Simon Levin

Validation of Cervical Cancer Screening Methods in HIV Positive Women from Johannesburg South Africa

Background HIV-infected women are at increased risk for developing cervical cancer. Women living in resource-limited countries are especially at risk due to poor access to cervical cancer screening and treatment. We evaluated three cervical cancer screening methods to detect cervical intraepithelial neoplasia grade 2 and above (CIN 2+) in HIV-infected women in South Africa; Pap smear, visual inspection with 5% acetic acid (VIA) and human papillomavirus detection (HPV). Methods HIV-infected women aged 18–65 were recruited in Johannesburg. A cross-sectional study evaluating three screening methods for the detection of the histologically-defined gold standard CIN-2 + was performed. Women were screened for cervical abnormalities with the Digene HC2 assay (HPV), Pap smear and VIA. VIA was performed by clinic nurses, digital photographs taken and then later reviewed by specialist physicians. The sensitivity, specificity and predictive valves for CIN-2 + were calculated using maximum likelihood estimators. Results 1,202 HIV-infected women participated, with a median age of 38 years and CD4 counts of 394 cells/mm3. One third of women had a high grade lesion on cytology. VIA and HPV were positive in 45% and 61% of women respectively. Estimated sensitivity/specificity for HPV, Pap smear and VIA for CIN 2+ was 92%/51.4%, 75.8%/83.4% and 65.4/68.5% (nurse reading), respectively. Sensitivities were similar, and specificities appeared significantly lower for the HPV test, cytology and VIA among women with CD4 counts ≤200 cells/mm3 as compared to CD4 counts >350 cells/mm3. Conclusions Although HPV was the most sensitive screening method for detecting CIN 2+, it was less specific than conventional cytology and VIA with digital imaging review. Screening programs may need to be individualized in context of the resources and capacity in each area.

Diverse and High Prevalence of Human Papillomavirus Associated with a Significant High Rate of Cervical Dysplasia in Human Immunodeficiency Virus–Infected Women in Johannesburg, South Africa

OBJECTIVE To evaluate the epidemiology of the human papillomavirus (HPV) type and correlate it with the Papanicolaou smears in human immunodeficiency virus-seropositive women in Johannesburg, South Africa. STUDY DESIGN In a cohort of 148 women, HPV DNA testing was performed with the Roche HPV genotyping test (Branchburg, New Jersey, U.S.A). Papanicolaou smears were performed by standard cytology utilizing 2001 Bethesda reporting guidelines. RESULTS The average age and CD4 count of the participants was 35 years and 255 cells per mm3, respectively. Fifty-four percent had abnormal Papanicolaou smears; 66% of the abnormal cytology was low grade changes, with 33% assessed as having high grade changes. HPV DNA was found in 95% of the 148 subjects assessed, with 83% having 1 or more HPV oncogenic types. Common oncogenic types were 16, 35, 53 and 18. When HPV results were stratified by CD4, there was a significant risk of an oncogenic HPV type in women with CD4 <200. Significant odds ratios for high grade lesions were seen in HPV types 16, 35, 51, 66, 69 and 73. CONCLUSION The results of HPV typing illustrate the diverse range of oncogenic HPV and high prevalence of oncogenic type. These results highlight the need for improved access to Papanicolaou smear screening for this population.

Highly active antiretroviral therapy and cervical dysplasia in HIV-positive women in South Africa

The risk of squamous intra‐epithelial lesions (SIL) is higher in HIV‐positive women. As these women begin to live longer due to highly active antiretroviral therapy (HAART), their risk of cervical cancer may increase. Few data exist regarding the effect of HAART on the incidence and progression of SIL in HIV‐positive African women. The aim of this study was to evaluate the effect of HAART on the incidence and progression of SIL in HIV‐positive women in South Africa.

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.

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.gov NCT01723956). 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.

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.

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.

Atypical squamous cells, cannot exclude high grade squamous intraepithelial (ASC-H) in HIV-positive women

Objective: South Africa has very high rates of both HIV infection and cervical pathology. The management of ASC-H is colposcopy and directed biopsy, but with so many women diagnosed with HSIL and a dearth of colposcopy centres in South Africa, women with cytologic diagnosis of ASC-H may not be prioritized for colposcopy. The aim of this study was to determine if HIV-positive women with a cytologic diagnosis of ASC-H should undergo immediate colposcopy or whether colposcopy can be delayed, within the context of an underfunded health care setting with so many competing health needs. Materials and Methods: A computer database search was performed from the archives of an NGO-administered clinic that offers comprehensive HIV care. All women with a cytologic diagnosis of ASC-H on cervical smears from September 2005 until August 2009 were identified. Histologic follow up was sought in all patients. Results: A total of 2111 cervical smears were performed and 41 diagnosed as ASC-H (1.94%). No histologic follow up data was available in 15 cases. Follow up histologic results were as follows: three negative (11.5%), five koilocytosis and/ or CIN1 (19.2%), ten CIN2 (38.5%) and eight CIN3 (30.8%). There were no cases of invasive carcinoma on follow up. Conclusion: The current appropriate management of HIV-positive women in low-resource settings with a diagnosis of ASC-H on cervical smear is colposcopy, despite the costs involved. In the future and if cost-effective in developing nations, use of novel markers may help select which HIV-positive women can be managed conservatively and which ones referred for more active treatment. More research in this regard is warranted.

Injectable and oral contraception and the incidence and progression of cervical disease in HIV-infected women in South Africa☆

BACKGROUND Few data exist regarding the effect of hormonal contraception (HC) on incidence and progression of cervical disease (e.g., cervical dysplasia, squamous intraepithelial lesions, cervical intraepithelial neoplasia) in HIV-infected African women. STUDY DESIGN We conducted an observational study of HIV-seropositive women in Johannesburg, South Africa. The effect of individual HC types on the incidence and progression of cervical disease was determined using Poisson regression to obtain adjusted incidence rate ratios. RESULTS We evaluated 594 HIV-infected women, with median follow-up time of 445 days; 75 of these women were receiving some form of HC (largely DMPA, NET-EN, or COCs) at baseline. Risks of incidence and progression of cervical disease were similar comparing women not receiving HCs to women receiving DMPA, NET-EN, or COCs both individually by HC-type and considering all HC together. CONCLUSIONS There was no statistically significant effect of particular HC methods or of HC use in general on rates of incidence or progression of cervical disease in this study. These results should reassure us that use of HC is unlikely to substantially increase risks of cervical disease among HIV-positive women.

Progression of cervical neoplasia in HIV-seropositive women with and without antiretroviral therapy in Johannesburg, South Africa

Background HIV-seropositive women have a higher risk of oncogenic HPV infection, cervical neoplasia, and cervical cancer than HIV-seronegative women. As HIV-seropositive women begin to live longer due to effective highly active antiretroviral therapy (HAART), their risk of developing cervical cancer may increase. Little data exist regarding the progression of cervical neoplasia in HIV seropositive women from sub-Saharan Africa.