Cidofovir Background Information

Cidofovir is an anti-viral drug that is being used experimentally to treat RRP. Background information on Cidofovir may be found in Snoeck et al., 1998 (J. of Med. Virology 5:219-225) and in RRP Newsletter issues Spring 98, Spring 99 . Results from some preliminary studies are encouraging. The following discussion on how cidofovir works was led by Dr. Tom Broker at the RRPF patient/doctor support session during the 1999 HPV meetingof how cidofovir works.

Cidofovir is absorbed by the host cell, which converts into an agent that kills cells which have HPV in it. It is essentially not absorbed by non HPV cells. This is called a pro-drug, which converts into an active drug. The selectivity is quite remarkable, such that, there is three orders of magnitude more absorption in papilloma cells vs. non disease cells. Thus it is speculated that this conversion to an active form will take place only in cells that have active HPV. It is also worth noting, that Dr. Broker feels that this is a very promising drug and the trials will tell us much more.

Adverse Reactions to Cidofovir:

Toxicity to kdineys in large systemic doses.
Some irritation to laryngeal tissue.

Reports and Clinical Studies Involving Cidofovir and RRP

[ from RRP Newsletter Summer 2000]

[December 1999]

Views of Marty Hoernemann's larynx before and after treament with Cidofovir.
Marty continues to be treated with Cidofovir by Dr. Frank Rimell at the University of Minnesota.

[ late November 1999]

Cidofovir: An Update from Pittsburgh
by Clark A. Rosen MD.
University of Pittsburgh Voice Center Pittsburgh, PA

For the last 18 months, I have been using Cidofovir injection in RRP for 
my most severe RRP patients that have failed I3C.  Intially I used the
dosing of 2.5mg/cc and did not remove any RRP except for biopsy.  The
injections were done in the operating room with general anesthesia every
two weeks until all the disease was gone.  This was a very successful
approach but it was hard on the patients to have anesthesia so
frequently.  I increased the concentration to 5mg/cc and got improved
results.
With the positive initial results, I then changed my protocol to removal
of all or the majority of RRP followed by immediate injection of
Cidovofir (5mg/cc) at the base of all the RRP locations.  I have been
using this approach for over 1 year and the preliminary results in 10
patients have been outstanding.  Five of the patients are presently
without any recurrences and the others have increased their surgical
interval by 3-4 times.  This is in a small group of patients with a
relatively short follow-up.  I presently have had no complications.  All
patients are pre-hydrated with saline prior to injection.  Follow-up
biopsies have shown no malignant changes in the residual or recurrent
disease.  I say residual because I believe that it is hard to inject all 
the disease the first time in patients with moderate or severe disease. 

[ from RRP Newsletter Fall 1999]

INTRALESIONAL CIDOFOVIR FOR RECURRENT RESPIRATORY PAPILLOMATOSIS IN CHILDREN

Seth M. Pransky^*, MD, Anthony E. Magit, MD, Donald B. Kearns, MD, D.Richard Kang, MD, Newton O. Duncan, MD (see extended abstract report below)

* Children's Hospital and Health Center of San Diego

[ reported on RRPF Discusion Board Nov 1999 ]

Cidofovir Studies at University of Iowa
by Diane Burke, RN

We are currently working on a clinical trial in collaboration with another institution in the use of intralesional injection of Cidofovir. We have currently treated 16 patients with the drug here and have been encouraged by the results, but hope to develop and expand the study, also hoping to provide the drug to patients at no cost.

[ from RRP Newsletter Spring 1999]

A Phase I/II Evaluation of Cidofovir Therapy for Recurrent Laryngeal Papillomatosis in Children

In 1997 a research group from Belgium reported (Wellens et at., Proceedings of the XVI World Congress of Otorhinolaryngology Head and Neck Surgery, Sydney, Australia) on the treatment of 17 RRP patients (mostly adults) using cidofovir (also known as HPMPC). The procedure involved intralesional injections during laser surgery. After follow up periods ranging from 2 to 27 months, it was reported that 13 of the 17 patients were in remission.

Based on these early encouraging results a clinical trial is being proposed in the U.S. It will be a Phase I/II mulit-centered trial sponsored by the NIH/NIAID Collaborative Anti-viral Study Group (CASG). The purpose of this study is to define the safety of cidofovir infiltration of laryngeal lesions following debulking. Enrollment in this dose escalating, double blind study will be offered to pediatric RRP patients with aggressive disease, meeting strict eligibility requirements.

If you are interested in obtaining additional details of this proposed study, it is suggested that attending physicians contact:

David Kimberlin, MD or Jan Kiell, RN 205-934-5316, 205-939-9595 Fax: 205-934-8559

[ from RRP Newsletter Spring 1998]

Cidofovir: A Report from Pittsburgh
by Clark A. Rosen MD.
University of Pittsburgh Voice Center Pittsburgh, PA
 

I have had several lengthy discussions with Dr. Wellens from Belgium, who has the most experience using HPMPC for RRP. In addition, I have reviewed the only printed manuscript regarding his results. I also have preliminary experience using this treatment modality for severe RRP.

Dr. Wellens is very encouraging regarding the potential to use HPMPC (Cidofovir) for the treatment of RRP. He states that he has had many complete cures of patients with RRP using HPMPC, even only using 3-4 injections. A critical review of his manuscript, that describes his initial success, reveals that very few patients have actually been cured of their disease. In addition, many patients required every other week injections prior to clearing their disease. The report also describes several patients who initially were cleared of their disease and stopped receiving injections and then recurred many months later. These patients were designated by Dr. Wellens to be a cure with a late ,,touch up?. I have used HPMPC in two adult patients, both with extensive supraglotic and glottic RRP that had failed I3C. Neither of the patients have had any side effects of the injections. Each patient has received injections of HPMPC in a concentration of 2.5mg/cc every other week under general anesthesia. Both patients had initial dramatic response to the first three injections, less RRP seen with each injection. The first patient I treated had some residual RRP in his larynx that I could not get rid of with the injection of HPMPC despite his receiving a total of 9 injections. The second patient has had three injections and is doing quite well but all her disease is not yet gone. Interestingly, she has developed a glottic web from where her bilateral RRP was injected. Presumably her RRP went away and a web formed in similar fashion as if she had surgical removal. What does all this mean? It is too early to draw any preliminary conclusions, but it appears that HPMPC is initially quite effective but that it may not cure RRP. Would repeated injections of HPMPC be better for patients than repeated surgery? Maybe, it will depend on the necessary interval of the injections. Further updates to follow.
 
 

Frequently Asked Questions:

Q: Where do I sign up? However, if they are not approved, where can someone go for the Cidofovir treatment ?

A: As the reports on this page indicate, there are a number of medical centers using Cidofovir to treat RRP via "off label" use, despite it not being as yet FDA approved for RRP. So finding a doctor to treat you with Cidofovir may not be very difficult. However, despite the early encouraging results, if your RRP is not very aggressive (surgeries at least every 2months or involvement in the trachea or below), it might be prudent to wait to see if Cidofovir proves to have long term efficacy and safety.
 
 

References:
 

De Clercq E

Verh K Acad Geneeskd Belg 1996;58(1):19-47; discussion 47-9

Therapeutic potential of Cidofovir (HPMPC, Vistide) for the treatment of DNA virus (i.e. herpes-, papova-, pox- and adenovirus) infections.

Rega Institute for Medical Research, Katholieke Universiteit, Leuven.

(S)-1-(3-Hydroxy-2-phosphonylmethoxypropyl)cytosine (HPMPC, Cidofovir, Vistide) is an acyclic nucleoside phosphonate with broad-spectrum activity against a wide variety of DNA viruses including herpesviruses [Herpes simplex virus type 1 (HSV-1) and type 2 (HSV-2), varicella-zoster virus (VZV), cytomegalovirus (CMV), Epstein-Barr virus (EBV), human herpesvirus type 6 (HHV-6) and equine and bovine herpesviruses], papovaviruses [human polyoma virus and human papilloma virus (HPV)], adeno-, irido-, hepadna-, and poxviruses. HPMPC has proved effective against these viruses in different cell culture systems and/or animal models. The mechanism of action of HPMPC is based upon the interaction of its active intracellular metabolite, the diphosphorylated HPMPC derivative HPMPCpp, with the viral DNA polymerase. HPMPCpp has been shown to block CMV DNA synthesis by DNA chain termination following incorporation of two consecutive HPMPC molecules at the 3'-end of the DNA chain. HPMPC confers a prolonged antiviral action, which lasts for several days or weeks, thus allowing infrequent dosing (i.e. every week or every two weeks). This prolonged antiviral action is probably due to the very long intracellular half-life of the HPMPC metabolites, particularly the HPMPCp-choline adduct. In clinical studies, HPMPC has proved efficacious in the treatment of CMV retinitis, following both intravenous injection (3 or 5 mg/kg, every other week) and intravitreal injection (single dose of 20 micrograms per eye). Initial clinical trials also point to the efficacy of both systemic (intravenous) and topical HPMPC (1% ointment) in the treatment of acyclovir-resistant HSV infections, and of topical HPMPC (ointment or injection) in the treatment of pharyngeal, laryngeal and anogenital HPV infections. HPMPC is now being pursued in the topical and/or systemic (intravenous) treatment of various infections due to CMV, HSV, VZV, EBV, HPV, polyoma-, adeno- and poxviruses.
 
 

Pransky SM, Magit AE, Kearns DB, Kang DR, Duncan NO

Arch Otolaryngol Head Neck Surg 1999 Oct;125(10):1143-8

Intralesional cidofovir for recurrent respiratory papillomatosis in children.

Pediatric Otolaryngology, Children's Hospital and Health Center, San Diego, Calif 92123, USA.

Objective. To assess the potential benefit of intralesional administration of cidofovir, an acyclic nucleoside phosphonate with activity against several DNA viruses, for treating severe respiratory papillomas in pediatric patients.

Design. Prospective case series.

Setting. Tertiary care children's hospitals

Patients. Five Pediatric patients with severe recurrent respiratory papillomatosis requiring laryngoscopy with CO2 LASER therapy more frequently than once a month to maintain airway patency. Each patient had between 12 and 33 laryngoscopies with LASER treatment prior to being injected with cidofovir.

Intervention/Methods. Microsuspension laryngoscopy with intralesional injection of cidofovir (VistideR) in conjunction with mechanical debulking and CO2 LASER of papillomas.

This pilot study consisted of five patients with RRP requiring LASER therapy more frequently than once a month to maintain airway patency. In addition to repetitive LASER treatments, these patients had failed other adjuvant medical therapy. Patients ranged in age from 2 years to 5 years and had no other medical problems, specifically renal or hepatic disease. Informed consent was obtained from the patients' parents according to the policies of Children's Hospital and Health Center of San Diego and Children's Hospital of Texas.

Papilloma stage was determined using a uniform grading format developed at the University of Alabama at Birmingham by Wiatrak (personal communication). This system is designed to quantify the extent of RRP based upon involved sites (larynx, trachea and other) and subsites with severity based on a four point rating scale (0=none;1=minimal involvement; 2=moderate involvement; 3=severe involvement). Baseline complete blood count and blood chemistries were obtained prior to the first injection and then repeated monthly. The cidofovir injection was performed under general anesthesia utilizing spontaneous ventilation using the Benjamin microsuspension laryngoscope. In some cases the inhalational anesthetic was supplemented by the use of propofol. No patient required endotracheal intubation, either before or after the injection of cidofovir. Debulking of the papillomas was done through a combination of cup forceps and CO2 laser. The cidofovir injection administrated was a maximum dose of 1 mg/kg. It was formulated initially at 2.5 mg/cc and injected in the areas most involved with the papillomas using a laryngeal needle (Karl Storz Endoscopy-America ,Inc., Culver City, Ca. Injection Needle, Luerlock, straight #8598B) The injection was performed so as not to generate airway obstruction. As we began to see a response from the medication and due to the limitation of the injectable volume in these small children, the concentration was changed to 5 mg/cc. All of the children were discharged home on the day of surgery. None routinely received systemic steroids antibiotics or probenecid.

Based upon the original data from Van Cutsem et al. and the clinical course of our patients, cidofovir was injected every 2 to 3 weeks.

Main Outcome Measure. Papilloma stage at time of serial laryngoscopies.

Results. One patient became disease free and three patients demonstrated a dramatic response to adjuvant therapy with cidofovir with 9 month follow-up after the last injection with cidofovir. One patient showed improvement in papilloma stage possibly related to concurrent therapy with interferon.
 
 

Discussion/Conclusions. This is the first report of the use of cidofovir for pediatric patients with severe RRP. The results of this preliminary report are quite promising and offer hope to those who are most severely affected with RRP. Although our report does not confirm complete eradication of disease in most of the patients, in contrast to the report of Snoeck, the marked improvement in the airway and significant reduction in the need for repetitive operative intervention (as well as improved voice) suggests that this form of therapy has tremendous value in pediatric patients with severe RRP.

The significant improvement noted in our patients after the initiation of cidofovir does not appear to be coincident with the anticipated spontaneous improvement of this disease that generally comes about after years of therapy and at adolescence. All of these patients had increasing disease demanding more frequent and aggressive operative intervention simply to maintain airway patency. Injection of cidofovir brought about an impressive response quite rapidly and seems to have permitted a sustained response in four of the five patients.

Intralesional injection of cidofovir seems to be of benefit in the treatment of severe respiratory papillomatosis in pediatric patients. Larger prospective studies with longer follow-up will be required before cidofovir can be considered an accepted means of managing this difficult disease.
 
 

Pransky SM, Brewster DF, Magit AE, Kearns DB

Follow-up study (Presented at the 1999 ASPO meeting)

Clinical and Histological Update on Ten Children Treated with Intralesional Cidofovir

The original five patients who received cidofovir have done extremely well. Four of the five presently have no evidence of papillomatosis and one has minimal disease. This is especially notable given how severe their RRP disease was at the initiation of cidofovir injections. They have improved from needing at least monthly surgical intervention to only requiring rare operative intervention since completing cidofovir therapy. This excellent response has made a profound impact on these children and their families.

Our follow-up period on these patients now ranges from 18 to 22 months with no evidence of any rebound effect. They all remain healthy and show no clinical or laboratory evidence of any toxicity from their treatment with cidofovir.

Unpublished reports of laryngeal cancer arising in two of the patients in the series done by Van Cutsem and Snoeck has caused concern within the pediatric otolaryngology community. With this in mind, we performed biopsies of the laryngeal mucosa in four of the original five patients more than one year following their last cidofovir injection. All had evidence of chronic inflammation, but no evidence of malignancy. We also contacted the Armed Forces Institute Of Pathology (AFIP), where the original biopsies taken by Van Cutsem and Snoeck were reviewed. The AFIP reports that two of the original biopsies (taken prior to cidofovir injections) were actually not papillomatosis, but carcinoma. The pathologists at AFIP were not given patient data with the slides they reviewed, so they cannot say whether this data relates to the patients in question.

With these concerns in mind, we modified our injection protocol in our new patients in an attempt to determine an ideal injection protocol that reduced exposure to cidofovir, yet provided a substantial and prolonged response. Each patient received four injections of cidofovir, given at two-week intervals at the concentration of 5mg per 1cc.

The initial response of all of the five new patients to cidofovir was as impressive as for the original five patients. All showed a remarkable reduction in their severity scores during their injection period. Following their injections a variable response to the treatment was seen.

In comparison to the original five patients, the second group does not appear to be responding as well to treatment with respect to long term control of their RRP. This may indicate that some patients need a more prolonged treatment course with cidofovir, as was done with our original five patients and in Snoeck's original report. Nevertheless, all ten of our patients did show a significant and often dramatic initial response to the treatment, indicating that cidofovir does inhibit the growth of HPV lesions.
 
 

Snoeck R, Wellens W, Desloovere C, Van Ranst M, Naesens L, De Clercq E, Feenstra L

J Med Virol 1998 Mar; 54(3):219-225

Treatment of severe laryngeal papillomatosis with intralesional injections of cidofovir [(S)-1-(3-hydroxy-2-phosphonylmethoxypropyl)cytosine].

Rega Institute for Medical Research, K.U.Leuven, Belgium.

Respiratory papillomatosis is a rare and often severe disease, usually localized in the larynx. It may cause respiratory distress and even life-threatening obstruction of the airways. Treatment is generally based on the evaporation of the lesions with a CO2 laser, but microsurgery, cytotoxic and/or cytostatic drugs, interferons, and vaccines are also used. Cidofovir [(S)-1-(3-hydroxy-2-phosphonylmethoxypropyl)cytosine] (HPMPC) was shown to suppress the growth of tumors induced by rabbit papillomavirus as well as human papillomavirus (HPV). The efficacy of cidofovir was assessed in 17 patients with severe respiratory papillomatosis. Cidofovir at a concentration of 2.5 mg/ml was injected directly in the different laryngeal papillomatous lesions during microlaryngoscopy under general anesthesia. Biopsies were taken before the treatment was started both for anatomopathology and viral typing. HPMPC kinetics in serum was monitored in three patients, the drug levels being determined by high-performance liquid chromatography. Complete disappearance of the papillomatosis was observed in 14 patients. Four patients relapsed and were successfully treated again with cidofovir. Of the three remaining patients, one progressed while under treatment with cidofovir, after an initial marked response. One patient had a partial remission and remained stable for more than 1 year after the last injection. He had a very aggressive and extensive disease originally. Finally, one patient was lost to follow-up after four injections. Intratumoral injections of cidofovir for the treatment of severe laryngeal papillomatosis is a powerful new therapeutic approach for this disease. Treatment was well tolerated, and no significant side effects were noted.
 
 

last updated on 10-28-99