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.