Antiviral Therapy 7:1–9

Review

Therapy for recurrent respiratory papillomatosis Karen J Auborn1,2 1

Department of Otolaryngology, Long Island Jewish Medical Center, The Long Island Campus of Albert Einstein College of Medicine, New Hyde Park, NY, USA 2 North Shore-Long Island Jewish Research Institute, BoasMarks Biomedical Science Research Building, Manhasset, NY, USA Corresponding author: Tel: +1 516 562 1184; Fax: +1 516 562 1022; E-mail: [email protected]

Human papillomaviruses types 6 or 11 are aetiological agents of recurrent respiratory papillomatosis, a disease characterized by benign exophytic tumours usually on the vocal cords. Surgery debulks the tumours, but these growths generally recur at regular intervals. Adjunct

medical treatments, aimed at containing the virus and growth of tumours, include indole-3-carbinol or its dimer diindolylmethane, interferon, photodynamic therapy and others. Preventive and therapeutic vaccines hold promise for eliminating the virus.

Recurrent respiratory papillomatosis

Figure 1. Laryngeal papilloma

Certain types of human papillomaviruses (HPVs), mainly HPV types 6 and 11, cause recurrent respiratory papillomatosis (RRP) [1,2]. These HPV types are considered to have a low oncogenic potential. In the early 1980s, HPV DNA was detected in laryngeal papillomas by Southern hybridization with related HPV types and HPV capsid antigen [1,2]. These same types of HPVs, the closely related HPV types 6 and 11, cause exophytic lesions in the genital tract [3]. Kreider et al. were able to produce typical papillomas cysts in xenografts in immunodeficient mice using laryngeal tissue infected with HPV-11 virus particles [4,5]. Highrisk oncogenic types of HPVs – HPV-16 and HPV-18 – which are commonly found in the genital tract, have been identified only rarely in RRP [6]. Subsequently, Steinberg et al. were able to show that HPV DNA is not only present in the laryngeal papillomas, but can be found in tissue that appears histologically normal, adjacent to lesions, establishing the presence of tissue with the potential to produce papillomas [7]. The disease RRP results in benign hyperplastic epithelial tumours (Figure 1) that are typically found on the vocal folds. However, the lesions can occur in all parts of the respiratory tract, including the orapharynx and the lungs. The primary symptom of the disease is hoarseness because the lesions interfere with vocal cord function, and bulky lesions can cause life-threatening airway obstruction. Other symptoms include respiratory fatigue, chronic cough and episodes of choking.

Tumour growth with grape-like appearance on vocal cords of patient with recurrent respiratory papillomatosis.

©2002 International Medical Press 1359-6535/02/$17.00

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A hallmark of the disease is the tendency of the papillomas to recur after removal, hence the name [8–10]. Generally, the disease is classified as juvenile onset (diagnosed before adolescence) or adult onset. In fact, most children with RRP have recurrences that require treatment every 2–3 months [11]. RRP is considered an orphan disease. In the USA, a recent survey from the Centers for Disease Control estimates the incidence for juvenile onset RRP to be 4.3/100 000 [11]. Similarly, the prevalence in Denmark is estimated at 3.6/100 000 and 3.9/100 000 for juvenile and adult onset, respectively [12]. Although the prevalence of RRP in juvenile disease is equal between boys and girls, men have a much higher ratio (4:1) than women in adult onset disease (RRP Foundation questionnaire). Evidence indicates that juvenile onset RRP results from vertical transmission from mother to child [13,14]. However, most babies exposed to maternal HPV do not develop RRP. The origin of the adult onset disease is not known. Many more individuals harbour latent HPVs in the respiratory tract than those who have ever had signs of RRP [15]. Papillomas tend to occur at the junction of squamous and ciliated epithelia, such as vocal cords, subglottis, laryngeal surface of the epiglottis and even the trachea [16]. The lesions themselves (Figure 2) typically exhibit a papillary growth pattern, metaplasia, koilocytes and dysplasia similar to condylomata in the genital tract [17]. The disease course is highly variable. The severity of disease is usually greatest in children. The frequency of recurrence and need for removal or debulking of papillomas varies greatly between individuals. Clinically, papillomas are often described as looking like a clump of grapes (Figure 1). For most individuals, surgery is required at regular intervals that can vary from every few weeks to every few years. Some individuals with severe cases may require a tracheotomy to maintain an airway. Spread of papillomas can occur, usually to the trachea, but also to more distal bronchopulmonary areas [8–10]. A tracheotomy may exacerbate this spread [16]. Malignant transformation is infrequent and more common when there is pulmonary involvement [18–21]. Irradiation and other DNA-damaging agents predispose individuals with RRP to malignant transformation [18]. Spontaneous remission is highly variable and unpredictable, and some individuals never obtain remission. The reasons for remissions, severity of disease or why most people infected with HPVs do not develop disease are unknown, but are probably multiple. Latent HPV is probably the source of recurrent lesions [7]. Hormonal, immunlogical and endocrine factors appear to influence the pathogenecity of a relevant HPV infection. For example, pregnancy appears to exacerbate RRP [22]. 2

Figure 2. Histology picture from a laryngeal papilloma showing papillary fronds (lower arrow) and numerous koilocytes (upper arrow)

The discovery that RRP has a viral aetiology, together with the growing knowledge of the molecular biology of HPVs improves the prospect for better management and treatment of RRP. Most new adjunct treatments have led to somewhat more effective treatments. These adjunct treatments are generally an approach to control expression of the virus and keep the virus quiescent. However, none of these treatments have been effective in eradicating the latent HPV. When little understanding of RRP existed, many treatment regimens were tried empirically with little success. Such treatments usually did not ameliorate the disease and often caused harm to the patient, and included irradiation, antibiotics, vaccines, podopyllin and steroids [8]. Increasingly, better management of the disease with surgery plus adjunct treatments aimed at keeping the virus quiescent have helped many people with RRP. The ultimate goal would be to eradicate the virus.

Management by surgery RRP is primarily managed by surgery. Removal of papillomas assures an adequate airway and typically improves the voice. The CO2 laser offers the advantages of minimal thermal injury to underlying tissues ©2002 International Medical Press

Treatment of recurrent respiratory papillomatosis

and haemostasis [23]. Various methods of airway management have been employed to manage these difficult airways during anaesthesia, including endotracheal intubation, spontaneous ventilation and jet ventilation [24]. Complications include scarring, webbing and alteration of the normal vocal cord mobility, all of which affect voice quality and may compromise the airway. Some surgeons prefer the traditional surgical tools to debulk papillomas since a vapour plume with infectious virus [25] is not created, and there is no possibility of laser burns. Either method requires a surgeon that is skilled in the specific procedure in order to minimize damage to the vocal cords. Some individuals require a tracheotomy to maintain an airway. Unfortunately, a tracheotomy often results in the subsequent development of tracheal and stomal papillomas.

Medical therapy A variety of medical treatments, usually as adjunct therapy used along with surgical excision of papillomas, have become available. The goal of these adjunct therapies is to reduce or eliminate the need for future surgeries. The relatively few individuals with RRP coupled with very different disease courses and responses to therapies have made evaluation of these therapies difficult. However, the RRP Foundation has made a concerted effort to keep statistics and evaluate the effectiveness of such therapies (see Table 1).

Indole-3-carbinol/diindolylmethane Indole-3-carbinol/diindolylmethane (I3C/DIM) is the most popular adjunct therapy, because of its virtual absence of toxicity. These compounds are derived from eating cruciferous vegetables (broccoli, cabbage, cauliflower, and so on) and are generally used at concentrations that people could achieve eating a diet rich in these vegetables, that is 200–400 mg per day. I3C results from autolysis of glucobrasscin, a storage product in these vegetables, and the condensation

product DIM occurs in acid environments, such as the stomach. I3C and DIM are commercially available and are sold separately as supplements. The quality of these compounds has generally improved as clinical studies have required precise documentation of their formulation. The rationale for this therapy is that these phytochemicals could induce a better oestrogen metabolite balance, and hence a cellular environment that discourages pathology caused by papillomaviruses. Certain HPV types, including HPV-6 and HPV-11, have a predilection for causing lesions in certain tissues that are either hormonally sensitive, such as the transformation zone of the cervix [26,27], or relevant to RRP, such as the vocal cords in the larynx [9,28]. Oestrogen binds to membranes derived from laryngeal tissue (both men and women), and this binding is increased in membranes derived from laryngeal papillomas [29]. 16α-hydroxylation of oestrone, a type of oestrogen metabolism that prolongs oestrogenic activities, is constitutively high in the larynx [30] and the transformation zone of the cervix [31], and increased in laryngeal papillomas and genital cells transformed by HPVs [31]. I3C or DIM (the dimer of I3C) induces an alternative oestrogen metabolism [32], namely 2-hydroxylation of oestradiol, resulting in 2-hydroxyoestrone, a metabolite that is not oestrogenic (see Figure 3). Moreover, 2-hydroxyoestrone is rapidly O-methylated to 2-methoxy-oestradiol and 2-methoxy-oestrone, compounds that are antiproliferative, apoptotic and anti-angiogenic [33]. After studies with mice indicated that a diet supplemented with I3C prevented papilloma cysts in xenografts of laryngeal tissue infected with HPV-11 [30], several studies determined that a diet rich in cruciferous vegetables or supplements of I3C/DIM [34–36] was a useful adjunct therapy for RRP. While more beneficial oestrogen metabolism appears to be a factor for prevention of RRP [30,35], I3C/DIM does have other activities that should not only help prevent the recurrence of papillomas, but also be useful in treatment of papillomatosis and

Table 1. Impact of adjuvant therapies for recurrent respiratory papillomatosis Therapy I3C/DIM Interferon Acyclovir Photodynamic therapy Ribavirin Retinoic acid Cidofovir Mumps vaccine

Number of users 121 56 31 19 3 16 12 14

No response (%) 44.6 42.9 64.5 68.4 33.3 62.5 8.3 21.4

Improved (%) 55.4 57.1 35.5 31.6 66.7 37.5 91.7 78.6

Complete remission (%) 19.0 7.1 12.9 5.3 0.0 0.0 25.0 21.4

Partial response (%) 36.4 50.0 22.6 26.3 66.7 37.5 66.7 57.1

Data courtesy of the Recurrent Respiratory Papillomatosis Foundation (RRPF). The RRPF surveys recurrent respiratory papillomatosis patients/families via questionnaire regarding their therapy and disease history. I3C/DIM, indole-3-carbinol/diindolylmethane. Antiviral Therapy 7:1

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Figure 3. Oestrogen metabolism

16α-Hydroxyoestrone α α

Oestrdiol

Oestrone

2-Hydroxyoestrone

Indole-3-carbinol induces 2-hydroxylation of E1 thus changing the ratio of 2-OHE to 16α-OHE.

prevention of malignant conversion. I3C/DIM is antiproliferative, down regulating CDK6 [37], and induces apoptosis in abnormally proliferating cells in the absence of p53 [38] – a pathway of apoptosis that can be made defective by the papillomaviruses [39]. Furthermore, I3C/DIM can prevent DNA damage by acting as a free radical scavenger [40,41]. Side-effects have been few. I3C/DIM induces many phase I and phase II enzymes [42–44], which is why many carcinogens are inactivated and oestrogen metabolism is rerouted, and because of this induction certain drugs can also be inactivated, which occurred with dilantin in the case of several RRP patients [36]. Specifically, medications that are metabolized by CYP1A1 or CYP1A2 (information provided by the drug manufacturer) should not be used in conjunction with I3C/DIM. DIM should be used if a patient takes antacids because I3C may not be converted to DIM in the stomach. Because of the anti-oestrogen activities, I3C/DIM may cause osteoporosis or other problems associated with lower oestrogen levels. However, mice on diets supplemented with I3C for more than 1 year did not show bone loss (G Gronowitz & K Auborn, 4

unpublished observation). In addition, I3C does not appear to cause problems with reproduction [43]. However, a few patients have anecdotally reported some bone loss that might have been caused by longterm use of I3C/DIM, thus suggesting that bone loss should be evaluated before and during treatment. Another oestrogen metabolite, 4-hydroxyoestrone, which was shown to cause kidney cancer in hamsters, can sometimes be induced by I3C/DIM [44]. Most relevant for the use of I3C/DIM in the treatment of RRP is the fact that some patients are refractory to the benefits of I3C/DIM for unknown reasons (Table 1). A recent placebo-controlled study using I3C for treatment of cervical intraepithelial neoplasia (CIN) II and III, found a statistically significant regression of CIN in patients treated with 200 or 400 mg/day I3C, given orally, compared with placebo, as determined by a 12-week biopsy [45]. None of the placebo group had complete regression compared with 47% of the treated groups. I3C/DIM should be effective for treatment of condylomata acuminata, the presumed source of juvenile RRP by vertical transmission [13,14]. DIM and several proteins induced by DIM decrease expression ©2002 International Medical Press

Treatment of recurrent respiratory papillomatosis

driven by HPV-11 regulatory sequences (K Auborn, unpublished observation). Because of the low toxicity associated with I3C/DIM, other adjunct treatments tend to be used for patients with severe RRP that have failed to respond to I3C/DIM.

Interferon Interferon has proved effective in ameliorating RRP by slowing down the recurrence rate. Most studies evaluated interferon α (IFN-α) including recombinant forms [46–48], and effectiveness appeared to be related to dosage [47]. When IFN-α binds to a specific cellsurface receptor, an active factor composed of two proteins forms and translocates to the cell nucleus, stimulating specific transcription. The cell then becomes resistant to a variety of viruses. The growth of some cells is slowed, and immunomodulatory actions occur. The side-effects of interferon are not pleasant, with serious complications reported in a subset of patients [49]. Flu-like symptoms usually occur, and liver function abnormalities may develop. Leukopenia and other serious problems are infrequent. Specifically for RRP, when interferon is discontinued, the disease recurs more severely than before the treatment. This ‘rebound’ effect can be mitigated by titrating downward when ending therapy problems. Although interferons have been effective in trials, the Food and Drug Association (FDA) has not approved their use for the treatment of this disease.

Photodynamic therapy Photodynamic therapy (PDT) has been in trials for RRP for over 10 years. Most studies have been carried out at the Long Island Jewish Medical Center, NY, USA [50]. A photosensitizing dye is given to the patient, and when the dye is exposed to light of a certain wavelength, a singlet oxygen reaction occurs resulting in the killing of cells. The dye has a predilection for tumours, including papillomas. It localizes to vascularized structures and is therefore retained longer in papillomas and other tumours because they typically become more vascularized than normal tissue. Hence, the cell killing exhibits an anti-angiogenic effect. Each agent has a different ‘wash-out’ time where the dye leaves the normal cells allowing a safe window for treatment. Older studies used the photosensitizing drug haematoporphyrin derivative (HPD). Unfortunately, this dye left the patient light sensitive for up to 2 months. Although improvement of RRP occurred in some patients with this regimen, trials with HPD did not result in a statistically significant number of extended remissions. Trials now underway with a different photosensitizing dye – Foscan or meso-tetra hydroxyphenyl chlorin (mTHPC) – are much more encouraging. In an ongoing study of PDT with mTHPC, patients received a single treatment. Antiviral Therapy 7:1

Preliminary results show that six of the seven patients to date with 1 or more years of follow-up are free of laryngeal disease. One patient with tracheal disease has shown some improvement, but did not achieve complete remission (M Shikowitz, Long Island Jewish Medical Center, personal communication). mTHPC has a much shorter exit time from tissue than HPD [51], and a patient is only light sensitive for 2 weeks. RRP initially worsens after treatment, but a delayed improvement occurs, with the possibility of complete remission. The reasons for this bi-phasal effect are not known. Theoretical concerns about light sensitivity and singlet oxygen reactions remain, since the resulting oxidation reactions have the potential to damage healthy cells. To date, the most significant side-effects have been sunburn reactions in patients that do not use precautionary measures [52].

Cidofovir Cidofovir [(S)-1-(3-Hydroxy-2-phosphonylmethoxypropyl)cytosine; HPMPC] appears to be very effective in the treatment of RRP, although the number of individuals treated with it remains small. Cidofovir is a nucleoside analogue, and has a broad spectrum of activity against a wide variety of DNA viruses by interfering with viral DNA synthesis, inhibiting angiogenesis and inducing apoptosis [53]. In animal studies, cidofovir causes regression of large lesions caused by the cottontail rabbit papillomavirus [54]. Cidofovir is used systemically, intralesionally and topically as an antiviral. For RRP, intralesional injections are used, and this method avoids some of the toxicity (kidney damage) associated with the compound [55]. The largest study of cidofovir as a treatment for RRP comes from Belgium [56], where investigators reported the complete disappearance of papillomas in 14 out of 17 patients with severe RRP. Smaller studies in the USA have yielded equally impressive results [57,58], including a case of RRP where the papillomavirus lesions had spread to the lungs [59]. A recent placebo-controlled study evaluated the efficacy of cidofovir topical gel for treatment of condylomata acuminata [60]. None of the patients in the placebo group had a complete response whereas 47% of the treated group experienced complete recovery. Adverse reactions to cidofivir are kidney toxicity, which is associated with systemic use, and some irritation to laryngeal tissue. Cidofovir is adsorbed by papilloma cells to a greater extent than normal cells and converted to the active nucleotide analogue. In theory, a certain amount of DNA damage would result in cells exposed to, but not killed by cidofovir. Long-term follow-up of patients should carefully evaluate possible malignant conversion. 5

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Acyclovir Acyclovir [9-(2-hydroxyethoxymethyl)guanine; ACV] is a purine analogue that is phosphorylated into its active form by thymidine kinases coded by herpes viruses [61]. Human thymidine kinases do not activate acycolvir, which is why this compound specifically kills cells with an active herpes virus infection. The analogue incorporates into DNA causing strand breaks in the viral DNA. The papillomaviruses, much smaller viruses than herpes viruses, do not code for any thymidine kinase. Therefore, the rationale for using acyclovir to treat RRP is uncertain. However, some clinical response was observed in a number of trials [62,63]. The hypothesis is that the clinical response may be correlated to co-infection with herpes simplex virus. Side-effects from acyclovir are uncommon.

Other therapies A very small number of patients have been treated with cis-retinoic acid or isotretinoin (accutane), ribavirin and cimetidine – an H2-receptor antagonist commonly used to treat peptic ulcers.

Retinoids Retinoids induce cell differentiation, inhibit proliferation and angiogenesis – processes incompatible with tumour growth – providing a basis for their use as adjunct therapy for RRP [64]. While success using cisretinoic acid for RRP has been documented [65–67], one study was suspended because patients experienced toxicity, and the therapy was ineffective [68].

Ribavirin Ribavirin is an antiviral commonly used for certain RNA viruses such as hepatitis C and respiratory syncytial virus [69,70]. Ribavirin is a guanosine analogue and inhibits synthesis of GTP by an effect on inosine monophosphate dehydrogenase, thus limiting RNA synthesis. A small, randomized study in Minnesota, USA showed that ribvirin resulted in an increased interval between surgery [71]. Side-effects are common, and include headache, fatigue and anaemia.

Cimetidine Cimetidine is immunomodulatory at high concentrations [72] and has been effective in treating a number of cutaneous diseases, including cutaneous warts [73,74]. It was successful in treatment of a single case of RRP [75], although some studies using cimetidine to treat cutaneous warts reported no difference from the placebo group [76].

Vaccines Emerging specific vaccines that should be effective against RRP are being developed, these include both 6

preventative and therapeutic vaccines or combinations [77–79]. The emphasis for HPV vaccines has been for cervical cancer and genital warts. However, the same viruses that cause many genital warts (HPV-6 or -11) are also the aetiological agents of laryngeal papillomas. The design of most preventative vaccines uses recombinant L1 viral capsid protein that reassembles into viral-like particles (VLPs). These VLPs produce neutralizing antibodies against the specific HPV type as shown with VLPs made from L1 of HPV-11 [80,81]. The protective effect of VLPs has been demonstrated in a number of animal models. For example, VLPs made from cottontail rabbit papillomavirus recombinant L1 protein protects rabbits from this virus [82]. A VLP vaccine against HPV-11 was well tolerated and induced high levels of neutralizing antibodies in a Phase I study [83]. Therapeutic vaccines target some non-structural virus proteins, usually the E6 or E7. Various candidate HPV vaccines are being tested using non-structural virus proteins. These vaccines are administered in vectors, peptides, or nucleic acids, or as components of chimeric VLPs. TA-GW is a vaccine that has the potential to be effective as both a therapeutic and a prophylactic vaccine [84]. TA-GW consists of a fusion protein L2 and E7 proteins coded by HPV-6. When administered together with an adjuvant, this vaccine shows considerable efficacy in the clearance of genital warts in Phase II trials [85]. Different from most therapies, the vaccine approach is clearly aimed at eliminating the virus, and holds promise not only for treating RRP, but also for reducing the number of individuals infected with the relevant HPVs.

Acknowledgements This study was supported by grant P50DC00203 from the National Institute on Deafness and Other Communications Disorders. We wish to thank Mark Shikowitz for his assistance with this manuscript.

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Received 19 February 2001; accepted 14 November 2001

Antiviral Therapy 7:1

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