Enhancing Cervical Cancer Prevention in South African Women: Primary HPV mRNA Screening with Different Genotype Combinations.

BACKGROUND: Cervical cancer prevention in regions with limited access to screening and HPV vaccination necessitates innovative approaches. This study explored the potential of a test-and-treat strategy using mRNA HPV tests to impact cervical cancer prevention in a high-prevalence HIV population. METHODS: A cervical screening study was conducted at three South African hospitals involving 710 under-screened, non-pregnant women (25 to 65 years) without known cervical diseases. Cytology, HPV testing, colposcopy, and biopsies were performed concurrently. Histopathologists determined final histological diagnoses based on biopsy and LLETZ histology. mRNA-HPV-genotyping for 3 (16, 18, 45) to 8 (16, 18, 31, 33, 35, 45, 52, 58) high-risk types was performed on leftover liquid-based cytology material. The preventive potential of the test-and-treat approach was estimated based on published data, reporting the causative HPV types in cervical cancer tissue from South African women. Treatment was provided as needed. RESULTS: The HPV positivity rate more than doubled from 3-type (15.2%; 95% CI: 12.6-17.8) to 8-type mRNA (31.5%; 95% CI: 28.8-34.9) combinations, significantly higher among HIV-positive women. CIN3+ prevalence among HIV-positive women (26.4%) was double that of HIV-negative women (12.9%) (p < 0.01). The 6-type combination showed the best balance of sensitivity, specificity and treatment group size, and effectiveness to prevent cervical cancer. A 4-type combination (16, 18, 35, 45) could potentially prevent 77.6% (95% CI: 71.2-84.0) of cervical cancer burden by treating 20% and detecting 41.1% of CIN3 cases in the study group. Similarly, a 6-type combination (16, 18, 31, 33, 35, 45), treating 25% and including 62% of CIN3 cases, might prevent 85% of cervical cancer cases (95% CI: 79.6-90.6) among HIV-positive and negative women. CONCLUSION: Employing mRNA HPV tests within a test-and-treat approach holds huge promise for targeted cervical cancer prevention in under-screened populations. Testing for mRNA of the 6 highest-risk HPV types in this population and treating them all is projected to effectively prevent progression from CIN3 to invasive cervical cancer while reducing overtreatment in resource-constrained settings.

Cytology compared with Hybrid Capture 2 human papilloma virus cervical cancer screening in HIV positive and HIV negative South African women.

OBJECTIVES: Cervical cancer is preventable and caused by persistent infection with oncogenic human papilloma virus (HPV) types. HPV screening is more sensitive and is the preferred screening test. HPV screening data are mainly from developed settings, and the purpose of this study was to investigate the performance of HPV screening in previously unscreened HIV positive and negative women. METHODS: In this cross sectional multicenter study, liquid based cytology and HPV testing were performed on women attending different clinics. Patients with positive screening tests had colposcopy and biopsy or large loop excision of the transformation zone. Some women with normal screening had colposcopy and biopsy. Data of women with histology results, and data of HIV positive and negative women were analyzed for comparison. For women without histology results, data were imputed using a statistical model. RESULTS: In 903 women with known HIV status, 683 (75.6%) had negative cytology, 202 women (22.4%) had abnormal cytology, and in 18 patients (2.0%) the results were uncertain. Mean age was 41.4 years (range 25-65). HPV tests were negative in 621 women (68.8%). In HIV positive women, 54.5% tested negative compared with 79.7% HIV negative women (p<0.0001). HPV screening had higher sensitivity (60.9%), but lower specificity (82.4%), compared with cytology (48.6% and 86.7%) for detection of cervical intraepithelial neoplasia (CIN) 2+ in all women. For detection of CIN 3+, HPV screening had higher sensitivity (70.4%) compared with cytology (62.9%), and specificity (75.5%) was lower compared with cytology at a threshold of atypical squamous cells of undetermined significance (ASCUS+) (82.4%). CONCLUSION: HPV screening was more sensitive than cytology in HIV positive and HIV negative women, but specificity was lower. Although HPV screening should be the preferred screening test, cytology is a suitable screening test in HIV positive women in low resource settings. TRIAL REGISTRATION NUMBER: NCT02956031.

Diagnostic value of sentinel lymph node scintigraphy and 2-[18F]-fluoro-2-deoxy-D-glucose positron emission tomography/computed tomography in the detection of metastatic lymph nodes in patients with early-stage cervical cancer.

Cervical cancer is staged clinically using the International Federation of Gynaecology and Obstetrics staging system. Although lymph node status does not form part of the staging, it has important prognostic and potential therapeutic implications. The aim of the study was to evaluate the role of sentinel lymph node (SLN) scintigraphy and 2-[18F]-fluoro-2-deoxy-D-glucose positron emission tomography/computed tomography (18F-FDG PET/CT) in detecting lymph node metastases in patients with early-stage cervical cancer. Thirty-six patients with early-stage cervical cancer underwent SLN detection during primary operation. Of the 36 patients, 28 patients underwent 18F-FDG PET/CT before surgery. The 18F-FDG PET/CT images were analyzed with the histopathological findings as the reference standard. The diagnostic performance of 18F-FDG PET/CT in the detection of nodal disease was reported in terms of accuracy value. The SLN detection rate was the highest (91.7%) using the combined method (lymphoscintigraphy, intraoperative gamma probe, and blue dye). Seven of the thirty-six patients had lymph node involvement (19.4%), of which five had preoperative 18F-FDG PET/CT imaging. On overall patient-based analysis, the sensitivity, specificity, positive predictive value, negative predictive value (NPV), and accuracy of 18F-FDG PET/CT were 40.0%, 78.3%, 28.6%, 85.7%, and 71.4%, respectively. The combination of radiolabeled nanocolloid with blue dye is safe and reliable and allows successful detection of SLNs in patients with early-stage cervical cancer in a population with high prevalence of human immunodeficiency virus. The specificity and NPV of 18F-FDG PET/CT are high and can be used in conjunction with SLN biopsy.

Central Pathology Review in SENTIX, A Prospective Observational International Study on Sentinel Lymph Node Biopsy in Patients with Early-Stage Cervical Cancer (ENGOT-CX2).

The quality of pathological assessment is crucial for the safety of patients with cervical cancer if pelvic lymph node dissection is to be replaced by sentinel lymph node (SLN) biopsy. Central pathology review of SLN pathological ultrastaging was conducted in the prospective SENTIX/European Network of Gynaecological Oncological Trial (ENGOT)-CX2 study. All specimens from at least two patients per site were submitted for the central review. For cases with major or critical deviations, the sites were requested to submit all samples from all additional patients for second-round assessment. From the group of 300 patients, samples from 83 cases from 37 sites were reviewed in the first round. Minor, major, critical, and no deviations were identified in 28%, 19%, 14%, and 39% of cases, respectively. Samples from 26 patients were submitted for the second-round review, with only two major deviations found. In conclusion, a high rate of major or critical deviations was identified in the first round of the central pathology review (28% of samples). This reflects a substantial heterogeneity in current practice, despite trial protocol requirements. The importance of the central review conducted prospectively at the early phase of the trial is demonstrated by a substantial improvement of SLN ultrastaging quality in the second-round review.

Use of a Sentinel Lymph Node Biopsy Algorithm in a South African Population of Patients With Cervical Cancer and High Prevalence of Human Immunodeficiency Virus Infection.

OBJECTIVES: Cervical cancer is common in resource-poor settings with high prevalence of tuberculosis, pelvic inflammatory disease, and human immunodeficiency virus (HIV) infection. There are no data regarding the sentinel lymph node (SLN) algorithm in these high-risk cancer populations. Our objectives were to establish the sensitivity, specificity, positive predictive value, and negative predictive value of the SLN algorithm in cervical cancer and to compare the detection rate of indocyanine green (ICG) versus blue dye versus technetium Tc 99m nanocolloid (Tc). METHODS: This prospective study was conducted at the University of Pretoria. Tc-nanocolloid tracer, ICG dye, and methylene blue (MB) were used to detect SLNs. Pathological ultrastaging was performed on hematoxylin-eosin- negative nodes. RESULTS: Results of 72 women were analyzed. The mean age was 47.2 years, 5.5% had a history of tuberculosis, 18.1% had pelvic inflammatory disease, and 65.3% were HIV positive. The SLN detection rate was 65.3%. Detection rate of MB was 56.9%; Tc, 69.4%; ICG, 87.5%; and the combination of MB and Tc, 91.7%. Pelvic nodal metastases occurred in 26.4%. The sensitivity, specificity, negative predictive value, and positive predictive value of SLN biopsy were 85.7%, 100%, 100%, and 98.33%, respectively. The false-negative rate was 14.3%, and it was 0% if the algorithm was applied. CONCLUSIONS: The SLN algorithm is a feasible option for use in cervical cancer women with a high prevalence of HIV infection. The detection rate is generally lower, but in select subgroups of women, it was comparable to that reported elsewhere. This is the first report of the use of SLN biopsy in a substantial group of HIV-infected women.

Oncogenic and incidental HPV types associated with histologically confirmed cervical intraepithelial neoplasia in HIV-positive and HIV-negative South African women.

BACKGROUND: In Africa, data on the relationship between oncogenic human papillomavirus (HPV) types, immune status and cervical preinvasive lesions are lacking. METHODS:  We investigated low-risk (lrHPV) and high-risk (hrHPV) HPV types in a cohort of women with cervical intraepithelial neoplasia (CIN) II/III confirmed on histological examination, in an urban setting with a high prevalence of HIV infection. RESULTS:  Of 270 women with confirmed CIN II/III, 45 were HIV-negative and 225 HIV-positive. HIV-infected women had significantly more HPV type infections, including all HPV (p<0.001) and hrHPV (p=0.014) types. The prevalences of one or more hrHPV type/s were 93.3% and 92.9% in HIV-negative and positive patients, respectively. The most prevalent hrHPV type among HIV-negative women was HPV 16, followed by HPV 52, 31, 35 and 58. Among HIV-positive women, HPV 16 was followed by HPV 58, 35, 51 and 52. Not yet qualifying qualify for highly active antiretroviral therapy (HAART) (CD4 count >350 cells/µL) or having received HAART for ≥12 months were negatively associated with HPV 18, 33, 45, 51, 52, 59 and 82. CONCLUSIONS:  In South Africa, burdened by the HIV pandemic, high numbers of high- and low-risk HPV type infections are present in women with cervical preneoplasia. HPV type distribution differs among varying levels of HIV-induced immune depletion.

A randomised controlled trial comparing oxytocin and oxytocin + ergometrine for prevention of postpartum haemorrhage at caesarean section.

BACKGROUND: Globally 166 000 women die annually as a result of obstetric haemorrhage. More than 50% of these deaths occur in sub-Saharan Africa. Uterine atony is the commonest cause of severe postpartum haemorrhage (PPH). Bleeding at or after caesarean section (CS) is responsible for >30% of maternal deaths due to obstetric haemorrhage in South Africa (SA). OBJECTIVE: To compare oxytocin alone with oxytocin + ergometrine in terms of primary prophylaxis for PPH at the time of CS. METHODS: This was a double-blind randomised controlled interventional study comparing oxytocin with oxytocin + ergometrine administered during CS. Patients were randomised to receive oxytocin alone intravenously as a bolus or oxytocin + ergometrine intramuscularly, with the placebo being an injection of sterile water. The study population consisted of women undergoing CS at Kalafong Provincial Tertiary Hospital in Atteridgeville, Gauteng, SA. RESULTS: Five hundred and forty women were randomised and data for 416 women, of whom 214 received oxytocin and 202 oxytocin + ergometrine, were available for analysis. In the oxytocin group 19 women (8.9%) required blood transfusion, compared with seven (3.5%) in the oxytocin + ergometrine group (p=0.01; relative risk = 2.78; 95% confidence interval 1.21 - 6.4). There were no statistically significant differences in the mean estimated visual and mean calculated blood loss. CONCLUSIONS: The overall need for blood transfusion was significantly reduced by about two-thirds in women receiving the oxytocin + ergometrine combination. Consideration should be given to using oxytocin + ergometrine for prophylaxis of PPH at CS.