Bulletin of Experimental Treatments for AIDS, No. 28; March, 1996
Mark Bowers, Managing Editor of Treatment Publications and a member of the Scientific Advisory Committee of the San Francisco AIDS Foundation.

Abbott Laboratories' large-scale clinical study of ritonavir tried to replicate the real-life situations in which the drug would potentially be used. Either 600 mg of ritonavir or placebo was given to participants twice daily in addition to their current nucleoside analog therapy. Thirteen percent (13%) of the 543 volunteers who received ritonavir died or experienced disease progression, compared with 27% of the 547 volunteers who received placebo. The mortality rates were 4.8% for the ritonavir group and 8.4% for the placebo group. See Mary Romeyn's review of the 3rd Conference on Retroviruses and Opportunistic Infections in this issue.

* Gore Meets Pharmaceutical Firms and Government Researchers On February 20, 1996, Vice President Al Gore met with representatives from 11 pharmaceutical companies, leading AIDS researchers and officials from the National Institutes of Health (NIH), the Department of Defense and the Food and Drug Administration (FDA). The agenda included AIDS vaccine development, therapeutics and microbicides. This was the meeting that was promised as a follow-up to the December 1995 White House Conference on HIV and AIDS. Gore promised the following:

- The Clinton Administration will work with international organizations such as the World Bank to increase investment in AIDS vaccine development and trials worldwide;

- The Administration will help facilitate the development of microbicides to enable women to protect themselves from HIV infection;

- The Vice President will facilitate ongoing discussions between the government and the pharmaceutical industry to identify promising areas of AIDS research that the government can support in order to stimulate private sector investment in the next generation of AIDS vaccines, therapeutics and microbicides;

- FDA will pursue additional measures to increase the number of anti-HIV therapeutics with pediatric indications.

* Generic AZT Prevented from Entering Market The U.S. Supreme Court refused to hear a case challenging the patent on AZT, the most widely used antiretroviral drug, thus preventing cheaper generic versions from being marketed. Burroughs-Wellcome, recently acquired by Glaxo, retains exclusive right of sale in the United States through the patent it has held since 1987. Generic AZT, at about one-half the price of the Glaxo product, is available in Canada and elsewhere.

* Baboon Cell Transfer On December 14, 1995, Jeff Getty became the first person ever to receive a bone marrow transplant from another species. Steven Deeks, MD, of San Francisco General Hospital, and Suzanne Ildstad, MD, of the University of Pennsylvania, prepared Getty with partial radiation therapy to remove any immune cells that might compete with the transplant. He then received stem cells and facilitator cells from a healthy baboon. The stem cells were expected to produce new T-lymphocytes that would be resistant to HIV infection; baboon T-lymphoctyes are not susceptible to infection with HIV. The new baboon-derived T-cells were expected to engraft (learn to adapt to a human environment) and begin to fight infections.

By February 1996, Getty was feeling better than he had for months. However, Deeks and Ildstad were unable to find signs that the baboon marrow had engrafted. Getty said that researchers looked twice for baboon DNA using polymerase chain reaction (PCR) tests, but found none one time and only a small amount the next. Nonetheless, Getty's CD4 cell counts returned to 1992 levels. Researchers now speculate that the radiation therapy that Getty received before the transplant accounts for his improved health. In the past, French researchers have used immunosuppressive steroids to treat people with AIDS with some limited success. The destruction of immune cells by radiation may have only partly accounted for Getty's improvement. He also has been on a triple combination antiviral regimen, which includes 3TC, AZT and the protease inhibitor indinavir (Crixivan).

Although the baboon cells apparently did not engraft, Getty is pleased and relieved that the transplant procedure proved to be safe and paves the way for future intriguing research. There are plans for another baboon bone marrow transplant, and interest in exploring the positive effects of the combination of radiation therapy and antiviral drugs in people with advanced HIV disease.

* Gene Therapy Recommendations The National Institutes of Health (NIH) regulates gene therapy research through the Recombinant DNA Advisory Committee (RAC). In 1995, NIH Director Harold Varmus, MD, appointed 2 advisory panels to assess NIH investment in gene therapy and examine the work of the RAC. The first panel, co-chaired by Arno Motulsky, MD, from the University of Washington in Seattle and Stuart Orkin, MD, from Harvard Medical School, reported their findings to Varmus on December 7, 1995. Their assessment is that gene therapy has been over-optimistically reported, and that it is still too early to expect clinical miracles from this fledgling area of research. None of the 100 protocols or 600 patents approved by the RAC have proven efficacy in humans so far. NIH allocates about $135 million to extramural and $61 million to intramural gene therapy research, while private industry invests about $200 million. The Motulsky-Orkin panel does not take issue with the amount spent, but wants the priorities to reflect the need to develop better gene transfer technology and animal models. Many studies have been hindered by an inability to effectively place desired genes into their target cells. More basic research also needs to be focused on the mechanisms of acquired and inborn genetic diseases, according to the report.

The second panel looked specifically at the scope of the authority of the RAC: should this body only evaluate the safety of proposed gene therapy protocols, or should it also evaluate the science behind the proposals for research? Can the RAC effectively do one without the other? Francis Collins, MD, Director of the National Center for Human Genome Research, thinks that the RAC could do both. Expanded authority for the RAC would place the discussions of the comparative merit of proposed gene therapy protocols in the public eye, since the deliberations of the RAC are conducted in public. Such discussions would possibly begin to temper the popular impression that gene therapy for HIV/AIDS and other life-threatening diseases is just around the corner, and would allow for steady, safe and rational development of the field.

Both reports agree that human gene therapy will eventually be a success, but it is now in a difficult stage of development. Effective technologies are being developed, and even disappointing clinical results do not mean that gene therapy is a failure.

* Viral Genetics Important in Long-Term Nonprogressors Science magazine reported in November on an Australian man, and 6 people who were infected with HIV through blood or blood products that he had donated. All of these individuals continue to have high CD4 cell counts and no symptoms of HIV disease after 10-14 years of infection. Researchers looked at the viral sequence of the strain of HIV that is common to all 7 people, and found that the nef gene had 3 deletions, with 2 more deletions in an area where the nef gene overlaps the long terminal repeat region. These researchers concluded that disease progression can be determined by the HIV genome. The intriguing possibility of crafting an effective attenuated HIV vaccine has also been raised.

* Ganciclovir is an Effective CMV Prophylaxis Drug The results from Syntex study 1654, reported at the 3rd Conference on Retroviruses and Opportunistic Infections, support the use of oral ganciclovir (Cytovene) in the prevention of primary cytomegalovirus (CMV) retinitis. The study confirms preliminary data presented at the 35th Interscience Conference on Antimicrobial Agents and Chemotherapy last September. In October, FDA approved oral ganciclovir for the prevention of CMV disease in persons with advanced HIV infection, based on the final analyses of Syntex 1654. The study randomized 486 volunteers to oral ganciclovir and 239 to placebo. Final data demonstrated a 49% risk reduction in the development of CMV disease compared to placebo.

Concerns about the development of resistance to ganciclovir because of the use of the drug for prophylaxis were allayed. Larry Drew, MD, of the University of California at San Francisco reported that in vitro testing of 40 CMV-culture isolates from urine showed less than 1% resistance after prophylaxis for a mean duration of 8.3 months (251 days).

* Doxil Approved for Treatment of KS On February 15, 1996, Sequus Pharmaceuticals announced that FDA and similar approval agencies in 15 European countries have approved the sale of liposomal doxorubicin (Doxil) for the treatment of Kaposi s sarcoma, a cancerous condition that affects 10-12% of people with AIDS in the United States. In the U.S., Doxil is indicated for patients whose disease has progressed despite prior combination therapy; in Europe, physicians may choose Doxil as a first-line therapy. Sequus employs a unique strategy (stealth technology) that helps the drug evade detection by the immune system longer than other approved chemotherapy drugs, and it remains in the body long enough to seek out and destroy cancer cells. The drug is concealed in a liposome (fat coating), then further coated in polyethelene glycol, an ingredient found in antifreeze. See Harvey Bartnof's in-depth article on Kaposi's sarcoma, this issue.

* New Preventive Vaccine Study The AIDS Vaccine Evaluation Group (AVEG) at the NIH has approved the initiation of a study of a new genetically engineered HIV vaccine in 140 volunteers at 6 sites in the U.S. The vaccine is the result of a collaboration between Pasteur MÄrieux/Connaught Laboratories in Paris, France, and BIOCINE Company in Emeryville, California. The vector for the vaccine is a canarypox virus, large enough to accommodate several HIV genes as well as the surface protein gp120 that has been the hallmark of many previous vaccine candidates. This vaccine candidate is unique in that it contains HIV core regulatory proteins that may spur a more vigorous and broader anti-HIV immune response in vaccinated volunteers. HIV negative men and women between the ages of 18 and 60 will receive either vaccine or placebo vaccinations over a 9-month period, and will be followed for over 1 year. Study sites are in St. Louis, MO; Rochester, NY; Seattle, WA; Nashville, TN; Birmingham, AL; and Baltimore, MD. Call the Center for Vaccine Development at (314) 268-5448 for further information.

* Chiron's Eye Implant Device Is Approved for CMV Retinitis The U.S. Food and Drug Administration (FDA) gave approval on March 5 to Chiron Vision to begin marketing a device that is implanted in the eyes of people with cytomegalovirus (CMV) retinitis. The device, called Vitrasert, was approved for use in combination with ganciclovir, an antiviral drug already approved for preventing or treating CMV disease. Ganciclovir, made by Hoffmann-La Roche and marketed under the name Cytovene, is available in oral and intravenous formulations. The Vitrasert device is surgically implanted in the eye to provide continuous delivery of ganciclovir to the vitreous fluid for up to 6 months. Vitrasert will sell for about $4,000 per implant.

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