Wednesday, April 20, 2005

Human Papillomavirus (HPV)

Via the excellent Alas, a Blog, I read an item about the human papillomavirus (HPV) vaccine and the Family Research Council, and I meant to post about it. FRC opposes the HPV vaccine because:

"Abstinence is the best way to prevent HPV", and "Giving the HPV vaccine to young women could be potentially harmful, because they may see it as a licence to engage in premarital sex".

FRC's stance is too uninformed to merit comment, and I'll leave it at that--there's just too much material to cover, to waste time on frivolous pronouncements. [Although, I must say, it would be interesting to know why reporters insist on getting quotes from FRC-type groups. They contribute nothing to the discussion. It doesn't seem like they have the conviction of their beliefs, and as such, can't be candid ("Based on our religion, we believe sexually active women, as well as random neonates are to be deprived of proper medical care."). Nor do they exhibit a knowledge of medical facts (e.g., for women, the proven benefits of genital cancer protection outweigh the potential risks of premarital sex; for neonates, at risk of life-threatening HPV diseases acquired via maternal transmission, sexual activity isn't even an issue).]

Back on topic, let's go over some facts about HPV, and the HPV vaccine.

[What follows is a brief, and selective discussion; reference articles used here, here, and here; some original text modified/rearranged for clarity.]

Before we start, keep in mind that human papillomavirus (genital warts), or HPV, and herpes simplex virus (herpes), or HSV, are not one and the same thing. [There are some pertinent similarities between the two: sexually transmitted, genital and nongenital lesions, different types, etc. For more on herpes simplex, go here.]

HPV Overview

Human papillomavirus (HPV) is a group of double-stranded DNA viruses [over 100 HPV types have been detected]; it produces lesions/tumors of the skin and mucous membranes. HPV can infect many different sites, including the larynx, skin, mouth, esophagus, and the anogenital tract.

The diseases caused by HPV fall into three categories [our focus is on the anogenital one]:

1. Nongenital Skin Disease (common warts, plantar warts, etc.)

Note: Common warts are not the same as genital warts and are caused by different HPV types.

2. Nongenital Mucous Disease (respiratory papillomatosis, cancer of the larynx, mouth, esophagus, etc.)

3. Anogenital Disease:

Note: Approximately 20 different types of HPV can infect the anogenital tract.

  • Genital warts [condylomata acuminata] (HPV types--6, 11, 30, 42, 43, 44, 45, 51, 52, 54)

  • Bowenoid papulosis (16, 18, 34, 39, 42, 45)

  • Bowen disease (16, 18, 31, 34)

  • Giant condylomata (Buschke-Löwenstein tumors) (6, 11)

  • Unspecified intraepithelial neoplasia (30, 34, 39, 40, 53, 57, 59, 61, 62, 64, 66, 67, 68, 69)

  • Low-grade intraepithelial neoplasia (6, 11, 43)

  • Intermediate intraepithelial neoplasia (31, 33, 35, 42, 44, 45, 51, 52)

  • High-grade intraepithelial neoplasia (16, 18, 56, 58)

  • Cancer of vulva (6, 11, 16, 18)

  • Cancer of vagina (16)

  • Cervical cancer (16, 18, 31)

  • Cancer of anus (16, 31, 32, 33)

  • Carcinoma in situ of penis (erythroplasia of Queyrat) (16)

  • Cancer of penis (16, 18)

    Note: About 90% of genital warts are caused by 2 specific HPV types (6 and 11) and are the least likely to have cancer-causing potential.

    Other less common types have been strongly associated with premalignant and malignant cervical cancers in women. HPV-16 is responsible for about 50% of cervical cancers, and types 16, 18, 31, and 45 together account for 80% of cancers.

    Now, in order to understand the thinking behind the HPV vaccine, you need to understand HPV replication, lesions, and their malignant potential, especially in women. [What follows is a gross oversimplification.]

    HPV Replication

    HPV infection results in local infections* which can be clinical (grossly apparent--e.g., the warty lesions on the labia/penis; subclinical (can't see lesion with naked eye--e.g., cervical lesions); or latent (detected only by DNA tests). Most HPV infections are latent; clinically apparent infections usually result in warts rather than cancers.

    *[In men, genital warts can infect the urethra, penis, scrotum, and rectal area. Lesions can also be hidden or undetectable (e.g., in the inner aspect of the uncircumcised foreskin).

    In women, genital warts usually occur in the moist areas of the vulva (e.g., on the labia, or vaginal lips), and in the anorectal area. Subclinical lesions are common on the cervix, and in the vaginal canal.]

    The viral particles are able to penetrate the skin and mucosal surfaces through microscopic abrasions in the genital area, which occur during sexual activity. Once cells are invaded by HPV, a latency (quiet) period of months to years may occur. [The exact incubation time is unknown, but most investigators believe the incubation period is 3 months.]

    Once inside the infected cell (the host), the virus starts to replicate. Low risk HPV types (6,11), the ones associated with the clinical, genital warts, lesions replicate without incorporating their genetic material into the host cell's DNA.

    In contrast, the high-risk HPV types (16,18) incorporate a portion of their genetic material into the host DNA. So what, you might ask?

    The incorporated viral genetic material can alter the host cell's growth regulation. [A healthy host cell has tumor suppressor genes; these genes inhibit the cell's unregulated growth. The virus inactivates the cell's tumor suppressor genes, resulting in unregulated host cell proliferation and cancerous transformation.] OK, but how does this explain preferentially vaccinating girls vs. boys? Two words: Transformation zone (TZ).

    If you recall your basic anatomy, the cervix, the lower part of the uterus, is partly located inside the vagina. Somewhere on the cervix there's an area of transition--from the vaginal-type tissue, to the uterine-type tissue. This area is called the TZ, and it's an area of active cellular change. Approximately 90% of cervical cancers occur in this small anatomic region. There is no TZ equivalent on the penis.

    So, the virus "likes" active tissue, like the TZ, and younger women [pregnant women also] tend to have a more active TZ vs. older women. But that is not the only HPV-related disadvantage young women have. They are also less likely to have developed immunity to HPV.

    To place immunity to HPV in context, we need to look at the type of lesions caused by the HPV virus.

    HPV Lesions

    The major complication from exposure of the vulva, vagina, or cervix to HPV is the development of dysplasia [the abnormal host cell changes caused by the virus]. This dysplasia is graded**--from low-grade, to high-grade, and cancerous changes.

    **[Progression of cervical dysplastic change to cancer occurs in a predictable pattern. The latent period between infection with a cancer-causing HPV virus and demonstration of Pap smear abnormalities can be measured in years. Once dysplastic changes are initiated, the degree of dysplasia typically slowly worsens as the cellular changes progress toward cancer. The host's cells first become atypical then demonstrate low-grade dysplastic changes followed by high-grade changes, and, ultimately, cancer develops. Spontaneous resolution of lesions at each level of dysplasia has been demonstrated, but this becomes less likely as severity increases. Rapid progression of dysplastic lesions to invasive cancer also has been described. (This is why all irregularities, regardless of lesion grade, need to be evaluated!)]

    Recall that the HPVs that infect the human cervix fall into 2 broad categories. The low-risk HPV types (6, 11), which usually cause genital warts, are associated with low-grade lesions but are rarely, if ever found in invasive cancer. These HPV infections are associated with mild dysplasia that is often transient in nature. Many patients with mild dysplasia of the vulva, vagina, or cervix experience spontaneous regression of these lesions. [The majority (78.3%) of low-grade lesions regress spontaneously. Genital warts may go away on their own in about 10-20% of people over a period of 3-4 months.]

    In contrast, the high-risk HPV types (mostly 16 and 18) in subclinical, cervical lesions, are found in 50-80% of dysplastic lesions, and in up to 90% of invasive cancers. Patients who are exposed to these high-risk HPV types are at risk for developing high-grade dysplasias or carcinomas. [The development of cancer occurs in a small percentage of these patients who do not have therapy for dysplasia.]

    So, HPV infections are transient in the vast majority of patients [infections clear spontaneously within months to a few years]. How is that possible?

    If you are immunocompetent***, your immune system kicks in and stops the viral replication. [Unless the woman is constantly exposed to different HPV types, the prognosis of immunocompetent women diagnosed with condyloma acuminata is excellent. Patients who do not develop immunity to HPV can develop potentially serious sequelae.]

    ***[Women who are immunocompromised due to immunosuppressive drugs or HIV infection are at higher risk of developing persistent disease. These women have a higher incidence of developing dysplasia of the vulva, vagina, or cervix.]

    Pregnancy and HPV

    During pregnancy, there is an increased prevalence of anogenital HPV infections--from the first to third trimester. [In the postpartum period there's a significant decrease; the warts often disappear on their own after pregnancy.] Dormant (quite) infections may become activated, and rapid growth can be observed.

    Factors responsible include suppression of immunity during pregnancy and hormonal changes.

    The risk of condyloma acuminata in pregnancy is 3-fold. First, the lesions can become large enough to obstruct labor. Secondly, the virus can be transmitted**** to the infant, resulting in laryngeal warts. [HPV can cause a very serious condition in children called recurrent respiratory papillomatosis (RRP). This is a life-threatening disease of the respiratory tract.] The warts appear and spread quickly, sometimes dangerously blocking the child's airway. Thirdly, pregnancy is a cofactor in the malignant transformation of HPV-infected tissue

    ****[Vertical transmission of HPV can occur via in utero exposure to amniotic fluid or transmission of HPV from the maternal genital tract. An incubation period of several months usually is required between virus infection at delivery and clinical manifestations in the infant. The average latency period is 3 months, but periods as long as 20 months have been reported.]

    Approximately 5% of all births in the U.S. are at risk for neonatal HPV exposure. But the good news is that the frequency of childhood laryngeal papillomatosis is extremely low (~ 2000 cases/year). This would imply the transmission rate from mother to infant is low

    Treatment

    A few words about HPV treatment.

    Anogenital HPV is a sexually transmitted infection. Approximately two thirds of individuals who have sexual contact with an infected partner develop genital warts. You have a 60% risk of getting the infection in a single sexual contact with someone who has genital warts.

    The only way to prevent HPV infection is to avoid direct contact with the virus, which is transmitted by skin-to-skin contact. [Because the warts themselves are infectious, avoid touching them.] Latex condoms offer some, but not complete, protection from transmission. However, always use a condom with vaginal, anal, or oral sex, because the virus may be found in the semen in the absence of visible warts.

    If your sexual partner has visible genital warts, avoid sexual contact until treatment is completed. [The sexual partner(s) of a woman with condyloma should be examined by a physician and treated if indicated. Often the examination of the male fails to reveal any visible condyloma. If need be, men can also undergo colposcopy; the examination is usually done by an urologist.]

    No single treatment is effective in eliminating warts and preventing them from coming back. [Here's a patient-friendly list of available HPV treatments.]

    An aside: Based on my clinical experience, let me single out one treatment for special praise: Aldara (Imiquimod). I've used all the available HPV treatments, and, in the medical group, Aldara stands out. In my experience, 100% success rate, and very well tolerated (a few instances of local skin irritation). If appropriate for you, I strongly recommend it. [And no, I have no financial connections to the company.]

    The important thing you should understand about HPV treatment is that when you treat HPV you do not eliminate the HPV infection; you're only eradicating an area of dysplasia. Think of it this way: A house has termites (house = your tissue; the termites = HPV virus). HPV treatment is equivalent to removing the part of the house with the worst termite damage, and the local termites. The rest of the house, and termites stay in place. [No evidence demonstrates that treatment eliminates HPV infection or that it decreases infectivity. In fact, warts may recur after treatment because of activation of latent virus present in healthy skin adjacent to the lesion.]

    Regardless of the mode of therapy chosen, recurrence rates are high for any patient with condyloma acuminata. Most patients who develop recurrent or persistent disease are diagnosed within 6 months of therapy.

    Finally, one more important point about treatment: Not everybody infected with HPV needs treatment. [This is not medical advice; use it as a discussion point with your own Ob/Gyn.] Because most HPV infections regress spontaneously when the immune system controls viral replication, the need to treat subclinical or mild disease is controversial. Treatment is not recommended for subclinical anogenital and/or mucosal HPV infection in the absence of coexistent dysplasia. Treatment usually is reserved for patients with visible vulvar warts.

    HPV Frequency

    Frequency of HPV infection in the population is difficult to estimate accurately. [Genital warts] are clinically apparent in 1% of the sexually active population. Molecular studies indicate 10-20% of men and women aged 15-49 years have been exposed to HPV. Prevalence of HPV is higher in certain populations. Data from sexually transmitted disease clinics indicate a prevalence rate of 4-13%.

    The prevalence of condyloma acuminata seems to be similar in men and women. One study from a sexually transmitted disease clinic in the state of Washington found 13% of men and 9% of women had condyloma acuminata.

    Based on clinical observations, incidence of HPV infection clearly has increased in the last 35 years.


    The highest rates of genital HPV infection are found in sexually active women younger than 25 years, even after correcting for the number of lifetime sexual partners. [The reason for the higher prevalence in younger women is not completely understood.] Most of these infections seem to be transient [One study found that the rate of HPV infection is twice as frequent in women younger than 30 years as it is in women older than 30 years.]

    Bottom line: The HPV vaccine is aimed at preventing persistent high-grade cervical lesions caused by HPV types 16 and 18, as well as low-grade lesions/genital warts caused by HPV types 6 and 11. Interim trail results have been very promising and, once approved, this vaccine will be a very important addition to women's healthcare.

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  • 18 Comments:

    At 1:37 AM, Anonymous Anonymous said...

    What side effects has the vaccine shown? Should potential recipients be notified of all potential risks and their likelihood and informed that abstinence is a risk free alternative?
    5in9years

     
    At 3:09 AM, Blogger ema said...

    5in9years,

    The only significant adverse event associated with the vaccine was mild to moderate pain at the injection site, Dr. Barr said.

    Abstinence is not a risk free alternative (e.g., here).

     
    At 3:29 AM, Anonymous Anonymous said...

    I doubt we'll agree on the definition of abstinence-signing a pledge card isn't exactly the same thing. I agree the vaccine may be a valid alternative. I'd be interested in whether other risks show up later on. As a parent of potential patients, we definitely have the right to know about them. I'm bothered that a vaccine with as yet unknown side effects automatically becomes a better alternative than avoiding a behavior. Who would you recommend be vaccinated?
    5in9years

     
    At 3:42 AM, Blogger Mithras said...

    The only way to prevent HPV infection is to avoid direct contact with the virus, which is transmitted by skin-to-skin contact. ... [A]lways use a condom with vaginal, anal, or oral sex, because the virus may be found in the semen in the absence of visible warts.

    I'm confused about something. If the virus is transmitted by skin-to-skin contact, why are condoms necessary for oral sex? I thought each virus was specific to the skin type it infects; e.g., the type which infects genital skin would not infect mouth skin. Is that incorrect?

     
    At 3:42 AM, Blogger bitchphd said...

    Anon, what if--god forbid--your girls are raped? Or what if, despite everything, they just once have a moment of weakness, even if they don't allow full penetration, but there's some genital contact? People do make mistakes. Are you willing to run the risk that your daughters will get cancer if they make a mistake, or if they are raped? What if they marry a man who, say, hasn't himself been abstinent, or has made a mistake of that sort once or twice?

    It seems to me that a vaccine that could prevent 90% of one type of cancer is one I'd want for my child.

     
    At 5:12 AM, Blogger ema said...

    mithras,

    Unfortunately, HPV isn't that specific. Genital HPV types can cause "oral" disease in both children (see the pregnancy section), and adults. Here's more on adult-onset recurrent respiratory papillomatosis:

    HPV, the same virus associated with cutaneous warts, genital condyloma, and cervical cancer, causes RRP [recurrent respiratory papillomatosis]. While more than 20 types of HPV can cause genital warts, only 2 of these, HPV-6 and HPV-11, cause the vast majority of cases of RRP.

    5in9years,

    I'm bothered that a vaccine with as yet unknown side effects automatically becomes a better alternative than avoiding a behavior.

    Two points, if I may. First, the vaccine didn't automatically become a beter alternative. It become a better alternative when, after testing, it was shown to be effective [e.g., 94% effective in preventing persistent HPV 16 infection and 100% effective against cervical intraepithelial neoplasia (CIN) grades 2 and 3, compared with placebo over 3.5 years]

    Second, I understand what you're saying about abstinence, but you're talking about theory; my point was about practice. Abstinence, as practiced in the real world, has not been shown to be effective. Moreover, preventing HPV by avoiding a behavior is an alternative only for people who decide never to become sexually active (remember, HPV infection takes 2 people).

    Who would you recommend be vaccinated?

    It's too early to say, but based on the avilable data women aged 16-23 years. [The study also included a small number of men, but I haven't seen the data on males yet.]

     
    At 8:38 AM, Anonymous Anonymous said...

    Good points. I still would not encourage my children (would it be available to males in order to protect future partners?) to receive such a vaccine until it had been on the market for several years. I tend to be skeptical of any claims of safety of new drugs and treatments.
    5in9years

     
    At 3:21 AM, Anonymous sachacat said...

    Vacines for diseases are not just about protecting one person. Vacines are about reducing the risks of a disease for EVERYONE by reducing the number of carriers of a disease. Being vaccinated against a disease is therefore a matter of good conscience.

     
    At 11:52 PM, Anonymous Anonymous said...

    About 80% of all women will acquire HPV. It would be awesome to have injections to prevent this. I would be the first to try it out, thats for sure?

     
    At 6:18 AM, Blogger SexualEnhance said...

    I skim a lot of blogs, and so far yours is in the Top 3 of my list of favorites. I'm going to dive in and try my hand at it, so wish me luck.

    I've got a site you might be interested in (mine is about acne ) I know, it sounds strange, but it's like anything, once you learn more about it, it's pretty cool. It's mostly about acne related articles and subjects.

     
    At 7:21 PM, Blogger DL1976 said...

    My girlfriend is waiting for a biopsy for her throat after her doctor found a lump, I am worried that this may be due to HPV related RRS after doing some research on the internet. I have been with my girlfriend for 9 months and have been faithful but when I was in my early and mid 20's I had many casual encounters with people (well over 30) who were pretty promiscous (as was I back then). I am worried because I know that HPV has no symptoms for men and its prevalence means I have a high likelihood that I have been exposed to it given my sexual history.I don't what to do,does having HPV mean that I will never be able to get married, have kids, or have a normal sexual relationship with my girlfriend? If she indeed does have something in her throat or larynx area as a result of HPV, does this stay with her for life? Are the vaccines being mentioned here also treat HPV or are thehy only preventative for those who don't have it? Finally, I cam across a company in California called Stressgen (www.stressgen.com) who is currently developing some sort of vaccine I think is called CoValt or HSPe7...does anyone know much about this...is it effective or even on the market? If so I would be interested in finding out if it is helpful for current HPV patients. I would greatly appreciate if anyone knows the answers to any of these questions, please email me at saywhat762@hotmail.com, I feel like HPV is a life sentence of sorts but I am more worried about my girlfriend and what this could mean for her, she in great discomfort right now and is waiting for the biopsy on her throat.
    Thanks
    D

     
    At 2:12 PM, Anonymous Anonymous said...

    I have been in a manogomis relationship for almost 2 years. my last pap smear in March 05 was normal, today I found out I have HPV, does that mean my partner gave it to me?

     
    At 7:38 AM, Anonymous Zapata said...

    What sachacat said, in spades. Vaccinations are required by society to protect US from YOU. Some vaccines (e.g., Whooping Cough) actually have a miniscule chance of killing the child who gets the vaccination, so the safest thing for _your_ child (not every child, just yours because your child is especially special) would be to not let your child get the Whopping Cough vaccine but make every other child get the vaccine (and take the risk). In the real world your child isn't any more special than anyone else's child so we make you get him/her vaccinated before we let the child come to elementary school. Perhaps someday getting this vaccination will be a requirement for any girl or boy to come to high school. Yes, I know your child doesn't need it but--guess what!--we don't believe you and want to protect our children from your child.

     
    At 1:52 PM, Anonymous Anonymous said...

    I was diagnosed with HPV after an abnormal Pap last June. Had the colpop, it was low risk. Then, in december, the pap smear came back normal. Now, in May, the pap smear is once again abnormal. Is this due to the same HPV strain being more high risk than thought, or is it probably infection with a diff strain as I had switched partners around the time of Jan?

     
    At 11:40 PM, Anonymous Anonymous said...

    I am at risk of developing cancer due to an HPV infection and would like to share one concern: does penetration help spread the 'virus-settlement' in my cervix? would that make my condition worse? - Please do express your level of certainty when you reply. Thank you very much

     
    At 7:37 PM, Anonymous Anonymous said...

    I am a 55 year old man currently being treated for tonsilar cancer that was caused by HPV-16.

    I know this because my tonsil biopsy was sent to John's Hopkins Hospital in MD and tested positive specifically for HPV-16. (Further, I've not any used tobacco products for 28 years.)

    My understanding is that about 1/3 of all oropharyngeal cancers are caused by HPV. The rest are caused by tobacco use. The prognosis is much better for those caused by HPV. So, if you must have this cancer, its better that it be due to HPV.

    I've enjoyed unprotected oral sex (cunnilingus) all my life and have had many sexual partners over the past 40 years. I am probably not going to quit oral sex (or use protection) now.

     
    At 7:49 PM, Anonymous Anonymous said...

    I'm the guy who posted that I am currently being treated for tonsilar cancer that was caused by HPV-16.

    I want to add that I have NOT been sexually active at all during the past 2.5 years and I had no symptoms prior to my recent diagnosis. From this I conclude that HPV can remain dormant (while presenting no symptoms) for many years.

    I strongly favor the use of HPV-prophylactic vaccines (like Guardasil or Cervarix) in young women AND young men. I also hope that researchers will soon develop a vaccine intended to TREAT existing HPV infections.

     
    At 6:21 AM, Anonymous aldara said...

    HPV are common viruses that can cause warts. There are more than 100 types of HPV. Most are harmless

     

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