Sangini S. Sheth, MD, MPH

Human papillomavirus (HPV) infection is associated with genital warts, precancerous lesions, and cancers in both men and women. Many cervical, vaginal, vulvar, anal, and oropharyngeal cancers are attributable to HPV, with cervical cancer constituting 84% of all HPV-associated tumors.

 Although most HPV infections clear naturally or become dormant thanks to the immune system, a significant number of women will develop cervical dysplasia after HPV exposure, and a subset of these women will eventually progress to cervical cancer. It is estimated that by age 50, approximately 80% of all women will have had exposure to or been infected with 1 type of HPV; approximately 10% of these women will proceed to develop persistent HPV infection, which increases their risk of cervical cancer.

Studies have shown a causal relationship between HPV and cervical cancer, and high-risk HPV serotypes such as HPV-16 and HPV-18 are connected to 70% of cervical cancer cases.

 HPV vaccines were developed to prevent HPV-related diseases by stimulating the production of neutralizing antibodies that protect against type-specific HPV infection. Currently, commercially available HPV vaccines utilize virus-like particles (VLPs) of the L1 major capsid protein, the injection of which induces high titers of systemic antibodies that ultimately prevent the HPV virus from infecting the host cell.

There are 3 main types of HPV vaccines on the global market: 1) a bivalent vaccine, Cervarix (GSK), composed of HPV-16/18 VLPs and the proprietary adjuvant AS04; 2) a quadrivalent vaccine, Gardasil (Merck), containing HPV-6/11/16/18 VLPs, and an aluminum salt adjuvant; and 3) a 9-valent (nonavalent) vaccine, Gardasil 9 (Merck), based on the quadrivalent vaccine but containing VLPs of 5 additional oncogenic HPV serotypes: 31, 33, 45, 52, and 58. The 9-valent HPV vaccine was introduced with the goal of preventing 90% of cervical cancer cases globally. In 2016, the 9-valent vaccine was approved by the FDA with a 2-dose schedule in girls and boys aged 9 to
14 years, and it has since become the only HPV vaccine available in the United States 

Despite almost 2 decades of high-quality research demonstrating that HPV vaccines have excellent safety profiles, a worrisome trend has developed: Many patients or their parents cite concerns about vaccine safety as the reason for declining HPV vaccination. A recent cross-sectional study that investigated HPV vaccination trends in the United States noted that the percentage of caregivers for unvaccinated adolescents who cited vaccine safety as the primary reason to defer vaccination rose from 13% in 2015 to 23.4% in 2018.

 Exposure to vaccine misinformation, particularly through social media, could be a contributing factor to vaccine hesitancy. Therefore, it is of paramount importance that clinicians effectively address these safety concerns and dispel misinformation about HPV vaccines.

Since their licensure, more than 135 million doses of HPV vaccines have been distributed in the United States (with more than 270 million doses distributed worldwide).

 HPV vaccines are considered extremely safe. The most common adverse events (AEs) associated with HPV vaccines are minor and transient: local AEs (pain, itchiness, swelling, and redness at the injection site) and mild systemic symptoms (headache, nausea).

Rarely, patients experience dizziness and syncope, although syncope has been found to be more common in adolescents after receiving any vaccine.

 The incidence of severe allergic reaction (anaphylaxis) is exceedingly low (0.3-3 per million).

 Prelicensure clinical trials of HPV vaccines established their favorable safety profiles, and in recent years, more population-based studies have supported these findings. A Cochrane review in 2018 showed that although local AEs were more common in vaccinated subjects than in placebo recipients, there was no significant difference in mild and serious systemic AEs between vaccinated subjects and placebo recipients.

Additionally, since 2007, the Global Advisory Committee on Vaccine Safety (GACVS; established by the World Health Organization) periodically reviews new safety data on HPV vaccines. GACVS has found no significantly increased risk of the any of following conditions: Guillain-Barre syndrome, autoimmune conditions, or venous thromboembolic AEs.

 Additionally, GACVS has found no causal association between HPV vaccine and conditions including complex regional pain syndrome and postural orthostatic tachycardia syndrome. Although HPV vaccination is not recommended during pregnancy per the American Academy of Obstetricians and Gynecologists (ACOG), routine pregnancy testing is not recommended prior to vaccination.

 According to research findings, inadvertent exposure to HPV vaccine during pregnancy was not associated with increased rates of spontaneous abortion or adverse birth outcomes.

 HPV vaccine is safe and recommended for breastfeeding women who have not been previously vaccinated.

More recent population-based studies focusing on the 9-valent HPV vaccine continue to demonstrate its excellent safety profile, which is similar to that reported in prelicensure trials and in trials with the quadrivalent HPV vaccine.

Many claims surrounding the HPV vaccine are not based in evidence and should be refuted accordingly. A concern sometimes voiced by parents is that their adolescent children are “not sexually active” and that receiving the HPV vaccine would promote unsafe sexual behaviors among adolescents.

However, research has shown no significant association between legislation to increase HPV vaccination and changes in adolescent sexual behavior.

 Additionally, HPV vaccination was not associated with increased rates of sexually transmitted infection in a large population of female subjects.

 These data provide evidence that the claims that HPV vaccination encourages unsafe sexual activity are unfounded. Another concern has been raised regarding whether the HPV vaccine causes decreased fertility. Two studies have found no evidence that the vaccine is associated with either primary ovarian insufficiency or increased infertility.

Natural infection with HPV triggers an immune response both by formation of neutralizing antibodies and by cell-mediated immunity via cytotoxic T lymphocytes; however, this response is slow and titers of antibodies from natural infection are much lower compared with those seen after HPV vaccination.

 Currently, immunogenicity is determined by evaluating seropositivity, geometric mean titer, and antibody stability. In a study of young women who received the 9-valent HPV vaccine (NCT00543543), seropositivity to HPV-16/18 approached 100%, and most participants
(77.5%-100%) remained seropositive after 60 months.

 Variations in antibody titers have been observed according to age, sex, vaccine type, and vaccine dosage, and multiple studies have suggested that vaccine-induced antibody titers are significantly higher in younger recipients.

 It is important to note that the relationship between immunogenicity from HPV vaccine and the vaccine’s efficacy is not clearly characterized. For all HPV vaccines, no minimum level of antibody titer has been established as a threshold for efficacy.

Regardless of vaccine type or population, HPV vaccination has been shown to generate a durable, long-term immunogenic response, with studies showing stable antibody levels even 10 years after the initial vaccination.

 Results of a recent study in women in Costa Rica (NCT00128661) showed that a single dose of HPV vaccine achieved near 100% seropositivity and generated antibody titers that were 9-fold higher than those provoked by natural infection and that persisted for more than 7 years.

 It is worth noting that a single dose of vaccine produces antibody titers lower than those produced by 2 or 3 doses, thus precluding noninferiority studies. Large studies with long follow-up times are needed to evaluate the true efficacy of single-dose vaccination regimens.

The efficacy of 2-, 4-, and 9-valent HPV vaccines against oncogenic HPV infection has been extensively evaluated through clinical trials. The most critical measure of HPV vaccine efficacy is prevention of invasive cancer. However, cervical cancer develops over many years after initial HPV infection and is often preceded by persistent cervical dysplasia, which is detected via routine screening. Therefore, prevention of invasive cancer was replaced by surrogate end points in HPV vaccine efficacy studies. These end points included 6-month persistent vaccine type–specific HPV infection, cervical intraepithelial neoplasia grade 2 or higher (CIN 2+), cervical adenocarcinoma in situ (AIS), and anogenital warts. All 3 vaccines demonstrated similarly high efficacy (summarized in 

The initial clinical trials were conducted in women 16 to 26 years old using a 3-dose vaccination schedule. Later studies also included adult women 26 to 45 years old, adolescents using the 2-dose schedule, and women who received only a single dose of vaccine. Analysis was performed in women without previous HPV infection (HPV-naïve population) and in the overall population (regardless of prior HPV infection status). Across HPV vaccine types, higher efficacy was observed in the HPV-naïve population.

For the quadrivalent vaccine, the overall efficacy against persistent HPV-6/11/16/18 infection was 87% in the HPV-naïve group. In the same group, efficacy against external genital lesions as well as CIN 2+ associated with vaccine-type HPV was greater than 98%.8,36,37 For women 24 to 45 years old, vaccination efficacy against persistent type-specific HPV infection, CIN 1+, and external genital lesions was still above 89% in the HPV-naïve group, and efficacy in the overall population was 67%.

 It is worth noting that cross-protection against other HPV serotypes has been observed for both bi- and quadrivalent vaccines. This is not surprising, given that the additional oncogenic HPV serotypes are genetically related to HPV-16/18. The bivalent vaccine has been shown to provide higher efficacy against HPV-31, -33, and -45 through cross-protection compared with the quadrivalent vaccine.38,39 The 9-valent vaccine has the added benefit of providing coverage against additional oncogenic HPV serotypes. The efficacy of the 9-valent vaccine in preventing persistent infection with the 5 additional oncogenic HPV serotypes was 95% in both HPV-naïve women and the overall population. Efficacy against high-grade disease was 97% in HPV-naïve women and 81% in the overall population.

Early clinical trials also demonstrated high vaccine efficacy even in women who failed to complete the full vaccination series and received only 1 to 2 doses of vaccine. This finding led to trials that evaluated the noninferiority of a 2-dose vaccination schedule in young adolescents (9 to 14 years old). In a surprising finding, mean antibody titers were significantly higher in adolescents who received 2 doses of vaccine than in women aged 16 to 26 years who received 3 doses.

 In women older than 26 years, all 3 vaccines continue to demonstrate efficacy against persistent HPV infection and precancerous lesions, although efficacy is more pronounced in HPV-naïve women.

 Given that vaccine efficacy is highest in young women who are HPV naïve, the current recommendation is to start vaccination for all individuals at ages 11 to 12 years (and as early as 9 years) with a 2-dose schedule. Individuals older than 15 years would benefit from a 3-dose regimen.

More than 15 years has passed since the introduction of the first HPV vaccine, and studies focusing on the real-world effectiveness of the vaccine and possible herd protection have been conducted. These studies examine the long-term impact of HPV vaccines, especially at the population level. Early data show that HPV vaccines are effective in preventing HPV infection, precancerous cervical lesions, genital warts, and cervical cancer in the community. Importantly, these studies show a reduction in HPV prevalence not only in the vaccinated population but also in the unvaccinated population. A recent US study reported that in the 11 years after the introduction of HPV vaccines, detection of quadrivalent vaccine–type HPV in vaccinated women was reduced by approximately 80%, from 35% to 6.7%. Additionally, a decrease in the prevalence of 9-valent vaccine–type HPV was also observed in vaccinated women. Moreover, among unvaccinated women, the prevalence of quadrivalent vaccine–type HPV was also reduced by 40%, suggestive of
herd protection.

Along with the decline in HPV-6/11 infections, a decrease in the prevalence and incidence of genital warts has been observed. A Danish study found that the overall incidence of genital warts, which had been increasing in the country until 2007, started to decline shortly after initiation of HPV vaccination, with the most significant decrease observed in young women with high HPV vaccination rates.

Additional studies have investigated the association between HPV vaccination and the incidence of HPV-attributable cancers. A retrospective, population-based, cross-sectional study showed that after vaccine approval, the rate of decrease in annual cervical cancer incidence in 20- to 24-year-olds grew to 9.5% compared with 2.3% prior to vaccine initiation. This finding suggests that the accelerated decrease in cervical cancer incidence in younger women may be related to HPV vaccination.

 Another Swedish study that examined the relationship between HPV vaccination and risk of invasive cervical cancer demonstrated that the incidence rate of cervical cancer in vaccinated women younger than 31 years was significantly lower than that in unvaccinated women, with the lowest incidence rate among women vaccinated before age 17.

Lastly, as HPV vaccines become more prevalent worldwide, public health research has been using modeling studies to predict the long-term effectiveness and impact of HPV vaccination in the community. Early data suggest that even in models where only girls are vaccinated, and with a low vaccination rate of 20%, herd effects could be achieved. In models where high coverage of HPV vaccination is achieved in both boys and girls, data suggest that it may even be possible to eliminate high-risk HPV types.

Although a therapeutic HPV vaccine that can treat HPV-associated precancerous lesions or cervical cancer is not yet available, several clinical trials are currently under way. More importantly, emerging evidence has suggested that there may be benefits for women undergoing surgical treatment for HPV-related disease in receiving adjuvant vaccination with the currently available prophylactic HPV vaccine after primary treatment. For this population, studies have revealed a reduction in risk of recurrent lesions (CIN 2+) caused by HPV-16/18 after adjuvant vaccination.

Currently, ACOG and the Centers for Disease Control and Prevention have recommended that the HPV vaccine could be offered to those aged 27 to 45 years who had not been previously vaccinated based on shared clinical decision-making.

 Although vaccine efficacy and effectiveness are lower in women in this age group, HPV vaccination may still offer benefits for
specific populations.

In May 2018, the World Health Organization Director-General announced a global call for action to eliminate cervical cancer.

 The HPV vaccine, shown to be safe and highly effective, especially when administered at an early age prior to initiation of sexual activity, is a critical component of the strategy to achieve this goal. High rates of HPV immunization will also have important effects on other HPV-associated cancers. In addition to continued investigation into the efficacy and effectiveness of single-dose vaccines, efforts to address vaccine hesitancy and improve access to HPV vaccination are critical to achieve the goal of lowering barriers to vaccination worldwide.

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Articles

Deep dive into HPV vaccines

Excellent. As we begin to wrap up this conversation, does anybody have any additional comments they'd like to make? Dr Sheth? Dr Hill?

 I ust wanted to comment that we didn't really get a chance to talk about this, but there are, I think, also some studies looking at artificial intelligence and deep learning algorithms to implement some of these technologies that we have for screening; triaging women with HPV related issues is also a kind of an exciting development. Again, we don't have a lot of time to go into it, but a lot of interesting studies are supporting that as a new technology that we can use for helping managing HPV related diseases.

Essentially using visual methods with artificial intelligence trained algorithms?

 Yes, my final thought is we focused a lot today on screening, of course we talked about vaccination, and the final piece is that women who have or people who have abnormal results, a key component of that is the linkage to care to follow up on abnormal results, and I think ultimately the goal of this conversation is to close the gap on cervical cancer or even working towards elimination. The last piece of that is that linkage of care of abnormal results, whatever form of screening, we may be using.

Right, very important points, clearly. Dr Stoler?

 I'd emphasize that last point that the whole purpose of screening is to find the precancer, and if you can't treat the precancer, you're not doing anything with screening. That being said, life is getting a little more complex. We talked about extended genotyping, dual stain, different algorithms. How is the clinician and/or patient supposed to keep this all straight? I think more important than artificial intelligence apply to Pap smears [Papanicolaou tests] as a way of improving the performance of pap smears is the development of information systems and apps like the ASCCP [American Society of Colposcopy and Cervical Pathology] has developed that will essentially allow the app or the program to acquire the data from the patient record. What's the Pap history? What's the HPV test? What's the type? Was dual stain done to then give the clinician more direct guidance? You don't have to remember what the HPV type is. You just need to know whether the patient is safe to get retested in 5 years vs they have to get a colposcopy vs their risk is so high that no matter what the colposcopy shows you might end up treating them anyhow. It's that synthesis of clinical data that we now have so much good data that really says we can more precisely at the individual level synthesize these data and give you a risk that clearly tells the clinician what should happen to the patient. I think we're going to see more and more of that as we go forward because clinicians don't want to really know which test and they don't have time to become necessarily as expert in all the nuances of laboratory testing and data analysis that the data really support.

Excellent. I'd like to thank all of our panel members for a really informative discussion, and I'd like to thank the viewers for watching this 

 viewpoint. If you enjoyed the content please subscribe for the newsletters, E-newsletters, to receive upcoming viewpoints and other great content right into your inbox. Thank you all so much, have a good day.

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Drs Emily K. Hill, Sangini S. Sheth, and Mark H. Stoler share practice pearls for HPV and cervical cancer screening and express their hope for emerging testing options.

Key Takeaways for HPV and Cervical Cancer Screening

The other approach to triaging HPV [human papillomavirus] positive women is to do genotyping. I think everyone is aware of the importance of knowing whether a woman is HPV 16 or 18 positive. We already alluded in this conversation about the high rate of cervical cancer precursors in women are HPV 16 positive. It's about 25 of those women will become CIN2 or 3 positive within 3 years of being diagnosed as having HPV 16. What about other genotypes? Some people are discussing extended genotyping which means you would look for other HPV genotypes such as 31 or 35. Dr Hill, are you aware of that data and have any thoughts about it?

 No, I'm sorry I don't know that I have enough expertise to speak on that. I might have to defer to the other panelists.

 I don't know the specific data except to know that there are increasing commercial tests available. I think I just saw something earlier this week that 31 was added to one of the assay journals and I often teach that this is an area that we're going to see change over the course of our clinical careers, the more specific genotyping.

Okay, fair enough. Dr Stoler, you were involved in some of those studies.

 Yes. I think there's more than 1 way to skin this cat, if you want to use that old phrase. The ASCCP [American Society of Colposcopy and Cervical Pathology] has promoted for many years in their guidelines equal management for equal risk. When HPV primary screening was FDA approved, it incorporated partial genotyping, namely HPV 16 and 18 genotyping because of that risk that I've already talked about with particularly HPV 16. If you're HPV 16 positive, you need to get a colposcopy. I don't care what your Pap smear [Papanicolaou test] shows even though Pap smear abnormality will stratify that risk even higher. You have ASC-H and HPV 16. Your risk is so high that you might consider treating the patient without biopsy. What we found out in epidemiological studies over the last 10 years is that the 12 other types that are masked in most of the prior FDA approved assays have differential risks. Just like 16 and 18 have the highest risk, we now know that 31 and 33 in the New Mexico study, (52 if you're in Asia, etc.) have risks that approach the risk of HPV 18. If you're going to take an HPV 18 positive person to colposcopy, why shouldn't you take the HPV 31 positive person to colposcopy? There is an assay on the market today, the Onclarity assay, that has gotten an FDA approval to reveal extended genotyping because it has the capability of unmasking the data that were already there. Other assays don't have that capability, but you can use dual stain to perform equivalently. I think what you're going to see going forward from the NCI [National Cancer Institute] and during guidelines project that's working with practices and manufacturers is that there'll be different ways depending upon which HPV assay is offered in the laboratory to get the right people the colposcopy in their triage step. You might do extended genotyping. You might do dual stain. In some places you might do even a combination, but the point is that not all HPV types are of equal virulence, if you will, in terms of promoting the development of precancer or the rate of transformation to invasive cancer and that we now have that data, so why not use it. I think you're going to see in some practices, HPV extended genotyping where they take into account the other genotypes as a way of improving triage specificity.

Experts in obstetric and gynecologic management provide insight on the role of HPV genotypes in cervical cancer risk.

Role of HPV Genotypes in Cervical Cancer 

As we move to HPV primary screening, the big issue is going to be triage of HPV-positive women. Currently, when we cotest, we use cytology as a triage. If you've got an abnormal cytology, you're managed differently than if you have a negative cytology, depending on whether or not you've got HPV 16 or 18. There are other triage methods which are currently available and under development. One of those is CINtec PLUS which is testing for p16 and Ki-67. P16 is a small molecular way marker for cell cycle progression as is Ki-67. Normal cells will not coexpress p16 and Ki-67 whereas neoplastic cells do. We can use that for cytology as a way of determining whether or not there is a CIN really present or not. Dr Stoler, you were involved in a large study which got FDA approval of CINtec. Can you talk about that?

 The IMPACT trial which led to the FDA approval as well as data retrospectively that you and I have published from the ATHENA study basically looked in the primary HPV screening algorithm at the performance of triage test. Either cytology is a triage at various cut points, ASCUS [squamous cells of undetermined significance] or above, LSIL [low-grade squamous intraepithelial lesion] or above vs dual stain cytology which is performed on the same kind of liquid-based cytology slide but is an immunohistochemical test. What we found in those studies repeatedly is that CINtec PLUS or p16 and Ki-67 dual stain as a scientific name for the procedure outperformed cytology by a significant fraction. Remarkably, it does something that's very rare in laboratory testing. It was 25% to 30% more sensitive meaning it found the CIN 3 in the HPV positive population or the precancers of the HPV positive population more effectively than cytology even at the lowest threshold of cytologic abnormality; it was simultaneously more specific at least in some of the analyses. You had the best of both worlds in terms of triage and the implication of these studies and why it was FDA approved is that in a primary screening algorithm you greatly improved the safety and efficacy of the triage procedure. You get the right patients to go to colposcopy and you don't colposcope or biopsy nearly as many women as you would with a cytology test as triage.

Mark H. Stoler, MD, FASCP, provides insight on the role of dual testing in the management of HPV positive women.

Role of Dual Testing in HPV Positive Triage Management 

Let's move on now to recent advances in screening and looking ahead. How do you all foresee cervical cancer screening guidelines changing as more HPV-vaccinated individuals reach the screening age? Do you think this is just going to get more as time goes on as our vaccination rates increase? Dr Sheth?

I think we may see more interest in the adoption of primary HPV screening so a change in the modality of screening. Two, as we have increased screening rates, we could see the intervals shift and we could see the age change of initiation of screening. It's hard to predict right now because the vaccine has been available to us for over 15 years, and we're still so far from that optimal vaccination rate that it's hard to know when we're going to get there.

What is your feeling about why we're so far from the optimal vaccination rate?

 I think there are a few factors at play. The vaccine has some bad press that is not founded in any science or evidence in terms of side effects. Then there's just a lack of understanding that it is a vaccine and therefore it should be offered and recommended to everyone, so there's often this [attitude of], “Well, who needs it.” Trying to assess risk where, like any preventative measure, the point is for everyone to get it. I think those 2 issues combined have made uptake challenging.

Not surprising. We have vaccine hesitancy in the United States given what we've seen with COVID. Dr Stoler, would you address this issue of the performance of HPV testing vs cytology in vaccinated populations?

Sure, but I want to make a quick comment to what was just said. There's a study that was just published. It was in many of the newspapers last week out of Virginia, where they found that 25% of the population haven't even heard of the HPV vaccine. This is 15 years after FDA approval that every pediatrician and family practice doc should be vaccinating their teenagers and 25% of adults have never heard of it.

Sure, Mark. There's been a lot of discussion about the performance of cytology vs HPV as we get more people vaccinated.

 As I said, screening performance is driven by prevalence. HPV vaccinated individuals with Gardasil 9 have a 90% decrease in the rates of infection for the 7 types that cause 90% of all cervical cancers. In those individuals, the only thing that will work is the more sensitive HPV test. I think in this conversation, whether you're doing cotesting because that's what's available or primary HPV, the important thing is if you're going to screen, you have to do HPV testing. Now, as the vaccination goes through the population, the prevalence will drop particularly the prevalence of the most important HPV types. What you'll see is decreasing rates of HPV in vaccinated individuals and decrease in screen positives, and the first things that will drop out are the most important drivers of cancer screening, which are the most high-risk type 16 and 18 that account for 70% of cervical cancer. Lower sensitivity tests like a Pap [Papanicolaou test] will just perform less and less. It's not only less sensitive. It becomes increasingly less specific. We know that most abnormalities on Pap are already nonspecific ASCUS [squamous cells of undetermined significance] cases. When we take ASCUS out, the performance of Pap testing is quite poor. Yet the meaning of those ASCUS cases for the types that are not included in the vaccine becomes less and less specific. Vaccinated populations will be ahead of the game in that their risk of precancer is decreased by almost 90% or more. They still need some screening for a while until the overall population prevalence drops and that screening has to be molecularly based with HPV.

Drs Sangini S. Sheth and Mark H. Stoler share their thoughts on the adoption of primary HPV screening and how they foresee changes to cervical cancer screening as more individuals get vaccinated.

Addressing the Impact of HPV Vaccination Uptake on Cervical Cancer Screening

There's lots of data to show that in the first few months of COVID depending on geographically where the surge was, as clinics and offices shut down doors, screening and preventative care took a huge hit, and that includes cervical cancer screening. It also includes vaccination. It seems that as surges moved on, screening rates did start to increase, but as we continue to go through these waves, I think most places have not resumed to the full rate of screening that everyone was seeing prior to the pandemic.

 Unfortunately, I would say we have problems with screening in Iowa at baseline even before COVID in terms of the number of cervical cancer patients that I see with invasive cancer; it is quite shocking, actually. I think there's definitely national data that screening rates for cervical cancer during the pandemic went down on the order of 80% to 90%, so there was a significant drop. Then I think you also have the backlog of people. You've got people who are aware that they need to do that screening, trying to catch up, and having trouble getting in or again forgetting about the need for that because they put it off for 2 years; then it sort of slips your mind entirely, so getting some of those women that would have come for screening back into our fold is a challenge.

 Certainly, with the older women who are, I would assume, more hesitant to come into the office than the younger women, you probably still have quite a backlog?

 We do. I think I can say that, at least anecdotally, we certainly saw some women with locally advanced or metastatic cancers who we might not have seen if we didn't have the pandemic to contend with in really all of the cancers I take care of including cervical cancer.

 Certainly, in the New York area, the rate of screening, since I read the Pap smears, I do 80 a day, typically abnormal, perhaps now and before the pandemic. During the height of the pandemic through about August, it was down to 2 or 3. People just were not getting screened.

Thomas C. Wright Jr., MD; Emily K Hill, MD; and Sangini S. Sheth, MD, MPH, FACOG, comment on the impact COVID-19 had on HPV and cervical cancer screening in their respective practices.