I had just finished an astounding book about a young woman who died of metastatic cervical cancer, when I saw an article in the December 2010 issue of Cancer Epidemiology Biomarkers & Prevention about an increase in HPV (human papilloma virus) rates after menopause. The impact of the book, and the scientific article, raised new questions for me about the true impact of HPV for women.
The book was The Immortal Life of Henrietta Lacks, written by Rebecca Skloot (Crown Publisher, 2010). Henrietta Lacks delivered a baby in September 1950, right after her thirtieth birthday. There was no mention at delivery, or her postpartum exam, of a cervical lesion. Yet three months later, she had a biopsy taken from her cervix of what the GYN described as ???grape jello???. Within a year Henrietta had died from cervical cancer.
Fast forward to 1984. A German virologist, H. zur Hausen, had just discovered HPV 18; he had discovered another high risk HPV strain (HPV 16) in the prior year. It was now suspected that HPV, especially the high risk strains, were responsible for cervical cancer. This was big news at the time. It was especially worrisome since genital HPV infections seemed to be sexually transmitted. The virologist obtained a tiny sample of Henrietta???s original biopsy and tested it for the presence of HPV 18. To quote the Rebecca Skloot???s book, ???The sample didn???t just test positive; it showed that Henrietta had been infected with multiple copies of HPV-18, which turned out to be one of the most virulent strains of the virus.??? (page 212).
As many of you know, ???high risk??? (HR) subtypes of HPV such as 16, 18, 52, and 59 are generally recognized as linked to both severely abnormal PAP smears and cervical cancer. High risk HPV subtypes are associated with 99.7% of all cervical cancers (Alt, 2006). Newer PAP smear tests have the capability to test a woman???s tissues for HPV 16 and 18. Both of the new HPV vaccines to be given to virginal girls immunize against HPV 16 and 18. Yet the vaccines are recent developments, so there are many of us who have been exposed to HPV ??? both high and low risk subtypes. This month???s blog will attempt to answer some of the most pressing questions about HPV:
How many of us have HPV?
Will I get an abnormal PAP smear?
Why aren???t there more abnormal PAP smears?
Can I ever get cured of an HPV infection?
Why would perimenopausal women seem to have an increase in HPV rates?
Should we rethink the new PAP smear guidelines?
How many of us have HPV?
The Centers for Disease Control has postulated that at least 80% of sexually active women will have evidence of an HPV infection by age 50 (CDC, 2004). In one study of 1,921 women, the presence of current HPV was almost 28%. These US women aged 14-59 years gave self-collected tissue samples using foam swabs which were then tested for the presence of HPV DNA. Among sexually active women, the likelihood of having current HPV depended upon age:
AGE INCIDENCE OF HPV
Age 14-19 24.5%
Age 20-24 44.8%
Age 25-29 27.4%
Age 30-39 27.5%
Age 40-49 25.2%
Age 50-59 19.6%
In addition to age, other risk factors included increasing numbers of either recent, or lifetime, sexual partners. Not all the HPV infections were with the ???high risk??? subtypes. Only 15.2% of infections were of the high risk types. It is also noteworthy that 24% of women had two types of HPV detected and 16% had three or more subtypes detected (Dunne, 2007).
HPV infections are known to be sexually transmitted among heterosexual couples. Marrazzo and colleagues (2001) did PAP smears and HPV testing on 248 women who had female sexual partners. Since 80% reported intercourse with a male at some point, the researchers compared the presence of HR- HPV between those with a recent (within last year) male partner (19.2% HR-HPV) and those with those who had never been with a male (2% HR-HPV).
Will I get an abnormal PAP smear?
Not everyone with a documented HPV infection will present with an abnormal PAP smear. One very large meta-analysis, including 157,879 women world wide, found a prevalence of 10.4% of HPV infection in those with normal PAP smears. The highest incidences were in Africa (22.1%) and Central America/Mexico 20.4%. The lowest incidences were in Europe 8.1% and Asia 8.0%. (de Sanjose, 2007).Given that 32% of these women were infected with HPV 16 or 18 (or both) there is an increased risk for the virus to cause future problems.
Why aren???t there more abnormal PAP smears?
One reason we don???t see more abnormal PAP smears is likely to be that we don???t screen women more frequently. Brown and colleagues (2005) followed 60 adolescent women for an average of two years. During that time each woman studied had an average of 42 vaginal or cervical swabs tested for presence of HPV DNA. That???s a screening swab every 7-10 days!
Over the two years, 49 of the 60 women tested were positive for HPV. Of those, 38.6% had high risk subtypes of HPV. The average time for a detectable HPV infection to disappear was 168 days (almost six months). However, those who had HR-HPV had infections which took an average of 226 days to become non-detectable. Where an abnormal PAP smear result was also present, infections were more likely to be high risk subtypes???and to take longer to resolve.
Can I ever get cured of an HPV infection?
As noted above, HPV infections do seem to go into remission, or become undetectable. There have been many other studies where young women were followed to see if the HPV infection would ???go away.??? One well done study (Ho, 1998) followed older adolescents over three years. At the end of the study some 43% became HPV positive. This confirms the ease with which HPV can be passed between sexual partners. Surprisingly, of this group of newly infected women, only 9% continued to show persisting evidence of HPV.
A group of 1,788 young women (age 16-23) were given PAP smears and HPV DNA testing every six months for up to four years. HPV 16 showed both the highest incidence and the longest duration of infection (20 months). The investigators reported that within a three years span HPV infections that became nondetectable could reappear. This happened, on average, in about 8% of infections (Insinga, 2010).
Similarly, in a group of 18-22 year olds given PAP smears and HPV DNA tests three times yearly, it took an average of 9.4 months for the HPV test to become negative after an infection was first detected. By two years out, 90% of infections were not detected. Yet, 19.4% of infections that became undetectable re-emerged within one year (Winer 2010).
It is now thought that HPV can be acquired and be ???dormant???. Then, in times of a lowered immune function (e.g., pregnancy, chronic illness, or use of immune suppression drugs), dormant viruses such HPV can produce significant infections. Based upon the newest data it would seem that the high risk subtypes are the most likely to persist.
Interestingly, the use of condoms may hasten regression of HPV infections and abnormal PAP smears. One hundred and forty eight women and their partners were randomly assigned to use condoms, or not, after the woman had been diagnosed with HPV. After two years of follow up, 23% of the condom using women, as opposed to 4% of non-condom users, had non-detectable levels of HPV. Condom users also had better regression of their CIN lesions (Hogewoning, 2003).
Why would perimenopausal women seem to have an increase in HPV rates?
A second peak of HPV prevalence has been observed among African, American and European women aged 45 years and older (de Sanjose, 2007). While absolute numbers of apparently new infections are low, persistent infections were higher in older (age 42 or above) Costa Ricans as compared to younger age groups (Rodriguez., 2010).
A closer look at the causes of increased HPV detection in older women was undertaken using 252 women with HPV compared to 265 women without HPV (Gonzalez, 2010). The greatest risk factor appeared to be 2 or more new partners (or partners with other lovers). In summary, new HPV infections in older women could be attributed to:
Recent sexual behavior: 21%
Past sexual behavior: 21%
Reduced immune system function: 12%
Thus, if you are an older woman who has been found to test positive for HPV as part of a routine screening, and you have no new sexual partners, it is likely a persisting, older onset infection. More investigations are needed to help understand if immune function is linked to the changes in sex hormone levels that occur at this age.
Should we rethink the new PAP smear guidelines?
The 2009 recommendations for cervical cancer screening are now:
Women over the age of 30 can now get PAP smears only every three years IF they have had three normal PAP smears in a row.
If women have risk factors (e.g., as prior abnormal PAPs), or have decreased immune functions (e.g., organ transplant recipients, HIV) they should get more frequent PAP smears.
Routine screening PAP smears should begin at age 21???not as a teenager.
Routine screening PAPs can be discontinued between ages 65 and 70 (American Cancer Society & US Preventative Health Task Force)
Women who have received the HPV vaccine to reduce cervical cancer are still subject to these standards. But as more data is gained this may be reassessed.
If a woman is low risk (e.g., fewer than three life time sexual partners, no prior history of abnormal PAP smears or high risk HPV) I believe the current PAP recommendations are appropriate. If you have known risk factors, consult with your GYN about what screening interval would be most appropriate for you.
The book was The Immortal Life of Henrietta Lacks, written by Rebecca Skloot (Crown Publisher, 2010). Henrietta Lacks delivered a baby in September 1950, right after her thirtieth birthday. There was no mention at delivery, or her postpartum exam, of a cervical lesion. Yet three months later, she had a biopsy taken from her cervix of what the GYN described as ???grape jello???. Within a year Henrietta had died from cervical cancer.
Fast forward to 1984. A German virologist, H. zur Hausen, had just discovered HPV 18; he had discovered another high risk HPV strain (HPV 16) in the prior year. It was now suspected that HPV, especially the high risk strains, were responsible for cervical cancer. This was big news at the time. It was especially worrisome since genital HPV infections seemed to be sexually transmitted. The virologist obtained a tiny sample of Henrietta???s original biopsy and tested it for the presence of HPV 18. To quote the Rebecca Skloot???s book, ???The sample didn???t just test positive; it showed that Henrietta had been infected with multiple copies of HPV-18, which turned out to be one of the most virulent strains of the virus.??? (page 212).
As many of you know, ???high risk??? (HR) subtypes of HPV such as 16, 18, 52, and 59 are generally recognized as linked to both severely abnormal PAP smears and cervical cancer. High risk HPV subtypes are associated with 99.7% of all cervical cancers (Alt, 2006). Newer PAP smear tests have the capability to test a woman???s tissues for HPV 16 and 18. Both of the new HPV vaccines to be given to virginal girls immunize against HPV 16 and 18. Yet the vaccines are recent developments, so there are many of us who have been exposed to HPV ??? both high and low risk subtypes. This month???s blog will attempt to answer some of the most pressing questions about HPV:
How many of us have HPV?
Will I get an abnormal PAP smear?
Why aren???t there more abnormal PAP smears?
Can I ever get cured of an HPV infection?
Why would perimenopausal women seem to have an increase in HPV rates?
Should we rethink the new PAP smear guidelines?
How many of us have HPV?
The Centers for Disease Control has postulated that at least 80% of sexually active women will have evidence of an HPV infection by age 50 (CDC, 2004). In one study of 1,921 women, the presence of current HPV was almost 28%. These US women aged 14-59 years gave self-collected tissue samples using foam swabs which were then tested for the presence of HPV DNA. Among sexually active women, the likelihood of having current HPV depended upon age:
AGE INCIDENCE OF HPV
Age 14-19 24.5%
Age 20-24 44.8%
Age 25-29 27.4%
Age 30-39 27.5%
Age 40-49 25.2%
Age 50-59 19.6%
In addition to age, other risk factors included increasing numbers of either recent, or lifetime, sexual partners. Not all the HPV infections were with the ???high risk??? subtypes. Only 15.2% of infections were of the high risk types. It is also noteworthy that 24% of women had two types of HPV detected and 16% had three or more subtypes detected (Dunne, 2007).
HPV infections are known to be sexually transmitted among heterosexual couples. Marrazzo and colleagues (2001) did PAP smears and HPV testing on 248 women who had female sexual partners. Since 80% reported intercourse with a male at some point, the researchers compared the presence of HR- HPV between those with a recent (within last year) male partner (19.2% HR-HPV) and those with those who had never been with a male (2% HR-HPV).
Will I get an abnormal PAP smear?
Not everyone with a documented HPV infection will present with an abnormal PAP smear. One very large meta-analysis, including 157,879 women world wide, found a prevalence of 10.4% of HPV infection in those with normal PAP smears. The highest incidences were in Africa (22.1%) and Central America/Mexico 20.4%. The lowest incidences were in Europe 8.1% and Asia 8.0%. (de Sanjose, 2007).Given that 32% of these women were infected with HPV 16 or 18 (or both) there is an increased risk for the virus to cause future problems.
Why aren???t there more abnormal PAP smears?
One reason we don???t see more abnormal PAP smears is likely to be that we don???t screen women more frequently. Brown and colleagues (2005) followed 60 adolescent women for an average of two years. During that time each woman studied had an average of 42 vaginal or cervical swabs tested for presence of HPV DNA. That???s a screening swab every 7-10 days!
Over the two years, 49 of the 60 women tested were positive for HPV. Of those, 38.6% had high risk subtypes of HPV. The average time for a detectable HPV infection to disappear was 168 days (almost six months). However, those who had HR-HPV had infections which took an average of 226 days to become non-detectable. Where an abnormal PAP smear result was also present, infections were more likely to be high risk subtypes???and to take longer to resolve.
Can I ever get cured of an HPV infection?
As noted above, HPV infections do seem to go into remission, or become undetectable. There have been many other studies where young women were followed to see if the HPV infection would ???go away.??? One well done study (Ho, 1998) followed older adolescents over three years. At the end of the study some 43% became HPV positive. This confirms the ease with which HPV can be passed between sexual partners. Surprisingly, of this group of newly infected women, only 9% continued to show persisting evidence of HPV.
A group of 1,788 young women (age 16-23) were given PAP smears and HPV DNA testing every six months for up to four years. HPV 16 showed both the highest incidence and the longest duration of infection (20 months). The investigators reported that within a three years span HPV infections that became nondetectable could reappear. This happened, on average, in about 8% of infections (Insinga, 2010).
Similarly, in a group of 18-22 year olds given PAP smears and HPV DNA tests three times yearly, it took an average of 9.4 months for the HPV test to become negative after an infection was first detected. By two years out, 90% of infections were not detected. Yet, 19.4% of infections that became undetectable re-emerged within one year (Winer 2010).
It is now thought that HPV can be acquired and be ???dormant???. Then, in times of a lowered immune function (e.g., pregnancy, chronic illness, or use of immune suppression drugs), dormant viruses such HPV can produce significant infections. Based upon the newest data it would seem that the high risk subtypes are the most likely to persist.
Interestingly, the use of condoms may hasten regression of HPV infections and abnormal PAP smears. One hundred and forty eight women and their partners were randomly assigned to use condoms, or not, after the woman had been diagnosed with HPV. After two years of follow up, 23% of the condom using women, as opposed to 4% of non-condom users, had non-detectable levels of HPV. Condom users also had better regression of their CIN lesions (Hogewoning, 2003).
Why would perimenopausal women seem to have an increase in HPV rates?
A second peak of HPV prevalence has been observed among African, American and European women aged 45 years and older (de Sanjose, 2007). While absolute numbers of apparently new infections are low, persistent infections were higher in older (age 42 or above) Costa Ricans as compared to younger age groups (Rodriguez., 2010).
A closer look at the causes of increased HPV detection in older women was undertaken using 252 women with HPV compared to 265 women without HPV (Gonzalez, 2010). The greatest risk factor appeared to be 2 or more new partners (or partners with other lovers). In summary, new HPV infections in older women could be attributed to:
Recent sexual behavior: 21%
Past sexual behavior: 21%
Reduced immune system function: 12%
Thus, if you are an older woman who has been found to test positive for HPV as part of a routine screening, and you have no new sexual partners, it is likely a persisting, older onset infection. More investigations are needed to help understand if immune function is linked to the changes in sex hormone levels that occur at this age.
Should we rethink the new PAP smear guidelines?
The 2009 recommendations for cervical cancer screening are now:
Women over the age of 30 can now get PAP smears only every three years IF they have had three normal PAP smears in a row.
If women have risk factors (e.g., as prior abnormal PAPs), or have decreased immune functions (e.g., organ transplant recipients, HIV) they should get more frequent PAP smears.
Routine screening PAP smears should begin at age 21???not as a teenager.
Routine screening PAPs can be discontinued between ages 65 and 70 (American Cancer Society & US Preventative Health Task Force)
Women who have received the HPV vaccine to reduce cervical cancer are still subject to these standards. But as more data is gained this may be reassessed.
If a woman is low risk (e.g., fewer than three life time sexual partners, no prior history of abnormal PAP smears or high risk HPV) I believe the current PAP recommendations are appropriate. If you have known risk factors, consult with your GYN about what screening interval would be most appropriate for you.