- Email: [email protected]
Do we need antivirals for genital herpes simplex virus and human papillomavirus infection?
International Journal of Antimicrobial Agents 12 (1999) 1 – 3
Leading article
Do we need antivirals for genital herpes simplex virus and human papillomavirus infection? G. Gross * Department of Dermatology and Venereology, Uni6ersity of Rostock, Rostock D-18055, Germany
Genital herpes simplex virus (HSV) and human papillomavirus (HPV) infections are two widespread infections that are hardly recognized by the public as sexually transmitted diseases (STD). According to a survey of the American Social Health Association only 17% of adults recognize genital herpes as a STD and only 3% are aware of genital warts being sexually transmitted [1]. About 500 000 cases of genital herpes are estimated each year in the USA [2] and more than 20 000 cases are reported from STD clinics in the UK [3]. Data taken from ten developed countries show that 107 million people are herpes simplex virus type 2 (HSV 2) seropositive [4]. HSV 2 infection, which is mainly responsible for genital herpes, has increased worldwide [5]. A recently published report by Fleming et al. showed that every fifth person in the USA older than 12 years is carrying HSV 2 [6]. The HSV 2 seroprevalence has increased by 30% between 1976 and 1994. This affected increase particularly white teenagers [6]. This is surprising, because at the same time intensive HIV-prevention campaigns were performed in the USA. The special features of genital HSV infection which make therapy so vital are that it is carried lifelong and patients may suffer from many recurrences. Fortunately primary disease affects only 1% of those who get infected. Primary herpes is a severe outbreak of disseminated vesicular lesions accompanied by local swelling, discharge and altogether more serious symptoms than those of recurrent disease. However, recurrences with minor symptoms continually affect people and cause distress and psychosocial problems. In addition stable partnerships may be jeopardized and quality of life reduced. The list of complications and risks of genital HSV infection make efficacious therapy highly desir* Tel.: +49-381-4949701; fax: +49-381-4949702.
able. This applies particularly to persistent genital erosions and ulcers that make transmission and acquisition of HIV a lot easier [7–9]. In the case of genital herpes during pregnancy, different modes of management are being used. It is important to consider systemic antiviral therapy for the mother and for the benefit of the unborn child, for whom HSV may be dangerous and even life-threatening [10]. It is common knowledge that current systemic antiviral therapies alleviate symptomatic genital herpes and act prophylactically when long term therapy is continued. Treatment with acyclovir is safe according to several studies of long term treatment of persons with recurrent genital herpes [11,12]. Recently, moreover, antiviral therapy of genital herpes has been considerably improved. Valaciclovir, the valylester of acyclovir if given orally, has the same antiviral activity as acyclovir, but has the potential for less frequent administration because of its superior pharmacokinetics [13,14]. Both first-episodes and recurrences are best treated by twice daily oral administration of 500 mg valaciclovir for 5 days. Suppressive therapy is one tablet daily during the first year, in cases with frequent recurrences (history of six to eight genital herpes recurrences per year). Intravenous acyclovir should be reserved for severe first-episode or primary genital herpes. Another compound developed for herpesvirus infections and also successfully used for genital herpes is famciclovir, the diacetylester of penciclovir. Famciclovir acts similarly to acyclovir and valaciclovir. Its efficacy in genital herpes is comparable. There is also better biovailability of famciclovir in comparison to acyclovir which allows a less frequent and more convenient dosing schedule. Dosing three times daily is necessary for first-episode and recurrent disease. Suppressive therapy requires two oral administrations per day [15]. A recently published observation in mice suggests that
0924-8579/99/$ - see front matter © 1999 Elsevier Science B.V. and International Society of Chemotherapy. All rights reserved. PII: S 0 9 2 4 - 8 5 7 9 ( 9 9 ) 0 0 0 0 4 - 7
2
G. Gross / International Journal of Antimicrobial Agents 12 (1999) 1–3
famciclovir when given as early as possible may be superior to valaciclovir in terms of decreased ganglionic latency and frequency of recurrences [16]. Data from animal experiments have led to comparative studies of famciclovir and valaciclovir for early treatment of genital herpes in human beings. Until now acyclovir-resistant HSV-strains have been found only in immunodeficient persons. Intravenous foscarnet therapy has a special role in these special conditions. It is fortunate that in most immunodeficient patients HSV infections respond favourably to acyclovir and its successors, giving beneficial results. Altogether we have got an antiviral therapy that works. In 60% of cases, however, genital herpes remains unrecognized by physicians. It follows that in future, diagnosing of HSV infections must be improved and antivirals are used appropriately. An important step forward would be to control asymptomatic herpes virus shedding and transmission by specific antivirals. Another important challenge for the future is the prevention of HSV reactivation and the development of vaccines. The other widespread viral STD is genital HPV infection [17–19], which has some similarities to infections caused by HSV. According to data from Koutsky and coworkers, and other epidemiological studies, the estimated prevalence of genital HPV infection among young women ranges from 20 to 46% in various countries [18–23]. Risk factors are early sexual activity and multiple partners [20 – 23]. Most external genital warts are benign tumours caused by low-risk HPV types such as HPV 6 and HPV 11 [24]. Cervical cancer, recently recognized as a STD, is mainly associated with highrisk HPV types such as HPV 16 and 18 [25]. Cervical cancer is the second most common malignancy in women with nearly half a million new cases diagnosed each year and 213 000 related deaths worldwide [26]. Anogenital cancer at other sites such as the vulva, penis and anus show a similar relationship to the different HPV types. However, the association between HPV and these cancers is not as close as with the cervix uteri [24]. This is especially true for vulvar cancer where two aetiologies have recently been hypothesized. In HPV infections, clinical lesions can coexist with subclinical infection. This is an important issue, since reactivation of HPV and (re)growth of clinical lesions is often seen despite repeated therapy. It has been thus postulated that therapy should include subclinical aceto-white areas around manifest warts [24]. HPV infection, which like HSV may be lifelong, affects only the epithelium with the basal cells as target cells. According to recent data from Kru¨ger Kjaer et al. [27] low-risk HPV infection might be more transient than infection with the oncogenic HPV types. Increased and persistent growths of genital warts are seen in immunodeficient patients such as in transplant recipients under immunosuppres-
sion, and in patients suffering from HIV-infection or Hodgkin’s disease [28,29]. Occasionally such large tumours may convert into malignancy, especially after long duration or after radiotherapy [30]. Recently attention has been focused on genitoanal warts and laryngeal papillomas in young children. This has lead to the recognition of the vertical transmission of HPV [31]. Nevertheless, in a large number of children with genitoanal warts sexual abuse has to be ruled out [32]. All in all external genital warts and other HPV-associated lesions represent a substantial public health problem especially since there is no sufficient therapy available so far. There are various therapeutic options [33]. Some of them can be applied by the patient, such as podophyllotoxin, imiquimod cream, a recently released local immunomodulator acting by inducing interferon-a and cytokines in the skin [34,35] or interferon-b gel given as an adjuvant after laser ablation [36]. Other therapies need to be administered by the physician. Most of these are painful and several sessions are often necessary. None of the many HPV therapies in use has proved to be superior [33]. In contrast to herpes virus infections no specific antiviral therapy against HPV has been proven so far. Clearance rates range between less than 20% and more than 80% as shown in several reports [33]. Recurrence rates are also fairly high. So, on the whole, these treatments are not fully satisfactory and a novel approach to therapy of HPV infection is needed. There are two main options: development of HPV specific vaccines and antiviral therapy, the latter of which seems to be an obvious choice for established clinical lesions. Cidofovir (HPMPC) is a prototype of antiviral compounds, which is active against HPV and HSV as well as against a large number of other DNA viruses including molluscum contagiosum [37,38]. Cidofovir gel has been developed for local therapy of cutaneous viral infections. Currently it is being used in several clinical trials for molluscum, genital warts and cervical dysplasia (CIN), in both immunocompetent and immunodeficient patients [38]. It is noteworthy that adjuvant interferon-b gel given as an adjuvant to laser ablation is active in genital warts and in molluscum contagiosum, preventing recurrence of lesions even in immunodeficient patients such as those suffering from AIDS [39]. References [1] American Social Health Association. Awareness of Sexually Transmitted Diseases: An International Study, 1995. [2] Centres for Disease Control and Prevention. Genital herpes infections — United States 1966 – 79. MMWR 1982;31:137–9. [3] Government Statistical Service. Sexually Transmitted Diseases, England 1995: new cases seen at NHS genito-urinary medicine clinics. London: HM Stationery Office, 1996:1 – 15.
G. Gross / International Journal of Antimicrobial Agents 12 (1999) 1–3 [4] Marchant Roe A. Genital herpes: recognizing and addressing patients’ needs. Herpes J 1997;4:36–41. [5] Mindel A. Genital herpes—how much of a public-health problem? Lancet 1998;351(Suppl. III):16–8. [6] Fleming DT, McQuillan GM, Johnson RA, et al. Herpes simplex in the United States 1976–1994. New Engl J Med 1997;337:1105– 11. [7] Kassler WD, Zenilman JM, Erickson B, et al. Seroconversion in patients attending sexually transmitted disease clinics. AIDS 1994;8:351 – 5. [8] Holmberg SD, Stewart JA, Gerber AR, et al. Prior herpes simplex virus type 2 infections as a risk factor for HIV infection. J Am Med Assoc 1988;259:1048–50. [9] Keef IP, Lee FK, van Griemsven GJ, et al. Herpes simplex virus type 2 and other genital ulcerative infections as a risk factor, for HIV-1 acquisition. Genitourin Med 1990;66:330–3. [10] Whitley R. Neonatal Herpes simplex virus infections. J Med Virol 1993;Suppl. 1:13–21. [11] Kaplowitz LG, Baker D, Gelb L, et al. Prolonged continuous acyclovir treatment of normal adults with frequently recuring genital herpes simplex virus infection. J Am Med Assoc 1991;265:747 – 51. [12] Tilson HH, Engle CR, Andrews EB. Safety of acyclovir: a summary of the first 10 years experience. J Med Virol 1993;Suppl. 1:67 – 73. [13] Mindel A, Brocklehurst P. The treatment of herpes simplex virus infections. In: Jeffries D, De Clerq E, editors. Antiviral chemotherapy. Chichester: Wiley, 1995. [14] The valaciclovir Study Group, Spruance SL, Tyring SK, Degregorio B. A large-scale, placebo-controlled, dose-ranging trial of peroral valaciclovir for episodic treatment of recurrent herpes genitalis. Arch Intern Med 1996;156:1729–35. [15] The Canadian Famciclovir Study Group, Sacks SL, Aoki FY, Diaz Mitoma F. Patient-initiated, twice-daily oral famiciclovir for early recurrent genital herpes: a randomized double-blind multicenter trial. J Am Med Assoc 1996;276:44–9. [16] Thackray AM, Field HJ. Comparison of the effect of famiciclovir and valaciclovir on pathogenesis of herpes simplex virus type 2 in a murine infection model. Antimicrob Agents Chemother 1996;40:846–51. [17] Ho GYF, Bierman R, Beardsley L, et al. Natural history of cervicovaginal papillomavirus infection in young women. New Engl J Med 1998;338:423–8. [18] Bauer HM, Ting Y, Greer CE, et al. Genital human papillomavirus infection in female university students as determined by a PCR-based method. J Am Med Assoc 1991;265:472–7. [19] Koutsky LA, Holmes KK, Critchlow CW, et al. A cohort study of the risk of cervical intraepithelial nesplasia grade 2 or 3 in relation to papillomavirus infection. New Engl J Med 1992;327:1272– 8. [20] Burk RD, Ho GYF, Beardsley L, et al. Sexual behaviour and partner characteristics are the predominant risk factors for genital human papillomavirus infection in young woman. J Infect Dis 1996;174:679 – 89. [21] Evander M, Edlund K, Gustafsson A, et al. Human papillomavirus infection is transient in young women: a population based cohort study. J Infect Dis 1995;17:1026–30. [22] Karlsson R, Jonsson M, Edlund K, et al. Lifetime number of partners as the only independent risk factor for human papillomavirus infection: a population based study. Sex Transm Dis 1995;22:119 – 27.
.
3
[23] Fairley CK, Chen S, Ugori A, et al. Human papillomavirus infection and its relationship to recent and distant sexual partners. Obstet Gynecol 1994;84:755 – 9. [24] Von Krogh G, Gross G. Anogenital warts. In: Orth G, Jablonska S, editors. Clinics in Dermatology, vol. 15(3). Elsevier, NY, 1997;355 – 368 [25] IARC Working Group. Human Papillomaviruses. IARC Monographs on the Evaluation of Carcinogenic Risks to Humans, vol. 64. Lyon: IARC, 1995. [26] Herrero R. Epidemiology of cervical cancer. Monogr Natl Cancer Inst 1996;21:1 – 6. [27] Kru¨ger Kjaer S, Van den Brule AJC, Bock JE, et al. Determinants for genital human papillomavirus (HPV) infection in 1000 randomly chosen young Danish women with normal PAP Swear: are there different profiles for oncogenic and nononcogenic HPV types? Cancer Epidemiol Biomarkers Prev 1997;6:799 –805. [28] Bryan JT, Stoler NH, Tyring SK, et al. High-grade dysplasia in genital warts from two patients infected with the human immumodeficiency virus. J Med Virol 1998;54:69 – 73. [29] Palefsky J. HPV-related disease in immunosuppressed individuals. In: Gross G, von Krogh G, editors. Human Papillomavirus Infections in Dermatovenereology. Boca Raton, FL: CRC Press, 1997:227 – 40. [30] Von Krogh G, Gross G, Barrasso R. Warts and HPV-related squamous cell tumours of the genitoanal area in adults. In: Gross G, von Krogh G, editors. Human Papillomavirus Infections in Dermatovenereology. Boca Raton, FL: CRC Press, 1997:259 – 304. [31] Armbruster-Moraes E, Joshimoto EM, Leao E, Zugaib M. Presence of human papillomavirus DNA in amniotic fluides of pregnant women with cervical lesions. Gynaecol Oncol 1994;54:152 – 4. [32] Obalek S, Jablonska S, Orth G. Warts and HPV-related squamous cell tumours of the genitoanal area in children. In: Gross G, von Krogh G, editors. Human Papillomavirus Infections in Dermatovenereology. Boca Raton, FL: CRC Press, 1997:305 – 12. [33] Gross G. Therapy of human papillomavirus infection and associated epithelial tumours. Intervirology 1998;40:368 – 77. [34] Edwards L, Ferenczy A, Eron L, et al. Self-administered topical 5% imiquimod cream for external anogenital warts. Arch Dermatol 1998;134:25 – 31. [35] Beutner KR, Tyring SK, Trofatter KF Jr., et al. Imiquimod, a patient-applied immune response modifier for treatment of external genital warts. Antimicrob Agents Chemother 1998;42(4):789– 94. [36] Gross G, Rogoszinski T, Scho¨fer H, et al. Recombinant interferon beta gel as adjuvant in the treatment of recurrent genital warts: results of a placebo-controlled double-blind study in 120 patients. Dermatology 1998;196:330 – 4. [37] Snoeck R, van Ranst M, Andrei G, et al. Treatment of anogenital papillomavirus infections with an acyclic nucleoside phosphonate analogue. New Engl J Med 1995;333:943 – 4. [38] De Clerq E. Acyclic nucleoside phosphonates in the chemotherapy of DNA virus and retrovirus infections. Intervirology 1998;40:295 – 303. [39] Gross G, Roussaki A, Brzoska J. Recalcitrant molluscum contagiosum in a patient with AIDS successfully treated by combination of CO2 laser swift lase and natural interferon beta gel. Acta Derm-Venereol 1998;78:309 – 10.
Leading article
Do we need antivirals for genital herpes simplex virus and human papillomavirus infection? G. Gross * Department of Dermatology and Venereology, Uni6ersity of Rostock, Rostock D-18055, Germany
Genital herpes simplex virus (HSV) and human papillomavirus (HPV) infections are two widespread infections that are hardly recognized by the public as sexually transmitted diseases (STD). According to a survey of the American Social Health Association only 17% of adults recognize genital herpes as a STD and only 3% are aware of genital warts being sexually transmitted [1]. About 500 000 cases of genital herpes are estimated each year in the USA [2] and more than 20 000 cases are reported from STD clinics in the UK [3]. Data taken from ten developed countries show that 107 million people are herpes simplex virus type 2 (HSV 2) seropositive [4]. HSV 2 infection, which is mainly responsible for genital herpes, has increased worldwide [5]. A recently published report by Fleming et al. showed that every fifth person in the USA older than 12 years is carrying HSV 2 [6]. The HSV 2 seroprevalence has increased by 30% between 1976 and 1994. This affected increase particularly white teenagers [6]. This is surprising, because at the same time intensive HIV-prevention campaigns were performed in the USA. The special features of genital HSV infection which make therapy so vital are that it is carried lifelong and patients may suffer from many recurrences. Fortunately primary disease affects only 1% of those who get infected. Primary herpes is a severe outbreak of disseminated vesicular lesions accompanied by local swelling, discharge and altogether more serious symptoms than those of recurrent disease. However, recurrences with minor symptoms continually affect people and cause distress and psychosocial problems. In addition stable partnerships may be jeopardized and quality of life reduced. The list of complications and risks of genital HSV infection make efficacious therapy highly desir* Tel.: +49-381-4949701; fax: +49-381-4949702.
able. This applies particularly to persistent genital erosions and ulcers that make transmission and acquisition of HIV a lot easier [7–9]. In the case of genital herpes during pregnancy, different modes of management are being used. It is important to consider systemic antiviral therapy for the mother and for the benefit of the unborn child, for whom HSV may be dangerous and even life-threatening [10]. It is common knowledge that current systemic antiviral therapies alleviate symptomatic genital herpes and act prophylactically when long term therapy is continued. Treatment with acyclovir is safe according to several studies of long term treatment of persons with recurrent genital herpes [11,12]. Recently, moreover, antiviral therapy of genital herpes has been considerably improved. Valaciclovir, the valylester of acyclovir if given orally, has the same antiviral activity as acyclovir, but has the potential for less frequent administration because of its superior pharmacokinetics [13,14]. Both first-episodes and recurrences are best treated by twice daily oral administration of 500 mg valaciclovir for 5 days. Suppressive therapy is one tablet daily during the first year, in cases with frequent recurrences (history of six to eight genital herpes recurrences per year). Intravenous acyclovir should be reserved for severe first-episode or primary genital herpes. Another compound developed for herpesvirus infections and also successfully used for genital herpes is famciclovir, the diacetylester of penciclovir. Famciclovir acts similarly to acyclovir and valaciclovir. Its efficacy in genital herpes is comparable. There is also better biovailability of famciclovir in comparison to acyclovir which allows a less frequent and more convenient dosing schedule. Dosing three times daily is necessary for first-episode and recurrent disease. Suppressive therapy requires two oral administrations per day [15]. A recently published observation in mice suggests that
0924-8579/99/$ - see front matter © 1999 Elsevier Science B.V. and International Society of Chemotherapy. All rights reserved. PII: S 0 9 2 4 - 8 5 7 9 ( 9 9 ) 0 0 0 0 4 - 7
2
G. Gross / International Journal of Antimicrobial Agents 12 (1999) 1–3
famciclovir when given as early as possible may be superior to valaciclovir in terms of decreased ganglionic latency and frequency of recurrences [16]. Data from animal experiments have led to comparative studies of famciclovir and valaciclovir for early treatment of genital herpes in human beings. Until now acyclovir-resistant HSV-strains have been found only in immunodeficient persons. Intravenous foscarnet therapy has a special role in these special conditions. It is fortunate that in most immunodeficient patients HSV infections respond favourably to acyclovir and its successors, giving beneficial results. Altogether we have got an antiviral therapy that works. In 60% of cases, however, genital herpes remains unrecognized by physicians. It follows that in future, diagnosing of HSV infections must be improved and antivirals are used appropriately. An important step forward would be to control asymptomatic herpes virus shedding and transmission by specific antivirals. Another important challenge for the future is the prevention of HSV reactivation and the development of vaccines. The other widespread viral STD is genital HPV infection [17–19], which has some similarities to infections caused by HSV. According to data from Koutsky and coworkers, and other epidemiological studies, the estimated prevalence of genital HPV infection among young women ranges from 20 to 46% in various countries [18–23]. Risk factors are early sexual activity and multiple partners [20 – 23]. Most external genital warts are benign tumours caused by low-risk HPV types such as HPV 6 and HPV 11 [24]. Cervical cancer, recently recognized as a STD, is mainly associated with highrisk HPV types such as HPV 16 and 18 [25]. Cervical cancer is the second most common malignancy in women with nearly half a million new cases diagnosed each year and 213 000 related deaths worldwide [26]. Anogenital cancer at other sites such as the vulva, penis and anus show a similar relationship to the different HPV types. However, the association between HPV and these cancers is not as close as with the cervix uteri [24]. This is especially true for vulvar cancer where two aetiologies have recently been hypothesized. In HPV infections, clinical lesions can coexist with subclinical infection. This is an important issue, since reactivation of HPV and (re)growth of clinical lesions is often seen despite repeated therapy. It has been thus postulated that therapy should include subclinical aceto-white areas around manifest warts [24]. HPV infection, which like HSV may be lifelong, affects only the epithelium with the basal cells as target cells. According to recent data from Kru¨ger Kjaer et al. [27] low-risk HPV infection might be more transient than infection with the oncogenic HPV types. Increased and persistent growths of genital warts are seen in immunodeficient patients such as in transplant recipients under immunosuppres-
sion, and in patients suffering from HIV-infection or Hodgkin’s disease [28,29]. Occasionally such large tumours may convert into malignancy, especially after long duration or after radiotherapy [30]. Recently attention has been focused on genitoanal warts and laryngeal papillomas in young children. This has lead to the recognition of the vertical transmission of HPV [31]. Nevertheless, in a large number of children with genitoanal warts sexual abuse has to be ruled out [32]. All in all external genital warts and other HPV-associated lesions represent a substantial public health problem especially since there is no sufficient therapy available so far. There are various therapeutic options [33]. Some of them can be applied by the patient, such as podophyllotoxin, imiquimod cream, a recently released local immunomodulator acting by inducing interferon-a and cytokines in the skin [34,35] or interferon-b gel given as an adjuvant after laser ablation [36]. Other therapies need to be administered by the physician. Most of these are painful and several sessions are often necessary. None of the many HPV therapies in use has proved to be superior [33]. In contrast to herpes virus infections no specific antiviral therapy against HPV has been proven so far. Clearance rates range between less than 20% and more than 80% as shown in several reports [33]. Recurrence rates are also fairly high. So, on the whole, these treatments are not fully satisfactory and a novel approach to therapy of HPV infection is needed. There are two main options: development of HPV specific vaccines and antiviral therapy, the latter of which seems to be an obvious choice for established clinical lesions. Cidofovir (HPMPC) is a prototype of antiviral compounds, which is active against HPV and HSV as well as against a large number of other DNA viruses including molluscum contagiosum [37,38]. Cidofovir gel has been developed for local therapy of cutaneous viral infections. Currently it is being used in several clinical trials for molluscum, genital warts and cervical dysplasia (CIN), in both immunocompetent and immunodeficient patients [38]. It is noteworthy that adjuvant interferon-b gel given as an adjuvant to laser ablation is active in genital warts and in molluscum contagiosum, preventing recurrence of lesions even in immunodeficient patients such as those suffering from AIDS [39]. References [1] American Social Health Association. Awareness of Sexually Transmitted Diseases: An International Study, 1995. [2] Centres for Disease Control and Prevention. Genital herpes infections — United States 1966 – 79. MMWR 1982;31:137–9. [3] Government Statistical Service. Sexually Transmitted Diseases, England 1995: new cases seen at NHS genito-urinary medicine clinics. London: HM Stationery Office, 1996:1 – 15.
G. Gross / International Journal of Antimicrobial Agents 12 (1999) 1–3 [4] Marchant Roe A. Genital herpes: recognizing and addressing patients’ needs. Herpes J 1997;4:36–41. [5] Mindel A. Genital herpes—how much of a public-health problem? Lancet 1998;351(Suppl. III):16–8. [6] Fleming DT, McQuillan GM, Johnson RA, et al. Herpes simplex in the United States 1976–1994. New Engl J Med 1997;337:1105– 11. [7] Kassler WD, Zenilman JM, Erickson B, et al. Seroconversion in patients attending sexually transmitted disease clinics. AIDS 1994;8:351 – 5. [8] Holmberg SD, Stewart JA, Gerber AR, et al. Prior herpes simplex virus type 2 infections as a risk factor for HIV infection. J Am Med Assoc 1988;259:1048–50. [9] Keef IP, Lee FK, van Griemsven GJ, et al. Herpes simplex virus type 2 and other genital ulcerative infections as a risk factor, for HIV-1 acquisition. Genitourin Med 1990;66:330–3. [10] Whitley R. Neonatal Herpes simplex virus infections. J Med Virol 1993;Suppl. 1:13–21. [11] Kaplowitz LG, Baker D, Gelb L, et al. Prolonged continuous acyclovir treatment of normal adults with frequently recuring genital herpes simplex virus infection. J Am Med Assoc 1991;265:747 – 51. [12] Tilson HH, Engle CR, Andrews EB. Safety of acyclovir: a summary of the first 10 years experience. J Med Virol 1993;Suppl. 1:67 – 73. [13] Mindel A, Brocklehurst P. The treatment of herpes simplex virus infections. In: Jeffries D, De Clerq E, editors. Antiviral chemotherapy. Chichester: Wiley, 1995. [14] The valaciclovir Study Group, Spruance SL, Tyring SK, Degregorio B. A large-scale, placebo-controlled, dose-ranging trial of peroral valaciclovir for episodic treatment of recurrent herpes genitalis. Arch Intern Med 1996;156:1729–35. [15] The Canadian Famciclovir Study Group, Sacks SL, Aoki FY, Diaz Mitoma F. Patient-initiated, twice-daily oral famiciclovir for early recurrent genital herpes: a randomized double-blind multicenter trial. J Am Med Assoc 1996;276:44–9. [16] Thackray AM, Field HJ. Comparison of the effect of famiciclovir and valaciclovir on pathogenesis of herpes simplex virus type 2 in a murine infection model. Antimicrob Agents Chemother 1996;40:846–51. [17] Ho GYF, Bierman R, Beardsley L, et al. Natural history of cervicovaginal papillomavirus infection in young women. New Engl J Med 1998;338:423–8. [18] Bauer HM, Ting Y, Greer CE, et al. Genital human papillomavirus infection in female university students as determined by a PCR-based method. J Am Med Assoc 1991;265:472–7. [19] Koutsky LA, Holmes KK, Critchlow CW, et al. A cohort study of the risk of cervical intraepithelial nesplasia grade 2 or 3 in relation to papillomavirus infection. New Engl J Med 1992;327:1272– 8. [20] Burk RD, Ho GYF, Beardsley L, et al. Sexual behaviour and partner characteristics are the predominant risk factors for genital human papillomavirus infection in young woman. J Infect Dis 1996;174:679 – 89. [21] Evander M, Edlund K, Gustafsson A, et al. Human papillomavirus infection is transient in young women: a population based cohort study. J Infect Dis 1995;17:1026–30. [22] Karlsson R, Jonsson M, Edlund K, et al. Lifetime number of partners as the only independent risk factor for human papillomavirus infection: a population based study. Sex Transm Dis 1995;22:119 – 27.
.
3
[23] Fairley CK, Chen S, Ugori A, et al. Human papillomavirus infection and its relationship to recent and distant sexual partners. Obstet Gynecol 1994;84:755 – 9. [24] Von Krogh G, Gross G. Anogenital warts. In: Orth G, Jablonska S, editors. Clinics in Dermatology, vol. 15(3). Elsevier, NY, 1997;355 – 368 [25] IARC Working Group. Human Papillomaviruses. IARC Monographs on the Evaluation of Carcinogenic Risks to Humans, vol. 64. Lyon: IARC, 1995. [26] Herrero R. Epidemiology of cervical cancer. Monogr Natl Cancer Inst 1996;21:1 – 6. [27] Kru¨ger Kjaer S, Van den Brule AJC, Bock JE, et al. Determinants for genital human papillomavirus (HPV) infection in 1000 randomly chosen young Danish women with normal PAP Swear: are there different profiles for oncogenic and nononcogenic HPV types? Cancer Epidemiol Biomarkers Prev 1997;6:799 –805. [28] Bryan JT, Stoler NH, Tyring SK, et al. High-grade dysplasia in genital warts from two patients infected with the human immumodeficiency virus. J Med Virol 1998;54:69 – 73. [29] Palefsky J. HPV-related disease in immunosuppressed individuals. In: Gross G, von Krogh G, editors. Human Papillomavirus Infections in Dermatovenereology. Boca Raton, FL: CRC Press, 1997:227 – 40. [30] Von Krogh G, Gross G, Barrasso R. Warts and HPV-related squamous cell tumours of the genitoanal area in adults. In: Gross G, von Krogh G, editors. Human Papillomavirus Infections in Dermatovenereology. Boca Raton, FL: CRC Press, 1997:259 – 304. [31] Armbruster-Moraes E, Joshimoto EM, Leao E, Zugaib M. Presence of human papillomavirus DNA in amniotic fluides of pregnant women with cervical lesions. Gynaecol Oncol 1994;54:152 – 4. [32] Obalek S, Jablonska S, Orth G. Warts and HPV-related squamous cell tumours of the genitoanal area in children. In: Gross G, von Krogh G, editors. Human Papillomavirus Infections in Dermatovenereology. Boca Raton, FL: CRC Press, 1997:305 – 12. [33] Gross G. Therapy of human papillomavirus infection and associated epithelial tumours. Intervirology 1998;40:368 – 77. [34] Edwards L, Ferenczy A, Eron L, et al. Self-administered topical 5% imiquimod cream for external anogenital warts. Arch Dermatol 1998;134:25 – 31. [35] Beutner KR, Tyring SK, Trofatter KF Jr., et al. Imiquimod, a patient-applied immune response modifier for treatment of external genital warts. Antimicrob Agents Chemother 1998;42(4):789– 94. [36] Gross G, Rogoszinski T, Scho¨fer H, et al. Recombinant interferon beta gel as adjuvant in the treatment of recurrent genital warts: results of a placebo-controlled double-blind study in 120 patients. Dermatology 1998;196:330 – 4. [37] Snoeck R, van Ranst M, Andrei G, et al. Treatment of anogenital papillomavirus infections with an acyclic nucleoside phosphonate analogue. New Engl J Med 1995;333:943 – 4. [38] De Clerq E. Acyclic nucleoside phosphonates in the chemotherapy of DNA virus and retrovirus infections. Intervirology 1998;40:295 – 303. [39] Gross G, Roussaki A, Brzoska J. Recalcitrant molluscum contagiosum in a patient with AIDS successfully treated by combination of CO2 laser swift lase and natural interferon beta gel. Acta Derm-Venereol 1998;78:309 – 10.