Prevalence of anogenital HPV infection, related disease and risk factors among HIV-infected men in inner-city Johannesburg, South Africa: baseline findings from a cohort study.

BACKGROUND: Persistent high-risk human papillomavirus (HR-HPV) infection is associated with the development of anogenital cancers, particularly in men living with HIV (MLWH). We describe the prevalence of anogenital HPV infection, abnormal anal cytology and anogenital warts (AGWs) in MLWH in Johannesburg, and explore whether HPV infection and receipt of antiretroviral treatment is associated with detection of abnormal anal cytology and AGWs. METHODS: We enrolled a cohort of 304 sexually-active MLWH ≥18 years, who completed a questionnaire and physical examination. Genital swabs were collected from all men and intra-anal swabs from 250 (82%). Swabs were tested for HPV DNA and genotypes, and anal smears graded using the Bethesda classification. Factors associated with anogenital disease were assessed by logistic regression models. RESULTS: Two thirds were receiving antiretroviral treatment, for a median 33 months (IQR = 15-58) and 54% were HIV-virologically suppressed. Only 5% reported ever having sex with men. Among 283 genital swabs with valid results, 79% had any HPV, 52% had HR-HPV and 27% had >1 HR-HPV infection. By comparison, 39% of the 227 valid intra-anal swabs had detectable HPV, 25% had any HR-HPV and 7% >1 HR infection. While most anal smears were normal (51%), 20% had ASCUS and 29% were LSIL. No cases had HSIL or cancer. Infection with >1 HR type (adjusted OR [aOR] = 2.39; 95%CI = 1.02-5.58) and alpha-9 types (aOR = 3.98; 95%CI = 1.42-11.16) were associated with having abnormal cytology. Prevalence of AGWs was 12%. Infection with any LR type (aOR = 41.28; 95%CI = 13.57-125.62), >1 LR type (aOR = 4.14; 95%CI = 1.60-10.69), being <6 months on antiretroviral treatment (aOR = 6.90; 95%CI = 1.63-29.20) and having a CD4+ count <200 cells/μL (aOR = 5.48; 95%CI: 1.60-18.78) were associated with having AGWs. CONCLUSIONS: In this population, anogenital HR-HPV infection and associated low-grade disease is common, but severe anal dysplasia was not detected. Findings reinforce the need for HPV vaccination in men for preventing both AGWs and HR-HPV infection. Given the absence of anal HSILs, however, the findings do not support the use of anal screening programmes in this population

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

Abstract 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$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

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

Background: Cervical 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 findings: WLHIV 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. Conclusions: In 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

Diagnostic accuracy of cervical cancer screening strategies for high-grade cervical intraepithelial neoplasia (CIN2+/CIN3+) among women living with HIV: A systematic review and meta-analysis

BACKGROUND: We systematically reviewed the diagnostic accuracy of cervical cancer screening and triage strategies in women living with HIV (WLHIV). METHODS: Cochrane Library, Embase, Global Health and Medline were searched for randomised controlled trials, prospective or cross-sectional studies published from database inception to 15 July 2022 reporting diagnostic accuracy of tests in cervical cancer screening and triage of screen-positive WLHIV. Studies were included if they reported the diagnostic accuracy of any cervical cancer screening or triage strategies for the detection of histologically-confirmed high-grade cervical intraepithelial neoplasia (CIN2+/CIN3+) among WLHIV. Summary data were extracted from published reports. Authors were contacted for missing data where applicable. Sensitivity and specificity estimates for CIN2/3+ were pooled using models for meta-analysis of diagnostic accuracy data. Study quality was assessed using the QUADAS-2 tool for the quality assessment of diagnostic accuracy studies. PROSPERO registration:CRD42020189031. FINDINGS: In 38 studies among 18,737 WLHIV, the majority (n=19) were conducted in sub-Saharan Africa. The pooled prevalence was 12.0% (95%CI:9.8-14.1) for CIN2+ and 6.7% (95%CI:5.0-8.4) for CIN3+. The proportion of screen-positive ranged from 3-31% (visual inspection using acetic acid[VIA]); 2-46% (high-grade squamous intraepithelial lesions, and greater [HSIL+] cytology); 20-64% (high-risk[HR]-HPV DNA). In 14 studies, sensitivity and specificity of VIA were variable limiting the reliability of pooled estimates. In 5 studies where majority had histology-confirmed CIN2+, pooled sensitivity was 56.0% (95%CI:45.4-66.1; I2=65%) for CIN2+ and 65.0% (95%CI:52.9-75.4; I2 =42%) for CIN3+; specificity for <CIN2 was 73.8% (95%CI:59.8-84.2, I2=94%). Cytology was similarly variable (sensitivity of ASCUS+ for CIN2+ range: 58-100%; specificity: 9-96%). In 28 studies, sensitivity of tests targeting 14-HR-HPV types was high (91.6%, 95%CI:88.1-94.1; I2=45% for CIN2+ and 92.5%, 95%CI:88.4-95.2; I2=32%) for CIN3+); but specificity for <CIN2 was low (62.2% (95%CI:57.9-66.4;I2=92%). Restriction to 8-HR-HPV increased specificity (65.8%; Relative specificity[RSpec] vs. 14-HR-HPV=1.17; 95%CI:1.10-1.24) with no significant change in sensitivity (CIN2+:85.5%; Relative Sensitivity[RSens]=0.94, 95%CI: 0.89-1.00; CIN3+:90%; RSens=0.96, 95%CI:0.89-1.03). VIA triage of 14-HR-HPV positive women decreased sensitivity for CIN2+ compared to HPV-DNA test alone (64.4% vs. 91.6%; RSens=0.68, 95%CI:0.62-0.75). INTERPRETATION: HPV-DNA based approaches consistently showed superior sensitivity for CIN2+/CIN3+ compared to VIA or cytology. The low specificity of HPV-DNA based methods targeting up to 14-HR-HPV could be improved significantly by restricting to 8-HR-HPV with only minor losses in sensitivity, limiting requirement for triage for which optimal approaches are less clear. FUNDING: World Health Organisation; National Cancer Institute; European Union's Horizon 2020 and Marie Skłodowska-Curie Actions programme

Prevalence of anogenital HPV infection, related disease and risk factors among HIV-infected men in inner-city Johannesburg, South Africa: baseline findings from a cohort study.

BACKGROUND: Persistent high-risk human papillomavirus (HR-HPV) infection is associated with the development of anogenital cancers, particularly in men living with HIV (MLWH). We describe the prevalence of anogenital HPV infection, abnormal anal cytology and anogenital warts (AGWs) in MLWH in Johannesburg, and explore whether HPV infection and receipt of antiretroviral treatment is associated with detection of abnormal anal cytology and AGWs. METHODS: We enrolled a cohort of 304 sexually-active MLWH ≥18 years, who completed a questionnaire and physical examination. Genital swabs were collected from all men and intra-anal swabs from 250 (82%). Swabs were tested for HPV DNA and genotypes, and anal smears graded using the Bethesda classification. Factors associated with anogenital disease were assessed by logistic regression models. RESULTS: Two thirds were receiving antiretroviral treatment, for a median 33 months (IQR = 15-58) and 54% were HIV-virologically suppressed. Only 5% reported ever having sex with men. Among 283 genital swabs with valid results, 79% had any HPV, 52% had HR-HPV and 27% had >1 HR-HPV infection. By comparison, 39% of the 227 valid intra-anal swabs had detectable HPV, 25% had any HR-HPV and 7% >1 HR infection. While most anal smears were normal (51%), 20% had ASCUS and 29% were LSIL. No cases had HSIL or cancer. Infection with >1 HR type (adjusted OR [aOR] = 2.39; 95%CI = 1.02-5.58) and alpha-9 types (aOR = 3.98; 95%CI = 1.42-11.16) were associated with having abnormal cytology. Prevalence of AGWs was 12%. Infection with any LR type (aOR = 41.28; 95%CI = 13.57-125.62), >1 LR type (aOR = 4.14; 95%CI = 1.60-10.69), being <6 months on antiretroviral treatment (aOR = 6.90; 95%CI = 1.63-29.20) and having a CD4+ count <200 cells/μL (aOR = 5.48; 95%CI: 1.60-18.78) were associated with having AGWs. CONCLUSIONS: In this population, anogenital HR-HPV infection and associated low-grade disease is common, but severe anal dysplasia was not detected. Findings reinforce the need for HPV vaccination in men for preventing both AGWs and HR-HPV infection. Given the absence of anal HSILs, however, the findings do not support the use of anal screening programmes in this population

Effectiveness of the cell block technique in diagnostic cytopathology

Background: One of the constraints of the conventional FNA smear is the limited material available for adjuvant diagnostic investigations including immunocytochemistry. The cell block technique employs the retrieval of small tissue fragments from a FNA specimen which are processed to form a paraffin block. It is widely accepted that cell block technique increases the cellular yield and improves diagnostic accuracy. The ability to obtain numerous tissue sections allows for multiple immunostains and other studies to be performed akin to paraffin sections produced in histopathology. Aims: To determine the effectiveness of the cell block technique by comparing cytomorphological preservation and immunocytochemistry (ICC) stains on paired cell block and conventional fine needle aspiration (FNA) samples. Materials and Methods: In this prospective study, material for both glass slides and cell blocks were collected simultaneously during fine needle aspirates from 47 samples comprising lung and liver masses. Grading of cellularity, morphological preservation, architectural preservation, immunocytochemical staining intensity and presence of background staining on paired FNA smears and cell block samples were compared. Each arm of the paired analysis was performed blindly without knowledge of the grading outcome of the other. The Kappa statistic (κ) was used to measure inter-rater agreement. Results: The 47 samples evaluated included FNAs from the lung, 24/47 (51%) and liver, 23/47 (49%). The immunocytochemistry stains consisted of 44/47 (94%) CK7; 44/47 (94%) CK20; 18/47 (38%) TTF1; 10/47 (21%) synaptophysin; 10/47 (21%) Hepar-1 and 7/47 (15%) AE1/3. There was no overall agreement in preservation of cytomorphological detail and ICC staining between the two methods. The Papanicolaou-stained conventional FNA smears fared better than the cell block for the evaluation of nuclear and morphologic characteristics. The ICC stains worked better on the cell block samples due to lack of background and aberrant staining. Conclusion: Direct FNA smears and cell blocks complement each other and our results indicate that both are needed in the diagnostic work-up of patients. The cost implications of performing both techniques on all FNA material warrants further evaluation

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

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

Performance of the Cellslide^® automated liquid-based cytology system amongst HIV-positive women

Background: Many women undergoing cervical screening as part of a national South African screening programme may be positive for HIV. The performance of liquid-based cytology (LBC) on samples from HIV-positive women needs to be determined. Objectives: The performance of the Cellslide® automated LBC system was evaluated as a possible alternative to conventional cytology in a national cervical cancer screening programme. Methods: Split samples from 348 HIV-positive women attending an HIV treatment clinic in Johannesburg, South Africa were examined by conventional cytology and monolayer LBC methods. All samples were stained, examined and reported in the same manner. Cytotechnologists were blinded to the conventional smear diagnosis if the LBC smear was screened and vice versa. Results: The same percentage of inadequate smears (1.4%) was obtained by conventional cytology and LBC. Atypical squamous cells of undetermined significance were observed in 5.2% of conventional smears and 4.0% of LBC smears. Low-grade squamous intraepithelial lesions were found in 35.6% of conventional smears and 32.7% of LBC smears. Only one conventional smear was categorised as atypical squamous cells – cannot exclude a high-grade lesion, whereas five such cases were identified on LBC. High-grade squamous intraepithelial lesions were seen in 21.6% of conventional smears and 23.3% LBC smears. No invasive carcinoma was identified. Conclusion: The performance of the Cellslide® LBC system was similar to that of conventional cytology in this population of high-risk HIV-positive women, indicating that it may be introduced successfully as part of a cervical cancer screening programme

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

Abstract 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$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