Human Papillomavirus Infections: Current Concepts, New Developments

' ' ' ' ' ' TGYNAECOLOGYT''' ' ' '

HUMAN PAPILLOMAVIRUS INFECTIONS: CURRENT CONCEPTS, NEW DEVELOPMENTS Alex Ferenczy, MD, Professor of Pathology, and Obstetrics and Gynaecology, McGill University, and The Sir Mortimer B. Davis] ewish General Hospital, Montreal, Quebec

ABSTRACT

New epidemiologic and biologic knowledge of the natural history of genital human papillomavirus (HPV) infections is rapidly being accumulated. There is overwhelming evidence that most HPV infections are transient, particularly in the adolescent, and are not cUnicaUy important. There is a smaU proportion of adult women, however, who harbour persistent HPV infections. These women are at considerable risk of developing high grade intra-epitheUal neoplasia, and, if undetected and untreated, invasive carcinoma. Screening, diagnostic, and management strategies should be tailored according to the HPV-related carcinoma risk potential of a specific area in the lower genital tract. The cervix is undoubtedly the site which carries the highest carcinoma risk among the areas along the lower genital tract. Molecular technology is now available for detecting and typing efficiently HPV DNA. This HPV testing has been shown to be useful in guiding management of women with minor grade cytologic atypia. The HPV ONA triage approach considerably reduces unnecessary colposcopies and the cost of managing this category of women. Several alternatives are available for treating patients with genital HPV infections. The most attractive advances made in the treatment of intra-epitheUal cervical lesions and external genital warts are the loop electrosurgical excision procedure and the topical application of an immuno-enhancer agent, respectively. The ultimate goal for the prevention and treatment of HPV infections is centred on the development of HPV vaccines. RESUME

De nouveUes connaissances sur le virus du papiUome humain (VPH) s' accumulent rapidement en epidemiologie et en biologie. Tout indique que Ia plupart des infections aVPH sont transitoires, en particuUer chez l' adolescente, et qu' eUes n' ont aucune importance cUnique. Une faible proportion de femmes adultes ant toutefois des infections persistantes aVPH. Ces femmes courent un risque considerable d' avoir une neoplasie intraepitheliale de grade eleve et, si cette affection passe inaper~ue et demeure non traitee, d'etre atteintes d'un carcinome invasif. Les strategies de depistage, de diagnostic et de traitement devraient etre adaptees au risque potentiel pour une zone specifique de l' appareil genital inferieur. Le col de l' uterus est sans doute Ia zone qui comporte le risque le plus eleve de carcinome parmi les zones de l' appareil genital in{erieur. Pour deceler et typer efficacement l'ADN du VPH, on dispose maintenant de Ia technologie moleculaire. Cette analyse du VPH s' est revelee utile pour orienter le traitement des femmes ayant une Iegere atypie cytologique. L' approche de triage des ADN du VPH reduit considerablement les colposcopies inutiles et le cout du traitement de ces femmes. Plusieurs choix s' offrent anous pour traiter les patientes atteintes d'infections genitales aVPH. Les progres les plus interessants realises dans le traitement des lesions cervicales intraepitheUales et des condylornes acumines sont, d' une part, l' excision electrochirurgicale al'anse

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' ' ' et, d'autre part, l' application topique d'un agent immunonwdulateur. La prevention et le traitement des infections aVPH visent, en definitive, aelaborer des vaccins contre le VPH.

1 SOGC 1997;19:369-81

KEY WORDS

HPV, cervix, squamous intraepitheliallesion, epidemiology, HPV DNA testing, electrosurgery, imiquimod, vaccines. Received on August 2nd, 1996. Revised and accepted on October 1st, 1996.

Approximately 50 percent of the male sexual consorts of women with clinically visible lesions and cervical intra-epithelial lesions have either condylomata or subclinical lesions on their penisesY In a latent form, HPV is not infectious. Indeed, infectivity requires structural proteins forming an envelope found only in fully formed virions. 4 The latter are located in terminally differentiated, squamous superficial, and intermediate epithelial cells. These cells are recognized as koilocytes in both clinical and subclinical lesions.

INTRODUCTION

Genital infections caused by human papillomaviruses (HPVs) are confined to the epithelium of the lower genital tract and are classified as clinical, subclinical, and latent. 1 Clinical lesions are seen with the naked eye and are the typical genital warts or condylomata acuminata. Subclinical lesions are demonstrated at magnification using a colposcope after application of a five percent acetic acid solution. Patients with latent infections have neither visible nor microscopic lesions, and are identified only by HPV DNA tests. The growth patterns ofHPV infection depend on the type of epithelium infected, the viral type, and the patient's cell-mediated immune status. For example, the cervical epithelium contains mainly subclinical lesions with predominantly high risk type HPV, whereas low risk viruses infect preferentially the external anogenital skin. The highest rates of HPV infection are found in the cervical and anal epithelium of HIV -positive, immunosuppressed female 2 and male homosexuaP patients, respectively.

NEW EPIDEMIOLOGY

The most important determinant of risk of contracting HPV infection is age. Latent HPV infection is most prevalent (60-80%) between the ages of 15 and 19. However, infection in these individuals appears to be transient, as prevalence decreases sharply to about ten and three percent by 30 and 50 years of age, respectively. 4•8 The high prevalence rates in adolescents and young adults are presumably due to sexual behaviour with an increased number of sexual partners. Sexual activityrelated variables are a particularly strong predictor of infection with high risk HPV types. 9 Women with persistent HPV infection with a high risk virus (as documented by consistently positive HPV tests) have a very high risk of developing high grade squamous intra-epithelial lesions (SILs). In one study, 49 percent of patients developed high grade SILs at two years. 10 Persistence has been related to increased age ( >30 years old), presence of high risk HPV types, and high quantities ofHPV DNA.u· 12 Overall, the currently available data indicate that most HPV infections are transient and are clinically insignificant. However, a small proportion of women remains with persistent HPV infection, and cervical carcinoma presumably arises from within this subset of women. In other words, persistent HPV infections are the biologic precursors of cervical carcinogenesis. Large scale epidemiologic cohort studies are under way to further our knowledge of the incidence of HPV infection

TRANSMISSION

Most HPV infections develop after sexual exposure. 4 This is particularly true for condylomata acuminata of the external anogenital skin. Direct contact, without vaginal or anal penetration, between external genital warts and anogenital skin in susceptible individuals (e.g. lesbians or infants born from mothers with warts) and oral sex, may also result in HPV transmission. On the other hand, HPV DNA found on a speculum, in the plume of smoke generated by electrocautery and COz laser vaporization of genital warts, and on the underwear of patients with external warts is considered very unlikely to induce infection of genital skin. 5•6 If HPV-contaminated instruments or clothes were infectious, one would expect many more recurrent HPV infections than are seen in patients previously diagnosed and/or managed for genital HPV infections.

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bupivacaine

' ' ' and co-factors that may enhance HPV transmission, and to predict the development of cancer precursors in relationship to viral persistence and viral burden. The rate of subclinical HPV infections of the cervix is in the order offive to ten percent, whereas the rate in men is unknown. About one percent of all sexually active females and males in North America have condylomata acuminata.4

mechanism and inactivation of cellular tumour suppressors p53 and Rb protein, by forming a complex with the HPV E6 and E7 oncoproteins. 14 Tumour suppressor inactivation leads to cell proliferation (immortalization). In most invasive cervical squamous cell carcinomas, the so-called high risk viruses are found integrated into the host nuclear DNA; whereas in the precursor forms, HPV DNA is in an episomal, extrachromosomal, physical state. It would, thus, appear that integration represents an important molecular step toward the development of invasive malignant growth. It must be realized that cervical cancer is a rare event compared to the prevalence of genital HPV infections. It is suspected that, in addition to HPV DNA integration, other exogenous factors are needed for the malignant transformation of immorta lized cells. These may be related to mutational enhancers including cigarette smoking, sex-steroids (progestogens), diet (low intake of vitamin A), and immunogenetic predisposition (HLA DQ-3). 4•8•14 Today, there is unequivocal biologic and epidemiologic evidence to consider HPV infections by HPV types 16 and 18 as necessary surrogate events for the development of cervical cancer.9 Using fresh tumour specimens and multiple testing with the super-sensitive polymerase chain reaction (PCR) technology, high risk HPV types can be found in nearly 100 percent of cervical cancers. 15 It has been consistently shown that HPV infection is the strongest independent risk factor for cervical cancer, with relative risk (RR) in the order of 20 to 70. Such rates are considerably higher than those for the association between smoking and lung cancer (RR 7-10), a cause and effect relationship that is universally accepted. The HPV-cervical carcinoma connection is also supported by the consistent epidemiologic findings of the strong influence of sexual activity on cervical carcinoma risk. Furthermore, two cohort studies on a combined series of 28,500 cytologically normal women indicated that RRs for developing HPV -related cervical SILs were over 20 for all SILs and 40 for high grade SILs, with 65 percent of HPV -positive women developing SILs (mainly low grade) by year four of follow-up .16•17 The worldwide incidence of cervical carcinoma is second only to breast carcinoma. In developing countries it is by far the most important malignancy, whereas in industrialized countries it is the tenth most common neoplasm. 18 Worldwide, annual cervical carcinoma death rates are in the order of 300,000. The overall five-year

CURRENT HPV TAXONOMY

Human papillomaviruses belong to the family papoviri-

dae and are DNA-containing viruses. They are epidermotrophic as they infect the squamous epithelium, including that of the lower genital tract. Among the 77 HPV types so far identified, 25 infect the epithelium of the lower genital tract.13 By convention, they are classified on the basis of their DNA sequences; less than 50 percent homology in DNA sequ ences defines a specific viral type. Of all HPVs, type 16 is the most frequent variant found in genital lesions. Clinically, HPVs are grouped according to their association with squamous cell neoplasia of the lower genital tract (Table 1). The low risk types are common in low grade SILs (LGSILs), rare in high grade SILs (HGSILs), and practically nonexistent in cancers. High risk HPV types 16, 18, 45, and 56 are strongly associated with cancer and HGSILs. They are subdivided into high risk HPV type 16 which is highly predictive of cancer and its high grade SIL precurso, and high risk HPV types 18, 45, and 56, which are strongly associated with cancer and less so with high grade SILs. 13 The HPV types 31 , 33, 35, 39, 51, 52, 58, 66, and 68 are considered intermediate risk biologically as they are seldom associated with cancer but are often found in both low and high grade SILs. For practical reasons, the intermediate risk HPV types are included in the high risk HPV group. HPV-CERVICAL CANCER CONNECTION

Human papillomavirus types 16, 18, 45, and 56 may integrate into the host cell genome. This phenomenon leads to disruption of the normal viral gene-regulatory

TABLE 1

-

HPV TYPES BY RISK OF GENITAL NEOPLASIA ~

Risk

Type

low

6,11,42-44,53-55

·-

High

16,18,45,56

Intermediate

31 ,33,35,39,51 ,52,58,65,66,68

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' ' ' survival rate for womeri with cervical carcinoma is 65 percent, lower than that for breast carcinoma. 19 In Canada, every year there are 1,500 new cases of cervical cancer and about 400 women die of their disease. In addition, for each invasive disease there are five cases of precursors (carcinoma in situ) diagnosed. 20

solution is of great value for determining the size and distribution of HPV infections in the cervix and vagina. On the cervix, most lesions are located within the transformation zone near the squamocolumnar junction. In the vagina, HPV infections are concentrated in its upper one-third, near the cervical portio. Routine colposcopic examination of the vulva is not recommended because acetowhite changes of the vulvar epithelium are not necessarily related to HPV infection. 1 In fact, in most instances, they are due to chronic inflammation (contact dermatitis) or such infection as candidiasis. It should be realized that the acetowhite staining reaction of the squamous epithelium is not pathognomonic of HPV infection. Acetowhite subclinical lesions by definition must be slightly elevated, with or without punctation pattern, whereas acetowhite epithelium is not elevated. In patients with biopsy-proven vulvar intra-epithelial neoplasia, colposcopic examination helps to locate small satellite lesions. These must be included in the treatment field to provide the highest possible cure rates.

SCREENING FOR CERVICAL NEOPLASM

HPV infections of the cervix can be detected by cytology screening. According to the Bethesda System (TBS) for reporting cervical-vaginal cytologic diagnoses, the cytologic alterations indicating HPV infections on Pap. smears range from low grade (LGSIL) to high grade squamous intra-epithelial lesions (HGSIL), to invasive squamous cell carcinoma. In Canada, the USA, Scandinavian, and other Western countries where mass cytologic screening for cervical cancer precursors is practised regularly, a dramatic decrease in both morbidity (6/100,000 women aged 20 and older) and mortality (3/100,000 women aged 20 and older) due to cervical cancer has been observedY Conversely, in developing countries, lack of cervical cancer screening is associated with a high incidence of cervical cancer (up to 80/100,000) which is the leading cause of death in women.

THE MALE PARTNER ISSUE

Traditional teaching recommended compulsory examination of the male consorts of HPV -infected women. Current data, however, do not indicate the cost-effectiveness of high magnification androscopy of the male partner without clinically visible lesions.ZZ First, less than 50 percent of current male partners are found to have subclinical lesions; second, treating subclinical lesions in the male partner does not reduce failure rates for vulvar and anal condylomata or squamous intra-epithelial lesions of the cervix; 23 third, unprotected intercourse (without condoms) after successful chemotherapy for squamous intra-epithelial lesions of the cervix is not associated with any higher incidence of new cervical disease (recurrences) than the incidence of cervical SIL in a sexually active but untreated female population. 24 These observations support the concept that recurrences after successful therapy in a monogamous sexual partnership are caused by the later activation of latent HPV DNA into an infectious virion state, rather than re-infection from the sexual partner. Viral testing of recurrent HPV infections in monogamous couples demonstrated HPV types similar to those previously treated, whereas in those practising polygamy, viral types differed in the treated and recurrent lesions. 25

CLINICAL ASSESSMENT

Infections by HPV are often multicentric and involve multiple sites along the lower genital tract. 1 In about one-third of women with condylomata acuminata and intra-epithelial neoplasia of the external anogenital skin, subclinical HPV infections of the cervix and/or vagina in the form of low and high grade intra-epithelial neoplasia, respectively, may be encountered. Ideally, colposcopic examination of these patients should be performed; however, if colposcopic expertise is not available, cytologic follow-up is an adequate management approach. Ana-receptive homosexuals with perianal warts have intra-anal and rectal lesions in up to 80 percent of case. 22 In heterosexuals engaging in anal intercourse, peri-anal warts develop as a result of contamination from vulvar or penile lesions, and in patients with intra-anal warts as a result of ana-digital insertions. COLPOSCOPY

While histology is the diagnostic gold standard of genital HPV infections, examination at magnification aided by topical application of a five percent acetic

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' ' ' referrals and costs for the diagnostic triage approach (Figure 1). The cost-effectiveness of the HPV -based triage can be further improved by eliminating an office visit for a repeat Pap. smear and HPV DNA testing. These results can be achieved when routine cytology uses liquid-based cell collection technology. Using this new approach, the harvested cells are suspended in a collection tube which contains a cell preserver (PreservCyt®) rather than being smeared on a glass slide. About ten percent of the suspended cells selected at random are transferred onto a glass slide by a cell processor (Thin Prep® slides), and the 90 percent residual cellular material can be used for HPV DNA testing. In this way, whenever the Thin Prep slide in a woman aged 25 and older is reported as ASCUS or LGSIL, Hybrid Capture TM HPV DNA assay is performed. 29 Because only high risk HPV -positive lesions are important, all patients testing positively are sent for colposcopy, whereas those with a negative test have a repeat Pap. test and HPV test. If the repeat combination is negative, the patient is very unlikely to have clinically significant lesions

CLINICAL ROLE OF HPV TESTING

Testing for HPV in the management of women with minor grade cytologic atypia has been shown to be useful by a number of independent investigators. 26 -29 lt is important to realize that the most frequent abnormality reported cytologically belongs to this category of diagnosis. It is suspected that about half of these diagnoses are false-positives, and only a relatively small proportion of patients with established low grade abnormalities ever progress to high grade SIU0 On the other hand, it is also an accepted concept that cytology is not a diagnostic, but rather a screening tool. In other words, a positive report often indicates the least severe abnormalities. For example, between seven and 20 percent of women with aninitial abnormal Pap. smear suggestive of atypical squamous cells of undetermined significance (ASCUS) and low grade squamous intra-epithelial lesions (LGSIL) have histologically confirmed high grade squamous intra-epithelial lesions (HGSIL).21 The latter are mainly encountered in women aged 25 and older with peak incident rates occurring at age 30. 16 lt follows that it is TABLE 2 more appropriate to focus on this relativeCOMBINATION OF CYTOLOGY AND HPV TESTING FOR DETECTING HGSIL IN ly small subset of high risk women than to ASCUS/ LGSIL PATIENTS use indiscriminately either a cytologic folProtocol % Sensitivity Colposcopies Referral Pap. Study low-up scheme or colposcopy for all (HGSIUt otal) per ~ HGSIL f or Colposcopy women with minor grade cytologic atypia. Cox eta/_ 1995 Colposcopy 100 14.5 6 _1 ASCUS 73 (15/ 217) (26) Pap. smear When screening for a disease using a 5_3 HCS 93* test with imperfect diagnostic indices (e.g. 7_1 Pap_+ HCS 100 cytology), the addition of a second test, 8_0 Wright eta/_1995 Colposcopy 100 (50/ 398) (27) 5.1 ASCUS or SIL 80 Pap. smear screening for different characteristics of the 5_3 78 HCS same disease, often results in increased senPap.+ HCS 96 5.9 sitivity of detection. Indeed, the combinaHatch et a/. 1995** Colposcopy 100 2.5 (126/ 311 ) (28) SIL Pap. smear 75 2.3 tion of cytology and HPV DNA testing 74 1.8 HCS detects over 90 percent of high grade SIL Pap.+ HCS 2.2 91 in women with an initial ASCUS/LGSIL Colposcopy 100 5.0 Hall eta/. 1996 *** Pap _smear 87 4.2 ASCUS or SIL (15/75) smear (Table 2). It appears, furthermore, HCS 93 4.0 that the combination approach produces Pap _+ HCS 100 4.1 significantly greater specificity (65%) than 100 8.3 Ferenczy et a/. 1996 Colposcopy 5.1 ASCUS or SIL (47/ 364) (29) Thin-Prep slide 87 either test alone or the use of a combinaHCS 77 4.8 tion of cytology and a randomly chosen Thin-Prep slide 95 5.4 adjunct test. 29 This results in higher negaHCS: Hybrid capture system . The sensitivity of HCS was 100% when HPVs 39 and 58 were added to the probe mix, indi· * tive predictive values for the combination eating the importance of an expanded probe set for HPV_The other studies in the table approach (97%) over those that are did not have HPVs 39 or 58 as part of the probe test. Endpoint was based on CIN 2/3_ ** observed with cytology or HPV testing Data are for high-risk HPV types only. alone (85%). This in tum translates into a Adapted from Lorincz A. Papillomavirus Report 1996;7(1 ): 1-5. Reproduced with permission. 30 to 50 percent reduction in colposcopic

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' ' ' FIGURE I

combination of C02 laser vaporization and subcutaneous injections of alpha-interferons. According to recent CDC/USA guidelines, genital warts are not an indication for Caesarian section (CS) delivery to prevent RLP.33 In fact, very rarely has RLP developed in neonates delivered by CS. 34 Caesarean section is appropriately carried out in women whose genital warts are so extensive that they interfere with labour and/or normal vaginal delivery. Genital HPV infections may be treated by a large variety of topical and physical techniques as well as immuno- stimulating agents. 34 None of these treatment options guarantees cure. Indeed, depending on the volume and site of infection, as well as the immune status of the individual, repeated treatments may be necessary in up to 50 percent of cases. It is important to remember that treatment aims at removing visible lesions only; available therapeutic means fail to inactivate latent HPV infection. Based on the decreasing point prevalence rates of latent REV infection 16 and the overall good clinical response to multiple therapies for genital HPV infections, inactivation of latent HPV DNA is successful in most patients via the cell-mediated arm of the immune system. T apical therapies use 50 to 85 percent bi- or trichloroacetic acid solution (BCA and TCA), the purified version of 25 percent podophyllin, i.e. 0.5 percent podofilox solution and five percent 5-fluorouracil in the form of cream (Efudex). The clinical value of Efudex therapy is controversial at best, and may be associated with severe side-effects including erosive vagino-vestibulitis, vaginal adenosis, and scarring of the external anogenital skin at worst. Certain national health agencies do not recommend its use. 33 If no other therapeutic alternatives are available, Efudex should be dispensed only by the treating physician and only to patients who are not hypersensitive to Efudex. Neither podofilox nor Efudex should be prescribed to pregnant patients because of potential toxicity for mother and newborn. Female patients treated with Efudex should use effective contraceptive means. Trichloroacetic acid is not absorbed into the blood circulation and is safe to use during pregnancy. Genital warts may be destroyed physically using cryocoagulation with liquid nitrogen or nitrous oxide, scissor excision, electro-excision and fulguration, and c~ laser vaporization. 22 These techniques are used for those vaginal and external genital skin lesions where conservative treatment with topical agents failed or their large size or overall extent prevents the use of topical chemicals to

HPV-BASED INTERMEDIATE TRIAGE FOR ASCUS/LGSIL SMEARS

- - - optional • only high/intermediate oncogenic risk virus probes

and can be followed at two-year intervals. Those patients whose HPV test is positive and have high viral burdens but are colposcopically and histologically negative(± 8% at age 25 years or older) are followed at six-month intervals with cytology for two years as they may be at risk for developing high grade SIL. Indeed, as suggested earlier, in several prospective studies up to 49 percent of women positive for high risk HPV DNA developed high grade SIL in the following two years. 10 The application ofHPV DNA testing as an adjunct to cervical cytology in a screening capacity is currently being investigated; the largest cohort study is supported by the NIH (RFPs NCI-CN-5504x-YY). TREATING GENITAL HPV INFECTIONS

The primary reason for treating genital HPV infections is to decrease as much as possible the incidence of and mortality due to cervical carcinoma, and perpetuation by transmission of cosmetically unacceptable external genital warts. Also considered is the risk of infection of the neonate's laryngeal epithelium by maternal HPV DNA which may result in recurrent laryngeal papillomatosis (RLP). About 60 percent of infants with RLP are born to mothers with genital warts. The risk of RLP is currently unknown; however, its low frequency (about 1,500 cases/3.6 million births/year in the USA) indicates a risk of0.04 percent of laryngeal infection in the newborn delivered vaginally. 31 Recurrent laryngeal papillomatosis used to be a severely debilitating and potentially life-threatening disease. Today, however, it is well-controlled by the

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' ' ' There is a consensus to use option 1 for HGSILs, as they are cancer precursors. 40 Treatment approaches include ablative (cryo-laser) therapy and more recently, the preferred method of the loop electrosurgical excision procedure (LEEP) or large loop excision of the transformation zone (LLETZ). Treatment results are in the order of 90 percent with a single, and 95 percent with multiple sessions, whereas complication rates do not exceed seven percentY The ideal approach to women with ASCUS/LGSIL smears uses the earlier-described alternate HPV -based triage. If this is unavailable, either option 1 or 2 is recommended for the management of these women. Indeed, both options have clinical merits, provided they are applied with a view as to whether the patient represents a low or high risk for having or developing clinically significant lesions (Table 3). The single most important demographic risk factor seems to be age. Most women aged 25 and younger have low grade SILs and most revert to normal. Cancer or high grade SILs are very rare in this age group. 16 Those of 25 or older are candidates for immediate colposcopic examination, as the likelihood of lesional tissue is high. Conversely, cytologic practices in which the false-positive rates are high (over 5% positive cytology) lead to too many unnecessary colposcopic examinations. In such situations, it is more economical to follow women with cytology to ascertain persistent cytologic abnormality. It is important to realize that a negative Pap. test has no significance in the face of a clinically suspicious cervix. Such patients should undergo colposcopy and biopsy at once to rule out invasive cancer. Conversely, a positive test suggestive of a low grade cytologic abnormality only indicates the least severe abnormality the

achieve successful clinical response. Depending on the extent and anatomical distribution of the lesions, most of these techniques require either local or general anaesthesia. Side effects and complications associated with physical destruction of warts and intra-epithelial neoplasia are low to negligible in experienced hands. Some patients with recalcitrant external anogenital lesions are treated with a combination of "wart de bulking" using electrosurgery or C02 laser ablation and postablation injections of interferons (IFN). The periphery of the treatment field is infiltrated subepithelially by IFN. It is surmised that IFN's antiviral, antiproliferative, and immunomodulatory properties are adequate to suppress latent HPV DNA and prevent recurrences of warts. In some hands, treatment results are highly acceptable. 35 Interferons have side-effects which include transient fever, fatigue, myalgia, and headache. NEW THERAPEUTIC DEVELOPMENTS AND STRATEGIES

A new topical agent, imiquimod, in the form of cream is commercially available in the USA and, it is hoped, will soon be in Canada. This is an immuneenhancer acting on cell-mediated immunity (interferons and interleukins). Multi-site, prospective, double-blind, placebo-controlled studies on a large number of patients have shown a two- to three-fold better response with five percent imiquimod cream in clearing external genital warts than placebo.33 Side-effects including burning, erosion, pruritus, and flu-like symptoms were mostly mild; the recurrence rate was low and compliance with therapy was excellent. The agent will be dispensed for home use. In addition to its therapeutic successes, it has an advantage over other topical agents in the ease of application to anatomical sites which normally require assistance to treat, e.g. anus . Other new products under clinical investigation include sublesionally injectable 5% 5 FU/epinephrine geP 7 and topical podofilox in the form of gel. 38 In current practice, three main options are proposed for the management of cervical HPV infections (squamous intra-epitheliallesions).39 These are: 1) colposcopy and biopsy for all patients and, if appropriate, therapy; 2) follow-up with Pap. smears at regular intervals for two years and colposcopy for those with persistent LGSIL; 3) HPV -based triage.

JOURNALSOGC

TABLE3 RISK FACTO RS IN PATIENTS WITH MINOR GRADE CYTOLOGIC ATYPIA* Low Risk Patient

High Risk Patient

Age (yrs)

< 25

> 25

Reliability for follow-up

High

Low

Past history of abnormal cytology or therapy

No

Yes

Known to physician

Yes

No

Monogamous

Polygamous

Sexual habits Cytology with high rates of false positive results

Yes

No

Clinically suspicious cervix

No

Yes

* initial smear

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' ' ' Prophylactic HPV vaccines using high antigenic, noncarcinogenic recombinant papillomavirus-like particles are close at handY They are highly protective against papillomavirus infections in cattle, dogs, and rabbits. It is foreseen that a polyvalent vaccine against HPV 16, 18, 45, and 56 could prevent 70 percent of cervical cancers. Therapeutic vaccines are more complicated to develop, because the nature of rejection antigens, the mechanisms operating in tumour regression (cell-mediated immune system via cytotoxic lymphocytes and cytokines), and the variability in the host capacity to elicit immune response are not well-knownY There are several ongoing basic and clinical investigations to gain insight into our understanding of the immune response to HPV-related cervical cancer and its precursors.

patient aged 25 years and older may have. For example, as many as 30 percent of patients with invasive cancer of the cervix may have had two ASCUS smears. Management algorithms of patients with minor grade cytologic abnormalities based on patients' risk factors are illustrated in Figure 2. Once persistent low grade SIL has been documented and invasive cancer ruled out by histology, the choice of therapy may be tailored to the size of the lesion and the position of its endocervical margin. Very large lesions with extension into the external os are treated best with loop electro-excision under local anaesthesia {central portion of the lesion) and electrofulguration of the periphery of the lesional tissue. Fortunately, most LGSILs are exocervical in their presentation, and can be easily and successfully ablated using cryotherapy. It is customary to follow patients for one year after either ablative or excisional therapy with cytology and colposcopy (first 3 to 6 months post-treatment visit) and cytology thereafter. If the results are negative, patients are followed regularly with cytology at annual intervals.

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HPV VACCINES The long term goal for the prevention and treatment of genital HPV infections, particularly cervical cancer, is centred on the development ofHPV vaccines.

FIGURE 2 MANAGEMENT OPTIONS FOR MINOR GRADE CYTOLOGIC ATYPIA

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