The 17th International HPV Conference was held in Charleston, SC from 9-15 January, 1999. There were 18 RRP patients/family members who attended (Some came from as far away as Chicago and Oklahoma City). Those who attended the conference are: Erin Woodyard Davis & husband, Caroline Dugger, Carmen & Bill Lazar, Pattie Mandl, Peggy & Barry McCracken, Chris Neuberger, James & Jeannine Pierce, Renee & James Randall,Marlene, Bill & Lindsay Stern (plus 2 others). The following paragraphs represent an effort to collate the feedback that all of the above attendees provided. This report will focus on those aspects of the conference relevant to RRP which in large part took place between Saturday January 9 and Monday January 11.

General Remarks:

All of the attendees indicated that they appreciated the opportunity to meet other RRP patients and families, face to face, and hear about the issues and emotions that they have faced in dealing with this disease. It was clearly a positive experience to be among other people who could understand what RRP can do to your life . Most RRP family members welcomed the opportunity to meet with RRP doctors outside of the office environment. Another major highlight from the RRP perspective, was an 1 1/2 hour scientific session devoted to RRP. We believe it was the first time RRP was exclusively scheduled as part of the main HPV conference.

Comments on selected sessions [Most of the details that follow were submitted by Caroline Dugger, Chris Neuberger, Renee Randall and Bill Stern]

Saturday, 9 January 1999

Special session: Advocacy for Public Health
[Congressman Spencer Bachus presented guidance on how to effectively convey a message or viewpoint to members of Congress - the following comments on this presentation are from Renee Randall]-
1) Before you start, you need to read your Congressman's or Senator's resume. Most of them are available on-line. Make sure you research what their platform is, what subcommittees they are on, and how they have voted on issues in the past. You also should check out who is on the subcommittee that is of interest to you (ie. Healthcare).

2) Writing your Senator or Congressman is the most common way of communication. It works if what you are doing is sending in a petition or form letter. What they do is collect all the form letters in one pile and look at them together. If the letter is personalized it will get more attention and has more chance of being reviewed by the Congressman or Senator. The actual letter should be short and sweet, then add attachments with all the detailed information. If the letter is long it will probably be looked at by a staffer and a form letter response sent back. Make sure that your letter addresses what exactly you would like them to do. Don't just tell a story with no suggested action, because if you do, it will be set aside. Also, sometimes the Congressman or Senator will not see it for over a month, so don't be surprised if you don't get a response back for some time.

3) The next, and usually a more successful method, is to make an appointment to visit your Congressman or Senator. If this is what you are going to do, there are several things you must consider.

When you call you are going to want to talk to their Scheduler. Remember to be very nice to this person because they are usually their personal assistant. If you don't make an impression here, you could have a tough time getting in. If possible, you may want to consider talking to someone who knows the Congressman or Senator personally. They may be able to get you an appointment faster than if you try yourself.

Most Congressmen and Senators have a staff which includes legislative assistants (LA) for each critical area (ie. Healthcare). If you are not able to get an appointment with the Congressman or Senator and you are offered an appointment with the LA, take it. It is also a good idea even if you do get an appointment with the Congressman or Senator to ask if the LA is available also. Basically what will happen when you visit and the LA is not there, the Congressman or Senator will turn everything (notes, etc.) over to the LA for action.

When you visit, make sure you have a set agenda. Talk in terms that they will understand. For instance, give them set numbers of constituents within their area who are affected by the disease. How many deaths within their area? How many children in their area? Talk about what funding, etc. is needed for, and what kind of numbers are they looking at. On healthcare issues, I can tell you a famous response from some of these guys is "I support funding for NIH," so make sure you can tell them what organizations help and which ones don't.

If they are not on the subcommittee which votes on the particular issue, make sure you tell them who you would like them to talk to on the subcommittee.

Remember that if a personal visit is done right it will make the best impression and get their attention.

The Value of Specific Non-nutritive Components in Foods in Prevention of Chronic Disease: Soy's Contribution to Our Health [Presented by Stephen Barnes from the University of Alabama Birmingham]

This presentation focused on the role soy products may have in the reduction in risk of several chronic diseases(including some types of cancer and osteoporosis). Presumably this is due to the many phytochemicals it contains. In particular it has the isoflavone genistein, which displays some interesting biochemical properties. It may act in a manner not too dissimilar to I3C, like a weak anti-estrogen, yet it also seems protective of bone density loss. Among a number of additional anti-tumerigenic virtues, genistein is also an anti-oxidant. In summary, foods with phytochemicals, such as soy , may play an increasing role in chemoprevention without unnecessary toxicity.

Keynote Lecture: Cell Structure and Carcinogenesis [Presented by Donald S. Coffey, Johns Hopkins School of Medicine]

This was a very entertaining talk, although perhaps not directly relevant for RRP. Improving our ability to carefully examine and extract information from data may help HPV and cancer research, was one of several themes

Sunday, 10 January 1999

RRP Foundation Support Network Meeting

Sunday morning the RRPF held a meeting that was attended by about 13 doctors and/or researchers in addition to all 18 RRP patients/parents. Each of the patients or a parent of a patient introduced themselves and told a brief history of their respective disease experience. Caroline Dugger, who was the only one in attendence with a tracheostomy, brought along draft copies of her book, " A tracheostomee's guide to care and well being".

Dr. David Bishai, a health economist from Johns Hopkins who is quite interested in the economic impact of RRP, asked about the costs of living with the disease as well as the pain and other issues of coping. Some of the patients expressed some of the cost issues in terms of lost time at work, forced retirement for one person as well as some stories of those with jobs that are very flexible in terms of taking time off to handle treatment of RRP. With regard to pain most patients and parents indicated that it was not a significant factor.

 Other discussion issues included the fears of dealing with RRP. Some parents of RRP children mentioned that fear of surgery was a major problem. Some of the patients expressed that it is harder to recover from surgery as an adult, while others were intimidated by the IV. Other issues included a discussion as to when should a patient be operated on and who should be the judge. Some folks believe in delaying surgery as long as possible, while others feel it is appropriate to have surgery sooner than later since it shortens the recovery time. The fear of a fire related to the laser igniting the endotracheal tube was raised by one adult patient. According to Dr. Mark Shikowitz, of L.I.J., today's technology makes this virtually impossible. He also stated that if a patient's anesthesiologist is not using some of the newer techniques, he will be happy to have his anesthesiologist discuss this with them.

There was a brief discussion with regard to the ability to "cough off papilloma", especially in the case of some patients with tracheostomies. Most doctors seemed skeptical.

There was a discussion regarding the value of specifically typing the papilloma. By knowing specific HPV types, it was suggested that it might be possible to identify those patients who might be more likely to have aggressive disease.

One doctor suggested that with the current turmoil of the insurance system and HMO's refusing care to some patients that it might be better to leave that typing unknown. Thereby, providing fewer reasons to exclude a patient from insurance coverage. On the other hand it was suggested by at least one researcher that knowledge of specific types could lead to more effective treatments targeted for a specific HPV type.

Some patients expressed some frustration with the time and process of getting certain therapies approved. Dr. Jerome Thompson, from the Univ. of Tennessee, explained the reasoning being the stringent requirements and what the medical community is looking for. The point of his discussion was to point out that it is only through stringent standards of trials do we get improved medical procedures vs. therapies that are not successful. While this may be frustrating to us as patients, it is ultimately in the best interest of all of us.

Dr. David Kimberlin, of U.A.B. and Dr. David Malis, of Brooke Army Med. Ctr. in San Antonio, discussed the status of a proposed study using Cidofovir . The study had been put on hold due to some deaths in Europe. Three in particular, further research indicated that pre-cancerous cells were found in all three cases prior to the start of Cidofovir. It is anticipated that they will be looking to fund a multi-center study soon and complete the study design.

Dr. Tom Broker, from UAB, added the following very encouraging comments about Cidofovir:

Cidofovir has been approved in the U.S. for treatment of cytomegalovirus retinitis in patients with aids. There is some concern over toxicity, especially when it is taken systemically.

HPV induces enzymes from host cells in order to grow. Induction is much higher in the host cell (100-1000 times) and this leads to the papillomas.

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.

Dr. Broker feels that this is a very promising drug and the trials will tell us much more.

The meeting concluded with a group picture of the RRP families.

Plenary Session: Recurrent Respiratory Papillomatosis

This scientific session on RRP began with an introductory clinical description of the disease by Dr. Haskins Kashima, from Johns Hopkins. The presentations were divided into two groups. The first part focused mainly on epidemiological aspects of the disease and was chaired by Dr. Bettie Steinberg, from L.I.J. The second group of presentations which dealt mostly with RRP therapies and treatments, was chaired by Dr. Kashima.

Bill Stern of the RRP Foundation, opened the presentations with a talk about the major impacts of RRP on the lives of patients and their families. The disease can be life threatening and is often characterized by great morbidity. Nearly everyone with RRP experiences a degree of voice disorder. Some so severe that they have virtually no voice, others are only slightly affected. Perhaps the most relentless aspect of this disease is the need for repeated surgeries. A chart of total number of surgeries for 17 juvenile onset patients with RRP (JORRP) for more than ten years (mean disease duration was 32 years, with a range from 14.5 - 62 years) indicated a mean of 89 surgeries with a 95% confidence interval of + or - 33. Perhaps the most life threatening aspect of RRP was the spread of the disease to the lungs, which occurred in about 5% of the cases according to the RRPF data.

Dr. Lori Armstrong from the Centers for Disease Control, followed with a presentation of initial results from their JORRP registry. Data has been collected from 23 medical centers nationally for active cases of RRP in children up to the age of 17 (they will continue to follow patients of age 18 and over if they are already in the registry). 389 children have been enrolled since January 1997. The mean disease duration is 4.3 years and the mean number of surgical procedures/year was 5.2. The CDC data indicate that children who were diagnosed at < 3 years of age are more likely to have more severe disease and children who had a tracheostomy were 4.7 times more likely to have distal spread of papilloma.

Dr. David Bishai from Johns Hopkins, presented preliminary results of a cost benefit analysis of preventing JORRP. The purpose being to quantify the cost of doing, or not doing a cesarean section (CS). The study looks at the medical costs of CS and medical costs associated with JORRP and makes an assumption of a mean of about 20 lifetime surgeries for JORRP patients. In summary, based on a variety of assumptions (including costs of pain and suffering to patients and parents), even with an efficacy as low as 50 CS to prevent one case of JORRP, the value of the social benefit of JORRP prevention would outweigh the costs associated with the necessary CS.

Dr. Keerti Shah from Johns Hopkins, discussed the risk factors for JORRP and the rationale for a multi-center study. The following is a summary of some of Dr. Shah's key points:

JORRP is preventable, since we are confident that in most cases transmission of HPV-6 or HPV-11 occurs in the infected maternal genital tract. In this regard it is quite similar in transmission to herpes. He speculates that the chances of developing RRP in a child born to "high risk" mothers presenting is about 1 in 35. A general population risk is estimated at about 1 in 3500. At present there are no guidelines on how JORRP might be prevented. In order to help establish some guidelines, a randomized trial is proposed to follow condylomatous mothers for five years (since 75% of all cases present within 5 years). If a formal trial is not possible, "we can at least observe". It does appear that CS would prevent 90% of all cases.

One of the issues raised during Q&A was a suggestion to debulk condylomas during pregnancy to reduce the viral load and perhaps help stem some of the risk. Dr. Shah agreed with this.

Dr. Ronald Ostrow, from the University of Minnesota, presented results from a double-blind, crossover clinical trial using Ribavirin for the treatment of RRP. Positive preliminary results involving Ribavirin as an adjunct for RRP had been established in animal studies and in a small uncontrolled pilot study involving human patients. This was a very well designed study which was tightly controlled. Despite a low enrollment (~10 or 11 patients), it was still possible to show that an increase in the interval between surgeries for those in the group using Ribavirin was statistically significant. Furthermore, while Ribavirin may have an impact in less than 6 months for some patients, its effect may be delayed or continue beyond its administration period for others.

Dr. Mark Shikowitz, from L.I.J., presented results of using Foscan (mTHPC) photo dynamic therapy (PDT)for the treatment of RRP. There are currently 16 patients enrolled in the protocol. 7 juvenile and 9 adults. At this time 8 patients have been studied long enough (defined as at least 12 months after treatment)to draw some preliminary conclusions . Five are said to be free of disease and two others have shown marked improvement. Improvement was not immediate, but rather, there appears to be a lag response. All patients continued to show disease at 3 months after treatment, with the significant improvement occurring at 6 or 9 months post PDT. The new PDT keeps the patient light sensitive for 2-3 weeks vs. the older drug which was often 2-3 months.

Dr. Karen Auborn, from L.I.J., talked about Indole-3-Carbinol (I3C) and RRP. In the presentation she indicated how estrogen plays at least a partial role in the susceptibility of the larynx to HPV. Animal models clearly support this. There are two major competing estrogen metabolites, i.e., C-2 and C-16a. It was found that 16a hydroxylation was significantly increased in laryngeal papillomas. Dr. Auborn discussed how I3C agents bind the AH receptor which induces 2 hydroxylation. Several clinical studies have since demonstrated this. First in mice and more recently in a human RRP patient trial. Unfortunately, in some patients I3C does not induce 2 hydroxylation. Although it appears quite safe, long term studies of the anti-estrogen I3C, at pharmacological doses are needed. In summary I3C and newer derivatives continue to show promise in treating papillomavirus - induced diseases.

Dr. Jerome Thompson, from the University of Tennessee, presented some toxicity case studies in the use of I3C. In two cases children experienced a recurrence of seizure activity that had been under control prior to taking I3C. It is believed that the I3C metabolic activity in the liver may alter seizure medication kinetics. Further study is needed to better document cases of possible I3C side effects.

Dr. Frank Rimell, of the University of Minnesota, presented his experience with regard to pulmonary papillomas. His own findings of papilloma spreading to the lungs in about 5% of cases, are similar to the RRP Foundation data. He indicates that management of pulmonary disease is quite difficult and is currently experimenting with a combination of very potent medications. 

Some additional presentations relevant to RRP [It was not possible for us to attend many other presentations, the following represent a few additional studies that we thought might be of interest to the RRP community.] 

A Phase 1 Trial of HPV6B Virus Like Particles (VLPs) as Immunotherapy for Genital Warts

Dr. Ian Frazier, from the University of of Queensland, Brisbane, Australia presented some preliminary results of a pilot study of immunizing patients with visible external genital warts with HPV6b VLPs. After between three and six injections, regression of genital warts was observed in 26 of 34 patients over a 20 week observation period. No patients developed any significant immediate local or systemic reactions to the immunisation. Based on these encouraging early results regarding efficacy and safety, it is proposed to undertake a placebo controlled tiral of VLP based immunotherapy.

Prevention of Papillomavirus Initiated Cancer by the Phytochemical Indole-3-Carbinol

Dr. Karen Auborn, from L.I.J., presented results from a mouse study. It was shown that HPV16 infected mice given estradiaol chronically, develop cervical cancer. Specifically, all mice in the experiemnts were implanted with slow release beta-estradiol pellets. Of those on a standard diet, 70% developed cervical cancer, whereas no mouse receiving a diet supplemented with 2000 ppm of I3C developed cervical cancer. At least within the context of this mouse study, I3C appears to be protective for cervical cancer.

Synergistic Activity of HPMPC and IFN-Alpha: A New Therapeutic Approach

Dr. Jeffrey A. Johnson, from Clemson University, presented (laboratory) results of using HPMPC (Cidofovir) and Interferon-alpha (IFN) in combination. The evaluation of this combination was prompted by their disparate mechanisms of controlling viral activity (i.e., HPMPC has been shown to suppress proliferation of HPV infected cells and IFN inhibits viral gene expression, allowing recovery of host cell cycle regulatory factors). The results of combined therapy experiments indicate a synergistic impact allowing potent biological activity at lower dosages than is often required when each drug therapy is used by itself. This presumably should result in a reduced risk of toxic side effects.

Evaluation of Cidofovir Gel in HPV type 11 Infected External Human Xenograft-Severe Combined Immunodeficiency (SCID) Mouse Model

Dr. W. Bonnez, from the University of Rochester, presented results of experiments using a cidofovir gel in a mouse model. 12 mice were skin grafted and the grafts were infected with HPV-11. After 10 weeks of viral growth the mice were randomly grouped and treated topically with 1% , 0.3% or 0% cidofovir gel. There was a statistically significant 50% regression of the HPV infected grafts in the mice treated with 1% cidofovir, however, it was associated with systemic and local side effects.

Immunological Treatment of Persistent High-Risk HPV Inections in Women with Intraepithelial Neoplasia
This poster was presented by Dr. Konrad Kurp, from the Center of Gynecology and Laboratory Medicine, Berlin, GE. An immunological treatment study involving 112 women with "high-risk" genital HPV infections was designed. The immunotherapeutic agent was LeukoNorm CytoChemia (i.e., a human leukocyte ultrafiltrate containing ribonucleopeptides). On average, the patients received 10 ( from 1 to 27) intramuscular injections. A summary of results were as follows: Adverse side effects were found in only 1 of 112 patients (and treatment in this patient was discontinued). A "complete" response was seen in 87 of 111 patients and the treatment was terminated and the treatment showed no efficacy in 13 of the original 112 patients, the other showed some degree of partial response.

Fish Oil Constituent Docosahexaenoic Acid(DHA) Selectivity inhibits growth of Human Papillomavirus immortalized Keratinocytes: A Function of Lipid Peroxidation

This poster was presented by Karen Auborn from L.I.J. The significance of this study is that omega-3-fatty acids and in particular their constituent DHA might be an adjunct therapy in the treatment and prevention of human paillomavirus disease. In addition to selectively inhibiting growth of HPV infected cells (not the normal cells), Omega-3-fatty acids modulate the immune system in a positive way. It was found that Alpha-tocopherol (Vitamin E) tended to abrogate the effects of DHA, perhaps implying that taking mega doses of Vitamin E while taking fish oil could be contra-indicated.

---------------------------------------------------------------------------------------

Many thanks to the organizing committee* of this 17th International Papillomavirus Conference in not only putting together a great scientific meeting, but also creating an environment surrounding the formal sessions that encouraged additional very valuable interaction among the attendees.

*Members of the Organizing Committee

Lucia A. Parisi-Creek, University of South Carolina School of Medicine

Kim E.Creek, University of South Carolina School of Medicine

Thomas R. Broker, University of Alabama at Birmingham

Louise T. Chow, University of Alabama at Birmingham

Karl R. Beutner, Solano Dermatology Associates

Mitchell Greenberg, Omnia, Inc.

and
Judith Hendrik - Organizing Secretariat