Human Papillomavirus-Based Cervical Cancer Prevention: Long-term Results of a Randomized Screening Trial

Department of Obstetrics and Gynecology, University of Cape Town, Cape Town, South Africa.
Journal of the National Cancer Institute (Impact Factor: 12.58). 09/2010; 102(20):1557-67. DOI: 10.1093/jnci/djq342
Source: PubMed


Screen-and-treat approaches to cervical cancer prevention are an attractive option for low-resource settings, but data on their long-term efficacy are lacking. We evaluated the efficacy of two screen-and-treat approaches through 36 months of follow-up in a randomized trial.
A total of 6637 unscreened South African women aged 35-65 years who were tested for the presence of high-risk human papillomavirus (HPV) DNA in cervical samples underwent visual inspection of the cervix using acetic acid staining and HIV serotesting. Of these, 6555 were randomly assigned to three study arms: 1) HPV-and-treat, in which all women with a positive HPV DNA test result underwent cryotherapy; 2) visual inspection-and-treat, in which all women with a positive visual inspection test result underwent cryotherapy; or 3) control, in which further evaluation or treatment was delayed for 6 months. All women underwent colposcopy with biopsy at 6 months. All women who were HPV DNA- or visual inspection-positive at enrollment, and a subset of all other women had extended follow-up to 36 months (n = 3639) with yearly colposcopy. The endpoint-cervical intraepithelial neoplasia grade 2 or worse (CIN2+)-was analyzed using actuarial life-table methods. All statistical tests were two-sided.
After 36 months, there was a sustained statistically significant decrease in the cumulative detection of CIN2+ in the HPV-and-treat arm compared with the control arm (1.5% vs 5.6%, difference = 4.1%, 95% confidence interval [CI] = 2.8% to 5.3%, P < .001). The difference in the cumulative detection of CIN2+ in the visual inspection-and-treat arm compared with the control was less (3.8% vs 5.6%, difference = 1.8%, 95% CI = 0.4% to 3.2%, P = .002). Incident cases of CIN2+ (identified more than 12 months after enrollment) were less common in the HPV-and-treat arm (0.3%, 95% CI = 0.05% to 1.02%) than in the control (1.0%, 95% CI = 0.5% to 1.7%) or visual inspection-and-treat (1.3%, 95% CI = 0.8% to 2.1%) arms.
In this trial, a screen-and-treat approach using HPV DNA testing identified and treated prevalent cases of CIN2+ and appeared to reduce the number of incident cases of CIN2+ that developed more than 12 months after cryotherapy.

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    • "HPV-DNA testing plus treatment with cryotherapy reduced the occurrence of CIN3+ by more than 77%, and VIA screening followed by cryotherapy reduced it by 38%, as compared to the control group with delayed treatment. Sensitivity for HPV-DNA and VIA was 90% and 53%, respectively, and specificity was 83% and 78% (Denny et al., 2010). Because HPV-DNA testing correctly identified both positive and negative women more often than VIA, using this test for screening was associated with less under-treatment as well as less over-treatment. "
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    ABSTRACT: Cervical cancer remains the most frequent cancer in women from the developing world. More than 88% of deaths occur in low-income countries, and it is predicted to climb to 91.5% by 2030. Although Pap-based screening programmes have shown to be effective in reducing the disease burden in high-resource countries, implementation and sustention of cytology-based programmes is quite challenging in low-resource settings. The present paper reviews evidence-based alternatives of screening methods, triaging algorithm, treatment of cervical precancerous lesions, and age-group at screening appropriate for low-income countries. Evidence shows that visual inspection methods using diluted acid acetic or Lugol's iodine, and HPV-DNA testing are more sensitive tests than the Pap-smear screening test. Visual inspection allows an immediate result and, when appropriate, may be immediately followed by cryotherapy, the so called "screen-and-treat" approach, achieved in a single visit, by trained nurses and midwives. Examples of cervical cancer prevention programmes in India and selected low-income countries are given.
    Preview · Article · Apr 2012 · Asian Pacific journal of cancer prevention: APJCP
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    • "Accuracy studies on VI showed contrasting results. While a recent meta-analysis mostly based on observational studies reports a 80% sensitivity (range, 79%-82%) and a 92% specificity (range, 91%-92%) of VIA in detecting high-grade precancerous lesions [28], several randomised trials have shown poorer performance of VIA (sensitivity of 55%) compared to HPV testing (sensitivity 90%) in both HIV-negative and HIV-positive women [9,29]. As cytology or HPV testing are currently not available, we believe that VI is the most appropriate approach that can at least promote the awareness and initiate the infrastructure for building cervical cancer screening in HIV clinics in Côte d'Ivoire. "
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    ABSTRACT: Cervical cancer screening is not yet standard of care of women attending HIV care clinics in Africa and presents operational challenges that need to be addressed. A cervical cancer screening program based on visual inspection methods was conducted in clinics providing antiretroviral treatment (ART) in Abidjan, Côte d'Ivoire. An itinerant team of midwives was in charge of proposing cervical cancer screening to all HIV-positive women enrolled in ART clinics as well as to HIV-negative women who were attending the Abidjan national blood donor clinic. Positively screened women were systematically referred to a colposcopic examination. A phone-based tracking procedure was implemented to reach positively screened women who did not attend the medical consultation. The association between HIV status and cervical cancer screening outcomes was estimated using a multivariate logistic model. The frequency of positive visual inspection was 9.0% (95% CI 8.0-10.0) in the 2,998 HIV-positive women and 3.9% (95% CI 2.7-5.1) in the 1,047 HIV-negative ones (p < 10-4). In multivariate analysis, HIV infection was associated with a higher risk of positive visual inspection [OR = 2.28 (95% CI 1.61-3.23)] as well as more extensive lesions involving the endocervical canal [OR = 2.42 (95% CI 1.15-5.08)]. The use of a phone-based tracking procedure enabled a significant reduction of women not attending medical consultation after initial positive screening from 36.5% to 19.8% (p < 10-4). The higher frequency of positive visual inspection among HIV-positive women supports the need to extend cervical cancer screening program to all HIV clinics in West Africa. Women loss to follow-up after being positively screened is a major concern in cervical screening programs but yet, partly amenable to a phone tracking procedure.
    Full-text · Article · Mar 2012 · BMC Public Health
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    • "In such settings, different strategies for managing the carcinogenic HPVpositive women may be implemented (Gage and Castle, 2010). For example, some programs may use an immediate screen-and-treat approach (Denny et al., 2010) without diagnostic verification of the presence of cervical pre-cancer by colposcopically directed biopsies, while other programs may require it. Of the latter, the prevalence of carcinogenic HPV DNA may be quite high, 10-20%, which may make colposcopy impractical in low-resource settings that have few trained colposcopists. "
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    ABSTRACT: The analytic performance of a low-cost, research-stage DNA test for the most carcinogenic human papillomavirus (HPV) genotypes (HPV16, HPV18, and HPV45) in aggregate was evaluated among carcinogenic HPV-positive women, which might be used to decide who needs immediate colposcopy in low-resource settings ("triage test"). We found that HPV16/18/45 test agreed well with two DNA tests, a GP5+/6+ genotyping assay (Kappa = 0.77) and a quantitative PCR assay (at a cutpoint of 5000 viral copies) (Kappa = 0.87). DNA sequencing on a subset of 16 HPV16/18/45 positive and 16 HPV16/18/45 negative verified the analytic specificity of the research test. It is concluded that the HPV16/18/45 assay is a promising triage test with a minimum detection of approximately 5000 viral copies, the clinically relevant threshold.
    Full-text · Article · May 2011 · Journal of virological methods
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