WOMEN'S HEALTH
May 1, 2006

Human Papilloma Virus and Cervical Cancer

Modern medicine's battle against cervical cancer is a tale of two worlds. In the developed world, it is a story of success. Thanks to Dr. George Papanicolaou's 1943 development of the Pap smear test, doctors can detect cellular changes that are precursors to cancer. If treated right away, these changes will not develop into cervical cancer. As a result, women who live in places where Pap smears are given regularly have seen their rates of cervical cancer plummet. From 1947 to 1982, for example, the incidence of cervical cancer among white American women fell by 75% and the death rate from cervical cancer by 80%. Currently, about 80% of women in the U.S. take regular Pap smear tests.

It is a different story in the developing world. Without the public health infrastructure to do cervical cancer screening or to evaluate Pap smear results, cervical cancer rates remain in the pre-1940s range. In many developing countries cervical cancer is still the most common cancer in women. Worldwide, there are 470,000 new cases and 230,000 deaths every year, compared to only 10,000 new cases and 3,700 deaths a year in the U.S.

...[H]uman papilloma virus (HPV) plays a key role in cervical cancer. HPV is transmitted through sex and virtually all cases of cervical cancer begin with HPV infection.

In the past few decades, however, researchers have discovered that a virus called human papilloma virus (HPV) plays a key role in cervical cancer. HPV is transmitted through sex and virtually all cases of cervical cancer begin with HPV infection. The good news is that we can test for HPV infection. There is hope that the combination of the Pap smear test with the right kind of HPV test, plus the development of new vaccines to prevent HPV infection, will lead to new, dramatic advances in the fight against cervical cancer in every part of the world.

What Is Human Papilloma Virus?
HPV comes in many shapes and sizes. There are more than 100 known papilloma viruses that affect humans, so many that they are given numbers, such as HPV type 6 or type 16. Some HPV types cause skin warts. Over 40 types of HPV affect the genital tract, some causing genital warts. Others cause infections of the cervix.

Some types of HPV are strongly associated with a high risk of developing cervical cancer. Types 16 and 18 are known carcinogens and are found in 70% of American women with cervical cancer. Scientists believe that HPV initiates a process that leads, over time, to the development of cervical cancer; and that other factors, such as cigarette smoking, poor nutrition and infection with the sexually transmitted disease chlamydia, stimulate and lay the groundwork for cervical cancer.

How Women Get Genital HPV
Genital HPV is transmitted through sex. It is staggeringly common. Most sexually active young women will become infected, 40% within 16 months after first having vaginal sex. These infections can be with a succession of different HPV types or with more than one type at a time. The infections cause few or no symptoms and women — and men, for that matter — rarely realize that they have been infected. Most infections are completely destroyed by the body's immune system in a matter of months and do no long term harm.

Most sexually active young women will become infected, 40% within 16 months after first having vaginal sex.

A small number of infections, however — five to ten percent — survive and remain within the body and it is these that cause problems. The virus becomes incorporated into the genetic structure of the cervical cells, beginning a process that will eventually develop into precancerous cells. These are the same changes that are picked up by Pap smears. Left undetected and untreated, they can develop into cervical cancer. This persistent infection is called chronic HPV infection and is the most important risk factor for the development of cervical cancer.

Women are most likely to get a genital HPV infection in their 20s. As women age their risk goes down with the build up of immunity and more conservative sexual habits. Because it can take 10 to 15 years for HPV-related changes to become cancer, women infected in their 20s would not be expected to develop cervical cancer until their late 30s or 40s.

Other Risk Factors
Long before HPV's key role in cervical cancer was known, several other risk factors had been identified. The discovery of HPV has provided a common thread that links most of these factors:
  • Having sex at an early age: this is explained by the fact that in adolescents the immature cervical cells are much more vulnerable to HPV and other infections.
  • Multiple sex partners: there will be increased opportunities to contract more types of HPV.
  • Cigarette smoking: there are carcinogens in cigarette smoke that promote the development of cancer in the cervix and elsewhere.
  • Decreased immunity: women receiving immunosuppressive drugs and those with HIV/AIDS have a poor immune response to HPV.

Now that we know that HPV underlies most of these risk factors, it is clear that the key to cervical cancer prevention is identifying long-term HPV infection. After all, a woman could have many sexual partners, and many HPV infections, but if her body fights off these HPV infections and she never develops a chronic HPV infection, she would be at a very low risk of getting cervical cancer. On the other hand, a women with none of these risk factors, but who develops one chronic HPV infection, would be at a high risk.

HPV Testing
Doctors now have two accurate blood tests for HPV. One, the antibody test, shows that someone once had an infection with a particular HPV type, but it does not say whether they are currently infected with the virus. In order to know that, there is second more specific test that checks vaginal or cervical secretions for viral DNA. This is called an HPV DNA test.

Most sexually active young women will become infected, 40% within 16 months after first having vaginal sex.

Is There a Chronic Infection?
As mentioned above, HPV infection is common in young women through their mid-twenties. Most infections, however, whether with high-risk or low-risk viruses, clear up on their own within 9 to 15 months. The key question is whether there is a chronic infection with a high-risk type of HPV, one that can set off the changes that can lead to cervical cancer. One way to find this out is to combine the current Pap smear test with HPV testing, which is already being done. This kind of testing has led to a better understanding of the changes seen on Pap smears. Some changes detected by Pap smears seem to return to normal on follow-up tests. These probably represent transient HPV infections. Others continue to progress in the direction of cervical cancer and they are the more dangerous chronic HPV infections.

Who Should Have an HPV Test?
Considering how HPV works, there is no point in doing an HPV DNA test in young women. Many young women will be positive for high-risk types but will not develop chronic infection. This is why, if you pay close attention to TV advertisements for HPV testing, you will hear the announcer say the test is for "women over 30." The goal is to pick up chronic high-risk HPV infection — even when the Pap test is negative — in a woman 30 and over. If you think that you might need an HPV test, in addition to a regular Pap smear, you should discuss the issue with your doctor or other medical professional.

A Vaccine Against Human Papilloma Virus
Detecting a chronic HPV infection is important. Even better would be a vaccine that prevents the infection in the first place. Such vaccines are now under development. In 2002 one vaccine was tested and proved 100% effective in protecting a small number of young women from HPV 16 infection. Other researchers are studying vaccines against a variety of different HPV types, including types 16 and 18, which account for about 70% of cervical cancers.

When an HPV vaccine does become widely available, [update: it is now available.] it may also be effective against other cancers because HPV types have been implicated in cancers of the vulva, vagina, penis and anus. Types 11 and 6 are associated with genital warts in both sexes and with a mouth and throat infection called recurrent respiratory papillomatosis (RRP), a rare and difficult to treat infection in children and adults How will these vaccines fit into the fight against cervical cancer? They have been tested on people without previous HPV infection and must be given before the women become sexually active.

In developed countries with a strong public health infrastructure, a three-shot program could be inserted into the regular childhood vaccine schedule. In resource-poor developing countries, where cervical cancer is the first or second cause of cancer death in women, a vaccine that protects a woman against cervical cancer for life would save countless lives. Right now what we don't yet know is how long immunity lasts. Would it last a lifetime? Could we create a single-shot vaccine? This would be important for resource-poor countries.

Preventing Cancer
It is exciting to think that a simple vaccination could bring cervical cancer rates around the world down to the levels seen in developed countries today, or even lower.

Now that the role of HPV in cervical cancer is known, prevention is a real possibility. Studies on statistics from five developing countries suggest that screening at age 35 with visual inspection of the cervix or HPV DNA testing could reduce a woman's risk of getting cervical cancer by close to 30% and that screening at age 35 and 40 would reduce lifetime risk by an additional 40%.

Another idea would be to do both an early vaccination and screening for high-risk HPV at ages 35 and 40. A one-shot vaccine containing the high-risk types prevalent in the region would be used. This would allow scarce resources to be concentrated on finding and treating women with persistent infection.

Finally, it may be time to rethink cervical cancer testing altogether. Perhaps we should be testing women 30 and over for chronic high-risk HPV infection first, and then do Pap tests.

Summary
Research has shown that chronic infection with a high-risk type of HPV is the primary cause of cervical cancer. The tools now exist to screen women for these infections and then to treat the cellular changes they cause. Vaccines are currently under development that can prevent HPV infections. As a result of these advances, there is great hope that we can further reduce cervical cancer rates in developed countries and dramatically lower these rates throughout the entire world.
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