New Threat to California Access; Activist Peron Qualifies for Governor's Race; NEW SCIENTIST Backgrounder (Available on Web) Reveals Suppressed WHO Analysis

Medical Advances with International Impact: Maternal Transmission; TB Prevention; Easier Sample Preparation

Oral Contraceptive / Nevirapine Interaction Trial, New York and San Francisco

IL-2 Without Antiretroviral Therapy, Trial Near Washington D.C.

FDA Publishes Conflict of Interest Rules for Clinical Trials


Drug Interactions: Resources for Patients and Professionals

By John S. James

Drug interactions are common in HIV treatment. But modern medical practice, with pressures to hurry due to cost control, may not leave enough time for physicians to make sure that they know about everything their patients are taking, and counsel them on potential risks. Not all drug interactions are harmful; some treatment combinations are designed to use interactions, and others can be adjusted to compensate for them. But patients may want to check their regimens to be aware of potential problems that they should bring to their doctor's attention.

Here are two AIDS-related drug interaction resources that are readily available. The first is written primarily for health care professionals, the other for patients.

* The Clinical Management of HIV/AIDS: Drug-Drug Interactions, by Charles Flexner, M.D., and Steven Piscitelli, Pharm. D.

This new one-hour CME (continuing medical education) module, written for physicians, pharmacists, and nurses but available to anyone through the World Wide Web, provides background on drug interactions as well as lists of what to watch out for. You can also submit your own regimen for an immediate computerized report on known potential interactions.

Most drug interactions fall into one or more of several classes, making them somewhat more predictable than might be expected. The background section of this training module--"How Drugs Interact: What You Need to Know" explains how most drugs are metabolized, and lists the five most important kinds of pharmacokinetic interactions, in which one drug affects the concentration of another ("inhibition of metabolism; induction of metabolism; altered drug absorption; inhibition of renal excretion; and displacement from plasma protein binding sites"). There are also pharmacodynamic interactions ("synergism or antagonism of drug effects, without alterations in the concentrations of either drug"). This section also describes the cytochrome P450 system, an important part of one of the two major ways the liver metabolizes drugs.

The next section, on questions health care providers need to ask themselves and their patients, lists practical issues which can be overlooked, such as:

- Prescription drugs from more than one physician and/or pharmacy;

- Non-prescription drugs including over-the-counter drugs, health foods and vitamins, alternative treatments, "underground" prescription or investigational drugs, illegal drugs, and investigational drugs through clinical trials.

- Pharmacy mistakes, such as confusing ritonavir with Retrovir(R) or Viramune(R) with Viracept(R).

- Whether adherence to the drug regimen is particularly important.

- Overlapping adverse effects of some drugs (especially pancreatitis, renal dysfunction, bone marrow suppression, and peripheral neuropathy).

The next section, "What Drugs are Most Likely to Be Involved in Drug Interactions," is organized around "the 'red flag' list" of five different groups of drugs that need special attention: "P450 inducers, P450 inhibitors, metabolized drugs with narrow therapeutic indices, renally cleared drugs with narrow therapeutic indices, drugs with specific requirements for absorption." Alternatives are suggested for many of the medications which can be problematic.

There is also a drug-food interaction table, a sample daily dosing schedule, and links to other Web sites with more information.

This drug interaction guide is published by HealthCare Communications Group, and is available at http://www.healthcg.com. The entire course can be printed easily, so if you do not have online access yourself, someone else could print the material for you.

Project Inform's Drug Interactions Fact Sheet, by Ben Chen

This simpler drug interaction guide has one page of introduction written for patients, and 17 pages of drug-drug interactions listed alphabetically by generic drug names. There is also a short glossary of terms used in describing the side effects. The introduction includes practical measures, such as the "brown bag medicine checkup--each time you see your health care provider, put all your medications, including over-the-counter and complementary products, in a bag and have your physician conduct a personalized review of your medicine for safety, appropriateness, compatibility, and instructions for use."

You can obtain a copy from Project Inform. Call the hotline, 800-822-7422 or 415-558-9051, 9 a.m. to 5 p.m. Pacific time Monday through Saturday--or write to Project Inform, 205 13th St., #2001, San Francisco, CA 94103--or get the information directly from http://www.projinf.org. The latest version, dated February 1998, will include information from the Retroviruses conference (Chicago, February 1-5).


Medical Marijuana Update

By John S. James

New Threat to California Patients' Access

Thousands of patients who urgently need marijuana for major medical problems are again facing a possible cutoff of their supplies from the buyers' clubs. The immediate problem is that on February 25 the California Supreme Court refused to review a decision of a California appeals court against the clubs. In December the appeals court had ruled on a 2-1 vote that a patient cannot designate a club as "primary caregiver" under Proposition 215, the voter-approved initiative to allow medical marijuana under California law. This ruling occurred in the case of a single club--the Cannabis Cultivators Club run by Dennis Peron--but has now become binding on lower courts throughout California. There are about 20 marijuana buyers' clubs in the state, and all are now seriously threatened.

The appeals court decision means that patients can legally obtain marijuana only by growing it themselves, or having their primary caregiver grow it for them; they can reimburse their caregiver for expenses. There is no legal way to obtain the seeds, however. And there are thousands of patients with wasting syndrome, or using chemotherapy, or with other serious conditions, who could not wait for the six months required to grow a flowering plant. Many could not grow their own due to their health status, or their living situation, due to the threat of eviction or arrest. In much of California police routinely arrest and charge patients for growing marijuana, despite medical documentation, following instructions from California Attorney General Dan Lungren, the major opponent of medical marijuana in the state.

The patients affected are those for whom no other treatment has worked, since doctors have been threatened and are unlikely to provide medical documentation unless there is no workable alternative. While it may seem easy to obtain marijuana illegally for recreational use, patients who need it medically are usually not part of that culture, and may be unable to find someone who would risk felony charges by providing it to them.

No one knows what will happen. The Cannabis Cultivators Club has said it will remain open, not to sell marijuana but to provide help in cultivation; it could face a raid or a civil injunction. There is widespread concern that closing the remaining clubs will create a medical emergency, as patients who urgently need the drug are forced to seek it from the worst source of supply, strangers on the street.

Meanwhile, Peron and five other cannabis clubs filed a legal brief responding to separate Federal action against them. The 34-page brief, submitted on February 27, is available at http://www.marijuana.org. (Several legal filings and court decisions on this Web site are useful for journalists and others seeking background on these issues.)

See also THE NEW YORK TIMES, "Moving to Semantical High Ground: California Marijuana Club Stands Firm Against Court Rulings," March 1, 1998, page 14 of the national edition. On the human impact, see the SAN FRANCISCO EXAMINER, "Wracked by Pain, but Defiant," March 3, 1998, page 1.

Peron Qualifies As Republican Candidate for Governor

Marijuana activist Dennis Peron has officially qualified as a candidate for governor of California, running against California Attorney General Dan Lungren in the Republican primary in June. This election will be the first one under California's new "open primary" system--meaning that any voter can vote in the Republican primary, even if they are registered Democrats or in other parties, or are independent (they can vote in only one party's primary, however). Peron could obtain a significant vote as a protest against Lungren.

For bumper stickers ("Hope, Empowerment, Compassion--For A Better World"), buttons, literature, and other material, contact the Peron for Governor campaign, 415-621-3986, or see http://www.marijuana.org.

NEW SCIENTIST Publishes Major Marijuana Report, Exposes Suppression of WHO Study Findings

"Marijuana Special Report," published February 21 in NEW SCIENTIST, includes 10 articles on marijuana. This report, a backgrounder not focused on medical use, is available at http://marijuana.newscientist.com/.

One of the articles, "High Anxieties: What the WHO Doesn't Want You to Know About Cannabis," revealed that a major World Health Organization report on marijuana, published last December, was supposed to contain an analysis showing that this drug is less harmful than alcohol or tobacco. This section was excluded after pressure from drug-war officials in the U.S. and the UN.

The suppressed analysis, which compared different kinds of harm caused by the different drugs, stated that the comparisons were "not to promote one drug over another but rather to minimize the double standards that have operated in appraising the health effects of cannabis." We do not know if the censored text has become public.

Apparently no U.S. newspaper reported this story, although it was carried in Reuters and published in newspapers elsewhere.

Comment:

What is striking about the politics of medical marijuana is the difficulty of reaching a workable compromise in Sacramento or Washington, even when many peoples' health and lives are at take. No one doubts that marijuana is far less dangerous than morphine, and certainly less subject to abuse; yet morphine is accepted as medicine, while medical marijuana is the target of a government crusade. Public opinion throughout the nation strongly supports allowing patients to use marijuana for relief or treatment of major illness; and many politicians campaign around the general principle of reducing government interference so that people can make the decisions which work for them. But on this treatment issue, freedom and compassion have been forgotten, and the machinery of government has been largely controlled by those with other ideas.


Medical Advances with International Impact

By John S. James

Some recent advances can be particularly important for developing countries where about 90% of people with HIV live. Public support will be will be crucial in improving treatment access for more people. These issues are becoming more prominent during preparations for the 12th World AIDS Conference, June 28 - July 3 in Geneva.

Simplified AZT Regimen Cuts Maternal-Infant Transmission in Half

On February 18 the U.S. Centers for Disease Control and the Ministry of Public Health of Thailand announced that a short course of AZT can greatly reduce the risk of transmission of HIV from mother to infant. The simplified regimen used AZT orally twice a day for the mother, starting at week 36 of pregnancy and continuing through labor. The drug was not given to the infant. The women in this trial were not breastfeeding.

This result means that we now know that a regimen suitable for developing countries can prevent maternal transmission of HIV. The next step is to push to make the treatment available to all HIV-positive pregnant women who want it--as well as supporting the ongoing research to find better prevention methods, perhaps using more than one drug.

The AZT regimen now used in rich countries to prevent maternal transmission has been unworkable in much of the world, mostly but not entirely because of the cost. The conventional treatment starts much earlier, at week 26 of pregnancy--but in many countries women do not come in for care until shortly before delivery. The women take AZT five times a day for the rest of the pregnancy, and then intravenously during labor; in addition, the infant receives AZT orally for two months. The new regimen can be started late, avoids all intravenous treatment, uses twice daily dosing, and requires much less of the drug. However it was not as effective as the more extensive regimen, reducing transmission about 50% (from 18.6% without AZT to 9.2% with AZT in the Thailand trial), vs. almost 70% (25% without AZT to 8% with AZT, in the earlier trial in the U.S.).

The new report also ends the divisive dispute on use of placebos in trials to reduce transmission in developing countries. From now on the placebo arms will be dropped or switched to the short-course AZT regimen, now that it is known to work.

Mark Harrington of the Treatment Action Group called on Glaxo Wellcome to "make AZT available to developing countries for a substantially reduced price, or give the drug away for free, as Merck did with its drug for African river-blindness. Over 500,000 children are born with HIV each year. Short-course AZT could prevent infection in at least half of these cases, saving millions of lives in the next few years."

UNAIDS, which coordinated the international research effort which included the Thailand trial, will hold a meeting of interested governments and agencies in Geneva at the end of March, "to find ways of rapidly and effectively implementing the results of this and other trials into public health policy as they become known."

Tuberculosis Prevention: Faster Two-Drug Regimen Found Effective

A trial in almost 1600 people with HIV found that a two-month regimen with two drugs (rifampin and pyrazinamide) was as effective as the conventional one-year regimen of isoniazid in preventing development of active tuberculosis, in persons who were known to be TB-infected as determined by a positive skin test. The two-month regimen is easier and less expensive to administer; it also seemed to have better survival (5.8 deaths per 100 patient years, vs. 6.7), although this difference was not enough to be statistically significant, meaning that it could have occurred by chance. The two-month regimen is likely to be preferred in the U.S., but could be more important in developing countries where preventive treatment has not been widely used so far because of cost. HIV can greatly accelerate the development of tuberculosis, which causes about a third of AIDS-related deaths in the world.

About 70% of the volunteers in this study were in the U.S., enrolled through government research programs. Others were in Haiti, Brazil, and Mexico. The results were reported at the 5th Conference on Retroviruses and Opportunistic Infections (F Gordin and others, A Randomized Trial of 2 Months of Rifampin (RIF) and Pyrazinamide (PZA) Versus 12 Months of Isoniazid (INH) for the Prevention of Tuberculosis in HIV-Positive(+), PPD+ Patients (pts) (late breaker abstract #LB5].)

Dried Blood Spots Allow Simpler Test for Viral Load, Newborn HIV Infection

Dried blood spots--a well-known method of preserving blood samples for certain tests--may be useful in some cases for measuring HIV viral load. The advantage is that the samples do not need refrigeration, nor require a centrifuge or other special equipment or supplies that are unavailable in many settings. Also, much less blood is used, an advantage particularly for infants. Three studies on dried blood spots were presented at the 5th Conference on Retroviruses and Opportunistic Infections, Chicago, February 1-5, 1998.

Viral load testing can be used to diagnose many HIV-infected infants in the first days or week of life, so that treatment can be started only for those who need it. The standard antibody test for HIV infection will not work until later, because all infants of HIV-infected women will test positive due to the mother's antibodies. One study suggested that samples can be pooled when screening for HIV infection, greatly reducing the cost of the testing, which could help in making medical care available to persons who otherwise would not receive it.

The three new studies are:

* S Cassol and others, Dried Blood Spots (DBS) for Monitoring HIV-1 RNA Load in Neonates and Infants [abstract #315]. This study used two different viral load test kits, the Roche Monitor PCR vs. NASBA, to measure viral load in stored dried blood spots, and compared the results to those of conventional viral load measurements using liquid plasma, which had been run earlier for the same infants. It concluded that "HIV-1 RNA recovery in DBS is feasible, highly reproducible, and compares favorably with conventional liquid plasma measurement, making it suitable for use in large-scale international field trials."

* AM Comeau and others, Use of Microsample Dried Blood Spot RNA Assays for Diagnosis of Pediatric HIV in the First Week of Life [abstract # 530]. Here the same team reported on tests of dried blood spots to diagnose HIV infection early after birth. The researchers concluded that "with slight modifications, RNA kits designed for viral load determinations can be used reliably on microsample DBS to detect the presence of HIV early in life."

* AM Comeau and others, Quality-Controlled Pooling Strategies for Nucleic-Acid Based HIV Screening: Using PCR as a Primary Screen on Dried Blood Spot Specimens in Population Studies [abstract #318].

This study looked at pooling part of the material from dried blood spot samples, to reduce the labor and the number of test kits needed to screen for HIV infection. In this case, pooling means combining several samples for an initial test; if the batch tests negative, then all the samples are known to be negative, and if the batch tests positive, then all samples in that batch must be tested individually. This procedure, applied to stored blood samples from newborns in this research project, reduced the number of tests to less than a third of what would otherwise have been required.


Oral Contraceptive / Nevirapine Interaction Trial, New York and San Francisco

A six-week pharmacokinetic trial to see if the oral contraceptive Ortho Novum affects levels of the antiretroviral nevirapine, or vice versa, is now recruiting women in New York and San Francisco.

Participants must have an undetectable viral load, CD4 count over 100, have no active infection, and be on a stable antiretroviral regimen (which cannot include current use of ritonavir or delavirdine, although previous use may be OK). There are additional entry criteria.

At the San Francisco site, participants will be compensated $500 on completion of the study; free parking will be provided, and transportation and child care costs can be reimbursed. At the New York site, volunteers will be compensated similarly. Some time in the clinic will be required for blood tests.

This may be the first trial for drug interactions between antiretrovirals and oral contraceptives.

For more information, in San Francisco call Sal Iacopelli, 415-353-6215. In New York, call Carsandra Diggs or Steve Nowling at the Clinical Trials Unit at Beth Israel Medical Center, 212-420-4519.


IL-2 Without Antiretroviral Therapy, Trial Near Washington, D.C.

The National Institute of Allergy and Infectious Diseases is recruiting persons with a CD4 count over 350 who do not plan to start antiretroviral therapy in the next year, for a phase II trial to determine the safety and efficacy of subcutaneous IL-2 without antiretrovirals for persons with relatively early HIV infection. They must have no antiretrovirals for six weeks before entering the trial, and "willingness to remain off antiretroviral therapy for 12 months or until a protocol-defined recommendation or required change is determined."

The only trial site is at the National Institutes of Health campus, in Bethesda, Maryland near Washington D.C.

For more information call Doreen Chaitt, R.N., M.P.H., 800-772-5464 ext. 428, or 301-402-0980 ext. 428.

FDA Publishes Conflict of Interest Rules for Clinical Trials

By John S. James

On February 2 the FDA published rules which, when they become effective in February 1999, will require disclosure of certain financial arrangements between pharmaceutical companies and certain clinical investigators, when a drug is submitted for marketing approval. Most of this information will come from the companies, since they already know what their financial arrangements with their investigators are; it appears that individual researchers will only need to disclose stock ownership in the sponsoring company. The FDA estimates that only one to ten percent of companies submitting applications for approval of drugs or devices will need to submit disclosures for one or more of their investigators. The FDA will decide case by case whether the information will be made public. The disclosure requirement applies to "any listed or identified investigator or subinvestigator who is directly involved in the evaluation of research subjects," and to immediate family members.

The purpose of the new rule is to prevent bias in safety and efficacy studies of drugs and medical devices. We note it here for three reasons:

* Clinical researchers may want to avoid the kinds of financial relationships which are likely to raise a red flag at the FDA--particularly "compensation made to the clinical investigator in which the value of the compensation could be affected by the study outcome; a proprietary interest by the investigator in the tested product, such as a patent; a significant equity interest in the sponsor of the covered study; or significant payments by the sponsor of the covered study of other sorts, such as a grant to fund ongoing research, compensation in the form of equipment, or retainers for ongoing consultation or honoraria." Disclosure will be required for stock ownership over $50,000 in the sponsoring company, or other payments over $25,000. The new rule does not prohibit any form of compensation; but companies and researchers may want to avoid those which will require disclosure, because they will subject the company's new drug application to extra scrutiny.

* Persons investigating conflict of interest in medical research can find detailed background in the 19,000-word FDA publication, which includes in-depth discussion of why certain provisions were and were not included in the new rule, answers objections from industry, and comparison of this rule with other government disclosure requirements.

* Even though the February 2 publication is a "final rule," certain parts are still open for public comment until April 3. After that, the FDA will submit the rule to the OMB (Office of Management and the Budget) for final approval, and there will be an additional period for public comment to OMB.

The published regulation appears in the FEDERAL REGISTER, February 2, 1998, volume 63 number 021, 63 FR 5233. If you are doing a computer search of the FEDERAL REGISTER, we found that the phrase "disclosable financial" was a useful search term for finding this publications. You can search the FEDERAL REGISTER without charge through the Web site of the National Archives and Records Administration, http://www.access.gpo.gov/nara/.

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