February 16, 2012

Hooey: "You can't get strain-specific testing for HPV." You can, and you might want to consider it.

When I first started looking into HPV, I read multiple places that genotyping or strain-specific testing was not commercially available. Then, when I asked my gynecologist to do an HPV test, the results came back listing four specific strains of HPV (31, 56, 66, and 83). Voila. I'd gotten genotyping without even asking for it.

So, "You can't get strain-specific testing for HPV" seems to be pretty much hooey. You can, you might get it even if you don't specifically ask for it, you probably can get it if you do ask, and there are some good reasons why you might want it. 

As usual, a bunch of geekery after the jump.

HPV is not one virus. It's hundreds.

Discussion of HPV testing or the HPV vaccine often talks about HPV as if it were just one virus. So there's "the HPV test" (what Digene wants us all to call their 13-strain high-risk HPV test), or "the HPV vaccine" (what Merck wants us all to call their 4-strain HPV vaccine). 

But HPV is not one virus. There are hundreds of genetically-distinct types of HPV that can infect human skin, and 40-some-odd of those are known to infect the human genital tract. Of those 40, somewhere between 13 and 20 or so are considered "high risk" strains capable of causing high-grade cervical dysplasia (HSIL, CIN2, CIN3) and cervical cancer. (Why is the number so approximate? Because there's a lot of disagreement about the risk profile of certain strains, and research is ongoing.) The rest of the strains are considered "low risk." Some "low risk" strains, notably HPV-6 and HPV-11, cause genital warts. Others don't do much of anything. Others can cause low-grade cervical dysplasia (LSIL, CIN1), but not advance to high-grade dysplasia or cancer.

Most "HPV tests" test for a grab-bag of high-risk HPV types. 

Most FDA-approved HPV tests detect a grab-bag of high-risk HPV types. These tests will not tell you which particular strains you have, only that you have one or more of the 13 or 14 strains they test for.
  • The Digene Hybrid Capture 2 DNA test detects HPV-16, -18, -31, -33, -35, -39, -45, -51, -52, -56, -58, -59, and -68. 
  • The Cervista HPV HR test detects the 13 strains covered by the Digene test, plus HPV-66. 
There are also a couple of FDA-approved HPV tests that do genotyping for HPV-16 and -18, but not any other types.
  • Cervista HPV 16/18 does genotyping for HPV-16 and -18 only. 
  • Roche's Cobas 4800 HPV test detects the same 14 grab-bag types detected by Cervista, but simultaneously genotypes for HPV-16 and -18. 
Why HPV-16 and -18? Together, they're responsible for about 70% of cervical cancers. HPV-16 is both very strongly oncogenic (cancer-causing) and fairly common. HPV-18 is fairly strongly oncogenic, and also tends to cause adenocarcinoma (cancer of the glandular cells lining the cervical canal) in addition to squamous cell cancer (cancer of the mucus membrane on the outside of the cervix). Because of its location, adenocarcinoma is not as easily detected by Pap smears, adenocarcinoma incidence is rising.

There are commercially-available genotyping tests.

There are commercially-available genotyping tests that can detect individual high-risk HPV strains. These include:

These tests are not FDA-approved. Frankly, I can't tell what the hell that means, aside from the fact that the labs or companies offering them haven't spent the time and money to productize the test and put it through the FDA's approval process so that they can make specific claims when marketing the test. Most of them have good research comparing their accuracy to other testing methods, and the test I was given was offered by a local pathology lab, was billed to my insurance, and my insurance paid it, so FDA approval doesn't seem to make any difference there. 

Why you might want a strain-specific or genotyping test. 

There are several reasons why you might want genotyping rather than a grab-bag test. As with so much, what kind of testing makes sense for you depends on your sexual history, your priorities, and your sexual plans.

  • You might want genotyping because you want to know if you have really high-risk HPV, or only kinda high-risk HPV. The 13 or 14 different HPV strains in the "grab bag" test vary considerably in how likely they are to cause dysplasia or cancer. For instance, if you have HPV-16 and an ASCUS Pap, some research shows that your risk of having CIN3 within 2 years is almost 40%. For HPV-31, that risk is about 15%. For HPV-51, that risk is only 5.6%. For HPV-56, it's 1.9%. I can think of a lot of life circumstances where this information could make a difference. Travel plans? Deciding whether to have new sexual partners? And frankly, if you're an anxious person at all, knowing that you might have HPV-16 but you don't really know? Extremely unhelpful. 
  • You might want genotyping in order to know whether you have a persistent infection or not. Let's say in 2008 you have an ASCUS Pap and they run a grab-bag test and it's positive. Then you have a couple of normal Paps, but your clinic doesn't do an HPV test with those because they don't do HPV testing with a normal Pap and you didn't ask. In the meantime you break up with one sexual partner and start a new relationship. Then in 2011 you have another ASCUS Pap, they do another grab-bag test, and it's HPV positive. At this point, two things are possible: 1) You've had the same strain of HPV for three or four years, meaning you have a persistent infection (and persistent infection is a necessary precursor for cervical cancer); or 2) You had a transient infection in 2008, your body cleared it, and you have another transient infection with a different strain now. With the grab-bag test, you have no way of knowing which situation you are in. 
  • If your Pap is normal, some clinical organizations recommend you be referred for colposcopy if you are positive for one of the higher-risk strains. (HPV-16 or -18, although research also suggests close monitoring of infections with HPV-31 and -45.)  This is because Pap smears often miss cellular abnormalities, and "National Cancer Institute studies have shown that women with HPV types 16 and 18 have about a 20% risk of progressing to CIN3 over 10 years despite negative Pap tests.

Why we're offered these grab-bag tests instead. 

They're cheaper. They're automated. Because they're FDA-approved, they're allowed to market, which means they're allowed to make all kinds of claims to physicians and lab managers, including things like claiming that their lower sensitivity (they will detect infections at about 5000 viral particles per ml of sample, as opposed to PCR-type tests, which can detect as few as 10-50 particles) is better because only such infections are "clinically relevant." That seems to be hooey--I can't find any research indicating that 5000 particles/ml is a clinically meaningful cutoff. It's just the cutoff the grab-bag tests happen to have because of the technology they use. (In fact, some research seems to show that viral load is highest in early infection and CIN1, dropping off as disease develops and advances to CIN3, meaning that infections with a lower viral load might actually be more dangerous. As with so much, this is an area of ongoing research.)

There's also the fact that these tests were the earliest market entrants, and most of them require labs to buy test-specific equipment, which creates a sunk-costs situation where the lab has an incentive to keep marketing and performing the test. If your doctor relies on the lab for information about what tests are "clinically useful," and the lab's invested a shit-ton of money in specialized equipment to run one of these grab-bag tests, then guess what tests the lab will say are clinically useful?

Finally, there's the "don't worry your little head about it" factor. As with so much else about HPV, there seems to be a philosophy that less patient information is better. The message is: Don't worry your little head about your specific risks, don't worry your little head about how long you've had this infection. It doesn't matter. If anything bad happens, we'll cut it out and you'll probably be fine. (Never mind that you might not feel so great about having a chunk of your genitals lopped off--what's with this abnormal attachment to your lady bits? Sheesh.) There's no reason for you to change your sexual practices, or change your screening frequency, or change your diet, or do anything to exercise any control over the situation. That's not really your business as a patient. Just leave it up to us. 

1 comment:

Anna said...

Thanks so much for this blog. I write a lot about HPV myself, and while I try to keep up with the research, there is SO much of it! The links you provide to relevant studies are incredibly helpful.