What are human papillomaviruses?
Human papillomaviruses (HPVs) are a group of more than 150 related viruses. They are called papillomaviruses because certain types may cause warts, or papillomas, which are benign (noncancerous) growths. Some types of HPV are associated with certain types of cancer. These are called “high-risk,” oncogenic, or carcinogenic HPVs.
Of the more than 150 types of HPV, more than 40 types can be passed from one person to another through sexual contact. Transmission can occur in the genitals, anal, or oral regions. Although HPVs are usually transmitted sexually, doctors cannot say for certain when infection occurred. About 6 million new genital HPV infections occur each year in the United States. Most HPV infections occur without any symptoms and go away without any treatment over the course of a few years. However, HPV infections sometimes persist for many years, with or without causing detectable cell abnormalities.
What kinds of cancer are related to HPV infection?
Infection with high-risk HPV is the major cause of cervical cancer. Almost all women will have an HPV infection at some point, but very few will develop cervical cancer. The immune system of most women will usually suppress or eliminate HPVs. Only HPV infections that are persistent (do not go away over many years) can lead to cervical cancer.
In 2011, more than 12,000 women in the United States are expected to be diagnosed with cervical cancer and more than 4,000 are expected to die from it . Nearly half a million women develop cervical cancer each year worldwide, and more than a quarter of a million die from it.
High-risk HPV types also cause most anal cancers. Although anal cancer is uncommon, more than 5,000 men and women in the United States are expected to be diagnosed with the disease in 2011 and 770 people are expected to die because of it .
Infection with high-risk HPV is also known to cause some cancers of the oropharynx, vulva, vagina, and penis.
Can HPV infection be prevented?
The surest way to eliminate risk for genital HPV infection is to refrain from any genital contact with another individual
For those who are sexually active, a long-term, mutually monogamous relationship with an uninfected partner is the strategy most likely to prevent HPV infection . However, it is difficult to determine whether a partner who has been sexually active in the past is currently infected.
Research has shown that correct and consistent condom use can reduce the transmission of HPV between sexual partners . However, because areas not covered by a condom can be infected by the virus they are unlikely to provide complete protection against transmission of infection.
The Food and Drug Administration (FDA) has approved two vaccines to prevent HPV infection: Gardasil® and Cervarix®. Both vaccines are highly effective in preventing infections with HPV types 16 and 18, two high-risk HPVs that cause about 70 percent of cervical and anal cancers. Gardasil also prevents infection with HPV types 6 and 11, which cause 90 percent of genital warts.
What are Gardasil and Cervarix?
The Gardasil vaccine is produced by Merck & Co., Inc. It is called a quadrivalent vaccine because it protects against four HPV types: 6, 11, 16, and 18. Gardasil is given through a series of three injections into muscle tissue over a 6-month period.
The FDA has approved Gardasil for use in females for the prevention of cervical cancer, and some vulvar and vaginal cancers, caused by HPV types 16 and 18, and for use in males and females for the prevention of anal cancer and precancerous anal lesions caused by HPV types 16 and 18. Gardasil is also approved for the prevention of genital warts caused by HPV types 6 and 11. The vaccine is approved for these uses in females and males ages 9 to 26.
The Cervarix vaccine is produced by GlaxoSmithKline (GSK). It is called a bivalent vaccine because it targets two HPV types: 16 and 18. This vaccine is also given in three doses over a 6-month period. The FDA has approved Cervarix for use in females ages 9 to 25 for the prevention of cervical cancer caused by HPV types 16 and 18.
Both Gardasil and Cervarix are based on technology developed in part by NCI scientists. NCI licensed the technology to two pharmaceutical companies—Merck and GSK—to develop HPV vaccines for widespread distribution.
Neither of these HPV vaccines has been proven to provide complete protection against persistent infection with other HPV types, although some initial results suggest that both vaccines might provide partial protection against a few additional HPV types that can cause cervical cancer. Overall, about 30 percent of cervical cancers will not be prevented by these vaccines. Also, in the case of Gardasil, 10 percent of genital warts will not be prevented by the vaccine. Neither vaccine prevents other sexually transmitted diseases, nor do they treat HPV infection or cervical cancer.
Because the vaccines do not protect against all HPV infections that cause cervical cancer, it is important for vaccinated women to continue to undergo cervical cancer screening. There could be some future changes in recommendations for vaccinated women.
How do HPV vaccines work?
The HPV vaccines work like other immunizations that guard against viral infections. The investigators hypothesized that the unique surface components of HPV might create an antibody response that is capable of protecting the body against infection, and that these components could be used to form the basis of a vaccine.
The HPV surface components can interact with one another to form virus-like particles (VLP) that are not infectious, because they lack DNA. However, these VLPs can attach to cells and stimulate the immune system to produce antibodies that can prevent the complete papillomavirus, in future encounters, from infecting cells.
Although HPV vaccines can help prevent future HPV infection, they do not help eliminate existing HPV infections.
How effective are the HPV vaccines?
Gardasil and Cervarix are highly effective in preventing infection with the types of HPV they target. The vaccines have been shown to provide protection against persistent cervical HPV 16/18 infections for up to 8 years, which is the maximum time of research follow-up thus far. More will be known about the total duration of protection as research continues.
HPV vaccination has also been found to prevent nearly 100 percent of the precancerous cervical cell changes that would have been caused by HPV 16/18. The data so far show duration of production for up to 6.4 years with Cervarix and for up to 5 years for Gardasil—in women who were not infected with HPV at the time of vaccination (7–10).
A recent analysis of data from a clinical trial of Cervarix found that this vaccine is just as effective at protecting women against persistent HPV 16 and 18 infection in the anus as it is at protecting them from these infections in the cervix.
Both Gardasil and Cervarix are designed to be given to people in three doses over a 6-month period. However, a recent study showed that women who received only two doses of Cervarix had just as much protection from persistent HPV 16/18 infection as women who received three doses, and the protection was observed through 4 years of follow up (12). Even one dose provided protection; however, these findings need to be evaluated with more research to determine whether fewer than three doses of the vaccine will provide adequate duration of protection. Nonetheless, this information may be helpful for public health officials who administer vaccination programs among groups of people unlikely to complete the three-dose regimen.
Why are these vaccines important?
Widespread vaccination has the potential to reduce cervical cancer deaths around the world by as much as two-thirds, if all women were to get the vaccine and if protection turns out to be long-term. In addition, the vaccines can reduce the need for medical care, biopsies, and invasive procedures associated with follow-up from abnormal Pap tests, thus helping to reduce health care costs and anxieties related to abnormal Pap tests and follow-up procedures .
The other cancers caused by HPV are less common than cervical cancer. However, there are no formal screening programs for these cancers, so vaccination has the potential to greatly reduce deaths from these cancers also.
How safe are the HPV vaccines?
Before any vaccine is licensed, the FDA must determine that it is both safe and effective. Both Gardasil and Cervarix have been tested in tens of thousands of people in the United States and many other countries. Thus far, no serious side effects have been shown to be caused by the vaccines. The most common problems have been brief soreness and other local symptoms at the injection site. These problems are similar to ones commonly experienced with other vaccines. The vaccines have not been sufficiently tested during pregnancy and, therefore, should not be used by pregnant women.
A recent safety review by the FDA and the Centers for Disease Control and Prevention (CDC) considered adverse side effects related to Gardasil immunization that have been reported to the Vaccine Adverse Events Reporting System since the vaccine was licensed (14). The rates of adverse side effects in the safety review were consistent with what was seen in safety studies carried out before the vaccine was approved and were similar to those seen with other vaccines. However, a higher proportion of syncope (fainting) and venous thrombolic events (blood clots) were seen with Gardasil than are usually seen with other vaccines.
Falls after syncope may sometimes cause serious injuries, such as head injuries. These can largely be prevented by keeping the vaccinated person seated for up to 15 minutes after vaccination. The FDA and CDC have reminded health care providers that, to prevent falls and injuries, all vaccine recipients should remain seated or lying down and be closely observed for 15 minutes after vaccination. More information is available from the CDC.
Who should get these vaccines?
Both Gardasil and Cervarix are proven to be effective only if given before infection with HPV, so it is recommended that they be given before an individual is sexually active. The FDA’s licensing decision includes information about the age and sex for recipients of the vaccine. The FDA has approved Gardasil for use in females and males ages 9 to 26 and Cervarix for use in females ages 9 to 25.
After a vaccine is licensed by the FDA, the Advisory Committee on Immunization Practices (ACIP) makes additional recommendations to the Secretary of the U.S. Department of Health and Human Services and the Director of the CDC on who should receive the vaccine, at what age, how often, the appropriate dose, and situations in which it should not be administered. ACIP is made up of 15 experts in fields associated with immunization.
For females, ACIP recommends that Gardasil or Cervarix vaccination be given routinely at ages 11 or 12, although the series may be started for girls as early as 9 years of age. Vaccination is also recommended for girls and women ages 13 to 26 who have not been vaccinated already or who did not complete the three-dose series. If a woman reaches the age of 26 before completing the three-dose series, ACIP recommendations say that she can still receive the remaining doses .
For males, ACIP recommends routine vaccination with Gardasil at ages 11 or 12 to prevent HPV infection. ACIP also recommends vaccinating males ages 13 to 21 who have not been vaccinated already or who did not complete the three-dose vaccination series. The vaccine may be given to males between the ages of 22 and 26 .
States can decide whether or not to require vaccination of children prior to their enrollment in schools or child care. Each state makes this decision individually. Information about specific state vaccine decisions is available from the National Network for Immunization Information .
Should the vaccines be given to people who are already infected with HPV?
Although Gardasil and Cervarix have been found to be generally safe when given to people who are already infected with HPV, the vaccines do not treat infection and they provide maximum benefit if a person receives them before he or she is sexually active .
It is possible that someone infected with HPV will still get residual benefit from vaccination, even if he or she has already been infected with one or more of the types included in the vaccines. However, this possibility is still under investigation.
At present, there is no generally available test to show whether an individual has been exposed to HPV. The currently approved HPV DNA test shows only whether a person has a current HPV infection, and it identifies the HPV type. But it does not provide information on past infections.
Should women who already have cervical cell changes get the vaccines?
ACIP recommends that women who have abnormal Pap test results, which may indicate HPV infection, should still receive HPV vaccination if they are in the appropriate age group because the vaccine may protect them against high-risk HPV types that they have not yet acquired. However, these women should be told that the vaccination will not cure them of current HPV infections and that it will not treat the abnormal results of their Pap test
HPV in India
A recent study has shown that the current available data on human papillomavirus (HPV) type and cervical cancer incidence do not support the epidemiological claims made by the Programme for Appropriate Technology in Health (PATH) regarding India having a large burden of cervical cancer.
In April 2010, the Indian Council of Medical Research suspended research on the feasibility and safety of HPV vaccine in Andhra Pradesh and Gujarat amid public concerns about its safety. The study was being done for two pharmaceutical companies by PATH and was supported by the ICMR.
The PATH, a U.S.-based not-for-profit non-governmental organisation undertook post-licensing observational studies on HPV vaccines in India on coverage, acceptability, feasibility and costs of the vaccines in Gujarat and Andhra Pradesh, funded by the Bill and Melinda Gates Foundation.
Cervical cancer is estimated to cause around 2,74,000 deaths a year, approximately 80 per cent of which occur in the developing world. Guidelines for cervical cancer screening are implemented in few States in India. HPV is associated with cervical cancer and of the 100 HPV types, 18 have been categorised as high risk types or possible high risk types for cervical cancer. HPV types 16 and 18 are said to account for approximately 70 per cent of all cervical cases in India.
According to the latest study, there is no general account in the literature of cancer surveillance in India. The two main agencies involved in reporting incidence, prevalence and mortality of cervical cancer in India are the National Cancer Registry Programme (NCRP) and the International Agency for Research on Cancer (IARC).
The latest study says that PATH does not cite any of the cancer data on Andhra Pradesh or Gujarat. There is no NCRP or other cancer registry in Andhra Pradesh, and neither C15 (Cancer Incidence in five continents) nor GLOBOCAN (global database across the world) published data for this State. Age-adjusted incidence rates are 10.16 in Hyderabad and 14.29 per 1 lakh in Nellore (2001-02).
There are two cancer registries in Gujarat, one urban and the other rural, which cover only Ahmedabad districts. The rural registry shows an age-adjusted incidence rate of 8.5 per 1 lakh (2006-08); the urban registry shows this rate as 9.1 per 1 lakh (2004-05). The coverage is 18.9 million people. Gujarat has low incidence rates and few data on mortality rates are available.
The study was to investigate whether to implement an HPV vaccination programme with PATH claiming that “in raw numbers, India has the largest burden of cancer of cervix of any country worldwide.” The new study says this claim is not supported by the references, moreover data from the cancer registries in Gujarat has not been cited. The two States were selected “based on cervical cancer burden and uptake of other vaccines being in the middle range for certain variables (eg. immunisation coverage).” There is no reference provided for this.
Contrary to PATH’s claim, the overall incidence and mortality rate of cervical cancer is low in India. Age-adjusted cervical cancer incidence rates of India are also low compared to estimates of 50 per 1,00,000 in Zimbabwe and 38.2 in Brazil.
However, the World Health Organisation advises that the epidemiology of the disease should be known and be of sufficient importance to justify its prioritisation, and that surveillance systems should be capable of assessing the impact of vaccine intervention following its introduction. “This study shows an absence of epidemiological data in support of HPV vaccine studies by PATH in the two States, let alone any roll out across the rest of India. Recent studies of HPV show an apparent decrease in cervical cancer incidence, which must also be taken into account,” says the study ‘Do cervical cancer data justify HPV vaccination in India? Epidemiological data sources and comprehensiveness’.
Of the five studies that PATH cites in relation to cervical cancer or HPV epidemiology, one study could not be traced; the home-based cancer registry report is not comprehensive and does not provide age-adjusted cervical cancer incidence rates and the three remaining studies did not examine epidemiology of cancer but reported HPV prevalence and type distribution. Only one study was conducted in A.P. and none in Gujarat. The three studies were conducted in rural populations in the south and urban populations in the south and north of India.
Cervical cancer surveillance in Gujarat and Andhra Pradesh is incomplete and the data that are available were not used or cited by PATH, the new study says.