Diagnostic accuracy of cervical cancer screening strategies for high-grade cervical intraepithelial neoplasia (CIN2+/CIN3+) among women living with HIV: A systematic review and meta-analysis

Kelly, Helen; Jaafar, I; Chung, Michael H.; Michelow, Pamela; Greene, Sharon A.; Strickler, Howard D.; Xie, Xianhong; Schiffman, Mark; Broutet, Nathalie; Mayaud, Philippe; Dalal, Shona; Arbyn, Marc; Sanjosé, Sílvia de

doi:10.1016/j.eclinm.2022.101645

Cited by 23 publications

(38 citation statements)

References 77 publications

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“…Many low and lower-middle income countries, including Tanzania, have already implemented cervical screening with VIA and it is therefore important to consider the possible role of VIA in screening programs in these settings. Current evidence demonstrates that primary screening with VIA has lower sensitivity and specificity than primary HPV testing, 13 meaning that for VIA to prevent as many cervical cancer cases as primary HPV testing, screening would need to be more frequent (three-yearly versus five-yearly) and we have shown via modelling that this would ultimately result in substantial over-treatment of precancerous lesions. However, this does not rule out use of VIA as a triage for women who screen positive for HPV DNA.…”

Section: Discussionmentioning

confidence: 88%

“…However, this does not rule out use of VIA as a triage for women who screen positive for HPV DNA. While data indicated that even as a triage to HPV, VIA reduces the number of identified CIN2+ lesions by approximately half, 13 the modelling suggests that if HPV positive but triage negative women attend for 12 month follow-up at a high rate of return, this will not substantially lower the overall efficacy of the screen, triage and treat HPV program.…”

Section: Discussionmentioning

confidence: 97%

“…Therefore, based on this evidence we consider a large range of possible VIA test sensitivity of 40-60%. 3,4,40 Further explanation of assumed test characteristics for VIA, HPV and cytology screening are provided in detail in the Appendix pp27. We assumed that, based on an updated systematic review performed for the Guidelines, that test sensitivity for women living with well-controlled HIV on antiretroviral therapy for two or more years, are similar to those for women with uncontrolled HIV infection.…”

Section: Scenarios For Evaluationmentioning

confidence: 99%

“…We assumed that, based on an updated systematic review performed for the Guidelines, that test sensitivity for women living with well-controlled HIV on antiretroviral therapy for two or more years, are similar to those for women with uncontrolled HIV infection. 13,37 To address uncertainties in both populations, a wide range of test performance characteristics were considered for VIA, HPV and cytology (see sensitivity analyses, Appendix pp11-13). This approach for determining functional test sensitivity and specificity in LMIC, and assuming the same screening test characteristics for women with HIV and women in the general population was agreed upon by the WHO GDG.…”

Section: Scenarios For Evaluationmentioning

confidence: 99%

“…1,2 Women with HIV are disproportionately affected by cervical cancer; they have a six-fold higher risk and account for 5% of all cervical cancer cases, despite the global prevalence of HIV being less than one percent. 3,4 The World Health Organisation (WHO) has called all nations to implement a triple-intervention strategy which aims to eliminate cervical cancer as a public health problem. 5 This strategy recommends that by the year 2030, 90% of girls are fully vaccinated with the HPV vaccine by 15 years of age, 70% of women are screened twice in their lifetimes by ages 35 and 45 years using a highperformance test, and 90% of women with detected cervical precancer or cancer receive appropriate treatment.…”

Section: Introductionmentioning

confidence: 99%

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Evaluation of the benefits and harms of alternative strategies for cervical screening and treatment in women living with HIV: modelling to support WHO 2021 cervical screening and treatment guidelines to prevent cervical cancer

Hall

Simms

Murray

et al. 2022

Preprint

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The WHO strategy for the elimination of cervical cancer sets 2030 targets for the scale-up of HPV vaccination, cervical screening, and pre-cancer and invasive cancer treatment. Screening and treatment of precancerous disease will be critical to reduce mortality in the short term, particularly in high HIV burden settings, due to the increased risk of cervical cancer among women living with HIV. To inform the development of new screening and treatment guidelines for women living with HIV, we modelled alternate scenarios for the screening test, frequency, and interval, and assessed the benefits and potential harms of cervical screening and precancer treatment in Tanzania, a country with a high burden of both HIV and of cervical cancer. We used a dynamic model of HPV and HIV co-infection, Policy1-Cervix-HIV, parametrised to Tanzanian demographic and epidemiological data, which captured HIV and HPV interactions. With the support of the WHO Guidelines Development Group for Screening and Treatment to Prevent Cervical Cancer (GDG) we assessed the impact of seven screening algorithms including primary visual inspection with acetic acid (‘VIA’), primary cytology, and primary HPV DNA (‘primary HPV’) with no triage, or triage using HPV16/18 genotyping, colposcopy, cytology, or VIA for women aged 25-50. Screening intervals of 3 years were considered for primary VIA and cytology, and intervals of 3, 5 or 10 years were considered for primary HPV. Screening and triage test performance was informed by updated systematic review evidence. We assumed 70% of women attended each routine screen, and 90% complied with follow-up or treatment. Outcomes include reduction in cervical cancer incidence and mortality as a measure of benefits, and number of precancer treatments (NNT) needed to prevent a death and preterm delivery events directly due to precancer treatment (‘additional preterm delivery events’) as a measure of the potential harms. A range of assumptions were considered in sensitivity and supplementary analyses. We found that, without screening, 5,263 cervical cancer cases (age-standardised incidence rate [ASIR] 104.0/100,000/year) and 4,467 cervical cancer deaths (age-standardised mortality rate [ASMR] 99.8/100,000) are predicted over the lifetime of 100,000 Tanzanian WLHIV. Primary HPV testing without triage every 3-years for women aged 25-50 years was effective in terms of cancer reduction, resulting in a 63.6% reduction in ASIR and 71.7% reduction in ASMR, and an NNT of 38.7 to prevent one cervical cancer death. However, triaging HPV positive women before treatment resulted in minimal loss of effectiveness with overall reduction in ASIR of 57.3-62.2% (range depends on triaging test used) and ASMR of 66.4-70.5% and was associated with more favourable NNTs (19.7-33.0). Primary screening with VIA or cytology at 3-yearly intervals resulted in lesser reductions in cervical cancer incidence and mortality and less favourable NNTs: for VIA, the overall reduction in ASIR was 50.6% and the reduction in ASMR was 54.2%, with an NNT of 107.5 to prevent a death. Extending the HPV screening interval from 3 to 5 years slightly decreased screening program effectiveness but increased efficiency. In conclusion, primary HPV testing approaches were the most effective, and optimised benefits-to-harms compared to primary VIA or cytology. Triaging HPV positive women before treatment reduces precancer treatments and improves efficiencies with minimal loss in effectiveness. However, uncertainties in the primary data exist and further empirical data on the effectiveness of screening in WLHIV will strengthen the evidence base for screening in this population. These findings informed updated WHO cervical screening and treatment guidelines; WHO now recommends that women living with HIV have primary HPV screening with triage before treatment for ages 25-50 every 3 or 5 years.

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Section: Discussionmentioning

confidence: 88%

Section: Discussionmentioning

confidence: 97%

Section: Scenarios For Evaluationmentioning

confidence: 99%

Section: Scenarios For Evaluationmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Evaluation of the benefits and harms of alternative strategies for cervical screening and treatment in women living with HIV: modelling to support WHO 2021 cervical screening and treatment guidelines to prevent cervical cancer

Hall

Simms

Murray

et al. 2022

Preprint

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

Downham,

Rol,

Forestier

et al. 2024

Intl Journal of Cancer

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Overexpression 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 < .01) with significant lower positivity in WLWH compared to HIV‐negative women (12% vs 25%, p < .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.

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Triage of HPV positivity in a high HIV prevalence setting: A prospective cohort study comparing visual triage methods and HPV genotype restriction in Botswana

Luckett,

Ramogola‐Masire,

Gompers

et al. 2023

Intl J Gynecology & Obste

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ObjectiveGuidelines for effective triage following positive primary high‐risk human papillomavirus (HPV) screening in low‐ and middle‐income countries with high human immunodeficiency virus (HIV)‐prevalence have not previously been established. In the present study, we evaluated the performance of three triage methods for positive HPV results in women living with HIV (WLHIV) and without HIV in Botswana.MethodsWe conducted baseline enrollment of a prospective cohort study from February 2021 to August 2022 in South‐East District, Botswana. Non‐pregnant women aged 25 or older with an intact cervix and no prior diagnosis of cervical cancer were systematically consented for enrollment, with enrichment of the cohort for WLHIV. Those who consented completed a questionnaire and then collected vaginal self‐samples for HPV testing. Primary HPV testing for 15 individual genotypes was conducted using Atila AmpFire® HPV assay. Those with positive HPV results returned for a triage visit where all underwent visual inspection with acetic acid (VIA), colposcopy, and biopsy. Triage strategies with VIA, colposcopy and 8‐type HPV genotype restriction (16/18/31/33/35/45/52/58), separately and in combination, were compared using histopathology as the gold standard in diagnosing cervical intraepithelial neoplasia (CIN) 2 or worse (CIN2+).ResultsAmong 2969 women enrolled, 1480 (50%) tested HPV positive. The cohort included 1478 (50%) WLHIV; 99% were virologically suppressed after a mean of 8 years on antiretroviral therapy. In total, 1269 (86%) women had histopathology data for analysis. Among WLHIV who tested positive for HPV, 131 (19%) of 688 had CIN2+ compared with 71 (12%) of 581 in women without HIV. Screening by 8‐type HPV genotype restriction was more sensitive as triage to detect CIN2+ in WLHIV 87.79% (95% CI: 80.92–92.85) and women without HIV 85.92% (95% CI: 75.62–93.03) when compared with VIA (WLHIV 62.31% [95% CI: 53.39–70.65], women without HIV 44.29% [95% CI: 32.41–56.66]) and colposcopy (WLHIV 70.77% [95% CI: 62.15–78.41], women without HIV 45.71% [95% CI: 33.74–58.06]). However, 8‐type HPV genotype restriction had low specificity in WLHIV of 30.88% (95% CI: 27.06–34.90) and women without HIV 37.06% (95% CI: 32.85–41.41). These results were similar when CIN3+ was used as the outcome. When combining 8‐type HPV genotype restriction with VIA as the triage strategy, there was improved specificity to detect CIN2+ in WLHIV of 81.65% (95% CI: 78.18–84.79) but dramatically reduced sensitivity of 56.15% (95% CI: 47.18–64.84).ConclusionsEight‐type HPV genotype restriction is a promising component of effective triage for HPV positivity. However, novel triage strategies in LMICs with high HIV prevalence may be needed to avoid the trade‐off between sensitivity and specificity with currently available options.Clinical trials registrationThis study is registered on Clinicaltrials.gov no. NCT04242823, https://clinicaltrials.gov/ct2/show/NCT04242823.

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Diagnostic accuracy of cervical cancer screening strategies for high-grade cervical intraepithelial neoplasia (CIN2+/CIN3+) among women living with HIV: A systematic review and meta-analysis

Cited by 23 publications

References 77 publications

Evaluation of the benefits and harms of alternative strategies for cervical screening and treatment in women living with HIV: modelling to support WHO 2021 cervical screening and treatment guidelines to prevent cervical cancer

Evaluation of the benefits and harms of alternative strategies for cervical screening and treatment in women living with HIV: modelling to support WHO 2021 cervical screening and treatment guidelines to prevent cervical cancer

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

Triage of HPV positivity in a high HIV prevalence setting: A prospective cohort study comparing visual triage methods and HPV genotype restriction in Botswana

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