by John S. James
On April 4 the FDA approved delavirdine (brand name
Rescriptor) "for the treatment of HIV-1 infection in
combination with appropriate antiretroviral agents when
therapy is warranted." This drug, developed by Pharmacia &
Upjohn of Kalamazoo, Michigan, is the second non-nucleoside
reverse transcriptase inhibitor approved (the first was
nevirapine -- Viramune(R) -- approved June 24, 1996).
Delavirdine must be used in antiretroviral combinations,
because when it was tried alone, the virus developed 50-fold
to 500-fold reduced sensitivity within eight weeks, in 14 of
the 15 patients in that trial. HIV which is resistant to
delavirdine is likely to be cross resistant to nevirapine and
other non-nucleoside RT inhibitors; however, cross resistance
is unlikely with protease inhibitors, or with nucleoside
analog reverse transcriptase inhibitors (AZT, ddI, etc.).
The main side effect of delavirdine is skin rash. Rash attributed to the drug has occurred in 18% of patients in phase II and III controlled trials, and has been severe enough to cause permanent discontinuation of delavirdine treatment in 4.3%.
Certain drugs must not be combined with delavirdine; others,
including some protease inhibitors, probably require dose
adjustments. For more information, see the package insert.
Approval HistoryThe FDA's Antiviral Drugs Advisory Committee, meeting in November 1996, came to a tie vote on whether delavirdine should be approved -- four in favor of accelerated approval, and four against. The reason for the ambivalence is the weakness of the data from those clinical trials which have been completed so far. On the other hand, there are suggestions that this drug might be important for some individuals, especially in combinations not yet tested in formal research. The trials which have been run were designed long ago, and did not study the combinations which would be chosen today. Three trials are reported in the FDA-approved package insert:
What is likely now is that physicians will try delavirdine in many different combinations, developing clinical experience. Meanwhile, Pharmacia & Upjohn will conduct new trials (required as a condition for approval) which hopefully will produce some definitive information on how best to use the drug.
Delavirdine will be priced at a "wholesale acquisition cost"
of $2,250 annually, considered fairly low relative to other
AIDS drugs. Persons now receiving delavirdine in the
expanded-access program will be given enough to have a 90-day
supply to allow them time to arrange for reimbursement.
For More InformationPersons needing help getting the drug paid for can call the company's reimbursement assistance line, 800/711-0807, 9 a.m. to 6 p.m. Eastern time Monday through Friday. Physicians or patients with clinical questions about the drug can call 800/432-4702, 8 a.m. to 8 p.m. Eastern time Monday through Friday.
The central tragedy of clinical-endpoint trials is that they mis-focus clinical research away from critical issues, in favor of unwieldy and ethically problematic trials addressing life-and-death issues which are philosophically compelling, but medically marginal in AIDS science and medicine today.
Nelfinavir Combination Therapy:
Six-month results from a clinical trial of the triple
combination of nelfinavir (VIRACEPT(R)) plus AZT plus 3TC (in
volunteers with little or no prior antiretroviral use) were
presented in January at the Fourth Conference on Retroviruses
and Opportunistic Infections (see AIDS Treatment News #265,
February 21, 1997). Recently, 10-month results (for those
volunteers in the ongoing trial with at least ten months
experience) were presented at the International Conference on
AIDS Research (ICAR), in Atlanta, by Sharon Chapman, Ph.D.
from Agouron Pharmaceuticals, Inc.
In the arm which included the approved nelfinavir dose of 750 mg three times a day, 87% of 74 volunteers with ten months of the combination treatment had viral load below the cutoff used of 1200 copies/ml (84% of these 74 volunteers were below 500 copies); CD4 counts increased by an average of 173. Of 12 of these volunteers who started the trial with a CD4 count under 50 (and an average viral load of 294,000 copies), 11 had a viral load below the cutoff.
In a separate study reported at the ICAR conference, researchers studied the same treatment combination in 12 antiretroviral-naive volunteers for one year, with intensive immunological monitoring. They reported durable suppression of virus in 11 of the 12 -- and resolution or improvement in a number of HIV-related symptoms. One volunteer who could not tolerate the regimen was switched successfully to d4T, 3TC, and indinavir; another, who had advanced HIV, had a virologic breakthrough but seemed to respond to a combination of ritonavir and saquinavir. This study also found a good antiviral response in lymph tissue and in semen.
by John S. James
PMPA, an antiretroviral being developed by Gilead Sciences,
Inc., has shown exceptional activity in some animal tests
(see AIDS Treatment News #248 and #236). Now the first human
multi-dose trial(1), reported this month at ICAR (the
International Conference on AIDS Research) in Atlanta, found
results which could be much more important than they may at
This trial found a median 1.1 log (13 fold) viral load reduction after one week of the once-daily treatment (plus an additional single dose given one week earlier), in the eight patients who received the highest dose tested. This is more impressive than it looks, for two reasons:
In other words, IF PMPA proves safe enough to use and otherwise workable, the currently available information suggests that it might be as active as the protease inhibitors, but without the resistance problems of those drugs. PMPA has a long intracellular half life, which should maintain trough levels and allow once-daily dosing.
Since PMPA itself must be given intravenously, further development will test Bis(POC)PMPA, a form of the drug which is taken orally(2). The next human trial, which should start in early summer, is planned to run for one month; this should be long enough to tell whether or not the short-term activity of the drug is comparable to that of protease inhibitors.
Note: PMPA and Bis(POC)PMPA should not be confused with PMEA and bis-POM PMEA, chemically similar drugs from the same company which are farther advanced in human trials, but probably have less anti-HIV activity.
Standard Treatments for HIV,
by Denny Smith
This is a brief guide to the antiretroviral drugs approved by
the FDA to treat HIV infection.
The current model of care is to use these drugs in combinations that keep both viral replication and drug toxicities as low as possible. HIV can easily develop resistance to any antiretroviral used alone, and so combination therapy has become the standard. However, the best combination, or sequence of combinations, has not been found, and may be different for each person. In making treatment decisions, the following should be considered:
The side effects described below for each drug may be the
most common or important ones, but everyone should be
prepared for other possible problems, which are noted at
length in the product insert available at pharmacies.
Reverse Transcriptase InhibitorsThese drugs work by inhibiting an enzyme -- reverse transcriptase -- which the virus needs to take over a cell's genetic machinery. The first five agents in this class are also called nucleoside analogs.
Non-Nucleoside Reverse Transcriptase Inhibitors
Protease InhibitorsThese drugs target a different enzyme of the virus -- protease -- which is essential for HIV to make working copies of itself. More than with most drugs, it is very important not to miss doses of the protease inhibitors, since HIV can develop resistance if drug levels in the body become too low.
ADAP Drug-Assistance Programs:
On April 17 the ADAP Working Group -- a coalition of advocacy
organizations and pharmaceutical companies involved in AIDS
treatment -- presented to Congress the results of a
pharmacoeconomic model showing how much it would cost to
provide triple combination treatment including protease
inhibitors to uninsured or underinsured patients likely to
seek this treatment in fiscal year 1998 (the year which
begins October 1, 1997). Additional funding of $131.7 million
will be required, bringing the total to $554 million.
Gary Rose of the AIDS Action Council called the funding "a sound public health investment that will save patient lives, bring many individuals with HIV and AIDS back into the workforce and dramatically reduce the costs associated with hospital and hospice care and of providing specialist treatment for a wide range of opportunistic infections and AIDS-related cancers, whose incidence has fallen dramatically over the 15 months since combination therapy with protease inhibitors has been widely adopted in medical practice." Modern antiretroviral treatment has repeatedly been shown to be cost effective, often saving more than drug costs by avoiding hospitalization and other treatment for opportunistic infections.
A new Federal standard, expected to be published in May in the MORBIDITY AND MORTALITY WEEKLY REPORT of the U.S. Centers for Disease Control and Prevention, is expected to define as standard of care that anyone with HIV who has a CD4 count less than 500 and a viral load greater than 10,000 should consider aggressive treatment with triple combination therapy.
The projection of future funding requirements took into account the growth in use of state AIDS Drug Assistance Programs, and likely changes in future prescribing practices.
Medicaid: Vice President Gore
On April 9 Vice President Al Gore announced his support for a
proposal by the AIDS Action Council to allow Medicaid to
cover early HIV treatment, for persons who are eligible for
Medicaid under existing financial criteria.
Currently, persons with HIV who meet Medicaid's income and property limits usually also need to be judged disabled before they are eligible for treatment. This is contrary to modern medical practice, because antiretrovirals work best when used long before major illness occurs. The proposed policy will save lives and prevent disability, and it might also pay for the cost of the drugs by avoiding unnecessary hospitalization and long-term care for advanced illness.
Medical Marijuana Wins
by Tadd Tobias
A federal judge in San Francisco has issued a temporary
restraining order (TRO) which effectively bars Federal
officials from taking punitive action against physicians in
California who recommend to patients medicinal use of
marijuana. Since the passage of Proposition 215 doctors have
been threatened with criminal prosecution, loss of
prescription writing privileges, and exclusion from Medicare
and Medicaid programs.
In response to the threats a class action lawsuit was filed January 14 by the American Civil Liberties Union, medical marijuana patients, and a group of prominent physicians. The lawsuit seeks to permanently bar any punishment of physicians for recommending or discussing marijuana. Lawyers for the plaintiffs contend that doctors have a constitutionally protected First Amendment right to free speech to discuss any treatment possibility (specifically marijuana) with their patients, and that speech limitations placed on physicians would amount to government intrusion in the doctor-patient relationship.
The restraining order is temporary and in effect pending ruling by the court on motions before it and during settlement process--which is ongoing with a federal judge acting as mediator between lawyers for the plaintiffs and the government. A settlement conference, scheduled for April 17, is intended to facilitate a negotiated resolution so that a full, lengthy trial can be avoided. Although that meeting had yet to occur at press time, Dave Fratello of Americans for Medical Rights (the sponsors of Proposition 215) speculated that settlement was unlikely because the government is unwilling to concede that marijuana is a legitimate treatment option. For that reason he expected that this process will continue to a full trial.
Attorneys for the plaintiffs are hopeful that a settlement can be reached. Jonathan Weissglass, of the San Francisco law firm of Alshuler, Berzon, Nussbaum, Berzon and Rubin, noted that the TRO was "binding both as to government sanctions imposed now, and as to sanctions imposed in the future for actions taken now."
At least in the near term, physicians in California can discuss with patients and recommend to them medicinal use of marijuana without fear of retaliatory actions by the federal government. Because of the risks involved doctors should be aware that the TRO may not apply to discussions with third parties such as buyers' clubs. Doctors have been advised, as a matter of prudence, to especially avoid anything that could be construed as facilitation of criminal activity -- for example, suggesting cultivation, buyers' clubs, or other means for acquiring marijuana. (It should also be noted that some buyers' clubs do not require a recommendation of marijuana from the doctor-- only a letter of diagnosis and symptoms. This might be important because the TRO does not specifically address the communication between doctors and buyers' clubs.) Additionally, doctors should be careful to make sure all conversations are documented in medical records and that the relationships are well established and ongoing with bona fide patients (since there have been concerns that the U.S. Drug Enforcement Administration might use impostor patients and informers).
For an update on the situation and the legal status of medical marijuana, contact Americans for Medical Rights, 1250 Sixth Street, #202, Santa Monica, CA, 90401, 310/394-2952, fax 310/451-7494.
In our review last issue of the AIDS/HIV TREATMENT DIRECTORY,
published by the American Foundation for AIDS Research
(AmFAR), we provided phone numbers for subscribing to the
Directory, and also for requesting a free copy of the current
edition, for persons who cannot afford a subscription. We
have been asked to also publish an address to order a copy by
mail -- especially for prisoners, who often cannot use a
telephone. The free copy can be ordered from the CDC National
AIDS Clearinghouse, P.O. Box 6003, Rockville, MD 20849.
Meetings Calendar for May 1997
National AIDS Cancer Conference, April 28-30, Bethesda,
Maryland. Sponsored by the U.S. National Cancer Institute. To
register, call 301/907-3844. Beginning April 21, daily online
summaries and searchable abstracts will be available at
National Conference on Women & HIV -- Innovation for Care, Policy and Prevention, May 4-7, Los Angeles. "The National Conference on Women & HIV provides an interdisciplinary forum on the HIV epidemic among women. More than 1,500 scientists, community providers, women with HIV infection and policy makers will explore the latest developments in scientific research, HIV prevention, and clinical care." Press contact: Jason Levine, 212/679-5959. Registration: Marge Risinger, 310/397-6338.
International AIDS Candlelight Memorial & Mobilization, May 4, in cities throughout the world. Contact: Loras Ojeda, Mobilization Against AIDS, 415/863-4676, fax 415/863-4740.
HIV Update: Contemporary Issues in Management, May 9-10, Boston. "The objective of this course is to update physicians caring for HIV patients. The overall emphasis will be the current recommendations for managing HIV infected patients in the ambulatory setting." Contact: Professional Meeting Planners, 617/279-9887 or 800/378-6857, fax 617/279-9875, email PMPMeeting@aol.com.
Community Programs for Clinical Research on AIDS (CPCRA), May 11-12, Reston, Virginia. Contact: Elaine Allison, CPCRA Operations Office, 301/230-9670, fax 301/230-7190, email eallison@opsctr.S-3.com.
NIH Conference on AIDS Wasting, May 20-21, National Institutes of Health campus, Bethesda, Maryland. Contact for program information: Dr. Fulvia Veronese, Office of AIDS Research, NIH, 301/496-3677, fax 301/496-4843. Contact for logistical or accessibility questions: Ms. Ann Borlo, Social & Scientific Systems, 301/986-4870, fax 301/913-0351, email acb@S-3.com.
Clinical Trials for the Treatment of Secondary Wasting and Cachexia: Selection of Appropriate Endpoints, May 22-23, National Institutes of Health campus, Bethesda, Maryland. Sponsored by the U.S. Food and Drug Administration, "This forum will focus on a multidisciplinary approach to the examination of advances achieved to date and the development of improved clinical trials to study potential interventions. In particular, the workshop format will emphasize study design issues including the selection of endpoints clinically appropriate for the condition being studied, e.g., cancer, HIV infection, etc." Contact: Life Sciences Research Office, 301/530-7030, email firstname.lastname@example.org.
3rd International Conference on Home and Community Care for Persons Living with HIV/AIDS, May 21-24, Amsterdam. Contact: phone +31-20-5664801, fax +31-20-6963228, email F.Wolters@inter.nl.net.
Clinical Care Options for HIV, May 29 - June 1, Laguna Niguel, California. "This meeting is designed for and limited to 400 experienced front-line primary HIV care physicians, clinical researchers, and other advanced front-line clinicians actively treating HIV+ patients, to discuss state-of-the-art treatment strategies with leading experts and colleagues, in a setting that is conducive to formal learning experience and informal networking." Contact: Registration coordinator, 1-888-448-1199, fax 508/478-7905, or register online at www.healthcg.com.
Copyright 1997 by John S. James.
Permission granted for noncommercial reproduction,
provided that our address and phone number are included
if more than short quotations are used.