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Despite the enthusiasm at the Eleventh International Conference on AIDS in Vancouver over recent advances in anti-HIV therapy, it will be a long time until there are manageable combinations of easy-to-tolerate drugs that work for everyone. New agents are needed particularly for the many individuals who already have failed on protease inhibitors. Researchers at Vancouver reported upon an array of new agents that have not seen substantial clinical testing. Most of these compounds seem promising in the test tube but have yet to demonstrate anti-HIV activity in people.
Given the activity of established drugs in the same class, some of the new reverse transcriptase and protease inhibitors seem destined to proceed smoothly through the clinical trials process. It is unclear to what extent such agents truly will increase people's therapeutic options because of problems such as cross-resistance and intolerance. The most significant advances may arise from the work of researchers who are looking for other aspects of HIV's lifecycle that could be as successfully exploited as reverse transcriptase and protease have been.
Eric de Clerq, M.D., of the Rega Institute for Medical Research in Belgium has long been working with compounds that block the way HIV binds to cells. Among these is dextran sulfate, one of the first anti-HIV drugs studied in people. De Clerq's team now has demonstrated that the virus can become resistant to the compound in cell culture studies by changing certain amino acids in the V3 loop of HIV's gp120 envelope protein (conference abstract Th.A.152). Although clinical study of dextran sulfate was discontinued because of its toxicity, the finding is significant because it helps explain where the virus is susceptible to attack by compounds such as dextran sulfate. Less toxic compounds might be developed to exploit this weakness in the virus envelope. One such drug, PRO 2000, was reported to be safe when administered as a ten-minute infusion to HIV-negative volunteers (abstract We.B.3129).
There were a number of poster and oral presentations on T-20, a compound made by Trimeris, Inc. (abstracts Tu.A.263, Mo.A.1080, L.B.A.6015). T-20, which mimics a small portion of the HIV envelope protein, blocks fusion sometime after HIV's envelope protein binds to the CD4 receptor. This binding changes the shape of the HIV surface protein so that the surface of the virus is brought into close proximity to the cell, allowing for fusion. T-20 interferes with this conformational change.
"T-20 is the most potent agent that we've ever looked at in [a mouse model for HIV infection]," according to Paul Black, M.D., Ph.D., of the Food and Drug Administration. In his study, the drug completely blocked HIV infection in a mouse model. Since the drug is a protein derived from part of HIV, there is a fear that its administration could provoke an antibody response that may inactivate it. Another potential problem is that the compound cannot be taken orally since it is broken down by acids and enzymes in the digestive tract. In its current form, the drug would have to be given as an injection two or three times a day. To cut down the number of injections, Trimeris is looking at second-generation drug candidates that persist longer in the blood. They also are considering administering the drug via "mini-osmotic pumps," small implanted devices that secrete a constant level of drug over time. These pumps could be implanted in the arm, supplying drug for weeks or perhaps longer. First, though, Trimeris Pharmaceuticals intends to determine whether the current form of T-20 has activity in people. Dose-ranging studies are planned to begin by the end of the year.
Reverse Transcriptase Inhibitors
The surprising activity of Glaxo-Welcome's new nucleoside analog 1592U89 (see August's Treatment Issues) has shown that it may be possible to optimize the potency of this class of drugs. Dr. Jan Balzarini, also of the Rega Institute for Medical Research in Belgium, presented data on a modified form of d4T that is 50- to 100-fold more potent in cell culture studies, because it enters cells more readily (abstract Mo.A.1012). Meanwhile, a group at Emory University working with a lipid-associated form of ddI in mice, found that the new agent more effectively reached and persisted in lymphoid tissue than standard ddI (abstract Mo.A.1079).
The National Cancer Institute has moved a new nucleoside analog, F-DDA, into phase I/II dose-ranging studies (abstract Mo.A.1076). The drug's active form is similar to ddI, though the ddI-resistant virus remains susceptible to F-DDA. Like ddI, F-DDA's activity in cell culture is increased by the addition of hydroxyurea and ribavirin. Unlike ddI, the new drug does not need to be formulated with a buffer, and thus should not cause the gastrointestinal side effects that make ddI so hard to tolerate. If the drug is found to be active in the dose-ranging study, it will be developed by U.S. Bioscience, makers of the anti-PCP drug trimetrexate.
Two posters presented the antiviral activity, resistance and safety profile of Hoechst-Bayer's NNRTI (non-nucleoside reverse transcriptase inhibitor) HBY-097 (abstracts Mo.A.1102, Mo.B.1326). In four studies with doses ranging from 375 to 3000 mg per day, the drug reduced viral load by an average of 1.38 to 1.63 logs (95.8 to 97.7%). Four out of ten patients treated with higher doses of HBY-097 developed a rash similar to that seen with nevirapine and delavirdine. The drug is currently in dose-ranging and drug interaction studies (including a study with indinavir, and another with AZT). Pivotal clinical studies are slated to begin next year. For more information call 800/TRIALS-A (800/874-2572).
Preclinical data were reviewed for DMP-266, an NNRTI discovered by Merck and now licensed to DuPont-Merck (abstract Mo.A.1077). This drug has established antiviral activity and is currently in phase II clinical trials (see May's Treatment Issues, page 8). While most NNRTIs are defeated by the evolution of just one resistance-conferring mutation in the HIV reverse transcriptase, it takes two to protect HIV against this drug. Nevertheless, two mutations in the enzyme have been shown to readily occur when NNRTIs are used with AZT alone or in other suboptimal combinations. It remains to be seen how quickly resistance to DMP-266 will occur in the current studies that combine the drug with indinavir or AZT/3TC.
Using NNRTIs in combination with more potent regimens may be the best hope for defeating NNRTI-resistant virus. A second option would be the development of compounds that can attack HIV resistant to nevirapine or delavirdine. Preclinical work has suggested that the virus would need to develop a unique mutation to evade the effects of HBY-097. In human studies, this novel mutation has yet to be seen. A mutation that causes resistance to delavirdine, though, was seen in two out of ten patients treated with HBY-097 at study end (fourteen days), but it is not yet clear how much or whether these mutations will allow the virus to resist the effects of this new drug.
Another promising group of agents has yet to enter clinical trials: Compounds owned by Uniroyal, related to UC10 (see Treatment Issues article, Overcoming Resistance to Reserve Transriptase Inhibitors; September 1995, page 9) have been shown to be active against virus containing all five of the major mutations that confer resistance to the other NNRTIs (abstract Mo.A.1051). Furthermore, the addition of the Uniroyal compounds to 3TC produces, in Dr. de Clerq's words, "a knock-out combination." In his laboratory experiments the virus could not become resistant to both drugs at the same time and still retain the ability to replicate. Though the Uniroyal compounds are not yet in the hands of an entity that develops drugs, Dr. de Clerq claims there is a good chance that they may be licensed to a pharmaceutical company in the near future and moved into clinical testing. He notes that these compounds are stable in human blood, and some have been shown safe and bioavailable in animals.
Integrase Inhibitors
A number of researchers spoke of the HIV integrase enzyme as the next important target of antiretroviral therapy. Integrase is an enzyme that integrates HIV genetic material into the host cell's DNA.
In one presentation, Edward Robinson, Ph.D., of University of California Irvine reported preclinical data on a class of compounds derived from Bolivian plants that inhibit integrase activity. Merck Pharmaceutical's Daria Hazuda, M.D., Ph.D., presented a poster on integrase inhibitors found by screening other natural products (abstract Mo.A.1020). Though the fungus-derived compounds she reported upon are very potent blockers of integrase catalytic activity in drug screening tests, they do not show activity against HIV when cultured with cells. Lack of activity in cell culture is a common problem with many of the integrase inhibitors that have been identified. Either the compounds do not effectively get into the cell, or doses that inhibit HIV are also lethal to the cells the drug is meant to protect.
Dr. Hazuda believes that further structural studies using these compounds, and others Merck has yet to announce, may show them how to modify the structures to create a potential drug candidate. This will take time: Dr. Hazuda commented, "We are several years away from developing clinically useful integrase inhibitors."
The one integrase inhibitor to reach human studies is Aronex's ARR-177, which now sports the name zintevir (abstract Th.B.943). This compound does not inhibit the "active" part of the integrase enzyme. Instead, it keeps integrase from binding to the HIV genetic material in the first place. Dose-ranging studies have recently begun in San Francisco.
Zinc Finger Inhibitors
HIV's zinc fingers are amino acid structures on the surface of one of HIV's core proteins. The zinc fingers capture and help package HIV genetic material into newly budding virions, and also appear to play a role during the earlier stages of cell infection. Two zinc finger inhibitors are currently in clinical studies. One owned by Parke-Davis has completed initial pharmacokinetic studies and will enter phase I/II dose-ranging studies within a month (see Treatment Issues article, Zinc Fingers-Next antiviral Target; October, 1995, pages 7-8). ADA, the other compound, is owned by the Dutch company Van de Velde and is now the subject of a European phase II study. According to William Rice, Ph.D., of the National Cancer Institute, the zinc finger mechanism of action for this drug was identified only recently. Both of these compounds, though, may become inactivated by common substances in the body. For example, Parke-Davis's zinc-finger inhibitor breaks down when exposed to glutathione, an antioxidant present in most cells.
Dr. Rice presented data on a new class of zinc finger inhibitors that are as active as the earlier compounds but not sensitive to glutathione or other antioxidants (abstract Th.A.150). Members of this class of chemicals are currently being studied for safety and activity in animal models.
Novel Protease Inhibitors
Dr. Masatoshi Taneka of the National Cancer Institute reported that his agency, in collaboration with the Kyoto Pharmaceutical University and Japan Energy Co., has discovered a protease inhibitor, KNI-241, that is not stopped by HIV that has developed resistance to other available protease inhibitors (abstract Tu.A.260). The same group had taken one protease inhibitor, KNI-272, into clinical trials, but this drug is defeated by the same resistance-conferring mutations that inactivate ritonavir and indinavir, and did not seem to be as potent as the approved drugs. Development of KNI-272 is being discontinued in favor of KNI-241.
Finally, Suvit Thaisrivongs, Ph.D., of Pharmacia & Upjohn presented preclinical data on its third and most powerful protease inhibitor (abstracts Tu.A.261 and Mo.A.1084). Because of its potency, the company believes it will be active despite its tendency to become bound to albumin in the blood, a problem that led to the discontinuation of Pharmacia & Upjohn's two previous lead compounds. The drug is relatively easy to make and is active against HIV resistant to any of the approved protease inhibitors. Phase I dose-escalation studies will begin in Michigan before the end of the year.
While many left the XI International Conference on AIDS in Vancouver pondering the prospects of HIV "eradication" and marveling over the suggestive combination therapy data, others left impressed by how the diagnosis, treatment and prophylaxis of opportunistic infections are improving. Viral infections (cytomegalovirus -- CMV), bacterial infections (Mycobacterium avium complex -- MAC), malignancies (Kaposi's sarcoma -- KS) and fungal infections (oral and esophageal candidiasis) were all featured in separate symposiums. Most of the treatment and prophylaxis trial data concerned FDA-approved drugs like ganciclovir and clarithromycin, which already have widespread use in the U.S. As it turns out, the data generated from these studies will make a major contribution to managing patients with AIDS.
Dr. Brosgart's presentation was much anticipated because she was going to reveal the "reason" why oral ganciclovir "didn't work." After a run-through of the basic study data, Dr. Brosgart revealed the reason: ddI. Patients on the placebo arm who were taking ddI (alone or in combination with other antivirals) had a very low rate of developing CMV: 64 of the patients in the placebo arm were taking ddI and only one developed CMV disease. Conversely, patients in the oral ganciclovir arm who were on ddI had a high probability of developing CMV disease.
Of note, Dr. Spector reported that the Syntex/Roche 1654 team did a post hoc analysis of all patients taking ddI but did not find the same results seen in CPCRA 027. Dr. Brosgart stood by her team's analysis but cautioned that the results should be interpreted carefully and that the supposed negative ddI and oral ganciclovir interaction should be investigated further. Other groups have previously noted that :
Quantitatively, CMV PCR-positive patients were stratified by their CMV viral load count into three groups, those with: less than 2,500 copies; 2,500-50,000 copies; and 50,000 to 150,000 copies. The patients with CMV counts below 50,000 benefited from oral ganciclovir: 20% of the oral ganciclovir patients developed CMV disease versus 40% of those on placebo. For those with CMV loads more than 50,000, oral ganciclovir's protective effect was no better than placebo. Of note, there were ten patients with over 150,000 copies (all randomized to the oral ganciclovir arm), all of whom went on to develop CMV disease.
Hence, this viral load sub-study tells us three things:
Oral Ganciclovir for Maintenance CMV Therapy
Jay Lalezari, M.D., of San Francisco (filling in for Dorothy Friedberg, M.D.) presented data from Syntex/Roche study 2226, a trial comparing three doses of oral ganciclovir (3, 4.5, or 6 grams) with IV ganciclovir (5 mg/kg daily) for CMV maintenance therapy (abstract Th.B.305). The median time to first progression was 41 days for 3 grams; 50 days for 4.5 grams; 57 days for 6 grams; and 70 days for IV treatment. The difference in time to progression between the low dose arm versus the IV arm was statistically significant.
These are important -- yet disquieting -- results. The 3 grams dose is what is currently recommended to thousands of patients, but it is not as effective as higher oral doses or using IV ganciclovir. Moreover, 3 grams is twelve pills a day and costs at least $15,000 a year. If one is to start taking 6 grams a day, that would be an impractical 24 pills a day costing over $30,000 a year.Hoffmann-La Roche at present is developing a 500 mg capsule to reduce the number of required pills. The price needs reducing, too.
The MAC symposium also was comprised of clinical trial data which had mostly been presented at previous AIDS meetings. The two most important studies presented, ACTG 196 (clarithromycin versus rifabutin versus a combination of the two for MAC prophylaxis) and the Canadian MAC treatment study CTN 010 (a combination of three drugs versus four) have been detailed in Treatment Issues articles (Summary of Data from ACTG 175 and Delta Trials, and ACTG 175 and Delta; October 1995, pages 2-3).
High Dose Clarithromycin Yields Excess Mortality
Of interest, and eliciting considerable protest by ACT UP, were the results (and their subsequent mishandling) of CPCRA 027 (abstract: LB.B.6025). CPCRA 027 was a MAC treatment study comparing two doses of clarithromycin (500 mg twice a day versus 1000 mg twice a day) in combination with other agents. This study was stopped early because a high mortality rate was observed in the group of patients receiving 1000 mg twice a day. As of February 6, ten of 45 (22%) patients in the 500 mg arm had died versus 17 out of 40 (43%) patients in the 1000 mg arm, a significant difference. No plausible explanation was given for this increase in mortality; to this date these findings still puzzle the principal investigators and statisticians. These findings of increased mortality with high-dose clarithromycin are similar to those observed in two previous MAC treatment trials.3 CPCRA 027 -- a study some believe to have been unethical from its inception -- was, in part, conducted in order to confirm or disprove those earlier findings of higher mortality.
Azithromycin Helps Prevent MAC and boosts PCP Prophylaxis
While the full data set of the azithromycin MAC prophylaxis study (MOPPS study 006-174) was not presented in Vancouver, analysis of its Pneumocystis carinii pneumonia (PCP) sub-study was detailed by Dunne and colleagues (abstract: Tu.B.410). This sub-study analyzed the incidence of PCP among rifabutin recipients versus those receiving azithromycin-containing regimens in this MAC prophylaxis trial of 693 patients with under 100 CD4 cells. With 95% of the patients on PCP prophylaxis (58% on TMP-SMX; 18% on dapsone, 19% on aerosolized pentamidine), 22.7% of those in the rifabutin arm developed PCP compared to 10.9% of those in the azithromycin arms. Thus, it is suspected that azithromycin (a macrolide) not only helps prevent the occurrence of MAC, but also adds to PCP prophylactic medications and reduces one's chance of developing PCP (the study was not designed or powered to evaluate the use of azithromycin as a PCP prophylaxis, though). Similar findings from ACTG 196, a MAC prophylactic study which used clarithromycin (a sister macrolide), will be presented in early 1997 (William Powderly, M.D., personal communication).
Kaposi's Sarcoma
Doxil versus Bleomycin + Vincristine
The results of a trial of Doxil versus the combination of bleomycin plus vincristine (BV) for the treatment of KS were presented in a late-breaking poster (abstract LB.B.6026). Doxil -- a liposomal encapsulated form of adriamycin, a common, yet powerful, cytotoxic chemotherapeutic agent -- was recently granted accelerated approval by the FDA for the treatment of relapse or refractory KS.
Both regimens were administered every three weeks by intravenous infusion, consisting of 15 mg/m2 of bleomycin and 2 mg of vincristine versus 20 mg/m2 of Doxil. Mostly conducted in Europe, this study enrolled 241 patients with 102 evaluable patients in the BV arm and 116 evaluable in the Doxil arm. Seventy percent of the patients had under 50 CD4 cells and no G-CSF was allowed. Of the Doxil patients, seven (5.8%) achieved a complete response and 64 (52.9%) achieved a partial response compared to one (0.8%) complete response and 27 (22.5%) partial responses achieved by the BV patients. The difference was statistically significant. At the end of treatment (when patients stopped drug) the response rates were lower in both arms: the rate of complete response was 3.3% and 35.5% for partial responses on Doxil versus no complete responses and 14.2% partial responses on BV.
While Doxil was found to be efficacious in treating patients' lesions, it was more bone marrow-suppressive with 76.1% of the Doxil patients registering an absolute neutrophil count (ANC) below 1500 compared to 52.5% of the BV patients. Paresthesia (numbness and tingling in the mouth) was more common for the BV patients (14.2% versus 3.3%) and oral candidiasis was found to be more common in the Doxil patients (28.9% versus 17.5%). No survival data were given.
These results are similar to those seen in a study comparing Doxil against ABV.4 Since both studies were conducted in chemotherapy-naive subjects and demonstrated Doxil's superiority, the FDA is likely to grant, Sequus, the makers of Doxil, full approval to market Doxil as first-line therapy.
New data on itraconazole oral solution (cyclodextrin) for the treatment of oral and esophageal candidiasis were presented in a number of sessions. Cyclodextrin is 30% to 60% more bioavailable than the standard itraconazole capsule when it is taken on an empty stomach. It is not available in the United States at present.
A study presented by Rabih O. Darouiche, M.D., compared the safety and efficacy of two doses of cyclodextrin with fluconazole (200 mg per day) for the treatment of thrush or oral candidiasis (abstract: Mo.B.117). A total of 190 patients (179 evaluable with a median CD4 cell count of 94) were enrolled to receive either itraconazole solution 200 mg daily for seven days or 14 days, or fluconazole 200 mg on day one and then 100 mg daily for 14 days.
There was no statistically significant difference between the three patient arms in terms of clinical response (freedom from lesions), fungal eradication (negative Candida culture) or relapse rates after four weeks' follow-up. Even so, the investigators concluded that itraconazole solution for 14 days was at least as effective (if not a bit better) as fluconazole in suppressing symptoms of oral candidiasis and in achieving a clinical and anti-fungal response.
Dr. Darouiche conducted an identically-designed study comparing the itraconazole solution to clotrimazole troches for the treatment of oral candidiasis. 149 patients (83% HIV-positive) were randomized to receive either the fourteen day dose of itraconazole or clotrimazole troches at 10 mg five times daily for 14 days.
There was no statistically significant difference between the treatment arms in their ability to achieve a clinical response: 77% for itraconazole solution versus 66% for clotrimazole. Itraconazole solution, however, was determined to be more effective in decreasing fungal colony counts and culture positivity: the itraconazole solution had a 66% response rate compared to 47% for clotrimazole.
In the itraconazole arm, 48 of the 53 (91%) patients were symptom-free at the end of treatment as compared to 49 of the 57 (86%) patients in the fluconazole arm. The median time to clinical response was 27 days for the itraconazole arm and 28 days for the fluconazole arm. At the end of treatment, an endoscopy determined cure occurred more often in the itraconazole patients (90%) than in the fluconazole patients (80%). Likewise, 92% of the itraconazole patients as compared to 78% of the fluconazole patients achieved fungal eradication. Relapse -- during the four-week follow-up period -- occurred in 18% of the itraconazole patients and 27% of the fluconazole patients.
All three studies support the efficacy of cyclodextrin/itra
conazole oral solution and will probably be used in Jannsen's application to the FDA. If it is priced fairly, cyclodextrin might be a more suitable option over fluconazole given the latter drug's high price, drug interactions and potential to cause resistance.
A thirteen-member international panel of HIV experts convened by the International AIDS Society-USA (IAS) released new antiretroviral treatment guidelines amid a turbulent crowd of demonstrators, researchers, HIV clinicians, people with HIV and AIDS and other participants of the XI International AIDS Conference in Vancouver, Canada, on July 6, 1996. These guidelines are essentially an updated version of those drafted at a meeting in January and published in the July 10 issue of the Journal of the American Medical Association. The panel endeavored to address the most common HIV and AIDS treatment scenarios in clinical practice, using the latest information available at the time the guidelines were drafted. But discussions at the Conference indicated that the guidelines have significant shortcomings because they do not take into account either the rapid evolution in anti-HIV therapy or the real-world limitations and complications practitioners will encounter in following even these now outdated recommendations.
Those with CD4 counts greater than 500 who are considering initiating therapy should be aware that there are no available data to support treatment at this early stage of HIV disease. Difficulties concerning a patient's tolerance to and acceptance of a given treatment, the expense of the treatment, the potential for development of viral resistance to the treatment and other problems associated with long-term toxicity are all major considerations in starting therapy at this point.
The panel also felt that therapy for those with HIV levels greater than five to ten thousand should be considered, but some members suggested that all patients with viral loads greater than 5,000 definitely should be treated. In addition to these guidelines, it was strongly recommended that all symptomatic patients (including those with oral candidiasis, hairy leukoplakia and other symptoms of mild immunodeficiency) should be treated with antiretroviral drugs, regardless of CD4 count or HIV viral load.
The panel did not address the critical issue that many clinicians and patients still do not have access to HIV viral load testing, and thus the recommendations based on viral load are not applicable for a substantial number of people.
The panel omitted the role of nevirapine in initial or follow-up regimens or the use of two protease inhibitors together, data concerning which were released in Vancouver. The recommendations also ignored d4T monotherapy altogether even though it is one of the stronger monotherapies available and widely used.
None of the recommended regimens included more than three drugs, despite the fact that many in the community are starting to use four or five antiretroviral drugs together, often in conjunction with supportive agents such as interferon alpha, interleukin-2, hydroxyurea and many other alternative and complementary therapies. Furthermore, the panel did not rank its recommendations based on preference. Various options appeared to be given equal weight in the report though some were supported by large-scale trials measuring disease progression and others were not.
Just how a patient's therapy should change would, of course, depend on the reasons for altering it. For example, if a patient's intolerance to a given drug is the primary reason for change, then finding drugs that the patient can tolerate is paramount. If the problem is treatment failure, then drugs with greater potency and different mechanisms of action are recommended, particularly those who do not exhibit cross-resistance. A change to the most potent regimen available, based on virologic, immunologic and clinical characteristics of the individual patient is recommended.
Several common examples of clinical scenarios were presented for patients who have been on the following regimens and require a change in therapy:
This last switch alternatively could include addition of a non-nucleoside reverse transcriptase inhibitor (NNRTI) like nevirapine. Again, the panel did not consider NNRTIs when the guidelines were originally drafted, and the NNRTIs' precise role remained poorly defined in the eyes of many attending the IAS seminar.
The absence of anything but AZT drew criticism from many obstetricians and gynecologists, who felt that such treatment is suboptimal. Limiting the recommendations to AZT failed to address those pregnant women with extensive prior experience with zidovudine or women who had been taking other antiretroviral drugs -- must they switch to AZT monotherapy two trimesters before giving birth? Some complained that no expert with experience treating HIV-positive pregnant women was included on the consensus panel.
Other important patient populations were not addressed by the panel. What treatment, if any, should be offered to long-term non-progressors or to patients with moderate viral loads of ten to twenty thousand? And finally, what should be done for those with markedly depleted immune systems (CD4 counts below 50), particularly those who have failed most if not all available treatments?
But many physicians were not swayed by Dr. Lange's outburst. They felt that asymptomatic patients would not tolerate years of triple drug therapy and that three drugs may be unnecessary in any case. "I can bring the viral loads of many of my patients below undetectable levels with just two drugs, so why do they need three?" asked Steven Miles, M.D., of the University of Los Angeles after Dr. Lange's session was over. - DG
On September 27, the FDA's Antiviral Drugs Advisory Committee will meet to consider licensing delavirdine (brand name: Rescriptor). This Pharmacia & Upjohn product is the second nonnucleoside reverse transcriptase inhibitor (NNRTI) to come before the committee. (The first was Boehringer Ingelheim's nevirapine -- see the June/July Treatment Issues). Delavirdine is currently available to the public through an expanded access program -- call 800/779-0070 for more information.
A major issue that remains unresolved with both delavirdine and nevirapine is how these drugs affect the body's metabolism of protease inhibitors. Like the protease inhibitor ritonavir, both NNRTIs affect the CYP3A enzyme system in the liver that breaks down many drugs. Nevirapine seems to increase destruction of protease inhibitors whereas delavirdine (and ritonavir) inhibits this loss. The result of these hepatic changes on protease inhibitor blood levels or efficacy has been little explored up to now.
Drug combinations that include both an NNRTI and a protease inhibitor appeal to many people with HIV. First are those who want to suppress HIV as much as possible early in disease through a four drug combination that also includes two nucleoside analogs. Then there are persons with advanced infection who have had long histories with nucleoside analogs. Their HIV may be largely resistant to these older agents.
As part of the run-up to the FDA meeting and to partially satisfy intense public interest, Pharmacia & Upjohn has released the preliminary results of its tests on combining delavirdine with the three marketed protease inhibitors. These initial data all come from tests with 13 or 14 HIV-negative volunteers and are hardly enough to make final recommendations.
After the longest and bitterest budget battle in state history, New York state legislators have passed a 1997 spending plan that for the first time commits state tax dollars to the local AIDS Drug Assistance Program (ADAP). Although most other states contribute their own resources to their ADAP programs, New York until this year gave almost nothing. The state will now contribute $8 million this year from the general fund and $12 million annually for the succeeding three years. These funds will come from a new health care program for uninsured New Yorkers.
The move will allow New York's beleaguered ADAP to stand on firmer financial footing. On January 1 of this year, citing growing demands and skyrocketing expenses, the state health department cut 129 drugs from the ADAP formulary and capped or eliminated primary care services for the more than 17,000 low-income, uninsured New Yorkers with AIDS who rely on the program.
A New York State health department advisory committee met on August 21 to formally decide how the new state money should be used. As of September 1, New York ADAP began covering HIV protease inhibitors, viral load evaluations and other crucial anti-HIV and opportunistic infection agents including nevirapine for HIV, cidofovir for CMV and DaunoXome for KS. Pursuant to the advisory committee's recommendations, New York ADAP also has restored some of the most important benefits and coverage of medications that were eliminated in January such as many antibiotic and psychotropic drugs. Two of the most expensive medications, Epogen and Neupogen, which are used to manage the bone marrow suppression caused by some of the covered therapeutic agents, are not expected to return to the ADAP list at this time, however.
New York's decision came after a massive grass-roots lobbying effort by AIDS organizations across the state. Thousands of New Yorkers registered their support with state officials, and editorial pages in central and western New York spoke in support of ADAP. Behind this campaign was a sense of indignation that as treatment breakthroughs were being announced in the news, New York was denying access to new therapies. The magnitude of New York's AIDS epidemic ensured a large public outcry.
No state has been hit harder by AIDS than New York. New York City alone has more AIDS cases than any state in the union, straining the heath care system to near breaking point. For the first time in 100 years, the life expectancy for males in New York dropped, due largely to the AIDS crisis, according to the City health department. Few New Yorkers remain untouched by this public health tragedy, and few political leaders can ignore this crisis.
The buyers' club has been openly selling marijuana primarily to people with AIDS- or cancer-related weight loss since 1991. The organization's raison d'être enjoys popular support in the region, and elected city officials have protected the club from police harassment. State Attorney General Dan Lungren ordered the assault on the compassionate-use organization without consulting local officials.
The California Attorney General's office says it was gathering evidence that healthy individuals were obtaining marijuana for recreational use through the club. But many see the raid as an obvious attempt to derail Proposition 215. This ballot measure, which goes before voters in November, would grant people in California the right to grow or purchase marijuana for personal medicinal use. The Attorney General opposes Proposition 215. Many of the organizers of the campaign, who were involved in the buyers' club, now must make time to contend with criminal investigations rather than work on the ballot effort, which the raid helps to discredit. Anyone who wishes to help or make financial contributions to the organization should contact Californians for Compassionate Use at 415/621-3986.
On the basis of these early promising results, large randomized studies were initiated. The discontinued trial sponsored by the National Eye Institute's Studies of the Ocular Complications of AIDS (SOCA) and the AIDS Clinical Trial Group (ACTG), had enrolled over 200 of the planned 320 patients with newly-diagnosed or recurrent CMV retinitis. All patients were treated with currently approved anti-CMV therapy, but half were randomized to receive MSL 109 (60 mg every two weeks) in addition to the other medications.
The investigators chose to perform the interim analysis after a Data and Safety Monitoring Board noted that more deaths had occurred among the patients who were receiving MSL 109. The difference in mortality only occurred in those patients with recurrent retinitis. According to Dr. Curtis Meinhart of SOCA, this may have been a fluke, since the incidence of death was lower than usual in those randomized to receive placebo. Be that as it may, the interim analysis found that the addition of MSL 109 did not delay time to progression (65 days in the MSL 109 arm versus 66 days in the placebo).
Two other large MSL 109 studies are still ongoing. One is a CMV prophylaxis study in bone marrow transplant patients. The Data and Safety Monitoring Board recommended introducing no changes to this study, after finding no increase in mortality or side effects in participants taking MSL 109.
A second study conducted by the ACTG, study #266, has been temporarily placed on hold. A number of this study's investigators were involved in the earlier small study that reported positive results from MSL 109. Since the doses in ACTG 266 are the same or lower than the ineffective doses used in the SOCA trial, the ACTG study team has recommended enrolling new patients at higher doses of MSL 109. Those already enrolled on the study would have the option of quitting the study or switching to the higher doses. This plan, though, is dependent upon approval by the specific medical centers supervising the trial, the ACTG, the National Institute of Allergies and Infectious Diseases and the FDA.
After the first twelve-week period, those on treatment had gained a statistically significant total of 1 kilogram compared to an increase of 0.1 kg on placebo. The group receiving nandrolone experienced a greater increase both in fat-free mass (2.3 kg versus 0.5 kg in those on placebo) and body cell mass, another measure of lean body mass (2.3 kg versus 1.0 kg in those on placebo), although the latter measure did not reach statistical significance. A large amount of the gained weight may have been water. Still, according to one of the investigators, Daniel Berger, M.D., "patients felt much better on drug."
Dr. Berger noted that "patients in other parts of the country are doing higher doses, but mostly we wanted to know whether it was safe for our patients." The steroid had no observed negative effect on viral load or immune status and increased levels of hematocrit (a measure of red blood cell level) and hemoglobin, which are low in many people with HIV, especially those on AZT. Levels of free and total testosterone decreased in the treated patients. A few patients withdrew from the study due to mood swings, restlessness or increased libido. Insomnia, impotence and acne were reported by some patients.
There have been fears, based on anecdotal observations, that anabolic steroids promote Kaposi's sarcoma. One volunteer treated with nandrolone developed KS. No changes in KS during the study were seen in three persons on treatment who had KS at baseline -- but one developed pulmonary KS one month after the study concluded. Although, the occurrence or worsening of KS may have little to do with use of the steroid, the study presenter at the International Conference, Dr. Gary Bucher of the Centers for Special Immunology site in Chicago, concluded that "Deca-Durabolin should be used with caution in patients with KS until larger studies are done."
The experience of the one woman in the study illustrates a potential danger of anabolic steroid use in women with HIV. She gained a few pounds, but stopped menstruating. After going off treatment, her weight remained stable, but her periods have not yet restarted.
The same investigators from the Centers for Special Immunology are planning a study comparing nandrolone to growth hormone in patients with wasting. The trial is slated to begin in the next three or four months. Treatment with human growth hormone, which was just approved by the FDA for use in AIDS wasting syndrome, costs about 100 times treatment with 100 mg per week of nandrolone.
In one of the studies, blood from 913 people was tested for HHV-8 antibodies by researchers from the University of California San Francisco (Nature Medicine, August 1996;2:862-863, 918-928). The team found strong evidence suggesting that the virus is sexually transmitted. The highest incidence of HHV-8 infection (35%) was seen among gay or bisexual men who became HIV-infected through sex. A high rate of HHV-8 infection was seen among HIV-negative people with syphilis, 8% of whom had antibodies to the virus. Only 3% of HIV-positive people with hemophilia (who acquired HIV through blood products) and only 1% of blood donors without sexually acquired diseases had evidence of HHV-8 infection. Finally, underscoring the link between the herpes virus and the malignancy, the researchers found that 83% of tested patients with KS had antibodies to HHV-8.
Very similar results were published in the New England Journal of Medicine (July 25, 1996; 335:233-41) by Shou-Jiang Gao, Ph.D. et al (in collaboration with Yuan Chang and Patrick Moore -- the Columbia University team that first identified HHV-8). These scientists found antibodies to HHV-8 in 80% of 40 HIV-positive gay men with KS. Only 18% of 40 HIV-positive gay men without KS tested positive for antibodies to the virus, and none of 122 HIV-negative blood donors, 22 patients infected with Epstein Barr Virus, or 20 men with HIV and hemophilia had HHV-8 antibodies.
Perhaps the most important finding of the study was that 21 of the 40 HIV-positive men with KS developed antibodies to HHV-8 six to 75 months prior to the appearance of KS lesions. The researchers believe that the development of antibodies to HHV-8 is not the result of reactivation of a latent virus in immune-compromised patients. They base this view on the very low rate of antibodies in comparable gay men with HIV but no KS. The data suggests that HHV-8 infection is newly acquired, probably through sexual relations.
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News >> Browse Articles
Browse Congress Articles
Obama to Propose Five-year Spending FreezePresident Obama will call for a five-year freeze in non-security, discretionary spending during his State of the Union speech Tuesday night, according to a White House official. The spending freeze will save roughly $400 billion through 2015, according to White House estimates. "In areas outside the freeze, we also will be looking for cuts and efficiencies," a White House official said. ...Published about 8 years ago |
Obama Pledges Massive Overhaul of GovernmentIn addition to a five-year discretionary spending freeze, President Obama on Tuesday night announced a reorganization effort to consolidate duplicative federal programs and reduce government waste. Government hasn't undergone a major restructuring in decades, leaving agencies with overlapping responsibilities, the president said during his State of the Union address. Efforts to cut waste haven't gone far enough, and administration officials in ...Published about 8 years ago |
House votes to exempt TRICARE from health reform billHouse lawmakers over the weekend voted to protect TRICARE and Defense non-appropriated fund health care beneficiaries from unintended consequences of national health reform. The exemption (H.R. 4887) applies to the health care coverage provided by the Defense Department to military service members, retirees and their families. It clarifies the tax code to stipulate that coverage provided by Defense is treated as ...Published about 9 years ago |
State Turning to Contractors for Support in IraqThe State Department will have to hire thousands of contractors to provide security and logistical support as the U.S. military begins to withdraw from Iraq in 2011, according to new findings by a congressional commission. Within 18 months, U.S. troops are scheduled to depart Iraq. But, the difficult work of rebuilding the war-torn nation will continue, with most of the responsibility ...Published almost 9 years ago |
Senate approves debt ceiling increaseThe Senate Thursday passed legislation to increase the statutory debt limit to $14.3 trillion, a $1.9 trillion boost, after adopting a pay/go amendment requiring any mandatory spending increases or tax cuts to be offset. "We've gone to the restaurant; we've eaten the meal, and now the only question is whether we are going to pay the check," Senate Finance Committee Chairman ...Published about 9 years ago |
Transportation Department furloughs endFurloughs at the Department of Transportation have come to an end and employees are to return to work Wednesday. In a press release Tuesday evening, Transportation Secretary Ray LaHood said, "I am pleased that the Senate has acted to break its logjam and extend the Highway Trust Fund for another 30 days. This means that our valued employees may return to ...Published about 9 years ago |
Senator puts blanket hold on presidential nomineesSen. Richard Shelby, R-Ala., has placed a blanket hold on all executive nominations on the Senate calendar in an effort to win concessions from the Obama administration and Pentagon on a variety of fronts affecting his home state, according to aides to Senate Majority Leader Harry Reid, D-Nev. Reid spokeswoman Regan Lachapelle said Shelby is blocking more than 70 pending nominations. ...Published about 9 years ago |
Senate bill aims to boost small business contractingCivilian agencies might soon be required to set aside a percentage of funds from multiple-award, multiagency contracting vehicles for small businesses. The provision, included in the 2010 Small Business Contracting Improvements Act introduced by Sens. Mary Landrieu, D-La., and Olympia Snowe, R-Maine, on Thursday, would require agencies to reserve for small firms a yet undetermined portion of orders placed against federal ...Published about 9 years ago |
Bill calls for feds who owe taxes to be firedCongressman Jason Chaffetz wants federal employees who don't pay their taxes to be fired. The Republican from Utah introduced a bill Wednesday and will offer it as amendment to legislation focused on vendors Thursday during a markup by the House oversight and Government Reform Committee. "We have about 100,000 federal employees how are seriously delinquent and have tax debt that is ...Published about 9 years ago |
House passes bill to pay furloughed DoT workersRep. Gerry Connolly wants to make sure the 2,000 or so Transportation workers who were furloughed last week get paid. The Virginia Democrat introduced a bill Tuesday and the House passed it this morning to pay the employees for the two days they were off due to the lapse in the Highway Trust Fund legislation. President Obama signed into law a ...Published about 9 years ago |
Senator holds up bill compensating furloughed Transportation workersA Republican senator is holding up legislation that would prevent Transportation Department workers furloughed earlier this month from losing pay. Sen. Tom Coburn, R-Okla., said he is upset by the bill's funding mechanism. "Time and time again, Congress intentionally waits until the last minute to consider important legislation and then declares the billions of dollars in foreseeable costs as emergency spending ...Published about 9 years ago |
Officials Stress Nuclear Threat, U.S. Strength During SummitWASHINGTON, D.C. - A historic two-day nuclear summit is getting underway in Washington Monday, with the Obama administration stressing the urgency of the threat of nuclear terrorism and residents of the nation's capital bracing for potentially massive traffic disruptions due to motorcades, street closures and security checkpoints. Even as President Obama met Sunday with a succession of global leaders to discuss ...Published about 9 years ago |
Getting Back to Job Creation BasicsPresident Obama recently noted that, by itself, government cannot replace the 8.2 million jobs lost over the past two years. What government can do, he said, is "help to create the conditions" for renewed hiring. We couldn't agree more. The question is whether Congress will do what is needed. The job situation is dire. But Republicans have apparently decided that grandstanding ...Published about 9 years ago |

subset: commoncrawl


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- Store
- >
- Clothing & Footwear
- >
- Jackets
- >
- British Military Thermal Green Fleece with collar
British Military Thermal Green Fleece with collar
Genuine British Military Surplus Fleece Jacket, full zip up front, two zip hip pockets, thumb hooks in sleeves.
Zip Front with two front zip pockets.
Sized by height of wearer /chest width
Olive Green
Grade 1 Military Surplus
On Sale
On Sale
British Military Thermal Green Fleece with collar
Genuine British Military Surplus Fleece Jacket, full zip up front, two zip hip pockets, thumb hooks in sleeves.
Zip Front with two front zip pockets.
Sized by height of wearer /chest width
Olive Green
Grade 1 Military Surplus
On Sale
On Sale
Reversible Thermal Insulated Softie Jacket
Canadian Army Winter White Suit
Complete suit assembly, consisting of white over jacket and over trousers.
Former Canadian army issue, used condition. Some minor discoloration on grade 1. We will ship the best ones first. May have a pink decommission mark.
Designed to fit over winter parka so if you wear a large normally you should fit a medium.
Grade 2 - quite discolored
Canadian Forces ECW Parka
The Canadian Army Extreme Cold Weather (ECW) Parka is a serious jacket designed for the harsh Canadian winter conditions.
The ECW parkas have a removable liner and hood so the jacket can be worn to suit all weather conditions.
With large front pockets and pockets in the liner you can fit all needed gear into this jacket with room to spare!
Please note some models are the newer version with zip pockets and some are the older version without.
Use with the trousers ECW combat & the winter white suit for the ultimate cold weather combat gear.
Grade 1 - Good Used Condition
Grade 2 Used Condition - snaps are rusty, would probably need replacement, a small tear on the bottom right along the drawstring.
Canadian Military Flight Suit
Canadian Military Flight Suit. Olive Green. Would be great for coverall for paint balling, painting or just working in the garage. Used
Size is measured as height/chest in inches.
Grade 1 - Excellent Used Condition
Grade 2 - Some discoloration from the sun, may have a few minor holes, may have been repaired by a squaddie.
Grade 3 - Great for a coverall, worse condition than the grade 2
US ACU Combat Shirt
Brand new with tags, or excellent used condition.
US Army Woodland Shirt
Canadian Naval Combat Nomex Jacket
Excellent condition Canadian Naval Combat Jacket. Lightweight, black, two pockets.
Canadian Army Wet Weather Parka
Outer shell for wet weather, not insulated. Zipper front with velcro flap, two front pockets, drawstring hood. OD Green
Grade 1 used condition - probably a bit dirty
Grade 2 used condition - has some red/orange staining
Canadian Military IECS Combat Parka Liner
Grade 1 used condition
Medical Technician Jacket Liner
Size is height/chest in inches.
Grade 1 Excellent Used Condition
Canadian Forces Over Coat
100% Wool Shell
Liner is 100% Acetate exterior with 100% Polyester batting.


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Category : Project Management.
Topic : Online project management free software. Author : Brianne Bradford.
Posted : Sun, Feb 24th 2019 10:45 AM.
Format : jpg/jpeg.
A project is undertaken to meet a specific goal or requirement, within a specified time frame. For example, if you are planning a wedding you would want to use a project management methodology. This is because if certain things are not pulled together by the wedding day, proverbial heads are going to roll. A process, however, could be thought of as a repeatable group of activities and tasks that will be done over and over again. Making coffee would be a good example of a process. Coordinating everything to pull off a successful wedding, however, is a project.


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Asko Refrigerator Repair
When you have a Asko refrigerator chock full of groceries to last you weeks, it can be very disappointing if it breaks down. When that happens, you need a trustworthy and reliable repairman who can fix it fast so that your food does not go bad. We specialize in Asko refrigerator repair and for many years, we have been serving thousands of our clients to repair their refrigerators. Backed by a team of factory trained technicians, we are capable of repairing any Asko refrigerator.
We will get your Asko refrigerator fixed the first time and without any delays. This is because we have thousands of trained service technicians located nationwide who are constantly trained to be up to date with the very latest technology. And since they can access just about any type of repair parts, they are able to repair any Asko refrigerator. It does not matter where you bought it because our technicians will repair it regardless.
If you need Whittier refrigerator repair, you should not look further because we are just a click or a call away. Just pick up the phone and call us or email us to get a prompt reply. Our service crew is composed of a national network of Asko refrigerator repair experts. We guarantee your satisfaction. If you call us today and schedule a repair, you will have nothing to lose.
Refrigerator Repair Asko CA
We are an ISP (Independent Service Provider) for Asko refrigerators. Becoming an ISP requires that we, the repair service provider, must adhere to certain standards. Some of these are initial as well as ongoing training, ability to maintain and also provide evidence of liability insurance, valid driver's licenses, necessary state licensing as well as passing both background and drug tests. While all these might seem quite obvious for any appliance repair business, there are several companies out there that don't have the requisite training. Nonetheless, they continue to claim to be the best appliance repair company.
While Asko appliances have certainly come a long way, they still are not yet foolproof. For one reason or another, Asko refrigerators will become faulty and thus need to be repaired. Therefore, if you realize that your freezer needs some servicing, the best thing to do is not to diagnose it yourself. Instead, you can save a lot of money, time and headache by calling our expert technicians to attend to your refrigerator. Our technicians will get any job done, whether you want repairs to be carried out at your office or home.
Asko Refrigerator Repair
If you call and make an appointment with us, our technicians ensure that they call before arriving. The first thing that they do before beginning the work is to give you an estimate. We are not like many companies that carry out the work only to hit you with a shocking bill at the end of the month. We can only proceed with the work if we are sure that you are comfortable with our quote.
Perhaps the best thing about us is that we will fix your Asko refrigerator problem the first time. This not only saves you time but also money because the problem will be solved once and for all and you can continue using your refrigerator as before. Because our technicians are insured and fully bonded, we are able to guarantee our work.
There are several reasons why you should choose us ahead of other Asko refrigerator repair companies. For starters, we have trained technicians who are factory authorized, meaning that they can handle just about any Asko refrigerator. Our customer service is also one of the best in the industry. We respond within hours of being called and repair the refrigerator the first time. Lastly, we charge very competitive prices. We are also ISP approved. Before we do anything, we first give you an estimate of what the repair will cost you.


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© Copyright 2016 Sunny Maldives Holidays Limited, all rights reserved.New Request for Quote Site Map About Maldives Careers Admin Privacy Policy Terms And Conditions TOL
Choose a package you want to book.
Lets us know which package choosed to check the room availability.
Once the room availability is check we will hold the room for 01 hour.
Within 01 hour you should pay and secure the package.
** Please note price of package are subject to change without prior notice
Select any 8 packages you wish
Selected packages will be shown on the bottom of the page
Then you can view all selected packages to compare
You can select maximum 8 packages at a time


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A slew of recent polls on public opinion surrounding the fiscal cliff show an eagerness to compromise and broad support for President Obama's position in the negotiations.
Results out Wednesday from a Wall Street Journal/NBC News poll showed about two-thirds of the public would support a middle position that includes Democratic demands to raise taxes on the nation's top earners, along with Republican demands for reductions to spending on Medicare and other entitlement programs.
Allowing tax rates to rise on the wealthy was especially popular, the poll showed, with more than 3 out of 4 of the 1,000 adults surveyed supporting the idea to solve the fiscal cliff, including 61% of Republicans.
The Wall Street Journal noted a sharp shift toward the general principle of compromise among Republicans in particular, with 61% now favoring giving some ground on budget matters compared to just 38% back in April.
When the president and House Republicans were compared head-to-head, the advantage appeared to be Obama's. Read more on WSJ/NBC poll on fiscal-cliff opinions.
A survey produced for ABC by Langer Research Associates, also reported Wednesday, had 49% approving of Obama's handling of the fiscal-cliff talks, while 42% disapproved. For Republican House Speaker John Boehner, only 25% approved, while 49% disapproved.
A Bloomberg National Poll, also covering 1,000 adults, had 64% saying Obama's re-election gave him a mandate to protect Social Security from "substantial budget cuts" and 62% saying the same in terms of preventing "fundamental change" in Medicare.
Should the parties fail to get a deal, the Wall Street Journal/NBC News survey said slightly more people would blame the Republicans than would blame the president, although a 56% majority would blame both.
— Michael Kitchen
Follow The Tell blog on Twitter @thetellblog


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STANDARDS FOR USE OF TECHNOLOGY IN GENEALOGICAL RESEARCH recommended by the National Genealogical Society; from The Computer Genealogist, a publication of The New England Historic Genealogical society March/April 1998, p. 14.
Mindful that computers are tools, genealogists take full responsibility for the results of their work, and therefor they --
+ learn the capabilities and limits of their equipment and software and use them only when they are the most appropriate tools for the purpose.
+ refuse to let computer software automatically embellish their work.
+ treat compiled information from online sources or digital databases like that from other published sources: useful primarily as a guide to locating original records, but not as evidence for a conclusion or assertion.
+ accept digital images or enhancements of an original record as a satisfactory substitute for the original only when there is reasonable assurance that the image accurately reproduces the unaltered original.
+ cite sources for data obtained online or from digital media with the same care that is appropriate for sources on paper and other traditional media and enter data into a digital database only when its source can remain associated with it.
+ always cite the sources for information or data posted online or sent to others, naming the author of a digital file as its immediate source, while crediting original sources cited within the file.
+ preserve the integrity of their own databases by evaluating the reliability of downloaded data before incorporating it into their own files.
+ provide, whenever they alter data received in digital form, a description of the change that will accompany the altered data whenever it is shared with others.
+ actively oppose the proliferation of error, rumor and fraud by personally verifying or correcting information, or noting it is unverified, before passing it on to others.
+ treat people online as courteously and civilly as they would treat them face-to-face, not separated by networks and anonymity.
+ accept that technology has not changed the principles of genealogical research, only some of the procedures.
Copyright 1997 by National Genealogical Society. Permission is granted to copy or publish this material, provided it is reproduced in its entirety, including this notice.
Return to Jefferson County NYGenWeb page
Return to Jefferson County Tidbits page
Copyright 2016 Jefferson County NYGenWeb — a member of the NYGenWeb Project
If you have any questions or comments about this page, please contact,
County Co-Coordinator Nancy Dixon or
Co-Coordinator Bruce Coyne.
Return to Jefferson County Genweb Page


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2017 ISI National Event Descriptions
General information is listed below for each event to be offered at our 2017 ISI national competition events.
Due to ice and time limitations, not every event will be offered at every competition. Please refer to the individual competition entry form for each competition to find out which events are offered for that particular competition.
Please refer to the current 2016 edition of the ISI Handbook for more complete event details and performance guidelines.
Skaters perform a program to music with emphasis on strong edges, flow, choreography, innovative moves and musical interpretation. There is no score for technical ability in this event. Event level is based on skater's freestyle test level.
Maneuver Limitations
Freestyle 1-3 / Bronze
FS4 and below
1.5 min.
Freestyle 4-5 / Silver
FS6 and below
1.5 min
Freestyle 6-7 / Gold
FS 8 & below
2 min
Freestyle 8-10 / Platinum
Any maneuvers
2 min
COUPLES 1-10 – Similar / Mixed
Two skaters perform their routine to music that requires maneuvers from their current Couples test level. This event is like a Freestyle skating program by two skaters in unison. Both skaters must pass the required Couples Test to compete in this event.
COUPLES SPOTLIGHT – Low / Bronze / Silver / Gold / Platinum
An entertaining spotlight program performed by two skaters using costumes and props. Couples will also be divided into Character / Dramatic / Light Entertainment categories so please mark the correct category box on your entry form.
Maneuver Limitations
Tot – Delta
FS1 and below
1 min
Freestyle 1-3 / Bronze
FS4 and below
1.5 min.
Freestyle 4-5 / Silver
FS6 and below
1.5 min
Freestyle 6-7 / Gold
FS8 and below
2 min
Freestyle 8-10 Platinum
Any maneuvers
2 min
DANCE 1-10 – Solo & Partner Dance – Similar / Mixed / Pro Partner
This is the skater's version of Ballroom Dancing. Test levels begin with basic steps and patterns, and then advance to a high performance level. All skaters must pass the required dance tests to compete in these events. Ice Dancing can be enjoyed at any age or level. Skaters are not required to pass the Delta test to participate in Ice Dance events. Skaters are no longer required to pass the entire dance test for the next higher level before competing individual dances from that next higher level that have already been passed.
For ISI national events, all dancers can choose to compete in any or all dances from their highest completed test level. A separate event entry fee is required for each dance selected.
Professionals and their students can compete together in the Pro Partner dance events at the student's current Ice Dance test level. The Professional must be a current ISI Professional member, but does not have to pay any entry fees for that event. The professional will not receive any medal for Pro Partner dance event participation.
This event is open to groups of 3-7 skaters of all levels and ages. Skaters will be judged on the performance value of the program. There are no required maneuvers, no maneuver limitations and there is no technical score for this event. The group should use music, costumes & props to enhance the theme while creating an entertaining performance. The costume & prop guidelines are the same as for Solo Spotlight events. Props are not allowed on warm-up. Event groups are divided by number of skaters first and then by age, if necessary. Duration: 3 minutes
FAMILY SPOTLIGHT (All Levels)
Two or more family members can perform an entertaining spotlight routine using costumes & props. If necessary, the event groupings are divided first by number of skaters and then by age groups and/or ability levels. Duration: 1.5 minutes
Regular figures are based on the original "school" figure eights. Skaters perform a required figure patterns 3 times on each foot. Judging is based on the size & shape of the circles, cleanliness of edges & pattern. All skaters must pass the required figure test to compete in these events.
Refer to the 2016 ISI Handbook for description of Creative Figure 1-10 and Free Figure 1-10 events.
|Figure 1
|Forward Outside Waltz Eight
|Figure 2
|Backward Outside Eight
|Figure 3
|Backward Inside Eight
|Figure 4
|Forward Outside Loop
|Figure 5
|Left Forward Inside Bracket
|Figure 6
|LFO Change Loop
|Figure 7
|LFO Paragraph Three
|Figure 8
|LFO Rocker
|Figure 9
|LBO Paragraph Double Three
|Figure 10
|The Flower
Freestyle skaters perform a one-minute program to music using various turns and connecting steps with limited jumps or spins. Skaters are judged on correct turns & edges as well as flow, variety of moves and choreography. Duration: 1 minute
The new ISI Free Dance events are based on the new Free Dance test levels (1-10). Each couple must pass the corresponding test level to compete in Free Dance events. For the competition event, each couple must perform a free dance program of their own design. It should express the couple's inspirational and artistic capabilities.
A program performed to music with emphasis on the required test level maneuvers from the skater's current Freestyle level. Various skills are required, depending on the test level. All skaters must pass freestyle test level to compete in this event.
Special Discounted Entry Fee for Freestyle Synchro events at 2017 national events!
Three to seven skaters from the same Freestyle level can enter this new form of group skating. They must perform the same identical Freestyle program in unison. All test level requirements must be included. All skaters must have passed the same freestyle test level to compete in this event. Skaters cannot skate above or below their freestyle test level.
Hockey Goalie
After a short warm-up, a designated shooter will attempt 10 shots on each goalie; five will be of the slap shot variety taken from inside the blue line, and five will be of the one-on-one variety where the shooter picks up the puch on the blue line and skates in on the oalie from any direction in an attempt to score. If the goalie catches or smothers the puck, play will stop. If a rebound comes out in front of the goad line, it is still playable and the shooter can take another shot. Goalies will be awarded one point for each save. No rebounds will be permitted on slap shots.
If a goalie is "against the book" (with no other competitors in their age group, they must stop 80% - or 8 out of the 10 shots - to receive 1st Place. For less than 8 saves, the goalie will receive 2nd Place.
Hockey Shooting
The skater will carry the puck on the stick while skating from one end of the rink to the other around a 4-cone course and will then skate toward the net and take a shot on goal. This is a timed event and the time will stop when the puck enters the net. The skater can shoot anytime after the 4th cone, but if they miss, they must get the puck and get it into the goal to stop the timing. The skater with the fastest time in that event group wins.
Hockey Skating
Skaters will race one or two at a time skating one forward lap around the rink carrying the puck on the stick. After completing the forward lap, the skater will drop the puck, keep the stick and skate another lap around the rink backwards. The skater with the fastest time in that event group wins.
There will be a short warm-up for each hockey event.
INTERPRETIVE 1-10 (Freestyle Levels Only)
Special Discounted Entry Fee for Interpretive events at 2017 national events!
Freestyle level skaters will hear a piece of music once off the ice; twice during the group warm-up; and once more before competing while they mentally choreograph a skating routine – with no help from friends, parents or coaches. The emphasis is on the skater's ability to choreograph an entertaining skating routine to music and not on the difficulty of the skating maneuvers performed.
For most national events, we will use a two-panel (A/B) format. Skaters will wear colored numbers during this event for easy identification by the Judges. There will be 2 skaters competing simultaneously on full ice. Those 2 skaters will not be competing against each other in the same group. One skater will be from Panel A and one from Panel B.
Forward spirals are allowed at all levels, but NO BACKWARD SPIRALS are allowed in this event at any level for the safety of all competitors - if the 2-panel format is used.
Maneuver Limitations
Freestyle 1-3 / Bronze
FS4 and below
Freestyle 4-5 / Silver
FS6 and below
Freestyle 6-7 / Gold
FS8 and below
Freestyle 8-10 / Platinum
Any maneuvers
Special Discounted Entry Fee for Jump & Spin events at 2017 national events!
Two skaters enter the ice as a team. The first skater performs their choice of a required jump 2 times, followed by the second skater performing their choice of a required spin 2 times. Only the best attempt of each required element will be judged. Only the technical accuracy of the required element is judged – the difficulty of the chosen element is not considered during judging for this event.
ALL JUMP & SPIN EVENTS will be done on ½ ICE ONLY.
Category Levels:
Both skaters must be in Pre-Alpha to Delta levels only.
Both skaters must be in Freestyle 1-3 / Bronze levels or below.
Both skaters must be in Freestyle 4-5 / Silver levels or below.
Both skaters must be in Freestyle 6-7 / Gold levels or below.
Both skaters must be in Freestyle 8-10 / Platinum levels or below.
If two skaters from different category levels wish to compete together, the team will be entered in the highest level of the two skaters.
Required Elements:
2-Foot Hop or Bunny Hop
2-Foot Spin
½ Flip or Toe Loop
2-Foot or 1-Foot Spin
½ Loop or Axel
Sit Spin or Back Spin
Dbl. Salchow or Dbl. Toe Loop
Layback or Flying Camel
Dbl. Loop or Dbl. Lutz
Flying Sit or Camel-Jump-Camel
KALEIDOSKATE (All Levels)
A group of 8 or more skaters perform a fun and entertaining group number. Minimal skating skills are required for this event. Each skater represents a piece of color – and those color pieces are used to choreograph and create constantly changing patterns, designs and formations on the ice. Creativity, use of color and props are also an important part of the overall "design".
Click here for more information and level details, or refer to the 2016 ISI Handbook.
OPEN PAIR - Bronze, Silver, Gold & Platinum
Open Pair event judging criteria includes: Correctness of Jumps, Correctness of Spins, Correctness of Turns & Edges, Variety of Moves, Music Interpretation, Posture, Choreography & Pattern, Presentation, Duration and General Overall (by all 3 judges).
Together two skaters perform a choreographed routine to music. This program should include all the required maneuvers from their current Pair test level. The event is similar to Couples. However, unlike Couples, Pairs includes pair lifts and pair spins. Both skaters must pass the required Pair Test to compete in this event.
PATTERN SKATING (Delta level and above)
This unique form of group skating is done by at least 4 people. Working off a common circle, skaters "draw" patterns, formations, and designs on the ice to music. The skaters skate in unison, all doing the same thing at the same time, each in their own area of the pattern. All kinds of maneuvers can be performed i.e. jumps / spins / footwork / spirals / etc. as long as the circular symmetry is predominantly evident throughout the routine.
Skater performs a one-minute program routine to music that emphasizes the required test level maneuvers from Pre-Alpha through Delta. Depending on each test level requirement, specific skating skills must be performed. All skaters must pass the Pre-Alpha – Delta test to compete in this event. Skaters must include one maneuver from Freestyle 1 in their program.
PRODUCTION TEAM (All Levels)
This team event is for groups of 8 or more skaters. Team will be judged on the performance value of the program. There are no required maneuvers and no technical score for this event. The group should use music along with elaborate costumes and props to enhance the theme while creating an entertaining performance. Skaters from all levels can participate in this event. Event entries will be divided in to Small / Medium / Large / Extravaganza categories, as registration warrants.
This new entertaining event requires the use of one hand-held prop listed below. The program should contain elements that employ the use of the prop throughout the routine. The skater must maintain control of the prop at all times. Props of the same kind (i.e. Ball / Hoop / Ribbon) must be grouped together and cannot be combined for competition event groups.
The skater chooses only one rhythmic prop per routine (ball, hoop or ribbon) and must maintain control of the prop at all times throughout the program. This means the prop must be used by the skater throughout the routine. It can be thrown, bounced or juggled but control should be maintained. The prop should not be put down on the ice while the skater does jumps & spins. No additional props are permitted.
Props are not allowed on the event warm-up. If it is obvious that skater's prop does not meet the following specifications, the panel Referee can determine if any point deduction should be taken.
Choice of One:
1. Hoop - Must be made from wood or plastic (from a rigid, non-bending material). The hoop diameter should measure between 2 feet 7 inches - 2 feet 11 inches. The hoop can have colored tap or fabric to match or contrast the skater's costume, but it cannot have any other decoration (i.e. fringe, lights, etc.) on the prop.
2. Ball - Must be made of rubber or plastic. The ball diameter should measure approximately 7-3/4 inches. The ball must be smooth (without any texture).
3. Ribbon - Stick must be made of wood, plastic or fiberglass. Stick length should be between 20-30 inches. Ribbon material must be one single piece of satin or a non-starched fabric. Ribbon width should be 2-4 inches wide and between 6 feet - 9 feet long - proportional to the size and ability level of the skater.
Maneuver Limitations
Freestyle 1-3 / Bronze
FS4 and below
1.5 min.
Freestyle 4-5 / Silver
FS6 and below
1.5 min
Freestyle 6-7 / Gold
FS8 and below
2 min
Freestyle 8-10 / Platinum
Any maneuvers
2 min
SOLO COMPULSORIES (Pre-Alpha – Freestyle 10 and Special Skater 1-10)
Special Discounted Entry Fee for Solo Compulsories events at 2017 national events!
Skaters are to perform only the three maneuvers selected by the competition director in any order with a minimum of connecting steps. Each maneuver may only be attempted one time. Additional maneuvers, such as any jump, spin, or gliding maneuver from a test level or any uncaptured move are not allowed. There is a 1-minute time limit for all levels.
Please Note: There is no penalty given for the quantity of swizzles, wiggles, strokes or crossovers in the Pre-Alpha, Alpha and Beta levels. Only the quality of these maneuvers should be comparatively judged.
Pre-Alpha – Freestyle 5 will be done on ½ ICE ONLY.
Freestyle 6 – 10 will be done on FULL ICE.
|Forward Swizzles / 2-Foot Glide / Backward Wiggles
|Forward Stroking / Left over Right Forward Crossovers / 1-Foot Snowplow Stop
|Backward Stroking / Left over Right Backward Crossovers / Left T-Stop
|RFI Mohawk Combo / LFI Mohawk Combo, / Hockey Stop
|Delta RFI Three-turn / LFI Three turn / Bunny Hop
|Freestyle 1
|Waltz jump / 2-foot spin / Forward Arabesque
|Freestyle 2
|Dance Step / 1-foot spin / ½ Lutz jump
|Freestyle 3
|Toe Loop jump / Change Foot Spin / Dance Step
|Freestyle 4
|Flip jump / Sit Spin / ½ Loop jump
|Freestyle 5
|Camel / Axel / Back spin
|Freestyle 6
|Double Salchow / Choice spin (Cross-foot/Layback/Sit-Change-Sit) / Split Falling Leaf
|Freestyle 7
|Two Walley jumps / Flying Camel spin / Double Toe Loop jump
|Freestyle 8
|Double Flip jump / Flying Sit Spin / Split Lutz
|Freestyle 9
|Double Lutz jump / Flying Camel into Jump Sit spin / Axel-Double Loop jump combination
|Freestyle 10
|Double Axel-Double Toe Loop combo / Death Drop / 3 Arabian Cartwheel or Butterflies
|Special Skater 1
|Fall, Get Up, March in Place
|Special Skater 2
|Forward Swizzle, 2-Foot glide, Teapot Dip
|Special Skater 3
|Forward Swizzles, Scooter Push (L or R), Backward Wiggles
|Special Skater 4
|T- Position Push, 1-Foot Swizzles (L or R), Forward Crossovers Standing Still
|Special Skater 5
|Forward Stroking, Snowplow stop, R/L Forward Crossovers
|Special Skater 6
|2-Foot Turn Fwd to Bkwd, Fwd 1-Foot Glides on a Curve, L 1-Foot Bkwd Swizzles
|Special Skater 7
|Backward Stroking, Choice of Stop, L/R Backward crossovers
|Special Skater 8
|RFI Mohawk, LFI Mohawk, RBO Edge on a Curve
|Special Skater 9
|RFO Three turn, LFO Three Turn, Choice of Stop
|Special Skater 10
|Bunny Hop, Lunge, LFI Three Turn
This category is open to skaters of all ages with physical or mental disabilities. Skaters will perform a program to music for 1 minute that includes all of the compulsory maneuvers from their test level. Skaters will be grouped by age, gender, and disability classification. The Special Skater event is based on the ISI Special Skater test levels 1-10. These tests must be registered with the ISI national office.
Above the Special Skater 10 (Delta) level, Special Skaters can take and pass the test levels in Freestyle, Figures, Couples, Pairs, Dance and Free Dance so they are eligible to compete in those events – along with Artistic, Footwork, Interpretive, etc. If requested, the Competition Director can put special skaters into a separate event group for those events.
SPOTLIGHT SOLO PROGRAM (All Levels)
This is an entertaining & "fun" routine that emphasizes the skater's acting ability and not technical skating skills. There is no score for technical merit in this event. The skater must pass a test for Tots, Pre-Alpha to Delta or Freestyle to determine the spotlight event level.
Spotlight events are divided into three categories listed below. Please mark the correct category on your entry form.
a) CHARACTER – a famous or easily identifiable character.
b) DRAMATIC – a theatrical performance that sets a mood and evokes an emotional response.
c) LIGHT ENTERTAINMENT – an entertaining or light-hearted performance.
Maneuver Limitations
Tot & Pre-Alpha – Delta
FS1 and below
1 min
Freestyle 1-3 / Bronze
FS4 and below
1.5 min.
Freestyle 4-5 / Silver
FS6 and below
1.5 min
Freestyle 6-7 / Gold
FS8 and below
2 min
Freestyle 8-10 / Platinum
Any maneuvers
2 min
STROKING (Alpha – Delta Only)
Skaters compete together in groups wearing colored numbers for easy identification by the Judges. They do only forward stroking in both directions and are judged on posture and correct stroking technique. Crossovers are optional at the end of the rink, but not required and not judged. This is the very basic skill of skating.
SYNCHRONIZED COMPULSORIES – Formation / Skating
Synchronized Formation and Skating teams must perform 4 or 5 required elements to music, with no additional moves permitted. Teams will be divided by age groups. For details of compulsory maneuvers and program duration limitations, please see the current 2016 edition of the ISI Handbook
SYNCHRONIZED TEAM - Dance / Formation / Skating
This is a group number for 8 or more skaters to perform in unison. They can incorporate various skating formations such as circles, pinwheels, lines, footwork sequences and dance steps. For complete description of Formation, Skating, and Dance categories, please see 2016 edition of ISI Handbook.
TEAM COMPULSORIES 1-10 (Freestyle Levels Only)
Six skaters (or seven skaters for FS6-10 levels) perform a lively and entertaining routine in which each skater performs one required test level maneuver (in the order listed in the 2017 edition of the ISI Handbook). Lively music with entertaining themes, great costumes and hand-held props are featured in this event. Skaters can compete on more than one team as long as those two teams are in different freestyle levels. Skater may skate above, but not below their own freestyle test level.
TEAM SURPRISE (All Levels) – DISCOUNTED EVENT FOR 2017!
Special Discounted Entry Fee for Team Surprise events at 2017 national events!
This is a new "team" version of Surprise events. Each team must have 4 skaters from the same category level (listed below). Each skater may only participate on one team. Skaters under 6 years are not permitted to compete in Team Surprise events. Teams can be made up of all males, all females, or any combination – as long as the resulting test level category is the same for ALL TEAM MEMBERS. Entries will be divided into competition groups based on the average age and/or test levels of all 4 team members.
Category Levels:
Low ALL team skaters must be in Pre-Alpha to Delta levels only.
Medium ALL team skaters must be in Freestyle 1-3 / Bronze levels & below.
Intermediate ALL team skaters must be in Freestyle 4-5 / Silver levels & below.
High ALL team skaters must be in Freestyle 6-10 / Gold / Platinum levels & below.
Skaters may skate in a higher team category than their current test level – but not in a lower team category. If entries are received with a team of skaters from different category levels, the team will be entered into the level of the highest skater.
These team "surprises" will be a relay-type event where every member of the team must complete a required task. Some events might be related to skating ability – and some may not – SO GRAB YOUR FRIENDS AND JOIN THE FUN ! ! !
This new production event is for your entire skating team. Skaters of all ages and advanced ability level can participate in this theatrical team event. This is a creative and artistic program usually based on a story or theme, using costumes, props and technical skating to enhance the production performance.
THEMED COUPLES SPOTLIGHT / THEMED PRODUCTION / THEMED SOLO SPOTLIGHT (All Levels)
These events will use the same guidelines as for regular Couples Spotlight, Production teams & Solo Spotlight events regarding levels, maneuver limitations, duration, and costume/prop restrictions. All programs in this event category must be related to this national event theme for 2017.
The theme chosen for our 2017 National events is "Out of this World" ... May the force be with you as you prepare your tribute to all things space related.
Tots (skaters age 6 and under) will perform a 1-minute program routine with music. They should only perform the required maneuvers from their test level. Additional maneuvers should not be included and will not be judged. 2-foot and/or 1-foot snowplow stops are permitted in Tot events. All Tot competitors must have their test registered with ISI to enter Tot competition events. Coaches will be allowed to help the skater from the ice door but will not be permitted on the ice during the national competition events.


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After an interesting list of Hollywood Celebrities Without Makeup, I thought of creating a post for our Bollywood Divas. I've always been mesmerized by their gorgeous skin and makeup but comparing their before and after makeup pictures makes me wonder… I think I should hire a Pro Makeup Artist or Brush Up my makeup skills. 😛 Jokes apart, I think …Read More »
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text:
Brianmoran01 needed a new logo design and created a contest on 99designs.
A winner was selected from 59 designs submitted by 16 freelance designers.
Koolstreet at http://koolstreet.com
I am the owner of Koolstreet, LLC. Our company sells vacation giveaway promotions and coupons to very large companies.
I am targeting large US based companies in the travel, sales, casino, and wedding industry. These customers are very corporate in nature and appreciate clean professional design.
I want a clean professional logo with our company's name "Koolstreet" in it. Our slogan can also be included. I have attached an image of the desired text and possible color scheme. Feel free to experiment with colors and design. If we can include a vacation or travel theme into the design that would be great because that is what we sell promotions for. The other design approach would be for digital marketing, business to business, and social media as that sums up our company as well.
Be creative :)
Find out how a design contest works or learn more about our logo design services.