Armando Baena

Short-term repeat HPV testing for triaging HPV-positive women in cervical cancer screening

Persistent HPV infection causes cervical cancer, but most infections are transient. Triage methods identify high-risk women needing further evaluation or treatment. We assessed short-term repeat HPV testing as an alternative triage option. In ESTAMPA, women aged 30-64 years were screened with HPV testing (HC2 or Cobas) and cytology. Screen positives were referred to colposcopy approximately two months after screening, where cervical samples were collected again for repeat HPV testing. We evaluated the performance of repeat HPV for CIN3+ among HPV-positive women and explored its combination with limited HPV genotyping (HPV16/18). Among 5390 HPV-positive women (including 629 CIN3 cases and 53 cancers), 61% retested positive at ~2 months (median: 1.8, interquartile range: 1.2-2.8). Repeat HPV sensitivity for CIN3+ was 81.5% (95% CI 77.2-85.2) for HC2 and 87.7% (83.7-90.8) for Cobas. Specificity was <50% with referral rates of 57.4% (55.7-59.0) and 68.2% (66.1-70.2) for HC2 and Cobas. HPV16/18 genotyping followed by repeat HPV among non-HPV16/18-positive women did not greatly improve performance. However, HPV16/18 positivity doubled the risk of CIN3+, supporting its combination with repeat HPV when available. Short-term repeat HPV testing could be a practical option for triaging HPV-positive women, either alone or in combination with limited HPV genotyping. ClinicalTrials.gov, NCT01881659.

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 &amp;lt; .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 &amp;lt; .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.

Genital infections in high-risk human papillomavirus positive Paraguayan women aged 30–64 with and without cervical lesions

Objective To determine the prevalence of genital infections (GIs), including sexual transmitted STIs: Neisseria gonorrhoeae, Chlamydia trachomatis, Mycoplasma genitalium, Trichomonas vaginalis, and opportunistic pathogens that generally do not cause STIs, non-classic STI: Ureaplasma urealyticum, Ureaplasma parvum and Mycoplasma hominis, in women with high-risk oncogenic human papillomavirus (hr-HPV) infection and their association with cervical lesions. Methods A cross-sectional study was carried out including 231 hr-HPV positive women. Of these, 46 has histologically confirmed cervical intraepithelial neoplasia 3 (CIN3) or more (including CIN3 and cervical cancer lesions-CIN3+). GIs were detected by multiplex real time PCR. Odds ratios (OR) were estimated to explore possible associations between GIs and the presence or absence of CIN3+ lesions. Additionally, we examined associations between sociodemographic, sexual, and clinical characteristics and the presence of GIs. Results In total, there were 174/231 cases of GIs corresponding to an overall prevalence of 75.3% (95%CI: 69.4–80.4), being non-classic STIs the most common (72.3%) compared to STIs (12.6%). The most prevalent non-classic STI and STI were U. parvum (49.8%) and C. trachomatis (7.4%), respectively. The odds of presenting GIs were 3 times higher in women under 46 years compared to older counterparts (OR: 3.32, 95%CI: 1.74–6.16), and in women with a normal Pap smear with inflammation compared to those without inflammation (OR: 3.31, 95%CI: 1.15–9.77). GIs were equally present in women with and without CIN3+ lesions. Conclusion We observed an association of GIs with inflammation in the Pap smear, but no association with CIN3+, as some of them are very common and likely part of the normal vaginal flora, suggesting that such infections do not appear to be cofactors in cervical carcinogenesis, although larger prospective studies are needed.

Field experience with the 8‐HPV‐type oncoprotein test for cervical cancer screening among HPV‐positive women living with and without HIV in LMICs

AbstractOverexpression of HPV‐oncoproteins E6 and E7 is necessary for HPV‐driven cervical carcinogenesis. Hence, these oncoproteins are promising disease‐specific biomarkers. We assessed the technical and operational characteristics of the 8‐HPV‐type OncoE6/E7 Cervical Test in different laboratories using cervical samples from HPV‐positive women living with (WLWH) and without HIV. The 8‐HPV‐type OncoE6/E7 Test (for short: “OncoE6/E7 test”) was performed in 2833 HIV‐negative women and 241 WLWH attending multicentric studies in Latin America (ESTAMPA study), and in Africa (CESTA study). Oncoprotein positivity were evaluated at each testing site, according to HIV status as well as type‐specific agreement with HPV‐DNA results. A feedback questionnaire was given to the operators performing the oncoprotein test to evaluate their impression and acceptability regarding the test. The OncoE6/E7 test revealed a high positivity rate heterogeneity across all testing sites (I2: 95.8%, p &lt; .01) with significant lower positivity in WLWH compared to HIV‐negative women (12% vs 25%, p &lt; .01). A similar HPV‐type distribution was found between HPV DNA genotyping and oncoprotein testing except for HPV31 and 33 (moderate agreement, k = 0.57). Twenty‐one laboratory technicians were trained on oncoprotein testing. Despite operators' concerns about the time‐consuming procedure and perceived need for moderate laboratory experience, they reported the OncoE6/E7 test as easy to perform and user‐friendly for deployment in resource‐limited settings. The high positivity rate variability found across studies and subjectivity in test outcome interpretation could potentially results in oncoprotein false positive/negative, and thus the need for further refinements before implementation of the oncoprotein testing in screen‐triage‐and‐treat approaches is warranted.

Performance of visual inspection of the cervix with acetic acid (VIA) for triage of HPV screen‐positive women: results from the ESTAMPA study

AbstractVIA is recommended for triage of HPV‐positive women attending cervical screening. In the multicentric ESTAMPA study, VIA performance for detection of cervical intraepithelial neoplasia grade 3 or worse (CIN3+) among HPV‐positive women was evaluated. Women aged 30‐64 years were screened with HPV testing and cytology and referred to colposcopy if either test was positive. At colposcopy visit, study‐trained midwives/nurses/GPs performed VIA ahead of colposcopy. VIA was considered positive if acetowhite lesions were observed in or close to the transformation zone. Ablative treatment eligibility was assessed for VIA positives. Performance indicators were estimated. Three thousand one hundred and forty‐two HPV‐positive women were included. Sensitivity for CIN3+ was 85.9% (95% CI 81.2‐89.5) among women &lt;50 years and, although not significant, slightly lower in women 50+ (78.0%, 95% CI 65.9‐86.6). Overall specificity was 58.6% (95% CI 56.7‐60.5) and was significantly higher among women 50+ (70.3%, 95% CI 66.8‐73.5) compared to women &lt;50 (54.3%, 95% CI 52.1‐56.5). VIA positivity was lower among women 50+ (35.2%, 95% CI 31.9‐38.6) compared to women &lt;50 (53.2, 95% CI 51.1‐55.2). Overall eligibility for ablative treatment was 74.5% and did not differ by age. VIA sensitivity, specificity, and positivity, and ablative treatment eligibility varied highly by provider (ranges: 25%‐95.4%, 44.9%‐94.4%, 8.2%‐65.3%, 0%‐98.7%, respectively). VIA sensitivity for cervical precancer detection among HPV‐positive women performed by trained providers was high with an important reduction in referral rates. However, scaling‐up HPV screening triaged by VIA will be challenging due to the high variability of VIA performance and providers' need for training and supervision.

Latin America and the Caribbean Code Against Cancer 1st Edition: Medical interventions including hormone replacement therapy and cancer screening

Prostate, breast, colorectal, cervical, and lung cancers are the leading cause of cancer in Latin America and the Caribbean (LAC) accounting for nearly 50% of cancer cases and cancer deaths in the region. Following the IARC Code Against Cancer methodology, a group of Latin American experts evaluated the evidence on several medical interventions to reduce cancer incidence and mortality considering the cancer burden in the region. A recommendation to limit the use of HRT was issued based on the risk associated to develop breast, endometrial, and ovarian cancer and on growing concerns related to the over-the-counter and without prescription sales, which in turn bias estimations on current use in LAC. In alignment with WHO breast and cervical cancer initiatives, biennial screening by clinical breast examination (performed by trained health professionals) from the age of 40 years and biennial screening by mammography from the age of 50 years to 74, as well as cervical screening by HPV testing (either self-sampling or provider-sampling) every 5-10 years for women aged 30-64 years, were recommended. The steadily increasing rates of colorectal cancer in LAC also led to recommend colorectal screening by occult blood testing every two years or by endoscopic examination of the colorectum every 10 years for both men and women aged 50-74 years. After evaluating the evidence, the experts decided not to issue recommendations for prostate and lung cancer screening; while there was insufficient evidence on prostate cancer mortality reduction by prostate-specific antigen (PSA) testing, there was evidence of mortality reduction by low-dose computed tomography (LDCT) targeting high-risk individuals (mainly heavy and/or long-term smokers) but not individuals with average risk to whom recommendations of this Code are directed. Finally, the group of experts adapted the gathered evidence to develop a competency-based online microlearning program for building cancer prevention capacity of primary care health professionals.

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 &amp;lt; 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 &amp;lt;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.