WHO Guideline: HPV DNA Detection as Primary Test for Cervical Pre-Cancer, Apuntes de Medicina

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WHO guideline for screening and treatment

of cervical pre-cancer lesions for cervical

cancer prevention, second edition

WHO guideline for screening and

treatment of cervical pre-cancer

lesions for cervical cancer

prevention, second edition

Acknowledgements v Acronyms and abbreviations vii Executive summary viii Background viii Methods viii Summary of screening and treatment recommendations to prevent cervical cancer x

1. Introduction 1 1.1 Background 1 1.2 Approaches to screening and treatment 3 1.3 Rationale for this new edition of recommendations 4 1.4 Phased approach for the development of the recommendations 5 1.5 Target audience 6 2. Methods 7 2.1 Groups contributing to the guideline development process 7 2.2 Scoping review and appraisal of the existing recommendations 9 2.3 Priority questions for review of evidence 10 2.4 Priority algorithms 11 2.5 Outcomes 11 2.6 Syntheses of evidence 12 2.7 Development of the recommendations 18 2.8 Management of the external peer review 19 3. Important considerations for the recommendations 20 3.1 Programme considerations 20 3.2 Screening and triage tests considered in this guideline 21 3.3 Treatment considerations 23

Contents

Contents iii

4. Recommendations and good practice statements on screening and 24 treatment to prevent cervical cancer 4.1 Recommendations and good practice statements: 24 general population of women 4.2 Recommendations and good practice statements: women living with HIV 31 4.3 Additional recommendation and good practice statement 38 for treatment not covered in previous guidelines for the general population of women and women living with HIV **5. Research gaps and further considerations 39

6. Dissemination and updating of the guideline 41** 6.1 Guideline dissemination and impact 41 6.2 Guideline update 42 References 43 Annexes 47 Annex 1: Guideline groups 48 Annex 2: Evidence-gathering teams and guideline task groups 58 Annex 3: Declarations of interests 60 Annex 4: Seven algorithms prioritized for Phase 1 of the guideline update 63 Annex 5: Standardized definitions used in this guideline 73 Annex 6: Additional information for screening and treatment 95 recommendations

ADDITIONAL SUPPORTING MATERIALS AVAILABLE ONLINE:

Web annex A: Syntheses of the evidence

Available at: https://www.who.int/publications/i/item/ (Includes IARC handbook materials and Supplementary materials 1–13)

Web annex B: Evidence-to-decision (EtD) tables

Available at: https://www.who.int/publications/i/item/ (Includes EtD for PICO questions 1–10)

Contents iv

James Killen, Gigi Lui, Diep Nguyen, Bernardo Nuche, Catherine Sauvaget, Holger Schünemann, Kate Simms, Ronaldo Silva, Karin Sundström, Katayoun Thaghavi, Cari van Schalkwyk and Brian Williams.

The following individuals acted as observers at the GDG meeting: Benjamin Anderson, J. (Hans) Berkhof, Smiljka de Lussigny, Eduardo Franco, Lisa Pei-Ching Huang, Krishna Jafa, Jose Jeronimo, Somesh Kumar, Ilana Lapidos-Salaiz, David Mesher, Jasantha Odayar, Groesbeck Parham, Carmen Pérez Casas, Felipe Roitberg and Heather Watts.

The WHO Secretariat included Maribel Almonte Pacheco, Prebo Barango, Partha Basu, Paul Bloem, Nathalie Broutet, Gary Clifford, Marilys Corbex, Myriam Cortes, Shona Dalal, Jean-Marie Dangou, Maeve De Mello, Gampo Dorji, Linda Eckert, Fayad El Sheikh, Elena Fidarova, Massimo Ghidinelli, Karima Gholbzouri, Rodolfo Gomez Ponce de Leon, Sami Gottlieb, Joumana George Hermez, Raymond Hutubessy, Andre Ilbawi, Naoko Ishikawa, Chandani Anoma Jayathilaka, Rajat Khosla, Warrick Junsuk Kim, Stephanie Yetunde Kuku, Hugues Lago, Beatrice Lauby-Secretan, Silvana Luciani, Priya Mannava, Dara Masoud, Manjulaa Narasimhan, Morkor Newman, Leopold Ouedraogo, Tina Purnat, Neena Raina, Ajay Rangaraj, Leanne Margaret Riley, Anita Sands, Tshidi Sebitloane, Mukta Sharma, Hai-rim Shin, Slim Slama, Vitaly Smelov, Howard Sobel, Ute Ströher, Adriana Velazquez Berumen, Lara Vojnov and Hongyi Xu.

Funding for the preparation, development and printing of the guideline was provided mainly by the UNDP-UNFPA-UNICEF-WHO-World Bank Special Programme of Research, Development and Research Training in Human Reproduction (HRP), with the support of the United States President’s Emergency Plan for AIDS Relief (PEPFAR) through the United States Agency for International Development (USAID), and Unitaid.

This guideline was edited and proofread by Green Ink.

Acknowledgements vi

AIS adenocarcinoma in situ

ART antiretroviral therapy

CIN cervical intraepithelial neoplasia

CKC cold knife conization

DOI declaration of interest

ERG External Review Group

EtD evidence-to-decision

GDG Guideline Development Group

GRC Guidelines Review Committee

GRADE Grading of Recommendations Assessment, Development and Evaluation

HPV human papillomavirus

HRP UNDP-UNFPA-UNICEF-WHO-World Bank Special Programme of Research,

Development and Research Training in Human Reproduction

IARC International Agency for Research on Cancer

IPD-MA individual patient data meta-analysis

LEEP loop electrosurgical excision procedure (also known as LLETZ)

LLETZ large-loop excision of the transformation zone (also known as LEEP)

NAAT nucleic acid amplification test

PEPFAR The United States President’s Emergency Plan for AIDS Relief

PICO population (P), intervention (I), comparator (C), outcome (O)

SDG Sustainable Development Goal

UNAIDS Joint United Nations Programme on HIV/AIDS

UNDP United Nations Development Programme

UNFPA United Nations Population Fund

UNICEF United Nations Children’s Fund

USAID United States Agency for International Development

VIA visual inspection with acetic acid

WHO World Health Organization

Acronyms and abbreviations

Acronyms and abbreviations vii

The Guideline Development Group (GDG) for this guideline was formed in early 2019, and the GDG, WHO Secretariat, methodologists and technical groups (see Annex 1 ) met several times to establish the PICO questions, methodology and timeline. The WHO Secretariat led and coordinated the whole process to ensure recommendations were developed in line with the WHO handbook for guideline development, second edition (2014). The methods for evidence synthesis and mathematical modelling were used as applied in the previous edition of the guideline, WHO guidelines for screening and treatment of precancerous lesions for cervical cancer prevention. Based on clinical expertise, research and knowledge of tests in development, the Guideline Development Group (GDG) initially identified the screening tests and clinical algorithms for screening and treatment that could be evaluated. The GDG prioritized seven algorithms for evaluation, and these informed the systematic reviews. In 2020, the systematic review teams performed the systematic reviews for each of the PICO questions and, in parallel, the systematic reviews that had been prepared for the International Agency for Research on Cancer’s IARC handbooks of cancer prevention: cervical cancer screening, Vol. 18 (2021) were integrated for the development of these recommendations.

When relevant evidence was not available in primary research, a mathematical model was used to estimate the risk of important outcomes (e.g. recurrence of high-grade cervical intraepithelial neoplasia [CIN], cervical cancer) associated with the use of different screening and treatment strategies. In addition, a modelling group was created to evaluate the impact and cost–effectiveness of the different screening and treatment algorithms. Furthermore, we searched the published literature for studies providing information on acceptability, feasibility and costing aspects of these algorithms, and conducted a survey on feasibility and values and preferences of people using these services. GDG meetings took place on a weekly basis between August 2020 and November 2020 to review and assess the evidence and agree on the final new and updated recommendations and good practice statements presented in this guideline.

Executive Summary ix

Screening and treatment approaches

• In the “screen-and-treat approach” , the

decision to treat is based on a positive primary

screening test only.

• In the “screen, triage and treat approach” , the

decision to treat is based on a positive primary

screening test followed by a positive second test

(a “triage” test), with or without histologically

confirmed diagnosis.

Summary of screening and treatment recommendations to prevent

cervical cancer

In this present publication, there is a total of 23 recommendations and 7 good practice statements.

• Among the 23 recommendations, 6 are identical for both the general population of women and for women living with HIV and 12 are different and specific for each population.
• Among the 7 good practice statements, 3 are identical for both the general population of women and for women living with HIV and 2 are different and specific for each population.

In Table 1 below we have grouped the recommendations and good practice statements in two columns for the general population of women (left column, nos. 1–14) and for women living with HIV (right column, nos. 21–34), while in Table 2, the populations are not separated (nos. 41 and 42).^1

There are currently 11 recommendations and 3 good practice statements for each population in Table 1, and an additional recommendation and good practice statement for both populations in Table 2.

(^1) There are gaps in these numbers because WHO intends to issue additional recommendations soon on screening tests and implemen- tation, which will be numbered as needed (expected to be 15–20 for the general population of women and 35–40 for women living with HIV).

Executive Summary x

Recommendations for the general population ofwomen

a

Strength ofrecommendationand level ofevidence

Recommendations for women living with HIV

a

Strength ofrecommendationand level ofevidence

3a.

In a screen-and-treat approach

using HPV

DNA detection as the primary screening test, WHOsuggests treating women who test positive for HPVDNA among the general population of women.3b.

In a screen, triage and treat approach

using

HPV DNA detection as the primary screening testamong the general population of women, WHOsuggests using partial genotyping, colposcopy, VIA orcytology to triage women after a positive HPV DNAtest (

Annex 4

Remarks: The benefits, harms and programmatic costsof the triage options are similar; therefore, the choiceof triage method will be dependent on feasibility,training, programme quality assurance and resourcesin countries. HPV16/18 genotyping could be integratedinto the HPV DNA test (refer to Annex 4 for specificdetails of the algorithms).

Conditionalrecommendation,moderate-certainty evidence

In a screen, triage and treat approach

using

HPV DNA detection as the primary screening testamong women living with HIV, WHO suggests usingpartial genotyping, colposcopy, VIA or cytology totriage women after a positive HPV DNA test (

Annex 4

Remarks: The benefits, harms and programmatic costsof the triage options are similar; therefore, the choiceof triage method will be dependent on feasibility,training, programme quality assurance and resourcesin countries. HPV16/18 genotyping could be integratedinto the HPV DNA test (refer to Annex 4 for specificdetails of the algorithms).

Conditionalrecommendation,moderate-certainty evidence

4. When providing HPV DNA testing, WHO suggestsusing either samples taken by a health-care provideror self-collected samples among both the generalpopulation of women and women living with HIV.

Conditionalrecommendation,low-certaintyevidence

24. When providing HPV DNA testing, WHO suggestsusing either samples taken by a health-care provideror self-collected samples among both the generalpopulation of women and women living with HIV.

Conditionalrecommendation,low-certaintyevidence

5. WHO recommends starting regular cervical cancerscreening at the

age of 30 years

among the general

population of women.

Strongrecommendation,moderate-certainty evidence

25. WHO suggests starting regular cervical cancerscreening at the

age of 25 years

among women living

with HIV. Remarks: Low-certainty evidence found that there arelikely to be small numbers of women living with HIVwith cervical cancer who are below the age of 25. Thisrecommendation applies to women living with HIVregardless of when they first tested positive for HIV.

Conditionalrecommendation,low-certaintyevidence

xii

Executive Summary

Recommendations for the general population ofwomen

a

Strength ofrecommendationand level ofevidence

Recommendations for women living with HIV

a

Strength ofrecommendationand level ofevidence

6. After the age of 50 years, WHO suggests screeningis stopped after two consecutive negative screeningresults consistent with the recommended regularscreening intervals among both the general populationof women and women living with HIV. Remarks: Neither VIA nor ablative treatment aresuitable for screening or treatment of women in whomthe transformation zone is not visible. Inadequatevisualization is typical after the menopause.

Conditionalrecommendation,low-certaintyevidence

26. After the age of 50 years, WHO suggests screeningis stopped after two consecutive negative screeningresults consistent with the recommended regularscreening intervals among both the general populationof women and women living with HIV. Remarks: Neither VIA nor ablative treatment aresuitable for screening or treatment of women in whomthe transformation zone is not visible. Inadequatevisualization is typical after the menopause.

Conditionalrecommendation,very low-certaintyevidence

7. Priority should be given to screening women

aged

30–49 years

in the general population of women.

When tools are available to manage women aged50–65 years, those in that age bracket who have neverbeen screened should also be prioritized.

Good practicestatement

27. Priority should be given to screening women livingwith HIV

aged 25–49 years

. When tools are available

to manage women living with HIV aged 50–65 years,those in that age bracket who have never beenscreened should also be prioritized.

Good practicestatement

8. WHO suggests a regular screening interval of

every

5 to 10 years

when using HPV DNA detection as the

primary screening test among the general populationof women.

Conditionalrecommendation,low-certaintyevidence

28. WHO suggests a regular screening interval of every 3 to 5 years

when using HPV DNA detection

as the primary screening test among women livingwith HIV.

Conditionalrecommendation,low-certaintyevidence

9. Where HPV DNA testing is not yet operational,WHO suggests a regular screening interval of every3 years when using VIA or cytology as the primaryscreening test, among both the general population ofwomen and women living with HIV.

Conditionalrecommendation,low-certaintyevidence

29. Where HPV DNA testing is not yet operational,WHO suggests a regular screening interval of every3 years when using VIA or cytology as the primaryscreening test, among both the general population ofwomen and women living with HIV.

Conditionalrecommendation,low-certaintyevidence

xiii

Executive Summary

a^ Rows shaded in blue indicate that the recommendation or good practice statement is identical for both the general population of women (left column) and women living with HIV (right column). In other rows, thewording of the recommendations differs for each population.

xv

Executive Summary

Recommendations for the general population ofwomen

a

Strength ofrecommendationand level ofevidence

Recommendations for women living with HIV

a

Strength ofrecommendationand level ofevidence

14. As programmes introduce HPV DNA testing, usethis test at the woman’s next routine screening dateregardless of the test that was used at prior screening.In existing programmes with cytology or VIA as theprimary screening test, rescreening with the sametest should be continued until HPV DNA testing isoperational among both the general population ofwomen and women living with HIV.

Good practicestatement

34. As programmes introduce HPV DNA testing, usethis test at the woman’s next routine screening dateregardless of the test that was used at prior screening.In existing programmes with cytology or VIA as theprimary screening test, rescreening with the sametest should be continued until HPV DNA testing isoperational among both the general population ofwomen and women living with HIV.

Good practicestatement

For both the general population and women living with HIV HPV: human papillomavirus; VIA: visual inspection with acetic acid.a Rows shaded in blue indicate that the recommendation or good practice statement is identical for both the general population of women (left column) and women living with HIV (right column). In other rows, thewording of the recommendations differs for each population.

Strength of recommendation andcertainty of evidence

41. Once a decision to treat a woman is made – whether from the general population of women or women livingwith HIV – it is good practice to treat as soon as possible within six months to reduce the risk of loss to follow-up.However, in women who are pregnant, good practice includes deferral until after pregnancy.In circumstances when treatment is not provided within this time frame, it is good practice to re-evaluate thewoman before treatment.

Good practice statement

42. WHO suggests large-loop excision of the transformation zone (LLETZ) or cold knife conization (CKC)for women from the general population and women living with HIV who have histologically confirmedadenocarcinoma in situ (AIS). Remarks: Loop excision may be preferred in women of reproductive age, in settings with greater availability ofLLETZ and by providers with greater expertise performing LLETZ. CKC may be preferred when interpretation of themargins of the histological specimen is imperative.

Conditional recommendation,low-certainty evidence

Table 2. Recommendation and good practice statement for treatment not covered in previous guidelines

Executive Summary xvi

Summary recommendation for the general

population of women

WHO suggests using either of the following

strategies for cervical cancer prevention among the

general population of women:

• HPV DNA detection in a screen-and-treat

approach starting at the age of 30 years with

regular screening every 5 to 10 years.

• HPV DNA detection in a screen, triage and treat

approach starting at the age of 30 years with

regular screening every 5 to 10 years.

Summary recommendation for women living

with HIV

WHO suggests using the following strategy for

cervical cancer prevention among women living with

HIV:

• HPV DNA detection in a screen, triage and treat

approach starting at the age of 25 years with

regular screening every 3 to 5 years.

The traditional method to screen women for cervical cancer has been cytology (the Papanicolaou test, also known as the Pap smear or smear test). When cytology results are positive, the diagnosis is confirmed by colposcopy, and appropriate treatment is informed by biopsy of suspicious lesions for histological diagnosis. In countries with effective cytology-based cervical cancer screening and treatment programmes, the mortality from cervical cancer has been reduced fivefold over the past 50 years (6). This screening approach has not been as successful in low- and middle-income countries (7).

Newer screening tests introduced in the last 15 years include visual inspection with acetic acid (VIA), and molecular tests, mainly high-risk HPV DNA-based tests, 3 which are suitable for use in all settings ( Table 1.1 ). More recently, even newer tests and techniques have been developed: (i) other molecular tests such as those based on HPV mRNA, oncoprotein detection or DNA methylation; (ii) more objective tests performed on cytological samples such as p16/Ki-67 dual staining; and (iii) more advanced visual inspection tests based on artificial intelligence/machine learning platforms (e.g. automated visual evaluation of digital images) (8–11).

Introduction 2

Molecular Cytologic Visual inspection

Nucleic acid amplification tests (NAAT) a » high-risk HPV DNA/ NAAT » mRNA

DNA methylation b

Protein biomarkers b » HPV antibodies » oncoproteins

Conventional Pap smeara

Liquid-based cytology (LBC) a

Dual staining to identify p and Ki-67a

Visual inspection with acetic acid or with Lugol’s iodine (VIA/VILI) a » naked eye » magnified by colposcope or camera

Automated visual evaluation of digital images b

Table 1.1 Three approaches to cervical cancer screening and future tests

a (^) Current tests b (^) Tests under evaluation (future tests).

(^3) In this guideline, “an HPV DNA test” refers to a high-risk HPV DNA test. An HPV DNA test is a nucleic acid amplification test (NAAT).

Introduction 3

In a screen-and-treat approach , treatment is provided based on a positive primary screening test alone, without triage (i.e. no second screening test and no histopathological diagnosis).

• When the patient is eligible for ablative treatment, this should ideally be done immediately, at the same visit as the screening test (the single-visit approach). At some facilities, this is not feasible and a second visit is needed (the multiple-visit approach).
• Women who are not eligible for ablation can have excisional treatment on the same day if the clinic has the capacity for large-loop excision of the transformation zone (LLETZ). 4 If LLETZ is not available on-site, women need to be referred for the excisional treatment or for further evaluation.

In a screen, triage and treat approach , the triage test is done if the primary screening test is positive, and the decision to treat is made when both the primary test and the triage test are positive.

• A positive triage test can lead to colposcopy with biopsy and histopathological examination for diagnosis to determine the appropriate treatment. The implementation of colposcopy and biopsy can be challenging, however, so this guideline also considers triage strategies that are not dependent on the availability of colposcopy.
• When the primary screening test is positive, and the triage test is negative, women need appropriate follow-up evaluation at a specified date according to the recommendations.

(^4) In this guideline, the term LLETZ is used to refer to excision of the transformation zone. In some countries, this terminology was changed to LEEP (loop electrosurgical excision procedure), and the two terms are often used interchangeably.

1.2 Approaches to screening and treatment

In this document, two approaches to screening and treatment are distinguished: the screen-and-treat approach and the screen, triage and treat approach.

Screening and treatment approaches

• In the “screen-and-treat approach” , the decision

to treat is based on a positive primary screening

test only.

• In the “screen, triage and treat approach” , the

decision to treat is based on a positive primary

screening test followed by a positive second test

(a “triage” test), with or without histologically

confirmed diagnosis.