February 11, 2009
At CROI 2009, I had the opportunity to sit down with Joel Palefsky, M.D., a prominent physician/researcher in the area of cancers related to human papillomavirus. We discussed an important study he presented at this conference regarding the link between anal intraepithelial neoplasia and anal cancer, and also talked about the methods by which these lesions can be prevented and treated.
Could we begin by you talking a little bit about what you do in San Francisco?
I'm a professor of medicine trained in infectious diseases; my primary interest is in human papillomaviruses, HPV, which is the most common sexually transmitted agent. I'm very interested in the diseases associated with HPV that have the potential to progress to cancer. This is a problem of particular interest in inmmunosuppressed people, especially HIV-positive people.
Much of our work is in doing clinical studies of HPV infection and its consequences in HIV-positive men and women, in studying the interaction between the two viruses in the laboratory, and in putting effort towards trying to understand how they interact to cause more of a problem than you'd get in an otherwise healthy person.
What did you present here at CROI?
At CROI, we were dealing with one of the key questions that remains in terms of trying to understand the significance of one of the findings that we've made over the years: What does it mean to have a lesion called high-grade anal intraepithelial neoplasia, or HGAIN?1 In the cervix, the equivalent of this is known as cervical intraepithelial neoplasia, or CIN. It's well known that this is a lesion that has the potential to progress to cervical cancer. We have a pap smear screening system in place now, which is designed to detect the high-grade version of CIN, to treat it before it can progress to cancer. That's why women have colposcopies and biopsies and ultimately [receive] treatment. This system has been very, very successful to reduce the rate of cervical cancer. That's the reason why women get their pap smears annually or every other year.
How is cervical cancer related to HPV?
It's caused by HPV, just like it is in the anus; it's the same strains of HPV, the most common of which is called HPV-16.
Over the years, we've taken the lessons that we've learned in the cervix and shown that the same problem exists in the anal canal. Since a high proportion of men who have sex with men [MSM] have anal intercourse, we suspected that HPV infection might be common. The equivalent of CIN, which is AIN, might be common, too.
We have found, in fact, that it is very common: Nearly all HIV-positive men who have sex with men have anal HPV infection. Over 60% of HIV-negative men who have sex with men have anal HPV infection. A high proportion of HIV-positive men have high-grade AIN -- over 50%, in fact.
I've read that you don't really need to have engaged in anal intercourse to have HPV in the anus.
That's true. In women, that's clear. We don't really know in men, since such a high proportion of MSM have had anal intercourse at least once. So from an epidemiologic standpoint, it's hard to tease that out. But we know in women that you can have anal HPV infection in the absence of anal intercourse -- though we think that anal intercourse is the most efficient way to get it. In fact, we've shown that there's more anal HPV in HIV-positive women than there is cervical HPV infection.
Is this due to "migrating" HPV?
It's due to anal intercourse, and some degree of migrating from the cervix, and some degree of what we call in medical-ese "foamites". Namely, carrier status of an inert object -- such as a finger, for example: It's possible that if a person touches a genital region of themselves in an infected area, or an infected area of a partner, and then touches somewhere else where there isn't HPV infection, it can spread it. Having fingers in and around the opening of the anus is very common in the course of sexual relations, so it's possible that fingers could also transmit HPV to the anal canal.
What's the likelihood? You said it's possible, but has it been proven?
It's not been proven, and it's very hard to study.
I would imagine.
But since we know that some people with anal HPV infection have never had anal intercourse, there are only so many other possibilities for how it could have gotten there. We know that people can auto-inoculate.
What are the recommendations in terms of preventing this? Are people getting anal pap smears?
People are not getting anal pap smears yet, and that's really coming back to why we did this poster. The issue is that people don't really know what the meaning of this high-grade AIN lesion is. Does it have the potential to progress to cancer or not? If it does, how do we best treat it, and can we prove that the treatment reduces the incidence of anal cancer, as has been shown in the cervix? Some of these pieces of information have not yet been obtained, and in the absence of that information, some individuals feel that it's not appropriate to make generalized recommendations for anal cytology screening, like we have in the cervix.
One of the things we're trying to do in our group is plug the gaps in information so we can make the case for screening -- which we, in fact, already do in San Francisco, because we feel that it is the right thing to do. Nevertheless, there are legitimate reasons to want to have all the information possible before embarking on this because it will be intensive, in terms of labor, required training and some expense.
What we set out to do in this poster was provide more information showing, in fact, that the high-grade AIN lesion is the true precursor to anal cancer. In our clinic -- the UCSF neoplasia clinic -- over the years, we followed many people and looked through our records of the last 10 years to find people who've developed anal cancer. Then we went to their medical records to see if we had ever diagnosed a high-grade AIN lesion in the exact area where the cancer actually developed.
In fact, we found about 65 cancers overall in the population that we studied, and of those, it was clear that the high-grade AIN lesion was the source of the cancer in about 23 of those people. The other people, we simply couldn't document it.
This is the very first proof, in fact, that high-grade AIN can progress directly to anal cancer. There have been a few scattered reports of people who have high-grade AIN who are then shown to have anal cancer later, but they were not followed prospectively to show that it was that area of disease, high-grade AIN, that actually progressed to the cancer.
With this kind of information, we feel that we're adding a little bit more to the argument that treatment of high-grade AIN may be useful to prevent the cancers. We still have lots more work to do: We have to show that we can successfully treat the high-grade AIN, and we need to ultimately demonstrate that that treatment reduces the incidence of cancer.
Is yours the only clinic of its kind in the country?
We were the world's first clinic devoted to AIN, and we've been training a lot of people since then. There have been others springing up around the country. Some of them have been designed just for clinical care, others just for research -- particularly in the setting of the AIDS Malignancy Consortium, which is another one of our major activities.
Do you expect there will be recommendations that get people anal pap smears in the future?
There already are. The state of New York, actually, is the very first to officially recommend anal pap smears for HIV-positive men and women. The problem with that is that, like in many other places, there isn't sufficient infrastructure to really allow for the full spectrum of services to be provided. The pap smear is really only the first step. Once you have the pap smear, you need to do an anoscopy to show where those abnormal cells in the pap smear came from. Then you need to biopsy the abnormal areas that you see. Then you need to treat those areas.
The anoscopy, the biopsies and the treatment are procedures that require quite a bit of training. There's a substantial amount of infrastructure that's required to fully take care of patients. So I applaud the state of New York for taking that first step, but we really need to develop the full infrastructure, to allow it to be implemented properly.
In terms of treatment, what happens if somebody is found to have an AIN lesion?
There's no specific treatment for the causative agent, such as HPV, so what we're stuck with is physical removal of the AIN lesion. Usually by any number of methods, but most of them are done in the office. It could be as simple as applying 85% trichloroacetic acid, TCA, which sounds awful because it's got the word "acid" in it, but it's actually very well tolerated by patients. More recently, we've been using a technique called infrared coagulation, or IRC, which involves putting a light probe into the anal canal under direct visualization, touching the tip of this light probe to the lesion, and delivering a pre-specified amount of energy. It kind of burns the tissue a little bit, but it's also very well tolerated because we put some local anesthetic in and most patients actually go right to work after the procedure.
That clears it up?
In many cases. It does sometimes require repeated applications after time, but we can clear up at least 70% or 80% of them within two or three applications of this technique.
How many places in the country are doing this technique?
It's still limited, but we're training people. We train people through our affiliation with the ASCCP, the American Society for Cervical Colposcopy and Pathology, where we have courses in high-resolution anoscopy. People come to our clinic, as well, to watch what we do, and there are increasingly others around the country who are experienced enough and training others, including in New York City.
It sounds like there's a lot progress still to be made.
This is really the beginnings of understanding the disease, I think.
The other important thing to understand here is that anal cancer is a relatively uncommon cancer, but in the population that we're concerned with -- HIV-positive MSM and women -- it's not an uncommon cancer. In fact, in HIV positive men who have sex with men, the incidence is roughly 10 times higher than the incidence of cervical cancer in the general population of women. These are numbers that we would not consider acceptable in women, and I feel like we ought not to consider them acceptable in anybody.
Do you feel, at a conference like this, that a lot of clinicians are aware of all this?
I think that it's happening more and more. At the early stages of the epidemic, people were rightly more focused on more immediate issues, such as surviving HIV infection itself and some of the opportunistic infections. Now that we're in the ART [antiretroviral therapy] era, the focus is shifting more to the chronic complications of HIV infection. This is sort of the perfect storm of that.
We know that it may take many years to go from high-grade AIN to cancer, and in the past, this wasn't as big an issue because people didn't live long enough. But now that people are surviving, and surviving in a healthy manner, and not being screened for their high-grade AIN, they now have the opportunity for that lesion to progress over time.
This is a preventable cancer. We haven't proven that yet, but we're pretty confident that it's preventable. So, people are now starting to pay more attention. Along with the fact that, as we predicted long ago, the incidence of cancer would go up in the ART era, for the reasons that I just mentioned -- as opposed to down, which is what we've seen for some of the other HIV-related cancers, like Kaposi's and non-Hodgkin's lymphoma. There's a number of recent publications showing that the incidence of anal cancer may be as high as 137 per 100,000, as compared with, for example, eight per 100,000, which is the incidence of cervical cancer in the general population.
If people want to get either checked or need treatment, I understand you have a Web site?
We do have a Web site: it's www.analcancerinfo.ucsf.edu. We have information on that Web site for providers as well as for patients, and we have a list of people who've trained with us -- though that list may or may not reflect the group that's actually doing the procedure in their own location. There's a lot of general information about the disease and what we know about it at this point.
I also strongly urge people who are interested in this disease to consider participating in some of the clinical trials run by the AIDS Malignancy Consortium, where we're trying to determine better treatments for the high-grade AIN, and also how to better prevent it.
You asked about prevention. One way is through condoms, which -- in the cervix, at least -- have been shown to prevent up to 70% of infections, when condoms are used 100% of the time. That's OK, but not great. Abstinence. [Laughs.] Not great. It may be that the long-term solution to this problem, ironically, may be the HPV vaccine.
But it's not available for men.
It is not available for men yet, but we've just completed a study of the vaccine in men, and the study will be coming out soon. The anal cancer is caused by the same types [of HPV] that are [prevented by] the vaccine for women. It could be that the vaccine, if given to men -- particularly before they become sexually active, because the vaccine only prevents initial infection -- might actually be the long-term solution to preventing anal cancer. If you don't get the virus, than you don't get the cancer.
Thank you very much.