The causal role of human papillomavirus infections in cervical cancer has been documented beyond reasonable doubt. The association is present in virtually all cervical cancer cases worldwide. It is the right time for medical societies and public health regulators to consider this evidence and to define its preventive and clinical implications. A comprehensive review of key studies and results is presented.

https://jcp.bmj.com/content/jclinpath/55/4/244.full.pdf

The causal relation between human papillomavirus and cervical cancer

https://www.thelancet.com/pdfs/journals/lancet/PIIS0140673607614160.pdf

Human papillomavirus and cervical cancer

Of the many types of human papillomavirus (HPV), more than 30 infect the genital tract. The association between certain oncogenic (high-risk) strains of HPV and cervical cancer is well established. Although HPV is essential to the transformation of cervical epithelial cells, it is not sufficient, and a variety of cofactors and molecular events influence whether cervical cancer will develop. Early detection and treatment of precancerous lesions can prevent progression to cervical cancer. Identification of precancerous lesions has been primarily by cytologic screening of cervical cells. Cellular abnormalities, however, may be missed or may not be sufficiently distinct, and a portion of patients with borderline or mildly dyskaryotic cytomorphology will have higher-grade disease identified by subsequent colposcopy and biopsy. Sensitive and specific molecular techniques that detect HPV DNA and distinguish high-risk HPV types from low-risk HPV types have been introduced as an adjunct to cytology. Earlier detection of high-risk HPV types may improve triage, treatment, and follow-up in infected patients. Currently, the clearest role for HPV DNA testing is to improve diagnostic accuracy and limit unnecessary colposcopy in patients with borderline or mildly abnormal cytologic test results.

Human Papillomavirus and Cervical Cancer

BACKGROUND: Human papillomavirus types 16 (HPV-16) and 18 (HPV-18) cause approximately 70% of cervical cancers worldwide. A phase 3 trial was conducted to evaluate a quadrivalent vaccine against HPV types 6, 11, 16, and 18 (HPV-6/11/16/18) for the prevention of high-grade cervical lesions associated with HPV-16 and HPV-18. METHODS: In this randomized, double-blind trial, we assigned 12,167 women between the ages of 15 and 26 years to receive three doses of either HPV-6/11/16/18 vaccine or placebo, administered at day 1, month 2, and month 6. The primary analysis was performed for a per-protocol susceptible population that included 5305 women in the vaccine group and 5260 in the placebo group who had no virologic evidence of infection with HPV-16 or HPV-18 through 1 month after the third dose (month 7). The primary composite end point was cervical intraepithelial neoplasia grade 2 or 3, adenocarcinoma in situ, or cervical cancer related to HPV-16 or HPV-18. RESULTS: Subjects were followed for an average of 3 years after receiving the first dose of vaccine or placebo. Vaccine efficacy for the prevention of the primary composite end point was 98% (95.89% confidence interval [CI], 86 to 100) in the per-protocol susceptible population and 44% (95% CI, 26 to 58) in an intention-to-treat population of all women who had undergone randomization (those with or without previous infection). The estimated vaccine efficacy against all high-grade cervical lesions, regardless of causal HPV type, in this intention-to-treat population was 17% (95% CI, 1 to 31). CONCLUSIONS: In young women who had not been previously infected with HPV-16 or HPV-18, those in the vaccine group had a significantly lower occurrence of high-grade cervical intraepithelial neoplasia related to HPV-16 or HPV-18 than did those in the placebo group.

/pdf/quadrivalent-vaccine-against-human-papillomavirus-to-prevent-bjulb1tioi.pdf

Quadrivalent vaccine against human papillomavirus to prevent high-grade cervical lesions

Summary We set out to estimate the age and genotype-specific prevalence of cervical human papillomavirus (HPV) DNA in women with normal cervical cytology worldwide by meta-analysis of a systematic literature review. Reports on HPV prevalence published between January, 1995, and January, 2005, were retrieved. To be included, studies required information on cervical cytology, plus detailed descriptions of study populations, methods used to collect cervical samples, and assays used for HPV DNA detection and typing. Final analyses included 78 studies that could be separated into women with normal cytology, and of which subsets of 44 and 48 studies had data on age and type-specific HPV prevalence, respectively. Overall HPV prevalence in 157 879 women with normal cervical cytology was estimated to be 10·4% (95% CI 10·2–10·7). Corresponding estimates by region were Africa 22·1% (20·9–23·4), Central America and Mexico 20·4% (19·3–21·4), northern America 11·3% (10·6–12·1), Europe 8·1% (7·8–8·4), and Asia 8·0% (7·5–8·4). In all world regions, HPV prevalence was highest in women younger than 35 years of age, decreasing in women of older age. In Africa, the Americas, and Europe, a clear second peak of HPV prevalence was observed in women aged 45 years or older. On the basis of these estimates, around 291 million women worldwide are carriers of HPV DNA, of whom 32% are infected with HPV16 or HPV18, or both. The HPV types most commonly detected are similar to those most commonly described in pre-neoplastic and cancer cases, although the relative contribution of HPV16 and HPV18 is substantially lower in cytologically normal women.

http://www.hu.ufsc.br/projeto_hpv/Worldwide%20prevalence%20and%20genotype%20distribution%20of%20cervical.pdf

Worldwide prevalence and genotype distribution of cervical human papillomavirus DNA in women with normal cytology: a meta-analysis.

ContextMore than half of the women diagnosed as having cervical cancer in the
United States have not been screened within the last 3 years, despite many
having had contact with the health care system. In many other regions of the
world, there is only limited access to cervical cancer screening.ObjectiveTo determine whether testing of self-collected vaginal swabs for human
papillomavirus (HPV) DNA can be used to screen for cervical disease in women
aged 35 years and older.DesignCross-sectional observational study comparing Papanicolaou smears with
HPV DNA testing of self-collected vaginal swabs.SettingOutpatient clinics in a periurban settlement outside of Cape Town, South
Africa, between January 1998 and April 1999.ParticipantsScreening was performed on 1415 previously unscreened black South African
women aged 35 to 65 years.InterventionWomen self-collected a vaginal swab for HPV testing in the clinic and
were then screened using 4 different tests: Papanicolaou smear, direct visual
inspection of the cervix after the application of 5% acetic acid, cervicography,
and HPV DNA testing of a clinician-obtained cervical sample. Women with abnormal
results on any of the screening tests were referred for colposcopy.Main Outcome MeasureBiopsy-confirmed high-grade cervical squamous intraepithelial lesions
or invasive cancer.ResultsHigh-grade squamous intraepithelial lesions were identified in 47 (3.4%)
of 1365 women adequately assessed, and there were 9 cases of invasive cancer.
Of women with high-grade disease, 66.1% (95% confidence interval 
[CI], 52.1%-77.8%) had high-risk HPV detected in self-collected vaginal samples, and 67.9%
(95% CI, 53.9%-79.4%) had an abnormal Papanicolaou smear (P = .78). The false-positive rates for HPV DNA testing of self-collected
vaginal samples and Papanicolaou smears were 17.1% (95% CI, 15.1%-19.3%) and
12.3% (95% CI, 10.5%-14.2%), respectively (P<.001).
A high-risk type of HPV DNA was detected in 83.9% (95% CI, 71.2%-91.9%) of
women with high-grade disease and 15.5% (95% CI, 13.6%-17.7%) of women with
no evidence of cervical disease using a clinician-obtained cervical sample.ConclusionsThese results indicate that HPV testing of self-collected vaginal swabs
is less specific than but as sensitive as Papanicolaou smears for detecting
high-grade cervical disease in women aged 35 years and older, and HPV testing
offers an important new way to increase screening in settings where cytology
is not readily performed.

https://jamanetwork.com/journals/jama/articlepdf/192260/joc91536.pdf

HPV DNA Testing of Self-collected Vaginal Samples Compared With Cytologic Screening to Detect Cervical Cancer

ContextCervical cancer is a leading cause of cancer-related death among women
in developing countries. In such low-resource settings, cytology-based screening
is difficult to implement, and less complex strategies may offer additional
options.ObjectiveTo assess the cost-effectiveness of several cervical cancer screening
strategies using population-specific data.Design and SettingCost-effectiveness analysis using a mathematical model and a hypothetical
cohort of previously unscreened 30-year-old black South African women. Screening
tests included direct visual inspection (DVI) of the cervix, cytologic methods,
and testing for high-risk types of human papillomavirus (HPV) DNA. Strategies
differed by number of clinical visits, screening frequency, and response to
a positive test result. Data sources included a South African screening study,
national surveys and fee schedules, and published literature.Main Outcome MeasuresYears of life saved (YLS), lifetime costs in US dollars, and incremental
cost-effectiveness ratios (cost per YLS).ResultsWhen analyzing all strategies performed as a single lifetime screen
at age 35 years compared with no screening, HPV testing followed by treatment
of screen-positive women at a second visit, cost $39/YLS (27% cancer incidence
reduction); DVI, coupled with immediate treatment of screen-positive women
at the first visit was next most effective (26% cancer incidence reduction)
and was cost saving; cytology, followed by treatment of screen-positive women
at a second visit was least effective (19% cancer incidence reduction) at
a cost of $81/YLS. For any given screening frequency, when strategies were
compared incrementally, HPV DNA testing generally was more effective but also
more costly than DVI, and always was more effective and less costly than cytology.
When comparing all strategies simultaneously across screening frequencies,
DVI was the nondominated strategy up to a frequency of every 3 years (incremental
cost-effectiveness ratio, $460/YLS), and HPV testing every 3 years (incremental
cost-effectiveness ratio, $11 500/YLS) was the most effective strategy.ConclusionCervical cancer screening strategies that incorporate DVI or HPV DNA
testing and eliminate colposcopy may offer attractive alternatives to cytology-based
screening programs in low-resource settings.

https://jamanetwork.com/journals/jama/articlepdf/193957/JOC10234.pdf

Policy analysis of cervical cancer screening strategies in low-resource settings: clinical benefits and cost-effectiveness.

ContextNon–cytology-based screen-and-treat approaches for cervical cancer prevention have been developed for low-resource settings, but few have directly addressed efficacy.ObjectiveTo determine the safety and efficacy of 2 screen-and-treat approaches for cervical cancer prevention that were designed to be more resource-appropriate than conventional cytology-based screening programs.Design, Setting, and PatientsRandomized clinical trial of 6555 nonpregnant women, aged 35 to 65 years, recruited through community outreach and conducted between June 2000 and December 2002 at ambulatory women’s health clinics in Khayelitsha, South Africa.InterventionsAll patients were screened using human papillomavirus (HPV) DNA testing and visual inspection with acetic acid (VIA). Women were subsequently randomized to 1 of 3 groups: cryotherapy if she had a positive HPV DNA test result; cryotherapy if she had a positive VIA test result; or to delayed evaluation.Main Outcome MeasuresBiopsy-confirmed high-grade cervical cancer precursor lesions and cancer at 6 and 12 months in the HPV DNA and VIA groups compared with the delayed evaluation (control) group; complications after cryotherapy.ResultsThe prevalence of high-grade cervical intraepithelial neoplasia and cancer (CIN 2+) was significantly lower in the 2 screen-and-treat groups at 6 months after randomization than in the delayed evaluation group. At 6 months, CIN 2+ was diagnosed in 0.80% (95% confidence interval [CI], 0.40%-1.20%) of the women in the HPV DNA group and 2.23% (95% CI, 1.57%-2.89%) in the VIA group compared with 3.55% (95% CI, 2.71%-4.39%) in the delayed evaluation group (P<.001 and P = .02 for the HPV DNA and VIA groups, respectively). A subset of women underwent a second colposcopy 12 months after enrollment. At 12 months the cumulative detection of CIN 2+ among women in the HPV DNA group was 1.42% (95% CI, 0.88%-1.97%), 2.91% (95% CI, 2.12%-3.69%) in the VIA group, and 5.41% (95% CI, 4.32%-6.50%) in the delayed evaluation group. Although minor complaints, such as discharge and bleeding, were common after cryotherapy, major complications were rare.ConclusionBoth screen-and-treat approaches are safe and result in a lower prevalence of high-grade cervical cancer precursor lesions compared with delayed evaluation at both 6 and 12 months.Trial Registrationhttp://clinicaltrials.gov Identifier: NCT00233727.

https://jamanetwork.com/journals/jama/articlepdf/201798/JOC50124.pdf

Screen-and-treat approaches for cervical cancer prevention in low-resource settings: a randomized controlled trial.

/pdf/screen-and-treat-approaches-for-cervical-cancer-prevention-1d155yhuy3.pdf

Screen-and-Treat Approaches for Cervical Cancer Prevention in Low-Resource Settings

BACKGROUND

Noncytologic methods of screening for cervical carcinoma and its precursor lesions are needed for resource-poor settings in which cervical carcinoma continues to be an important cause of morbidity and mortality.



METHODS

Two thousand nine hundred forty-four women ages 35–65 years were recruited from Cape Town, South Africa and screened using a combination of a Papanicolaou (Pap) smear, human papillomavirus (HPV) DNA testing, direct visual inspection after the application of a 5% acetic acid solution (DVI), and cervicography. Cervicography was considered primarily as a method with which to quality control the DVI examinations. Women with squamous intraepithelial lesions (SIL) or carcinoma on Pap smear, positive DVI examination (acetowhite lesion or cervical ulcer/growth), high levels of high risk HPV DNA (relative light units [RLU] > 10× positive control), or positive Cervigram™ were referred for colposcopy and cervical biopsy.



RESULTS

Pap smears were positive in 8.1% of all women screened and identified 65 (78%) of all cases of biopsy confirmed high grade disease (high grade SIL or invasive carcinoma). DVI and cervicography were classified as positive in 18.1% and 10.5%, respectively, of women screened and identified 58 (67%) and 46 (58%) of all cases of high grade disease, respectively. The results of HPV DNA testing varied depending on the cutoff value used to define a positive result. At the standard cutoff level (RLU > 1× positive control), 16.2% of women screened were classified as high risk HPV DNA positive, as were 63 women with high grade disease (73%).



CONCLUSIONS

DVI and HPV DNA testing identified similar numbers of high grade SIL (cervical intraepithelial neoplasia Grade 2,3) and invasive carcinoma cases as Pap smears. However, both classify considerably more women without cervical disease as being test positive. Cancer 2000;89:826–33. © 2000 American Cancer Society.

Amy Pollack

Papers

HPV DNA Testing of Self-collected Vaginal Samples Compared With Cytologic Screening to Detect Cervical Cancer

Policy analysis of cervical cancer screening strategies in low-resource settings: clinical benefits and cost-effectiveness.

Screen-and-treat approaches for cervical cancer prevention in low-resource settings: a randomized controlled trial.

Screen-and-Treat Approaches for Cervical Cancer Prevention in Low-Resource Settings

Evaluation of alternative methods of cervical cancer screening for resource‐poor settings