February 7, 2012

Hooey: "Older women are more at risk if they get HPV because their bodies have a harder time clearing HPV."

This is something you used to be told if you were over 30 or 35 and turned up with a new case of HPV. I strongly suspect it's something that women are still being told, because an over-35 friend of mine who had a positive HR-HPV test and an ASCUS Pap in 2007 was told this at a well-regarded women's clinic in our city. (And! Update! It's also something I was told at a well-regarded women's clinic in our city in 2012.)

It it true? Short answer: No, it's pretty much hooey, these studies found it was hooey, and a lot of the research showing it was hooey had been published by the early 2000s. If you're being told this today, your doctor needs to go do some reading and stop scaring old chicks for no good reason.

How about the long answer?

OK, first, some vocabulary, a few basics about HPV natural history, and a reminder about the differences between Pap testing and testing for HPV.

  • "Incident infection" - A new HPV infection.
  • "Prevalent infection" - An HPV infection that is not new.
  • CIN - Cervical Intraepithelial Neoplasia. In plain English, precancerous changes to the cervical cells. CIN 1 represents relatively minor changes, and CIN 1 often regresses back to normal. CIN 2 is intermediate, and also regresses about half the time. CIN 3 represents fairly severe precancerous changes, and regresses less often. In the US, CIN 2 and 3 are generally treated by removing the affected cells, either by laser, freezing, or an electrified wire loop (LEEP). Cervical precancer treatment and overtreatment are the subject of another post. 
Basics about HPV natural history
  • After infection, HPV can cause low-grade changes to cervical cells fairly rapidly (in just a few months), or it can take a while to cause those changes.  
  • After infection, HPV can cause high-grade changes to cervical cells fairly rapidly (in 6-8 months or so), or it can take a while to cause those changes.   
  • HPV usually takes years or decades to cause cervical cancer.
  • About 70% of women with an incident HPV infection will clear the virus within 1 year, and 90% of women will clear the virus within 2 years.
  • Only persistent HPV infections can cause cervical cancer.
  • The longer an HPV infection has persisted, the more likely it is to keep persisting. The more recent an HPV infection is, the more likely it is to clear.
In visual form, high-risk HPV clearance rate over time looks like this:

Why am I using a crappy graph I drew myself with a flair pen? Mainly because if you want the real data, you shouldn't rely on me. You should go here (http://aje.oxfordjournals.org/content/158/5/486.long) and read that study, which has a good bibliography of other studies and also breaks out HPV clearance rate by HPV type. 

As you can see, if you've got a new HPV infection, you're over there on the steep part of the clearance curve, and your chances of getting rid of it pretty soon are pretty good. But if you've had the infection for 18 months or 2 years, the curve is starting to flatten out and the chances of clearing it are lower.

A reminder about Pap testing vs. testing for HPV
  • Pap tests detect cell changes.
  • Pap tests have been in routine use in the US since the 1950s.
  • HPV tests detect viral DNA. 
  • HPV tests have been in use in research since the early 1990s.
  • HPV tests have been in wide use in doctors' offices since the mid 2000s, depending on where you are and whether your doctor is an early adopter or not. 
  • Pap tests fail to detect abnormal cells between 10 and 50% of the time, depending on the lab. (The false negative rate, false positive rate, reasons for them, and inherent subjectivity of Pap testing a subject for a whole 'nother post. For now I just want to say: YOU NEED TO KEEP GETTING YOUR PAP TEST. Precisely because the Pap may not catch changes right when they happen, repeating the test every year makes it most likely that cellular abnormalities will be detected before they become cancerous.)
So, what do the current studies say about older women and incident HPV infections?

In a nutshell, they say that older women clear incident HPV infections just as fast or faster than younger women do, and that incident HPV infections are not more likely (and may be slightly less likely) to progress to CIN 2 or 3 in older women. For example:
  • Predictors of human papillomavirus persistence among women with equivocal or mildly abnormal cytology. 
  • Maucort-Boulch et al.,  Int J Cancer. 2010 Feb 1;126(3): 684-91, abstract only at  http://www.ncbi.nlm.nih.gov/pubmed/19609952 The full study is not available free, but the conclusion in the abstract is this: "We conclude that new HPV infections in older women are not riskier by the metric of viral persistence than those in younger women." The study included the following graph demonstrating that conclusion: 

See? The clearance curve for incident infections in older women is the same (or faster) than in younger women. 
  • Longitudinal Study of HPV Persistence and CIN Grade 2/3: Critical Role of Duration of Infection, Rodriguez et al., J. Natl Cancer Inst. 2010 March 3; 102(5): 315-324, full text available at http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2831050/?tool=pubmed This study is part of the pretty damn awesome Guanacaste Natural History Study, which is awesome because it had a large sample size (over 10,000 women) and extended over many years. A lot of what we know about HPV natural history, we know from this study, and a lot of what we will know in the future will be from studies that build on it. It was sponsored by the National Cancer Institute, started in 1993, and concluded in 2004. Anyway, this sub-study within the Guanacaste study is important because part of the analysis excluded HPV infections detected at the study baseline, and only looked at HPV infections that were newly detected during the study. Conclusion: Newly detected HPV infections are not more likely to persist or progress to CIN 2 or 3 in older women. In fact, if you look at study Table 4, the absolute risk of a new infection progressing to CIN 2+ was lower in the older age groups. (Nevertheless, if you read the whole study, it makes a bunch of hypotheses about "weakening immune response" in older women and "temporary loss of immune control" despite the fact that the actual study results would seem to show an equivalent or stronger immune response in older women. This whole area of hooey will be the subject of another post.)
  • Determinants of Clearance of Human Papillomavirus Infections in Colombian Women with Normal Cytology: A Population-based, 5-Year Follow-up Study, Molana et al., Am. J. Epidemiol. (2003) 158 (5):486-494, full text available at http://aje.oxfordjournals.org/content/158/5/486.long. This study investigated risk factors for clearance vs. persistence of HPV in about 2000 women aged 13-85 years. Money quote: "we did not confirm any unfavorable effect of age on clearance." However, this study selected women who were positive for HPV at the study baseline, not women who were negative for HPV at baseline and began testing positive later. This means the study probably included some women whose HPV infections were not new, but already persistent. Nevertheless, it found that older women did NOT have a harder time clearing HPV.
  • Epidemiology of Acquisition and Clearance of Cervical Human Papillomavirus Infection in Women from a High-Risk Area for Cervical Cancer, Franco et al., J Infect Dis. (1999) 180 (5): 1415-1423, full text available at http://jid.oxfordjournals.org/content/180/5/1415.long   Conclusion: Duration of infection with oncogenic (high-risk) HPV was not significantly different between women older and younger than 35 years old. However, low-risk HPV infections persisted longer in younger women.
  • Incidence, duration, and determinants of cervical human papillomavirus infection in a cohort of Colombian women with normal cytological results, Munoz et al., J Infect Dis. 2004 Dec 15;190(12):2077-87. Full text available at http://jid.oxfordjournals.org/content/190/12/2077.long     Conclusion: Duration of infection with high-risk HPV was slightly longer in older women, but duration of infection with low-risk HPV was slightly shorter.
Then where the hell did this bunk-ass theory come from?

I blame the patriarchy, but I also blame the evolution of our knowledge about HPV and the design and conclusions of earlier studies.

I blame the patriarchy because "there's something kinda inherently wrong with older women" has been a standby in sexist medicine since sometime before the first white coat. (Go take a look at materials from the Women's Health Movement from the 1970s if you're interested in this. I'm not going to Feminism 101 you and explain it all here.) It's kind of a path of least resistance for a lot of people's thinking, even when there are other hypotheses at hand.

I blame the design and conclusions of earlier studies and the evolution of our knowledge about HPV because it looks like basically, this is what happened: Studies were done about clearance and persistence of HPV. Those studies included women of various ages who were HPV-positive at study baseline. Because researchers did not yet know what the HPV clearance curve looks like, they did not realize how important it was to separate incident from prevalent infections. Because older women on average have longer sexual histories, they will, in such a study, have more already-persistent infections than younger women will. Those persistent infections kept persisting because that's what persistent infections do, and the presence of those continuing persistent infections distorted the study conclusions. For an example of this dynamic, see this well-cited study from 1994: http://www.ncbi.nlm.nih.gov/pubmed/8106758.

Is there a grain of truth in the idea that high-risk HPV infections are more concerning when they're detected in older women?

Yes. If you're over 30 and have never been tested for HPV before, a positive HPV test could represent a new infection, or it could represent an infection that has persisted for decades. With no prior testing, it's not really possible to know. Even if you've had normal Pap tests before, it could be that you've had HPV for a long time because Pap tests only detect cellular changes, Pap tests often miss cellular changes even when they are present, and HPV can take a long time to cause cellular changes.

So a first-time HPV test that's positive in an older woman can represent either an incident infection or a persistent one, and deserves to be treated with more care than a positive HPV result in a younger woman. (Although there's also something to be said about your own knowledge of your sexual history--if you've just started dating after a 15-year marriage to your extremely monogamous high-school sweetheart, your conclusion that it's a recent infection is probably pretty solid.)

However, with more and more doctors following the recommendation that women over 30 get an HPV test with their yearly Pap, more and more women over 30 have a track record of prior negative HPV tests. In those women, a new positive HPV test is in all likelihood a new infection, and according to the studies above, isn't any more worrisome or likely to persist than a new infection in a younger woman.