Keith Sigel: I don’t think inflammation specifically was a big component of what we were investigating here. Chronic inflammation and even local inflammation do appear to contribute to many of the comorbidities, including cancer, that we’re seeing in people living with HIV. I do think it could be a contributor for these HPV-associated cancers. It’s probably less of an issue than just this immunosuppression that Kevin was alluding to—or maybe immune dysfunction that we think is leading to persistence of HPV, and that this persistence of HPV is probably a big component of a lot of different components that are driving both precancer and cancer, specifically in the anus.
Wilder: Probably in the general public, however we define that, people—and even clinicians—probably think that maybe men who have sex with men may be more at risk for HPV-related anal cancer than women. What should health care providers do in clinical practice to be thinking about women with HIV, in terms of anal cancer?
Sigel: The New York State AIDS Institute has really been a leader in this area, and I believe has advocated for screening among women with HIV. At the very least, I think that one thing that can be taken away from what we did is that for women that have known other genital HPV infection—and even that have dysplastic lesions—there’s probably a reasonable chance that they’re going to have anal HPV infection. And just locally in our clinic, we do see quite a bit of anal precancers among women living with HIV.
Again, probably the reason that there isn’t as much concern is that people probably are not as clued in to the idea that there is this sort of amplification of HPV disease in the setting of HIV. So they’re not thinking as much about this being a disease of women.
Globally, if you look outside of HIV, one of the most important things to remember is that anal cancer is actually a disease largely of women in the United States. The majority of cases of anal cancer in the United States are in women without HIV. And we’ve actually shown, using national data, that the incidence of anal cancer is growing rapidly in the United States and is going to actually overtake cervical cancer, probably in the next 10 years.
So, our group is very focused on this. We also think that there needs to be more attention to the idea of screening, perhaps targeted screening of women with HIV, for anal cancer—certainly ones that are known to have HPV infection at other genital sites—and that the same treatment pathway that we use for men should be considered in these women.
Are We Under-Screening Women Living With HIV?
Wilder: Let’s talk about the study and the idea that precipitated it. Why did you decide to conduct the study, what were the population and methods, and what did you find?
Sigel: The reason that we did this was a lot of what you had referred to. We still felt like we didn’t have a great understanding of the prevalence of HPV among women with HIV, and also what to do when you diagnose HPV infection in the cervix or in the vagina, and in other areas? What does that mean for anal risk? Also, if you don’t diagnose HPV in those areas, what does that mean for anal cancer risk? This really was spurred out of a concern that we were potentially under-surveilling women living with HIV for anal HPV-associated disease.
Weiss: We were fortunate to have access to data from a large anal cancer screening program at the Mount Sinai Health System in New York City. This study in particular was a retrospective chart review, inclusive of pathology findings, biopsy results, and notes from the clinicians conducting the procedures.
We identified a group of women who were living with HIV and had been screened for anal cancer between 2012 and 2019. They had all undergone anal HPV testing, cervical HPV testing, and a high-resolution anoscopy, or an anal screening test that Dr. Sigel will tell you a little bit more about.
We were interested in assessing for some of the outcomes that Dr. Sigel mentioned: What is the concordance of cervical and anal HPV infection? If people do have anal HPV infection, is there the presence of concurrent cervical infection? Then we compared the proportions of HPV strain types by anatomic site and were really interested in whether or not those strains persisted over time, or whether they were cleared.
What we ended up finding in this particular cohort of women—it’s a group of about 140 women living with HIV—[is] that anal HPV infection was much more common than cervical infection. And, interestingly enough, the type of anal HPV—specifically the high-risk HPV strain—was often not concordant between the cervix and the anus. That means that a particular strain could be present in the anus and there might be no HPV infection in the cervix. The persistence of that infection was strongly associated with the development of anal precancer lesions.
Wilder: You mentioned that there are multiple strains of HPV. Are there any that are more common in causing anal cancer than others? What are the differences in these strains?
Weiss: That’s a great question. There are a number of different HPV strains, or HPV types (and the language is used a little bit interchangeably). There’s a two-way stratification. There are some strains that we consider to be higher risk, and some considered to be lower risk. That’s really related to the development of precancer or cancer.
The main strains that we consider higher-risk HPV are HPV 16 and HPV 18. Really, we think the difference between these strains is that those strains are associated with changes in the genome, with genetic changes that directly contribute to the development of precancer and cancer. Specifically for anal cancer, we think that HPV 16 is the most prevalent strain that is contributing to development.
Wilder: You mentioned high-resolution anoscopy. What is this procedure? What does it do, and who would need to get it?
Sigel: High-resolution anoscopy, which we call HRA, is a procedure that’s practiced by specialists, often colorectal surgeons and infectious disease specialists who have undergone special training. It’s analogous to a similar procedure that is done in the cervix, called a colposcopy.
The reason it’s called high-resolution anoscopy is because the anal canal is actually reasonably small, and these lesions are not that big. They use a special scope that amplifies the area, and they’re watching it on a video screen, like what you’ve probably seen for colonoscopies.
They use a scope to expand and amplify the area, and then the provider applies special stains that help to identify abnormal areas of tissue. The provider will then biopsy areas that are suspicious for precancer, or even cancer.
If the biopsies show that there is precancer, particularly high-grade precancers, then they will prescribe various treatments. Sometimes they do electrocautery ablation or refer the patient to a surgeon for removal. Sometimes there are medications that can be used at home instead of those procedures. If they identify cancer, then the patient is referred to a surgeon for more extensive procedures.
Our procedure for referral for high-resolution anoscopy is, patients that are at risk of anal cancer are initially screened with an anal Pap smear, which is a cytology test that can be done by a primary care physician. If that test is abnormal, then we will refer them for high-resolution anoscopy to actually determine if there truly are any of these precancerous lesions.
Sometimes we’ll refer patients just because we find high-risk HPV, such as HPV 16. And sometimes we refer patients because there are other abnormalities that a provider will find, that they aren’t sure about, maybe on a rectal exam. So, they refer them to HRA to figure out what’s going on.
It’s a pretty pivotal step in the anal cancer screening process. It was also a key part of this study.
A Surprising Lack of Connection Between Cervical HPV and Anal HPV
Wilder: Can you share more details about what the study found, and if there are any implications for clinical practice?
Weiss: Yes, definitely. I can talk a little bit about the conclusions, and then we can tag team some of the implications.
I think we have this presumption, based on previous literature, that the cervix is the main reservoir for HPV infection. It was a bit of a surprise for us that our data did not show this. More specifically, we saw a relative lack of connection between cervical HPV and anal HPV infection in this cohort. We can talk about some of the reasons why anal HPV infection may have been more common in this cohort, but that was certainly, I think, the most eye-opening finding for us.
Relative to clinical practice, Dr. Sigel will talk a little bit more about this, but I think there’s messaging here that can support other public health messaging about continuing to screen people living with HIV, whether women or men, for anal cancer and for anal HPV.
Sigel: I would agree with everything Kevin said. What this really says is that there are probably women that have anal HPV infection that may not have cervical disease or cervical infection. So, we need to potentially cast a wider net, in terms of the groups that we’re going to screen for anal precancers.
Another interesting issue is, if a patient has high-risk HPV in the anus but not in the cervix, or in the cervix and not in the anus, what does that mean for vaccination? Should we potentially vaccinate to protect infection of the other site? I don’t think there’s any data that I’m aware of that could tell us either way on that question. But it does raise some interesting issues related to vaccination.
The bottom line is that for persistent HPV infection in the anus, those patients seem to be at the highest risk for high-grade anal precancers, and that if you see HPV in one place, you can’t necessarily assume that it is or isn’t in the other place. These are two key issues in this population.
Wilder: In this particular cohort, was everyone virally suppressed? Was anyone not undetectable? What did T cells look like? I’m also wondering, was there any qualitative data? Were there any conversations around sexual health and sex? And what kind of sex did the women have? Did the women only have vaginal-penile intercourse? Did they have anal-penile intercourse?
Weiss: One thing I’ll clarify is that this is the first iteration of this study. We wanted to pilot this sort of analysis with a smaller cohort. The next steps that we’re thinking about are expanding this to the entire anal cancer screening cohort, and we’re working on the methodology to do that. That’s going to involve a little more work, in terms of mining the free text in the doctors’ reports.
One of the things relative to what you were talking about, in terms of conversations about sexual behavior, we may find some of that within the free text, in terms of a physician saying, “We had a conversation about this. And here were some of the goals that were set.” We do have some quantitative data on that, that we’re still working on connecting, but that’s one initial thought for the qualitative data.
In regards to some of the questions you asked about—for example, like viral load suppression—I’m happy to share some of the data that was present on the CROI abstract but was not part of the presentation. In the cohort that we analyzed, the median viral loads for many of the groups that we looked at were very low, and bordering on the range of viral load suppression. On average, this was a cohort of women who generally were engaged in care. This was a clinical cohort, rather than a community cohort, of women living with HIV. So, we have women who were more likely to be engaged in care, and potentially more likely to be adhering to treatment recommendations, like taking ARVs [antiretrovirals].
Then, just to give you a numerical sense, the median CD4 count in the group of women who had persistent infection was 684—and in the group that cleared, it was 590. So, certainly, this group of women were more likely to be taking ARVs. I’ll leave it to Dr. Sigel to talk about the community side of that, and whether that’s different from the clinic population that he’s seeing.
Sigel: We typically screen people that are sort of more stable from an HIV perspective. This cohort, in general, has pretty good immune function and reasonably high rates of viral suppression. So I would say it’s pretty representative of an engaged-in-care cohort of women. That’s good, because it actually makes it somewhat more representative of the types of patients that would be considered for screening in the general population of patients living with HIV.
Can HPV Go Away or Become Undetectable?
Wilder: I’m thinking about the bad state of affairs for sexual health education in the United States. But if people actually do get any kind of sexual health education, they may get a talk about human papillomavirus. It usually comes with a discussion about genital warts—and then a person may say, “And HPV can put you at risk for cervical cancer.” I don’t think there is much discussion about anal cancer.
Is there any kind of bridge between HPV and genital warts and a leap to cancer? Or are those just two completely different things?
Sigel: The HPV types that cause warts can cause cancer. But the HPV types that can cause cancer don’t always cause warts. So, there certainly is a link. There can be instances where patients will have warts, and actually portions of the wart will actually evolve into cancer. The wart really does represent typically some of the earliest stages of anal precancer, but not usually the more advanced stages.
So, the short answer is: There is a relationship, but it’s not necessarily a direct relationship. And just because a person doesn’t have warts doesn’t mean they can’t develop cancer.
Wilder: When you were presenting at CROI, you talked about the clearing of the virus. Can we have a conversation about a person naturally being able to clear HPV? And if they can, why does this happen? How does it happen? And why wouldn’t it happen?
Sigel: This is a little bit of a tricky issue. I think the thing that we can most definitely say with the way that we test for HPV is that HPV becomes undetectable. Kind of like when we measure HIV, HIV becomes undetectable. Many of us think that although true clearance of HPV—like, it’s completely gone—is perhaps a possibility, it’s very difficult to measure. Many times, what we’re seeing is actually that the HPV may still be present, but it’s not replicating anymore, and it’s not present on the tests. But that also probably means that it’s not at risk of causing disease.
So we do use the term clearance, but it’s a tricky term. It does not necessarily mean that it’s truly gone—although it could. I’d say that’s a little bit of a controversial area. Again, the one thing that I think you can say is if the HPV is not present on the test, with multiple tests, and there’s no evidence of any sort of HPV-associated disease, then it’s likely that the risk of HPV-associated disease is very low. Does that make sense?
Wilder: Yes, it does. And it makes me wonder: Do we need to come up with some different language?
Sigel: This is a tough area because people want to feel like they’re clear of HPV. And I totally understand that. It’s a useful public health message to say that these are things that we can do to help you clear HPV. It’s a tough distinction. That’s about all I can say.
Wilder: What are the things that you would tell someone to help them clear HPV?
Sigel: For people living with HIV, one thing that I would strongly encourage is that they do their best to be adherent with their antiretrovirals so that they have maximum immune health. If people are in the appropriate age range for the HPV vaccine, I would also definitely recommend the HPV vaccination. There may be a role for HPV vaccination in people that are already infected with HPV. It may help to boost immunity. I don’t think that that’s been proven, but it’s something that we speculate.
Another big one is smoking. There’s reasonable evidence that smoking probably is associated with more measurable HPV replication and persistence, and that smoking is another big thing that we can try to impact to help people so that they don’t have detectable HPV.
Wilder: We certainly know that there are high rates of smoking in communities of people living with HIV. So that would definitely be something to bring up.
Sigel: We’ve seen in previous studies associations with more anal precancers in smokers. And it’s not a big surprise. It’s probably a very complex relationship, but I would not be surprised if some of it was related to HPV pre-existence.
Wilder: Can you clarify the HPV vaccination age limitation?
Sigel: It’s changed in the last year or two, and it’s up through age 45. I’m a believer that we should be giving it to everybody, of all ages.
The issue is that it’s actually very difficult to detect the benefits of it in older people, just because it’s more difficult to study. But many of us think that probably it induces some degree of immunity that’s probably beneficial, even in people that already have HPV.
Wilder: Some of the participants in the study that had both cervical and anal HPV, right?
Wilder: I’ve always been told, “Hey, look, the majority of the world has HPV.” I’m trying to understand, from the perspective of a non-clinician: With HPV being very easy to transmit, if you have it in your cervix, could you easily transmit it through touching the vaginal area and then maybe touching the anal area, versus through anal sex? Are there different ways of transmission that people aren’t thinking about?
Sigel: Tracking that kind of thing can be kind of tough. But I have talked about this with other clinicians that specialize in HPV-related diseases, and we all think that there are certainly situations where it is transmitted without sex, basically, from one anatomic area to another.
You do see situations where there’s anal HPV infection and you have pretty substantial confidence that there hasn’t been any sex. We think that that is a possibility.
You mentioned the ubiquity of HPV. One of the big issues here: There is a lot of HPV going around. The thing that we see in the presence of HIV that is most concerning is, you’ll see situations where you have high levels of HPV replication and persistence that are going on for many years after the infection, where people without HIV may be exposed to some of these high-risk HPVs. But then they get into this, quote-unquote, clearance situation that we discussed earlier, where it seems like the replication is really suppressed.
It certainly is floating around a lot. But HIV kind of sets this fire, and it’s probably not just this replication issue, but a lot of different other things combined. It really is, I think, a special issue in this population. It’s why anal cancer is one of the leading cancers in people living with HIV, and yet it’s a very rare cancer in the general population.
Getting From Study Cohort to Clinical Practice
Wilder: Thinking about this initial pilot study, can each of you talk about one thing that you would hope that a clinician would learn from hearing about this study?
Weiss: On my end—and maybe I can generalize this to someone who’s currently in training to become a clinician—the way we typically learn about conditions, and the way we learn about things in school, it is really the broad strokes. Like, here are all of these different conditions.
We do focus a little bit—in this particular case, here are some conditions that we think are associated with increased risk in people living with HIV.
What a lot of it comes down to is—my previous work was also in a similar area—establishing better patient-provider relationships. What we’re talking about here are very sensitive concerns in a lot of cases. We’re talking about sexual history. We’re talking about genital or anal sites.
Many clinicians are excellent at this. And this is always part of the guidelines, whether it’s the CDC guidelines, the ACIP [Advisory Committee on Immunization Practices] guidelines, or the New York State guidelines. But I think that’s so easy to take for granted. It has been a pleasure to work with Dr. Sigel and others, who are dedicated clinicians, who are focused on asking, “How can we best support our patients?” and “What are all of the things we should be thinking about?” We alluded to this a little bit earlier, in terms of focusing less on HIV, but all of the things associated with HIV. We should be thinking about smoking cessation. We should be thinking about screening for HPV. We should be thinking about mental health.
I’m grateful to have worked with people who have the holistic, best interest of patients at heart. That’s something we can never emphasize enough, alongside these guidelines. Here are the recommendations for screening, and here are the recommendations for testing. But also, we should be continuing to build these therapeutic, trusting relationships with patients.
Sigel: Kevin, I definitely appreciate that.
The one thing I would say, from a very tangible level, is this is the beginning of a lot of work that we want to do to really understand the risk that women with HIV have for these lesions and for anal cancer. But I think that the most tangible, small thing that I would say to the provider community is, if you have women living with HIV who have any sort of anal complaints, this needs to be on your radar. And don’t just necessarily chalk things up to hemorrhoids and things like that. So, maybe have a greater appreciation, or a lower threshold, for looking into some of these HPV-associated things if people have anal complaints.
Whether or not we should be broadening our screening is a great question. We’re very pro-screening, but there is a lot of prospective data that we need to be able to emphasize screening. That’s something we’re working on. But I do think that, like I said, this is really the beginning of the journey for figuring out what we need to be doing.