Diagnostic Accuracy Of Cervical Cancer Screening And Screening-Triage Strategies Among Women Living With Hiv-1 In Burkina Faso And South Africa: A Cohort Study

BackgroundCervical cancer screening strategies using visual inspection or cytology may have suboptimal diagnostic accuracy for detection of precancer in women living with HIV (WLHIV). The optimal screen and screen-triage strategy, age to initiate, and frequency of screening for WLHIV remain unclear. This study evaluated the sensitivity, specificity, and positive predictive value of different cervical cancer strategies in WLHIV in Africa.Methods and findingsWLHIV aged 25-50 years attending HIV treatment centres in Burkina Faso (BF) and South Africa (SA) from 5 December 2011 to 30 October 2012 were enrolled in a prospective evaluation study of visual inspection using acetic acid (VIA) or visual inspection using Lugol's iodine (VILI), high-risk human papillomavirus DNA test (Hybrid Capture 2 [HC2] or careHPV), and cytology for histology-verified high-grade cervical intraepithelial neoplasia (CIN2+/CIN3+) at baseline and endline, a median 16 months later. Among 1,238 women (BF: 615; SA: 623), median age was 36 and 34 years (p < 0.001), 28.6% and 49.6% ever had prior cervical cancer screening (p < 0.001), and 69.9% and 64.2% were taking ART at enrolment (p = 0.045) in BF and SA, respectively. CIN2+ prevalence was 5.8% and 22.4% in BF and SA (p < 0.001), respectively. VIA had low sensitivity for CIN2+ (44.7%, 95% confidence interval [CI] 36.9%-52.7%) and CIN3+ (56.1%, 95% CI 43.3%-68.3%) in both countries, with specificity for <= CIN1 of 78.7% (95% CI 76.0%-81.3%). HC2 had sensitivity of 88.8% (95% CI 82.9%-93.2%) for CIN2+ and 86.4% (95% CI 75.7%-93.6%) for CIN3+. Specificity for <= CIN1 was 55.4% (95% CI 52.2%-58.6%), and screen positivity was 51.3%. Specificity was higher with a restricted genotype (HPV16/18/31/33/35/45/52/58) approach (73.5%, 95% CI 70.6%-76.2%), with lower screen positivity (33.7%), although there was lower sensitivity for CIN3+ (77.3%, 95% CI 65.3%-86.7%). In BF, HC2 was more sensitive for CIN2+/CIN3+ compared to VIA/VILI (relative sensitivity for CIN2+ = 1.72, 95% CI 1.28-2.32; CIN3+: 1.18, 95% CI 0.94-1.49). Triage of HC2-positive women with VIA/VILI reduced the number of colposcopy referrals, but with loss in sensitivity for CIN2+ (58.1%) but not for CIN3+ (84.6%). In SA, cytology high-grade squamous intraepithelial lesion or greater (HSIL+) had best combination of sensitivity (CIN2+: 70.1%, 95% CI 61.3%-77.9%; CIN3+: 80.8%, 95% CI 67.5%-90.4%) and specificity (81.6%, 95% CI 77.6%-85.1%). HC2 had similar sensitivity for CIN3+ (83.0%, 95% CI 70.2%-91.9%) but lower specificity compared to HSIL+ (42.7%, 95% CI 38.4%-47.1%; relative specificity = 0.57, 95% CI 0.52-0.63), resulting in almost twice as many referrals. Compared to HC2, triage of HC2-positive women with HSIL+ resulted in a 40% reduction in colposcopy referrals but was associated with some loss in sensitivity. CIN2+ incidence over a median 16 months was highest among VIA baseline screen-negative women (2.2%, 95% CI 1.3%-3.7%) and women who were baseline double-negative with HC2 and VIA (2.1%, 95% CI 1.3%-3.5%) and lowest among HC2 baseline screen-negative women (0.5%, 95% CI 0.1%-1.8%). Limitations of our study are that WLHIV included in the study may not reflect a contemporary cohort of WLHIV initiating ART in the universal ART era and that we did not evaluate HPV tests available in study settings today.ConclusionsIn this cohort study among WLHIV in Africa, a human papillomavirus (HPV) test targeting 14 high-risk (HR) types had higher sensitivity to detect CIN2+ compared to visual inspection but had low specificity, although a restricted genotype approach targeting 8 HR types decreased the number of unnecessary colposcopy referrals. Cytology HSIL+ had optimal performance for CIN2+/CIN3+ detection in SA. Triage of HPV-positive women with HSIL+ maintained high specificity but with some loss in sensitivity compared to HC2 alone.Author summaryWhy was this study done?Invasive cervical cancer is the second most common cancer among women in low- and middle-income countries and a leading cause of cancer-related death in women in sub-Saharan Africa.Women living with human immunodeficiency virus (WLHIV) have an increased risk of cervical cancer and precancer. The majority of WLHIV live in low- and middle-income countries, where access to cervical cancer screening and treatment of precancerous cervical lesions is limited.Screening approaches most commonly used in sub-Saharan Africa, including visual inspection of the cervix and cervical cytology, which checks for cervical cell abnormalities, have shown variable diagnostic accuracy to detect precancerous lesions. Molecular-based screening approaches, such as human papillomavirus (HPV) DNA testing, which screens for oncogenic HPV infection, have shown high sensitivity for cervical precancer but can result in over-referral to colposcopy, a procedure to determine eligibility for treatment.The optimal screening test, age to begin screening, and frequency of screening for WLHIV remain uncertain.What did the researchers do and find?We evaluated several cervical cancer screening strategies in over 1,200 WLHIV in sub-Saharan Africa.We found that an HPV DNA test identified a greater number of women with precancer compared to visual inspection and cytology methods. However, there was a greater proportion of women without precancer who had a positive HPV DNA test, meaning a triage test using cytology or visual inspection was required to determine treatment eligibility.Simple user-applied modifications to the HPV-DNA-based test resulted in fewer women without precancer testing positive and fewer women needing triage.In settings with adequate infrastructure, cervical cytology was a useful triage test for HPV-positive women.What do these findings mean?Our data contribute to the evidence on choice of screening strategies for detection of cervical precancer among WLHIV in low- and middle-income settings.HPV DNA tests can play an important role in cervical cancer screening, especially in the era of universal antiretroviral therapy and where availability of self-sampling will facilitate screening participation.Prevention of cervical cancer should rank high as a public health priority in sub-Saharan Africa since WLHIV represent a group at very high risk of cervical precancer.