The performance of single and combination test strategies using visual inspection, cytology, high-risk HPV DNA and HPV16/18 to screen South African women with and without HIV-infection.

BACKGROUND: Cervical cancer screening strategies should ideally be informed by population-specific data. Strategies recommended for secondary prevention, are often inadequately studied in populations with high cervical disease burdens. This report describes the test performance measured against CIN2 + /CIN3 + histology in HIV-positive women (HPW) and HIV-negative women (HNW) with the aim to determine the most effective strategies to identify South African women at risk. METHODS: Primary screening using visual inspection, cytology and HPV DNA (cobas®) was performed in two South African provinces on 456 HPW and 639 HNW participating in the multicentric DiaVACCS trial. Histology was obtained for 91.7% screen-positive and 42.7% screen-negative participants, and unavailable histology was determined by multiple imputation to adjust for verification bias. Cross-sectional test performance was calculated for single and combination test strategies with and without intermediate risk categories using different cut-offs. Minimum acceptability for sensitivity and specificity, treatment and follow-up numbers were considered to evaluate strategies. RESULTS: The only single test to reach acceptability in HPW was cytology (LSIL) [sensitivity 71.2%; specificity 90.5%; treatment 33.4%]; in HNW only HPV (hr) qualified [sensitivity 68.2%; specificity 85.2%; treatment 23.5%]. The universally best performing strategy which also resulted in smaller treatment numbers without intermediate risk group was primary HPV(hr), with treatment of both HPV(16/18) and cytology (ASCUS +) [HPW: sensitivity 73.6%; specificity 89.7%; treatment 34.7%. HNW: sensitivity 59.1%; specificity 93.6%; treatment 13.9%]. DNA testing for hrHPV (any) and hrHPV (16/18) was the best universally acceptable strategy with an intermediate risk category (early follow-up) in HPW [sensitivity 82.1%; specificity 96.4%; treatment 17.1%; follow-up 31.4%] and HNW [sensitivity 68.2%; specificity 96.7%; treatment 7.6%; follow-up 15.9%]. In comparison, using both HPV (16/18) and cytology (ASCUS +) as secondary tests in hrHPV positive women, decreased follow-up [HPW 13.8%, HNW 9.6%], but increased treatment [HPW 34.7%, HNW 13.9%]. CONCLUSION: Using hrHPV (any) as primary and both HPV16/18 and cytology as secondary tests, was universally acceptable without an intermediate risk group. Strategies with follow-up groups improved screening performance with smaller treatment numbers, but with effective management of the intermediate risk group as prerequisite.

Utility of Extended HPV Genotyping as Primary Cervical Screen in an Unscreened Population With High HIV Co-Infection Rate.

OBJECTIVE: Screening with primary human papillomavirus (HPV) testing has been evaluated in highly prescreened populations with lower HPV and HIV prevalence than what is the case in South Africa. High prevalence of HPV and underlying precancer in women living with HIV (WLWH) affect the clinical performance of screening tests significantly. This study investigates the utility and performance of an extended genotyping HPV test in detection of precancer in a population with a high coinfection rate with HIV. METHODS: A total of 1,001 women aged 25 to 65 years with no cervical cancer screening in the preceding 5 years were tested with cytology and primary extended genotyping HPV testing. The cohort of 1,001 women included 430 WLWH (43.0%) and 564 HIV-negative (56.3%) women. RESULTS: Abnormal cytology (atypical squamous cells of undetermined significance or higher) was significantly higher in WLWH (37.2% vs 15.9%) and high-grade squamous intraepithelial lesion or above (23.5% vs 5.2%). The WLWH also tested positive more often for any HPV type (44.3% vs 19.6%; p < .0001) The specificity for cervical intraepithelial neoplasia 2+ at 91.2% of a combination of HPV types, 16/18/45 (very high risk) and 31/33/58/52 (moderate risk), performed better than cytology or any HPV-positive result to predict cervical intraepithelial neoplasia 3+ on histology. The additional genotype information supports direct referral to treatment or colposcopy in a larger proportion of the screen-positive population. CONCLUSIONS: The potential contribution of extended genotyping is demonstrated. The ideal choice of sensitivity and specificity ultimately depends on the health budget. More information will allow a screening algorithm, guiding management according to risk.

Validation of ASCL1 and LHX8 Methylation Analysis as Primary Cervical Cancer Screening Strategy in South African Women with Human Immunodeficiency Virus.

BACKGROUND: Compared with women who are human immunodeficiency virus (HIV) negative, women with human immunodeficiency virus (WWH) have a higher human papillomavirus (HPV) prevalence and increased cervical cancer risk, emphasizing the need for effective cervical cancer screening in this population. The present study aimed to validate methylation markers ASCL1 and LHX8 for primary screening in a South African cohort of WWH. METHODS: In this post hoc analysis within the DIAgnosis in Vaccine And Cervical Cancer Screen (DiaVACCS) study, a South African observational multicenter cohort study, cervical scrape samples from 411 HIV-positive women were analyzed for hypermethylation of ASCL1 and LHX8 genes, HPV DNA, and cytology. Sensitivities, specificities, and positive and negative predictive values of primary methylation-based, HPV-based and cytology-based screening were calculated for the detection of cervical intraepithelial neoplasia of grade 3 or higher. RESULTS: Single markers ASCL1 and LHX8 resulted in a good performance for the detection of cervical intraepithelial neoplasia of grade 3 or higher, with sensitivities of 85.9% (95% confidence interval [CI], 78.2%-93.6%) and 89.7% (83.0%-96.5%), respectively, and specificities of 72.9% (67.3%-78.5%) and 75.0% (69.5%-80.5%). Combining markers ASCL1 and LHX8 resulted in a lower sensitivity compared with HPV testing (84.6% vs 93.6%, respectively; ratio, 0.90 [95% CI, .82-.99]) and a higher specificity (86.7% vs 78.3%; ratio 1.11 [1.02-1.20]) and reduced the referral rate from 46.8% to 33.4%. ASCL1/LHX8 methylation had a significantly higher sensitivity than cytology (threshold, high-grade intraepithelial squamous lesion or worse), (84.6% vs 74.0%, respectively; ratio, 1.16 [95% CI, 1.01-1.32]) and similar specificity (86.7% vs 91.0%; ratio, 0.95 [.90-1.003]). CONCLUSIONS: Our results validate the accuracy of ASCL1/LHX8 methylation analysis for primary screening in WWH, which offers a full-molecular alternative to cytology- or HPV-based screening, without the need for additional triage testing.

Combining cervical cancer screening for mothers with schoolgirl vaccination during human papillomavirus (HPV) vaccine implementation in South Africa: results from the VACCS1 and VACCS2 trials.

OBJECTIVE: The platform provided by human papillomavirus (HPV) vaccination for linked public health interventions to improve cervical cancer prevention remains incompletely explored. The Vaccine And Cervical Cancer Screen (VACCS) cross-sectional observation trials aimed to evaluate the efficacy of school-based HPV vaccination linked with maternal cervical cancer screening. METHODS: Girls from 29 schools in two provinces in South Africa were invited in writing to receive HPV vaccination. Two approaches to informed consent were compared, namely an audiovisual presentation (VACCS1) and in written format (VACCS2). Markers of vaccine uptake and coverage were calculated, namely uptake among the invited and consented cohorts, and rates of completion and sufficient vaccination. Mothers and female guardians received educational material about cervical cancer, and either a self-sampling device or an invitation to attend existing screening facilities. Knowledge was assessed via structured questionnaires (before and after), and screening uptake was self-reported and directly assessed and compared between these approaches. RESULTS: Vaccine acceptance among 5137 invited girls was similar for the two methods of consent; 99.3% of consented girls received a first dose; overall completion rate was 90.5%. More girls were vaccinated using a two-dose (974/1016 (95.9%)) than a three-dose regimen (1859/2030 (91.6%)). The questionnaire (n=906) showed poor maternal knowledge which improved significantly (p<0.05) after health education; only 54% of mothers reported any previous screening. The offer of a self-sampling device (n=2247) was accepted by 43.9% of mothers, but only 26% of those invited to screen at existing facilities (n=396) reported subsequent screening. CONCLUSIONS: Successful linking of primary health interventions to control cervical cancer was demonstrated. School-based HPV vaccination, linked to health education, self-sampling, and molecular screening resulted in significant improvements in knowledge and screening.

Challenges in lower limb lymphoedema assessment based on limb volume change: Lessons learnt from the SENTIX prospective multicentre study.

BACKGROUND: Lower limb lymphoedema (LLL) is the most disabling adverse effect of surgical staging of pelvic lymph nodes. However, the lack of standardisation of volumetric LLL assessment hinders direct comparison between the studies and makes LLL reporting unreliable. The aim of our study is to report outcomes from a prospective trial that have implications for LLL assessment standardisation. METHODS: In the prospective international multicentre trial SENTIX, a group of 150 patients with stage IA1-IB2 cervical cancer treated by uterine surgery with bilateral sentinel lymph node biopsy was prospectively evaluated by objective LLL assessment, based on limb volume change (LVC) using circumferrential limb measurements and subjective patient-reported swelling. The assessments were conducted in six-month periods over 24 months post-surgery. RESULTS: Patient LVC substantially fluctuated in both positive and negative directions, which were comparable in frequency up to ±14% change. Thirty-eight patients experienced persistent LVC increase >10% classified as LLL, with nine months median time to onset. Some 34.2% of cases experienced onset later than one year after the surgery. Thirty-three patients (22%) experienced transient oedema characterised as LVC >10%, which resolved without intervention between two consequent follow-up visits. No significant correlation between LVC >10% and a patient-reported swelling was observed. CONCLUSIONS: Given that we observed comparable fluctuations of the the lower-limb volumes after surgical treatment of cervical cancer in both positive and negative direction up to ±14%, the diagnostic threshold for LLL diagnosis based on LVC should be increased to >15% LVC. The distinction of transient oedema from persistent LLL requires repeated measurements. Also, as one-third of LLL cases are diagnosed >1-year post-surgery, a sufficient follow-up duration needs to be ensured. Patient-reported swelling correlated poorly with LVC and should only be used as an adjunct to objective LLL assessment. TRIAL REGISTRATION: ClinicalTrials.gov: NCT02494063.

Sentinel lymph node mapping and intraoperative assessment in a prospective, international, multicentre, observational trial of patients with cervical cancer: The SENTIX trial.

BACKGROUND: SENTIX (ENGOT-CX2/CEEGOG-CX1) is an international, multicentre, prospective observational trial evaluating sentinel lymph node (SLN) biopsy without pelvic lymph node dissection in patients with early-stage cervical cancer. We report the final preplanned analysis of the secondary end-points: SLN mapping and outcomes of intraoperative SLN pathology. METHODS: Forty-seven sites (18 countries) with experience of SLN biopsy participated in SENTIX. We preregistered patients with stage IA1/lymphovascular space invasion-positive to IB2 (4 cm or smaller or 2 cm or smaller for fertility-sparing treatment) cervical cancer without suspicious lymph nodes on imaging before surgery. SLN frozen section assessment and pathological ultrastaging were mandatory. Patients were registered postoperatively if SLN were bilaterally detected in the pelvis, and frozen sections were negative. TRIAL REGISTRATION: ClinicalTrials.gov (NCT02494063). RESULTS: We analysed data for 395 preregistered patients. Bilateral detection was achieved in 91% (355/395), and it was unaffected by tumour size, tumour stage or body mass index, but it was lower in older patients, in patients who underwent open surgery, and in sites with fewer cases. No SLN were found outside the seven anatomical pelvic regions. Most SLN and positive SLN were localised below the common iliac artery bifurcation. Single positive SLN above the iliac bifurcation were found in 2% of cases. Frozen sections failed to detect 54% of positive lymph nodes (pN1), including 28% of cases with macrometastases and 90% with micrometastases. INTERPRETATION: SLN biopsy can achieve high bilateral SLN detection in patients with tumours of 4 cm or smaller. At experienced centres, all SLN were found in the pelvis, and most were located below the iliac vessel bifurcation. SLN frozen section assessment is an unreliable tool for intraoperative triage because it only detects about half of N1 cases.

Risk Assessment and Management of Venous Thromboembolism in Women during Pregnancy and Puerperium (SAVE): An International, Cross-sectional Study.

The clinical burden of obstetric venous thromboembolism (VTE) risk is inadequately established. This study assessed the prevalence and management of VTE risk during pregnancy and postpartum outside the Western world. This international, noninterventional study enrolled adult women with objectively confirmed pregnancy attending prenatal care/obstetric centers across 18 countries in Africa, Eurasia, Middle-East, and South Asia. Evaluations included proportions of at-risk women, prophylaxis as per international guidelines, prophylaxis type, factors determining prophylaxis, and physicians' awareness about VTE risk management guidelines and its impact on treatment decision. Data were analyzed globally and regionally. Physicians ( N = 181) screened 4,978 women, and 4,010 were eligible. Of these, 51.4% were at risk (Eurasia, 90%; South Asia, 19.9%), mostly mild in intensity; >90% received prophylaxis as per the guidelines (except South Asia, 77%). Women in Eurasia and South Asia received both pharmacological and mechanical prophylaxes (>55%), while pharmacological prophylaxis (>50%) predominated in Africa and the Middle-East. Low-molecular-weight heparin was the pharmacological agent of choice. Prophylaxis decision was influenced by ethnicity, assisted reproductive techniques, caesarean section, and persistent moderate/high titer of anticardiolipin antibodies, though variable across regions. Prophylaxis decision in at-risk women was similar, irrespective of physicians' awareness of guidelines (except South Asia). A majority (>80%) of the physicians claimed to follow the guidelines. More than 50% of women during pregnancy and postpartum were at risk of VTE, and >90% received prophylaxis as per the guidelines. Physicians are generally aware of VTE risk and comply with guidelines while prescribing prophylaxis, although regional variations necessitate efforts to improve implementation of the guidelines.

School-based human papillomavirus vaccination: An opportunity to increase knowledge about cervical cancer and improve uptake of screening.

BACKGROUND: Poor knowledge about cervical cancer plays a role in limiting screening uptake. HPV vaccination provides an untested platform to distribute information that could possibly improve knowledge and screening coverage. OBJECTIVE: To measure changes in knowledge and screening uptake when information and screening opportunities were provided to mothers of adolescent HPV vaccine recipients. METHODS: During an HPV vaccine implementation project in the Western Cape (WC) and Gauteng Province (GP), South Africa, information about cervical cancer was provided to parents during a lecture, written information was distributed, and mothers were then invited to either screen at their clinic (WC) or use a self-screening kit (GP). A structured questionnaire was used to test cervical cancer knowledge and screening practices, comparing these before and after the project and between the two screening groups. RESULTS: Complete data for both questionnaires were available for 777 of 906 recruited women. Initial knowledge was poor, but on retesting 6 months later, knowledge about symptoms (p<0.005), screening (p<0.005) and vaccination (p<0.05) improved significantly after the information session and school-based HPV vaccination. In the second questionnaire, women reported significantly more screening and the last reported screening test was more recent. This improvement was more favourable in GP than in the WC (41% v. 26% reporting screening in the past 12 months). CONCLUSION: These results demonstrate how adolescent HPV vaccine programmes can help to control cervical cancer among mothers by offering information and screening. It is important not to lose this opportunity to educate mothers and their daughters and offer effective methods to prevent cervical cancer in both generations.

The Vaccine and Cervical Cancer Screen (VACCS) project: Linking cervical cancer screening to HPV vaccination in the South-West District of Tshwane, Gauteng, South Africa.

BACKGROUND: Cervical cancer is preventable, but still highly prevalent in South Africa (SA). Screening strategies in the country have been ineffective, and new ways to prevent the disease are needed. OBJECTIVES: To investigate the feasibility of linking cervical cancer screening in adult women to human papillomavirus (HPV) vaccination in schoolgirls. METHODS: Ten primary schools in the South-West District of Tshwane, Gauteng Province, SA, took part in the study. Cervical cancer and HPV vaccine information was provided to schoolgirls and their parents. Consented schoolgirls were vaccinated and their female parents were invited to participate in self-screening. RESULTS: Among 1 654 girls invited for vaccination, the consented and invited uptake rates were 99.4% and 64.0%, respectively. Vaccine completion rates were higher in schools where the vaccination programme was completed in the same calendar year than in those where it was administered over two calendar years. Of 569 adult females invited, 253 (44.5%) returned screen tests; 169 (66.8%) tested negative and 75 (29.6%) positive for any high-risk HPV (hrHPV). There were no differences in level of education, employment status or access to healthcare between women with positive and those with negative screen results. CONCLUSIONS: Implementation of HPV vaccination in a primary school-based programme was successful, with high vaccine uptake and completion rates. Self-screening reached the ideal target group, and it is possible to link cervical cancer screening to the cervical cancer vaccine by giving women the opportunity of self-sampling for hrHPV testing. This is a novel and feasible approach that would require some adaptive strategies.