‘Cervical cancer is a disease that clearly reveals inequalities’

In an interview with Agência FAPESP, world-renowned HPV researcher Luisa Villa explains why cervical tumors still kill thousands of Brazilian women, even though they are almost entirely preventable with vaccines and screening.

By Karina Toledo  |  Agência FAPESP – Celebrated annually on March 4, International Human Papillomavirus (HPV) Awareness Day highlights one of the leading causes of cancer death among women in Brazil: cervical cancer. Although nearly 99% of cases can be prevented through vaccination and screening, the disease continues to spread in Brazil. The main reason, warns one of the world’s leading experts on the subject, Luisa Villa, is inequality.

illa has a degree in biological sciences and a Ph.D. in biochemistry, both from the University of São Paulo (USP). She was a researcher at the São Paulo branch of the Ludwig Institute for Cancer Research (1983–2011), which operated in partnership with the A.C.Camargo Cancer Center. She served as the center’s director from 2006 to 2010. From 2009 to 2017, Villa coordinated the National Institute of Science and Technology for Papillomavirus Diseases – HPV Institute. This institute is supported by FAPESP and the National Council for Scientific and Technological Development (CNPq). Villa is currently a professor at the USP Medical School (FM) and the head of the Cancer Innovation Laboratory at the Center for Translational Research in Oncology at the São Paulo State Cancer Institute (ICESP).

In the 1980s and 1990s, Villa participated in studies that were fundamental to understanding the natural history of HPV, that is, mapping the life cycle of the virus in the human body. The results revealed that only persistent infections with high-risk types, such as HPV-16 and 18, lead to tumor development. These findings provided the scientific basis for the global approval of the quadrivalent vaccine in 2006 and its subsequent implementation in Brazil’s national public health network, the Sistema Único de Saúde (SUS), in 2014.

Brazil is currently reaping the benefits of this work, with significant vaccination coverage – 82% among girls aged 9 to 14 and 67% among boys – and the recent incorporation of molecular tests for HPV screening into the public health system. However, Villa warns that the number of cervical cancer cases is still rising in Brazil, with an estimated 19,000 new cases by 2027. This reflects late diagnoses in unvaccinated generations and failures in traditional Pap smear screening.

According to Villa, cervical cancer lays bare Brazilian inequalities, killing mainly women in remote regions without access to early diagnosis. The major national challenge today is not only combating denialism and vaccine hesitancy but also ensuring that cutting-edge technology, such as molecular testing and vaginal self-sampling, reaches every corner of the country.

In an interview with Agência FAPESP, the winner of the 7th Carolina Bori Science & Women Award, presented by the Brazilian Society for the Advancement of Science (SBPC), reflects on the translational nature of her studies, the importance of encouraging new generations of women in science, and the persistence required to turn basic research into lives saved.

Agência FAPESP – You began researching HPV in the early 1980s. What was known about the virus and its link to cancer at the time?
Luisa Villa – In the early 1980s, when I was at the Ludwig Institute for Cancer Research under the direction of Professor Ricardo Brentani [1937–2011], I knew nothing about HPV or tumor-causing viruses. But I was already becoming interested, because it was a growing field. Brentani returned from a meeting abroad and told me, “I was with my friend Harald” – and I had no idea he was referring to the future Nobel laureate, Harald zur Hausen [1936–2023]. And this friend said: “There’s a lot of cervical and penile cancer in Brazil; why don’t you study that?” It all started there. Since I was well-versed in molecular biology techniques, such as gene identification – and back then everything was done indirectly, since we didn’t have sequencing like we do today – we began studying a series of penile tumors, which are very rare in most parts of the world but a bit more common in Brazil. That was our first publication. Since the 1970s, there had been evidence of a link between HPV and cancer, of the virus’s connection to warts, and of cases where women with cervical cancer had partners who also developed penile tumors. These were very early studies, but they suggested the presence of a sexually transmitted agent. Starting in the 1980s, there was tremendous growth in that field.

Agência FAPESP – In the 1990s, you coordinated a study considered fundamental to understanding HPV, the Ludwig-McGill study. What was discovered through that research?
Villa – That study arose from a collaboration with Eduardo Franco, who has been working at McGill University [Canada] for many years. We designed that study to understand the natural history of the virus. A cohort of nearly 2,500 women was established in São Paulo, which was followed for at least five years, and in some cases up to ten years. One of the objectives was to understand whether, when a woman acquires HPV, her risk of developing a cervical lesion differs from that of a woman without HPV. And which behaviors and other variables influence that process. That allowed us to determine who’s at risk of developing cervical lesions. We found that not just any HPV infection caused them. It was essential that they were high-risk oncogenic viral types, particularly HPV-16 and HPV-18, which, as we now know, are present in the vast majority of cervical tumors and precursor lesions. The second key finding was that not every infection with these types poses a risk. Some may be transient, meaning the immune system itself eliminates the virus. Others persisted. The women in our cohort returned every six months and we collected and tested for HPV in cervical cells. In some women, we observed the persistence of the same high-risk HPV type for two or three years, and it was those women who, after some time, developed precancerous lesions. That result showed in which cases we need to intervene to prevent cancer.

Agência FAPESP – And what determines whether or not the infection will be persistent? Is it simply the ability of the immune system to fight the virus?
Villa – It’s actually a combination of factors. The main one is the immune response. In an immunologically competent woman, the immune system recognizes that the cells are slightly altered and triggers an inflammatory process. It’s worth noting that, in most cases, this occurs silently; there are no classic signs of inflammation, such as redness, swelling, or pus. That’s why women often don’t even realize they have HPV. Sometimes the virus isn’t completely eliminated and remains dormant in the body until something – such as a stressful event – causes a drop in immunity. Additionally, behavior can contribute to the persistence of the infection. Individuals who engage in frequent sexual activity with multiple partners are at higher risk of continued infection, and eventually, the immune system may be unable to fight off the virus. Smoking is a very important risk factor because it compromises the immune system. Another is the use of birth control pills, especially older ones, which have high hormonal doses. There are also less significant factors, such as nutritional status and genetic background. In some populations, the risk appears to be higher due to genetic factors, but that hasn’t yet been well established.

Agência FAPESP – Are the newer, lower-dose birth control pills also a risk factor?
Villa – Apparently much lower. In any case, women who use the pill continuously should be more vigilant regarding a persistent HPV infection, a lesion, or recurrent infections. Now, it’s very clear that oral contraception is essential for women’s well-being. We can’t simply say, "Stop taking the pill." Some might eventually choose other contraceptive methods.

Agência FAPESP – How did the findings from that cohort contribute to the development of the vaccine and its implementation in the public health system?
Villa – They outlined which population we should focus on initially, even when it was still unknown whether the vaccine would be immunogenic, effective, and, above all, safe. That was critical for the Phase 1 and 2 clinical trials. We had the opportunity to participate in Phase 2, the results of which were published in The Lancet Oncology in 2005. Just over 500 women aged 16 to 25 from Brazil and the Nordic countries were included. The results confirmed that the quadrivalent vaccine is safe and highly immunogenic. It was the first study to show a reduction in infections and certain associated diseases in vaccinated women compared to unvaccinated women. Of course, the clinical trials for that vaccine were conducted by the pharmaceutical industry, but there was a significant contribution from basic science researchers.

Agência FAPESP – Your studies were also important for extending vaccination to boys and for implementing molecular testing in the SUS, right?
Villa – Yes. In the late 1990s and early 2000s, we proposed another cohort of men, concurrent with the Ludwig-McGill study, in a study known by the acronym HIM, for “HPV in men.” It was fundamental for establishing the natural history of infections in men and served as the basis for the clinical trials that showed the vaccine was also immunogenic, safe, and effective in men. Later, all these findings contributed to the inclusion of molecular testing in the SUS, which occurred recently. Undoubtedly, that’s an even more direct contribution of basic science studies conducted worldwide, including by us here in Brazil. We showed that not all HPV types lead to the development of lesions. What was done in the past was to test, and when the result was positive for any type of HPV – even low-risk types, which is very common – the woman was told she was at risk for cancer. That created a lot of confusion and led to inappropriate treatments. Some doctors performed extensive cauterizations and even surgeries, compromising the reproductive capacity of young women. Once the concept was established that it must be a high-risk type and that the infection must be persistent, we began to ask: “Can I use the HPV test for population screening?” For 70 years, screening had been done with the Pap smear, and that saved many lives, but many women also went home with a result that wasn’t accurate. And there were people who died of cervical cancer even after a morphological test with a negative result. So, after many studies, we saw that women screened by the molecular test who tested positive for HPV-16 and HPV-18 were the ones at risk of developing the disease. Based on that, various algorithms were designed, various approaches to management. The results clearly showed that for those without HPV, the risk of cervical cancer is practically zero. Therefore, those women can be monitored every five years, or even less frequently in some countries. Those with HPV-16 or 18 should be carefully examined by a doctor immediately, as about 20% already have a lesion. If a woman has another type of oncogenic HPV, she can be monitored after a year or two. To my knowledge, about 15 municipalities in the country are already introducing HPV testing in the public health system. But I think there’s still a little way to go before that’s fully established.

Agência FAPESP – In your assessment, have all these studies conducted in Brazil placed the country in an advantageous position with regard to the prevention of cervical cancer?
Villa – Brazil has definitely benefited – and continues to benefit greatly – from field research. A major investment has been made over the past ten years in a study called POP-Brasil, on the prevalence of HPV, sponsored by the Ministry of Health and conducted at Moinhos de Vento Hospital in Porto Alegre [state of Rio Grande do Sul]. We participated in the first phase of the study, which revealed that 50% of Brazilian youth aged 16 to 25 may have HPV. Our group had already observed that, but the study confirmed it across all of Brazil’s state capitals. That put the country at the forefront of approving the vaccine in 2006, shortly after its approval in the United States and some other countries in the Northern Hemisphere. However, there was a long delay in implementing the plan, which only began offering the vaccine for free in 2014, first for girls, and then, in 2017, for boys. Brazil has joined the group of countries that understand what’s happening with HPV and associated diseases within their borders, and that have robust epidemiological research and highly significant basic research. That has given government agencies the confidence to implement these practices and certainly places Brazil among the countries where there’s a possibility of reducing the incidence of cervical cancer – if we continue to properly apply the guidelines of the Pan American Health Organization and the World Health Organization. More developed countries have rates of ten cases per 100,000 women and aim to lower that to four per 100,000. We have rates of 20 per 100,000. And if you go to some states in the Northeast, North, or the center of the country, that rate can reach 30 per 100,000, so our task is greater. According to recently published data from INCA [National Cancer Institute], the projection for 2027 is nearly 19,000 new cases. The last estimate was 17,000. The disease is still on the rise, therefore. In the most remote areas of the country, in rural zones, the disease still kills many people.

Agência FAPESP – According to official data, more than 80% of girls aged 9 to 14 and nearly 70% of boys have already been vaccinated against HPV. Why, then, is the number of cases still rising?
Villa – The young people who were vaccinated in 2016, ten years ago, are now around 20 years old. They won’t develop precancerous lesions; that’s already been proven. In women who haven’t been vaccinated, these lesions take time to appear; they usually emerge around age 30 or 35, and if there’s no screening, they won’t be detected, and some of them will develop cancer. We’re seeing a reduction in cases in countries with more than ten years of vaccination and high coverage rates when comparing the vaccinated population with the unvaccinated. In Brazil, we already have an article showing that has occurred, published in late 2025. But how many girls have been vaccinated in Brazil? Four million? Ten million out of a population of 220 million? And what about the women who haven’t received the vaccine and need to continue being screened? How many have access to screening? In state capitals, we have evidence that 80% undergo Pap smears, but I doubt the same is true in the country’s most remote regions. Sometimes the sample is even collected where there’s a health clinic, but the woman doesn’t return to find out the result, which could be cancer. So that’s a serious problem for Brazil, as it is for African countries, as it is for populations in isolated regions, who don’t have the same access to care. It’s a disease that clearly reveals inequalities. There are alternatives that are beginning to be discussed, such as vaginal self-sampling for the HPV test, which is performed by the woman herself using a swab, and the sample can then be examined at a central laboratory. That’s the proposal to save more lives in the country.

Agência FAPESP – So, in your view, does inequality still hinder cervical cancer prevention more than vaccine hesitancy or scientific denialism?
Villa – Clearly. Today there are very significant disinformation campaigns in the country, but women are very special; they pay close attention to information and know their bodies. The issue is that sometimes they can’t get help when they need it. Sometimes they bleed for a year or two and endure it, until the pain drives them to take a bus or a truck for hours to reach a center where they can be examined. Often it’s already too late. There are groups that bring information to remote areas, and women respond. As the slogan “No Woman Left Behind” [an adaptation of the central principle of the UN’s 2030 Agenda: No one left behind] says, no one can be left out of awareness campaigns – I include men, who also suffer from HPV-related cancers. Both must be well-informed. To mark International HPV Awareness Day, the ICESP organized a major public event on Paulista Avenue [a landmark of the city of São Paulo] in partnership with the International Papillomavirus Society.

Agência FAPESP – The vaccine currently offered through the SUS protects against four types of HPV, while the one offered in the private sector covers nine. From a public health perspective, would it be worthwhile to extend the nonavalent vaccine to everyone?
Villa – The vaccine available through the SUS can prevent at least 70% of cervical cancer cases and 90% of genital warts. The nonavalent vaccine, which includes five additional high-risk viral types in addition to types 16 and 18, prevents 95% of cervical cancers. That’s why that was the vaccine chosen in most national immunization programs. In Brazil, since the investment has already been made in a quadrivalent vaccine, it continues to be administered and the benefit is very significant, but it could be even greater with the introduction of the nonavalent vaccine for everyone.

Agência FAPESP – Based on everything we’ve discussed, we could say that your research has had a very direct and significant impact on the health of women in Brazil and around the world. Was that translational nature of the studies something you always sought, or did it happen naturally?
Villa – In all honesty, I think I only realized the magnitude of what I started 40 years ago after observing the introduction of vaccination in various countries around the world. When I saw the impact in the real world, I think that’s when it really sank in. Today I can look back and feel privileged to have had that opportunity.

Agência FAPESP – Did the fact that you’re a woman influence your career in any way, for example, in choosing your research topic? Did you have to deal with any kind of prejudice?
Villa – I didn’t experience direct prejudice, particularly because, for nearly 30 years, I was at an institution with a director, Professor Brentani, who had a very clear vision that everyone can contribute to science, regardless of whether they’re a woman or a man. And I was truly very supported by him and my colleagues; we sought to do good science. And I don’t think I researched the issue of the cervix because I’m a woman. I’ve always had a deep interest in understanding the mechanisms of diseases caused by microorganisms, influenced as I was by my doctoral advisor, Dr. Sérgio Olavo Pinto da Costa [1930–2023]. At the time, I was studying yeast genetics, but I was always very drawn to what microorganisms could do – both positively and negatively – causing various diseases. Basic research has always fascinated me greatly. Of course, from the moment I realized that this work could be translated into saving lives, everything took on a whole new significance.

Agência FAPESP – Your career path can certainly serve as an inspiration to young women interested in pursuing a career in science, as evidenced by the award recently presented to you by the SBPC. What message would you like to share with them?
Villa – Anyone who is curious should explore that curiosity, in any field. It often requires some sacrifices, a lot of determination, and a lot of persistence. Pursue your dreams; I pursued mine and was very fortunate to find places that opened their doors to me and encouraged me. It’s not enough to have the desire within you; you need to find places where that desire can be fulfilled. If you haven’t yet found a place where your curiosity can be fulfilled, keep looking.