHIV infection) will be invited to join the study. 
They will be given time to read the patient information sheet and written informed consent 
will be taken by a study team member. Women will be recruited into one of two cohorts: 
(Cohort 1) Aged ≥ 18 and sexually active, (Cohort 2) Aged ≥ 18 and not sexually active.  
At enrolment, a single study visit will be required for both cohorts, during which, a venous 
blood draw of 6mls will be taken plus an optional additional 30mls (36mls total) and an 
optional urine sample for the Biobank. Participants will be asked to complete a short 1-page 
questionnaire and a data collection sheet will be completed by study staff. Women enrolled 
into cohort 1 will also have a speculum examination and a cervical sample will be tested for 
hr-HPV using the Cepheid GeneXpert HPV and sent for cytology in routine NHS laboratories.  
Results of cervical cytology and cervical hr-HPV testing will be given to the study participants 
in cohort 1. This will either be at an arranged second visit, or via a phone consultation, email 
or letter depending on the preferences of the individual. Referral to colposcopy services will 
be made in accordance with current national clinical pathways for any young woman with 

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abnormal cytology results. In the case of normal cytology in the presence of hr-HPV, these 
women will also be referred for colposcopic examination. The blood HPV serology are for 
research purposes only and hence individual results will not be given back to the study 
participants. At the end of the study, aggregate results will be shared with the study 
participants.  
The HPV vaccination is now available to all women in the UK aged less than 25 years. If 
women have not been vaccinated at the time of enrolment but are subsequently 
vaccinated, we will consent them for repeat serological testing at the next clinic 
appointment following the completion of the HPV vaccine course. 
5. PARTICIPANT ENTRY 
5.1 Screening 
Young adults living with perinatally acquired HIV-1 attending the 900 clinic at Imperial 
College Healthcare NHS Trust London, or the Team clinic at the Mortimer Market Centre, 
aged 18 years and older. 
5.2 Inclusion criteria 
• Cohort 1: 
o PaHIV females age 18 years and older 
o Sexually active 
o Able to give informed consent  
• Cohort 2: 
o PaHIV females age 18 years and older 
o Able to give informed consent  
5.3 Exclusion criteria 
• Cohort 1: 
o Pregnancy 
o Not sexually active 
o Previous total abdominal hysterectomy 
o Unable to give informed consent 
• Cohort 2: 
o Unable to give informed consent 
5.4 Withdrawal criteria 
Each participant has the right to withdraw from the study at any time.  In addition, the 
Investigator may discontinue a participant from the study at any time if the Investigator 
considers it necessary for any reason.  
Participants who withdraw from the study will have their censored data included in the 
study analysis unless specifically requested by the individual not to include it. Any stored 

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samples remaining on withdrawn participants will be either destroyed or remain within the 
laboratory for future testing depending on the participant’s wishes.   
The reason for withdrawal will be recorded in the CRF.  
 

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6. STUDY PLAN 
 
6.1 Visit summary  
The study will consist of one visit, plus an optional second visit, and where possible these 
will coincide with routine clinical visits:  
• Screening, patient information and consent 
• Study visit 1 (may be at the same time as screening, provided sufficient time has 
been given to read the patient information sheet and understand the study) – all 
participants   
• Study visit 2, results – optional for cohort 1 
  
6.2 Screening visit: Patients will be assessed against the above inclusion and exclusion 
criteria and will be asked if they wish to participate if they are eligible for the study.  
  
To all eligible individuals, an explanation of the study will be provided along with a copy of 
the participant information sheet. They will be given as much time as they need to consider 
their participation and will be informed that participation is voluntary and a decision not to 
participate will not affect their clinical care.  The participant must personally sign and date 
the latest approved version of the Informed Consent form before any study specific 
procedures are performed, in the presence of a study team member.  
  
Written and verbal versions of the Participant Information and Informed Consent will be 
given to participants detailing no less than: the exact nature of the study; what it will involve 
for the participant; the implications and constraints of the protocol, and any risks involved in 
taking part. It will be clearly stated that the participant is free to withdraw from the study at 
any time for any reason without prejudice to future care, and with no obligation to give the 
reason for withdrawal.  
 
Optional sub-study: Consent for an additional donation of blood and urine sampling to the 
Biobank for future research is optional and consent for the use of any remaining blood 
samples taken as part of this protocol for use in future research into the immune system 
and viral infections as part of the Communicable Diseases Research Biobank will also be 
obtained.   
  
The participant will be allowed as much time as wished to consider the information, and the 
opportunity to question the Investigator, their GP or other independent parties to decide 
whether they will participate. Written Informed Consent will then be obtained and a copy of 
the signed Informed Consent will be offered to the participant. The original signed form will 
be retained.  
 
Visit 1 will either be at the time of the screening visit, their next routine clinic visit or as an 
additional study visit depending on participant preferences.  
 
6.3 Visit 1: At visit 1 (either the same day as study enrolment or scheduled to another date 
as per participant preference) each participant will have their eligibility and consent in the 
trial confirmed. Clinical and demographic information will be recorded on the study CRF and 
will include:  

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• Age  
• Ethnicity  
• Current CD4 count  
• Current CD4:CD8 ratio 
• Current HIV-1 RNA viral load  
• Nadir CD4 count  
• Length of viral suppression <50 copies/ml  
• Current antiretroviral therapy  
• Concomitant medications  
• Smoking 
• Menarche 
• Coitarche 
• Obstetric history  
• Gynaecology history including previous smear results 
• Contraception  
• HPV vaccination history (including age at vaccination, type, number of doses) 
• Other vaccination history 
• CD4 count at time of first HPV vaccination (if known) 
• Lifetime number of sexual partners 
• Diagnosed STIs 
• History of genital warts 
• Consent to access GP records for HPV vaccination details where GP aware of status 
 
Investigations:  
• Cervical smear test 
• Cervical sampling for hr-HPV testing 
• Blood for serology  
• Optional Blood and urine for Biobank 
6.4 Visit 2 (optional for cohort 1, 2-4 weeks later): Attendance for results of the cervical 
cytology and hr-HPV will be made with the research team. If a participant does not wish to 
attend for a second visit they will be given the option to get their results by phone, letter or 
email. All other tests are considered research tests and the individual results will not be 
given back to the study participant. Any abnormal cervical cytology result will be referred to 
local colposcopy services in accordance with local and British guidelines. Women who test 
positive for any hr-HPV will also be referred to colposcopy for the purposes of this study. 
Consent will be sought to collect outcome data following gynaecology referral.  
6.5 Visit 3: For those women who receive HPV vaccination after enrolment into the study, 
repeat blood tests will be taken at the next clinic visit after completion of the vaccine 
course. 
The study procedures algorithm can be seen in Figure 1. 

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7. STUDY PROCEDURES  
7.1 Cervical sampling for smear test and hr-HPV testing 
Cervical cytology will be performed by a trained healthcare professional in accordance with 
current guidance in England for liquid based cytology using a disposable plastic speculum for 
speculum examination. A 1ml aliquot will be analysed for hr-HPV using the Cepheid 
GeneXpert HPV. 
The risks to the participant of the procedure are discomfort and vaginal bleeding after the 
procedure.  The participant may also feel discomfort vaginally following the speculum 
examination. 
7.2 Venepuncture and urine 
Participants will be consented to donate 6mls for serological testing, and an optional 
additional 30 mls of blood and a urine sample to be stored in the Biobank at Imperial 
College. This will be used for additional research testing for future viral and immune studies. 
Where possible blood taking will coincide with routine clinical monitoring blood taking. 
The risks to the participant of venepuncture are pain and bruising following the procedure. 
The participant may also feel faint due to a vaso-vagal response or hypotension, and in this 
case the venepuncture will cease and the patient will be laid flat until recovery.   
HPV antibody serology: 1 x Red top 6 mls  
BioBank EDTA: 5 x purple top 6ml to 30 mls  
Total samples at Visit 1:   
* Blood: One 6ml Red top tube: 6ml 
* Blood: (sub-study) Five 6ml EDTA samples for research: 30 mls  
* Smear test and HPV testing: One liquid based cervical cytology  
* Urine: (sub-study) One universal container 
Total samples at Visit 3 (if applicable): 
* Blood: One 6ml Red top tube: 6ml 
* Blood: (sub-study) Five 6ml EDTA samples for research: 30 mls  
All samples will be sent under the unique study number: cohort 1: SHiP/1/000/0, cohort 2: 
SHiP/2/000/0 
 
 

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8. DEFINITION OF END OF PROGRAMME  
The end of the study is the date of final follow up of the final participant be that colposcopy 
or final smear results visit. The final results of the study will be shared with all participants 
as a letter and information sheet with explanation. A specific results-sharing participant 
meeting will be organised to allow further study results to be explained as required.  
9. STATISTICAL ANALYSIS  
• Summarising data: Characteristics of the study population will be described using mean 
and standard deviation, median and interquartile range, or number and percentage as 
appropriate. This information will also be stratified by age group. 
• Primary outcome: The prevalence of cervical abnormalities within the cohort and by age 
group (18-24 and ³25) will be calculated 
• Secondary outcomes: 
o The prevalence of hr-HPV by type in young women with PaHIV will be calculated 
and stratified by age group 
o The prevalence of CIN2+ in young women with PaHIV will be calculated and 
stratified by age group 
o Comparison of HPV positivity with cervical abnormalities in young women with 
PaHIV 
o Characterisation of immunological and other correlates with hr-HPV carriage,  
cervical cytology results, CIN2+ and HPV type-specific antibody titres using the 
appropriate statistical test (Pearson’s chi squared, Fisher’s exact, Wilcoxon rank 
sum) 
o A measurement of HPV type-specific antibody titres in HPV vaccinated and 
unvaccinated young women with PaHIV, and a comparison with e.g. antibody 
titres to hepatitis B vaccination 
o Correlations of HPV-antibody titres and current immune function (CD4 count) 
and CD4 count at the time of vaccination 
o Acceptability will be assessed by the proportion of women who are offered 
enhanced cervical screening but decline. 
o Cost effectiveness will be assessed by evaluating the yield of abnormal results 
(cytology and hr-HPV) versus the cost of the tests 
 
 
 

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10. DATA MANAGEMENT  
10.1 Access to data  
Direct access will be granted to authorised representatives from the Sponsor or host 
institution for monitoring and/or audit of the study to ensure compliance with UK GCP and 
GDPR regulations.  
10.2 Data recording and record keeping  
a) CRF  
The demographic and clinical data will be collected in the study CRF. Any relevant hard 
copies of source data will be filed locally under patients’ unique identifier in accordance 
with Data Protection Act agreed practice. In all locations, any hard copy patient data will be 
stored in locked, filing cabinets with access restricted to pre-specified essential users.  
b) Confidentiality  
Information related to participants should be kept confidential and managed in accordance 
with the Data Protection Act, NHS Caldecott Principles, The Research Governance 
Framework for Health and Social Care, and the conditions of Research Ethics Committee 
Approval.  
c) Record Retention and Archiving  
The investigator will retain essential documents for 10 years as per Imperial College London 
policy (the sponsor). This includes subject files and other source data (including copies of 
protocols, CRFs, original reports of test results, correspondence, records of informed 
consent, and other documents pertaining to the conduct of the study). Documents will be 
stored in such a way that they can be accessed/data retrieved at a later date. Consideration 
will be given to security and environmental risks.  
No study document will be destroyed without prior written agreement between the 
Sponsor and the investigator. Should the investigator wish to assign the study records to 
another party or move them to another location, written agreement must be obtained from 
the Sponsor.  
11. QUALITY ASSURANCE PROCEDURES  
The study may be monitored, by the study sponsor, or audited in accordance with the 
current approved protocol, ICH GCP, relevant regulations and standard operating 
procedures.  
 
 

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12. ADVERSE EVENTS 
12.1 Definitions 
(a) Adverse Event (AE): any untoward medical occurrence in a patient or clinical study 
subject.  
(b) Serious Adverse Event (SAE): any untoward and unexpected medical occurrence or effect 
that:  
• 
Results in death  
• 
Is life-threatening – refers to an event in which the subject was at risk of death at the 
time of the event; it does not refer to an event which hypothetically might have 
caused death if it were more severe  
• 
Requires hospitalisation 
• 
Results in persistent or significant disability or incapacity  
• 
Is a congenital anomaly or birth defect  
Medical judgement should be exercised in deciding whether an AE is serious in other 
situations. Important AEs that are not immediately life-threatening or do not result in death 
or hospitalisation but may jeopardise the subject or may require intervention to prevent 
one of the other outcomes listed in the definition above, should also be considered serious.  
12.2 Reporting procedures 
All adverse events should be reported. Depending on the nature of the event the reporting 
procedures below should be followed. Any questions concerning adverse event reporting 
should be directed to the Chief Investigator in the first instance.  
(a) Non serious AEs  
All such events, whether expected or not, should be recorded.  
(b) Serious AEs  
A SAE form should be completed and sent to the Chief Investigator within 24 hours.  
All SAEs should be reported to the Research Ethics Committee where in the opinion of the 
Chief Investigator, the event was:  
• 
‘related’, i.e. resulted from the administration of any of the research procedures; and  
• 
‘unexpected’, i.e. an event that is not listed in the protocol as an expected occurrence  
Reports of related and unexpected SAEs should be submitted within 15 days of the Chief 
Investigator becoming aware of the event. The Chief Investigator must also notify the 
Sponsor of all SAEs.  
 

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Local investigators should report any SAEs as required by their Local Research Ethics 
Committee, Sponsor and/or Research & Development Office. 
Contact details for reporting SAEs: 
 jrco@imperial.ac.uk  
Chief Investigator email Tamara Elliott, tamara.elliott@nhs.net  
13. ETHICAL AND REGULATORY CONSIDERATIONS  
Ethics approval will be sought through the Research Ethics Committee and Health Research 
Authority.  
(i) Initial Approval  
Prior to the enrolment of participants, the IEC/IRB must provide written approval of the 
conduct of the study at named sites, the protocol and any amendments, the Participant 
Information Sheet and Consent Form, any other written information that will be provided to 
the participants.   
(ii) Approval of Amendments  
Proposed amendments to the protocol and aforementioned documents must be submitted 
to the IEC/IRB for approval as instructed by the Sponsor. Amendments requiring IEC/IRB 
approval may be implemented only after a copy of the IEC/IRB’s approval letter has been 
obtained.   
Amendments that are intended to eliminate an apparent immediate hazard to subjects may 
be implemented prior to receiving Sponsor or IEC/IRB approval. However, in this case, 
approval must be obtained as soon as possible after implementation.  
14. DECLARATION OF HELSINKI  
The study will be conducted in accordance with the principles of the Declaration of Helsinki.  
15. GOOD CLINICAL PRACTICE  
The study will be conducted in accordance with relevant regulations and with Good Clinical 
Practice, and in accordance with all applicable regulatory requirements including but not 
limited to the Research Governance Framework and the Human Tissues Act 2004.  
The protocol, informed consent form and participant information sheet will be submitted to 
an appropriate REC and host institution(s) for written approval.  
The Investigator will submit and, where necessary, obtain approval from the above parties 
for all substantial amendments to the original approved documents.  
 
 

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16. REPORTING  
An End of Study notification and final report will be submitted to REC, host organisation and 
Sponsor. Main laboratory research outcomes will be reported to the study participants in 
aggregate prior to public presentation of the study data.  
17. PARTICIPANT CONFIDENTIALITY  
The study staff will ensure that the participants’ anonymity is maintained at all times. All 
documents will be stored securely and only accessible by study staff and authorised 
personnel. The study will comply with the Data Protection Act, which requires data to be 
anonymised as soon as it is practical to do so.  
18. EXPENSES AND BENEFITS  
Participants will be financially reimbursed for their participation in the study: 
• Cohort 1: £20 
• Cohort 2: £10 
19. OTHER ETHICAL CONSIDERATIONS  
We are offering cervical cytology examination outside the current age range recommended 
by NHS England. The research question is to explore the value of doing this amongst women 
with PaHIV, a unique cohort of high-risk individuals.  
A potential ethical risk is that participants feel obligated to enrol in the study. This will be 
mitigated through correct explanation of voluntary nature of both the cervical testing and 
blood sample donation.  
Individuals consenting to donate cervical samples will be informed of results, and any 
abnormal results will be referred for colposcopy, and managed as clinically appropriate. This 
is not research but standard clinical care, although these tests are being offered to women 
at a younger age than current guidelines.  
Counselling about the meaning of hr-HPV will be carefully given with information made 
available. The tests may lead to anxiety and concern about cancer and these will be dealt 
with as appropriate according to individual situations and careful counselling by expert 
gynaecology services.  
A maximum of 30ml of additional research blood will be taken. The only side effect of 
having blood taken will be the chance of bruising or vasovagal/syncopal response for which 
procedures will be in place to minimize risk. Where possible blood will be taken in 
conjunction with routine clinic bloods.    
 
 

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20. FINANCE  
The study sponsor is Imperial College London. The core costs will be covered by funding 
from Imperial Health Charity. Additional funding is being sought and will support future 
research costs if successful. 
21. INSURANCE  
NHS indemnity operates in respect of the clinical treatment which is provided. Imperial 
College London holds negligent harm and non-negligent harm insurance policies which apply to this 
study 
22. PUBLICATION POLICY  
The Investigators will be involved in reviewing drafts of the manuscripts, abstracts, press 
releases and any other publications arising from the study. Authorship will be determined in 
accordance with the ICMJE guidelines and other contributors will be acknowledged.  
23. ADMINISTRATIVE MATTERS  
23.1 Source data  
Source Data will be patient medical records, laboratory reports and a short 1-page 
questionnaire.  
23.2 Language  
CRFs will be in English. Generic names for concomitant medications should be recorded in 
the CRF wherever possible. All written material to be used by subjects must use vocabulary 
that is clearly understood, and be in the language appropriate for the study site.  
23.3 Electronic Recording of data  
Source data will be entered and stored on an electronic database. This database will be held 
at Imperial College NHS Trust and will be password protected. 
23.4 Study Management Structure   
Study management Group: will oversee the day-to-day running of the trial and the members 
will be primarily the clinical and data management teams.   
23.5 Quality Control and Quality Assurance  
Quality Control will be performed according to Imperial Clinical Trials Unit internal 
procedures. The study may be audited by a Quality Assurance representative of the 
Sponsor. All necessary data and documents will be made available for inspection.  

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The results may be published or presented by the investigator(s), but the Sponsor will be 
given the opportunity to review and comment on any such results before any presentations 
or publications are produced.  
Preparation of a manuscript for rapid publication will be the responsibility of the chief 
investigator. High priority will be given to this and it is anticipated that a report will be 
completed within two months of completion of the study.   
24. RESULTS DISSEMINATION  
When completed the results of the study will be shared with participants through a 
participant results summary information sheet given at their next clinic appointment and 
they will have the opportunity to ask questions relating to the study.  
Data will be presented at conferences and National and international meetings as well as 
submitted for publication in open peer reviewed journals when appropriate.  
25. REFERENCES 
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Guidance on the management of sexual and reporductive health for adolescents 
living with HIV 2011. HYPNET/CHIVA/BASGG/BHIVA. 2011;1–46.  
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de Sanjose S, Quint WG, Alemany L, Geraets DT, Klaustermeier JE, Lloveras B, et al. 
Human papillomavirus genotype attribution in invasive cervical cancer: a 
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3.  
Massad LS, Xie X, Burk R, Keller MJ, Minkoff H, DʼSouza G, et al. Long-term cumulative 
detection of human papillomavirus among HIV seropositive women. AIDS. 2014 Nov 
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4.  
Massad LS, Seaberg EC, Wright RL, Darragh T, Lee Y-C, Colie C, et al. Squamous 
Cervical Lesions in Women With Human Immunodeficiency Virus. Obstet Gynecol. 
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Clifford GM, de Vuyst H, Tenet V, Plummer M, Tully S, Franceschi S. Effect of HIV 
infection on human papillomavirus types causing invasive cervical cancer in Africa. J 
Acquir Immune Defic Syndr. 2016;73(3):332–9.  
6.  
Moscicki A, Ellenberg JH, Farhat S, Xu J. Persistence of Human Papillomavirus 
Infection in HIV-Infected and -Uninfected Adolescent Girls: Risk Factors and 
Differences, by Phylogenetic Type. J Infect Dis. 2004 Jul 1;190(1):37–45.  
7.  
Angus B, Brook G, Awosusi F, Barker G, Boffito M, Das S, et al. British HIV Association 
guidelines for the routine investigation and monitoring of adult HIV-1-positive 
individuals 2016 BHIVA guidelines for the routine investigation and monitoring of 
adult HIV-1-positive individuals Writing Group. 2016.  
8.  
de Martel C, Shiels MS, Franceschi S, Simard EP, Vignat J, Hall HI, et al. Cancers 
attributable to infections among adults with HIV in the United States. AIDS. 2015 Oct 
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9.  
Moscicki A, Ellenberg JH, Crowley-Nowick P, Darragh TM, Xu J, Fahrat S. Risk of High-
Grade Squamous Intraepithelial Lesion in HIV-Infected Adolescents. J Infect Dis. 2004 
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10.  
Moscicki A-B, Ellenberg JH, Vermund SH, Holland CA, Darragh T, Crowley-Nowick PA, 
et al. Prevalence of and Risks for Cervical Human Papillomavirus Infection and 
Squamous Intraepithelial Lesions in Adolescent Girls. Arch Pediatr Adolesc Med. 2000 
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Brogly SB, Watts DH, Ylitalo N, Franco EL, Seage GR, Oleske J, et al. Reproductive 
health of adolescent girls perinatally infected with HIV. Am J Public Health. 2007 
Jun;97(6):1047–52.  
12.  
Moscicki A-B, Puga A, Farhat S, Ma Y. Human papillomavirus infections in nonsexually 
active perinatally HIV infected children. AIDS Patient Care STDS. 2014 Feb;28(2):66–
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Croucher AP, Jose S, McDonald S, Foster C, Fidler S. Sexual and reproductive health in 
a UK cohort of young adults perinatally infected with HIV. Sex Transm Infect. 2013 
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14.  
Primary HPV testing update - PHE screening [Internet]. [cited 2018 Oct 28]. Available 
from: https://phescreening.blog.gov.uk/2018/03/01/primary-hpv-testing-update/ 
15.  
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HPV screening Public Health England leads the NHS Screening Programmes. 2017.  
16.  
WHO guidelines WHO guidelines for screening and treatment of precancerous lesions 
for cervical cancer prevention.  
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of Health D. Understanding the National Cervical Screening Program Management 
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Cervical screening: approved HPV tests for HPV triage and test of cure - GOV.UK 
[Internet]. [cited 2018 Nov 25]. Available from: 
https://www.gov.uk/guidance/cervical-screening-approved-hpv-tests-for-hpv-triage-
and-test-of-cure 
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Mesher D, Stanford E, White J, Findlow J, Warrington R, Das S, et al. HPV Serology 
Testing Confirms High HPV Immunisation Coverage in England. PLoS One. 
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21.  
Giacomet V, Penagini F, Trabattoni D, Viganò A, Rainone V, Bernazzani G, et al. Safety 
and immunogenicity of a quadrivalent human papillomavirus vaccine in HIV-infected 
and HIV-negative adolescents and young adults. Vaccine. 2014 Sep 29;32(43):5657–
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Kahn JA, Xu J, Kapogiannis BG, Rudy B, Gonin R, Liu N, et al. Immunogenicity and 
safety of the human papillomavirus 6, 11, 16, 18 vaccine in HIV-infected young 
women. Clin Infect Dis. 2013 Sep;57(5):735–44.  
23.  
Kojic EM, Kang M, Cespedes MS, Umbleja T, Godfrey C, Allen RT, et al. 
Immunogenicity and safety of the quadrivalent human papillomavirus vaccine in HIV-
1-infected women. Clin Infect Dis. 2014 Jul 1;59(1):127–35.  
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Cespedes MS, Kang M, Kojic EM, Umbleja T, Godfrey C, Webster-Cyriaque JY, et al. 
Anogenital human papillomavirus virus DNA and sustained response to the 
quadrivalent HPV vaccine in women living with HIV-1. Papillomavirus Res 
(Amsterdam, Netherlands). 2018 Aug 16;6:15–21.  
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Levin MJ, Moscicki A-B, Song L-Y, Fenton T, Meyer WA, Read JS, et al. Safety and 
immunogenicity of a quadrivalent human papillomavirus (types 6, 11, 16, and 18) 
vaccine in HIV-infected children 7 to 12 years old. J Acquir Immune Defic Syndr. 2010 
Oct;55(2):197–204.  

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