[Question #1729] Questions about immune response to low-risk infections

69 months ago
Hi Doctors

11 years ago, I had about 3-4 warts that were treated, quickly went away, and never returned. My questions:

1. I recently spoke with several people in an online virology community. I learned that unlike high-risk oncogenic types sometimes do, low-risk types do not have the tendency or ability to integrate themselves into the host cell chromosome. It was explained to me that because of this, the body will (is more likely to?) rid itself completely of the remaining low-risk viral particles through natural turnover of skin than high-risk types. All this info was very comforting (especially considering I've gone 11 years symptom-free), and these people seemed knowledgeable, but at the same time they are strangers on the internet, so I wanted to ask what is your opinion on their responses and the consensus that seemed to be drawn there? You can see some answers I received verbatim to my general question below:

Q: I am wondering if because HPV does reside in epithelial cells (which I think as regular skin cells, are commonly dying and regrowing), would it theoretically be possible for low-risk hpv viral particles remaining in the skin post-infection to get eliminated from the body over time along with regular dead skin shedding? What about after many years (2, 5, 10, 15 years?)

A1: They get shed and lost just like they would in an active infection. The only reason they are present continually with an active infection is because they are being 'renewed' like new rows of shark teeth. Once the infection is finally cleared there is no more viral particle production and those would be lost quite rapidly.
A2: When I say "virus is cleared", I mean the viral DNA is gone from its reservoir cell (the epithelial stem cell). Once that is gone, you don't have new viral particles being produced, and those particles that are hanging out on/in the skin will be lost during the natural turnover of the skin. This process wouldn't take long. It's more on the order of weeks, rather than years.
A3: It would not take that long. Viral particles themselves aren't that stable and they would likely interact with antibodies, complement system proteins, and so on. The upper layer of skin cells are metabolically dead and so they cannot produce the viral particles, either. This happens to all of the HPV that does't integrate, I believe. It is constantly being lost [via skin shedding], but without an infection to replenish it the number will drop to zero.

2. I cannot find a clear answer on how to get a low-risk type-specific HPV DNA test in a clinical setting, or if it is even possible. According to the Quest Diagnostics website, they have these tests, but then I always read that you can't just casually walk into a clinic and ask for an HPV test like you would, say a chlamydia test, especially not a low-risk type and especially not in the absence of a simultaneous pap. What if I just want to test my general vulval/vaginal area? 

3. I found this interesting article: http://www.livescience.com/52089-hpv-vaccine-warts-treatment.html. I am not so naive to think this means we can go around treating warts with Gardasil, but it did get me thinking. If I had HPV-infected skin cells treated with Aldara, stimulating an immune response against what was most likely either type 6 or 11, killing the infected skin cells and causing the warts to disappear, then I got Gardasil shortly after (I did), would that Gardasil have joined forces with my immune system in its creation of antibodies and an immunological footprint to further prevent recurrence? In simpler words, could the Gardasil possibly have helped at the time in effectively ridding my body of the virus and/or preventing recurrence forever? 

Thank you much
H. Hunter Handsfield, MD
69 months ago
I'm sorry you feel a need to return after the detailed and reassuring discussions you had with Dr. Hook in two recent threads. Although those discussions are quite detailed, I skimmed them and agree with all he told you. And your current questions largely repeat your previous ones; if these particular questions weren't asked directly, the answers nevertheless should be obvious from the previous discussions.

I also believe you are diving far too deeply into the weeds in your online research about HPV, and your questions thus reflect misunderstandings of context, natural history, and level of risk. My strong recommendation is that you concentrate on the risks that you have or will someday acquire an important health problem from HPV, or that you will transmit HPV to a partner. The chance of the first is extremely low: the large majority of HPV infections never cause disease of any kind; and when they do, usually they are trivial health problems, like warts or pap smear abnormaligies that are easily treated to effectively prevent future cancer. If those risks are low, the biological explanations for them really should not be a concern.

1) I don't see any important disagreement between the three replies you have had in other online discussions. One important fact is that the research doesn't permit absolutely clear answers on some of these issues, hance there are nuanced differences between experts. None of their replies suggest any significant risk that you now have, or will ever have, an important problem from HPV.

2) To my knowledge, testing for low risk (non cancer-causing) HPV types are not widely available because they have little clinical use. A positive or negative result would make no difference in the person's health, treatment, or risks. If you were to have a positive result for a low risk type, no treatment would be prescribed or would be useful unless and until visible warts were present.

3) There is no evidence that either imiquimod (Aldara) or the HPV vaccine (Gardasil) enhances the effect of the other, or that combined treatment would speed HPV clearance.

So my advice is to do your best to move on without so much worry about HPV. It simply isn't a big deal and should not be such a concern to you.

Best wishes--  HHH, MD

69 months ago
Hi Dr. Handsfield,

Thanks for your response. It is not that I am worried about my own health risks, I know they are very very low. I am more worried about the small risk at this point of transmitting to others. Aside from that, I am just generally interested in the science behind it all and find it very rewarding to learn more about the nuances of it from discussion with actual scientists. Especially considering there is so much misinformation on the web.

1. I know there is no disagreement in the 3 virologists' replies, nor do any of them suggest I have any risk, rather the opposite; they all corroborate quite a reassuring consensus that the virus is most likely completely gone from my body at this point. I was curious if you could lend any credence to the consensus as well (though I know in biology there are no absolutes).

2. Low-risk hpv testing might not be useful from a medical/public health standpoint, but from an individual/relationship/psycho-social standpoint it would be of great use, especially if readily available for all genders. I'm sure many would agree with me. 

3. I guess more so than asking about assisting with clearance, I am wondering if the administering of Gardasil post-infection would have helped prevent the small possibility of recurrence years later, as well as further help prevent the small possibility of reinfection with the same strain?

Just want to reiterate that I am not worried about my own health risks. Rather trying to learn as much as I can about this virus I have (had?) in my body for future reference and for the reference of partners!

H. Hunter Handsfield, MD
69 months ago
I understand your main concern is transmission, not your own health. But even the transmission issue doesn't make much sense. Your medical history does not make you any more likely than anyone else to transmit HPV. As you know, it is impossible to guarantee that you don't have a transmissible genital HPV infection. But if you do, it's no more likely in you than in most sexually active women. If we assume a new male partner who has had, say, 10 other partners; and further assume that your relationship doesn't become committed and that he will have sex with 5 more women in the next two years. Among those 15 partners, we can safely assume 12 have had HPV and 5-7 have active, transmissible infections at the time of sex. The chance he will acquire a new HPV infection is not materially higher because he had sex with you than it would be if you never met him. In the off chance that he does acquire HPV from you, he'll probably never know it. And even if he gets an HPV infection with warts or other symptoms, or becomes the source of someone else's infection, it will never be possible (or logical) to trace it back to you. And there are no practical ways to prevent any of this, beyond vaccination. So why worry?

1) I agree with the consensus of the three experts quoted. The way I often put it is that the immune system usually clears active (transmissible) HPV infections over a few months; that HPV DNA may persist indefinitely, but not necessarily; if it does, the presence of DNA doesn't necessarily mean an active, transmissible infection; but reactivation of a distant past infection may occur (usually harmlessly).

2) I disagree most sexually active people would agree with that statement or with the desire of being tested for asymptomatic low risk (or even high risk) HPV infections. There are studies showing that most people either don't think about genital HPV at all; or if they do, they accept the truth that most infections are minor (to the point of never causing symptoms) and usually not associated with important health risks. And hopefully they get vaccinated -- but the very fact that many (most?) young people don't get immunized, even after being informed of the benefits, supports the notion that HPV is out-of-sight, out-of-mind for most people.

3) Gardasil post-infection has been proved to have no effect on recurrence or warts or other HPV manifestations. Reinfection with the same HPV type is uncommon, even without immunization. OTOH, immunization provides much higher anti-HPV antibodies than natural infection does, so it is possible that vaccination provides an additional measure of prevention. However, this is specualative; I'm not aware of any research on it.

One more comment reply will meet the two follow-up comments and replies included with each original question. And since repetative questions are discouraged, this is going to have to be your last question on the topic. So consider the issues carefully before taking your last shot!

69 months ago
Alrighty then! Here goes... 

I understand and agree 100% with your logic in the first paragraph. I continue to worry though simply because most people don't. I know this because I read their opinions online and there comes a point where you wonder whether your personal behaviour in regards to infectious disease should be dictated by logic and science, or if it should be dictated by the majority opinions of the society in which you live. In fact, I am probably LESS likely to transmit warts than someone whose status is unknown, simply because I know my clearance timeline and because I've been vaccinated. However, because I had overt warts at some time in the distant past, I become a leper of sorts to the misinformed people and those in the studies you speak of that don't generally ever think about hpv. But I digress...

1. You say I keep asking repetitive questions, but I don't think they are repetitive. With all due respect, I can't help but feeling like both you and Dr. Hook have been evading the nuance in my questions around this issue in particular (please don't take offense, perhaps my layman questions don't make sense in the scientific context, or perhaps I'm not communicating well enough... that's very likely, I'm not a great communicator). My point is that what the virologists seem to be saying (maybe I'm missing something here) is that low-risk HPV does not tend to/does not have the ability to integrate into host DNA like high risk types have a tendency to sometimes do. Therefore, assuming my infection was with a common, presumably well-studied low-risk type... the assumption can be made with some certainty that viral DNA has not persisted (because it did not integrate, and because a decade of skin shedding is a lot of skin shedding). Comments?

2. When I said many would agree with me, I should have specified many of the minority of us unlucky enough to know about our infections would agree with me. I think it would do wonders for reducing the ridiculous stigma, as well as reduce much of the anxiety about the many unknowns of this elusive virus (am I still contagious? are my abnormal paps caused by a type that can give my partner warts? was my infection caused by a type covered by the vaccine? etc.).

3. You say, "Gardasil post-infection has been proved to have no effect on recurrence or warts." That is very interesting. One would think the type-specific antibodies provided by the vaccine would mobilise to action should a past infection try to reactive years later. 

While we're on the subject of the vaccine, I've thought of something else. I've read that those vaccinated with the quadrivalent Gardasil vaccine have shown higher infection rates for types not covered by the vaccine than those not vaccinated at all. Here's the study: http://www.abstractsonline.com/plan/ViewAbstract.aspx?mID=3682&sKey=7f019f73-accb-484e-becc-5ecc405f8ec5&cKey=e2313b32-d6ac-4443-ab2d-49c368ea3b89&mKey=19573a54-ae8f-4e00-9c23-bd6d62268424 . So, should I go get Gardasil 9? I'm in my late twenties with years of ongoing on/off abnormal paps, positive high-risk hpv tests, colposcopies, and biopsies. It's starting to get a bit annoying.

Anyways thanks again for the chat and for entertaining my extensive lines of questioning. I can't promise I won't be back in the future, though perhaps this kind of forum is not an appropriate platform for "diving deep into the weeds"... :)

All the best
69 months ago
Just a quick addendum to point 3! I found this study which claims Gardasil does reduce risk of hpv disease recurrence post-treatment: http://www.onclive.com/publications/obtn/2010/march2010/gardasil_reoccurrence_hpv_disease . Has this research been debunked?
H. Hunter Handsfield, MD
69 months ago
1.  I would have thought low risk integrates with host DNA just as readily as high risk. But I'm an STD clinician, not an HPV virologist. I suppose they may be right and maybe that explains different likelihoods of long term persistence. As both Dr. Hook and I have said, you may well know more about HPV biology and immunopathology than we do.

2.  I'm not convinced that even the majority of people who know they are (or have been) infected with HPV feel the way you do. But I agree that more knowledge would help reduce stigma.

3.  You probably understood the typo:  "...no effect on recurrence OF warts...." In any case, the research on this is sold. Antibody is an easily measured aspect of immunity, but not the only component of immunity to most infections and often not the most important, especially in viral infections. Antibody alone prevents new infection, but probably has little role in limiting progression or preventing recurrence of established infections.

The investigators in the study you cite are highly accomplished and respected, but several other studies have not shown higher rates of non-vaccine types after vaccination. Most experts believe this is not espoecially common. That said, most people who meet basic vaccination criteria (mostly age <26) probably would benefit from Gardasil 9 to protect against 5 addtional high risk types. OTOH, those 5 types account for only about 20% of HPV related cancers (70% are due to HPV16 or 18), so many people at risk wouldn't consider it a very important additional benefit. In any case, I would not recommend it at your age. The risk of new HPV infections is low beyond age 26 (which is why vaccine efficacy hasn't even been studied over that age); and the statistical probability is that you and most others your age probably have already been infected with some of the 5 additional types.

The last citation you provide doesn't seem to be peer reviewed research, and it doesn't agree with other studies and expert consensus.

And that winds up this thread. Take care.