Correction: Costs and cost-effectiveness of LEEP versus cryotherapy for treating cervical dysplasia among HIV-positive women in Johannesburg, South Africa.

[This corrects the article DOI: 10.1371/journal.pone.0203921.].

Costs and cost-effectiveness of LEEP versus cryotherapy for treating cervical dysplasia among HIV-positive women in Johannesburg, South Africa.

BACKGROUND: Cervical cancer incidence is significant in countries, such as South Africa, with high burdens of both HIV and human papillomavirus (HPV). Cervical cancer is largely preventable if dysplasia is diagnosed and treated early, but there is debate regarding the best approaches for screening and treatment, especially for low-resource settings. Currently South Africa provides Pap smears followed by colposcopic biopsy and LEEP if needed in its public health facilities. We estimated the costs and cost-effectiveness of two approaches for treating cervical intraepithelial neoplasia grade 2 or higher (CIN2+) among HIV-infected women, most of whom were taking antiretroviral treatment, at a public HIV treatment facility in Johannesburg, South Africa. METHODS: Method effectiveness was derived from an intention-to-treat analysis of data gathered in a clinical trial completed previously at the study facility. In the trial, women who were diagnosed with CIN2+ and eligible for cryotherapy were randomized to cryotherapy or LEEP. If women were CIN2+ at six months as determined via Pap smear and colposcopic biopsy, all women-regardless of their original treatment assignment-received LEEP. "Cure" was then defined as the absence of disease at 12 months based on Pap smear and colposcopic biopsy. Health service costs were estimated using micro-costing between June 2013 and April 2014. Capital costs were annualized using a discount rate of 3%. Two different service volume scenarios were considered, and results from an as-treated analysis were considered in sensitivity analysis. RESULTS: In total, 166 women with CIN2+ were enrolled (86 had LEEP; 80 had cryotherapy). At 12 months, cumulative loss to follow-up was 12.8% (11/86) for the LEEP group and 13.8% (11/80) for cryotherapy. Based on the unadjusted intention-to-treat analysis conducted for this economic evaluation, there was no significant difference in efficacy. At 12 months, 83.8% (95% CI 73.8-91.1) of women with CIN2+ at baseline and randomized to cryotherapy were free of CIN2+ disease. In contrast, 76.7% (95% CI 66.4-85.2) of women assigned to LEEP were free from disease. On average, women initially treated with cryotherapy were less costly per patient randomized at US$ 118.00 (113.91-122.10), and per case "cured" at US$ 140.90 (136.01-145.79). Women in the LEEP group cost US$ 162.56 (157.90-167.22) per patient randomized and US$ 205.59 (199.70-211.49) per case cured. In the as-treated analysis, which was based on trial data, LEEP was more efficacious than cryotherapy; however, the difference was not significant. Cryotherapy remained more cost-effective than LEEP in all sensitivity and scenario analyses. CONCLUSIONS: For this cost-effectiveness analysis, using an intention-to-treat approach and taking into consideration uncertainty in the clinical and cost outcomes, a strategy involving cryotherapy plus LEEP if needed at six months was dominant to LEEP plus LEEP again at six months if needed for retreatment. However, compared to other studies comparing LEEP and cryotherapy, the efficacy results were low in both treatment groups-possibly due to the HIV-positivity of the participants. Further research is needed, but at present choosing the "right" treatment option may be less important than ensuring access to treatment and providing careful monitoring of treatment outcomes.

Cost-Effectiveness of Cervical Cancer Screening in Women Living With HIV in South Africa: A Mathematical Modeling Study.

BACKGROUND: Women with HIV face an increased risk of human papillomavirus (HPV) acquisition and persistence, cervical intraepithelial neoplasia, and invasive cervical cancer. Our objective was to determine the cost-effectiveness of different cervical cancer screening strategies among women with HIV in South Africa. METHODS: We modified a mathematical model of HPV infection and cervical disease to reflect coinfection with HIV. The model was calibrated to epidemiologic data from HIV-infected women in South Africa. Clinical and economic data were drawn from in-country data sources. The model was used to project reductions in the lifetime risk of cervical cancer and incremental cost-effectiveness ratios (ICERs) of Pap and HPV DNA screening and management algorithms beginning at HIV diagnosis, at 1-, 2-, or 3-year intervals. Strategies with an ICER below South Africa's 2016 per capita gross domestic product (US$5270) were considered "cost-effective." RESULTS: HPV testing followed by treatment (test-and-treat) at 2-year intervals was the most effective strategy that was also cost-effective, reducing lifetime cancer risk by 56.6% with an ICER of US$3010 per year of life saved. Other cost-effective strategies included Pap (referral threshold: HSIL+) at 1-, 2-, and 3-year intervals, and HPV test-and-treat at 3-year intervals. Pap (ASCUS+), HPV testing with 16/18 genotyping, and HPV testing with Pap or visual triage of HPV-positive women were less effective and more costly than alternatives. CONCLUSIONS: Considering per capita gross domestic product as the benchmark for cost-effectiveness, HPV test-and-treat is optimal in South Africa. At lower cost-effectiveness benchmarks, Pap (HSIL+) would be optimal.

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.

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.

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.

Characterizing breast conditions at an open-access breast clinic in South Africa: a model that is more than cancer care for a resource-limited setting.

BACKGROUND: While most breast-related research focuses on cancer, presentation of symptomatic persons in non-screened environments requires understanding the spectrum of breast diseases so as to plan services in resource-constrained settings. This study presents the variety of breast disease managed at a government, open-access breast clinic in South Africa. METHODS: We performed a retrospective file review using a systematic random sample of patients 18 years and above presenting for breast care over a 14-month period. We collected demographics, clinical characteristics, management and final diagnoses from the first visit and twelve subsequent months. RESULTS: The final sample contained 365 individuals (97 · 5% women). Most were black, unmarried and South African citizens with a median age of 43 years (IQR 31-55) . Of those reporting their status (24 · 1%) 38 · 6% were HIV-positive. A mass (57 · 0%) and/or pain (28 · 5%) were the most common symptoms. Imaging and breast biopsies were required in 78 and 25% of individuals, respectively. Nearly half of biopsies identified breast cancer (44 · 1% of women ≤40 and 57 · 3% for women >40). Benign conditions (47 · 7%) and no abnormality (18 · 2%) were common final classifications among women. There was no difference between the final classifications of patients who self-referred versus those who were formally referred from another health care provider. Nearly half of the participants (46 · 6%) travelled 20 km or more to attend the clinic. CONCLUSIONS: Benign breast conditions far outweighed cancer diagnoses. As breast cancer awareness increases in resource-limited countries, facilities offering breast care require administrative and clinical preparation to manage a range of non-cancer related conditions.

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.

Costs and Cost Effectiveness of Three Approaches for Cervical Cancer Screening among HIV-Positive Women in Johannesburg, South Africa.

BACKGROUND: South Africa has high rates of HIV and HPV and high incidence and mortality from cervical cancer. However, cervical cancer is largely preventable when early screening and treatment are available. We estimate the costs and cost-effectiveness of conventional cytology (Pap), visual inspection with acetic acid (VIA) and HPV DNA testing for detecting cases of CIN2+ among HIV-infected women currently taking antiretroviral treatment at a public HIV clinic in Johannesburg, South Africa. METHODS: Method effectiveness was derived from a validation study completed at the clinic. Costs were estimated from the provider perspective using micro-costing between June 2013-April 2014. Capital costs were annualized using a discount rate of 3%. Two different service volume scenarios were considered. Threshold analysis was used to explore the potential for reducing the cost of HPV DNA testing. RESULTS: VIA was least costly in both scenarios. In the higher volume scenario, the average cost per procedure was US$ 3.67 for VIA, US$ 8.17 for Pap and US$ 54.34 for HPV DNA. Colposcopic biopsies cost on average US$ 67.71 per procedure. VIA was least sensitive but most cost-effective at US$ 17.05 per true CIN2+ case detected. The cost per case detected for Pap testing was US$ 130.63 using a conventional definition for positive results and US$ 187.52 using a more conservative definition. HPV DNA testing was US$ 320.09 per case detected. Colposcopic biopsy costs largely drove the total and per case costs. A 71% reduction in HPV DNA screening costs would make it competitive with the conservative Pap definition. CONCLUSIONS: Women need access to services which meet their needs and address the burden of cervical dysplasia and cancer in this region. Although most cost-effective, VIA may require more frequent screening due to low sensitivity, an important consideration for an HIV-positive population with increased risk for disease progression.

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.

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.

Effect of 2 referral intervals on diagnostic discordance between cytology and histology at a colposcopy clinic.

OBJECTIVE: To determine the effect of the time interval between cervical cytology screening and histology at treatment on grade of cervical disease. METHODS: In a retrospective cross-sectional study at a colposcopy clinic in Soweto, Johannesburg, South Africa, data were compared from women with cytologic abnormalities referred for colposcopy between April 2003 and June 2010 to determine whether early (≤ 180 days) or late (> 180 days) referral had an impact on dysplasia grade. RESULTS: In the early and late referral groups, there were 213 (13.43%) and 201 (14.63%) women, respectively, with upgrading of cervical dysplasia (P=0.35), and 1373 (86.57%) and 1173 (85.37%) women, respectively, with downgrading or no change (P=0.35). Risk factors for upgrading were HIV infection (odds ratio [OR], 1.63; P<0.001) and condom use (OR, 1.30; P=0.02). Four cases (0.68%) of invasion among women with low-grade squamous intraepithelial lesion (LSIL) and 50 cases (2.11%) among women with high-grade SIL (HSIL) were not detected by cytology. Risk factors for invasive disease on histology were age (OR, 1.09 per year; P<0.001), parity (OR, 1.32 per pregnancy; P<0.001), and HSIL on cytology (OR, 3.17; P=0.03). CONCLUSION: There was no difference in the up- or downgrading of cervical dysplasia between the 2 referral groups.

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/mm(3). 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/mm(3) as compared to CD4 counts >350 cells/mm(3). 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.

Cervical intra-epithelial neoplasia in HIV-positive women after excision of transformation zone - does the grade change?

OBJECTIVE: After previously reporting the presence of disease by cytology findings after treatment for cervical intra-epithelial neoplasia (CIN) in 64.6% of HIV-infected women and in 13.0% of HIV-negative women, we aimed to determine the severity of cytological disease after treatment in HIV-infected women. METHODS: We studied HIV-infected (N=571) women treated at the Colposcopy Clinic at Chris Hani Baragwanath Hospital, Gauteng, between April 2003 and December 2006. We compared the initial histology results with Pap smears ≥6 months later, and evaluated factors associated with reduction in the grade of disease. RESULTS: Mean age was 36.68 (SD+7.33) years; mean parity was 2 (SD+1.46); mean CD4+ count was 242.70 cells/mm3 (SD+187.56); 262 (45.80%) were receiving antiretroviral treatment. Persistent disease was detected on the repeat Pap smear in 199 (65.03%); of these, 223 (72.88%) were of a lesser grade than in the original histology results. Of the 152 with histologically confirmed CIN3, 67 (44.08%) had improved to a lesser grade, and 54 (44.63%) had normal cytology results. Among the latter two subject groups (n=141) who had CIN2 histologically, 91 (64.53%) had improved, 29 (20.57%) remained unchanged, and 20 (14.88%) had CIN3; 13 (4.25%) patients with CIN1 returned for follow-up; 11 (84.62%) of these had normal Pap smears and 2 (15.38%) had CIN3. CONCLUSION: Recurrences were of a lesser degree than initial histology results. This reduction in the grade of disease was related to CD4+ count, complete excision and parity. Antiretroviral therapy use did not improve outcome, perhaps owing to low initial CD4 counts.

Cytomorphology of unusual infectious entities in the Pap test.

Rare entities in the Pap test, including neoplastic and non-neoplastic conditions, pose challenges due to their infrequent occurrence in the daily practice of cytology. Furthermore, these conditions give rise to important diagnostic pitfalls. Infections such as tuberculosis cervicitis may be erroneously diagnosed as carcinoma, whereas others, such as schistosomiasis, are associated with squamous cell carcinoma. These cases include granuloma inguinale (donovanosis), tuberculosis, coccidioidomycosis, schistosomiasis, taeniasis, and molluscum contagiosum diagnosed in Pap tests. Granuloma inguinale shows histiocytes that contain intracytoplasmic bacteria (Donovan bodies). Tuberculosis is characterized by necrotizing granulomatous inflammation with Langhans-multinucleated giant cells. Coccidioidomycosis may show large intact or ruptured fungal spherules associated with endospores. Schistosoma haematobium is diagnosed by finding characteristic ova with a terminal spine. Molluscum contagiosum is characterized by the appearance of squamous cells with molluscum bodies. This article reviews the cytomorphology of selected rare infections and focuses on their cytomorphology, differential diagnosis, and role of ancillary diagnostic studies.

Fine needle aspiration of salivary gland masses in HIV-infected patients.

Salivary gland disease is an important manifestation of HIV-infection. The aim of this study was to evaluate the cytologic findings of salivary gland fine needle aspiration (FNA) in South African human immunodeficiency virus (HIV)-infected patients. A retrospective review was performed on confirmed HIV-positive patients who underwent FNA of various body sites, including salivary glands, over a 5-year period. There were 495 (14.1%) salivary gland FNAs out of a total of 3,501 HIV-positive patients. This included 260 (52.5%) parotid, 226 (45.7%) submandibular, 2 (0.4%) sublingual, and 7 (1.4%) specimens labeled as a salivary gland aspirate, exact site not provided. Patients were of average age 34 years (range 9 months to 63 years) with a female: male ratio of 1:0.6. There were 37 (7.5%) inadequate FNAs and 22 (4.4%) that contained normal gland constituents only. Most diagnoses were benign and comprised 168 (33.9%) reactive lymphadenopathy, 115 (23.2%) benign lymphoepithelial cysts, 62 (12.5%) mycobacterial infections, and 52 (10.5%) abscesses, of which 10 had associated mycobacterial infections. Neoplasms accounted for 31 (6.7%) diagnoses including 11 pleomorphic adenomas, 13 lymphoma, 3 Kaposi sarcoma, 1 squamous cell carcinoma, 1 metastatic carcinoma, and 1 rhabdomyosarcoma. There were four epidermoid inclusion cysts, three non-specific sialadenitis, one mucocele, and one spindle cell lesion not able to be further characterized. FNA is a useful procedure to evaluate salivary gland lesions in an HIV-infected population, allowing prompt management to be undertaken and obviating the need for surgery in many instances, an important consideration in an underfunded public health care system.

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

BACKGROUND: 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. METHODS: A prospective observational study of HIV-seropositive women was conducted over 5 years in an HIV treatment clinic in Johannesburg, South Africa. The participants consisted of 601 women on and off HAART who had repeat Pap smears greater than 6 months apart. The effect of HAART use on incidence and progression rates of SIL was determined using multivariate Poisson regression to obtain incidence rate ratios (IRRs), adjusted for age, CD4 count and other potential confounders. RESULTS: Median follow-up time was 445 days (inter-quartile range 383, 671). The crude rate of incidence of any SIL was 15.9 episodes (95% confidence limit (CL) 12.7, 19.9) per 100 person-years; the crude rate of all progression of cervical dysplasia among women was 13.5 episodes (95% CL 11.3, 16.1) per 100 person-years. HAART use was associated with a robust reduction in the rate of incidence and progression of cervical lesions, adjusted IRR=0.55 (95% CL 0.37, 0.80). Sensitivity analyses confirmed this main association held for incidence and progression when they were considered separately, and that the result was not dependent on the length of HAART exposure. CONCLUSION: HAART use was associated with a reduction in the rate of both incidence and progression of cervical lesions among HIV-positive women.

A review of the cytomorphology of Epstein-Barr virus-associated malignancies.

The Epstein-Barr virus (EBV) is a member of the herpes family of viruses and is very common in humans. EBV is most often associated with infectious mononucleosis. However, it is estimated that 1% of tumors including lymphoproliferative, epithelial and mesenchymal are linked to EBV infection. EBV has a tropism for certain epithelial cells, lymphocytes and myocytes. Like other herpesviruses, EBV has both lytic and latent phases of infection. In the latent form, EBV-encoded genes ensure the survival of the viral genome, allowing it to circumvent the host's immune surveillance by limited expression of viral proteins and carries with it the risk of neoplastic transformation. Cytologists are likely to encounter EBV-associated malignancies in cytology material but unlike other herpesviruses, EBV does not evoke a viral cytopathic effect. The manifestation of EBV-related tumors is also often variable depending upon the patient's immune status. Therefore, knowledge of the patient's EBV status and immune competence (e.g. HIV-infection or transplant-related immunosuppression) combined with the cytomorphology and results of ancillary studies are often all required to make a diagnosis of EBV-associated malignancy. This review discusses the unique cytomorphology and ancillary studies required to diagnose EBV-related neoplasms.

Bacterial vaginosis as a risk factor for high-grade cervical lesions and cancer in HIV-seropositive women.

OBJECTIVE: To assess the effect of bacterial vaginosis (BV) on the risk of high-grade squamous intraepithelial lesions (HSIL) among HIV-seropositive women. METHODS: A hospital-based prospective cohort study of HIV-seropositive women was conducted in Johannesburg, South Africa from January 2005 to September 2009. Multivariate log-binomial and Poisson regressions were used to estimate prevalence and rate ratios, respectively. RESULTS: Among 1954 HIV-seropositive women, the baseline prevalence of HSIL was 17%. BV prevalence was high (54%) and showed no association with prevalence of HSIL (adjusted prevalence ratio, 1.12; 95% confidence intervals (CI), 0.92-1.35) nor with cervical lesion progression at follow-up visit (n=503) (adjusted rate ratio: 1.00; 95% CI, 0.65-1.53). CONCLUSION: Among HIV-seropositive women, BV was not associated with an increased risk of HSIL or cervical lesion progression.