AIDS Treatment News
April 18, 1997

Delavirdine (Rescriptor(R))
Approved

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 History

1. In a one-year comparison of delavirdine plus AZT vs. AZT alone, the combination was significantly better than AZT monotherapy in reducing viral load. (But this information is less relevant today than when the trial was designed, since the comparison -- AZT monotherapy -- is inadequate.)
   
2. Another one-year trial compared delavirdine plus ddI vs. ddI alone. This trial found no difference in viral load, CD4 count, or clinical disease progression, except for a trend toward improvement in these blood tests only during the first few weeks.
   
3. Another study showed a trend toward lower viral load with the triple combination of delavirdine plus AZT plus ddI, vs. AZT plus ddI or other combinations tested.
   

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 Information

Comments

1. An observational report from the expanded-access program indicated that there might have been an average of more than a one-log drop in viral load from adding delavirdine to failed combination regimens containing indinavir (Crixivan(R)) -- possibly because delavirdine seems to increase blood levels of indinavir, and might help maintain trough levels. (Note: The labeling suggests a reduction of the indinavir dose if the drugs are combined.) More study is needed on possible benefits of combining these drugs.
   
2. We urgently need research on measuring blood levels in order to individualize doses of drugs such as protease inhibitors, to reduce the likelihood of drug failure due to individual variations in absorption.
   
3. Clinical endpoint trials: There is debate now on whether to change the FDA approval process to accept sustained reduction in viral load as proof of benefit, without also requiring "clinical endpoint" trials (which need volunteers to die or become seriously ill in a comparison group, in order to prove that a drug helped). Delavirdine will probably have to go through such trials, under current regulations. This is unfortunate, since the information really needed is how to use the drug to help reduce viral load to undetectable levels and keep it there -- not to re-demonstrate that viral load reduction is beneficial. We need studies on how to combine antiretrovirals to reduce the likelihood of drug failure -- and body-count trials are poorly suited for this purpose.
   

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:
Ten-Month Report

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.

PMPA --
First Human Results

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:

1. Because of the half-life of HIV in the blood, the maximum possible decline after one week of therapy would be about 1.1 log -- even for a drug that completely stopped new virus production. In this trial, PMPA produced a median decline of 1.1 log, suggesting that the decline was close to the theoretical maximum. This viral load improvement was roughly equivalent to what is seen from protease inhibitors after one week of therapy. (The trial could not be extended, because a trial must follow a protocol which is based on safety concerns -- especially when testing a new drug with very little data from human experience.)

   Animal trials with SIV (simian immunodeficiency virus, often used as a model for HIV) have found two to three log viral load reductions with PMPA alone after four weeks of therapy.
   

2. Animals with SIV have been treated with PMPA for about two years, and no resistance has been seen (with AZT, resistance is seen in about four months). Also, laboratory attempts to create HIV which is resistant to PMPA have had little success. Only one resistance mutation has been found, and it gives only a three-fold loss of sensitivity -- probably not enough to keep the drug from working.

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.

References

1. Barditch-Crovo P, Deeks S, Kahn J, and others. PMPA: Safety, pharmacokinetics, and antiretroviral activity when administered as a single dose and for seven consecutive days to patients with HIV infection. International Conference on AIDS Research, Atlanta, April 1997.
   
2. Bischofberger N, Naesens L, De Clercq E, and others. Bis(POC)PMPA. An orally bioavailable prodrug of the antiretroviral agent PMPA. 4th Conference on Retroviruses and Opportunistic Infections, January 22-26, 1997 [abstract #214].

Standard Treatments for HIV,
Spring 1997

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:

1. Adherence to the prescribed dosing schedule will help prevent treatment failures.
   
2. There is a growing consensus that whenever antiretroviral treatment is used, the goal should be to keep the viral load so low that it is undetectable.
   
3. Any change in a combination should involve at least two drugs, since switching or adding just one can make it easy for the virus to become resistant.
   
4. New Federal guidelines on antiretroviral therapy, representing a consensus of medical experts, are scheduled to be released shortly, and should be consulted.
   

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 Inhibitors

• AZT, also called zidovudine, is marketed under the brand name Retrovir(R), and can be combined with most other antiretrovirals. AZT is valuable for treating cognitive problems caused by HIV because it penetrates the central nervous system better than most of the other drugs. It can cause headaches and stomach upset, but these often go away after a couple weeks. Over extended periods of use, it can cause anemia (low production of red blood cells), neutropenia (low white cells) and myopathy (damage to muscle fibers). These problems resolve if the drug is discontinued. The usual prescription for AZT is two capsules (200 mg) taken three times a day, or one 300 mg capsule taken twice a day. The dose used for treating cognitive/motor slowing or dementia is twice the regular dose: 1200 mg a day.
  
• ddI, also known as didanosine, is sold under the brand name VIDEX(R), and can be combined with any other antiretroviral. However, ddI, ddC, and d4T can each cause pancreatitis and peripheral neuropathy, so any combination of these drugs must be carefully monitored. If you experience abdominal pain, or tingling and numbness in your toes or fingers, call your healthcare provider immediately; otherwise, long-term damage may result. The usual prescription for ddI is two tablets (125 or 200 mg, depending on body weight) taken twice a day on an empty stomach with water.
  
• ddC, also called zalcitabine, is sold as HIVID(R), and can be combined with any other antiretroviral. However, ddC, ddI, and d4T can each cause pancreatitis and peripheral neuropathy, so any combination of these drugs must be carefully monitored. If you experience abdominal pain or tingling and numbness in your toes or fingers, call your provider immediately; otherwise, long-term damage may result. The usual prescription for ddC is one tablet (0.75 mg) taken three times a day.
  
• d4T, also known as stavudine, is marketed as ZERIT(R), and can be combined with most other antiretrovirals. However, d4T, ddI, and ddC can each cause pancreatitis and peripheral neuropathy, so any combination of these drugs must be carefully monitored. If you experience abdominal pain or tingling and numbness in your toes or fingers, call your provider immediately; otherwise, long-term damage may result. The usual prescription for d4T is one capsule (20, 30 or 40 mg, depending on body weight) taken twice a day.
  
• 3TC, also called lamivudine, is marketed as Epivir(R). 3TC can be combined with any other antiretroviral and may resensitize HIV to AZT in people whose virus has become resistant to that drug. It can cause headaches and insomnia in some people, but these usually go away after a few weeks. The usual prescription for 3TC is one tablet (150 mg) taken twice a day.
  

Non-Nucleoside Reverse Transcriptase Inhibitors

• Nevirapine is sold under the brand name Viramune(R). It has been combined with all other antiretrovirals. Nevirapine can cause a serious rash, but this may be avoided by starting with a low dose, one tablet taken once a day for two weeks, and then doubled to the usual prescription: one tablet (200 mg) twice a day. Nevirapine may lower the blood levels of other antiretrovirals, so ask your provider about dose adjustments for those drugs.
  
• Delavirdine (brand name Rescriptor(R)) has been used with all other antiretrovirals. Like 3TC, delavirdine may resensitize the virus to AZT in people who have become resistant. And like nevirapine, it can cause a rash in some people. The usual prescription for delavirdine is four pills (400 mg) taken three times a day.
  

Protease Inhibitors

• Nelfinavir is approved under the trade name VIRACEPT(R). It has been combined with all of the nucleoside analogs, but its use with the other drugs is not well documented. It is potent, easy to tolerate, and virus which grows resistant to it might not be resistant to the other protease inhibitors. It can cause stomach upset or headaches in some people, and should be used with caution with certain other medications. The usual prescription for nelfinavir is three tablets (750 mg) taken three times a day with food. Try not to miss any doses of this drug, or the virus could become resistant.
  
• Saquinavir is sold under the brand name Invirase(TM). It can be combined with most other antiretrovirals, and may work especially well with ritonavir, using the low doses tested in clinical trials. Saquinavir can cause mild stomach upset and elevated liver enzymes, and should be used with caution with certain other medications. The usual prescription for saquinavir--unless combined with ritonavir--is three capsules (600 mg) taken three times a day with food. The current formulation of saquinavir is very poorly absorbed, but taking it with grapefruit juice helps to increase blood concentrations. A better formulation will probably be available this year. Try not to miss any doses of this drug, or the virus may become resistant.
  
• Ritonavir is marketed as Norvir(R). Ritonavir can be combined with most other antiretrovirals, but should not be used with indinavir. However, ritonavir may work especially well in combination with saquinavir, using the low doses tested in clinical studies. There are many medications that should be taken with caution or not at all with ritonavir, so tell your provider exactly what other drugs you are on, prescribed or otherwise. Ritonavir can cause stomach upset, generalized discomfort and tingling or numbness around the mouth. These might by avoided by starting with a low dose, three capsules taken twice a day with food, and adding one capsule each dose every couple days until the usual prescription is tolerated: six capsules (600 mg) taken twice a day. That dose will be lower if combined with saquinavir. The capsules should be stored in a refrigerator. Try not to miss any doses of this drug; the virus may become resistant.
  
• Indinavir is sold under the brand name Crixivan(R). Indinavir can be used with most other antiretrovirals, but should not be combined with ritonavir. Indinavir can cause stomach upset, kidney stones and generalized discomfort, although drinking plenty of fluids may prevent the kidney stones. It should be used with caution with certain other medications, so make sure your provider knows about everything you are taking. The usual prescription for indinavir is two capsules (800 mg) taken three times a day on an empty stomach with a large glass of water. Try not to miss any doses of this drug, or the virus could become resistant.
  

Miscellaneous

• Hydroxyurea is marketed as Hydrea(R) and is used to treat a number of different cancers. While it is not widely considered a standard anti-HIV drug, and not FDA approved for this purpose, we include it because it has been shown in research to inhibit a human enzyme -- ribonucleotide reductase -- which the virus needs. Like AZT, hydroxyurea can cause anemia and neutropenia, although this is unlikely using the low dose usually prescribed for HIV: one capsule (500 mg) once or twice a day.
  

ADAP Drug-Assistance Programs:
Funding Projections for 1998

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
Supports Early Treatment

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
Temporary Restraining Order

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.

AIDS/HIV TREATMENT
DIRECTORY:
Mailing Address

Meetings Calendar for May 1997

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 ckitaguchi@lsro.faseb.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.