February 2, 2012

Hooey: "HPV Vaccines don't work if you've already been exposed to HPV."

If you rely on news sources and health websites for your information, you've probably heard that the HPV vaccination is "less effective after a person is sexually active," or "does not work for women already exposed to HPV."

Is this true? Short Answer: No, it's pretty much hooey. Is it important for young women to consider vaccination before they become sexually active? Yes. Does this mean the vaccines don't work for older women or women who have been exposed to HPV in the past? No.

While neither Gardasil nor Cervarix will help clear a current active HPV infection, both Cervarix and Gardasil are effective at preventing future HPV-16 and -18 infections in women previously exposed to HPV-16 and -18, and previously exposed women have a strong immune response to the vaccines. Gardasil reduced the incidence of persistent future HPV infections by 86.1% in previously-exposed women over 35, and Cervarix reduced those infections by 95.8% in women of all ages.

So, even if you are older, have a lengthy sexual history, or have had HPV-related cervical abnormalities before, you may want to consider HPV vaccination if you are currently testing negative for HPV-16 or -18 and anticipate new sexual partners. In fact, this may be even more true if you're over 35, because natural immunity to HPV wanes over time.

How about the long answer?

As usual, after the jump.

As usual, some background and vocabulary, because to understand what it means for these vaccines to be effective in women previously exposed to the HPV strains they cover, you need to understand what's meant by "effective" and "exposed." It also helps to have some understanding of how natural immunity to HPV works (or doesn't work).

The background...
When you are "exposed" to a particular strain of HPV, usually an infection develops. In the vast majority of cases, that infection can be detected by tests that look for HPV DNA in a tissue sample or Pap smear. (This is the "HPV test" you get at your doctor's office.) Then, within about two years, 90% of infected women "clear" the virus, and it is no longer detectable via a DNA test of cervical or vaginal tissue. Some portion of infected women, but not all, also develop antibodies to that strain of HPV. Antibodies do not help clear the virus, but they can provide some protection against future infection. (Although as we'll see, this protection from natural immunity is not very strong or effective.)

Antibodies are also strain-specific--even if you do develop antibodies to one strain of high-risk HPV, those antibodies will do nothing to protect you against a different strain of high-risk HPV. So if you've heard from your doctor that "you've probably already been exposed to HPV and you already have antibodies," that's hooey. Even if you do develop antibodies, you'll only have antibodies to the particular strain(s) you were infected with--NOT all high-risk strains.

Most studies show that slightly more than half of women infected with high-risk HPV will develop antibodies to the strain they are infected with. That means that the other half will not develop antibodies, and will have no protection against reinfection with the exact same strain in the future. Women who rapidly clear an infection with high-risk HPV are even less likely to develop antibodies against future infection.

Even when antibodies develop, those antibodies are not particularly long-lived--some studies show that they persist for an average of only 3 years. They are also relatively weak--other studies have shown that for most women natural immunity is often too weak to prevent reinfection with the same strain of HPV, even in people who still have natural antibodies to that strain--only the women with the highest level of natural antibodies are well-protected from reinfection. These studies and others have led some researchers to conclude that "natural immunity does not play a role in controlling the extent of reinfections." (Others are more guarded and just say natural antibodies are of "uncertain effectiveness.")

(What studies say about HPV and men will be the subject of a whole 'nother post, but it looks like men develop even lousier natural immunity to HPV than women do. One study published 2011 found only a minority of infected men ever develop HPV antibodies at all. Then a different study from 2012 found no relationship between the presence of HPV antibodies and HPV reinfection in men--meaning that even when men develop natural antibodies, they don't really do 'em any good.)

...And the vocabulary...
  • If you have a currently detectable HPV infection in your genital tract, you have been "exposed" to that strain of HPV, and you are also "DNA positive" for that strain of HPV.
  • If you have antibodies in your blood to a particular strain of HPV, you have been "exposed" to that strain of HPV, and you are also "seropositive" for that strain of HPV.
Note that because not everyone infected with a particular strain of HPV ever develops antibodies, you can be DNA positive for that strain without ever being seropositive for it. And because HPV infection can clear from the genital tract, if you do develop antibodies, you can later be seropositive for that strain without being DNA positive for it. Or you could be both DNA positive and seropositive, if you had a current genital tract infection to which you had developed antibodies, but which had not (yet) cleared. Or, you could be infected with HPV, be DNA positive, and then later be both DNA negative and seronegative if you cleared the infection and never developed antibodies to it.

...And a couple of key facts about the currently available HPV vaccines, Gardasil and Cervarix.
  • The HPV vaccines create antibody levels at least 10 times higher than natural immunity. This means they do a better job of preventing infection with HPV, and they also last longer than natural immunity--for Cervarix, over 7 years so far, as opposed to 3 for natural immunity. 
  • The HPV vaccines do not help your body get rid of an HPV infection you already have. So if you are DNA-positive for one of the vaccine strains, the vaccine won't help boot that infection out of your body any better or faster than if you had no vaccination at all. But it will give you antibodies to that strain, and those antibodies will be stronger and longer-lasting than the ones you might develop naturally.
So wait, weren't we talking about whether HPV vaccines work if you're already exposed?

Yes, but I'm not going to use the word "exposed" anymore because it's imprecise. I'm going to use the terms "seropositive" and "DNA positive."

Neither HPV vaccine seems to help clear an active infection with HPV. So if you are DNA positive for a particular strain of HPV, the vaccine will not help you clear that strain and will also not protect you from disease caused by your current infection with that strain.

However, if you are seropositive but not DNA positive for the HPV strains covered by the vaccine, both vaccines offer pretty darn good protection against reinfection with that strain. The vaccines are not as effective in seropositive women as in women who have never been exposed to HPV, but that is not because the vaccines don't effectively stimulate your immune system to prevent infection with the virus--they seem to work fine that way. It's because vaccine effectiveness is measured by comparing two groups of women--one group who got the vaccine, and one group who didn't.

To measure vaccine effectiveness in seropositive women, you compare the rate of new HPV infection in vaccinated seropositive women with the rate of new HPV infection in unvaccinated seropositive women. However, some seropositive women have some residual immunity to HPV (not all of them, and not great immunity, but some). So when you compare vaccinated women to unvaccinated women, the vaccine will always have lower effectiveness for seropositive women than for women with no HPV exposure, because the unvaccinated seropositive women already have some immunity from their natural antibodies.

And that's roughly what you see in the Gardasil study of vaccine effectiveness in seropositive women. Take a look at Table 6. Now, one thing that sucks about this study is that the number of subjects ultimately wasn't large enough to get much statistical power in the conclusions (the authors acknowledge that toward the end of the writeup). So, for example, in seropositive women 35-45 years old, there was 1 persistent infection out of 139 women in the vaccine group, and 8 persistent infections out of the 158 women in the placebo group. That gives a vaccine effectiveness of 86.2%, but because the sample size is so small, that could be due to chance.

But another interesting pattern is in the vaccine effectiveness for older seropositive women as compared to younger seropositive women--among younger seropositive women, there were 2 persistent infections among the 145 women in the vaccine group, but only 3 persistent infections among the 154 women not receiving the vaccine. So for these women, the vaccine ends up being much less effective than for older women, mainly because the unvaccinated women aren't getting many infections. Again, the numbers are not large enough to draw really firm conclusions, but this is pretty consistent with the studies that show HPV immunity fading quickly over time.

What's the take-home message?

If you aren't currently testing DNA positive for HPV-16 and -18, both HPV vaccines can substantially reduce your chances of contracting or re-contracting these types in the future. In fact, even if you are currently testing DNA positive for HPV-16 and -18, the vaccines will do a better job of preventing future reinfection than natural antibodies (because remember, only about half of infected women ever develop antibodies, and even for those who do, they only last an average of 3 years and don't do a great job of preventing reinfection). Depending on your sexual history, sexual plans, and your tolerance for vaccine risk vs. HPV risk, vaccination could be something to consider even if you're older or already have known HPV exposure.

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