Human Papillomavirus in Cervical Screening

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Dr. Jack Cuzick:  "Thank you to the organizers for giving me a chance to talk about some of the work we’ve been doing in terms of looking at new approaches to screening for cervical cancer.  I think possibly the first thing one has to ask, given that we’ve got the Pap smear which we know is reasonably effective, is why would we want to entertain any kind of new screening test at all?  In the UK we had a screening program which was introduced around 1960-1965 with virtually no effect on cervical screening mortality, it was decreasing by about 2% per year for a long time and carried on doing so until it was reorganized to be a very active program with call and recall in quality control in the late eighties at which time we got a very, very rapid reduction in mortality.  So if you’re going to do cervical screening you actually have to do it extremely well to get the results, and we’ve now got about a 50% reduction in the UK based on a very high quality program but a screening program not done well has had no effect and it really has to be very intensively done.  

The other thing that’s interesting is that if you look in Scotland where the program was actually well organized from the beginning, they got very early and rapid reductions in mortality but in fact down to, as Dr. Nazeer said, about a 60%-70% reduction, and since that time there’s been pretty much a flattening, in fact, there’s a valley there.  That data has not gone any lower and, in fact, it suggested that by screening with Pap smears it was able to get rid of about 60%-70% of cervical cancer but not really much more.  

In a recent audit of the British program we’ve actually found now that with the success we’re having of the remaining cancers, about half of them have completely normal Pap smear histories and half of the cancers in women under the age of seventy are actually occurring in women who have been apparently completely well screened.  Why think about HPV testing?  I think the obvious reason is it is now absolutely clear that the human papilloma virus actually is the cause of cervical cancer, and a most conservative estimate you could possibly come up with says that 90% of cervical cancer is associated with the human papilloma virus.  Very detailed studies have shown that it’s more like 99% but just using routine tests a whole range of studies have shown well over 90%-95% of all the cancers are caused by this virus.  So if you’ve got a cause of the virus it’s an obvious thing to screen for.  

Now, I guess about a year ago we were asked by the British government to actually review the evidence on the role of HPV testing in cervical cancer and, in fact, we produced this 200-odd page report for the Health Technology Investigations looking at reviewing all of the data looking at the role of HPV testing in a cervical screening program.  Basically, there are really three possible roles; the one that I think is most clearly established is in the management or triage of borderline and mild smears where, as you know, about 5% of smears in the UK and really worldwide have got these very minor ASCUS or borderline changes.  HPV positivity associated with that is the basis for rapid referral.  For HPV negative, they’re more likely to be reactive changes, which can probably be ignored.  The other possible role which hasn’t been as fully established is looking at post-treatment surveillance of women who have had CIN-3 diagnosed and treated to determine more quickly whether or not there’s been complete excision of the lesion and to reduce the surveillance if that is clear.  The idea here is that almost all of these lesions are HPV positive initially, and if they go HPV negative after treatment, that’s a very good indication that they’ve been completely excised.  If they remain HPV positive, there’s probably residual disease that needs to be attended to.  I want to show you briefly some of the conclusions of that report and that is the clearest role for HPV testing is in the management of women with borderline or mildly dyskaryotic smears and mildly abnormal smears.  That was one of the first major conclusions of this project.  

Now the more exciting role of HPV and the more challenging one is what is the role of HPV testing in primary screening that is not to follow-up on a mildly abnormal smear or in management but to actually look at its role in primary screening?  There are a number of possible ways of actually using it in primary screening, either as an adjunct to cytology that is to do HPV testing in addition to the Pap smear to improve your sensitivity, and we know that we’ll get better sensitivity clearly if you do both of those.  One of the problems that is certainly apparent in Britain and many countries is that the Pap smear itself has an inadequate rate of the order of about 8% or 9%, which doesn’t occur with HPV testing so women who have an inadequate Pap smear can be evaluated strictly on the HPV test itself.  

Another area, which I think is terribly important particularly in terms of cost is that if you have a better test you can screen less often and that adding HPV testing to the Pap smear offers the possibility of extending the screening interval; in the UK possibly from three years to five years, in the U.S. maybe from one year to three years.  I think you have to go step wise and in parts of the developing world maybe from five years to ten years or just once in a lifetime.  Also, there’s the possibility of self-sampling, and in some cases it improves coverage, women who don’t want to come for a smear may well be able to take a sample at home.  I want to review briefly some of the evidence on the data that’s available concerning the role of HPV testing as a primary screening technique.  

We did the first study in 1995, and it was published in the LANCET.  Even using some of the older tests, not the more modern ones, we found very striking evidence that HPV picked up substantially more disease than the Pap smear.  The Pap smear, in fact, even if you went right down to ASCUS was only picking up about half of the high-grade lesions in this younger population.  Half of the CIN and TCIN-3’s were actually negative on cytology, and in this study we only looked at four HPV types - 16, 18, 31, and 33 and there we picked up 75%.  Now with the more modern tests the sensitivity is substantially improved, in particular, using either what’s called consensus PCR or the Hybrid Capture micro-teacher second-generation test.  The sensitivity is extremely high, and this is just a list of studies, which are being added to almost monthly in comparison of the sensitivity of HPV testing.  That is how much high-grade lesions it picks up compared to the Pap smears and high-grade lesions are either HSIL in the American Bethesda or CIN, TCIN-3 in the more classical studies.  Now a number of studies are all showing uniformly that the sensitivity for HPV is substantially higher than the Pap smear and on average is running about 90%, so 90% of the lesions are actually being picked up by HPV as compared to only about two-thirds by the Pap smear.  We clearly have a more sensitive test here.  

I think a general principle which should be apparent in all screening is that much of the cost of the screening is actually the doctor’s time and the patient’s time to come to get screened, and if we’re actually going to do screening and go out into the population and inflict, if you like, a new test on individuals or offer a new test, it really should be the best test you possibly could employ, and ideally it should be done infrequently.  One approach that we’ve been looking at in another area, for example, in colorectal cancer screening is a once in a lifetime sigmoidoscopy to try to prevent colorectal cancer.  Ideally, you want to do a very good test and you want to do it infrequently, and HPV would appear to offer improvements over the Pap smear in terms of that particular issue.  

Now the next two conclusions - we actually do ten conclusions but we won’t have a chance to show them all to you - is that I think it’s fairly clear from the data that HPV testing with either a conscientious PCR method or the Hybrid Capture second generation has a very high sensitivity for high grade CIN, in fact, virtually always exceeding that of cytology and certainly identifying cases missed by cytology so it clearly is a more sensitive test.  If you’re going to screen and do it well, you should actually use the best test you’ve got.  But we do acknowledge that there is still a weakness that needs sorting out and that is HPV testing that’s currently done is less specific than cytology so you get more people who are what are called false positives.  They are actually positive for HPV but they don’t actually have a high-grade lesion.  It’s about 3%-10% of normal women aged over 35 and when you go to younger women, that just about doubles anywhere up to 20%-25% of younger women are HPV positive.  Now, again, I think it’s useful when thinking about screening to try and think about the natural history of the disease.  Basically, I think this is a simple sort of schema of what’s going on with cervical cancer.  We start out with an HPV infection which is extremely common, most of those infections actually regress spontaneously over 6-9 months and have nothing whatsoever to do with cancer.  But for reasons which are undoubtedly due to immunological factors but we don’t really fully understand, about 10% of these cases will actually go on to develop a persistent HPV infection.  

Once you’ve got a persistent HPV infection, then it really is just a matter of time until you get cervical cancer.  Eventually the oncogenic proteins that these viruses produce will lead to failure and dis-regulation by interfering with P53 and VRB mechanisms for cellular regulation, and that will lead to high-grade lesions and eventually cancer.  There may be important carcinogens such as smoking, which we don’t know so much about but the key step really is developing this persistent infection.  The best data for that are those from Dr. Meir’s group looking at women who had either persistent infections, and you can see all of that progression of disease, but basically, all of the high grade disease and progressive disease were in women who had persistent HPV infections.  I think all but four of them were in that group and the four other CIN-3’s were actually in women who were negative originally but developed an HPV infection with a high-risk type which went on to then become CIN-3 in a short time.  So persistent viral infection with a high-risk type of HPV is the crucial factor in cervical cancer.  

Now one of the other issues that needs to be dealt with and we’re currently doing a trial, I’ll show you the schema here, which is ongoing to look at 12,000 women.  We know that many of the infections are actually going to be transient and we’re looking particularly at women who have borderline or cytologically negative lesions, which are HPV positive to try to learn how best to manage those.  I think the outstanding question in HPV testing is whether or not those women can actually be followed-up for 6-12 months to see whether or not the HPV regresses or whether it’s more efficient to refer them immediately for colposcopy and simply have a look, and that’s essentially the focus of our current study.  

So just to come to some of the final conclusions, one of the things that I think comes out is the fact that the sensitivity has now become so high for HPV testing that it may not be necessary to use cytology at all in the initial testing, the potential exists, certainly not fully proven yet but using HPV as the sole method of primary screening particularly for older women.  For younger women, many of those infections are going to be transient and it’s probably going to be necessary to follow the HPV tests with cytology to see whether or not they need immediate referral or whether or not they can be followed-up by repeat HPV testing at six months to a year but this is an area where the recommendation was that more research is needed to actually determine how best to manage these women.  One of the other conclusions that we drew, and I think this will be talked about a bit more in the next talk, is that HPV testing has the potential to be used in self-collected cervical samples.  This could improve coverage in reaching those that are not in participating screening programs and offers a whole new approach to screening in general.  The conclusions were the sensitivity of self-sampling should be evaluated, since the publication of that, there have been some results showing that it really does work pretty well, and I’m sure we’ll hear more about that, and looking at ways to build this into a screening program seem highly warranted now.  

Finally, I want to point out that HPV testing really is something that can be done quite simply instead of having to have trained specialists looking through microscopes for very subtle changes on cytology.  We simply have a robot here, which does all of the work.  This is just simply a Beckman robot that does virtually all of the work and the results are essentially analyzed type output and anybody can see which ones are positive although you can get an actual quantitative output by putting those through an analyzer reader.  This is basically a micro-teachable output, you get a yellow color when there’s HPV present and these are the four positive controls.  Even from this very acute angle, I can see which ones are positive.  I hope you can see much more clearly.  If you want to get an estimate of viral load that’s really quite easy as well by just putting those through the analyzer reader.  

Lastly, just to sum up where I think we stand now with HPV, in terms of the ASCUS borderline cytology, our recommendation was that there should be limited implementation with full evaluation that the evidence is really strong enough now that we don’t need to do big studies to look at the results of that.  Subsequent to our report, the old study has come to the same conclusion in the United States that it’s time to be getting on with using HPV testing in the ASCUS environment.  The primary screening area really is still a research area, there’s a need for a large trial, key issues of whether or not HPV testing can be the primary test by itself or whether it needs to be used as an adjunct to cytology, and only a big trial will give us answers to that.  We need to do some modeling to look at the best ways to use HPV testing with cytology.  In the area of post-treatment surveillance, there needs to be some more focus studies, there hasn’t been a lot of good work in that area.  What we’ve seen looks good but that needs to be looked at a bit more carefully, and lastly, we have to recognize that HPV isn’t the only new technology.  These big trials need to look at its role in conjunction with new technologies and particularly liquid cytology which makes HPV testing much easier to do, you don’t need to take an extra sample.  But these things all need to be put together now and evaluated really very fully.  But HPV is moving along really quite rapidly for a new test and looks very exciting.  

Thank you."