© 2003 by Oxford University Press
Journal of the National Cancer Institute Monographs, No. 31, 117-124,
2003
© 2003 Oxford University Press
ARTICLE |
Chapter 17: Genital Human Papillomavirus Infections—Current and Prospective Therapies
Correspondence to: Margaret Stanley, Ph.D., Department of Pathology, University of Cambridge, Tennis Court Rd., Cambridge CB2 1Q0, U.K. (email: mas{at}mole.bio.cam.ac.uk).
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ABSTRACT |
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 Top Abstract IntroductionAnogenital HPV-Associated...Current TherapiesFuture ProspectsSummaryReferences |
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Many therapies are available for the treatment of human papillomavirus (HPV)-associated disease, particularly external genital warts. However, at present, these therapies aim to remove the lesion rather than specifically target HPV infection. When disease and infection are local, as in cervical intraepithelial neoplasia (CIN), excisional therapies removing lesion and transformation-susceptible cells are highly effective. However, when infection is regional, as is usually the case for the anogenital warts, vulval intraepithelial neoplasia (VIN), anal intraepithelial neoplasia (AIN), penile intraepithelial neoplasia, and vaginal intraepithelial neoplasia, then current treatments are generally inadequate, with high recurrence rates. Future therapies will be directly or indirectly antiviral, targeting HPV protein functions or enhancing the ability of the immune system to resolve infection or inducing apoptosis indirectly in HPV-infected cells. In the short to the medium term, immunotherapies for low-grade disease are the most likely to be in the clinic. Vaccines targeting the E1 and E2 early proteins combined with immunomodulators or conventional adjuvants that induce a strong cell-mediated HPV antigen-specific response and good immune memory would be the predicted combination. Vaccines designed to target high-grade intraepithelial disease, even when used in combination with immunomodulators, are unlikely to effect lesion clearance in more than a fraction of the cases. However, they may have a role as adjunct therapy after cervical conization to prevent the recurrence of CIN or HPV reinfection. They certainly appear to have a role in multifocal disease, such as VIN and AIN, where partial clearance may be effected and lesion size reduced enough for effective ablative or excisional therapy. It seems unlikely that anti-HPV chemotherapies specifically targeting HPV protein functions will be in the clinic in the medium term. However, agents such as indole-3-carbinol have shown efficacy in small clinical trials, and if these effects are confirmed in larger, randomized, placebo-controlled trials, they could be clinically useful.
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Introduction |
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TopAbstractIntroductionAnogenital HPV-Associated...Current TherapiesFuture ProspectsSummaryReferences |
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Human papillomaviruses (HPVs) are associated with a spectrum of epithelial proliferative diseases ranging from benign warts to intraepithelial neoplasms (1). Because the latter may progress to frank invasive carcinoma, HPV infection is not just the cause of cosmetic nuisances but is associated with considerable morbidity and mortality. Other chapters in this monograph document that genital HPV infections are common sexually transmitted diseases (STDs). Genital warts, for example, have an estimated incidence of 2.4 cases per 1000 of the population per year, but the prevalence of the virus types that principally cause them, HPV type 6 (HPV6) and its relatives, is probably larger. The same order of relative frequencies applies to the high-risk HPV types (HPV types 16 and 18 and their relatives) that are associated with intraepithelial neoplasms and carcinomas. It is likely that the prevalence of these infections is a considerable underestimate, since the viruses are distributed in the genital mucosa in a regional rather than in a localized manner.
Effective therapies for these infections are a high priority, but progress in the achievement of these objectives has not been rapid for several reasons. There are difficulties in studying the biology and pathogenesis of these viruses that have a unique and complex replication cycle. HPVs are exclusively intraepithelial pathogens with a replication cycle, which is both time and differentiation dependent. The viral replication cycle is one in which viral infection is targeted to basal keratinocytes, but high-level expression of viral proteins and viral assembly occur only in differentiating keratinocytes in the stratum spinosum and granulosum of squamous epithelium. In vitro systems that generate large amounts of infectious virus are not available. The viral genome is small—8 kilobases of double-stranded DNA—and encodes a maximum of eight genes, six of which encode nonstructural or the early proteins E1, E2, E4, E5, E6, and E7 and two of which encode structural or the late proteins L1 and L2. Viral genes are differentially expressed both temporally and spatially throughout the infectious cycle (Fig. 1
).
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A further complication of these infections is the phenomenon of latency. HPV DNA may remain present, but quiescent, within cells either before or after active infection. The virus may be held as a latent infection (expression of a limited set of latency-associated transcripts, but no production of infectious virus) from the outset, or it may have caused a subclinical or unnoticed clinical infection. Spontaneous wart regression is immune mediated but this does not result in virus clearance (at least in animal infections), and viral genomes can be detected in apparently normal epithelium many months and years after wart regression (2,3). However, the strong cell-mediated immunity that engenders regression of HPV-infected lesions probably controls latent infection and, in healthy immunocompetent individuals, recurrence of disease is unlikely. In contrast, immunosuppression predisposes to reactivation, as is demonstrated by the high levels of genital HPV infection and neoplasia seen in immunosuppressed organ-transplant recipients and in those with human immunodeficiency virus infection. Antiviral chemotherapies are essential for such patients. In addition to the pathobiologic hurdles, new medical therapies for HPV lesions must meet quite stringent criteria. Inducing responses is not enough; the therapy must induce regression without recurrence for at least 6–12 months.
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ANOGENITAL HPV-ASSOCIATED DISEASE |
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TopAbstractIntroductionAnogenital HPV-Associated...Current TherapiesFuture ProspectsSummaryReferences |
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HPV infection of the anogenital skin and mucosa results in lesions with two morphologies—anogenital warts (condyloma acuminata) and squamous intraepithelial lesions (SILs). Condylomata are associated predominantly, but not exclusively, with infection by HPV6 and its relatives. These are frank, polypoid growths that generate infectious virus and have a low-to-negligible risk of malignant progression. SILs are classified histologically and form a distinct spectrum of histologic atypia. In the cervix, these lesions are graded on the degree to which they have lost cytoplasmic maturation and exhibit cytologic atypia. In Europe, three grades are recognized cervical intraepithelial neoplasia (CIN): CIN 1—mild, CIN 2—moderate, and CIN 3—severe. The Bethesda classification for cytology used in the United States recognizes two classes—low-grade SILs (LGSILs) (CIN 1) and high-grade SILs (HGSILs) (CIN 2/3). In the vagina, vulva, anus, and penis, a similar but not identical spectrum of changes can be identified (vaginal intraepithelial neoplasia [VAIN], vulval intraepithelial neoplasia [VIN], anal intraepithelial neoplasia [AIN], and penile intraepithelial neoplasia [PIN]), but the likelihood of progression of these lesions to frank malignancies is still unclear. It is probable, but not unequivocally proven, that the majority of these intraepithelial lesions are a result of HPV infection. There is considerable confusion about the terminology used to define these lesions and, to ensure clarity, in this review the term HGSIL includes CIN 2/3, AIN 3, PIN 3, VIN 3, and VAIN 3: LGSIL encompasses CIN 1 and the equivalent lesions in other sites.
LGSILs at any site can be associated with both high- and low-risk HPV types, although high-risk types predominate (4). Most of the lesions maintain the virus as an episome and support a complete virus replication cycle, and viral gene expression is tightly regulated. Late genes are expressed and virus particles are generated. Warts and LGSILs at all sites are likely to be amenable to the same therapeutic strategies.
HGSILs (at least in the cervix) are associated almost exclusively with high-risk types. In general, because of the defects in cellular differentiation that characterize these lesions, high-grade CINs do not support a complete viral infectious cycle. Late gene expression is either lost or substantially reduced, the viral DNA sequences may be integrated into the host genome, and the expression of the E6 and E7 oncogenes is deregulated with the expression of these oncoproteins throughout the epithelium. CIN 3 is characterized by chromosomal aneuploidy and genetic instability and can progress to malignancy. The evidence that HGSILs at other sites also exhibit genetic instability is incomplete but, at least for VIN and AIN, looks increasingly likely (5,6). The genetic instability of these high-grade lesions and the changes in viral gene expression that occur in association with this means that these lesions may not be amenable to the same therapeutic strategies as low-grade lesions. CIN 3 arises almost exclusively at the squamo–columnar junction. Disease, therefore, is localized, even though infection may be regional, and ablative therapies may be highly effective. However, AIN, PIN, VAIN, and VIN are often multifocal, both disease and infection are regional, and ablation may not be feasible or, if attempted, ineffective.
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CURRENT THERAPIES |
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TopAbstractIntroductionAnogenital HPV-Associated...Current TherapiesFuture ProspectsSummaryReferences |
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The objectives of the therapy for an STD are as follows: 1) eradication of infection, 2) elimination of symptoms, 3) prevention of long-term sequelae, and 4) interruption of transmission.
These objectives are only partially met in the current therapies that are not targeted antiviral therapies but either attempt the physical removal of the lesion or the induction of nonspecific inflammation, thereby inducing a bystander immune response. Inevitably, therefore, they do not address the issue of the underlying HPV infection. In general, for HPV infections, highly effective systemic therapy is not available, eradication of infection is not a reasonable objective, and, furthermore, treatment of disease has not been shown convincingly to reduce the rates of transmission. Treatment of genital warts is symptomatic, with the primary goal of eliminating or reducing the size of clinically apparent lesions. The goal in the treatment of cervical SILs is to prevent progression to more severe disease.
Current therapies for anogenital HPV infections fall into four main categories: 1) ablation, 2) cytotoxic agents, 3) photodynamic therapy, and 4) immunomodulators.
Ablative therapies for genital warts include cryotherapy, scissor excision, laser therapy, and electrosurgery. Physically ablative therapies are often highly effective in the short term but recurrence rates can be high, since only the visible lesion is excised and latently infected keratinocytes may persist.
High-grade CIN is a precancerous condition; these lesions are not treated as HPV infections but are treated with ablative therapy by surgical specialists. Treatment modalities are summarized in Table 1 [reviewed in (7)]. A widely used and proven technique, loop diathermy and cone biopsy, provides a tissue specimen suitable for histopathologic assessment that will confirm that the lesion has been completely excised and excludes invasive cancer. Overall, excisional therapy is very effective in the treatment of high-grade CIN because the disease is confined. However, it does not necessarily eliminate HPV infection from the cervix and upper genital tract, and there is a small but statistically significant risk of recurrence (8), indicating that targeted antiviral therapies could be of value as adjuncts to surgery.
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The treatment of cervical LGSILs is a clinical problem [reviewed in (7)]. Treatment approaches can be categorized as follows: 1) surveillance by cytology—this risks missing the small number of women who harbor high-grade disease and are at risk of disease progression; 2) routine ablation—this overtreats, since most CIN 1’s are self-limiting HPV infections that will naturally regress with time; and 3) selective ablation—the ideal management situation but presumes that those at risk of disease progression can be identified, a situation that may be possible with the use of HPV testing either as an adjunct to, or instead of, cervical cytology (9).
VIN is another clinical problem. The natural history of VIN is poorly understood. VIN 3 is frequently multifocal, with a peak incidence in women aged 35 years. Surgical treatment is frequently mutilating and, even after extensive surgical procedures, recurrences are common. The emotional trauma associated with vulval surgery, particularly in younger women, is considerable, and there is the risk of the development of psychosexual disease. New and effective therapies for VIN are a priority.
Cytotoxic agents are widely used in the treatment of genital warts [reviewed in (10)]. They are topical preparations that kill cells on contact, irrespective of HPV status, by antiproliferative or chemodestructive modes of action. Adverse local reactions can be severe and recurrence rates are high. Podophyllin, a mixture of cytotoxic compounds derived from the roots of the Podophyllum species, is a topical therapy for genital warts, but it does not meet the World Health Organization guidelines for plant-based products; the most widely used formulation is in the form of podophyllotoxin as an alcohol solution or cream (Europe) or a gel (United States) that can be self-applied by the patient. The mechanism of action is thought to be due to the binding of lignans to microtubule proteins with cell cycle arrest at metaphase. It is contraindicated in pregnancy. Trichloroacetic acid is a clinic-based topical therapy that has a local caustic action effectively generating a chemical burn of the wart. It is as effective as podophyllotoxin, but it can result in ulceration, dermal scarring, and secondary infections if inappropriately applied. It has, however, no systemic toxicity and can be used during pregnancy. These preparations have been used in small trials to assess their value in the treatment of CIN and VIN but are not part of the accepted treatment algorithms for mucosal HPV infections.
5-Fluorouracil (5-FU) has been available as a 5% cream for several years, but its use on external genital lesions is limited because of the marked degree of inflammation that it generates. It is not approved for this use in the United States. 5-FU is a pyrimidine analogue and acts by blocking the transport of extracellular thymidine, thereby inhibiting the thymidine salvage pathway. It is a known teratogen, and its use is contraindicated during pregnancy. 5-FU is used as a therapeutic modality in women with VIN, but the results are very variable, with failure rates of up to 90% reported in some studies (11). Ulceration and pain are common side effects.
Photodynamic Therapy
Photodynamic therapy (PDT) has shown variable efficacy as a modality for the treatment of HPV infections. The mechanism of action is activation of a photosensitizer by light leading to the release of highly reactive oxygen species. This activation leads to tissue destruction that may activate host-immune defenses in a bystander fashion. Photosensitizers may be administered systemically or topically. Topical administration is an appealing strategy for lesions such as CIN, VIN, and genital warts, but small trials using aminolevulinic acid as the photosensitizer in PDT for cervical SILs have shown variable efficacy (12). The clinical response to PDT in VIN has been examined in two studies (13,14). Good responses have been seen in low-grade VIN, and partial responses have been seen in high-grade VIN. An important observation has been that the failure to respond to PDT was associated with down-regulation of class I major histocompatibility complex (MHC) alleles on the neoplastic cells, suggesting that PDT acts as an immunomodulator (15).
Immunotherapy
Viral infections have been controlled traditionally by prophylactic vaccination and this should, in the long term, be the case for HPV. In the short to the medium term, however, therapeutic intervention to enhance or induce effective immune defenses to established infections is an attractive strategy. Such therapies have the potential for treating inapparent infection and/or disease, in addition to clinically visible lesions. A Th1-biased cell-mediated immune response is critical for regression of HPV-induced disease (16). Antibody plays little or no role in established HPV infections but contributes to the prevention of reinfection with the same HPV type. Agents, therefore, that enhance or induce strong cell-mediated immune responses would be predicted to be effective HPV therapies, at least for low-grade disease.
Interferons
Interferons (IFNs) have antiproliferative, antiviral, and immunomodulatory properties. They have been evaluated in the context of both low- and high-grade HPV-related disease (17). IFNs, most frequently IFN 
, have been administered topically, systemically, and intralesionally, results have been highly variable. Intralesional therapy is painful, and systemic therapy is associated with flu-like symptoms such as fever and myalgia. Treatment is expensive and there is limited efficacy. There is no evidence that IFN is of value in the treatment of either low- or high-grade HPV-associated disease, and it is not recommended for routine clinical practice in the treatment of these lesions.
Immunomodulators
Imidazoquinolones.
The central importance of the innate immune system (epithelial barriers, phagocytes, and complement) and, in particular, dendritic cells and macrophages in activating the appropriate antigen-specific immune response is now clearly recognized. Pharmacologic agents that modulate dendritic cell and macrophage function could, therefore, have therapeutic value. Imiquimod, formulated as the self-applied topical therapy Aldara, is such a molecule, acting as a ligand for toll-like receptor 7 (18)-activating macrophages and dendritic cells to release IFN and other proinflammatory cytokines (19). It has shown efficacy and safety in clinical trials for the treatment of external HPV-infected genital warts (20). It is feasible that imiquimod will have a therapeutic effect on intraepithelial disease, but no placebo-controlled trials on CIN have been reported to date and the drug is not licensed for this use. A small trial showing some efficacy in the treatment of VIN has been reported recently (21). Immunomodulators, such as the imidazoquinolones, of which imiquimod is an example, that induce the production of proinflammatory cytokines have the potential to induce potent local inflammatory side effects, and their use on lesions in the vagina and cervix will require caution. However, this class of compounds does generate a cytokine milieu that activates dendritic cell migration and leads to a Th1 lymphocyte-biased response. The first generation of molecules shows clinical efficacy and the second generation of molecules for treating genital viral infections is in clinical trial (22). The identification of the cellular receptor is of major importance for future drug development, and molecules such as the imidazoquinolones represent a most promising therapeutic opportunity.
Cimetidine. Cimetidine, an antagonist of the H-2 class of histamine receptors, is known to have immunomodulatory properties. Oral cimetidine at a high dose has been used in the treatment of cutaneous and genital warts, recurrent respiratory papillomatosis, and conjunctival papillomatosis, particularly in children (23). Placebo-controlled, double-blind studies and open-label comparative trials have failed to demonstrate efficacy (23) for cutaneous viral warts, and there is no good evidence that this drug is of value in the treatment of HPV-induced disease.
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FUTURE PROSPECTS |
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TopAbstractIntroductionAnogenital HPV-Associated...Current TherapiesFuture ProspectsSummaryReferences |
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The current therapies are not targeted antiviral therapies but either attempt the physical removal of the lesion or the induction of nonspecific inflammation, thereby inducing a bystander immune response. Inevitably, therefore, they do not address the issue of the underlying HPV infection, and recurrence rates are high. The targeting of virus-specific proteins and functions is clearly a key objective for future therapies, but others may be directed to the pathologic sequelae of HPV infection, and there is some experimental evidence that supports both of these strategies.
Therapeutic Vaccines
An obvious strategy is therapeutic vaccination [reviewed in (24)]. LGSILs and HGSILs should be considered separately when discussing therapeutic vaccines. There are more potential antigenic targets in LGSIL compared with HGSIL because the complete viral infectious cycle occurs in the former, although not usually in the latter. Low-grade disease is homogeneous, thus permissive viral replication is the norm and the lesions are genetically stable; in an immunocompetent individual, an effective therapeutic vaccine should result in lesion clearance and no recurrence. HGSIL is heterogeneous, permissive viral replication is not the norm, the lesions are genetically unstable with the probability that immune parameters of importance, such as the cytokine milieu and HLA expression, will be disregulated, and there is variation in HPV gene expression (and, therefore, antigen expression) both between the patients and within the individual patient. Therefore, it is distinctly possible that there will be a spectrum of responses to vaccination ranging from complete through partial to no clearance of the clinical disease.
Studies on experimental oral mucosal papillomavirus infections in the dog (a good model for LGSILs and warts) certainly indicate that E7 is not the optimal antigen. In these studies, immunization with E1 or E2 protein (codon modified to enhance expression) is effective both prophylactically and therapeutically (25–27). In these experiments, animals immunized with E7 were not protected, despite high-level expression of E7 protein. These data from animal models have implications for the design of HPV vaccines. They suggest that the early proteins to be included in vaccines for the prevention of infection or the treatment of LGSILs or warts should be E1 and E2. Such vaccines could well be combined with immunomodulators, such as cytokines or the imidazoquinolones, to maximize the response. Prime/boost strategies combining DNA and/or protein and/or recombinant viral vaccines may have potential as immunotherapies for benign or low-grade HPV-induced disease. An important question is whether therapeutic vaccination will, even if successful at clearing lesions, eliminate infection or whether it will result in the control of residual latent virus by immunosurveillance. Prophylactic vaccination (i.e., vaccination before exposure to the pathogen) either with late or early proteins does prevent viral latency, but the spontaneous immune-mediated regression of papillomas in animals does not (3,28).
Immunotherapies for HPV-associated high-grade precancers and invasive cancers are problematic [reviewed in (24)]. There are only two possible antigenic targets, E6 and E7, since these are the only viral proteins that will be expressed in all of the HGSILs. However, the formidable problems facing vaccines for HGSILs and invasive cancer relate to the neoplastic phenotype. These lesions are genetically unstable, with the potential to rapidly evolve immune escape mechanisms. Tolerance to viral antigens, modulation of the cytokine milieu, and down-regulation of MHC class I alleles on the neoplastic keratinocytes are associated with progressive CIN (29), possibly VIN (15), and invasive cancers, all of which pose tough barriers for immunotherapies. Having said this, it is important to remember that only a proportion of CIN 3 progresses to invasive carcinoma, although the size of the progressive fraction is not known. There is evidence that lesions classified as CIN 3 regress, presumably by immune mechanisms, and this certainly implies that therapeutic vaccination could be of value although not, in my view, as a stand-alone therapy. It is worth repeating that the heterogeneity of these lesions implies that the responses to therapeutic vaccines will be variable and the end points for therapeutic vaccines targeting HGSILs may be different from those designed to treat LGSILs and warts. A variable response to vaccine in patients with HGSILs is certainly evident from the small phase I trials (Table 2) that have been carried out (30–33). It seems likely that the way forward for HPV-targeted immunotherapies in HGSIL and malignant disease is as an adjunct therapy combined with other treatment modalities.
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Antivirals Therapies
Anti-HPV chemotherapies are necessary for several reasons. Antiviral therapy has the potential to treat both inapparent HPV infection as well as visible clinical disease. There is a substantial population of HPV-infected, immunosuppressed individuals who, at the present time, cannot be treated with immunotherapy—drugs are their only option. Multifocal lesions such as VIN are not amenable to ablation and may not respond to immunotherapy, but they could be targeted by chemotherapy. Furthermore, antiviral agents, unlike immunotherapies, may not be HPV type restricted in their efficacy, all of which should make the development of these agents a high priority for funding agencies and pharmaceutical companies.
Traditionally, antiviral therapies have targeted viral enzymes. The papillomaviruses encode only one enzyme, the E1 helicase, rather limiting the traditional approaches. The remaining early genes, E2, E4, E5, E6, and E7, function largely by macromolecular interactions with host DNA and proteins. The interactions that mediate the functions of the E proteins are not readily amenable to drug design and the high-throughput screening necessary to identify candidate molecules. A key research area is the identification of appropriate HPV protein to host–protein interactions that are accessible to small molecule inhibitors.
Antisense technology is, in theory, a totally rational antiviral strategy, since oligonucleotides can be designed that specifically recognize and inhibit the normal processing of viral messenger RNAs. A limited number of studies (34,35) have shown that antisense oligos to E1, E2, E6, and E7 have reactivity in in vitro assays. However, there are problems with the delivery and stability of antisense molecules, and advances in the chemistry are needed before the full potential of this technology can be realized.
Papillomavirus genes are expressed in a differential manner, both temporally and spatially, throughout the replication cycle. The treatment of active lesions could target any early protein; however, if the objective is to treat the infection as well as the lesion, then latently infected cells will have to be eliminated. Viral latency is very poorly understood, but all of the evidence indicates that only the E1 and E2 genes are transcribed and, therefore, are the only targets (2). E1 is an adenosine triphosphate-dependent helicase and acts as an initiator of HPV replication by binding in a complex with E2 to the origin of replication. The unwinding of DNA starts and cellular replication proteins, such as DNA pol and DNA primase, are recruited. Disruption of these interactions could, theoretically, be achieved by small molecule inhibitors, and since E1 is the most conserved HPV protein, it is possible that an inhibitor would have broad reactivity against many HPV types. E2 has a central role in the control of HPV replication and transcription, it is expressed throughout the viral life cycle, and it is an attractive antiviral target. Small molecule inhibitors of E2/DNA binding have been identified (36), and this is an area of considerable research effort.
Paradoxically, antiviral chemotherapies for HGSIL may benefit from the neoplastic phenotype. It is increasingly evident that genetically unstable neoplastic cells escape death by apoptosis only because a series of abnormal conditions exist together. More important, the evidence is that changing only one of these can tip the balance and can trigger apoptotic cell death. The currently accepted view is that the combined actions of the high-risk E6 and E7 oncoproteins are essential for the maintenance of the neoplastic phenotype and the evasion of apoptosis (1). Abrogation of either E6 or E7 function (or both) in neoplastic cells by targeting gene expression or protein–protein interactions should be an effective strategy. In vitro data using HPV-expressing immortalized keratinocytes suggest that this is a feasible approach. In a recent study (37), peptide aptamers, molecules selected for in vivo binding to HPV16 E6 that selectively block E6 action intracellularly, were isolated and expressed in HPV-positive and HPV-negative cells. The HPV-positive cells underwent apoptosis and died, but the HPV-negative cells were unaffected. In another approach, HPV-expressing cervical carcinoma cells have been infected with recombinant viruses expressing full-length E2 protein. E2 binds the HPV early promoter and represses the transcription of E6 and E7, resulting in the expression and stabilization of p53 and the reactivation of the pRb-mediated cell cycle checkpoint control, with the immediate onset of replicative senescence and eventually apoptosis (38,39).
The induction of apoptosis is probably the underlying mechanism in several other therapeutic strategies that have been or are being tested.
Retinoids
Retinoids, a class of natural or synthetic compounds related to vitamin A, have been suggested as putative chemoprevention agents in CIN and in cervical cancer. These compounds (all-trans-retinoic acid, 13-cis-retinoic acid, and the aromatic retinoids) exert antiproliferative effects and induce differentiation in epithelial cells via binding to specific nuclear receptors of the steroid/thyroid superfamily of transcription factors, but they have no specific anti-HPV activity. In in vitro experiments with HPV-immortalized keratinocytes or cervical carcinoma cell lines, retinoids of all classes have been shown to down-regulate E6/E7 transcription and to alter expression of apoptosis-related molecules (40,41).
The potential of retinoids as chemopreventive agents for genital HPV disease is questionable. The role of dietary intake of vitamin A and the protection against the development of SIL is still uncertain (42,43), although in animal experiments vitamin A deficiency leads to squamous metaplasia, a precursor in the SIL spectrum. The therapeutic efficacy of topically applied retinoids in CIN is unproven. There are encouraging data from a randomized double-blind Chinese study with the synthetic retinoid retinamide II (44) but less impressive results in a Korean study (45) with 13-cis-retinoic acid, in which a reduction in HPV DNA was achieved but no change in colposcopic appearance was evident. Oral retinoids in combination with systemic IFN have been evaluated in several studies (46,47) in advanced squamous cell carcinoma of the cervix, but even when combined with cytotoxic agents, such as cisplatin, all regimens have proven to be ineffective.
Indole-3-carbinol
Indole-3-carbinol (I-3-C), a naturally occurring constituent of cruciferous vegetables, has been shown to have chemopreventive effects in preclinical studies. I-3-C has antiestrogenic activities and induces apoptosis (48). Mice transgenic for HPV16 E6/E7 chronically exposed to 17
-estradiol develop cervical cancer. However, when these animals are fed a diet supplemented with I-3-C, their incidence of cancer reduced dramatically (49). The effects of oral I-3-C as a therapeutic for CIN were tested in a small placebo-controlled trial (50). A total of 30 patients with biopsy-proven CIN were randomly assigned to receive placebo or I-3-C (200 or 400 mg/day, respectively) orally over a 12-week period. None of the placebo group showed regression of CIN, and four of eight in the 200-mg/day arm and four of nine in the 400-mg/day arm showed regression. This small clinical trial together with the preclinical data on transgenic animals is encouraging, and results from larger trials are awaited with interest.
Cidofovir
Cidofovir is a cytidine analogue that has shown some efficacy as a topical therapy for HPV diseases including CIN 3 (51). The drug inhibits viral DNA polymerases, but its effect in HPV infections appears to result from the induction of apoptosis (52).
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SUMMARY |
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TopAbstractIntroductionAnogenital HPV-Associated...Current TherapiesFuture ProspectsSummaryReferences |
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Many therapies are available for the treatment of HPV disease—especially genital warts. Conventional therapies are aimed at removing lesions rather than eliminating the underlying infection. When disease and infection are local, as is the case with CIN where the lesion is confined predominantly to the transformation zone, then ablative therapies that remove both the lesion and the susceptible tissues are highly effective. Lesion detection is the major hurdle in that scenario. However, when infection is regional, as is usually the case for the anogenital warts, VIN, AIN, PIN, and VAIN, then current treatments are generally inadequate with high recurrence rates.
Future therapies will be directly or indirectly antiviral, targeting HPV protein functions or enhancing the ability of the immune system to resolve infection or inducing apoptosis indirectly in HPV-infected cells. Monotherapies are not likely to be effective and the way forward must be the combinations of treatment that eliminate the lesion and prevent recurrence. In the short to the medium term, immunotherapies for low-grade disease are the most likely to be in the clinic. Vaccines targeting the E1 and E2 early proteins combined with immunomodulators or conventional adjuvants that induce a strong cell-mediated HPV antigen-specific response and good immune memory would be the predicted combination. Vaccines designed to target high-grade intraepithelial disease, even when used in combination with immunomodulators, are unlikely to effect clearance in more than a fraction of the cases. However, they may have a role as adjunct therapy after cervical conization to prevent the recurrence of CIN or HPV reinfection. They certainly appear to have a role in multifocal diseases, such as VIN and AIN, where partial clearance may be effected and lesion size may be reduced enough for effective ablative therapy.
The substantial population of immunosuppressed individuals with HPV infection and disease is unlikely to benefit from the immunotherapies and antiviral agents are desperately needed. Unfortunately, it seems unlikely that anti-HPV chemotherapies specifically targeting HPV protein functions will be in the clinic in the medium term. However, agents such as I-3-C have shown efficacy in small trials, and if these effects are confirmed in larger, randomized, placebo-controlled trials, they could be clinically useful in the short term.
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