Human Papillomavirus Vaccination Prior to Loop Electroexcision Procedure Does Not Prevent Recurrent Cervical High-grade Squamous Intraepithelial Lesions in Women Living With Human Immunodeficiency Virus: A Randomized, Double-blind, Placebo-controlled Trial.

BACKGROUND: Women living with human immunodeficiency virus (HIV), especially in sub-Saharan Africa, are at high risk for cervical high-grade squamous intraepithelial lesions (HSIL) and cervical cancer. These women have high HSIL recurrence rates after loop electroexcision procedure (LEEP). Retrospective studies suggest that human papillomavirus (HPV) vaccination improves response to treatment of cervical HSIL. METHODS: We performed a double-blind, randomized clinical trial enrolling 180 women living with HIV in Johannesburg, South Africa, diagnosed with cervical HSIL by colposcopic biopsy. Women received quadrivalent HPV vaccine or placebo (1:1) at entry, week 4, and week 26. LEEP was performed at week 4. Colposcopic-directed biopsies and cervical cytology were performed at weeks 26 and 52. The primary endpoint, cervical HSIL by histology or cytology at either week 26 or 52, was compared between arms using χ 2 analysis. RESULTS: Participant characteristics included median age of 39 years and median CD4 count 489 cells/µL, and 94% had HIV suppression. One hundred seventy-four women completed the vaccine/placebo series and had evaluable results at week 26 or 52. The proportion experiencing the primary endpoint was similar in the vaccine and placebo groups (53% vs 45%; relative risk, 1.18 [95% confidence interval, .87-1.6]; P = .29). HSIL recurrence was associated with a LEEP biopsy result of HSIL and detection of HSIL at the margins of the LEEP sample. CONCLUSIONS: This study did not support HPV vaccination to prevent recurrent HSIL after LEEP in women living with HIV. Recurrent HSIL was high despite virologic suppression. Improved treatments are needed for HSIL to reduce the burden of cervical cancer among women living with HIV. CLINICAL TRIALS REGISTRATION: NCT01928225.

A survey of knowledge and attitudes relating to cervical and breast cancer among women in Ethiopia.

BACKGROUND: Breast cancer and cervical cancer are the two leading cancers among women in Ethiopia. This study investigated knowledge and attitudes related to these two types of cancer among women in 4 zones of Ethiopia. This is the first study employing a validated questionnaire to investigate knowledge and attitudes relating to breast and cervical cancer in Ethiopia. METHODS: A community based cross-sectional study was conducted from September to November 2015 in the North Shewa zone (Amhara region), Gamo Gofa zone (Southern Nations, Nationalities and Peoples' region) and zones 1 and 3 (Afar region) of Ethiopia. A total of 799 women aged 18 years and older participated in the survey. Multiple logistic regression analysis was used to investigate the association of possible predictors with breast and cervical cancer knowledge. RESULTS: A total of 799 women aged 18 years and older participated in the survey. Of the women interviewed, 63.0% had heard of breast cancer and 42.2% had heard of cervical cancer. Among those who had heard of breast cancer, 21.3% (107/503) had heard of breast cancer screening and 1.4% of women aged 40 years and older had undergone at least one breast screening examination. Fewer than half of the participants provided the correct response to questions related to risk factors for breast and cervical cancer. Among those who had heard of cervical cancer, 41.5% (140/337) had heard of cervical cancer screening and 3.3% had undergone at least one cervical cancer screening examination. Women with primary and higher levels of education were more likely to have heard of breast cancers (OR = 3.0; 95% CI: 2.1-4.2; p < 0.001) and cervical cancer (OR = 1.9; 95% CI: 1.4-2.6; p < 0.001). From the overall attitude score, the majority of the women were found to have negative attitudes towards breast cancer (67.4%) and cervical cancer (70.6%). CONCLUSIONS: This study found that the overall knowledge of risk factors for breast cancer and cervical cancer among women was low. Lack of cancer awareness, and lack of education in general, are the most potent barriers to access and care, and should be addressed through multi-faceted strategies including peer-education, mass media and other community-based interventions.

Cervical cancer risk and impact of Pap-based screening in HIV-positive women on antiretroviral therapy in Johannesburg, South Africa.

Data on invasive cervical cancer (ICC) incidence in HIV-positive women and the effect of cervical cancer screening in sub-Saharan Africa are scarce. We estimated i) ICC incidence rates in women (≥18 years) who initiated antiretroviral therapy (ART) at the Themba Lethu Clinic (TLC) in Johannesburg, South Africa, between 2004 and 2011 and ii) the effect of a Pap-based screening program. We included 10,640 women; median age at ART initiation: 35 years [interquartile range (IQR) 30-42], median CD4 count at ART initiation: 113 cells/µL (IQR 46-184). During 27,257 person-years (pys), 138 women were diagnosed with ICC; overall incidence rate: 506/100,000 pys [95% confidence interval (CI) 428-598]. The ICC incidence rate was highest (615/100,000 pys) in women who initiated ART before cervical cancer screening became available in 04/2005 and was lowest (260/100,000 pys) in women who initiated ART from 01/2009 onward when the cervical cancer screening program and access to treatment of cervical lesions was expanded [adjusted hazard ratio (aHR) 0.42, 95% CI 0.20-0.87]. Advanced HIV/AIDS stage (4 versus 1, aHR 1.95, 95% CI 1.17-3.24) and middle age at ART initiation (36-45 versus 18-25 years, aHR 2.51, 95% CI 1.07-5.88) were risk factors for ICC. The ICC incidence rate substantially decreased with the implementation of a Pap-based screening program and improved access to treatment of cervical lesions. However, the risk of developing ICC after ART initiation remained high. To inform and improve ICC prevention and care for HIV-positive women in sub-Saharan Africa, implementation and monitoring of cervical cancer screening programs are essential.

A randomized clinical trial comparing cervical dysplasia treatment with cryotherapy vs loop electrosurgical excision procedure in HIV-seropositive women from Johannesburg, South Africa.

BACKGROUND: Mortality associated with cervical cancer is a public health concern for women, particularly in HIV-seropositive women in resource-limited countries. HIV-seropositive women are at a higher risk of high-grade cervical precancer, which can eventually progress to invasive carcinoma as compared to HIV-seronegative women. It is imperative to identify effective treatment methods for high-grade cervical precursors among HIV-seropositive women. OBJECTIVE: Randomized controlled trial data are needed comparing cryotherapy vs loop electrosurgical excision procedure treatment efficacy in HIV-seropositive women. Our primary aim was to compare the difference in the efficacy of loop electrosurgical excision procedure vs cryotherapy for the treatment of high-grade cervical intraepithelial neoplasia (grade ≥2) among HIV-seropositive women by conducting a randomized clinical trial. STUDY DESIGN: HIV-seropositive women (n = 166) aged 18-65 years with histology-proven cervical intraepithelial neoplasia grade ≥2 were randomized (1:1) to cryotherapy or loop electrosurgical excision procedure treatment at a government hospital in Johannesburg. Treatment efficacy was compared using 6- and 12-month cumulative incidence posttreatment of: (1) cervical intraepithelial neoplasia grade ≥2; (2) secondary endpoints of histologic cervical intraepithelial neoplasia grade ≥3 and grade ≥1; and (3) high-grade and low-grade cervical cytology. The study was registered (ClinicalTrials.govNCT01723956). RESULTS: From January 2010 through August 2014, 166 participants were randomized (86 loop electrosurgical excision procedure; 80 cryotherapy). Cumulative cervical intraepithelial neoplasia grade ≥2 incidence was higher for cryotherapy (24.3%; 95% confidence interval, 16.1-35.8) than loop electrosurgical excision procedure at 6 months (10.8%; 95% confidence interval, 5.7-19.8) (P = .02), although by 12 months, the difference was not significant (27.2%; 95% confidence interval, 18.5-38.9 vs 18.5%; 95% confidence interval, 11.6-28.8, P = .21). Cumulative cervical intraepithelial neoplasia grade ≥1 incidence for cryotherapy (89.2%; 95% confidence interval, 80.9-94.9) did not differ from loop electrosurgical excision procedure (78.3%; 95% confidence interval, 68.9-86.4) at 6 months (P = .06); cumulative cervical intraepithelial neoplasia grade ≥1 incidence by 12 months was higher for cryotherapy (98.5%; 95% confidence interval, 92.7-99.8) than loop electrosurgical excision procedure (89.8%; 95% confidence interval, 82.1-95.2) (P = .02). Cumulative high-grade cytology incidence was higher for cryotherapy (41.9%) than loop electrosurgical excision procedure at 6 months (18.1%, P < .01) and 12 months (44.8% vs 19.4%, P < .001). Cumulative incidence of low-grade cytology or greater in cryotherapy (90.5%) did not differ from loop electrosurgical excision procedure at 6 months (80.7%, P = .08); by 12 months, cumulative incidence of low-grade cytology or greater was higher in cryotherapy (100%) than loop electrosurgical excision procedure (94.8%, P = .03). No serious adverse effects were recorded. CONCLUSION: Although rates of cumulative cervical intraepithelial neoplasia grade ≥2 were lower after loop electrosurgical excision procedure than cryotherapy treatment at 6 months, both treatments appeared effective in reducing cervical intraepithelial neoplasia grade ≥2 by >70% by 12 months. The difference in cumulative cervical intraepithelial neoplasia grade ≥2 incidence between the 2 treatment methods by 12 months was not statistically significant. Relatively high cervical intraepithelial neoplasia grade ≥2 recurrence rates, indicating treatment failure, were observed in both treatment arms by 12 months. A different treatment protocol should be considered to optimally treat cervical intraepithelial neoplasia grade ≥2 in HIV-seropositive women.

Cost-effectiveness of using the Cervex-Brush (broom) compared to the elongated spatula for collection of conventional cervical cytology samples within a high-burden HIV setting: a model-based analysis.

BACKGROUND: From 2010 to 2014, approximately 2 million Pap smears from HIV-infected women were submitted to the South African National Health Laboratory Services (NHLS) through the national cervical cancer screening programme. The objective of this analysis was to determine whether using the plastic Cervex brush ("broom") would be a cost-effective approach to improve cytology specimen quality as compared to the wooden spatula used currently. METHODS: A decision analysis model was built using the expected adequacy rates for samples collected with the spatula (<$0.02) and broom ($0.23) and the probability of detecting cervical dysplasia. NHLS data was used for testing volumes and rates of HIV-positivity, suitability of specimens, and presence of endocervical cells. Expected positivity of Pap smears in HIV-infected women (73 %), odds ratios of the effectiveness of the broom (OR: 1.57), and improved sensitivity when endocervical cells present (OR: 1.89) are from literature. NHLS costs were used for the collection devices and conventional cytology ($4.89). Cost of clinic visit is from WHO CHOICE ($8.36). RESULTS: In 2010, 80 % of specimens submitted to NHLS were adequate for evaluation; in 2014, only 54 % met the same criteria. For HIV-infected women, according to the guidelines model, using the wooden spatula costs $6.25 million per year, $16.79 per woman tested. Under intended practice, for each additional HSIL case detected among HIV-infected women, the South African cervical cancer screening programme could save $13.64 (95 % CI: $13.52 to $13.76) by using the broom as its standard of care collection device through increased collection of endocervical cells and consequent reduction in repeat Pap smears. CONCLUSION: Under a wide range of parameters tested using a simulation model, the more expensive plastic broom could save the South African cervical cancer screening programme money and increase detection of high-grade cervical dysplasia in HIV-infected women compared to the current wooden spatula.

Evaluation of a cervicography-based program to ensure quality of visual inspection of the cervix in HIV-infected women in Johannesburg, South Africa.

OBJECTIVE: To determine whether a quality assurance (QA) program using digital cervicography improved the performance of a visual inspection with acetic acid (VIA) to detect cervical intraepithelial neoplasia grade 2 or worse (CIN 2+) in HIV-infected women in Johannesburg, South Africa. MATERIALS AND METHODS: Visual inspection with acetic acid was performed among HIV-infected women, aged 18 to 65 years, in Johannesburg, South Africa. Nurses received 2 weeks of training on the VIA procedure. The VIA interpretation was performed in real time. The VIA results were then photographed using a retail available digital camera. A gynecologist and medical officer reviewed the VIA digital images within 2 weeks of the procedure. Colposcopic biopsy was performed on all women with positive VIA and 25% negative VIA results. Sensitivity and specificity of VIA for the detection of CIN 2+ were compared between the nurses and physicians at the beginning and at the end of the study. RESULTS: Positive VIA results were found in 541 (45%) of the 1,202 participating women. The sensitivity of VIA to predict CIN 2+ was improved from 65% to 75% (p = .001) with the addition of digital cervicography and specialist review. There was no statistical difference in the sensitivity of the VIA readings when comparing the first 600 participants to the final 593 participants between the nurses (p = .613) and physicians (p = .624). CONCLUSIONS: Quality assurance performed by specialists using digital cervicography improved the sensitivity of VIA. There was no difference in sensitivity in interpreting VIA between the beginning and the end of the study. Quality assurance should form a cornerstone of any VIA program to improve sensitivity in detecting CIN 2+ lesions.

Mapping the cervical cancer screening cascade among women living with HIV in Johannesburg, South Africaa.

OBJECTIVE: To map the cervical cancer screening cascade among women living with HIV attending a public-sector cytology screening program in Johannesburg, South Africa. METHODS: We conducted a retrospective cohort study of routinely collected clinical data captured in an electronic medical record system. Women (≥18 years) living with HIV with an abnormal Pap result between January 2013 and May 2018 were included. The proportion of women who received follow-up consistent with extant clinical guidelines, stratified by their initial Pap smear result, was examined. RESULTS: The study included 2072 women: 1384 (66.8%) with a low-risk Pap result, 681 (32.9%) with a high-risk Pap result, and 7 (0.3%) with suspected cancer. Only 174 (25.6%) women with a high-risk Pap result underwent guideline-indicated management within 18 months. Among women with a low-risk Pap result, 375 (27.1%) received follow-up within 1 year; the cumulative incidence of follow-up increased to 63.1% at 3 years. All women with suspected cancer either received a colposcopic biopsy or were referred for further treatment. CONCLUSION: Attrition among South African women living with HIV who attended cervical screening in an urban public-sector program was high. Developing tailored interventions to address bottlenecks in the care cascade and improve cervical screening outcomes will be central to eliminating cervical cancer.

Prevalence of Anal Human Papillomavirus (HPV) and Performance of Cepheid Xpert and Hybrid Capture 2 (hc2) HPV Assays in South African HIV-Infected Women.

OBJECTIVES: This study investigated anal high-risk HPV (HR-HPV) prevalence in HIV-infected women using the Cepheid Xpert HPV assay and compares its performance with that of Hybrid Capture-2 (hc2). METHODS: A total of 199 HIV-infected women were recruited from Helen Joseph Hospital, Johannesburg. Stored ThinPrep anal swabs that had previously been tested using hc2 were tested for HPV using Xpert. RESULTS: The HR-HPV prevalence by Xpert was 40.8% and similar to hc2 (41.8%) with overall agreement of 86.7%; Cohen's kappa 0.73 (95% CI 0.63-0.82). High grade squamous intraepithelial lesions (HSIL) was associated with increasing number of multiple HPV infection (P < .001). Xpert and hc2 were similarly sensitive (77.4% and 77.4%, respectively) and specific (66.1% and 64.8% respectively) for HSIL detection. HPV16 (OR: 14.0, 95% CI: 3.9-48.0, P < .0001), HPV39/68/56/66 (OR: 4.1, 95% CI: 1.4-12, P = .01) and HPV51/59 (OR: 2.8, 95% CI: 1.1-7.6, P = .04) were independently associated with anal HSIL. CONCLUSIONS: Xpert HPV typing is a promising anal screening test in HIV-infected women that performs similarly to hc2.

Cryotherapy Reduces Progression of Cervical Intraepithelial Neoplasia Grade 1 in South African HIV-Infected Women: A Randomized, Controlled Trial.

BACKGROUND: HIV-infected women are at an increased risk of cervical cancer, especially in resource-limited countries. Cervical cancer prevention strategies focus treating cervical high-grade squamous intraepithelial lesions (HSIL). The management of low-grade squamous intraepithelial lesions (LSIL) in HIV-infected women is unknown. SETTING: HIV treatment clinic in Johannesburg, South Africa. METHODS: We randomized HIV-infected women with histologic cervical LSIL to cervical cryotherapy vs. no treatment (standard of care). Cervical high-risk human papillomavirus testing (hrHPV) was performed at baseline. All women underwent cervical cytology and colposcopic biopsies 12 months after enrollment. The primary end point was HSIL on histology at month 12. Chi-square was used to compare arms. RESULTS: Overall, 220 HIV-infected women were randomized to cryotherapy (n = 112) or no treatment (n = 108). Median age was 38 years, 94% were receiving antiretroviral therapy; median CD4 was 499 cells per cubic millimeter, and 59% were hrHPV positive. Cryotherapy reduced progression to HSIL: 2/99 (2%) in the cryotherapy arm and 15/103 (15%) in the no treatment arm developed HSIL, 86% reduction (95% confidence interval: 41% to 97%; P = 0.002). Among 17 HSIL end points, 16 were hrHPV+ at baseline. When restricting the analysis to hrHPV+ women, HSIL occurred in 2/61 (3%) in the cryotherapy arm vs. 14/54 (26%) in the no treatment arm, 87% reduction (95% confidence interval: 47% to 97%; P = 0.0004). Participants in the cryotherapy arm experienced greater regression to normal histology and improved cytologic outcomes. CONCLUSIONS: Treatment of cervical LSIL with cryotherapy decreased progression to HSIL among HIV-infected women especially if hrHPV positive. These results support treatment of LSIL in human papillomavirus test-and-treat approaches for cervical cancer prevention in resource-constrained settings.

Prevalence of Anal HPV and Anal Dysplasia in HIV-Infected Women From Johannesburg, South Africa.

BACKGROUND: Anal cancer is a relatively common cancer among HIV-infected populations. There are limited data on the prevalence of anal high-risk human papillomavirus (HR-HPV) infection and anal dysplasia in HIV-infected women from resource-constrained settings. METHODS: A cross-sectional study of HIV-infected women aged 25-65 years recruited from an HIV clinic in Johannesburg, South Africa. Cervical and anal swabs were taken for conventional cytology and HR-HPV testing. Women with abnormal anal cytology and 20% of women with negative cytology were seen for high-resolution anoscopy with biopsy of visible lesions. RESULTS: Two hundred women were enrolled. Anal HR-HPV was found in 43%. The anal cytology results were negative in 51 (26%); 97 (49%) had low-grade squamous intraepithelial lesions (SIL), 32 (16%) had atypical squamous cells of unknown significance, and 19 (9.5%) had high-grade SIL or atypical squamous cells suggestive of high-grade SIL. On high-resolution anoscopy, 71 (36%) had atypia or low-grade SIL on anal histology and 17 (8.5%) had high-grade SIL. Overall, 31 (17.5%) had high-grade SIL present on anal cytology or histology. Abnormal cervical cytology was found in 70% and cervical HR-HPV in 41%. CONCLUSIONS: We found a significant burden of anal HR-HPV infection, abnormal anal cytology, and high-grade SIL in our cohort. This is the first study of the prevalence of anal dysplasia in HIV-infected women from sub-Saharan Africa. Additional studies are needed to define the epidemiology of these conditions, as well as the incidence of anal cancer, in this population.

Choropleth Mapping of Cervical Cancer Screening in South Africa Using Healthcare Facility-level Data from the National Laboratory Network.

BACKGROUND: In South Africa, cervical cancer remains among the most common cancers and a leading cause of cancer death. Co-infection with HIV increases the risk of developing cervical pre-cancer and cancer. We analysed National Health Laboratory Service cervical cytology data to investigate geographic variations of Pap smear coverage, quality, and high grade lesions. METHODS: Facility-level data were extracted from the NHLS for April 2013-March 2014. We present results and choropleth maps detailing coverage, adequacy and high-grade Pap smear cytology abnormalities defined as Pap smears suspicious for invasive carcinoma, high-grade squamous intraepithelial lesions (HSIL) or atypical squamous cells: cannot exclude HSIL (ASC-H). RESULTS: 4,562 facilities submitted 791,067 cytology slides. The interquartile range (IQR) for Pap smear coverage among HIV-infected women was 26-41%; similar to coverage in women aged 30 and older (IQR: 26-42%). 6/52 districts had adequacy rates above the national standard (70%) and 2/52 districts had adequacy rates below 35%. We observed marked variation in Pap smear abnormalities across the country, with the proportion of high-grade cytology abnormalities ≥0.3% in 17/52 districts. CONCLUSION: Using district-level choropleth maps, we are able to display variations in Pap smear coverage, quality, and results across South Africa. This approach may be used to improve resource allocation, achieving better equity in cervical cancer prevention.

Prospective One Year Follow Up of HIV Infected Women Screened for Cervical Cancer Using Visual Inspection with Acetic Acid, Cytology and Human Papillomavirus Testing in Johannesburg South Africa.

BACKGROUND: Cervical cancer is the most common cancer in Sub-Saharan Africa. There are little of HIV-infected women one-year after screening using visual inspection with acetic acid (VIA), HPV or cytology in sub-Saharan Africa. METHODS: HIV-infected women in Johannesburg South Africa were screened one year later by Pap smear, VIA and human papillomavirus (HPV) testing. Women qualified for the 12 month follow-up visit if they had a negative or cervical intra-epithelial neoplasia (CIN) 1 results at the baseline visit. Modified Poisson regression was used to analyse associations between patient baseline characteristics and progression. RESULTS: A total of 688 of 1,202 enrolled at baseline study who were CIN-2+ negative and qualified for a 12 month follow-up visit. Progression to CIN-2+ was higher in women with positive VIA results (12.6%; 24/191) than those VIA-negative (4.4%; 19/432). HPV-positive women at baseline were more likely to progress to CIN-2+ (12.3%; 36/293) than those HPV-negative (2.1%; 7/329). Cytology-positive women at baseline were more likely to progress to CIN-2+ (9.6%; 37/384) than cytology-negative women (2.5%; 6/237). Approximately 10% (10.4%; 39/376) of women with CIN 1 at baseline progressed to CIN 2+. Women who were VIA or HPV positive at baseline were more likely to progress aIRR 1.85, CI 95% (1.46 to 2.36), aIRR 1.41 CI 95% (1.14 to 1.75) respectively. CONCLUSION: Progression to CIN-2+ in HIV-infected women is significant when measured by baseline positive VIA, HPV or Pap and yearly screening by any method should be considered in this population if possible.

Xpert human papillomavirus test is a promising cervical cancer screening test for HIV-seropositive women.

This study investigated the performance of Cepheid Xpert human papillomavirus (HPV) assay in South African human immunodeficiency virus (HIV)-infected women and compared its performance with that of hybrid capture-2 (hc2). METHODS: Stored cervical specimens from HIV-infected women that had previously been tested using hc2 were tested using Xpert. RESULTS: The overall HR-HPV prevalence was found to be 62.0% (720/1161) by Xpert and 61.2% (711/1161) by hc2. 13.6% (158/1161) were HPV16 positive, 18.8% (218/1161) were HPV18/45, 37.3% (434/1161) were HPV31/33/35/52/58, 12.7% (147/1161) were HPV51/59 and 23.3% (270/1161) were HPV39/68/56/66. Overall agreement with hc2 was 90%; Cohen's kappa was 0.78 (95% CI 0.74-0.82) indicating substantial agreement. Detection of HPV16, HPV18/45, and HPV31/33/35/52/58 were independently associated with cervical intraepithelial neoplasia (CIN)-2+ (P<0.0001 for each); while HPV51/59 and HPV39/68/56/66 were not. Women infected with HPV16, HPV18/45 or HPV31/33/35/52/58 were found to have significantly higher amounts of HPV DNA detected for those with CIN2+ compared to those without CIN2+, P<0.0001 for each. Xpert and hc2 were similarly sensitive (88.3% and 91.5%, respectively) and specific (48.4% and 51.0%) for CIN2+ and CIN3 (sensitivity: 95.8% and 97.9%; specificity: 41.4% and 42.8%). CONCLUSIONS: Xpert is a promising screening test in HIV-infected women that performs similarly to hc2.