|
|
Published in the Bulletin of Experimental Treatments for AIDS March 1997 issue, by the San Francisco AIDS Foundation. |
News Briefsby Ronald Baker, PhD, and Mark Bowers Nelfinavir (Viracept)By mid-March 1997, the Food and Drug Administration (FDA) is expected to grant accelerated approval for nelfinavir (Viracept), the new protease inhibitor drug from Agouron Pharmaceuticals. The drug should become available in pharmacies shortly after the FDA approval announcement. Nelfinavir is a potent inhibitor of HIV replication. In a recent study, after 24 weeks, the triple combination of nelfinavir/AZT/3TC produced undetectable viral load levels among 81% of previously untreated patients, and increased median CD4 cell counts by 160 cells/mm3. In a 12-week study of 22 patients taking the 3-drug combination of nelfinavir/d4T/ddI, the median CD4 count increased by 200 cells/mm3. Diarrhea is the most common adverse side effect associated with nelfinavir use, but appears manageable using anti-diarrheal medications. Agouron has developed and tested a pediatric formulation of nelfinavir, and has requested FDA accelerated approval of the drug for use in both children and adults. Nelfinavir will become the first protease inhibitor available to infants and children. An expanded-access program offers the drug free to children between the ages of 2 and 13. The pediatric formulation is a powder that can be mixed in milk, formula or soft foods. The dose is 20-25 mg/kg 3 times daily. For further information, physicians and parents may call 1-800-621-7111, Monday through Friday from 8 a.m. to 6 p.m. EST. Perhaps the greatest advantage of nelfinavir is that initial resistance to the drug does not necessarily confer cross-resistance to the other protease inhibitors. HIV that is resistant to nelfinavir remains sensitive to indinavir, ritonavir, saquinavir and 141 (the new protease inhibitor drug from Glaxo Wellcome), according to Agouron. This favorable resistance profile offers a compelling reason to use nelfinavir first (as part of a 3-drug combination), before the other protease inhibitors. If the regimen fails due to the development of HIV resistance to nelfinavir, patients would still have the option to switch to other protease in-hibitors. Nelfinavir is also effective against AZT-resistant HIV. 141 (Vertex-478)141 is a second generation protease inhibitor designed by Vertex Pharmaceuticals and licensed for development to Glaxo Wellcome, Inc. A series of Phase II studies is ongoing to test 141 in combination with either AZT/3TC or 1592 (a new nucleoside analog from Glaxo Wellcome) or other protease inhibitors. Earlier Phase II testing showed that HIV resistance to 141 does not develop during 4 weeks of monotherapy, an encouraging sign that this new protease inhibitor has an unusually favorable resistance profile. Results of laboratory testing of 141 suggest that the resistance profile of the drug shows little overlap with those of other protease inhibitors currently available or in development. Glaxo Wellcome scientists report that the level of brain penetration of 141 is superior to that achieved by any currently available HIV therapy or any other protease inhibitor under development. Results of a small Phase I/II study of 141 in combination with 1592 show a median decrease in HIV viral load of 2.08 log copies/mL and a median CD4 cell increase of 79 cells/mm3. 141 is expected to enter Phase III testing in early 1997. Treatment activists are anxious to make the drug available as soon as possible through expanded access to individuals failing other protease inhibitor drugs. Community discussions with Glaxo Wellcome on this issue are ongoing. Expanded Distribution for IndinavirBeginning in May 1997, Merck will expand distribution of indinavir (Crixivan) to pharmacies nationwide. Currently Stadtlanders Pharmacy in Pittsburg is the primary distributor of indinavir. Merck has sent letters and registration packets to more than 65,000 pharmacies nationwide outlining the new distribution program. Pharmacists will help count and track the number of people taking indinavir to ensure that patients using the drug will have uninterrupted supply for refills. Paid Prescriptions, a subsidiary of Merck-Medco Managed Care, will administer the new distribution program. Ritonavir and EcstasyInternet reports of the death of Phillip Kay on October 6, 1996, from an apparent overdose of MDMA or "ecstasy," an illegal drug popular among dance club aficionados, has sparked interest in the interaction between MDMA and Abbott Laboratories' protease inhibitor drug ritonavir (Norvir). Blood levels of MDMA recorded at the coroner's inquest revealed a concentration equivalent to about 22 tablets of MDMA, a toxic overdose. Kay's partner maintains that Kay took only 2.5 tablets. It appears that the very high blood concentration of the drug was caused by the inhibiting action of ritonavir on the cytochrome P450 system in the liver that breaks down MDMA and many other drugs. P. Kon, of Abbott Laboratories in England, explained that the company will not conduct drug interaction studies that include illegal drugs and will not issue a general alert. He added that some 3-10% of the population is genetically predisposed to poorly metabolize MDMA, increasing blood levels of the drug in such individuals by 5- to 10-fold. A recent letter from Abbott (available to physicians upon request) predicts a moderate increase in heroin blood levels, a more than 3-fold increase in methadone blood levels and a 2- to 3-fold increase in amphetamine blood levels in people taking ritonavir. No drug interaction is predicted between cocaine and ritonavir. For more information, U.S. physicians may call Abbott at 800-633-9110. Vitamin B-12 and Disease ProgressionA benefit of supplementary vitamin B-12 (cobalamin) was uncovered by Alice M. Tang, MD, and colleagues from Johns Hopkins University. The researchers reported in the February Journal of Nutrition that HIV positive men seem to develop AIDS more quickly if they are deficient in vitamin B-12. In a study of 310 HIV positive gay and bisexual men, those with adequate levels of the vitamin did not progress to AIDS for 8 years, compared to 4 years for those with deficient vitamin levels. Vitamin B-6 and folic acid had no similar association with disease progression. B vitamin deficiencies are also associated with the development of peripheral neuropathy. For more information, see Peripheral Neuropathy, this issue. Needle ExchangeThe Director of the National Institutes of Health, Harold Varmus, MD, has approved a randomized, controlled study of free needle exchange compared to referral to commercial sources of clean needles (needles may be purchased over the counter in Alaska, the site of the study). Critics of the study charge that failure to provide clean needles to all study participants is "immoral and unethical" because previous studies have uniformly proven the value of needle exchange programs in preventing new infections. Varmus approved the $2.4 million study provided that all participants are offered vaccination against hepatitis B. Participants will include both current and former injection drug users in order to assess the rate of relapse when clean needles are available. Current estimates indicate that as many as 50% of all new HIV infections occur among intravenous drug users, and another 20% among their sex partners. Dozens of studies of the more than 100 small needle exchange programs around the country uniformly conclude that needle-exchange programs work. Needle exchange has been endorsed by the National Academy of Sciences, the Centers for Disease Control and Prevention (CDC) and the General Accounting Office. Peter Lurie, MD, of the Center for AIDS Prevention Studies at UCSF, estimated that 10,000 lives could have been saved by an aggressive expansion of needle-exchange programs. The National Institutes of Health convened a conference on February 11-13 to discuss the issue of HIV prevention. The conference statement supports needle exchange programs, and cites the intervention as a highly effective strategy in AIDS prevention. The report stated that needle exchange is associated with a 30% or greater reduction in HIV incidence among injection drug users, does not increase drug use or encourage new people to begin using drugs, and can increase the likelihood of users entering drug treatment. Health and Human Services Secretary Donna Shalala acknowledged that needle exchange may be an effective prevention intervention, but did not remove the ban on federal funding of such programs. Medical MarijuanaOn December 30, 1996, the Clinton administration announced that letters would be sent to physicians warning that they risk losing their federal registration that allows them to write prescriptions if they prescribe medical marijuana. The announcement is intended to blunt the effects of new laws in California and Arizona that permit the use of medical marijuana. The administration has no immediate plans to challenge the legality of the new laws. Marijuana has been used medically to reduce eye pressure due to glaucoma, to reduce nausea in patients undergoing cancer and AIDS chemotherapy. To stimulate the appetite of people with AIDS-related wasting and to manage intractable pain. Through spokesman "Drug Czar" General Barry R. McCaffrey, the White House cited the lack of controlled clinical research on the benefits of smoked marijuana. McCaffrey failed to mention that such research has consistently been prevented by federal agencies. The administration's stance was immediately denounced by grassroots AIDS activist groups. ACT UP/Golden Gate pointed out that clinical evidence would exist if federal drug policy enforcers did not block every effort to study marijuana for AIDS-related wasting and other possible indications. Donald Abrams, MD, of the Community Consortium of Bay Area Physicians in HIV/AIDS, has submitted for review a study of the effects of smoked marijuana on appetite, viral load, lean body mass and levels of hormones to the National Institutes of Health. The study was co-authored by leading researchers in endocrinology, virology and immunology. Despite FDA and institutional review board approval, the study was returned to Abrams unrated (the lowest possible research priority) in June 1996. Now, Abrams plans to re-write the study to focus on toxicology concerns, appealing to the current political objections to marijuana emanating from McCaffrey and the White House. Abrams is particularly vexed by the long-term political fight required before any reasonable medical research can be conducted. At a January 27, 1997 meeting, the San Francisco Medical Society publicly reviewed 75 scientific studies of the therapeutic benefit of marijuana and the New England Journal of Medicine published an editorial blasting the Clinton administration's stance on medical marijuana. Both agreed that the benefits of smoked marijuana include relief from pain, nausea and vomiting brought on by cancer and AIDS drugs. In January, officials from the Drug Enforcement Agency (DEA) visited Robert Mastroianni, MD, at his office in rural California and questioned him about recommending medical marijuana to 3 of his patients. He was reportedly insulted and intimidated. Alarm spread quickly through the California physician community. On February 14, the Bay Area Physicians for Human Rights filed suit in District Court to restrain the federal government from punishing physicians who distribute or recommend marijuana to their patients. Although the plaintiffs offered to settle the suit if the government agreed to stop the prosecution of physicians, McCaffrey rejected the offer. A hearing for the Conant vs. McCaffrey suit is scheduled for March 21. A federal advisory panel of medical experts met for 2 days in February to examine the issue of research on medical marijuana. The panel stated that smoked marijuana may have some medicinal value, and concluded that further study of the drug is warranted. Breakthroughs of the YearThe prestigious scientific journal Science recognized the development of protease inhibitor drugs and the discovery of chemokines as the most significant developments in scientific research in 1996. Chemokines and their receptors provide major advances in understanding the pathogenesis of HIV disease and provide new avenues for drug and vaccine development. Much new information about chemokine research and AIDS was reported at the Fourth Conference on Retroviruses and Opportunistic Infections (held January 22-26, 1997). For more information about the new field of chemokine research, see the feature beginning on page 22 and coverage of the conference beginning on page 29. Ronald Baker, PhD, is Editor-in-Chief of BETA and Director of Treatment Education and Advocacy at the San Francisco AIDS Foundation. Mark Bowers (MB) is Managing Editor of Treatment Publications at the San Francisco AIDS Foundation. Page last updated 1 April 1997 |
|
|
