John W. Sellors

A new HPV-DNA test for cervical-cancer screening in developing regions: a cross-sectional study of clinical accuracy in rural China

BACKGROUND A new test (careHPV; QIAGEN, Gaithersburg, MD, USA) has been developed to detect 14 high-risk types of carcinogenic human papillomavirus (HPV) in about 2.5 h, to screen women in developing regions for cervical intraepithelial neoplasia (CIN). We did a cross-sectional study to assess the clinical accuracy of careHPV as a rapid screening test in two county hospitals in rural China. METHODS From May 10 to June 15, 2007, the careHPV test was done locally by use of self-obtained vaginal and provider-obtained cervical specimens from a screening population-based set of 2530 women aged 30 to 54 years in Shanxi province, China. All women were assessed by visual inspection with acetic acid (VIA), Digene High-Risk HPV HC2 DNA Test (HC2), liquid-based cytology, and colposcopy with directed biopsy and endocervical curettage as necessary. In 2388 women with complete data, 441 women with negative colposcopy, but unsatisfactory or abnormal cytology or who were positive on HC2 or the new careHPV test, were recalled for a second colposcopy, four-quadrant cervical biopsies, and endocervical curettage. An absence of independence between the tests was not adjusted for and the Bonferroni correction was used for multiple comparisons. FINDINGS Complete data were available for 2388 (94.4%) women. 70 women had CIN2+ (moderate or severe CIN or cancer), of whom 23 had CIN3+. By use of CIN2+ as the reference standard and area-under-the-curve analysis with a two-sided alpha error level of 0.0083, the sensitivities and specificities of the careHPV test for a cut-off ratio cut-point of 0.5 relative light units, were 90.0% (95% CI 83.0-97.0) and 84.2% (82.7-85.7), respectively, on cervical specimens, and 81.4% (72.3-90.5) and 82.4% (80.8-83.9), respectively, on vaginal specimens (areas under the curve not significantly different, p=0.0596), compared with 41.4% (29.9-53.0) and 94.5% (93.6-95.4) for VIA (areas under the curve significantly different, p=0.0001 and p=0.0031, for cervical and vaginal-specimen comparisons for the careHPV test, respectively). The sensitivity and specificity of HC2 for cervical specimens were 97.1% (93.2-100) and 85.6% (84.2-87.1), respectively (areas under the curve not significantly different from the careHPV test on cervical specimens, p=0.0163). INTERPRETATION The careHPV test is promising as a primary screening method for cervical-cancer prevention in low-resource regions.

A critical assessment of screening methods for cervical neoplasia

The objective of cervical cancer screening is to reduce cervical cancer incidence and mortality by detecting and treating precancerous lesions. Conventional cytology is the most widely used cervical cancer screening test. Although cytology has been effective in reducing the incidence of and mortality from cervical cancer in developed countries in both opportunistic and—more dramatically—organized national programs, it has been less successful and largely ineffective in reducing disease burden in low‐resource settings where it has been implemented. Liquid‐based cytology, testing for infection with oncogenic types of human papillomaviruses, visual inspection with 3–5% acetic acid, magnified visual inspection with acetic acid, and visual inspection with Lugols iodine have been evaluated as alternative tests. Their test characteristics, and the applications and limitations in screening, are discussed with an emphasis on the work of the Alliance for Cervical Cancer Prevention over the past 5 years.

Cervical cancer as a priority for prevention in different world regions: An evaluation using years of life lost

The relative importance of cancer of the cervix among several important causes of mortality (from cancer and other diseases) has been evaluated by estimating the years of life lost (YLL) by young and middle‐aged women (25–64 years old) in different regions of the world. The life years were weighted to reflect their importance to the individual and to society. On a global basis, cancer of the cervix is responsible for about 2% of the total (weighted) YLL, fewer than for other causes of mortality in this age group. However, it is the most important cause of YLL in Latin America and the Caribbean. It also makes the largest contribution to YLL from cancer in the populous regions of SubSaharan Africa and South‐Central Asia where the actual risk of loss of life from this cause is higher, although overshadowed by noncancer deaths (from AIDS, TB and maternal conditions). The overall picture is not very sensitive to the age weighting function used. The fact that most of the loss of life is preventable, and that simple technologies have been developed that make this practicable, means that cervical cancer has an even higher profile from the perspective of resource allocation in low income settings.

The accuracy of clinical findings and laparoscopy in pelvic inflammatory disease

The accuracy of clinical diagnosis for pelvic inflammatory disease was determined in 95 women who presented with pelvic pain to primary care physicians and then were referred to gynecologists. Laparoscopy or laparotomy with endometrial biopsy and fimbrial minibiopsy revealed that prevalence of pelvic inflammatory was 46% (44/95) and positive and negative predictive values of gynecologists were 74% (23/31) and 67% (43/64) (p = 0.0002). If histopathologic diagnosis was the standard, clinical accuracies of the gynecologists were no better than chance (p = 0.43), suggesting an expectation bias for visual diagnosis. Laparoscopy had a sensitivity of 50% (12/24) and a specificity of 80% (40/50) for salpingitis if the standard was fimbrial histopathologic diagnosis (p = 0.01). These results support the routine use of laparoscopy, supplemented when negative by endometrial and fimbrial minibiopsy, to accurately diagnose pelvic inflammatory disease.

Tubal factor infertility: an association with prior chlamydial infection and asymptomatic salpingitis.

In 265 Canadian women, with and without tubal factor infertility (TFI), we compared Chlamydia trachomatis cultures of endocervical swabs, endotubal swabs and biopsies, serology, and past history. A history of pelvic inflammatory disease (PID) was absent in 69.2% of TFI women, despite visual evidence of tubal damage. C. trachomatis was not isolated in any of 52 patients with TFI (TFI group), 114 having tubal ligation (STER group), or 99 patients having hysterectomy (HYST group). However, chlamydial antigen was detected with an immunochemical method in 1 of 16 tubal biopsy specimens from TFI women. The prevalence of chlamydial IgM or IgG antibody in serum was significantly higher (P less than 0.0001) in the TFI group (79.1%) than in the other two groups (relative odds, 6.3; 95% confidence interval: 2.5, 16.8). In seropositive (IgG or IgM) subjects, there was a significant (P = 0.003) and strong (relative odds, 5.1; 95% confidence interval: 1.5, 18.1) association between chlamydial IgA antibody and TFI. In women with TFI, there was no significant association between IgM or IgG seropositivity (P = 0.56). or IgA seropositivity (P = 0.53), and a negative history for PID. These findings are consistent with the hypothesis that C. trachomatis is a major cause of TFI following PID, which may or may not be asymptomatic.

New Technologies in Cervical Cancer Screening

A shift to a molecular approach to cervical cancer screening is the most likely solution to the goals of improved screening in both the developed and developing world. The impetus for new screening technologies in the developed world is predominately driven by the need to increase positive predictive value and reduce over-management of low-grade and often transient abnormalities (i.e., increase specificity). Rapid tests, where results can be given to a patient within the same visit, are anticipated to have the greatest impact in low resource settings in low and middle income countries (and in disadvantaged sub-populations in high-income countries) where substantial loss to follow up cripples the effectiveness of cervical cancer screening programs. Clinical validation will be required before these tests are implemented in routine screening programs.

Performance of high-risk human papillomavirus DNA testing as a primary screen for cervical cancer: a pooled analysis of individual patient data from 17 population-based studies from China.

BACKGROUND Controversy remains over whether high-risk human papillomavirus (HPV) DNA testing should be used as a primary screen for cervical cancer. The aims of our study were to assess whether HPV DNA testing could be applied to cervical-cancer screening programmes in China, as well as other similar developing countries. METHODS We did a pooled analysis of population-based cervical cancer screening studies done in mainland China from 1999 to 2008 with concurrent HPV DNA testing (Hybrid Capture 2 assay; Qiagen, Gaithersburg, MD, USA), liquid-based cytology (LBC), and visual inspection with acetic acid (VIA). Eligible women were sexually active, not pregnant, had an intact uterus, and had no history of cervical intraepithelial neoplasia (CIN), cervical cancer, or pelvic irradiation. All women positive for any test were referred for colposcopy and biopsy. Cervical lesions were diagnosed by directed or random biopsy. We assessed the diagnostic accuracy of HPV DNA testing for the detection of CIN grade 3 or greater. FINDINGS 30,371 women from 17 cross-sectional, population-based studies in various parts of China were screened. 1523 women were subsequently excluded because of inadequate HPV DNA specimens or they did not have a biopsy taken, which included women with atypical squamous cells of undetermined significance; low-grade squamous intraepithelial lesion or worse; positive HPV, negative cytology, and missing or positive colposcopy results; and unsatisfactory cytology results. HPV DNA testing had a higher sensitivity of 97·5% (95% CI 95·7-98·7) for detection of CIN grade 3 or worse, and a lower specificity of 85·1% (82·3-87·9), compared with cytology (sensitivity 87·9% [95% CI 84·7-90·7], specificity 94·7% [93·5-96·0]) and VIA (54·6% [48·0-61·2], 89·9% [86·8-93·0]). Sensitivity did not vary by study or age (<35 years, 35-49 years, ≥50 years); however, specificity did vary with age (p<0·0001) and was highest in women younger than 35 years (89·4%; 95% CI 86·1-91·5). An increase in the positive cutoff point from the manufacturer recommended 1 pg/mL to 2 pg/mL led to a decrease in the overall HPV DNA positivity from 16·3% to 13·9% (p<0·0001), which could result in a decrease in referral rates, although sensitivity was slightly lower (97·5% to 95·2%). An increase in the cutoff point to 10 pg/mL in women younger than 35 years maintained a high sensitivity 97·7% (95% CI 87·7-99·9) and increased specificity to 93·5% (95% CI 91·9-94·6). INTERPRETATION HPV DNA testing is highly sensitive and moderately specific for CIN grade 3 or worse, with consistent results across study sites and age groups-including women younger than 35 years. A rise in the cutoff point might be beneficial for future screening programmes in China, especially when screening women younger than 35 years.

Training for cervical cancer prevention programs in low-resource settings: Focus on visual inspection with acetic acid and cryotherapy

The modern approach to cervical cancer prevention, characterized by use of cytology and multiple visits for diagnosis and treatment, has frequently proven challenging and unworkable in low‐resource settings. Because of this, the Alliance for Cervical Cancer Prevention (ACCP) has made it a priority to investigate and assess alternative approaches, particularly the use of visual screening methods, such as visual inspection with acetic acid (VIA) and visual inspection with Lugols iodine (VILI), for precancer and cancer detection and the use of cryotherapy as a precancer treatment method. As a result of ACCP experience in providing training to nurses and doctors in these techniques, it is now widely agreed that training should be competency based, combining both didactic and hands‐on approaches, and should be done in a clinical setting that resembles the service‐delivery conditions at the program site. This article reviews ACCP experiences and perceptions about the essentials of training in visual inspection and cryotherapy and presents some lessons learned with regard to training in these techniques in low‐resource settings.

Prevalence of human papillomavirus and cervical intraepithelial neoplasia in China: a pooled analysis of 17 population-based studies.

High‐risk (HR) human papillomavirus (HPV) prevalence has been shown to correlate well with cervical cancer incidence rates. Our study aimed to estimate the prevalence of HR‐HPV and cervical intraepithelial neoplasia (CIN) in China and indirectly informs on the cervical cancer burden in the country. A total of 30,207 women from 17 population‐based studies throughout China were included. All women received HPV DNA testing (HC2, Qiagen, Gaithersburg, MD), visual inspection with acetic acid and liquid‐based cytology. Women positive for any test received colposcopy‐directed or four‐quadrant biopsies. A total of 29,579 women had HR‐HPV testing results, of whom 28,761 had biopsy confirmed (9,019, 31.4%) or assumed (19,742, 68.6%) final diagnosis. Overall crude HR‐HPV prevalence was 17.7%. HR‐HPV prevalence was similar in rural and urban areas but showed dips in different age groups: at age 25–29 (11.3%) in rural and at age 35–39 (11.3%) in urban women. In rural and urban women, age‐standardized CIN2 prevalence was 1.5% [95% confidence interval (CI): 1.4–1.6%] and 0.7% (95% CI: 0.7–0.8%) and CIN3+ prevalence was 1.2% (95% CI: 1.2–1.3%) and 0.6% (95% CI: 0.5–0.7%), respectively. Prevalence of CIN3+ as a percentage of either all women or HR‐HPV‐positive women steadily increased with age, peaking in 45‐ to 49‐year‐old women. High prevalence of HR‐HPV and CIN3+ was detected in both rural and urban China. The steady rise of CIN3+ up to the age group of 45–49 is attributable to lack of lesion removal through screening. Our findings document the inadequacy of current screening in China while indirectly raising the possibility that the cervical cancer burden in China is underreported.

Regional Distribution of Antibodies to Herpes Simplex Virus Type 1 (HSV-1) and HSV-2 in Men and Women in Ontario, Canada

ABSTRACT This study estimated the regional and age- and gender-specific seroprevalences of herpes simplex virus type 1 (HSV-1) and HSV-2 in Ontario, Canada. Stored serum specimens from subjects aged 15 to 44 years, including men (n = 979), women not under prenatal care (n = 638), and women under prenatal care (n = 701) submitted for routine viral serology were randomly selected according to regional population size from public health laboratories. HSV-1 and HSV-2 testing was done with the MRL enzyme immunoassay (EIA) (Focus Technologies), and HSV-2 was also tested by the Gull/Meridian EIA. Specimens discordant for HSV-2 antibodies between the two EIAs were resolved by a recombinant immunoblot assay (Focus Technologies). The overall age- and gender-standardized seroprevalences of HSV-1 and HSV-2 were 51.1% (95% confidence interval [CI], 50.1 to 52.1) and 9.1% (95% CI, 8.6 to 9.7), respectively. The seroprevalence of HSV-1 antibodies increased from 26.9 to 54.7% in men between 15 to 16 and 40 to 44 years of age, from 32.0 to 88.7% in women not under prenatal care, and from 55.2 to 69.2% in women under prenatal care. The seroprevalence of HSV-2 increased from 3.8 to 21.3% in men between 15 to 16 and 40 to 44 years of age, from 0 to 18.9% in women not under prenatal care, and from 3.4 to 23.1% in women under prenatal care. HSV-2 results were discordant for 3.3% (76 of 2,318) of specimens. Both types of HSV antibodies appeared to be acquired earlier among women under prenatal care than among men and women not under prenatal care. Antibodies were more prevalent among people in northern Ontario (72.9% of subjects [range, 68.4 to 77.4%] for HSV-1 and 13.7% of subjects [95% CI, 10.2 to 17.2%] for HSV-2) than elsewhere.