[Question #2179] HPV clearance clarification

47 months ago
Hi Dr. Hook,

I have long followed you and Dr. Handsfield's counsel around HPV clearance and disclosure, and many years ago when I had (and presumably cleared) a wart infection, I understood and believed the logic/science behind your counsel, and proceeded on with life without giving it much further thought. Now, due to recent events and new partners, I am revisiting that old infection once again.

A lady last week wrote in asking how she could be diagnosed with HPV after a long, faithful and monogamous marriage and many years of negative tests. You told her, "We used to think that the infections then went away/resolved entirely but I think that current understanding is that it is more accurate to assume infections become quiescent but that from time to time infected persons may shed the virus." I have to admit this was very disheartening to read, as I have long assured myself I have nothing to worry about; I have gone without recurrence far beyond the CDC's 2-year clearance figure. However, I understand there are still a lot unknowns and we are constantly learning new things, so I am hoping you can shed some light.

So, what is this new knowledge that is seemingly turning current thought toward no longer believing HPV infections are transient? I do remember reading research from Johns Hopkins published c. 2012/2013 stating peak in HPV infection in peri-menopausal women might very well be reactivation, but I also remember feeling the methodology was quite flawed and inconclusive (e.g. only considered "new partners" as in <6 mos., and couldn't possibly account for wayward spouses common at that age). Is there new research beyond this? Is it possible some infections are transient and truly go away, while others lay dormant? If so, is there evidence to show likelihood of one outcome vs the other? Additionally, does any new research refer to high-risk infections only, or to low-risk infections too? The research I referred to previously only looked at 14 high-risk types, and as I have always understood it, low-risk types are much weaker and infection with them less able to persist in the body even at low, undetectable levels.

Thank you

Edward W. Hook M.D.
Edward W. Hook M.D.
47 months ago
I'll try to help.  You are asking questions which now relate to several papers, some as yet unpublished, which appear to indicate that in older persons there is occasional HPV which can be detected using molecular techniques. following clearance of infection.  Precisely how common this is or its significance is not clear and, in our opinion, this is not something to worry too much about .  The significance of this finding is not clear and certainly for you, having cleared your earlier infection, my advice remains the same- you should go forward without concern regarding your potential to infect future partners and, as long as you continue to practice routine , recommended screening, without fear of cancer.  Should you have an abnormal PAP smear or persistent HPV detected, your gynecologists can take next steps (there are many possible, depending on the abnormality detected).

s far as the focus of the studies we are now referring to, most have focused on HPV 16 or other, so-called, "high risk" HPV types (I do not like this term since most persons with HPV 16 do not suffer any long term complication or sequelae).

Admittedly, this I still being sorted out through ongoing studies but my bias is that were it a serious risk factor, studies performed to date would have demonstrated it.  I urge you not to worry or to let these new data negatively impact how you live your life.  EWH
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47 months ago
Thanks Dr. Hook.

I've recently started the first round of the Gardasil 9 vaccine - I got this very shortly after being with 3 new partners within the past 3 months, so statistically I'm being exposed to at least one new strain of HPV, probably more. I am wondering, if administered shortly post-exposure, but still in the incubation period, is there a possibility the vaccine will prevent the infection from coming to fruition? 

After you mentioned molecular testing techniques, I found news from the past week about a company that is doing molecular combing, looking at DNA strands to see if "high-risk" HPV DNA has integrated itself into the host genome, to more accurately predict cancer. The study I believe is referred to as EXPL-HPC-002. I wonder if this is what you were referring to? After learning about that, I did further digging and found this research from 2004 which, from what I can tell, essentially concludes that in general, high-risk vs low-risk HPVs have very different life cycles and survival mechanisms. It seems low-risk HPVs are a bit more suicidal (on an individual level, but perhaps more efficient in the bigger evolutionary picture), in that they have the habit of creating warts in order to spread, which are easily detected by the immune system alerting it to attack and eliminate the virus, whereas the high-risk HPVs are a bit sneakier and can integrate and persist undetected for longer periods of time. Are you familiar with this research? Is it well-reputed and/or still valid? 

I also found this very newly released research (today) that shows most often than not, in head and neck cancers, HPV 16 is persisting in an episomal state, rather than integrated into the DNA. Do we know anything about the ability of low-risk HPVs to persist in episomal form?

Thanks again
Edward W. Hook M.D.
Edward W. Hook M.D.
47 months ago
I'm please to hear you are getting vaccinated.  As you point out, statistically you may well have been EXPOSED to HPV but I would remind you that not all exposures lead to infection.  Whether or not having started the vaccine offers you any additional protection is unclear and probably unlikely.  The immune response to the vaccine begins several weeks after initial vaccination and is most likely protected shortly after the 2nd vaccination.  The 3rd vaccination appears to mostly consolidate the duration of protection.  I would not count on it preventing infection if you had one starting before or around the time you received your first vaccination.

The research that you found looks at the state of integration of HPV DNA into the host DNA which speaks to the pathological process which is thought to be part of the process of increasing the risk for development of pre-cancerous lesions.  Such tests however would not be more likely to detect HPV than other tests. 

I am unaware of any data to suggest that the presence of a wart as caused by HPV types 6 and 11, vs inapparent infection such as caused by HPV 16 and other somewhat higher risk types changes the immune response to HPV and find it unlikely as both are present and stimulate an immune response.  EWH 
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47 months ago
Hi Dr Hook,

Thank you for your prompt response. If the vaccine will not prevent the infection that began around the same time as innoculation, will it at least help to attack/clear the infection more quickly?

I am a bit confused where you said - "Such tests however would not be more likely to detect HPV than other tests." My reason for bringing up that 1st research was not about any perceived different kind of testing, but because it seemed to imply a distinct difference between the ability of low-risk vs. high-risk types to persist long term (that is, high-risk types integrate, while low-risk types don't). From the last paragraph:

Consequently, it is tempting to speculate that life cycles of mucosal high-risk and low-risk HPVs differ fundamentally. High-risk HPVs can frequently persist in an infected host cell at a low copy number for decades, often without causing clinically overt lesions. This is remarkable given that squamous epithelial cells are turned over very rapidly. A relatively small number of basal epithelial cells have characteristics of stem cells and constantly produce differentiation-competent squamous epithelial cells to maintain the integrity of the epithelium throughout the life of the organism (reviewed in reference 2). One might envision a scenario in which high-risk HPVs have evolved to be able to maintain their infected host cell in a stem cell-like state in order to establish a persistent infection. The high-risk HPV-specific biological activities of E6 and E7 may reflect this strategy. Low-risk HPVs may have evolved a life cycle that is optimized to rapidly produce copious amounts of progeny virus and readily form large productive lesions to maximize transmission of the virus to a new host. Such a model may predict that different HPVs may infect distinct target cells and that there may be differences in the persistence of viral genomes in infected host cells.

The reason I am interested is because this suggests to me that it is more likely for low-risk types to go away/resolve entirely, than say, type 16. Which is why I was wondering if the research is well-reputed/still seen as valid and relevant?

I am also not sure to what question you are responding with this: "I am unaware of any data to suggest that the presence of a wart as caused by HPV types 6 and 11, vs inapparent infection such as caused by HPV 16 and other somewhat higher risk types changes the immune response to HPV and find it unlikely as both are present and stimulate an immune response". Re: the 2nd study I linked, I was wondering whether low-risk types have ever been found to persist long-term in episomal form (as opposed to integrated into host DNA), similar to what was found in the study to be happening with high-risk type infections of the head and neck?

Anyways, I guess this is my last go, looking forward to your response.

Best
Edward W. Hook M.D.
Edward W. Hook M.D.
47 months ago
There is no evidence that vaccination changes the natural history of established HPV infection.  Some investigators have suggested that this might occur but at this time there is no scientific evidence that it does and I suspect that if vaccination did have a major roll in resolution of HPV infections, that would be well know by now.

I think you are over reading the significance of integrated vs episomal HPV.  Research on this topic has been quite extensive and while it is believed that an integration step increases risk for HPV related precancerous lesion progression, the precise role, frequency and biological significance is as yet undetermined and widely debated. The tendency of so-called high risk HPV to persist longer than lower risk types is well documented but not explained by the effect of integration.  As the author you quote indicates, that statement is speculation and while it makes for a logical story, it is unproven and has no known impact on the health of any single individual.   

My response in the final paragraph of your response was directed to your statement that "....in that they have the habit of creating warts in order to spread, which are easily detected by the immune system alerting it to attack and eliminate the virus, whereas the high-risk HPVs are a bit sneakier and can integrate and persist undetected for longer periods of time... and was meant to indicate the immune response to different HPV types is similar and the association of risk for pre-malignant changes in a small proportion of persons with higher risk HPV infections is a reflection of the virus, not the immune response to infection.    Sorry if that was not clear.

The questions your are asking about HPV biology, and episomal vs. intergrated HPV DNA are getting into areas of ongoing research which is, as yet unsettled.  While I appreciate your interest in the topic, I would caution you not to worry too much about it.

I hope some of my comments have been helpful to you. As you know, as this is the 3rd response to your questions, this thread will be closed later this evening. Take care.  EWH
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