REVIEW

THERAPY OF GENITAL HUMAN PAPILLOMAVIRUS INFECTIONS. PART I: INDICATIONS FOR AND JUSTIFICATION OF THERAPY MARK R. LING, M.D., PH.D.

the terms "gross lesions," condylomata, and warts interchangeably to refer to any visible lesions. Subclinical (sc) lesions are those which are visible only with the use of enhancing techniques. Most frequently, this involves the use of 3 % to 5% acetic acid applied to the areas of interest for 5 to 10 minutes. The HPV infected areas are whitened by the acetic acid, the so-called "acetowhitening" phenomenon. They are subsequently identified visually, often with an optical magnifying device like a colposcope. This technique is well-established in gynecology.-' In men, it has gained increasing acceptance and is often referred to as "peniscopy" or "androscopy."'*"'' Subclinical lesions can be found in any anogenital site. SC lesions show histologic evidence of HPV infection, either by the presence of benign koilocytosis, or less frequently, intraepithelial neoplasia.*'"* Most recently, the existence of latent HPV infection has been shown. The availability of highly sensitive probes for the presence of HPV DNA, including DNA hybridization and in particular, the polymerase chain reaction technique (PCR), has allowed the demonstration of HPV DNA in areas which are acetowhite-negative,' and which in addition show none of the histologic features of HPV infection.'" Latent disease is defined as the presence of HPV DNA in areas with no clinical or histologic evidence of HPV infection. The biological significance of latent disease is unclear. This clinically normal skin may act as a "reservoir" for HPV, accounting for the remarkable persistence of the virus despite therapy." Conversely, it may ultimately turn out that such low numbers of HPV DNA copies are of no biologic significance. This question is unanswered currently. Another aspect of HPV infection is the oncogenic potential of the virus. As reviewed recently by Reid and Lorincz,'^ there is a strong relationship between HPV infection and cervical intraepithelial neoplasia (CIN). The role of HPV in promoting progression of CIN to invasive cancer is less well estahlished, but evidence suggests that expression of the viral E6 and E7 genes may lead to cellular transformation.*^ It must be emphasized that infection with HPV, even with the high-risk types such as 16 and 18 is not sufficient to cause cancer: up to 10% of normal women are infected with cancer-associated HPV types, and the great majority will not develop cervical cancer.'''

Genital human papillomavirus (HPV) infections are an increasingly important subject for physicians treating mucocutaneous diseases. Explosive progress in molecular biology has deepened our understanding of HPV, while simultaneously introducing confusion into the management of these infections: what was dogma just a few years ago is often now fallacy. As a result, the clinical practitioner is confronted with a maze of choices with little consensus to guide him/herself. Perhaps the only reliable rule is that today's opinions will be disproved in the future. Nevertheless, it is important to review the available information carefully and critically. A detailed discussion of the biology, epidemiology, clinical manifestations, and diagnosis of HPV infection will be discussed in part II of this review (in press). In this series of two articles, I will concentrate on the rationale behind treatment of HPV infection, followed by a detailed assessment of the methods available to treat such infections.

CLINICAL MANIFESTATIONS OF GENITAL HPV INFECTION

The clinical presentation of genital HPV disease has been well-reviewed recently.^-^ There are a few basic concepts that bear repeating here. Perhaps the most critical concept is the differentiation between clinical, subclinical, and latent HPV disease. Clinical disease is the presence of lesions in the anogenital region, which are visible to the naked eye without any additional enhancing techniques. The spectrum of such diseases is broad, and differs in men and women. In men, the typical presentation is with verrucous papular lesions, but so-called "flat" warts are also encountered. In women, the spectrum of clinical lesions depends on site. Verrucous lesions similar to male penile lesions can be seen on the vulva, and less commonly in the vagina, where flat warts are more common. Most HPV infections in the vagina and on the cervix are not visible to the naked eye. For the purposes of this article, I will use From the Department of Dermatology, Emory University School of Medicine, Atlanta, Georgia. Address for correspondence: Mark R. Ling, M.D., Emory Clinic Section of Dermatology, 1365 Clifton Road, N.E., Adanta, GA 30322. 682

Human Papillomavirus Infection

Other manifestations of the mucosal-specific HPV types that cause genital warts have been described. Association with perlungual and perianal squamous cell carcinomas appear likely,'-^ while claims relating HPV to other cancers such as prostate cancer are poorly substantiated.'^'''^ Another condition clearly caused by mucosal HPV is laryngeal papillomatosis,, which while benign can be the cause of substantial morbidity in infected patients.'*

fection with any form of therapy eliminates future infectivity. Until our understanding progresses further, much of what we do will rely on tradition and hopeful optimism that we are doing something useful. The issue of infectivity has become murky since the recognition of subclinical and latent forms of infection. There is little doubt that gross clinical disease is contagious. It is estimated that there is a 50% risk of infection after a single sexual encounter with an infected partner.^^ Treatment to eliminate gross lesions seemed appropriate to eliminate the infection, and thus the risk of transmission. Unfortunately, increasing evidence shows that following treatment and resolution of gross lesions, a state of either SC or latent disease almost always persists, even after extremely aggressive therapy. The evidence that apparently successful treatment of gross lesions does not eliminate the virus completely is not surprising given our experience with other viruses—witness herpes simplex and varicella zoster. Extremely high recurrence rates after treatment of genital warts with any therapy are common,-''"-*' In the past, such recurrences were often blamed on inadequate treatment of the partner, who would act as a reservoir for the virus. As first one, then the other patient was treated, they would reinfect the other ad infinitum, the "ping pong effect."-' As a correlate to this, partners were counselled to use condoms while under treatment to increase the success of treatment. It has become common for physicians to require that partners of patients under treatment for HPV infection be screened and treated for clinical or subclinical disease as well. The "fatal flaw" in this virtually universal dogma is that the source of clinical recurrence is almost certainly not the partner, but the patient him/herself. Ferenczy published one of the first clear demonstrations of this phenomenon," Twenty men and women with anogenital warts were treated with laser. Biopsy specimens were taken at the time of treatment from normal-appearing mucosa 10 mm away from the edge of clinically visible lesions. Over the next 3 months, recurrences occurred in 7 of 20 patients. Of the seven recurrences, six occurred in patients with demonstrable HPV DNA in the biopsies taken from surrounding clinically normal mucosa. The implication was that surrounding subclinically infected tissue could act as a reservoir for HPV, leading to subsequent gross recurrences. The likelihood that sc/latent disease was responsible for clinical recurrences led to attempts to treat sc/latent lesions as well. Carpiniello studied 162 men who were partners of women with either gross condylomata or CIN.-"' They were examined using acetowhitening and colposcopy to detect subclinical infection. Sixtyfour were found to have evidence of clinical or subclinical disease. Forty-three subsequently had all areas of SC disease ablated with laser. After an average of 8 months follow-up, 22 of 43 treated (51%) had recurrent SC or gross disease.

GOALS OF THERAPY

There are three reasons to treat HPV disease. Cosmesis Visible warts are disfiguring. If they become large and confluent enough, they can be repeatedly traumatized or infected. They can grow large enough to obstruct the urethra or vagina." It is reasonable to treat the patient with visible skin lesions on these grounds alone. Contagion As our ability to detect HPV has increased, we have begun to appreciate the enormous prevalence of infection. An attempt to quantify the prevalence of HPV infection in Finland found that clinically or Pap smear-identified HPV infections were found in 3 % of healthy 22year-old women.^" An estimated annual incidence of new infection of 8% suggested a lifetime risk of HPV infection of 79%. Estimates of prevalence in clinically normal American women based on examination, cytologies, or DNA hybridization have ranged from 10% to 18%,''''^ Using the ultrasensitive polymerase chain reaction (PCR) technique, even larger numbers of clinically asymptomatic patients have been shown to harbor HPV. Bauer et al.^-^ used the PCR technique to examine 467 women presenting for annual routine gynecologic examination to a university health service in California, Forty-six percent of these women were shown to be infected with HPV. There is less information regarding prevalence in men. At least 50 to 80% of male partners of women with HPV infections will show evidence of clinical or subclinical HPV infection.^'''^'' If the high estimates of prevalence in women are correct, it is likely that large numbers of men are also infected. The prevalence of HPV infection in this country appears enormous, likely representing the most common of the sexually transmitted diseases. Ideally, the treatment of HPV infection would prevent transmission of the virus to uninfected people. This remains the major justification for treatment in the minds of most physicians. Unfortunately, this is one of the areas where our understanding of HPV is the least complete. There is no proof that treating HPV in683

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at least SC disease. (3) Treatment is very unlikely to eliminate the virus completely. Therefore, both partners will have acquired a lifelong infection with HPV by the time one is diagnosed with HPV infection. (4) Since both partners are already infected, and since subsequent recurrences appear to develop from the patient's own latent/sc disease, there is little to justify treatment of SC or latent disease in either partner to "prevent recurrences." The same can be said of prescribing abstinence or condom use to "prevent reinfection." (5) There is little justification for routine screening of patients to diagnose SC HPV infection, since treatment for SC disease is ineffective. Despite this evidence, such screening remains popular. Epperson, for example, has advocated androscopy for "all men who are at risk for |HPV] infection."^' Given the prevalence of clinical and subclinical/latent infection in the population, this would appear to include, at the least, all sexually active people who at some time had sex without a condom. Recently, objective clinical data have been reported which directly contradict the contention that routine screening by colposcopy or "androscopy" of partners of HPV-infected patients is necessary. Krebs has described the first controlled studies on the effects of treating male partners of women with HPVrelated disease. The first retrospectively examined 390 women treated for cervical dysplasia,''' One hundred and ninety of them had their male partners examined with colposcopy and treated for any identified HPV infection. The men were asked to use condoms until the women's lesions had resolved. They were compared with 200 matched controls also treated for cervical dysplasia, whose partners were not examined or treated for HPV infection or told to use condoms. The CIN treatment failure rates among the women were 6,8 and 7,5% in the partner-treated and non-treated groups, not significantly different.

Even higher failure rates have been described when more specific tests for HPV infection have been used. Riva et al. reported their experience with 25 women with subclinical HPV infection of the lower genital tract proven on biopsy.^' In a rather heroic effort, they treated all 25 by an extensive vaporization with laser of the surface of the entire lower genital tract. Cervical tissue was ablated to a depth of at least 5 mm, and other areas to submucosal depth. Male partners were treated concurrently if HPV infection was diagnosed. Morbidity was extensive, with all patients experiencing moderate to severe pain, 19 developing fever, three with urinary tract infections, and five with chronic vulvar pruritus following treatment. Despite this extremely aggressive approach, at 3 months follow-up, 22 of 25 (88%) still had histologically demonstrable evidence of subclinical HPV infection. Similar high rates of persistent or recurrent disease have been reported after the use of other highly touted treatments such as interferon.^^'^^ The notion that treatment of sc/latent disease to eliminate the virus is futile is now commonly recognized in gynecologic practice. Reid et al. have stated that in an extensive experience treating HPV disease in women, they have concluded that "success refers to long-term freedom from clinical [visible] recurrence. In our opinion, the question of whether latent HPV DNA remains at the treatment site is of no practical relevance."^'' It is likely that those involved in the management of men with HPV disease will soon come to the same conclusion. The other question, which is not answered, is how infectious SC or latent disease is. It is likely that SC lesions are actively infectious. They show histologic and molecular evidence of active replication of HPV virions.^^ Swabs of normal-appearing skin can be shown to contain HPV DNA.^^ Clinically, it is not unusual for a woman newly diagnosed with subclinical cervical disease to have a partner with no history of gross lesions, suggesting that transmission from SC lesions must have occurred. The infectivity of latent disease is less clear, and no substantiatable opinion on this can be offered. If elimination of gross lesions leaves residual SC or latent infection, and if such SC or latent lesions are still infectious, then treatment to eliminate contagiousness is not possible. It is a reasonable hope that since gross lesions carry much higher numbers of virions, they will turn out to be substantially more infectious than SC/latent infections, which would further justify the practice of treating gross lesions; however, once only SC or latent disease remains, evidence suggests that further attempts at treatment will not further reduce the risk of transmission. The following conclusions can be drawn: (1) HPV infections are very efficiently transmitted from gross lesions. It is likely that transmission can occur from subclinical lesions as well. (2) The likelihood is very high that if one partner presents with evidence of HPV infection, the other partner is already infected with

Similarly, Krebs retrospectively compared 180 women treated for condyloma acuminatum whose male partners were screened and treated for HPV infection to 180 matched controls also treated for condylomata, whose partners were not treated or told to abstain from intercourse or use condoms.'*' Again, the striking result was that the partners of treated men did no better (16.7% failure rate) than the partners of untreated men (18.9%). This was despite the detection and attempted treatment of HPV infection in 68% of men who were screened. Thus routine partner screening and treatment failed to improve the outcome in treating either condylomata, or cervical dysplasia. These are critically important reports which, if substantiated, will prove the ineffectiveness of routine partner screening. Carcinogenesis Treatment of HPV disease has been justified as a method to prevent the development of cancer. Until recently, this has centered entirely on the role of HPV in 684

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the pathogenesis of cervical cancer. This is by far the most common and most dangerous of the cancers associated with HPV. The role of HPV treatment in the prevention of cervical cancer remains unclear, despite the clear-cut association of infection with this cancer. The treatment of HPV disease to prevent cervical cancer is a logical outgrowth of the success of cervical screening in preventing cervical cancer. While the use of the Pap smear and other techniques such as cervicography and colposcopy has not eradicated cervical cancer even in this country, it is clear that under optimal circumstances, the use of such techniques can dramatically reduce the morbidity and mortality caused by cervical cancer. Estimates are that effective screening for cytologic atypia will reduce the mortality of cervical cancer by approximately 90%,-''^ Over a lifetime, screening is estimated to reduce the chances of a 20-year-old woman dying from cervical cancer from approximately 118 in 10,000 to about 11 in 10,000. When it became clear that HPV infection was highly associated with CIN, and very likely invasive cancer as well, it was assumed that successful treatment of HPV infection would similarly reduce the toll of cervical cancer. Unlike cervical cytologic screening, however, large controlled trials of such attempts at treatment of HPV infection have not been conducted. The evidence cited above showing the remarkable persistence of the HPV in latent, subclinical, or clinical guise despite the most vigorous of therapies has led to a decline in enthusiasm for such treatment. Treatment of benign HPV infection (i,e., koilocytosis without dysplasia) is highly unlikely to succeed in eliminating the virus completely. On the other hand, the treatment of CIN in the conventional fashion, independent of whether it is in the setting of an HPV infection or not, remains a highly successful method of preventing cervical cancer. This can be done with a number of methods, such as Pap smears, cervicography, and colposcopy, in a manner which is well established in the practice of gynecology. Since we cannot cure HPV infection, and we are successful in treating cervical dysplasia, the conclusion appears clear: management of HPV-related cervical dysplasia and cancer requires that CIN is detected at an early stage and treated appropriately. Patients with HPV infections deserve appropriate screening for dysplasia, which may ultimately utilize HPV testing to determine the relative risk for cancer associated with the particular strain of HPV they are infected with, Reid and Lorincz have suggested that the addition of HPV typing to a Pap smear and cervicography may be the most sensitive and specific, as well as cost effective, set of screening tests available to prevent cervical cancer.'^ Cervical HPV infection in the absence of CIN is likely to not require treatment. Can treatment of HPV be justified to reduce the risk of other forms of cancer? Some reports have claimed that a large percentage of male partners of women with HPV-related cervical dysplasia demonstrate squa-

mous cell carcinoma in situ., often referred to as "bowenoid papulosis." Barrasso found that 44% of partners of women with CIN had penile intraepithelial neoplasia.^'' This high prevalence of bowenoid papulosis does not match the usual estimates of the frequency of this disease.'"' While under-reporting of such pre-cancers may reflect the tendency to not biopsy penile lesions, one certainly does not encounter invasive penile SCC often. This suggests that the natural history of HPV-associated penile intraepithelial neoplasia may be quite different from CIN. At this time, it is difficult to advocate extensive screening for such an infrequent cancer.

CONCLUSIONS

What can then be summarized from these data on the role of treatment of HPV infection? (1) Treatment of visible warts is justifiable, both from an esthetic standpoint as well as to reduce the possible viral "burden," which may enhance transmission of infection. (2) Treating subclinical disease is likely to fail, and thus is unlikely to reduce the risk of transmission of infection. Similarly it does not appear to increase the chance of successful treatment of a partner for gross HPV disease or cervical dysplasia. Therefore, routine screening for subclinical disease is difficult to justify. (3) Women with subclinical HPV infections should be monitored appropriately, and treated if necessary, for cervical dysplasia, but not treated for HPV infection in the absence of dysplasia, since such treatment rarely succeeds in eliminating the virus. Part II of this review will discuss specific methods available to treat HPV infections.

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Therapy of genital human papillomavirus infections. Part I: Indications for and justification of therapy.

REVIEW THERAPY OF GENITAL HUMAN PAPILLOMAVIRUS INFECTIONS. PART I: INDICATIONS FOR AND JUSTIFICATION OF THERAPY MARK R. LING, M.D., PH.D. the terms...
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