Viremic – Cases in HIV

Announcer:
Welcome to Viremic–Cases in HIV, a podcast that explores quandaries in adult HIV clinical care. In each episode, Drs. Eileen Scully and Christopher Hoffmann, HIV specialists at Johns Hopkins, discuss a case, review challenges in the plan of care, and highlight evidence and guidelines that inform clinical decision-making. Now, here is your host, Chris Hoffmann.

Dr. Christopher Hoffmann:
Welcome to Viremic. I’m Chris Hoffman, and I’m delighted to be joined today by a special guest, Dr. Bruce Hirsch. He’s an infectious diseases and HIV specialist and thoughtful colleague based at Northwell Health in New York, where he’s a specialist in HIV care and infectious diseases. We’re talking today because he’s the lead author on the recently updated New York State AIDS Institute clinical guidelines for anal cancer screening.

Bruce, I’m a big fan of your thoughtful approach to patient care and clinical decision-making. Welcome.

Dr. Bruce Hirsch:
Chris, it’s such a pleasure to be here. I’ve been enjoying your podcast, as I’ve mentioned to you, and it’s such a privilege to be working with patients with HIV for decades and decades. It’s so different than when we started a few decades ago.

Chris:
Well, I’m excited to be learning more about anal cancer and anal cancer screening from you today. One of the challenges I face with anal cancer screening is confidence in being sure that I’m doing the right thing in both preventing anal cancer but also making sure that I’m not sending my patients for unnecessary or too many procedures. I certainly try to dot my i’s and cross my t’s in primary care, but anal cancer screening and prevention is sometimes a struggle for me.

I do have a case for you today, but before we get into the case, I think it would be good to review some of the basics of anal cancer and anal cancer prevention. So, I’m gonna give a little bit of background and then invite you to provide a little more depth. Anal cancer has both high morbidity and mortality, with a 5-year survival of advanced anal cancer of only about 30%.

Survival is better with locally invasive cancer, but it’s still only about 60% to 70%, and the morbidity of treatment is high, with a combination typically of XRT, chemotherapy, and possibly surgery, which is typically an abdominal perineal resection, which has substantial morbidity that can include urinary and fecal incontinence, sexual dysfunction, colostomies, and other morbid aspects. All of those listening and you also, Bruce, who have cared for people with anal cancer certainly have seen this and know that this is a nasty disease and one that I certainly don’t want my patients to develop.

It’s also helpful to note that this is very common, especially among people living with HIV. People with HIV have a 10- to 20-fold higher risk of anal dysplasia and anal cancer than people who are not living with HIV. And among people living with HIV, there are about 60 per 100,000 anal cancer cases per year.

People who are receptive partners for anal sex, the rates are even higher, although it’s unclear if anal intercourse itself is the primary risk factor. The rates are so high that anal cancer among men who have sex with men living with HIV are similar to the rate of prostate cancer among men and about 2- to 3-fold higher than lung or colon cancer, cancers that we consider common and often have extensive screening programs for.

I want to turn it over to you now, Bruce, for any reflections on the epidemiology or the biology of cancer.

Bruce:
I also find the epidemiology compelling. If the rate of anal cancer in men who have sex with men is estimated at 130 per 100,000 person years, it compares with prostate cancer at 119 per 100,000 person years. It is much higher than colon cancer, which is 50 per 100,000 person years, and it is multiples of cervical cancer prior to cervical cancer screening, which was 30 to 40 per 100,000 person years.

We now have information that anal cancer is preventable in many cases, that there is the opportunity to interrupt the progression of dysplasia to anal cancer and to make the diagnosis of anal cancer earlier so that the treatment is better tolerated. The usual treatment of chemo, radiation, and surgery for advanced anal cancer is a rough treatment, and to be able to prevent this cause of morbidity is compelling.

Chris:
It certainly motivates me to try to understand how I can prevent it. Starting with prevention, something that I perhaps don’t use as much as I should among my patient population, but do advise, is vaccination. Do you mind commenting a bit on the role of HPV vaccination in prevention of anal cancer.

Bruce:
The Gardasil 9 HPV vaccine has been available since 2014, and it is an effective and safe vaccine. It contains viral-like proteins consisting of capsid proteins and has protection against 7 of the most common high-risk HPVs, of which there are 12, and 2 HPV types that are associated with development of warts. It is indicated for all people starting at age 9 and early adolescence prior to sexual exposure, prior to exposure to HPV, which is the most common sexually transmitted infectious disease. If we have immunity prior to exposure to HPV, we are protected from HPV.

The vaccine is effective. It results in 10- to 100-fold antibody response when compared with infection. It’s associated with long-term immunity. CD4 activity is involved. It is a cancer-preventing vaccine.

In this era of vaccine hesitancy, the vaccine rates leveled off in the year 2022, and I just read that Merck is reporting a 25% decrease in sales of this vaccine in early 2025, which is a tragedy. As advocates for the health of all patients, of all people, I think this cancer-preventing vaccine is very, very important.

Many of our patients come into care having been exposed to HPV, but Gardasil 9 prevents and protects against the other types. One of the things that we’re adopting in practice is to provide Gardasil 9 for all individuals with HIV from age 9 up to age 45, which is the FDA approval, giving a degree of protection against some of the additional high-risk HPV types that can complicate anal health and cause anal dysplasia.

Chris:
Well stated, Bruce. I’m going to get right into a case now, and then you can comment perhaps on whether you would provide my patient with Gardasil 9. Overall, we’ll discuss screening and management of anal dysplasia for this individual.

So, getting right onto the case, this is a composite patient, very similar to a number of patients. We have 42-year-old man living with HIV for some time. His nadir CD4 count was 320. He’s currently on Biktarvy, has an undetectable viral load. His CD4 count now is above 500. He is a gay man with both top and bottom sex, that is, anal receptive sex or butt sex.

He was last screened 3 years ago for anal cancer with a Pap smear, anal Pap smear, and the cytology was read as ASCUS or atypical squamous cells of unclear significance. At the time, no HPV typing was done, and he has not had any follow-up since then. In addition, he has not received the Gardasil 9 vaccine.

He remained sexually active with the same partner and is happy with his sex life, hasn’t had any STDs in the past several years, drinks socially, doesn’t use any recreational drugs or chem sex, and he smokes about 5 to 10 cigarettes a day, although acknowledges that he would like to quit and understands it’s probably not so good for his health.

So, Bruce, starting with the vaccine question, how would you approach this patient.

Bruce:
This patient is at increased risk for anal dysplasia and anal cancer. We do not know his previous HPV typing, but there is evidence that men who have sex with men may be exposed with multiple HPV types. He remains sexually active and there is the potential for risk to other HPV types. The vaccine is safe and well tolerated, and although it will not have any benefit on the HPV that he’s been exposed to already, it will give a degree of protection against future types.

Most of us are offering Gardasil 9 in this context. For people who have HIV, the dose, as you know, is 3 doses. The second dose, 1 to 2 months after the first; the last dose 6 months after the first. Those intervals seem to be helpful in terms of long-term immune benefit. It’s an additional preventive step that makes sense given the epidemiology that we described before.

Chris:
I did encourage him to get the Gardasil 9. He is 42, so he’s within the FDA recommended range, although I certainly sometimes go above that age range in recommending Gardasil to my patients.

I wanted to move now on to anal cancer prevention. I repeated the Pap smear when I saw him. But Bruce, can you go into a little bit of a description of the Pap smear and how it is interpreted?

Bruce:
Yes, and we want to understand engaging our patient in the magnitude of risk to develop anal dysplasia. Some of the risk factors that you’ve described are favorable and some of the risk factors are not.

He does not have extensive comorbidities. He doesn’t have diabetes that you’ve mentioned, and your description implies to me that he’s not having active anal symptoms. He is a smoker, and tobacco use is a risk factor for anal cancer. Tobacco ingestion brings substances that can cause cancer systemically into the circulation and may have an impact on the immune system. Smoking cessation is a part of general primary care in any event but also has a role on this circumstance.

Understanding that he has high risk, the anal cancer screening certainly makes sense. The screening begins with symptoms—ask him if he has any discharge from the anus, any anal itch, any anal pain, any bleeding, any masses that are present. The other steps in anal cancer screening includes a digital anal rectal exam, where a lubricated finger is placed into the anal canal and the anal wall is palpated to make sure that there’s no masses, that there’s no areas of involvement. For practitioners that do not have access to HRA, to high resolution anoscopy, for practitioners that are not being able to do anal Pap test, that is anal cancer screening. It’s suboptimal, but it helps to diagnose anal cancer earlier where it’s treatable and helps minimize morbidity.

The anal Pap test is very analogous to cervical Pap test. The anal Pap test involves taking a nylon swab, a plastic swab, and moistening it, and placing it into the anal canal 2 or 3 inches, moving it in a circular direction while pulling it out, and then placing it in liquid cytology solution, agitating it to have the cells come off, and to allow it to be read.

The anal cytology results are very, very useful. If there’s no abnormalities, that can be very reassuring. The cytologist does check to see if the anal Pap test is adequate, if there’s evidence of cells from the transitional zone that indicates a high-quality anal Pap test. The cytology is very important. Different cytology results include ASCUS, atypical squamous cells of uncertain significance, and low grade squamous intraepithelial lesions (LSIL), or high grade. High grade is what we’re looking for. These lesions can be helpful in making decisions about the next steps. Many of us are doing HPV typing along with the anal Pap test. To be able to have high-risk HPV result from the Pap test is a marker of higher risk for the patient and an indicator that we need to go on for high-resolution anoscopy.

Chris:
Great, thanks for that, Bruce. One of the questions that sometimes comes up in my mind, and I need to sometimes explain to patients who ask me about the value of the Pap, is the evidence that actually doing this Pap will help identify ways to reduce the risk of anal cancer.

Bruce:
The Pap tells us whether or not a high-resolution anoscopy needs to be done. The Pap is evidence that this patient may be harboring high grade squamous epithelial lesions, and high-grade lesions are exactly the lesions that we want to find because those are the ones that have a potential over subsequent years to turn into anal cancer.

We now have good evidence that intervening, that treating high-grade lesions makes a difference. The New England Journal of Medicine in 2022 published the ANCHOR study, the Anal Cancer High-Grade Squamous Intraepithelial Lesions Outcome Research Trial.

This was a phase 3 trial at 25 US sites that analyzed people who were living with HIV over the age of 35, all of them harboring high-grade lesions. The 4,400 or so patients were randomized to 2 groups. One was a monitoring arm, and they were evaluated with frequent high-resolution endoscopy. The other one was a treatment group. When high-grade lesions were encountered, the high-grade lesions were treated.

In this study, most of the patients were treated with a cautery technique called hyfrecation, which is currently the most common treatment that we use. In the 2,071 patients in the treatment group, 9 went on to anal cancer. In the 2,080 patients in the monitoring group, 21 went on to anal cancer. The treatment reduced the risk of anal cancer in this group with high-grade lesions by about 60%, and this is over a follow-up period of about 26 months. This was statistically significant. The study was stopped prematurely, and the results were published and disseminated and have been able to substantiate our recommendations to intervene in these high-grade patients. Looking for high-grade lesions and treating high-grade lesions significantly reduces the risk of developing anal cancer.

Chris:
Yeah, certainly the ANCHOR findings are very compelling for anal cancer screening or anal dysplasia screening and intervening with high grade dysplasia.

If we move back now to my patient, he reported no symptoms. On digital rectal exam, I did not palpate any masses or induration, and the anal Pap came back with LSIL and HPV 16. So, this is not the high-grade dysplasia that was part of the ANCHOR study. Tell me how you would interpret this and how this fits into the ANCHOR Study Protocol.

Bruce:
These findings indicate high risk. HPV16 is strongly associated with high-grade lesions and subsequent risk of anal cancer. The finding of HPV16 is evidence that there may be high-grade lesions that are present, and, in and of itself, if it’s encountered, is an indication to go on to high-resolution anoscopy.

The finding of cytologic abnormalities of low grade, which in of itself is not significant, on anal Pap may indicate that in the company of these low-grade changes, there may be high grade changes as well. So our recommendation for a person who has atypical squamous cells of uncertain significance or low grade squamous intraepithelial lesions is that if they have high risk HPV, they need to be evaluated by high resolution anoscopy because around that low grade dysplasia, high grade dysplasia is so frequently present as well, and that’s what we want to find and that’s what we want to intervene on. That’s the opportunity to decrease morbidity and decrease the frequency of anal cancer.

Chris:
Yeah, I think that’s so helpful. If the cytology is completely normal and there are no high-risk HPVs, certainly no HPV 16 or 18, then I think we can be fairly confident that there is no high-grade dysplasia. Is that correct?

Bruce:
That is correct.

Chris:
But if we see changes on cytology, whether it’s ASCUS or LSIL, then there’s the possibility of high-grade changes as well because of the lack of specificity of the test. In addition, even if everything looks normal on cytology, but we see HPV 16, the chance of high-grade cytology or high-grade changes (dysplasia) is significant, and any one of those situations should be considered likely to have high grade dysplasia and go on to high resolution anoscopy. Is that your approach?

Bruce:
Thank you for stating it so clearly. That’s absolutely correct. We’re looking for trouble to prevent problems. The anal cytology is sensitive for dysplasia, but not specific for high-grade, and the company that low grade changes keep sometimes include high-grade as well.

Chris:
I find it useful to walk through that when I’m referring a patient to HRA because it requires, first of all, a doctor’s appointment, and many of my patients are not so enthusiastic of going to a doctor, but then HRA itself is uncomfortable. Biopsies can cause pain for several days afterwards. and it’s an invasive procedure. So, I want to be really confident that I am recommending the correct thing for my patients.

The way that I try to think about this is that if they have these changes, HPV 16 certainly, LSIL, ASCUS with any high-risk HPV, or certainly if they have HSIL, then there’s a chance of high-grade dysplasia. So, they meet the criteria for ANCHOR and should be evaluated further with biopsy for high-grade dysplasia. If the biopsy on HRA shows high-grade dysplasia, then treatment of that dysplasia. Is that the way you approach it also?

Bruce:
That’s my approach as well, and I point out to my patients how successful they are. Your patient has an undetectable viral load. Your patient has a CD4 count above 500. Your patient has the likelihood of longevity and living for a very long time, and during that period of prolonged survival, we need to assure that he will continue to flourish. Your patient has the prospect of living a very long and healthy life. And it’s exactly because of your patient’s success that interventions like this, preventing problems that would be a disaster and an impact on his life, need to be taken.

Chris:
Thanks for that, Bruce. So, I discussed HRA with this patient I’m very fortunate within Hopkins system and in Baltimore to have multiple providers who perform HRA. I referred him and he had HRA follow-up. I do have some patients that are a little harder to get to commit to going to an HRA appointment and are very hesitant or delay scheduling. How do you review the value of HRA with patients who are hesitant or skeptical?

Bruce:
I have similar challenges with some of my patients. The framing of referring to the patient’s success and likely longevity is sometimes useful, but sometimes it’s not. I stay engaged with the patient. I offer them over and over again and work with them to be able to augment their health.

Chris:
Continuing on with my patient, I did send him to HRA. He had a biopsy. He did have HSIL identified. He returned to the HRA provider who did an ablation of that area. What are some of the follow-ups after that ablation that he should go through?

Bruce:
After undergoing an ablation, it’s generally recommended to have a follow-up HRA within 6 months to assure that the ablation is complete. The follow-up high-resolution endoscopy evaluates the area that was ablated and evaluates the tissues around that area of ablation, performs biopsies, looks for other lesions that might have been missed, and assesses that the patient had a complete response.

After a follow-up HRA is performed and the patient is assured that there is no active high-grade lesions remaining, in general, we perform follow-up HRAs at annual intervals going forward.

Chris:
When does a patient graduate from HRA and come back to your or my routine anal cancer screening? And when do we need to make sure they’re returning to the HRA provider?

Bruce:
We generally continue doing annual HRAs. If there are 2 negatives, that is a marker of lower risk, and then we can decrease the frequency of anal Pap screening from doing it once a year, to doing it every 3 years.

Chris:
Okay, very helpful.

So just wrapping up with my patient before getting to some questions around the controversies around anal cancer screening—I did get him started on the Gardasil 9 series of 3 injections, referred him for HRA where he had that, and have encouraged him to return at the 6 months after his ablation. Then we’ll certainly encourage him to continue follow up with HRA for as long as that’s needed, until it’s clear that he has no high-grade dysplasia and can return to management with the standard symptoms digital rectal exam and Pap smears.

I’ve also spoken to him about smoking cessation, and I’m hoping that the consideration that stopping smoking entirely will reduce his risk for progression of dysplasia will be enough to push him to stop smoking.

I think it’s useful to raise some of the controversies or criticisms of current screening for anal cancer. I’m going to start with the ANCHOR study and just see what some of your takes are on this. One is that it showed a reduction in anal cancer, but over a fairly short timeframe, and there were no mortality endpoints evaluated. How do you view those criticisms of ANCHOR?

Bruce:
The ANCHOR study investigators, I believe, were correct to cross over those in the monitoring arm to active treatment based on their significant findings. We certainly look forward to longer term follow up on those patients and to see how they continue to do. The diagnosis of anal cancer in itself, I think, is a hard end point.

Chris, what are the thoughts that you have about the limitations of the ANCHOR study?

Chris:
Well, I think, just as you said, they certainly, given the findings, couldn’t continue to randomize individuals and follow them without an intervention. Longer term studies will be helpful. ANCHOR was an amazing study. It’s a tough study to do, and I think the amount of data that we’ll have will probably be limited in the next few years at least to provide further guidance.

There have been some ecological studies that suggest that the introduction of anal cancer screening with Pap smears followed by HRA can reduce anal cancer. There was a study conducted by the Kaiser California group that suggested a trend toward reduction in anal cancer after they introduced those screening techniques. I’d love to see more data.

I do think that the cervical cancer example is helpful. Certainly, there’s a difference between the anus and the cervix, but it’s still helpful to see the impact both of Gardasil on cervical cancer in countries where it’s really been scaled up like Australia, where there’s hardly any new cervical cancer, as well as cervical Pap smears and the impact of that on cervical cancer mortality and invasive cervical cancer.

Bruce:
I’m impressed with some recent epidemiology studies. I’m thinking of a 2024 study that documented leveling off in anal cancer risk and the fact that that leveling off was uneven and that there were different rates and different experiences in different parts of the country where there were different standards of practice. On the West Coast, on the Northeast, there seems to have been a significant decrease in the development of anal cancer. These are areas of HIV subspecialty care in which strategies such as anal cancer screening has been adopted. We’re seeing it reflected not because of differences in biology across different parts of the country, but in differences in terms of clinical practice, and I think that helps inform and support your point.

Chris:
Yeah, I agree. Those are also compelling findings.

Bruce, I think you also have an interest in some of the biology of anal cancer and HPV induced dysplasia. Did you want to comment on that?

Bruce:
HPV reminds me a little bit of HIV. The HPV gains entry into cells in the anal canal. The area of the transformation zone is dynamic. There’s a lot of reactive cells. The lining is somewhat thinner in that area, and that’s a particular area of high risk of HPV infection and HPV transformation.

HPV transmission is skin-to-skin and is the most common sexually transmitted disease that we have in our society. High-risk HPV produces oncoproteins. The E6 oncoprotein degrades tumor suppressor protein P53 and helps promote neoplasia. The E7 oncoprotein inactivates retinoblastoma protein and helps induce proliferation. The immune response, the initial immune response is such an important defense against HPV. Most people exposed to HPV do not go on to develop cancer. That initial defense is dependent on the innate immune response in K cells, for example, on cell-mediated immunity, specifically CD4 and CD8 cytotoxic p-lymphocytes, as well as humoral immunity.

Findings that describe increased risk of high-grade dysplasia from HPV that focus on nadir CD4 count and the duration of CD4 depletion in HIV patients, I think is very informative. It generates this concept among clinicians that keeping the patient healthy, having the patient’s HIV well controlled, starting HIV therapy as early as possible to minimize the duration of severe immune suppression has numerous benefits throughout the body, and the HPV example is yet another example of that.

The HPV oncoproteins results in decreased MHC class one expression, chronic inflammation, and oxidative stress, impacts on the innate cells. We know people who have poorly controlled diabetes have elevated insulin and IGF-1, which are growth factors for tumors, including anal cancer. The primary care of these individuals is global—treating the entire person, the entire body, helps engender numerous virtuous benefits that cycle on each other and enables our patients to live a healthy life without intercurrent illness.

Chris:
I love that, Bruce. So, preventing anal cancer starts with maintaining viral suppression, optimizing CD4 count recovery if there was a low CD4 count, helping with smoking cessation, and overall doing what we can to optimize somebody’s health—managing diabetes and other comorbidities, providing vaccination for human Papillomavirus with the Gardasil 9. And then along with all that, the more direct assessment of dysplasia with the assessment of symptoms, digital rectal exam, and Pap smear followed by high resolution anoscopy if there’s a signal that high grade dysplasia may be present.

Is there anything you wanted to add in terms of anal cancer prevention, Bruce?

Bruce:
It’s such a privilege to work with people who are living long and healthy lives. It’s such an amazing fact that you and I are discussing anal cancer prevention just a few decades after we saw so many people die quickly and tragically of untreatable HIV infection. This is a completely different era. This is a different phase of HIV care, and the opportunity to prevent a preventable cancer in our long-lived HIV patients is truly a privilege.

Chris:
Well said. And thanks so much, Bruce. This conversation has been an absolute pleasure, and I hope that our listeners have enjoyed it as much as I have.

Bruce:
Thanks so much, Chris. It’s a pleasure to be with you.

Announcer:
Thanks for listening to Viremic. If you enjoyed the show, please subscribe wherever you listen to podcasts. We’ll be back in a couple of weeks with a new case to discuss.

Viremic is sponsored by the Clinical Guidelines Program, a collaborative effort of the New York State Department of Health AIDS Institute and the Johns Hopkins University Division of Infectious Diseases.

Visit the program’s website at HIVguidelines.org.

The podcast is produced and edited by Mary Beth Hansen and Brian Hatcher with appreciated assistance from Jesse Ciekot and Laura LeBrun Hatcher.

Viremic’s case discussions are presented for informational purposes only and are not offered as medical or clinical practice advice for patients or clinicians. Any mention of specific medications or commercially available products is a description of use, not an endorsement.