F

K A R E N F. K E L L E Y , M P H M I R I A M A. G A L B R A I T H , R N , M P H S T E N H. V E R M U N D , M D , P H D

Gevtital Human Papillomavirus Infection in Women Objective: To enhance nurse clinicians’ knowledge of genital human papillomavirus infection in women. Data sources: Several literature searches using the following terms, dating back to 1986: human papillomav irus (HPV), females, human, cervical neoplasia, risk factors, condylomata acuminata, detection, epidemiology, pathology, psychology, Papanicolaou test, immunosuppression, HIV infection, and AIDS. Study selections: Forty-three formal research studies regarding the association of various types of HPV infection with cervical intraepithelial lesions, the putative precursor lesionsfor cervical neoplasia; the outcomes of diagnostic techniques for HPV types; the outcomes of diagnostic/ screening techniques for abnormal cervical cells; the association of risk factors for acquiring HPV infection; or the outcomes of therapy. Some additional references were chosen for their presentation of epidemiologic or surveillance data, others for their scientijic discussions on related topics. Data extraction: Data were abstracted according to summary measures of the parameter of interest in the sample studied. In most instances, it was the prevalence of HPV, cervical neoplasia, or frequency of use of screening tests. Data synthesis: Immunosuppressed clients are at particular risk for HPV-mediated cervical neoplasia. Conclusion: Because Papanicolaou tests are an efective screening tool, cervical cancer is easily detectable. The nurse may facilitate treatment. This is an especially important issue for young women, among whom sexual activity is growing-with attendant increases of HPV and HIV infection. Accepted: May 1992

November/December 1992

or many years, epidemiologic research has indicated a connection between multiple sexual partners and cervical cancer (Cobb, 1990), and more recent virologic studies have implicated human papillomavirus (HPV) in the oncogenic process (Morrison et al., 1991; Reeves et al., 1989; Ritter et al., 1988). Consultations on genital warts, the principal clinical manifestation of HPV infection, have increased tenfold from 1966 to 1987 to more than 1.8million (Aral & Holmes, 1990), suggesting that HPV infection is one of the most common sexually transmitted diseases. Despite the high prevalence and potential pathogenicity of the virus, many health professionals are not familiar with HPV, in part because it is usually asymptomatic. Its biology is also not well characterized because all attempts to grow the virus in tissue culture have failed. Clinical diagnosis can be made in only a minority of cases (i.e., in persons with genital warts); in general, researchers must use cytologic or technologically sophisticated molecular biologic methods for a reliable diagnosis. Although there is no good chemotherapy, some treatment modalities are used for clinically apparent lesions. Women who engage in multiple unprotected sexual encounters or who have sexual partners at high risk for sexually transmitted diseases are especially vulnerable to HPV infection and its long-term sequela, cervical cancer; these

HPVis an extremely

common infection among sexually active women.

women should be considered prime educational and screening candidates. This article reviews the pathology of HPV, its transmission patterns, and the clinical management of infected patients. It discusses how nurse clinicians can be effective in the primary prevention of HPV and how they can facilitate early diagnosis and treatment of cervical neoplasias in women.

De$nition and Prevalence HPV may cause warts anywhere on human epithelial surfaces, including the cervix, vagina, and vulva. These warts may be visible on the external genitalia (see Figure l), but the majority of genital tract infections are asymptomatic and inapparent on routine clinical inspection. To date, more than 60 molecular types of HPV have been identified, of which about 15 have been isolated in the genital tract. Some of these

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HIV-negative participants), and women attending a colposcopy clinic in the same city were found to have a 60% prevalence of HPV infection (Ritter et al., 1988; Vermund et al., 1991). Adolescents attending a general clinic had a 38% prevalence of HPV (Rosenfeld, Vermund, Wentz, & Burk, 1989). Reporting HPV data with age-specific rates is advisable, given the lower prevalence rates noted in older women (Morrison et al., 1991). Data from selected HPV prevalence studies Certain types of HPV are associated with the development of cervical dysplasia. Figure 1. Ti pica1 gtnital condvloma accuminatu (wart)in an adolescent white ,fitmale (X2). (Courtay. Walter D. Rosenjeld. MD. MonteJiore Medical Centw l3ron.n: N Y . )

types are believed to be relatively harmless and selflimiting, whereas others have demonstrated the potential to progress to advanced cervical lesions, including invasive cancer (Syrjanen et al., 1987). For example, HPV types 16, 18, 31, 33, 35,45, 51, 52, and 56 are more pathogenic than types 6 and 11 (Reid & Lorincz, 1991). Flat condylomata, warts that do not protrude far beyond the epithelial surface and that are, therefore, generally invisible without the use of a colposcope, may be associated with those HPV types considered pathogenic (Schneider, Kirchmayr, & Gissmann, 1988). Because infection is not reportable and is not routinely assessed, there are no reliable estimates of HPV prevalence in the general North American population. Furthermore, investigators' techniques differ substantially in cell-sampling strategies (e.g., scrape/swab, scrape/cytobrush, and cervical lavage), in molecular hybridization techniques [e.g., ViraPap (Digene Diagnostics, Inc., Silver Spring, MD), Southern blot, and polymerase chain reaction], and in populations sampled (Brandsma, Burk, Lancaster, Pfister, & Schiffman, 1989; Vermund et al., 1989b). Worldwide prevalence of HPV infection is similarly unknown. Nearly all published studies have been limited to women living in larger cities in industrialized countries. Investigators have found different prevalence rates of HPV using identical methods in various populations of chiefly black and Hispanic women in a single borough of New York City. Women from the Bronx, New York, who were at high risk for infection with the human immunodeficiency virus (HIV) had a 39% prevalence of HPV (53% in HIV-positive participants and 22% in

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show lower rates of HPV infection among women attending health clinics for gynecologic examinations, higher rates among women at risk for HIV infection, and the highest rates among women with abnormal Pap smears (see Table 1). The link between HPV and invasive cervical cancer currently represents the virus' greatest known health threat to women, a threat that appears to be magnified in those who are immunosuppressed (Vermund & Kelley, 1991). HPV infection is common among women with HIV disease, and strong associations have been found between HPV infection and squamous intraepithelial lesions in symptomatic HIVinfected women (Vermund et al., 1991). With the growing number of women with HIV infection and the growing use of antiretroviral therapy, which prolongs their lives, there will be an expanding pool of women susceptible to persistent HPV infection and, therefore, cervical cancer (Maiman, 1991). Other findings suggest that HPV may pose an even more serious threat to women. In at least two studies, a history of genital warts was associated with risk for HIV infection (Quinn et al., 1988; Winkelstein, Samuel, Padian, & Wiley, 1987). If the violation of epithelial integrity from HPV were to facilitate HIV inoculation, as is postulated with genital ulcerative diseases, such as chancroid, syphilis, and herpes (Vermund, Sheon, Galbraith, Ebner, & Fischer, 1990), then HPV infections in zones of high HIV endemicity in North America may actually contribute to the spread of HIV.

Transmission and Risk Factors Genital sexual contact is likely to be the primary route of HPV transmission, although in cases of oral or anal sex, HPV can be transmitted to or from the mouth, throat, or anus. Infection generally occurs in areas that receive trauma during sex, but it may also spread to

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Genital HPV 1nf;ction

Table 1. Selected U.S.HPV Prevalence Studies Reference

Location

Sample

Methodology

Rate PA)

Ritter et al., 1988

Bronx, NY

CVL. Southern blot

60

Kiviat et al., 1989

Seattle, WA

Abnormal Pap/CIN ( N = 191) STD clinic ( N = 454) SH clinic ( N = 545)

Scrape/swab, dot/blot hybridization

STD clinic, 11

SH clinic, 9

Vermund et al., 198913 Goldberg et al., 1989

Bronx, NY Bronx, NY

Colposcopy clinic patients ( N = 48) Colposcopy patients ( N = 74)

Sexually active adolescents ( N = 297) Upper SES, private gynecologic practice patients ( N = 398) HIV+ or at risk for HIV infection ( N = 96)

CVL and scrape/swab,

35

Swab, Southern blot

13

CVL, Southern blot

HIV+, 53 ViraPap 11 PCR, 46 Southern blot, 73

Rosenfeld, Vermund, Wentz, and Burk, 1989

Bronx, NY

Lorincz et al., 1990

Washington, DC

Vermund et al., 1991

Bronx, NY

Bauer et al., 1991

Berkeley, CA

University health service ( N = 467)

Swab, ViraPap, PCR

Morrison et al., 1991

Bronx, NY

Inner-city women with abnormal Pap

CVL, Southern blot ( N = 83), PCR ( N = 65)

( N = 148)

Cytologically normal

Bronx, NY

Jailed women ( N = 114)

38

HIV-, 22

CVL, Southern blot ( N = 61), PCR ( N = 59)

( N = 120)

Bickell, Vermund, Holmes, Sayfer, and Burk, 1991

44

Southern blot CVL and scrape/Cytobrush, Southern blot CVL, Southern blot

CVL, Southern blot

PCR, 85

Southern blot, 16 PCR, 39 35

CIN, cervical intraepithelial neoplasia; CVL, cervicovaginal lavage; HPV, human papillomavirus; PCR, polymerase chain reaction; SES, socioeconomic status; SH, student health; STD, sexually transmitted disease.

adjacent areas of the genital tract. Male-to-male sexual spread has been demonstrated (Gal, Meyer, & Taylor, 1987), but female-to-female sexual spread has not been studied. Whether the virus can be vertically transmitted from mother to fetus (transplacentally or intrapartum) is unknown. Many children with recurrent respiratory papillomatosis are assumed to have contracted the infection intrapartum (Abramson, Steinberg, & Winkler, 1987; Smith, Johnson, Cripe, Pignatari, & Turek, 1991), but it is not known what proportion of childhood cases are attributable to the perinatal period. Furthermore, although HPV infection may be encountered in 5-30% of pregnant women, childhood papillomatosis is rare. The transmission of HPV is likely to be dependent

November/December 1992

upon the same risk factors as those associated with the transmission of other sexually transmitted diseases. These risk factors include unprotected sex with an infected male, repetitive exposure to the virus, and, possibly, a higher risk of transmitted infections in an immature adolescent cervix compared with an intact mature cervix (Brookman, 1990). Men with histories of promiscuity or sexually transmitted infections and men with penile cancer all may be associated with higher risks for HPV and cervical disease in their sexual partners. For example, the wives of itinerant salesmen and mariners are known to suffer from higher rates of cervical cancer, presumably related to HPV infections contracted by their husbands while away from home (Beral, 1974).

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Women who are immunosuppressed are at particularly high risk of HPVmediated pathology.

Table 2. Postulated Cofactors in HPV Pathogenesis 1. High-risk sexual behavior

Natural History Once the virus is transmitted, its natural history is likely to be subject to the influence of cofactors. Conditions affecting the cervical and vaginal epithelium may influence the persistence or accelerate the biologic progression of HPV to neoplasia. Among them is the presence of local toxins, such as from cigarette smoking (Brock et al., 1989); smoking constituents are found in high concentrations in cervical mucus (Schiffman et al., 1987). Similarly, serum nutrient levels, including vitamin C (Romney et al., 1985) and beta-carotene (Palan, Romney, Mikhail, Basu, & Vermund, 1988), have been suggested as cofactors, presumably because of their roles in epithelial stabilization. The use of oral contraceptives has been associated with both condylomata (Daling, Sherman, & Weiss, 1986) and cervical cancer (Brinton et al., 1986). However, alternative explanations of the association can be proffered. For example, confidence in the efficacy of birth control pills to prevent pregnancy may make the user feel freer to engage in sexual contacts without the protection of barrier contraceptives, thereby increasing the potential for exposure to HPV. Also, it has been suggested that oral contraceptives may blunt the local immune response to HPV (Koutsky, Galloway, & Holmes, 1988). It is plausible that the suppression of cellular immunity plays an important role in the prevalence of genital HPV and its progression to neoplasia. Studies of women undergoing immunosuppressive therapy (Halpert et al., 1986), women infected with HIV (Vermund et al., 1991), women identified as having local immunosuppression in the genital tract (Carson et al., 1986), and pregnant women (Schneider, Hotz, & Gissmann, 1987) have all reported a higher frequency of HPV and cervical abnormalities than in immunocompetent controls. An HPV-infected woman who smokes cigarettes, who has a history of oral contraceptive use, who is immunosuppressed, who is exposed to viral reinfection through multiple, unprotected sexual encounters, or who has further cervical insult with herpes simplex virus or other sexually transmitted infections is thought to be at higher risk for the progression of HPV infection to cervical cancer than are HPVinfected women without exposure to these cofactors. The precise mechanism of pathogenesis associated with such cofactors is unclear, and it is plausible that

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2.

3. 4. 5. 6. 7. 8.

9.

10.

Sex for money Early first coital activity Multiple sexual partners Lack of barrier contraceptives High-risk male partner (e.g., multiple sexual partners, HPV-infected sexual partners) Poor access to health care, including infrequent Pap screening Immunosuppression as a result of cancer, HIV, organ transplantation, or pregnancy Smoking Coinfection (e.g., herpes simplex virus, syphilis, HIV) Carcinogenic HPV type (e.g., types 16, 18, 3 1 , 3 3 , 3 5 ,

4 5 , 51, 52, 56) Persistence of HPV High intensity of HPV infection (i.e., molecular biologic tests revealing a high “copy” number, that is, the number of viruses in 2 single cell) Nutritional deficiencies, e.g., beta-carotene, ascorbic acid Use of oral contraceptives

HIV, h u m a n immunodeficiency virus; HPV, h u m a n papillomavirus

the women with exposure to them may also be at higher risk of HPV infection per se (see Table 2 ) . Studies that control for selected patient characteristics will be more useful in teasing out putative cofactors (Vermund et al., 1991).

Diagnosis and Screening HPV infection can be diagnosed indirectly by its clinical, cytologic, or pathologic manifestations, or by direct identification of the virus, which requires more sophisticated molecular diagnostic studies (see Table 3). Only direct diagnostic tests can provide a clinician with information on the type of HPV present.

Indirect analysis Although insensitive compared with molecular techniques, the most common diagnostic test for the presence of HPV is the Pap smear. The presence of koilocytes, a morphologic change distinguished by hyperchromatic nuclei and perinuclear depression occurring as a result of HPV replication (Melnick,

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Genital HPV Infection

Table 3. Comparison of Clinical and Laboratory Methods Currently Used to Diagnose Genital HPV

HPV diagnostic methods

Detects minimally productive infection

Detects different types

Biopsy required

Relative sensitivity for H P P

for HPV

Comments

Pap smear

Yes

No

No

++

+++

Inspection with the unaided eye

No

No

No

+

+++

colposcopy, cervicography, magnification with hand lens Electron microscopy

No

No

No

++

+

Detects the presence of koilocytes occurring as a result of HPV replication Detects productive infection associated with frequent transmission Necessary for obtaining tissue samples for DNA typing and diagnosis of neoplasia

No

No

Yes

+

++++

No

No

No

No

Yes No

++ +

+ +

Filter in situ hybridization Exfoliated cells

Yes

Yes

No

++

++

Dot hybridization Tissue Exfoliated cells

Yes Yes

Yes Yes

Yes No

+++ +++

+++ +++

Yes Yes

Yes Yes

Yes

+++

No

+++

++++

Yes

Yes Yes

Yes No

++++ ++++

Stain for papillomavirus group antigen Tissue Exfoliated cells

Southern blot Tissue Exfoliated cells Polymerase chain reaction Tissue Exfoliated cells

Yes

Relative speclJicity

++++ ++++b

Time consuming; detects 25-50% of histologically evident infections Positive in about 50% of histologically evident infections; no correlation between positive result and subsequent clinical course N o DNA extraction, high background problem; need relatively high copy number/cell to detect Relatively fast, simple, and suitable for widespread screening; less specific than Southern blot for HPV typing Detects new types; very labor intensive; not suitable for widespread screening Detects new types; not suitable for widespread screening

++++b

Adapted from Koutsky, Galloway, and Holmes (1988) HPV, human papillomavirus. a +, ++, and ++++ reflect lowest to highest sensitivity and specificity on the basis of limited data from studies of diagnostic test performance. In the absence of contamination or carry-over.

+++,

Rawls, & Adam, 1989), is indicative of HPV infection and generally warrants follow-up with a colposcopic examination (see Figures 2 and 3). Clinical detection of warts in the genital tract provides a specific diagnosis but misses the majority of HPV infections, which are asymptomatic. Flat condylomata, for example, are asymptomatic but can be observed on colposcopic ex-

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amination, most readily after using an acetic acid swabbing to highlight cervical abnormalities. Direct analysis Southern blot experiments are recognized as sensitive approaches that provide typing information (Schneider, 1987). However, Southern blot is also time con-

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suming, expensive, and poorly suited for widespread screening. A number of alternative diagnostic strategies are popular-in particular, dot (or spot) hybridization (Schneider, 1987), which is commercially available in kits such as ViraPap and ViraType (Digene Diagnostics, Inc., Silver Spring, MD). These techniques lend themselves better to mass screening than does Southern blot. Although available as a research technique only, the amplification of viral DNA is now possible with polymerase chain reaction techniques. It is not known, however, whether polymerase chain reaction is so sensitive as to detect DNA fragments in women whose viral burden is clinically inconsequential; this limits the test’s clinical utility. Electron microscopy and immunoperoxidase tissue staining (Schneider, 1989; Shu, 1989) also directly detect HPV virus, but their sensitivities are unacceptably low compared with molecular diagnostics (Koss, 1987). The utility of any of these techniques for detecting the virus directly is dependent on the quality of the cell samples drawn from the patient. The scrape/swab technique, as used in the Pap smear, is practiced widely, but samples collected by this method are often insufficient for research-quality studies (Kiviat et al., 1989; Vermund et al., 198913). A second technique, cervicovaginal lavage, samples cells from the cervix and vagina by spraying 10 mL of saline solution at the cervix and then collecting it from the posterior vaginal fornix. This method of cell collection has been shown to be superior to both scrape/swab (Vermund et al., 1989b) and scrape/Cytobrush@ (Medscand USA, Inc., Hollywood, FL [Goldberg et al., 19891) for the molecular diagnosis of HPV, but it is not likely to be used Figure 2. Normal cervical cells (X350). (Courtesy. Leopold Koss. MD, MonteJiore Medical Center. Bronx, NY.)

Figure 3. Koilocytes (X500). Note the large abnormal and sometimes multiple nuclei and the presence ofsharp[y demarcated perinuclear cavities. or halos. which gave rise to the name o f these cells (koilos = hollow). (Courtesy. Leopold Koss. MD. Mont~oreMedical Center, Bronx, NY.)

widely in routine clinical practice. (Cytobrushm, the commercial name for a tiny brush with angled bristles, is used to sample endocervical cells and harvests cells in greater volume than does a cotton swab [Goldberg et al., 19891.) Currently, regular Pap smears and clinical examinations are deemed adequate for HPV screening because no treatment is indicated in the absence of dysplasia. However, strong arguments are being made to introduce HPV assessments or high-resolution photographs of the cervix (cervicographs), or both, as adjunct screening tools (Reid et al., 1991). By increasing screening sensitivity upon a single clinical encounter, these may prove cost effective in high-risk populations of women who do not often avail themselves of a preventive health-care system (Bickell, Vermund, Holmes, Sayfer, & Burk, 1991).

Treatment Some cases of HPV respond to treatment. HPV has also been noted to regress on its own or, conversely, to progress independently of treatment (Nash, Burke, & Hoskins, 1987). Reinfection may occur easily, regardless of treatment, either by transmission from an infected partner, from regrowth of HPV-infected cells, or from the presence of HPV in epithelium that appears normal. Several treatment modalities, including chemical ablation, surgery, and immunologic therapies, are used and continue to be investigated in the treatment of genital warts. HPV infections are not curable with chemotherapy, as many bacterial infections

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Table 4. Protocols f o r Exfoliation Cytologic Screening Risk factors for cervical cancer

Screening recommendations

Factors indicating low risk N o coital experience Monogamous relationship Hysterectomy for nonmalignant disease Good access to health care; regular screening Factors indicating high risk Early age at first coitus Multiple sexual partners Oral contraception Cigarette smoking Immunosuppression

Begin regular screening soon after the initiation of coital activity or at age 18; after obtaining two negative annual smears, screen every 3 years if status remains low risk

Coinfection Poor access to health care; infrequent screening History of abnormal cytology with treatment

Daughter of a woman who received diethylstilbestrol during early fetal organogenesis

Screen annually

Screen every 6-12 months, and consider obtaining HPV test, or cervicography, or both Screen at least every 12 months, and consider cervicography Offer screening when patients present for treatment of other conditions Screen every 3 months for 2 years, then every 6 months for 3 years, and then annually if screen results are negative Begin screening at onset of menses or at age 14; if patient is sexually active, screen every 6-12 months

Adapted from Ginsberg (1991)

are with antibiotics. Rather, the goal of therapy is to control the growth of and discomfort due to lesions, as well as any neoplastic progressions. Therapy should always be accompanied by continued cytologic screening (see Table 4 ) .

was effective in therapy-resistant vaginal condylomata (Krebs, 1991). Furthermore, the use of 5-fluorouracil on a weekly or biweekly schedule to prevent vulvar and vaginal condylomata in immunosuppressed women has been successful (Krebs, 1991).

Chemotherapy Topical application of cytotoxic agents, such as podophyllin and trichloroacetic acid, is the easiest form of treatment of genital warts and may be used as the first course of action against the lesions. However, although lesions may initially respond to these treatments, recurrence rates are high (Stone, Becker, Hadgu, & Kraus, 1990). A side effect is scarring, which may occur with the use of either agent if the resin is not removed soon enough after its application. Podophyllin is also a teratogen and, therefore, must be used with caution in a population of women who may become pregnant. Virucides such as 5-fluorouracil are more expensive and potentially more toxic than other chemotherapeutics and also cause side effects. One study found that weekly application of 5-fluorouracil

Surgery or ablation Destructive or ablative therapies against visible lesions are usually employed only after chemotherapy has failed, when the lesions are extensive, or when squamous intraepithelial lesions or cervical intraepithelial neoplasia are noted on the Pap smear or biopsy. Electrocautery, cryotherapy, laser therapy, and conventional excision have all been used and provide immediate relief to the patient with a much smaller risk of relapse than with chemotherapies (Byrne et al., 1988;Jensen, 1985; Stone et al., 1990; Yliskoski, Saarikoski, Syrjanen, Syrjanen, & Castren, 1989). Of these methods, cryotherapyand the CO, laser have been the most successful. The disadvantages of all of these surgical treatments are their increased cost, the occasional need for general or local anesthesia, and side

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effects such as bleeding. Measures to ameliorate the discomfort of caustic therapy and surgery include the use of analgesics, warm baths, and the curtailment of vigorous physical activity to diminish bleeding. lmmunotherapies Investigational therapy centers on the use of interferon, applied either intralesionally or systemically. Several studies have confirmed initial observations that HPV-induced lesions regress with treatment, recur when treatment is stopped, and regress once again when treatment is reinitiated (Weck & Whisnant, 1987). Side effects of this therapy are severe at high doses; low doses, however, may be effective and may result in fewer side effects (Gross, Ikenberg, Roussaki, Drees, & Schopf, 1986). The need for long-term treatment makes immunotherapy an unlikely alternative for all but the most extensive and intractable cases. Nursing Implications Although many questions remain regarding the transmission, natural history, and pathogenesis of HPV, nurses can play a substantial role in combating the spread of HPV and reducing its pathogenic consequences. Despite the fact that HPV has been etiologically tied to cervical cancer, with appropriate screening and follow-up care, cervical cancer is a preventable disease.

The Pap smear is an eflectiue screening tool f o r identifying women with cervical dysplasia.

because the cytologic sample might become contaminated with blood. Estimates of the rate of false-negative Pap smear results range from 10-50% (Fetherston, 1983), and use of a cytology laboratory with excellent quality control procedures is suggested to assure valid results. Women who are screened infrequently by the Pap smear can be offered HPV screening and/or cervicography to improve screening sensitivity (Bickell et al., 1991; Reid et al., 1991; Ritter et al., 1988). Patient education at the time of screening The utility of patient education during the screening process has been demonstrated (Barsevick & Lauver, 1990; Lauver & Rubin, 1991). Nurses should anticipate the information needed by women to understand and cope with the results of screening. It is likely that an optimistic message regarding the preventability of cervical cancer will motivate a woman to undergo appropriate follow-up care. Counseling the HPV-infected woman If the patient is discovered to have HPV infection, the

The Papanicolaou Test The Pap smear can detect abnormal cervical cells and is an important screening tool to identify women with disease. Of particular importance to clinicians are the techniques and timing (during the menstrual cycle) for obtaining an optimum sample and appropriate schedule for screening (Ginsberg, 1991). The schedule should be tailored to the patient’s composite of risk factors (see Table 4). The prime time for cell recovery to detect cervical dysplasias in premenopausal women, and postmenopausal women who are receiving combination hormonal therapy, is the first half of the menstrual cycle (i.e., after menses and before ovulation). HPV detection does not appear to be affected by the hormonal variations that occur during the menstrual cycle. However, less than adequate samples for filter in situ hybridization have been recovered during menses from women who use oral contraceptives (McNicol et al., 1990). Pap smears are not done during menses because of the difficulty in visualizing the cervix and

nurse should discuss the sexual mode of acquisition, treatment options (if genital warts or squamous intraepithelial lesions are present), prevention of both reinfection and transmission to others using barrier methods, and measures in the patient’s realm of control that may forestall any progression to cervical cancer. For example, cigarette smoking and a diet deficient in beta-carotene may accelerate the pathogenic course of the virus (Palan et al., 1988; Schiffman et al., 1987). Additionally, patients should be advised to undergo Pap smear screening at intervals of at least every 12 months to detect cervical neoplasia early. Women who are immunosuppressed (CD4+ cell counts less than 200/mm3) should be considered at higher risk for cervical neoplasia and should be screened by Pap smear at least twice a year (Schafer, Friedman, Mielke, Schwartlander & Koch, 1991; Vermund et al., 1991). Patients who require caustic therapy for warts should be informed of the implications for sexual activity: Abstinence from oral and vaginal intercourse is necessary during therapy and afterward for several weeks, and the long-term use of barrier contraceptives may be suggested. Although condoms offer protection

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for the cervix, vagina, and penis, the perineal areas are still exposed, which may be problematic for women with wlvar warts and women who are exposed to men with crural warts. The news of abnormal Pap smear results can be stressful and can even provoke negative feelings toward sexual activity (Campion et al., 1988). The nurse can provide an opportunity for the patient to voice any anxieties about her perceptions of the implications of an abnormal result, as well as any frustrations experienced because of the need for temporary sexual abstinence or the therapy per se. Referrals for ongoing counseling may be appropriate in cases where shortterm counseling has not been successful. Optimally, an HPV-infected woman with a steady sexual partner will receive counseling together with that partner. The patient’s sexual partner requires education concerning HPV infection, treatment modalities, the rationale for modifying sexual practices, and how he can help support his partner. He should be encouraged to be tested and treated for HPV infection and to reduce high-risk sexual behavior, such as having multiple sexual partners and failing to use barrier contraception. Finally, the patient and her partner should be screened for other sexually transmitted diseases when appropriate, including syphilis, gonorrhea, chlamydia, Trichomonas, and HIV. Recognizing women at high risk f o r HPV infection The cardinal behavioral risk factors for HPV infection are coital activity at an early age, multiple sexual partners, and a high-risk male partner. The proportion of adolescent women engaging in premarital sexual activity in the United States has increased from 29% in 1970 to 52% in 1988, and women who begin coital activity before age 18 tend to have more sexual partners than those who begin after age 19 (Centers for Disease Control, 1991). It is important to convey the need for cervical screening once sexual activity is initiated, to discuss the risk of contracting sexually transmitted infections, to teach protective techniques, and to suggest communication strategies to use with a sexual partner to increase the use of barrier contraceptives. Adolescents who engage in sexual experimentation tend to have difficulty envisioning the consequences of their behavior (Hein, 1989;Vermund et al., 1989a), which may not become manifest for many years. In addition, embarrassment and fear restrain many adolescents from seeking Pap smears (Harlan, Bernstein, & Kessler, 1991) and from obtaining and using barrier contraceptives (MacDonald et al., 1990). Nurses who reinforce health-seeking behaviors, fully

November/December 1992

explain procedures, and encourage questions can assist adolescents in taking effective precautions against HPV and other sexually transmitted diseases. Women in their late teens and early twenties have been found to have the highest rates of both subclinical HPV infection and genital warts (Kiviat et al., 1989). Analysis of demographic data on women with cervical cancer has identified particular high-risk groups. Invasive cervical cancer occurs most frequently in women age 50 and older, whereas younger women (under age 4 0 ) experience higher rates of in situ cervical cancer (Devesa, Young, Brinton, & Fraumeni, 1989). The National Cancer Institute (1990) has found that blacks and Hispanics have especially high rates of cervical cancer. In fact, the cervix is the third most common site of incident cancer cases among black and Hispanic women and holds sixth place among white women (Page & Asire, 1985). Poverty may be more relevant than race or ethnicity to the incidence of cervical cancer. A study in Kentucky conducted over three time intervals, 1971-1975, 1976-1980, and 1981-1985, revealed mortality rates from cervical cancer that were twice the national average. The women studied lived in rural Appalachian counties, where 99% of the population is white and 25% of the families live below the poverty level (Tucker, Friedell, Stallones, Thompson, & Bagby, 1988). Harlan et al. (1991) suggested that, compared with blacks and whites, Hispanics were least likely to undergo Pap screening. Hispanic Americans tend to have lower median incomes and larger families; further, in 1987, nearly 26% of all U S . Hispanic families had incomes below the poverty level, compared with 9.7% of the general U.S. population (DeNavas, 1989). Poor women often lack knowledge related to Pap screening, have less formal education, and are less likely to be able to afford health insurance or have transportation to obtain Pap smears (Harlan et al., 1991). Programs that target women of modest means, and Hispanic women in particular (by providing personnel who speak Spanish and materials written in Spanish), are sorely needed. Cultural differences may affect the way the nurse should give advice. For instance, traditional Hispanic marital relations are based on strong Roman Catholic beliefs in which the husband predominates in decision making, including the choice of birth control methods. A desire to be faithful to church teaching may necessitate a decision against the use of artificial birth control (Mays & Cochran, 1988). Of course, appropriate medical advice should be proffered regardless of a patient’s religion, but awareness of a given religious perspective can facilitate a particular educa-

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Although HPV has been etiologically tied to cervical cancer, with appropriate screening and follow-up care, cervical cancer is a preventable disease.

cians, can playa vital role in preventing the spread and consequences of HPV.

Refer en ces

Although data for 1991 are not currently available, the number of new cases of cervical cancer in the United States in 1991 was projected to be 13,000, and the number of deaths due to cervical cancer was expected to be 4,500 (National Cancer Institute, 1990). In addition, the number of new cases of cervical cancer in Canada in 1991 was projected to be 1,200, and the number of deaths from cervical cancer was forecast to be 370 (National Cancer Institute of Canada, 1991). During the 1970s and 1980s, the incidence and mortality rates for invasive cervical cancer slowly decreased, in large part because of early detection by Pap smears (Devesa et al., 1989) and treatment of dysplasia. Although the use of the Pap smear has become much more widespread, the celebration of this success must be tempered by the observation that the rate of decrease has recently slowed, possibly owing to sexual liberalization, the drug epidemic, or HIV disease. As long as unprotected sexual activity is prevalent and viral sexually transmitted diseases remain without a cure, nurses, as health educators and clini-

Abramson, A.L., Steinberg, B.M., & Winkler, B. (1987). Laryngeal papillomatosis: Clinical, histopathologic and molecular studies. La yngoscope, 97, 678-685. Aral, S.O., & Holmes, K.K. (1990). Epidemiology of sexual behavior and sexually transmitted diseases. In K.K. Holmes, W. Cates, Jr., S.M. Lemon, & W.E. Stamm (Eds.), Sexually transmitted diseases (pp. 19-36). New York: McGraw-Hill. Barsevick, A.M., & Lauver, D. (1990). Women’s informational needs about colposcopy. Image-The Journal of Nursing Scholarsh@,22, 23-26. Bauer, H.M., Ting, Y., Greer, C.E., Chambers, J.C., Tashiro, C.J., Chimera, J., Reingold, A., & Manos, M.M. (1991). Genital human papillomavirus infection in female university students as determined by a PCR-based method. Journal of the American Medical Association, 265,472477. Beral, V. (1974). Cancer of the cervix: A sexually transmitted infection? Lancet, 1, 1037-1040. Bickell, N.A., Vermund, S.H., Holmes, M., Sayfer, S., & Burk, R.D. (1991). Human papillomavirus, gonorrhea, syphilis and cervical dysplasia in jailed women. American Journal ofpublic Health, 81,1318-1320. Brandsma, J., Burk, R.D., Lancaster, W.D., Pfister, H., & Schiffman, M.H. (1989). Inter-laboratory variation as an explanation for varying prevalence estimates of human papillomavirus infection. International Journal of Cancer, 43, 260-262. Brinton, L.A., Huggins, G.R., Lehman, H.F., Mallin, K., Savitz, D.A., Trapido, E., Rosenthal, J., & Hoover, R. (1986). Long-term use of oral contraceptives and risk of invasive cervical cancer. International Journal of Cancer, 38, 399-444. Brock, K.E., MacLennan, R., Brinton, L.A., Melnick, J.L., Adam, E., Mock, P.A., & Berry, G. (1989). Smoking and infectious agents and risk of in situ cervical cancer in Sydney, Australia. Cancer Research, 49, 4925-4928. Brookman, R. (1990). Adolescent sexual behavior. In K.K. Holmes, W. Cates, Jr., S.M. Lemon, &W.E. Stamm (Eds.), Sexually transmitted diseases (pp. 77-83). New York: McGraw-Hill. Byrne, M.A., Taylor-Robinson, D., Wickenden, C., Malcolm, A.D., Anderson, M.C., & Coleman, D.V. (1988). Prevalence of human papillomavirus types in the cervices of women before and after laser ablation. BritishJournal of Obstetrics and Gynaecology, 95, 201-202. Campion, M.J., Brown, J.R., McCance, D.J., Atia, W., Edwards, R., Cuzick, J., & Singer, A. (1988). Psychosexual trauma of an abnormal cervical smear. BritishJournal of Obstetrics and Gynaecology, 95, 175-181. Carson, L.F., Twiggs, L.B., Fukushima, M., Ostrow, R.S.,

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tional message, presenting it in a sympathetic and sensitive way.

Conclusion A significant need exists for further research on HPV

and cervical cancer. Among the areas that should be researched are the following: interventions to decrease unprotected sexual activity in adolescents and young adults; surveys of sexual practices among young adults, including specific ethnic groups; interventions influencing cofactors related to the development of cervical cancer; interventions that promote the use of Pap screening programs, particularly in the inner city, areas of ethnic minority populations, areas of high endemic HIV infection, and areas with poor women; supportive and educative interventions for emotional and informational needs related to HPV infection.

Genital HPV Infection

Faras, A.J., & Okagaki, T. (1986). Human genital papilloma infections: An evaluation of immunological competence in genital neoplasia-papilloma syndrome.American Journal of Obstetrics and Gynecology, 155, 784789. Centers for Disease Control. (1991). Premarital sexual experience among adolescent women-United States, 19701988. Morbidity and Mortality Weekly Report, 39, 929932. Cobb, M.W. (1990). Human papillomavirus infection.Journal of the American Academy of Dermatology, 22, 547566. Daling, J.R., Sherman, K.J., (3r Weiss, N.S. (1986). Risk factors for condylomata acuminatum in women. Sexually Transmitted Diseases, 13, 16-18, DeNavas, C. (1989). The Hispanicpopulation of the United States: March 1988. Washington, DC: U.S. Government Printing Office. Devesa, S.S., Young, J.L.,Jr., Brinton, L.A., & Fraumeni, J.F., Jr. (1989). Recent trends in cervix uteri cancer. Cancer, 64, 2184-2190. Fetherston, W.C. (1983). False-negative cytology in invasive cancer of the cervix. Clinical Obstetricsand Gynecology, 26, 929-937. Gal, A.A., Meyer, P.R., &Taylor, C.R. (1987). Papillomavirus antigens in anorectal condyloma and carcinoma in homosexual men.Journal of theAmerican MedicalAssociation, 257, 337-340. Ginsberg, C.K. (1991). Exfoliative cytologic screening: The Papanicolaou test. Journal of Obstetric, Gynecologic, and Neonatal Nursing, 20, 39-46. Goldberg, G.L., Vermund, S.H., Schiffman, M.H., Ritter, D.B., Spitzer, C., & Burk, R.D. (1989). Comparison of cytobrush and cervicovaginal lavage sampling methods for the detection of genital human papillomavirus. American Journal of Obstetrics and Gynecology, 161, 16691672. Gross, G., Ikenberg, H., Roussaki, A., Drees, N., & Schopf, E. (1986). Systemic treatment of condylomata acuminata with recombinant interferon-alpha-2a: Low-dose superior to the high-dose regimen. Chemotherapy, 32, 537541. Halpert, R., Fruchter, R.G., Sedlis, A., Butt, K., Boyce, J.G., & Sillman, F.H. (1986). Human papillomavirus and lower genital neoplasia in renal transplant patients. Obstetrics and Gynecology, 68, 251-258. Harlan, L.C., Bernstein, A.B., & Kessler, L.G. (1991). Cervical. cancer screening: Who is not screened and why? American Journal of Public Health, 81, 885-890. Hein, K. (1989). AIDS in adolescence: Exploring the challenge. Journal ofAdolescent Health Care, 10, 10s-35s. Jensen, S.L. (1985). Comparison of podophyllin application with simple surgical excision in clearance and recurrence of perianal condylomata acuminata. Lancet, 2, 1146-1 148. Kiviat, N.B., Koutsky, L.A., Paavonen, J.A., Galloway, D.A., Critchlow, C.W., Beckmann, A.M., McDougall, J.K., Peterson, M.L., Stevens, C.E., Lipinski, C.M., & Holmes,

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prevalence of human papillomavirus in the lower genital tract of pregnant women. International Journal of Cancer, 40, 198-201. Schneider, A., Kirchmayr, R., & Gissmann, L. (1988). Human papillomavirus preceding intraepithelial neoplasia in serial cervical smears [Letter]. Lancet, I, 989. Schneider, V. (1989). Microscopic diagnosis of HPV infection. Clinical Obstetrics and Gynecology, 32, 148-156. Shu, L.L. (1989). Diagnosis of human papillomavirus infection in uterine cervix by immunoperoxidase technique. Materia Medica Polona, 21, 28-30. Smith, E.M., Johnson, S.R., Cripe, T.P., Pignatari, S., & Turek, L. (1991). Perinatal vertical transmission of human papillomavirus and subsequent development of respiratory tract papillomatodis. Annals of Otology, Rhinology, and La yngology, 100,479-483. Stone, K.M., Becker, T.M., Hadgu, A., & Kraus, S.J. (1990). Treatment of external genital warts: A randomized clinical trial comparing podophyllin, cryotherapy, and electrodesiccation. Genitourinary Medicine, 66 16-19. Syrjanen, K., Mantyjarvi, R., Vayrynen, M., Syrjanen, S., Parkkinen, s., Yliskoski, M., Saarikoski, s., & Castren, 0. (1987). Evolution of human papillomavirus infections in the uterine cervix during a long-term prospective follow-up. Applied Pathologv, 5, 121-135. Tucker, T., Friedell, G., Stallones, L., Thompson, J., & Bagby, J. (1988). Cancer mortality in rural Appalachian Kentucky (Appalachian Data Bank Report #6). Lexington, Kentucky: University of Kentucky, Markey Cancer Center. Vermund, S.H., Hein, K., Gayle, H.D., Cary, J.M., Thomas, P.A., & Drucker, E. (1989a). Acquired immunodeficiency syndrome among adolescents: Case surveillance profiles in New York City and the rest of the United States. American Journal of Diseases of Children, 143, 1220-1225. Vermund, S.H., & Kelley, K.F. (1991). Human papillomavirus in women: Methodologic issues and role of immunosuppression. In M. Kiely (Ed.), Reproductive andperinatal epidemiology (pp. 143-168). Boca Raton, FL: CRC Press. Vermund, S.H., Kelley, K.F., Klein, R.S., Feingold, A.R., Schreiber, K., Munk, G., & Burk, R.D. (1991). High risk of human papillomavirus infection and cervical squamous intraepithelial lesions among women with symptomatic human immunodeficiency virus infection. American Journal of Obstetrics and Gynecology, 165, 392400. Vermund, S.H., Schiffman, M.H., Goldberg, G.L., Ritter, D.B., Weltman, A., & Burk, R.D. (1989b). Molecular diagnosis of genital human papillomavirus infection: Comparison of two methods used to collect exfoliated cervical cells. American Journal of Obstetricsand Gynecology, 160, 304-308. Vermund, S.H., Sheon, A.R., Galbraith, M.A., Ebner, S.C., & Fischer, R.D. (1990). Transmission of the human immunodeficiency virus. In W.C. Koff, F. Wong-Staal, & R.C.

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Kennedy (Eds.), AIDS research reviews (pp. 81-136). New York: Marcel Dekker. Weck, P.K., & Whisnant, J.K. (1987). Therapeutic approaches to the treatment of human papillomavirus diseases. Cancer Cells, 5, 393-402. Winkelstein, W., Jr., Samuel, M., Padian, N.S., & Wiley, J.A. (1987). Selected sexual practices of San Francisco heterosexual men and risk of infection by the human immunodeficiency virus [Letter].Journal of the American Medical Association, 257, 1470-1471. Yliskoski, M., Saarikoski, S., Syrjanen, K., Syrjanen, S., & Castren, 0. (1989). Cryotherapy and C0,-laser vaporization in the treatment of cervical and vaginal human papillomavirus (HPV) infections. Acta Obstetricia et Gynecologica Scandinavica, (58,619-625.

Address for correspondence: Karen F. Kelley, MPH, New York State Department of Health, Corning Tower Building, Empire State Plaza, Albany, NY 12237. Karen P. Kelley is a research scientist with the AIDS Epidemiology Program, New York State Department of Health, Albany, New York. Miriam A. Galbraith is a nurse consultant in the Vaccine Trials and Epidemiology Branch in the Division of AIDS at the National Institute of Allergy and Infectious Diseases, National Institutes of Health (NIH), Bethesda, Maryland. Sten H. Vermund is chief of the Vaccine Trials and Epidemiology Branch Zn the Division of AIDS, National Institute of Allergy and Infectious Diseases, NIH, Bethesda, Maryland.