HPV Screening

Screening aims to detect persistent HPV infections before cancer develops so they can be surgically removed.

Anal Cancer Screening

"Anal cancer and cervical cancer screening: key differences" says
"There are no national screening guidelines for anal cancer... This article provides an overview of anal cancer screening while highlighting its differences from cervical cancer screening and the remaining obstacles and controversies to implementation of a successful anal cancer screening program."
A clinical trial is underway to study whether routine screening can help prevent anal cancer.

Oropharyngeal Cancer Screening

"HPV-associated Oropharyngeal Cancers--Are They Preventable?" says
"cytologic evaluation of the oropharynx, although useful in detecting invasive oropharyngeal cancers, may have limited utility as a screening modality for detecting precancer. These findings argue against the potential for secondary prevention of HPV-associated oropharyngeal cancers through screening for and preventing the progression of precancer and highlight the opportunity for primary prevention through prophylactic HPV vaccination."

Cervical Cancer Screening

The American Cancer Society guidelines recommend
"For women 21-29 years of age, screening with cytology alone every 3 years is recommended... HPV testing should not be used to screen women in this age group, either as a stand-alone test or as a cotest with cytology.
Women ages 30-65 years should be screened with cytology and HPV testing ("cotesting") every 5 years...
Women over 65 years of age with evidence of adequate negative prior screening and no history of CIN2+ within the last 20 years should not be screened for cervical cancer...

Future research might support HPV testing alone for screening..."

One of the papers referenced in those guidelines, "Cervical cancer risk for women undergoing concurrent testing for human papillomavirus and cervical cytology: a population-based study in routine clinical practice" made the value of cotesting clear in Figure 1; five years after initial cotesting, the cumulative risk of CIN3+ was 0.16% for women who tested negative for both HPV and Pap, 0.86% for women who tested positive on Pap but negative on HPV, 4.7% for women who tested positive on Pap test (without regard to HPV), and 7.6% for women who tested positive on HPV test (without regard to Pap).

The five-year interval between cotest screening was chosen to provide approximately the same level of protection as the previously recommended three-year interval with just the Pap test alone.

"Age-specific evaluation of primary human papillomavirus screening vs conventional cytology in a randomized setting" looked at using HPV tests alone as the first line of screening, and found:

Primary HPV DNA screening with cytology triage is more sensitive than conventional screening. Among women aged 35 years or older, primary HPV DNA screening with cytology triage is also more specific than conventional screening and decreases colposcopy referrals and follow-up tests.

"The clinical effectiveness and cost-effectiveness of primary human papillomavirus cervical screening in England: extended follow-up of the ARTISTIC randomised trial cohort through three screening rounds" said

"Utilising partial genotyping at the primary screening stage to identify women with HPV 16/18 and referring them to colposcopy was the most effective strategy... HPV testing as an initial screen was significantly more protective over three rounds (6 years) than the current practice of cytology and the use of primary HPV screening could allow a safe lengthening of the screening interval."

"Positive High-Risk HPV Test with Negative Cytology -- A Conundrum and Blessing of Our Latest Technology" says

"Using a triage strategy after hrHPV testing is less expensive in dollars and numbers of women referred to colposcopy who are falsely positive than is the cotestingstrategy put forth by the most recent ASCCP management guidelines..."

"Is It Time to Introduce HPV Self-Sampling for Primary Cervical Cancer Screening?" says

"Offering a simple, inexpensive, and convenient self-test that respects individual privacy may improve the participation of women who might be otherwise reluctant to undergo screening and those who live in areas with poor access to health care."
and links to a number of studies that have investigated this approach, with some success.

More recently, an FDA advisory panel reviewed evidence that the cobas HPV test was more effective than Pap smears, and voted 13 to 0 to recommend its use as a front-line screening technique. The FDA has not yet acted on this recommendation.

Cervical Cancer Screening effectiveness vs. age

"Effectiveness of cervical screening with age: population based case-control study of prospectively recorded data" said
"There is no evidence that screening women aged 22-24 reduced the incidence of cervical cancer at ages 25-29 (odds ratio 1.11, 95% confidence interval 0.83 to 1.50). ... Screening was associated with a 60% reduction of cancers in women aged 40, increasing to 80% at age 64."
Following that study, Wales began cervical cancer screening at age 25.

Cervical Cancer Screening Program Coverage

According to the U.S. National Cancer Institute's "Cancer Trends Progress Report",
"In 2010, 74 percent of women aged 18 and older had a Pap test within the past 3 years. ... These rates were down for all women (from 81 percent in 2000)..."

"Invasive cervical cancer and screening: what are the rates of unscreened and underscreened women in the modern era?" said

"It has been reported that approximately 50% of invasive cervical malignancies are diagnosed in patients who have never been screened and that 10% of the remaining cervical cancer patients have not had a Pap smear in the 5 years before diagnosis. We sought to determine whether this holds true among a university-based gynecologic oncology patient population. ... Results: ... The length of time from last reported Pap smear to diagnosis of invasive cervical cancer ranged from 1 to 65 years, with a median of 3 years."
In other words, half of all cervical cancer in the US happens because women are not getting their Pap tests on time.

Increasing screening uptake

"Interventions for patients, providers, and health care organizations" is a review of research into ways to increase cancer screening rates. It said, for example:
Providers fail to recommend screening. The literature emphatically underscores the importance of a provider's recommendation for patient participation with breast cancer, cervical cancer, and CRC screening. Studies have found consistently that individuals who report provider recommendation or encouragement are more likely to complete screening48 and that patients with no recent screening report the lack of a provider recommendation as a common barrier. [49-53] ... Numerous studies have shown that patients with a regular source of care are more likely to participate in cancer screening...
(In other words, screening is more likely if patients visit doctors and doctors recommend screening. This seems somewhat basic, but perhaps the basics are the first place to look for improvements.)

Avoiding overscreening

Screening has costs and risks as well as benefits, and doing it too often redues the cost/benefit and risk/benefit ratios.

"Cervical cancer screening intervals, 2006 to 2009: moving beyond annual testing" reported

After normal co-testing results, most respondents (67.1% to 93.8%) recommended Papanicolaou tests sooner than recommended by guidelines.
When designing interventions for providers, some thought should be given not only to increasing recommendations for screening when appropriate, but also to decreasing recommendations for screening when inappropriate.

Risks of screening + treatment

If screening finds CIN2+, The ACS Screening Guidelines state that "CIN2 is the widely accepted threshold for treatment", even though many CIN2 lesions regress on their own. Treatment often means a LEEP procedure.

"Pregnancy outcome following loop electrosurgical excision procedure (LEEP) a systematic review and meta-analysis" (Jin, 2014) says

"LEEP was associated with a higher risk of severe preterm delivery (<32 weeks, relative risk 1.98, 95% CI [1.31, 2.98]...), extreme preterm delivery (<28 weeks, RR, 2.33, 95 % CI [1.84, 2.94]...), preterm premature rupture of the membranes (RR, 1.88, 95 % CI [1.54, 2.29]...), and low birth weight (<2,500 g, RR, 2.48, 95 % CI [1.75, 3.51]...) 55/1,742)."

(Cost-)Effectiveness of Vaccination in Addition to Screening

Here are a number of papers that touch on the question of whether adding vaccination to current screening protocols is helpful and/or cost-effective.

Note: discounting, or the idea that lives saved in the distant future are worth less than lives saved today, has a huge effect in QALY figures. Be sure to make sure the discount rate matches when comparing them!

"Projected Clinical Benefits and Cost-effectiveness of a Human Papillomavirus 16/18 Vaccine" (Goldie, Kohli, rima, Weinstein, Wright, Bosch, and Franco, 2004; cited by 517) said

"Future costs and life years were discounted at an annual rate of 3%. ...
the incremental cost-effectiveness ratio of adding a vaccine with 90% efficacy against persistent HPV infections to current screening practice in the United States is less than $25 000 per quality-adjusted life year."

"Epidemiology of HPV 16 and cervical cancer in Finland and the potential impact of vaccination: mathematical modelling analyses" (Barnabas, 2006; cited by 223) said

"The most effective strategy is vaccination combined with current screening protocols, compared to both screening alone and vaccination alone."

"Cost-effectiveness of cervical cancer screening with human papillomavirus DNA testing and HPV-16,18 vaccination" (Goldhaber-Fiebert, 2008; cited by 135) said

"When we used current US screening practice as a comparator and hypothetically assumed that screening behavior would not change in future birth cohorts, adding preadolescent vaccination provided an additional 36% reduction in cancer risk."

"Cost-effectiveness of human papillomavirus vaccination in the United States (Chesson 2008; cited by 99) said

" the cost per QALY gained by adding routine vaccination of 12-year-old girls to existing screening practices ranged from $3,906 to $14,723 under base-case parameter values (depending on the model version we applied) and ranged from < $0 (cost-saving) to $122,976 in the sensitivity analyses when several key parameter values were varied.
... the potential benefits of preventing anal, vaginal, vulvar, and oropharyngeal cancers offer nontrivial improvements in the estimated cost-effectiveness of HPV vaccination. The inclusion of these additional benefits decreased the cost per QALY gained by vaccination by ~ $2,200 ..."
(The discount rate used was 3%.)

"Cost-effectiveness analysis of human papillomavirus vaccination in the Netherlands" (de Kok, 2009; cited by 62) said

"The low cervical cancer incidence and mortality rates in the Netherlands are associated with an efficient national screening program, in which women are invited to have a free Pap smear every 5 years from age 30 to 60 years.
Adding one vaccination (of three doses) with lifelong effectiveness to the current screening program in the Netherlands [led to] 60% fewer life-years lost (2470 life-years) and 61% fewer QALYs lost (2680 QALYs). ... The cost-effectiveness ratios with discounting at 0% were ... EUR 10 100 per QALY gained and with discounting at 3%, EUR 53 500 per QALY gained."

"Screening, prevention and treatment of cervical cancer -- a global and regional generalized cost-effectiveness analysis" (Ginsberg, 2009; cited by 38) said

... based on projections of the future price per dose (representing the economic costs of the vaccination excluding monopolistic rents and vaccine development cost) vaccination is the most cost-effective intervention.

"HPV16/18 vaccination to prevent cervical cancer in The Netherlands: model-based cost-effectiveness." (Coupe, 2009; cited by 34; text) said

"For our base-case scenario in which 85% of the girls aged 12 years were vaccinated against types 16/18 (95% efficacy, lifelong protection), the model predicted a decrease of 60% in the number of cervical cancer cases and cervical cancer deaths...
Following the Dutch guidelines, the discounting rate per year for costs and health effects were set at 4% and 1.5%, respectively.
at the current price indication of EUR 125 per dose, HPV16/18 vaccination of 85% percent of 12-year-old girls (95% efficacy, lifelong protection) is likely to be a cost-effective addition to screening as the computed ICER of EUR 19,500 per QALY lied close to the current cost-effectiveness threshold in The Netherlands of EUR 20,000 per QALY. If a booster at age 30 years will be required to achieve lifelong protection, the cost price per dose should decrease to EUR 100 per dose to reach the ICER threshold of EUR 20,000 per QALY."

"Cost-effectiveness of HPV vaccination compared with Pap smear screening on a national scale: a literature review" (Techakehakij, 2008; cited by 34) said

"the range of incremental cost-effectiveness ratios (ICERs) from six articles is between $16,600 and $27,231 per quality-adjusted life year (QALY) gained."

"Health and economic impact associated with a quadrivalent HPV vaccine in Italy" (Mennini, 2009; cited by 32) said

"The HPV vaccination in association with the current screening programme would allow to avoid 1432 cases of cervical cancer (-63.3%) and 513 deaths (-63.4%) compared to screening only, with an incremental cost-effectiveness ratio (ICER) of 9569 euros per additional quality-adjusted life-year (QALY) gained."

"Economic evaluations of massive HPV vaccination: within-study and between study variations in incremental cost per QALY gained" (Puig-Junoy, 2009; cited by 25; text) said

"The most influential source of uncertainty is the duration of the vaccine protection. Between-study variations are mainly due to three causes: methodological differences, assumptions, and local conditions in the application area.

Prices are important sources of variation in the cost per QALY between studies. For instance, the price of the vaccine ranges from $2 per dose in studies for developing countries (Diaz et al., 2008; Goldie et al., 2008) to $120-$150 in USA and UK (Chesson et al., 2008; Dasbach et al., 2008; Goldhaber-Fiebert et al., 2008; Goldie et al., 2004; Jit et al., 2008; Kim and Goldie, 2008). We can therefore look at the local price as endogenous, in the sense that it could be set to such a level as to make the vaccine cost-effective, given local conditions and social ability to pay for a QALY (local ICER threshold). There is an underlying price bargaining process, in free market countries as well as in price regulating countries, and the Australian case is a good example ( Roughead et al., 2008). In fact, price setting is a key point, often veiled, in the recommendation debate."

"Expanding the National HPV Immunisation Program to Include Males: a Health-Economic Approach and Decision-making mentions that Australia first rejected vaccinating boys as non-cost-effective, but accepted it after the vaccine manufacturers lowered their price.

Methylation as Biomarker for Cancer

There is research on measuring methylation of various host and viral genes as an additional diagnostic tool. See e.g. "Methylation marker analysis of self-sampled cervico-vaginal lavage specimens to triage high-risk HPV-positive women for colposcopy", "Epigenetics of human papillomaviruses, " Quantitative measurement of Human Papillomavirus type 16 L1/L2 DNA methylation correlates with cervical disease grade", and "A comparison of methylation levels in HPV18, HPV31 and HPV33 genomes reveals similar associations with cervical precancers".

See also

Copyright 2011, 2012, 2013, 2014 Dan Kegel
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