Maribel Almonte

Impact of knowledge of human papillomavirus positivity on cervical cytology performance in Latin America

Abstract Background Cervical cytology is recommended by the World Health Organization as a triage option in human papillomavirus (HPV)-based cervical cancer screening programs. We assessed the performance of cytology to detect CIN3+ without and with knowledge of HPV positivity. Methods Women were screened with cytology and HPV across ESTAMPA study centers in Latin America. Screen-positives were referred to colposcopy with biopsy and treatment as needed. Cytology was initially interpreted without knowing HPV results. A subset of cytologies from HPV-positive women were reinterpreted at the same laboratories, with knowledge of HPV status, blinded to previous cytology and histological diagnosis. Performance indicators for cytology to detect CIN3+ without and with knowledge of HPV positivity were estimated. Findings A total of 4087 women were included, of which 490 had histologically confirmed CIN3+ (455 CIN3 and 35 cancers). Cytology sensitivity without knowledge of HPV positivity for CIN3+ was 47.2% (95% CI = 42.5 to 51.9), whereas with knowledge of HPV positivity, the sensitivity was higher (58.9%, 95% CI = 54.2 to 63.5; P < .0001). The specificity without knowledge of HPV was 89.4% (95% CI = 88.2 to 90.5), whereas with knowledge of HPV positivity was 78.9% (95% CI = 77.4 to 80.4; P < .0001). Performance estimates varied by study center for cytology without knowing the HPV positivity (range = 32.8%-61.5% for sensitivity; range = 80.7%-98.6% for specificity). Similarly, performance varied with knowledge of HPV positivity (36.1%-93.4% for sensitivity; 39.6%-98.6% for specificity). Conclusion The increase in sensitivity of cytology with HPV knowledge was limited and highly variable, reinforcing the need for alternative triage methods to support cervical cancer elimination goals.

Multicentric study of cervical cancer screening with human papillomavirus testing and assessment of triage methods in Latin America: the ESTAMPA screening study protocol

Introduction Human papillomavirus (HPV) testing is replacing cytology in primary screening. Its limited specificity demands using a second (triage) test to better identify women at high-risk of cervical disease. Cytology represents the immediate triage but its low sensitivity might hamper HPV testing sensitivity, particularly in low-income and middle-income countries (LMICs), where cytology performance has been suboptimal. The ESTAMPA (EStudio multicéntrico de TAMizaje y triaje de cáncer de cuello uterino con pruebas del virus del PApiloma humano; Spanish acronym) study will: (1) evaluate the performance of different triage techniques to detect cervical precancer and (2) inform on how to implement HPV-based screening programmes in LMIC. Methods and analysis Women aged 30–64 years are screened with HPV testing and Pap across 12 study centres in Latin America. Screened positives have colposcopy with biopsy and treatment of lesions. Women with no evident disease are recalled 18 months later for another HPV test; those HPV-positive undergo colposcopy with biopsy and treatment as needed. Biological specimens are collected in different visits for triage testing, which is not used for clinical management. The study outcome is histological high-grade squamous intraepithelial or worse lesions (HSIL+) under the lower anogenital squamous terminology. About 50 000 women will be screened and 500 HSIL+ cases detected (at initial and 18 months screening). Performance measures (sensitivity, specificity and predictive values) of triage techniques to detect HSIL+ will be estimated and compared with adjustment by age and study centre. Ethics and dissemination The study protocol has been approved by the Ethics Committee of the International Agency for Research on Cancer (IARC), of the Pan American Health Organisation (PAHO) and by those in each participating centre. A Data and Safety Monitoring Board (DSMB) has been established to monitor progress of the study, assure participant safety, advice on scientific conduct and analysis and suggest protocol improvements. Study findings will be published in peer-reviewed journals and presented at scientific meetings. Trial registration number NCT01881659

Cervical Cancer Screening and Treatment Algorithms Using Human Papillomavirus Testing—Lessons Learnt from a South African Pilot Randomized Controlled Trial

Abstract Background: To report quantitative and qualitative results on cervical cancer human papillomavirus (HPV)-based screening and treatment algorithms, with/out triage with visual inspection after acetic acid (VIA), followed by ablative treatment (AT). Methods: Women 30 to 54 years old from Durban, South Africa were recruited, regardless of human immunodeficiency virus (HIV) status, randomized into one of two study arms and screened for HPV. VIA triage arm: HPV-positive women were triaged using VIA, biopsied and received AT if VIA positive and eligible; no triage arm: eligible HPV-positive women received AT. Women ineligible for AT were referred to colposcopy. Women were asked about side effects immediately and 1 week after AT. Retention to screening and treatment algorithms was compared between arms. Results: A total of 350 women [275 HIV-uninfected and 75 women living with HIV, (WLWH)] were allocated to receive HPV testing with VIA triage (n = 175) or no triage (n = 175). HPV prevalence was 28% [95% confidence interval (CI) = 23–33]; WLWH: 52% (95% CI = 40–64) versus HIV-uninfected: 21% (95% CI = 17–27; P < 0.05). Among women who underwent VIA triage with histologic diagnosis, 3/17 were VIA negative with cervical intraepithelial neoplasia (CIN)2+; 14/18 were VIA positive with <CIN2. Retention to screening and treatment algorithms was high (92%). Conclusions: This pilot demonstrated the feasibility of implementing screening and treatment algorithms, including performing triage and treatment in one visit; however, VIA triage did not reduce overtreatment and missed some precancerous lesions. Impact: This study reports on implementation feasibility of two World Health Organization screening and treatment algorithms (with/out VIA triage). Although the retention to screening and treatment algorithms was high in both arms, the question of how best triaging HPV-positive women deserves further consideration, particularly for WLWH. See related In the Spotlight, p. 763

Cervical Cancer Screening With Human Papillomavirus Testing

HPV testing for primary cervical cancer screening of women over 30 years of age is likely to become the standard of care in the near future in many areas of the world. Its high sensitivity can significantly improve the effectiveness of screening programs and its prolonged negative predictive value can allow extension of screening intervals. However, a single HPV test has low positive predictive value and can lead to unnecessary workup and over-treatment and generate unnecessary distress. This multi-centric study will screen 50,000 women with HPV testing and compare several triage approaches that can follow HPV testing in order to make an HPV-based screening programme efficient, affordable and sustainable.