Topical Cidofovir for Treatment of Resistant Viral Infections

Written By: Sam Savage

Published Date: September 21, 2006 Last Edited: September 21, 2006

By McElhiney, Linda F

Abstract

Cidofovir is a broad-spectrum antiviral agent with activity against several DNA viruses. An application to approve the use of topical cidofovir for acyclovir-resistant herpes virus infection was denied by the US Food and Drug Administration owing to the lack of phase III clinical trial data. The manufacturer stated that, as of 1997, no further controlled studies were planned or in progress to evaluate topical cidofovir in herpes simplex infections. It is unknown whether there are plans to conduct controlled studies of topical cidofovir for HPV or MVC infections. However, numerous case reports and published studies describe successful use of topical cidofovir to treat resistant and severe forms of viral infections such as molluscum contagiosum, condylomata acuminata, verruca vulgaris, herpes simplex virus infection, genital warts, and gingival infection with human papillomavirus. Because of the mutagenic properties of cidofovir, compounding the preparation is considered hazardous. Since most retail pharmacies do not have the safety equipment necessary to compound hazardous preparations, a compounding pharmacist can play a vital role in preparing topical cidofovir cream or gel.

Cidofovir, a broad-spectrum antiviral agent, is a potent nucleoside analog of deoxycytidine monophosphate. It is commercially available as an intravenous (IV) dosage form. It is the only treatment approved by the US Food and Drug Administration (FDA) for cytomegalovirus (CMV) retinitis in patients with human immunodeficiency virus infection (HIV) or acquired immunodeficiency syndrome (AIDS). Several studies and case reports describe the successful use of compounded topical cidofovir cream or gel to treat viral cutaneous diseases.

Pharmacology

Cidofovir is a water-soluble polar molecule. When incorporated into the host cell, cidofovir undergoes two stages of phosphorylation to form the active intracellular metabolite cidofovir diphosphate. This metabolite acts as a competitive inhibitor and an alternate substrate for CMV DNA polymerase. It is incorporated into the growing CMV DNA strand and blocks further viral DNA synthesis and replication. Cidofovir has a long half-life (17 to 65 hours) because human CMV DNA polymerase cannot excise the incorporated active metabolite of cidofovir from the viral DNA.

Antiviral agents such as acyclovir and ganciclovir are dependent on virally encoded thymidine kinase for activation. Since cidofovir has a different mechanism of action, strains of herpes virus that are resistant to acyclovir, ganciclovir, or foscarnet remain sensitive to cidofovir, as demonstrated in studies by Mendel et al1 and Morphin et al.2

The pharmacokinetic properties of cidofovir in humans are limited to IV administration. Cidofovir is excreted renally, 80% to 100% by renal tubular secretion, with less than 6% protein binding. It does, however, have a black box warning that it may cause nephrotoxicity leading to acute renal failure or death after IV administration of one to two doses. Cidofovir also can cause neutropenia and has been shown in animal studies to cause cancer, birth defects, and hypospermia.3

Unlabeled Uses for Cidofovir

Several cutaneous diseases are caused by DNA viruses, as follows:

* Condylomata acuminata

* Genital warts (human papillomavirus [HPV])

* Herpes simplex virus infection

* Gingival HPV infection

* Molluscum contagiosum (MCV)

* Verruca vulgaris

Published studies and case reports have described the use of topical dosage forms of cidofovir to successfully treat resistant and severe forms of these viral infections with minimal or no adverse events. However, compounded cidofovir creams or gels are prohibitively expensive (approximately $1,000 per ounce) and should be reserved for cases in which all other conventional treatments have failed.

HPV Gingival Infection

Human papillomaviruses constitute a large group of double- stranded DNA viruses, at least 90 specific identified strains. HPV lesions can occur anywhere on the cutaneous surface, but are observed mainly on the extremities, genitalia, and oral mucosa. HPV infections are most common in patients who are immunocompromised, and these patients have more problems with extensive, recurrent, and resistant infections. Certain HPV strains promote dysplasia and squamous cell carcinomas in the oral mucosa. Lesions in the mouth can be transmitted sexually or by nail biting in patients with periungual warts.

Even though the success rate of the following therapies ranges from 40% to 100%, HPV recurrences are frequent after treatment with conventional therapies, such as the following:

* Chemotherapeutic agents (podofilox, retinoic acid, trichloroacetic acid)

* Cytodestructive methods (liquid nitrogen, electrocautery, or carbon dioxide laser photocoagulation)

* Immunostimulants (interferon alpha, imiquimod)

Calista described the treatment of a 45-year old man with AIDS who developed a recalcitrant gingival HPV infection. Several conventional therapies were tried over a 2-year time period with little or no success. A 1% cidofovir cream was compounded, and the patient was instructed to apply the cream to each lesion using a small spatula once daily for 5 consecutive days (no Saturdays or Sundays) for 2 weeks. The lesions flattened within a 24-hour period and completely resolved by the end of the 2-week course. The patient experienced no local or systemic side effects, and reported no recurrence within the subsequent 12 months.4

Genital Warts

HPV is the most common sexually transmitted viral disease in the world and is the cause of anogenital warts. Again, patients with a compromised immune system, such as those with HIV infection, are at greatest risk for this type of infection. In these patients, HPV infection may produce more extensive lesions and have a lower therapeutic response and higher recurrence rate than in immunocompetent persons. The same conventional therapies used to treat gingival HPV infection are also used for anogenital warts; however, they often fail to eradicate subclinical disease and latent virus.

Matteelli et al conducted a randomized, placebo-controlled, single-blinded, crossover pilot study to determine the tolerability and efficacy of topical 1% cidofovir cream for the treatment of external anogenital warts in HIV-infected patients. Six patients were randomized to use the 1% cidofovir cream, and another six to use placebo cream. Eventually, the placebo group also received the 1% cidofovir cream. The cream was applied 5 days per week for 2 weeks, and this treatment period was followed by a 2-week observation period. Treatment with cidofovir reduced total wart area by more than 50% compared to placebo in seven (58%) patients. Four (33%) of the treated patients showed a 1% to 50% reduction in wart area, and only one patient had no response at all. Fifty percent of patients experienced local mucosal erosion as a side effect of therapy, and one third of those patients had to discontinue therapy, but there were no systemic side effects. The mucosal erosion resolved within 7 days, leaving no permanent scarring. This study demonstrated that cidofovir is effective in a very short course of therapy, which may improve patient compliance and reduce the need for long-term therapy.5

Orlando et al conducted an open, randomized, prospective study to evaluate the efficacy of electrocautery (ST), topical cidofovir (CT), and a combination of electrocautery and cidofovir (SCT) in the treatment of genital warts. Seventy-four patients were randomly assigned to one of the three treatment groups: 29 in ST, 26 in CT, and 19 in SCT. The CT group applied cidofovir 1% gel 5 days per week for a maximum of 6 weeks, and the SCT group applied cidofovir 1% gel 5 days per week for 2 weeks within 1 month of electrocautery. Although electrocautery was rapidly effective (93.1% complete resolution), 73.68% of the ST group experienced relapse within 66 days. The CT group achieved a 76.2% rate of complete resolution, but the relapse rate was much lower (35.29%) than in the ST group. The combination SCT group achieved 100% complete resolution and a 27.27% relapse rate.6

Molluscum Contagiosum

MCV is a pox virus that commonly causes a self-limiting infection in children. In immunocompromised patients, however, MCV infection can cause severe disfigurement, leading to social isolation and poor quality of life. The infection may be very difficult to resolve in these patients, and secondary bacterial infection is a common complication. There are numerous case reports describing use of compounded cidofovir cream to resolve MCV infection in both children and adults.

Davies et al published the first case report in which topical 1% cidofovir (in unguentum Merck) was used to treat MCV.7 A 12-year- old boy in whom primary immunodeficiency syndrome was diagnosed in early infancy developed MCV lesions over 75% of his skin surface. The lesions were acutely inflamed within 2 to 3 weeks of beginning topical cidofovir therapy, but shortly thereafter they resolved dramatically. The patient experienced no systemic side effects, skin discoloration, or scarring. At the time of the report, the patient was continuing treatment and recurrence of the le\sions had been minimal.7

Meadows et al reported complete resolution of MCV after 1 month of therapy with a 3% cidofovir cream (in Dermovan) compounded by a local pharmacist. The patient was a 37-year-old HIV-positive Hispanic man who had been afflicted with MCV lesions for 3 years. He applied the cream each morning, Monday through Friday, for 2 weeks. Moderate acute inflammation developed during the second week, but it resolved spontaneously 2 weeks later along with the lesions. At the time of the report, the patient had remained clear of MCV recurrence for 5 months.8

The first report of topical cidofovir use for generalized and facial MCV in children with AIDS was published by Torro et al. Both patients, an 8-year-old African American boy and a 4-year-old Hispanic boy, had hundreds of umbilicated pearly and skin-colored papules disseminated over the entire body, including the face. In fact, the children had severe facial disfigurement and suffered from debilitating social isolation. A 3% cidofovir cream was compounded and applied to the lesions once daily, 5 days a week, for 8 weeks. Nonfacial lesions were also occluded with adhesive tape for at least 12 hours. Both patients developed redness and painful erosions at the sites of previous lesions 5 to 15 days after initiating the therapy, but the adverse reactions resolved during the 2-day weekend period of treatment rest. The lesions healed, leaving superficial scars and post-inflammatory hypopigmentation and hyperpigmentation. Large lesions healed with varioliform scars. Neither child experienced systemic adverse effects. All of the treated lesions showed complete clinical resolution after 8 weeks. The 8-year-old patient had no recurrence during a 21-month follow-up period. At the end of the study, both patients experienced significant improvement in self-esteem and resumed social activities.9

Compounding Topical Cidofovir

Topical cidofovir cream or gel is compounded from the commercial parenteral cidofovir (Vistide) solution and a cream or aqueous gel base. Because of the drug’s mutagenic properties, compounders formulating this preparation should take cytotoxic or antineoplastic precautions. The National Institutes of Health recommends that cidofovir be prepared in a Class II laminar airflow biological safety cabinet or barrier isolator. Compounding personnel should wear chemotherapy gloves and closed-front surgical gowns with knit cuffs during the preparation. If the compounder is accidentally exposed to cidofovir, the exposed area should be washed and flushed with copious amounts of water. All materials in contact with the cidofovir should be disposed of in a waterproof, puncture-proof container or “chemo bucket” and incinerated in an authorized high- temperature incinerator. Since the amount of cream or gel compounded is usually less than 40 grams, the syringe method of preparation is ideal; the procedure is outlined in the accompanying box.

Additional different cidofovir formulations are provided with this article.

Propylene glycol may increase the absorption and bioavailability of cidofovir, especially on abraded skin.10 Since cutaneous lesions due to viral infections typically cause skin damage and may cover an extensive area of the skin, the author recommends that this excipient not be used, to reduce the chance of systemic absorption and adverse side effects.

Patient Monitoring and Counseling

Prior to initiating topical cidofovir therapy, the patient should undergo serum tests of kidney function to establish baseline renal function. The patient’s renal function should be evaluated periodically during therapy to monitor for nephrotoxicity. A white blood cell count with differential also should be done periodically during therapy to monitor for neutropenia. These are precautionary measures, since there have been no reported systemic adverse effects from the topical use of cidofovir.

The patient or caregiver should be advised that acute inflammation, redness, or open lesions may develop about 1 week after initiating therapy. These acute effects often resolve spontaneously during the 2-day rest period or within a 2-week period. If the effects worsen or become too painful, the prescriber should be contacted to re-evaluate the therapy.

Conclusion

Cidofovir is a broad-spectrum antiviral agent with activity against several DNA viruses. Many of these infections develop into recalcitrant infections in high-risk patients. Topical cidofovir has shown promising results in reported case studies and pilot studies. An application to approve the use of topical cidofovir for acyclovir- resistant herpes virus infection was denied by the FDA owing to the lack of phase III data. In 1997, the manufacturer stated that no further controlled studies were planned or in progress to evaluate the use of topical cidofovir in herpes simplex infections.10 It is unknown whether there are plans to conduct controlled studies for HPV or MCV infections.

Since most retail pharmacies do not have the safety equipment necessary to compound hazardous preparations, a compounding pharmacist can play a vital role in compounding topical cidofovir cream or gel. The pharmacist also may assist the physician in obtaining compassionate use supplies for indigent patients in need of this therapy since the drug is very expensive.

It is hoped that more studies will be conducted to confirm the initial reports regarding the therapeutic efficacy and lack of systemic side effects of topical cidofovir. Until a commercial product is developed, marketed, and affordably priced to allow it to be routinely prescribed for these infections, the compounding pharmacist can provide this viable treatment option for patients to resolve infections, prevent severe disfigurement, improve self- esteem and social interactions, and ultimately enhance quality of life.

Syringe Method of Preparation for Topical Cidofovir

METHOD OF PREPARATION

1. Weigh the vehicle base.

2. Backload the vehicle base into a disposable 60-mL syringe.

3. Place the syringe into a hood or barrier isolator.

4. Use a chemoprotective device, such as the PhaSeal (Baxa Corporation, Inglewood, Colorado), to withdraw the desired amount of cidofovir into another disposable 60-mL syringe.

5. Detach the chemoprotective device from the syringe containing the cidofovir.

6. Attach a Luer Lock-to-Luer Lock connector to the syringe.

7. Connect the syringe containing the cream or gel base to the connector.

8. Inject the contents of the syringes back and forth between the two syringes until the cream or gel is thoroughly mixed with the cidofovir solution and the mixture is smooth and consistent in texture.

9. Detach the connector.

10. Empty the syringes.

11. Transfer the mixture to a clean ointment jar or ointment tube.

12. Cap, seal, and label the jar or tube.

Formulations for Topical Cidofovir Cream or Gel

METHOD OF PREPARATION

1. Select the formula you wish to prepare.

2. Calculate the required quantity of each ingredient for the total amount to be prepared.

3. Combine the ingredients based on the selected formula.

4. Package in an appropriate container.

5. Label the container.

STABILITY

Although no stability studies on cidofovir cream or gel have been published, it is reasonable to assign a beyond-use date of 30 days to allow for a full month of therapy with the preparation.

Note: These formulations are prepared at Clarian Health Partners, Inc., Indianapolis, Indiana.

References

1. Mendel DB, Barkhimer DB, Chen MS. Biochemical basis for increased susceptibility to cidofovir of herpes simplex viruses with altered or deficient thymidine kinase activity. Antimicrob Agents Chemother 1995; 39(9): 2120-2122.

2. Morphin F, Snoeck R, Andrei G et al. Phenotypic resistance of herpes simplex virus 1 strains selected in vitro with antiviral compounds and combinations thereof. Antivir Chem Chemother 1996; 7: 270-275.

3. Vistide (cidofovir injection) [package insert]. Louisville, KY: Cardinal Health; 2000.

4. Calista D. Resolution of recalcitrant human papillomavirus gingival infection with topical cidofovir. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2000; 90(6): 713-715.

5. Matteelli A, Beltrame A, Graifemberghi S et al. Efficacy and tolerability of topical 1% cidofovir cream for the treatment of external anogenital warts in HIV-infected persons. Sex Transm Dis 2001; 28(6): 343-346.

6. Orlando G, Fasolo MM, Beretta R et al. Combined surgery and cidofovir is an effective treatment for genital warts in HIV- infected patients. AIDS 2002; 16(3): 447-450.

7. Davies EG, Thrasher A, Lacey K et al. Topical cidofovir for severe molluscum contagiosum. Lancet 1999; 353(9169): 2042.

8. Meadows KP, Tyring SK, Pavia AT et al. Resolution of recalcitrant molluscum contagiosum virus lesions in human immunodeficiency virus-infected patients treated with cidofovir. Arch Dermatol 1997; 133(8): 987-990.

9. Toro JR, Wood LV, Patel NK et al. Topical cidofovir: A novel treatment for recalcitrant molluscum contagiosum in children infected with human immunodeficienty virus 1. Arch Dermatol 2000; 136(8): 983-985.

10. Zabawski EJ Jr, Cockerell CJ. Topical and intralesional cidofovir: A review of pharmacology and therapeutic effects. J Am Acad Dermatol 1998; 39(5 Pt 1): 741-745.

Linda F. McElhiney, PharmD, RPh

Clarian Health Partners, Inc. * Indianapolis, Indiana

Address correspondence to Linda F. McElhiney, PharmD, RPh, Clarian Health Partners, Inc. 550 N. University Boulevard, UH 1451, Indianapolis, IN 46202. E-mail: [email protected]

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