The Study for the "Cervical Cancer Screening and Treatment Algorithms Study Using HPV Testing in Africa"
Phase: PHASE3
Conditions: HPV Infection
Sponsor: International Agency for Research on Cancer

 
 
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The Cervical cancer Screening and Treatment algorithms study using 
HPV testing in Africa (CESTA) 
 
Multi-country generic protocol 
 
 
 
 
June 2019 
 
(v4.0) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
 
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Table of Contents  
 
Table of Contents ................................................................................................................................. 2 
1. 
Executive Summary ...................................................................................................................... 4 
2. 
Background ................................................................................................................................... 6 
 
Clinical need .......................................................................................................................... 6 
2.1.
 
HPV and cervical cancer in HIV-positive women .................................................................. 8 
2.2.
 
HPV testing in cervical screening .......................................................................................... 9 
2.3.
 
VIA testing in cervical screening .......................................................................................... 10 
2.4.
 
Treatment of pre-cancerous lesions ................................................................................... 10 
2.5.
2.5.1. 
Cryotherapy.................................................................................................................. 11 
2.5.2. 
Thermal ablation .......................................................................................................... 12 
2.5.3. 
Large loop excision of the transformation zone (LLETZ) procedure ............................ 13 
 
Smartphone enhanced visual inspection with acetic acid (SEVIA) ..................................... 14 
2.6.
 
The use of cervical intraepithelial neoplasia (CIN) and Lower Anogenital Squamous 
2.7.
Terminology Standardization (LAST) terminology for cervical histology ....................................... 15 
3. 
Modules of the CESTA study ....................................................................................................... 16 
 
CESTA Module 1: Randomised control trial of two algorithms, screening with HPV tests 
3.1.
followed by VIA as a triage and treatment (HPV + VIA + treat), vs screening with HPV test 
followed by treatment (HPV + treat) among HIV-positive women in South Africa and HIV-
negative women in Senegal ........................................................................................................... 17 
3.1.1. 
Primary Objectives: ...................................................................................................... 17 
3.1.2. 
Secondary Objectives: .................................................................................................. 17 
 
Study outline CESTA Module 1 ............................................................................................ 18 
3.2.
3.2.1. 
CESTA Module 1 among HIV positive women in South Africa (see figure 2) .............. 18 
3.2.2. 
CESTA Module 1 among HIV negative women in Senegal (see figure 3) .................... 20 
 
Rationale for choice of target age for cervical screening ................................................... 23 
3.3.
 
Gold standard for disease detection ...................................... Error! Bookmark not defined. 
3.4.
 
Cost and Cost-effectiveness methods ................................................................................. 23 
3.5.
3.5.1. 
Modelling approach ..................................................................................................... 23 
3.5.2. 
Costs ............................................................................................................................. 24 
3.5.3. 
Data collection ............................................................................................................. 26 
3.5.4. 
Effectiveness and cost-effectiveness evaluation ......................................................... 26 
 
Statistical methods Module 1 Algorithms study ................................................................. 27 
3.6.
3.6.1. 
Sample size and power calculations ............................................................................ 27 
 
Ancillary studies .................................................................................................................. 29 
3.7.

 
 
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CESTA Module 2: Randomized controlled trial to compare the cure rate of CIN2+ in HIV 
3.8.
positive women treated by thermal ablation and cryotherapy (see figure 3) .............................. 29 
3.8.1. 
Primary Objectives: ...................................................................................................... 29 
3.8.2. 
Secondary Objectives: .................................................................................................. 30 
 
Study outline CESTA Module 2 ............................................................................................ 30 
3.9.
 
Statistical methods Module 2 Cure rate study ................................................................ 31 
3.10.
3.10.1. 
Sample size and power calculations ......................................................................... 31 
4. 
Study Methods ............................................................................................................................ 32 
 
Eligibility and exclusion criteria for CESTA participation (Modules 1 and 2) ...................... 32 
4.1.
4.1.1. 
Eligibility criteria ........................................................................................................... 32 
4.1.2. 
Exclusion criteria .......................................................................................................... 33 
 
Randomisation procedures ................................................................................................. 33 
4.2.
 
Duration of subject participation ........................................................................................ 33 
4.3.
5. 
Ethical considerations ................................................................................................................. 34 
 
 
 
 

 
 
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1. Executive Summary 
The main objectives of CESTA are (1) to compare the efficacy of two cervical cancer screening 
algorithms: HPV test followed by visual inspection with acetic acid (VIA) and treatment (HPV + 
VIA + treat) and HPV test followed by immediate treatment (HPV + treat). The study will be 
conducted to address its objectives in women living with HIV (from now on called HIV positive 
women) and HIV negative women; (2) to compare the cervical intraepithelial neoplasia grade 2 
or 3 (CIN2/3) cure rates of treatment with cryotherapy and thermal ablation (TA) 12 months 
after the treatment in HIV positive women; and 3) to model the comparative cost-
effectiveness of the two screening and treatment strategies described in (1) and the 2 
treatment methods described in (2). 
The study will be carried out through 2 modules as the study outlines differ considerably for 
the Algorithms objective (Obj 1) and the cure rate objective (Obj 2). The cost-effectiveness 
study (Obj 3) will be carried out in both modules with the epidemiological comparisons aligned 
with the respective modules.   
Module 1 will study the main objectives 1 and 3 among 3,000 HIV positive women in South 
Africa and 7,500 HIV negative women in Senegal.  
HIV positive women will be recruited from HIV care clinics, also called antiretrovirals (ARV) 
clinics in the Durban area, South Africa. After giving informed consent, women will be 
screened with HPV testing and those that are HPV positive will be randomized at a 4:1 ratio 
into HPV + VIA + treat (Arm 1) and HPV + treat (Arm 2) in 1 of the 2 CESTA study clinics. 
Women in Arm 1 will receive VIA and only positive for VIA will be treated. In Arm 2, all HPV 
positive women will be treated. Women that are eligible for ablative treatment will be 
randomized into treatment with TA or cryotherapy in both arms. Others will be referred to 
colposcopy. After VIA in Arm 1 or before treatment in Arm 2, the nurses will collect 2-4 
biopsies on all HPV positive women. The biopsies will be used as gold standard for disease 
detection. The first 200 women treated will be followed up intensely for 4 weeks to assess 
side-effects and levels of HIV shedding. Subsequently treated women will be called by 
telephone after 1 week and 1 month to assess side-effects and satisfaction with the 
procedures. Smartphone enhanced VIA (SEVIA) with patient navigation will be used in 1 of the 
2 study clinics. 2-3 Pictures are taken with the SEVIA smartphone tool after application of 
acetic acid to the cervix. The pictures are sent in a secure way to expert reviewers who provide 
feed-back to the nurse in real time. The application can also be used to track adherence of the 

 
 
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women to the screen and treat procedures or referral and send automated reminders of 
appointments. Outcomes on performance of VIA and patient adherence will be compared 
between study clinic that uses SEVIA and the one not using SEVIA. All women who were HPV-
positive or were treated will be called back after 1 year for a follow-up visit. Women will be 
screened with HPV testing and VIA and 2-4 colposcopy-directed biopsies will be taken from all 
HPV positive women. Women with remaining/recurrent CIN2+ disease will receive appropriate 
management.  
HIV negative women will be recruited from the communities in the Dakar area. They will be 
screened in 1 of 4 CESTA study clinics. Procedures will be similar as in HIV positive women, 
except that the randomization rate will be 3:1 for Arm 1 and Arm 2 and that the women 
eligible for ablative treatment will be all treated with TA. SEVIA will be applied in 2 of the 4 
study clinics to compare SEVIA outcomes in those clinics using it or not. Follow-up of treatment 
side-effects and women’s satisfaction will be by telephone after 1 week and after 1 month. 
Similar to HIV positive women, all HPV positive women or those treated will be invited for a 1-
year follow-up visit with the same procedures as described above. 
The cost-effectiveness study will answer questions on the comparative value and efficiency of 
the two screening arms and two treatments respectively, using epidemiological data collected 
through the clinical study for the effectiveness portion of the analysis. Cost data collected 
through questions embedded in the clinical questionnaires and by more in-depth but limited 
interview will be supplemented by administrative data where necessary to form the cost 
portion of the analysis. The study will use a well-validated cervical cancer model. 
 
Module 2 will study the main objectives 2 and 3 among 920 HIV positive women with CIN2/3 in 
South Africa. An estimated 143 women will have CIN 2/3 on biopsy from Module 1 and can be 
directed to participate in Module 2. A remaining 777 women with CIN2/3 will need to be 
recruited through 8-9 ARV clinics. Since 2018, women are screened routinely with liquid based 
cytology (LBC) in South Africa. We will invite women with LBC results of low-grade squamous 
intraepithelial lesions or worse (LSIL+) to participate in the CESTA Module 2 study in 1 of the 2 
CESTA study clinics dedicated to Module 2. After giving informed consent, 2-4 cervical biopsies 
will be taken by the study nurses. Women with biopsy results <CIN2 will be referred back to 
the ARV clinic for routine cervical cancer screening. Women with CIN2/3 and that are eligible 
for ablative treatment will be randomized into TA and cryotherapy. Others will be referred to 

 
 
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colposcopy for appropriate management. Similar to Module 1, women will be called by 
telephone after 1 week and 1 month to assess side-effects and satisfaction with the treatment. 
All women who were CIN2/3 and were randomized to ablative treatment or referred to 
colposcopy will be invited for a 1 year and 2 year follow-up visit. Similar as in Module 1, 
Women will be screened with HPV testing and VIA and 2-4 colposcopy-directed biopsies will be 
taken from all HPV positive women. Women with remaining/recurrent CIN2+ disease will 
receive appropriate management. 
The cost-effectiveness study will assess the comparative value and efficiency of the two 
treatment methods. 
  
2. Background 
 Clinical need 
2.1.
Cervical cancer remains a serious public health problem, with more than 500,000 new cases 
and 300,000 deaths occurring every year, particularly in developing countries where 87% of 
cases occur. Although rates of cervical cancer vary considerably, cervical cancer ranks first or 
second in all individual sub-Saharan countries, while it is the leading cause of cancer deaths at 
56,444 cases per year [1] in the subcontinent. Cytology based cervical cancer screening 
programs have successfully reduced cervical cancer incidence in developed countries but, with 
few exceptions, not in low- and middle income countries (LMIC). Programs using cervical 
cytology, which detects cellular changes indicating cervical intraepithelial neoplasia or cancer, 
are very complex to implement properly and the method has limited sensitivity and low 
reproducibility, which imposes the need for repeating tests frequently. This results in high cost 
and logistic complications which hamper the implementation and success of cytology-based 
screening programs in LMIC. Alternative screening methods have been developed, the two 
most studied being testing for human papillomavirus (HPV) and visual inspection with acetic 
acid (VIA). VIA can be implemented at low cost and allows for an immediate result to be given 
to the patient. This can be followed by a treatment at the same visit. However, VIA is operator 
dependent, lacks reliable means of quality assurance control, has a low positive predictive 
value and results in overtreatment of large numbers of women [2]. 
It is now clear that a group of 13 human papillomavirus (HPV) types are the causal agents of 
cervical cancer and that HPV 16 and 18 are responsible for about 70% of all cervical cancer. 

 
 
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HPV is a very common infection usually acquired shortly after initiation of sexual activity, but 
most infections are cleared by the immune system within 2 years after acquisition and only a 
few persist and progress to cancer.    
The recently introduced HPV vaccine has the potential to prevent 70% of cervical cancers, and 
a newer version has the promise to offer even more protection against cervical cancer. 
Vaccination needs to take place before the beginning of sexual activity, the target age 
recommended by the WHO for vaccination being 9-14 years old [3]. The protective effect on 
cervical cancer incidence, however, will only be noted several decades later, as the peak of 
cervical cancer incidence is in women in their mid-forties. Even in the most optimistic scenario 
where vaccination coverage in the target age group would reach 100% within the 10 coming 
years in all countries of the world, based on Globocan data we estimate that nearly 28 million 
women will still be affected by cervical cancer in the coming 40 years [1]. 
Therefore cervical cancer screening programs remain a high priority for most countries but 
especially for developing countries, where most cervical cancer cases occur. 
In 2014 WHO updated its evidence-based recommendations for comprehensive cervical cancer 
control including vaccination, screening, treatment and palliative care [WHO 2014]. An 
important gap in the evidence, emphasized by the international expert panel, was the lack of 
clinical data directly comparing screening by HPV testing with or without VIA triage testing in 
HIV negative as well as HIV positive women. Notably data on the benefits, side-effects and 
cost-effectiveness of the screen and treat algorithms using these tests were lacking [4]. This 
lack of evidence results in recommendations on the use of algorithms without indications on 
what would be the most cost-effective approach in which conditions. 
Therefore, the 2 screen and treat algorithms of interest that need to be carefully compared 
and evaluated in order for WHO to provide strong recommendations to low- and middle-
income countries (LMIC) are: (1) Screening by HPV test followed by VIA for triage of HPV 
positive women and; (2) Screening by HPV test alone; each followed by ablative treatment of 
screen-positives. We will also compare two ablative treatment methods for cervical precancer: 
cryotherapy and the novel thermal ablation. WHO has recently recommended that TA or 
cryotherapy can be used to treat eligible cervical legions, however these recommendation 
were based on weak evidence in HIV negative women and non-existent evidence for HIV 
positive women.   
Each of the aims will be evaluated in different modules: Mod 1, a randomised controlled trial 
(RCT) to compare the efficacy of the two screen-and-treat algorithms, and Module 2, another 

 
 
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RCT to compare the 12 and 24 months CIN2+ cure rates of each ablative treatment. The first 
module will be carried out among HIV positive and HIV negative women in South Africa and 
Senegal, respectively. The comparison will be based on HPV positive women with histological 
high grade squamous intraepithelial lesions or worse (HSIL+) adequately treated, those left 
untreated and those who were treated and did not have confirmed disease (overtreatment) 
randomized to each algorithm.  
The second module will be carried out in HIV positive women with histologically diagnosed 
CIN2/3 at the time of randomization. The third aim on cost-effectiveness will be evaluated 
within each module to provide a complete picture on cervical cancer screening strategies in 
the context of the cervical cancer elimination initiative. 
 
 HPV and cervical cancer in HIV-positive women 
2.2.
Most healthy women clear HPV infection on their own, while clearance in women with human 
immunodeficiency virus (HIV) is more limited, and women with HIV are more likely to 
experience progressive cervical changes [5]. Studies suggest that HIV-infected women were 
respectively 1.8, 2.1 and 2.7 times more likely to display high, intermediate and low risk HPV 
infections in the cervix than HIV uninfected women [5, 6]. Thus, HIV-positive women have 
higher rates of HPV persistence and progression to invasive cancer when compared to HIV-
negative women and in sub-Saharan Africa, HIV-infected women are 6 times more likely than 
HIV uninfected women to develop cervical cancer [7].  
The effect of antiretroviral therapy (ART) on cervical cancer precursor lesions (CIN2+) was 
evaluated in a recent meta-analysis. It was found that women living with HIV on ART have a 
lower prevalence of both high-risk HPV and CIN2+ lesions, compared to HIV positive women 
not on ART. Furthermore, a reduction in the incidence and progression of CIN2+ lesions was 
seen in women on ART, and an increase in regression of CIN2+ lesions. Notably, these effects 
remained after adjusting for immune restoration indicators such as CD4 cell count and 
duration of ART use [8].  
HIV positive women typically have more remaining/recurrent disease after treatment of pre-
cancerous lesions. These will be discussed in the sections of the respective treatments.  
 

 
 
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 HPV testing in cervical screening 
2.3.
Practically every invasive cancer and the vast majority of CIN 2/3 express high-risk (hr) HPV [9]. 
Currently, there are several laboratory tests for detection of cervical HPV infection which have 
high sensitivity and are highly reproducible.  These tests are recommended by WHO and 
considered to replace cervical cytology for primary screening. More and more countries are 
introducing HPV tests in their programme. They are highly sensitive to detect cervical cancer 
precursors (sensitivity typically >90%), highly reproducible, and have the capacity to detect 
more disease at an earlier stage [10]. In addition, HPV testing has a high negative predictive 
value that allows extension of the screening interval, with consequent savings that can 
compensate the possibly higher cost of the test compared to cytology or VIA. An additional 
advantage of HPV testing is the possibility to use vaginal specimens that are self-sampled by 
the woman. It has already been shown that this approach can increase the coverage of a 
screening program [11]. Recently, several HPV tests have been developed that are technically 
easier to implement and provide results more rapidly, compared to the conventional HPV 
tests. Two of those tests, the careHPV test (Qiagen) and HPV GeneXpert test (Cepheid) were 
recently prequalified by the WHO in-vitro diagnostics group, which would make procurement 
easier for middle and low income countries.  
Screening with HPV has the problem that transient HPV infections are very common, 
particularly among young women, where the majority of infections will regress spontaneously.  
Even among women over 30 years of age, HPV infection still tends to regress and only in a 
fraction of cases with persistent infection, it can lead to true cancer precursors and cervical 
cancer. Thus, one of the main issues to resolve is how to triage HPV positive results, i.e. to 
identify, for further evaluation and treatment, those HPV-positive women who are most likely 
to have or to develop in the near future significant disease that requires treatment. Direct 
treatment of HPV-positive women results in overtreatment, as the positive predictive value of 
HPV testing is around 15%. In general, a degree of overtreatment with cryotherapy is accepted 
because the treatment is safe with no adverse effects, well tolerated and serious side effects 
such as cervical stenosis are extremely rare [12]. In addition, ablation treatment of the cervix 
may have a prophylactic effect on future infections with HPV. Recent work has also shown that 
the junction between the ecto- and endocervix harbours embryonic reserve cells that have the 
potential to transform into neoplastic cells when infected with oncogenic HPV, and that their 
destruction may be protective of future cervical neoplastic developments [13]. In high-income 

 
 
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countries (HIC), triage of HPV positive women is usually done by cytology. In LMIC, where it is 
challenging to implement good quality cytology, triaging by visual inspection with acetic acid 
(VIA) is recommended, as well as no triage approach [4]. One of the major concerns is that the 
addition of VIA which has a known limited sensitivity may jeopardize the overall performance 
of both tests combined.  
 
 VIA testing in cervical screening 
2.4.
VIA is a technique in which cervical neoplastic lesions are visually diagnosed after application 
of 3-5% acetic acid without using any magnification device. The examination can be performed 
by any trained health worker, mostly nurses. The training in VIA is still not standardized and 
especially supervision after initial training is very difficult to organize. Therefore the technique 
remains subjective as it is based on the interpretation of what is seen by the health care 
provider after application of the acetic acid on the cervix. As a result, the reported test 
characteristics of VIA vary greatly,. One recent multi-country study in Nicaragua, Uganda and 
two sites in India, reported sensitivity between 22% in one site in India and 74% in Uganda 
with specificity of 95% and 67%, respectively, and associated positivity rate of 6% and 34%, 
respectively [14]. One advantage of the technique is that it allows a single-visit approach in 
which women are screened and treated with ablative treatment (cryotherapy or thermal 
ablation) at the same clinic visit.  
In case of a screen and treat algorithm that does not involve VIA (e.g. HPV testing), a variant of 
VIA is applied before ablative treatment, in order to assess that the woman does not have any 
condition that would make her ineligible for ablative treatment, such as a lesion or squamo-
columnar junction (SCJ) that reaches endocervically, an apparent lesion that covers >75% of 
the ectocervix, and suspicion of invasive cancer. All other cases are amenable for treatment, 
even without visible lesion.   
 
 Treatment of pre-cancerous lesions  
2.5.
Recent WHO guidelines recommend ablation by cryotherapy or thermal ablation, and excision 
by large loop excision of the transformation zone procedure (LLETZ, also called LEEP) as 
different forms of out-patient surgical treatment of CIN2/3. 
 

 
 
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2.5.1. 
Cryotherapy 
Cryotherapy consists of freezing the lesion and underlying tissue to a temperature of 
at least -20° Celsius. The treated tissue necrotises and is replaced by new healthy 
epithelium. A reusable probe is applied to the cervix and the freezing is obtained 
through decompression of either carbon dioxide (CO2) or nitrous oxide (N2O) gas. The 
main side-effect is a watery vaginal discharge for up to 2-3 weeks, which is generally 
well tolerated. The equipment is simple, no electricity is needed and the technique is 
relatively easy to perform. Cryotherapy can be provided by a variety of healthcare 
personnel including general doctors, nurses, midwives and auxiliary health workers 
who can be trained in short sessions. For those reasons, cryotherapy is very suited for 
LMIC. In addition, it can also be used in a single visit screen-and-treat approach in 
combination with a screening test that provides immediate results, such as VIA. One 
potential impediment of the technique is the inadequate availability or elevated cost 
of the freezing gas. Lesions that are not eligible for cryotherapy are those that reach 
>2mm in the endocervical canal; are larger than the cryoprobe; cover more than 75% 
of the ectocervix; and should be treated with LLETZ. Lesions that are suspicious of 
invasive cancer should be biopsied and treated according to diagnostic work up.  
A meta-analysis showed that cryotherapy is 92% and 85% effective to eliminate CIN2 
and CIN3, respectively (cure : normal cytology at follow-up) [15]. 
In a recent meta-analysis of studies reporting cryotherapy and LLETZ in HIV positive 
and HIV negative women, Debeaudrap P. et al. observed that residual or recurrent 
high-grade lesions were detected in 21.6% of women treated with cryotherapy, 
compared to 12.6% after LLETZ among HIV-positive women treated for CIN2+/HSIL+ 
[16]. These patients were twice as likely to suffer from treatment failure compared to 
HIV-uninfected women. The authors mentioned that there were no studies reporting 
on cure rates of thermal ablation in HIV positive women fitting the inclusion criteria of 
the meta-analysis. Greene S. et al. recently reported a RCT among 400 HIV-infected 
women with cervical intraepithelial neoplasia CIN 2/3 disease that were randomized to 
receive cryotherapy or LLETZ. At 12-months, more women treated with cryotherapy 
experienced recurrent HSIL than those who underwent LEEP (27% vs 18%; P=0.031). At 
24 months, HSIL increased in both arms and remained significantly higher in the 
cryotherapy arm (37% vs 26%; P=0.018). Overall, the rate of recurrence of HSIL+ was 

 
 
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21.1 per 100 woman-years after cryotherapy and 14.0 per 100 woman-years after 
LLETZ [Greene S. et al. Cryotherapy versus loop electrosurgical excision procedure 
among HIV-infected women (JAMA (in press)).  
 
2.5.2. 
Thermal ablation  
Thermal ablation is another ablative treatment for CIN, also previously called ‘cold 
coagulation’. The equipment is fairly simple and treatment is based on a 20-40 seconds 
application (multiple if needed) of a reusable metallic probe that is electrically heated 
to 100° Celsius, leading to epithelial and stromal destruction of the lesion. The 
equipment weighs less than 4 kg, which makes it easily portable to field clinics in 
developing countries. Recently light weight hand held and battery operated models 
have been developed. Like cryotherapy, thermal ablation can be provided by a variety 
of healthcare personnel including primary healthcare workers and is typically 
performed without anaesthesia. The WHO guideline review committee has recently 
approved recommendations for the use of TA, which will soon be officially published. 
Similar to cryotherapy, TA is recommended for CIN2/3 lesions, confirmed by histology 
or not in the context of screen and treat programs.  
A previous meta-analysis by Dolman et al. [17] was recently updated by Randall et al. 
[18]. The update includes 23 reports among 6371 patients treated for histologically 
confirmed CIN2/3. Lesions were considered as cured if follow-up colposcopy/biopsy 
was <CIN2 or normal follow-up cytology. Overall cure rate for women treated for 
CIN2/3 or CIN3 were 94% and 89%, respectively.  
The WHO guideline development group concluded that comparing the effects of 
thermal ablation to cryotherapy indirectly, there is moderate certainty evidence that 
the benefits and harms of these two treatments were similar. The great majority of 
these studies were carried out among HIV negative women. 
In some studies, especially those from Scotland and UK, used a 2-probe method, in 
which treatment of the visible glandular epithelium with a small conical probe 
followed by treatment of the ectocervix with a flat probe. Other studies reported the 
use of a one-probe method. The WHO expert guideline development group concluded 
that although application methodology was not always clearly described in the reports, 

 
 
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evidence showed that more women may be cured with a 2-probe method (95%; 
95%CI, 93-98%) than a 1-probe method (85%; 95%CI 80-90%).  
Although the WHO TA recommendation extended to HIV positive women, it was 
recognized that any recommendation for this group was based on very low certainty 
evidence. In fact, there were no comparative studies evaluating the benefits and 
harms of thermal ablation compared to other treatment methods or no treatment in 
HIV positive women with histologically confirmed CIN 2-3.  Assessment of cure of 
cervical lesions is complicated in HIV positive women and the utility of HPV testing in 
this context is limited. Thermal ablation, having a different mechanism of action 
compared to cryotherapy, may perform differently in this group. In fact, the efficacy of 
cryotherapy in HIV positive women has been shown to be limited. The recent WHO 
guidelines stress that the need for comparative studies is urgent particularly in women 
living with HIV, where there is little information about cures with thermal ablation, and 
no information about other important outcomes, such as HIV shedding or risk of 
transmission after treatment.  
 
2.5.3. 
Large loop excision of the transformation zone (LLETZ) procedure  
Excisional treatment by LLETZ uses a high-voltage electric current to excise the cervical 
neoplastic tissue and the transformation zone. The cutting electrodes are loops of very 
fine (0.2 mm) metal wire to achieve different widths, depths, and configurations of cut. 
LLETZ is the most used out-patient excisional treatment modality of CIN in HIC. The 
LLETZ equipment includes an electrical generator and a smoke evacuator to evacuate 
fumes that obliterate the view of the operating site and may contain the HPV virus 
particles. The wire loops are mostly dispensable single use and not always easily 
available in LMIC. Treatment by LLETZ requires much higher surgical skills on the part 
of providers and equipment infrastructure than required for ablation techniques such 
as cryotherapy or thermal ablation. They are mostly performed by doctors, although in 
some settings, specially trained nurses may provide LLETZ. Though this technique may 
be slightly more effective in the treatment of CIN2/3, it is more difficult to implement 
and therefore cryotherapy is currently more practiced in LMIC for the treatment of 
CIN2/3. In those countries, LLETZ is mostly used at a referral level for the treatment of 
cases that are not eligible for cryotherapy.  

 
 
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 Smartphone enhanced visual inspection with acetic acid (SEVIA)  
2.6.
The performance of VIA is very subjective and variable and there is to date no standardized 
way to provide supervision after initial VIA training to the health care provider. The SEVIA 
platform is developed to manage and to send cervical VIA images to in a secure way to 
certified reviewers in order to provide feed-back and online supervision to the nurses [19]. 
The cervical images sent are reviewed within a few minutes by “expert” skilled health 
providers, so the health workers (in most cases, nurses) receive real-time supportive 
supervision. In this manner, nurse providers are able to offer high quality cervical cancer 
screening services without requiring in-person supervision. The non for profit platform was 
originally developed in partnership with the Ministry of Health in Tanzania and researchers 
from Queens University in Canada. The success of the SEVIA program has now resulted in its 
integration into the Tanzanian National Cervical Cancer Program for active (real-time) data 
management and related processes. SEVIA is now in high-demand, being adapted where 
necessary and trialed in six other countries in East and West Africa. 
The costs of taking SEVIA to scale are modest, and when the platform is used at scale, the cost 
‘per woman screened’ drops as screening numbers increase. SEVIA will soon be evaluated in 
clinical trials in Sudan, first with a demonstration site, followed by a scale-up program of VIA 
“screen and treat” by a multi-disciplinary cadre of community midwives, nurses, and medical 
assistants in nine states, in collaboration with the Ministry of Health and WHO.  
Novel “patient navigation” tools are being developed and implemented within the SEVIA 
platform. Patient navigation, first implemented in 1990, is a barrier-focused intervention that 
targets a defined set of health services required to complete a process of cancer-related care 
[20]. The provision of patient navigation services has been shown to reduce delays in patients 
accessing the continuum of cancer care services, with an emphasis on timeliness of diagnosis 
and treatment and a reduction in the number of patients lost to follow-up in high-income 
countries. The patient navigation tools for CESTA will be informed by the literature (scoping 
review in progress), and previous experience with mHealth navigation for breast cancer early 
diagnosis by community health workers in rural Bangladesh [21]. In our study, we will assess 
the difference in performance of VIA and VAT as well as attrition rates in clinics that use 
SEVIA, compared to clinics that do not. 
 

 
 
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 The use of cervical intraepithelial neoplasia (CIN) and Lower Anogenital Squamous 
2.7.
Terminology Standardization (LAST) terminology for cervical histology  
 
Histology will is classified using the cervical intraepithelial neoplasia (CIN) classification. CIN1 
corresponds to HPV infection, CIN3 is a highly reproducible cancer precursor and CIN2 is an 
intermediate and poorly reproducible category and represents a mixture of HPV infections 
(CIN 1) and true cancer precursors (CIN3). Despite the uncertainty associated with CIN2, it is 
recommended as the cut-off for treatment, that is, women with CIN2 or worse lesions (CIN2+) 
should receive adequate treatment [4]. The use of histological high-grade intraepithelial 
lesion (HSIL) has recently been proposed under the Lower Anogenital Squamous Terminology 
Standardization (LAST) project [22]. LAST incorporates the current knowledge of HPV biology 
and the use of biomarkers to improve diagnosis, such as p16 immunohistochemistry (IHC) 
particularly for evaluating whether a diagnosis of CIN2 represents true high-grade cervical 
disease. Histological HSIL includes CIN2 p16 positive, CIN3 and adenocarcinoma in situ (AIS), 
better reflecting precancer lesions. Therefore, the gold standard for final outcome analysis of 
this study will be histological HSIL to compare the performance of HPV testing with VIA triage 
followed by treatment with that of HPV followed by treatment, but we will use CIN2 as a cut-
off for treatment as currently recommended.  

 
 
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3. Modules of the CESTA study 
Figure 1: Modules of the Cervical cancer Screening and Treatment algorithms study using HPV testing in Africa (CESTA) 
 
 

 
 
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The CESTA study aims at comparing two algorithms for screening and treatment of high-grade 
cervical pre-cancer lesions in populations of HIV positive and HIV negative women; in addition the 
study aims to compare the efficacy (cure rate) of cryotherapy and thermal ablation in HIV positive 
women. The CESTA study is therefore comprised of 2 modules.  
Module 1 is a randomised controlled trial of 2 screen and treat algorithms: screening women with 
HPV test followed by triage with VIA and treatment versus screening women with HPV test 
without VIA triage and followed by treatment in HIV positive women (in South Africa, women 25 – 
54 years) and among HIV negative women (in Senegal, women 30 – 54 years).  
Module 2 is a randomised controlled trial to compare the cure rates of thermal ablation versus 
cryotherapy in HIV positive women aged 25-54 years with CIN2/3; module 2 will also be carried 
out in South Africa. 
 
 CESTA Module 1: Randomised control trial of two algorithms, screening with HPV tests 
3.1.
followed by VIA as a triage and treatment (HPV + VIA + treat), vs screening with HPV test 
followed by treatment (HPV + treat) among HIV-positive women in South Africa and HIV-
negative women in Senegal  
3.1.1. 
Primary Objectives: 
1. To compare the efficacy of HPV + VIA + treat and of HPV + treat cervical cancer 
screening algorithms by comparing the proportion of women with histological HSIL 
that receive treatment or not through each algorithm in HIV positive and HIV negative 
women. 
2. To model the cost-effectiveness of the HPV + VIA + treat and  HPV + treat strategies, in 
HIV negative and HIV positive populations. 
 
3.1.2. 
Secondary Objectives: 
1. To assess the proportion of overtreatments (in women with no lesions or CIN1) that 
was avoided by VIA triage. 
2. To assess the VIA performance in clinics using Smartphone Enhanced VIA (SEVIA) 
compared to clinics that don’t. 
3. To assess patient adherence to study visits in clinics using SEVIA compared to clinics 
that don’t. 
4. To assess the performance of VIA as a test of cure 1 year after treatment. 

 
 
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5. To estimate the HPV infection clearance rate after one year of the treatment. 
6. To describe the safety and side effects of cryotherapy and thermal ablation. 
7. To assess and compare the HIV shedding among women treated with cryotherapy and 
thermal ablation. 
8. To measure the HPV results agreement between self-collected and clinician-collected 
samples in HIV positive women. 
9. To explore the acceptability of thermal ablation versus cryotherapy among treated 
women. 
 
 Study outline CESTA Module 1 
3.2.
The CESTA Module 1 is a double-level randomized study with the main objective to evaluate 
the efficacy of two cervical screen-and-treat algorithms in HIV positive and HIV negative 
women separately. 
 
3.2.1. 
CESTA Module 1 among HIV positive women in South Africa (see figure 2) 
 
3000 HIV-positive women will be screened with HPV testing and HPV-positive women will be 
randomized in a 4:1 ratio to be triaged by VIA and treated (arm 1, HPV+VIA+treat) or treated 
right away (arm 2, HPV+treat). 
The study will recruit women aged 25-54 years. Recruitment will be done mainly in HIV care 
clinics in South Africa. After informed consent, women will be administered short 
questionnaires on demographics and sexual history, and socio-economic characteristics. A 
health economics questionnaire focused on participant travel time and expenditures will also 
be administered. Women will then be asked to self-collect a vaginal sample and afterwards, a 
nurse will collect a cervical sample, both samples will be used for HPV testing. Any woman 
who refuses consent or opts out after consent will be referred to routine cervical cancer 
screening. 
Participants will be given an appointment to the CESTA study clinics to collect their HPV result. 
HPV positive women will be randomised to arms 1 or 2 using the envelop method with pre-
printed assignment cards.  
 
 

 
 
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ARM 1:  
A nurse will carry out a speculum examination and collect an endocervical swab to measure 
HIV shedding. She will then perform VIA and in half of the CESTA study clinics, the nurse will 
take 2-3 pictures of the cervix using the SEVIA smartphone application. 2-4 biopsies will be 
collected at the squamo-columnar junction (SCJ) from all quadrants that show aceto-white 
changes or at 12 and 6 ‘o clock if no acetowhite changes are visible. All eligible women for 
ablative treatment will be further randomised to sub-arms A (cryotherapy) and B (thermal 
ablation).  
VIA positive women not eligible for ablative treatment will be referred to the colposcopy clinic 
for appropriate referral and management.  
The VIA examination is inadequate if the SCJ is not entirely visible. In this case, an 
endocervical brush will be collected for cytological examination and the woman will be 
referred to colposcopy once the cytology result is known.  
Women with CIN2+ on biopsy who have not been treated based on screening results from 
arm 1 will also be randomised to sub-arms A and B if eligible for ablative treatment or 
referred to colposcopy otherwise. 
 
ARM 2: 
Study procedures in this arm are mostly similar to Arm 1. A nurse will carry out a speculum 
examination and collect an endocervical swab to measure HIV shedding. She will then 
perform a visual assessment for treatment using acetic acid (VAT, see section 2.4) to assess if 
the patient is eligible for ablative treatment and in half of the study clinics, 2-3 pictures will be 
taken with the SEVIA App. After VAT, 2-4 biopsies will be collected at the SCJ from all 
quadrants that show aceto-white changes or at 12 and 6 ‘o clock if no acetowhite changes are 
visible. 
All women that are eligible for ablative treatment will be treated and randomised into sub-
arm A (cryotherapy) and sub-arm B (thermal ablation) as in Arm 1; women with VAT not 
eligible for ablative treatment will be referred to the colposcopy clinic for appropriate referral 
and management. 
 Similar as for VIA, the VAT examination is inadequate if the SCJ is not entirely visible. In this 
case, an endocervical brush will be collected for cytological examination and the woman will 
be referred to colposcopy once the cytology result is known.  
  

 
 
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In both arms, endocervical sample collection for HIV shedding will be done after 1, 2, 3, and 4 
weeks in 100 women (each arm) who received treatment (modes of selection for these 
women still needs to be decided). At those respective visits, women will answer a 
questionnaire on perceived side-effects and acceptability of treatment. Women who do not 
come back for HIV shedding sample collection will be called by telephone after 1 week and 1 
month to assess perceived side-effects and acceptability of treatment. The nurse will take the 
necessary actions if serious side-effects are reported.  
In addition, all treated women will be recalled at 12 months for a follow-up visit including HPV 
testing, VIA with colposcopy and biopsy on HPV positive women, and those with CIN2+ will be 
treated as appropriate. 
 
The SEVIA App will only be applied in half of the study clinics, in order to allow to assess its 
effect on the quality of VIA and attrition rates. As described above in section 2.6, the nurses 
who use SEVIA will receive feed-back on their VIA or VAT assessment some minutes after they 
took the pictures and reported their own VIA/VAT assessment to the SEVIA platform. The 
original VIA/VAT assessment of the nurse will be used for study purposes, but we will assess 
at the end of the study if there was a difference in performance for the nurses that got 
supervision through SEVIA, compared to those who did not. The SEVIA application will also 
contain a patient navigation functionality. Women who agree will provide their telephone 
number and the SEVIA app will send automated reminders for their appointments. In case 
women are referred to colposcopy, the SEVIA system will also inform the staff at the 
colposcopy clinic about this referral and create alerts for women that missed an appointment.  
 
Women who exit the study at any point will be counselled about the standard of care 
screening recommendations for HIV positive women in South Africa (3 yearly screening). 
 
3.2.2. 
CESTA Module 1 among HIV negative women in Senegal (see figure 3) 
The study among HIV-negative women in Senegal is similar to the study design described 
above for HIV positive women, with the exception that, given the lower prevalence of HPV 
infection and disease, 7500 women aged 30 -54 will be included and randomized in a 3:1 ratio 

 
 
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to arm 1 (HPV + VIA + treat) and arm 2 (HPV + treat) and that treatment will be done by 
thermal ablation only.  
Women will be recruited from the communities around the CESTA study clinics and will be 
invited to attend cervical cancer screening at the study clinics. Community health education 
organisations will be involved to create cervical cancer awareness in the community. Study 
information leaflets will be developed and distributed in the communities by community 
health workers. Where possible, invitations to participate in the study will be handed out.  
After informed consent, women will be administered short questionnaires on demographics 
and sexual history, and socio-economic characteristics. A health economics questionnaire 
focused on participant travel time and expenditures will also be administered. Women will 
then be asked to self-collect a vaginal sample and afterwards, a nurse will collect a cervical 
sample, both samples will be used for HPV testing. Any woman who refuses consent or opts 
out after consent will be referred to routine cervical cancer screening. 
Participants will be given an appointment to the CESTA study clinics to collect their HPV result. 
HPV positive women will be randomized to arms 1 or 2 using the envelop method with pre-
printed assignment cards.  
 
ARM 1:  
A nurse will carry out a speculum examination and perform VIA and in half of the CESTA study 
clinics, the nurse will take 2-3 pictures of the cervix using the SEVIA App. 2-4 biopsies will be 
collected at the SCJ from all quadrants that show aceto-white changes or at 12 and 6 ‘o clock 
if no acetowhite changes are visible. All eligible women for ablative treatment will be treated 
by thermal ablation.  
VIA positive women not eligible for ablative treatment will be referred to the colposcopy clinic 
for appropriate referral and management.  
The VIA examination is inadequate if the SCJ is not entirely visible. In this case, an 
endocervical brush will be collected for cytological examination and the woman will be 
referred to colposcopy once the cytology result is known.  
Women with CIN2+ on biopsy who have not been treated based on screening results from 
arm 1 will also be recalled and treated with TA eligible for ablative treatment or referred to 
colposcopy otherwise. 
 
 

 
 
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ARM 2: 
Study procedures in this arm are mostly similar to Arm 2 among HIV positive women (section 
3.2.1). A nurse will carry out a speculum examination and perform a VAT to assess if the 
patient is eligible for ablative treatment and in half of the study clinics, 2-3 pictures will be 
taken with the SEVIA App. After VAT, 2-4 biopsies will be collected at the SCJ from all 
quadrants that show aceto-white changes or at 12 and 6 o’clock if no acetowhite changes are 
visible. 
All women that are eligible for ablative treatment will be treated by TA; women with VAT not 
eligible for ablative treatment will be referred to the colposcopy clinic for appropriate referral 
and management. 
VAT examination is inadequate if the SCJ is not entirely visible. In this case, an endocervical 
brush will be collected for cytological examination and the woman will be referred to 
colposcopy once the cytology result is known.  
 
In both arms, women who receive treatment will be called by telephone after 1 and 4 weeks 
and a questionnaire on perceived side-effects and acceptability of treatment will be taken by 
the nurse. The nurse will take the necessary actions if serious side-effects are reported.  
In addition, all treated women will be recalled at 12 months for a follow-up visit including HPV 
testing, VIA, colposcopy and biopsy on HPV positives, and those with CIN2+ will be treated as 
appropriate. 
 
The SEVIA App will only be applied in half of the study clinics, in order to allow to assess its 
effect on the quality of VIA and attrition rates. Similar as described above in section 3.2.1, the 
nurses who use SEVIA will receive feed-back on their VIA or VAT assessment some minutes 
after they took the pictures and reported their own VIA/VAT assessment to the SEVIA 
platform. The original VIA/VAT assessment of the nurse will be used for study purposes, but 
we will assess at the end of the study if there was a difference in performance for the nurses 
that got supervision through SEVIA, compared to those who did not. The SEVIA application 
will also contain a patient navigation functionality. Women who agree will provide their 
telephone number and the SEVIA app will send automated reminders for their appointments. 
In case women are referred to colposcopy, the SEVIA system will also inform the staff at the 
colposcopy clinic about this referral and create alerts for women that missed an appointment.  
 

 
 
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Women who exit the study at any point will be counselled about the standard of care 
screening recommendations in Senegal and at which services they can be accessed. 
 
 Rationale for choice of target age for cervical screening  
3.3.
This study will target HIV positive and HIV negative women separately. The WHO recommends 
that: 1) cervical screening should target women 30 years of age and older because of their 
higher risk of cervical cancer, 2) priority should be given to women aged 30–49 years, and 3) 
for women of HIV positive status or unknown HIV status in high HIV endemic areas, screening 
should start as soon as a woman or a girl has tested positive for HIV and is sexually active 
(WHO screening recommendation update 2014). As the study aims to evaluate the efficacy of 
screen-and-treat cervical screening algorithms using HPV testing, the start age of HIV positive 
women to be included in the study will be 25 years of age, to avoid increasing the 
overtreatment rate as it is known that the prevalence of HPV is higher among young women 
(less than 30 years) and can be >50% among HIV positive women [23].  
WHO recommends age 49 as the upper age limit for screening with VIA. VIA is less effective in 
women older than 50 years, because the squamocolumnar junction is less visible in post-
menopausal women. In this study we want to include women up to the age of 54, in order to 
compare the performance of HPV testing with or without VIA triage including an age group 
above 50 years old.  
 
 Cost and Cost-effectiveness methods 
3.4.
3.4.1. 
Modelling approach 
We will use the ‘Policy1-Cervix’ model platform developed by Cancer Council NSW to model 
the long-term impact and cost-effectiveness of the interventions. ‘Policy1-Cervix’ is an 
extensively validated dynamic model of HPV transmission, HPV vaccination, cervical 
precancer, cancer survival, screening, diagnosis and treatment. The model has been used for a 
number of HPV vaccine evaluations, including HPV vaccination in both girls and boys, catch-up 
vaccination, and the introduction of nonavalent vaccine. The model has also been used to 
evaluate screening implementation in organized national cervical cancer screening programs 
in high-income countries and in vaccination and screening in urban and rural areas of middle-
income countries. In connection with the Cervical Cancer Elimination Initiative, the model 

 
 
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platform is being used to evaluate the potential impact of screening and HPV vaccination on a 
global scale.  
 
In the context of this study, the model will incorporate a cervical cancer natural history 
specific to HIV positive women for application in South Africa. Each country model will be fit 
to epidemiological data collected from the clinical trial (e.g. age-specific HPV prevalence, HPV 
type prevalence and distribution, CIN2 prevalence and distribution) and where necessary, 
supplemental data from countries with similar cervical cancer outcomes and from the 
literature. Modelled natural history outputs will be validated against expected outcomes from 
the literature or other relevant sources. 
 
The clinical trial patient pathways (i.e. the screen-and-treat algorithms) for each study arm 
respective to each study country will be modelled in the platform and country-specific costs 
collected alongside the trial will be integrated with each intervention. Modelled cost outputs 
will also be validated against expected values from the literature and relevant sources. Future 
costs will be estimated by applying official GDP inflators for each country. The patient-
navigation component of the CESTA trial will not be included in the modelling. 
 
Other model outputs will include counts of HPV tests, biopsies, laboratory thermoablation 
treatment, cryotherapy treatment, CIN2 detected and colposcopies. 
 
3.4.2. 
Costs 
The assessment of costs will be conducted from the health service provision and the patient 
perspective. 
 
 

 
 
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Table 1. Overview of costs and data collection methods 
 
Costs included 
Estimation method 
Data sources 
Provider 
Direct medical costs of cervical 
cancer screening and treatment 
and follow-up (HPV test, VIA, 
biopsy, lab fees, thermoablation, 
cryotherapy, colposcopy, clinical 
staff, medical supplies). 
Ingredient approach 
Observation, records, 
primary data collection 
 
Other recurrent and capital costs 
(overhead costs such as building, 
utilities), programme costs (e.g. 
costs of community recruitment in 
Senegal). 
Step-down costing for 
overhead costs; 
ingredient approach 
for other 
Health facility records 
and primary data 
collection 
Patient/client 
Direct medical (e.g. ancillary drugs ) 
and non-medical costs (food and 
round-trip transportation) 
- 
Questionnaire 
 
Indirect costs (time costs) 
Human capital method 
Questionnaire 
 
 
Health services costs: Direct medical costs on screening, diagnosis and treatment of 
precancerous lesions will be calculated using a micro-costing approach whereby quantities of 
resources used will be measured and multiplied by their respective unit cost or price. These 
will include the costs of staff (time and by type), consumables, equipment, quality assurance 
and control (for VIA) and transportation of cervical samples. We will use the micro-costing 
approach to estimate the cost of (i) HPV DNA testing, (ii) VIA testing, (iii) colposcopy, 
(iv) biopsy and (v) pre-cancer treatment (thermocoagulation and cryotherapy). Aggregate 
health facility expenditures (e.g. utilities) and capital costs (e.g. building, equipment and 
furniture) will be allocated to the different interventions provided using a step-down costing 
approach. Step-down costing will only be performed if required (e.g. if new facilities are set 
up). In addition to these costs, we will also consider programmatic costs. In South Africa this 
will include the cost of setting up recruitment at ART clinics and diversion to the appropriate 
clinical site. In the case of Senegal where recruitment will take place in the community, this 
will include the costs of information, education and communication (IEC) materials (e.g. 
advertisements on the radio, community sensitization activities), staff training, monitoring 
and evaluation and supervision. 
 

 
 
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Woman’s costs: For the patient perspective, we will collect data on direct medical, non-
medical and indirect costs. Direct non-medical costs include the cost of transportation to and 
from home or work to the different health facilities and food. Indirect costs consist of time 
losses resulting from travelling to and from the health facilities, waiting and receiving care. 
These time losses will be valued with the human capital method using income data collected 
from women and/or published wage rates. 
 
3.4.3. 
Data collection 
Health services costs: Data on direct medical costs will be collected in association with 10% of 
the study participants. All costs incurred for the various interventions will be identified 
through observation of processes, time sheets where available and extensive consultation 
with the medical, laboratory and programmatic staff. Observations will include time-and-
motion measurement of the various staff procedures and will be done by trained research 
staff. Data on overheads will be obtained from the health facilities directly. 
 
Women’s costs: To measure the costs incurred by study participants, repeated measurements 
on non-medical costs and travelling and waiting time will be carried out at each visit of the 
study participant to the health facility. Data will be collected through the administration of 
questionnaires by the research staff at each visit to the clinical sites. More in depth data to 
probe and validate time costs will be collected through convenience sampling of 10% of the 
participants using in-person interviews. During the first visit, the questionnaire will also 
include information on socio-demographic characteristics and income. 
 
3.4.4. 
Effectiveness and cost-effectiveness evaluation 
For each screening arm, we will calculate the predicted average lifetime reduction in the age-
standardised rate of cervical cancer incidence and mortality, as well as the number of deaths 
averted and histologically confirmed high grade lesions. 
In terms of cost-effectiveness, we will use a limited societal perspective with a lifetime time 
horizon and 3% discounting. The relative performance of the different screening strategies 
will be expressed in terms of the incremental cost-effectiveness ratio, representing the 
additional cost of a strategy divided by its additional benefit, compared to the next least 
expensive alternative and expressed as cost per quality-adjusted life year (QALY) and cost per 
life-years saved. Other outcomes include cost per CIN2 detected and cost per treatment 

 
 
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performed. We will also estimate the annual budget impact of the different interventions and 
annual resource utilisation in terms of number of colposcopies, biopsies, precancer 
treatments, HPV tests, triage tests and other relevant procedures when considering scaling-up 
of the interventions.  
 
 Statistical methods Module 1 Algorithms study 
3.5.
For main objective 1, we will use three different indicators: 1) percentage of HPV positive 
women with detected histological HSIL+ treated in each arm, 2) percentage of HPV positive 
women without histological HSIL+ lesions treated in each arm, and, 3) percentage of HPV 
positive women that are referred to colposcopy by VIA in arm 1 or VAT in arm 2. Proportions in 
each arm will be compared using Chi-square likelihood ratio tests. In addition, 95% confidence 
intervals will be estimated for each proportion and used graphically for comparison. 
 
3.5.1. 
Sample size and power calculations 
For the first objective, to compare the performance of the algorithms, the sample size has 
been calculated for the three indicators defined above. We used the percentage of HPV 
positive women with HSIL+ who were treated for the sample size calculation as it is the 
indicator that requires the largest sample size. 
For HIV positive women, we assumed several features as follows: HPV testing sensitivity of 
95%, 85% eligibility for ablative treatment and an overall attrition of 20% for both arms. 
Additionally, for Arm 1 (HPV+VIA), we assumed a VIA sensitivity among HPV positive women 
of 75% and 4% VIA result of suspected cancer or VIA inadequate. Using a randomisation ratio 
of 4:1 to Arm 1 and Arm 2, we will need to detect 125 histological HSIL+ cases in Arm 1 and 25 
histological HSIL+ cases in Arm 2. 
With 3000 HIV positive women attending screening, assuming 50% HPV positivity [24-26] and 
50% VIA positivity, and a prevalence of 5% HSIL we will have at least 85% power to detect a 
difference of 24% (72.8% in Arm 1 vs 97% in Arm 2) with two-sided type error I 0.05 (see Table 
2 and Table 3). In summary, under all assumptions stated, 1500 HPV positive women will need 
to be included. 
 
 

 
 
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Table 2. Differences expected according to number of histological HSIL+ cases treated and 
<HSIL women overtreated in HIV positive women 
Outcomes 
Total 
Arm VIA (1) 
Arm HPV (2) 
Difference 
Total HSIL+ cases (n) 
150 
120 
30 
  
Total HSIL+ HPV positive 
cases (n) 
143 
114 
29 
 
Total HSIL+ treated (n) 
111 
83 
28 
  
Total <HSIL treated 
(overtreatment) (n) 
742 
487 
254 
  
% of treatment among 
HSIL+ HPV positive 
women 
  
72.8% 
97.0% 
24% 
% of overtreatment 
among HPV positive 
women 
  
41% 
85% 
44% 
 
Table 3. Number of HIV positive women to be screened 
Sample size 
Parameter 
n arm VIA (1) 
n arm HPV (2) 
Prevalence of HSIL+ 
0.05 
  
  
Expected number of HIV 
positive women (n) 
3000 
2400 
600 
Power 
>85% 
  
  
 
 
Similarly for HIV negative women, randomising in a 3:1 ratio to Arm 1 or Arm 2, under the 
same assumptions for sensitivities (HPV 95%, HPV, VIA 75% in HPV positives, 85% eligibility for 
ablative treatment in Arms 1 and 2, and 20% attrition overall), we will need to detect 113 
HSIL+ cases in Arm 1 and 38 in Arm 2 to compare the percentage of women with HSIL+ 
treated under each algorithm. With a sample size of 7500 HIV negative women, assuming 15% 
HPV prevalence [27], 50% VIA positivity, 2% prevalence of HSIL+, and two-sided type error I of 
0.05, we will have at least 85% power to detect a difference of 24% (72.8% in Arm 1 and 97% 
in Arm 2) in the percentage of HPV positive women with HSIL+ treated (see Table 4 and Table 
5). In summary, under all the assumptions stated, 1125 HIV negative HPV positive women will 
need to be included. 
 
 
 

 
 
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Table 4. Differences expected according to number of HSIL+ cases treated and <HSIL women 
overtreated in HIV negative women 
Outcomes 
Total 
Arm VIA (1) 
Arm HPV (2) 
Difference 
Total HSIL+ cases (n) 
150 
113 
38 
  
Total HSIL+ HPV positive 
cases (n) 
143 
107 
36 
 
Total HSIL+ treated (n) 
112 
78 
35 
  
Total <HSIL treated 
(overtreatment) (n) 
553 
323 
230 
  
% of treatment among 
HSIL+ HPV positive women 
  
72.8% 
97.0% 
24% 
% of overtreatment among 
HPV positive women 
  
38% 
82% 
43% 
 
 
Table 5. Number of HIV negative women to be screened and randomized 
Sample size 
Parameter 
Arm VIA (1) 
Arm HPV (2) 
Prevalence of HSIL+ 
0.02 
  
  
Expected number of HIV 
negative women (n) 
7500 
5625 
1875 
Power 
>85% 
  
  
 
 
 Ancillary studies 
3.6.
We will obtain aliquots from HPV samples from participants in the study that will be stored at 
-80C. These samples can later be used to evaluate the performance of novel screening and 
triage methods for cervical cancer (HPV genotyping, oncoprotein tests, automated visual 
evaluation (AVE), and others). 
 
 CESTA Module 2: Randomized controlled trial to compare the cure rate of CIN2+ in HIV 
3.7.
positive women treated by thermal ablation and cryotherapy (see figure 4) 
3.7.1. 
Primary Objectives: 
1. To compare the CIN2/3 cure rates of treatment with cryotherapy and thermal ablation 
12 months after the treatment in HIV positive women. 

 
 
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2. To model the cost-effectiveness of treatment of CIN2/3 by cryotherapy vs. thermal 
ablation in HIV positive populations. 
 
3.7.2. 
Secondary Objectives: 
1. To compare the CIN2/3 cure rates of cryotherapy and TA 24 months after the 
treatment in HIV positive women. 
2. To compare the histological HSIL cure rate of cryotherapy and TA after 12 and 24 
months. 
3. To assess patient adherence to study visits in clinics using SEVIA or not. 
4. To assess the performance of VIA as a test of cure 1 year after treatment. 
5. To estimate the HPV infection clearance rate after one year of the treatment. 
6. To describe the safety and side effects of cryotherapy and thermal ablation. 
7. To assess and compare the HIV shedding among women treated with cryotherapy and 
thermal ablation. 
 
 
 Study outline CESTA Module 2 
3.8.
The CESTA Module 2 is a randomised controlled trial to compare the cure rate of cryotherapy 
to thermal ablation HIV positive women. Women with diagnosed cytological LSIL+ (LSIL; HSIL; 
or ASC-H) at one of the estimated 8-9 involved ARV clinics in South Africa, all situated 
preferably around Durban, will be invited to one of the CESTA clinics. A total of 920 HIV 
positive women with CIN2/3 will need to be included in this module to obtain sufficient study 
power (see section 3.10.1). Some estimated 143 women will already be detected with CIN2/3 
in the CESTA Module 1 and can therefore be invited to participate in the CESTA Module 2. This 
mean that we estimate that CESTA module 2 will need to identify another 777 women with 
CIN2/3.  
Since 2018, women are routinely screened at ARV clinics with liquid based cytology every 3 
years in South Africa. We will access the results of those women already screened at the 
clinics with permission of the clinics administration and the women themselves. 
Women with LSIL+ will attend the closest CESTA study clinic. After informed giving written 
informed consent, the nurse will take some short questionnaires on demographics and sexual 
history, and socio-economic characteristics. A health economics questionnaire focused on 

 
 
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participant travel time and expenditures will also be administered. The nurse will collect 2-4 
biopsies, with the same procedure as described under Module 1 (section 3.2.1.). Women will 
then receive an appointment for an additional biopsy results visit. At that visit, all women with 
CIN2 or 3 without glandular lesions and eligible for ablative treatment through VAT will be 
randomized in a 1:1 ratio into cryotherapy and thermal ablation, performed by the nurse at 
the same visit after taking 2-3 pictures with the SEVIA application. Ablation ineligible women 
will be referred to colposcopy and will be managed and treated appropriately including LLETZ. 
Women with normal or CIN1 biopsy results will be exited from the study and referred back to 
the ARV clinic to follow the South Africa standard care recommendations, i.e. rescreening 
after 1 year.  
The VAT examination is inadequate if the SCJ is not completely seen and in that case, the 
nurse will obtain an endocervical brush for cytology and the women will be sent to the 
colposcopist when the cytology results are available. 
Similarly as in Module 1 (section 3.2.1), women who receive treatment will be called by 
telephone 1 and 4 weeks after treatment and answer a questionnaire on perceived side-
effects and acceptability of treatment. The nurse will take the necessary actions if serious 
side-effects are reported.  
In addition, all treated women will be recalled at 12 and 24 months for a follow-up visit 
including HPV testing, VIA, colposcopy and biopsy on all HPV positive women, and those with 
CIN2+ will be treated as appropriate. The SEVIA application will also be used for quality 
control of the VAT by the nurse, and for patient navigation, as described in Module 1. 
 
 Statistical methods Module 2 Cure rate study 
3.9.
For primary objective 1, we will compare the CIN2/3 cure rates of treatment with cryotherapy 
(Arm A) or thermal ablation (Arm B) after 12 months of treatment among HIV positive women 
using Z-test for comparison of proportions in intention-to-treat and per-protocol analyses. 
 
3.9.1. 
Sample size and power calculations 
The sample size is based on: 1) the expected difference between the cure rates of cryotherapy 
and thermal ablation, 2) the lower of the two expected cure rates, and, 3) the prevalence of 
HSIL+ cases eligible for ablative treatment.  

 
 
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Larger samples sizes will be needed for comparing smaller differences and for comparing cure 
rates closer to 50%. It is expected that cure rates will be on the range of 70-75% in HIV 
positive women [28]. Assuming the lowest cure rate to be 70%, 10% difference between cure 
rates, 20% ineligible for ablative treatment in each arm, 20% attrition after 12 months of 
treatment, 920 HSIL+ HIV positive cases will be needed in total (387 cases per arm, 146 
ineligible) to estimate the 10% difference with 80% power and two-sided type error I of 0.05. 
For larger differences or the lowest cure rate above 70%, the power to detect the differences 
will be higher. 
 
Table 6. Number of HSIL+ cases and statistical power for the cure rate objective 
Difference* 
(%) 
N total 
Attrition 
(+20%) 
Subtotal 
Total with 
20% 
ineligibility 
n per 
arm 
8 
942 
236 
1178 
1472 
618 
8.5 
830 
208 
1038 
1297 
545 
9 
734 
184 
918 
1147 
482 
9.5 
656 
164 
820 
1025 
431 
10 
589 
147 
736 
920 
387 
Power = 80%. *Starting at 70% 
 
From Module 1, we expect to identify 143 HSIL HPV positive cases (see Table 1). Therefore, we 
will need to include in this module 777 HSIL cases. Assuming a prevalence of 5% HSIL and a 
sensitivity of HPV test of 95%, 16,340 HIV positive women should be screened to complete the 
920 HSIL cases. 
 
 
4. Study Methods  
For study methods specific for modules 1 and 2 we refer to the sections describing the study 
outline of the different CESTA modules (3.2.– 3.5; 3.9).  
 
 Eligibility and exclusion criteria for CESTA participation (Modules 1 and 2) 
4.1.
4.1.1. 
Eligibility criteria 
1. Willing to disclose HIV status 

 
 
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2. HIV negative women aged 30-54 years; HIV positive women aged 25-54 years 
3. Mentally competent to give informed consent 
4. Physically able to have a pelvic exam 
 
4.1.2. 
Exclusion criteria 
1. Women reporting no previous sexual activity 
2. History of cervical cancer 
3. Treatment for cervical precancer in the last six months 
4. Hysterectomy 
5. Pregnancy 
6. Serious pre-existing medical conditions (e.g. history of bleeding disorders, serious physical 
or mental disease) 
 
 Randomisation procedures 
4.2.
The method of randomization will be through the use of pre-printed cards. Each 
randomisation will have its own set of cards with allocations to one of the screen-and-treat 
study arms (1: HPV + VIA + treatment or 2: HPV + treatment) and to one of the treatment 
arms (A: cryotherapy or B: thermal ablation). The Soares big stick design (BSD) [29] algorithm 
will be used. This algorithm assures the best allocation randomness in a comparison of 14 
methods [30]. Using R software, the output of this algorithm is a csv file with the participant 
number and the arm allocation. The same procedure will be applied on HIV positive and HIV 
negative women included in the study. 
 
 Duration of subject participation 
4.3.
For all women, the study will include one round of HPV testing. HPV negative women will finish 
their participation in the study after this first round.  
In Module 1, all HPV positive women with or without VIA triage will have a follow-up HPV test 
at 12 months, and will end their participation if the HPV test at 12 months is negative or after 
<CIN2 histology on biopsy collected at the colposcopy visit or after treatment (LLETZ or other) 
for CIN2+. 

 
 
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34 
In Module 2, women with CIN2/3 on biopsy will be randomized into TA or cryotherapy. 
Women that are ineligible for ablative treatment will be referred to colposcopy for appropriate 
management and all other women with LSIL+ cytology will be exited from the study and 
referred back to the ARV clinic for follow up according to South African standard of care. All 
treated women will attend a FU visit at 12 mo. and 24 mo. with HPV testing, VIA, and 
colposcopy-directed biopsies on HPV positive women to detect remaining/recurrent disease. 
At the time of exit, all women will be given clear indications on how to continue with regular 
screening or with any needed follow-up under the local health system. 
 
5. Ethical considerations 
The study will be approved by the IARC and local ethical committees of participating countries: 
currently being the Biomedical Research Ethics committee (BREC) at the University of KwaZulu-
Natal and the “Comité National d’Ethique pour la Recherche en Santé” under the Ministère de 
la Santé et de l’Action Sociale, Dakar. All women in the study will sign informed consent forms 
approved by IARC’s and the local ethical committees. 
The informed consent form will include details on the background, procedures of the study, 
risks and benefits, statement of confidentiality, specimen use and study staff to contact 
(informed consent document in annex). 
The study is considered minimal risk and the procedures are standard practice in cervical 
cancer screening programs. The clinical procedures to be performed were developed by a 
team of clinicians including colposcopists mainly considering the safety of the participants in 
terms of reduction of cervical cancer risk, and all the procedures are consistent with standard 
medical practice and/or WHO recommendations, including thermal ablation. 
We will make sure that women understand that they will continue to have access to their 
usual medical care even if they refuse to participate in the study.  We will also assure that 
women who accept to participate are aware that they can withdraw from the study at any 
point without affecting their access to their regular cervical cancer screening.  Also women will 
be informed that they can refuse to respond any question of the risk factor questionnaire or 
refuse to provide specimens without affecting their participation in the rest of the study.  
 
 

 
 
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Figure 2: Flowchart CESTA Module 1 Algorithms study in HIV POSITIVE women (South Africa) 
 
 
 
 
 

 
 
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CESTA_protocol_11062019.docx 
 
Figure 3: Flowchart CESTA Module 1 Algorithms study in HIV NEGATIVE women (Senegal) 
 
 
 
  
 
 

 
 
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CESTA_protocol_11062019.docx 
 
Figure 4: Flowchart CESTA Module 2 Cure rate study (HIV positive women, South Africa) 
 

 
 
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