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A Call for More Cautious
Antiretroviral Treatment

By John S. James AIDS Treatment News #337

pills.jpg - 13.00 K Keith Henry, M.D., a well-known AIDS physician and the medical director of the HIV Clinic at Regions Hospital in St. Paul, Minnesota, has called for a "cautious, patient-focused" approach to HIV treatment, in an article published February 15 in Annals of Internal Medicine. (1). His article, and an accompanying editorial(2) by Oren J. Cohen, M.D., of the U.S. National Institute of Allergy and Infectious Diseases, offer well-informed, balanced discussions of both the advantages and disadvantages of early, aggressive treatment--and the need to reconsider the hit-hard-hit-early philosophy, now that it is clear that eradication is unlikely with current interventions, and that decades of treatment might be necessary.

For example, Dr. Henry describes the enormous benefit of modern antiretrovirals: "Deaths in our HIV population decreased 85% in a 1-year period" when protease inhibitor based therapy was introduced. But he also notes that hope for eradication, "perhaps more than any other assumption...powered enthusiasm for immediately beginning treatment." With eradication not currently possible, he urges a new evaluation of risks and benefits of aggressive vs. conservative antiretroviral treatment.

"Early, aggressive therapy often prematurely exposes patients to risks for medication-related side effects and resistance. A more cautious, patient-focused, long-term approach to therapy would help foster studies of alternative strategies, such as delayed initiation of therapy, protease-sparing therapy, class-sparing therapy, planned drug interruptions, switches in therapy, and immune-based therapy. It is time for clinicians to rethink their approach to the treatment of HIV infection."

Dr. Henry also discusses the financial incentives that direct research toward short-term studies of particular drugs in treatment-naive patients, for example, when most patients are treatment-experienced, and long-term treatment strategy studies are needed. "It is frustrating that an increasing number of clinical studies focus more on what is good for the drug than on what is good for the patient. Little attention is paid to reasonable salvage regimens or use of regimens that involve drugs from different companies."

And Dr. Henry calls for more support for the clinic services which are necessary if patients' medical care, including the difficult drug regimens, is to be properly managed. "The key role of HIV specialists, nurses, case managers and pharmacists is not emphasized enough so that support for the need to supervise the difficult use of these new drugs is often lacking. In today's setting, the most important person involved in the process is the one who answers a question, helps with a medication schedule, or adds insight into care."

The article, with a link to the accompanying editorial, is available online to anyone (you do not need to subscribe to the journal) at:

1. Henry K. The case for more cautious, patient-focused antiretroviral therapy. Annals of Internal Medicine. February 15, 2000; volume 132, number 4, pages 306-311.

2. Cohen OJ. Antiretroviral therapy: time to think strategically. Annals of Internal Medicine. February 15, 2000; volume 132, number 4, pages 320-322.
St. John's Wort Warning: Do Not Combine with Protease Inhibitors, NNRTIs

By John S. James

stjohnwort.jpg - 9.32 K The FDA has warned physicians and patients that St. John's wort, an herbal treatment often used for depression, should not be combined with certain drugs--including many antiretrovirals. The reason is that St. John's wort speeds up the body's elimination of some drugs, resulting in low blood levels--which can be dangerous in some cases because the medications do not work as intended. With anti-HIV drugs, the danger is that low blood levels can allow the virus to develop resistance (just as if too little drug had been taken).

So far, St. John's wort has only been tested for interaction with the protease inhibitor indinavir (Crixivan(R)). However, this kind of drug interaction is well known, and it is believed that the problem is also likely to affect other protease inhibitors, and possibly also non-nucleoside reverse transcriptase inhibitors (for example, efavirenz and nevirapine). Since modern antiretroviral treatment in the U.S. usually uses at least one drug from one of these classes, the practical consequence is that St. John's wort should not be taken concurrently with antiretroviral treatment.

The new warning followed a study(1) carried out at the U.S. National Institutes of Health, and published in The Lancet on February 12. HIV-negative volunteers took standard doses of indinavir for one day, then took one dose on the second day-- after which blood plasma levels of indinavir were measured. Then they took St. John's wort (a preparation with standardized hypericin content was used) for two weeks--and while continuing the St. John's wort, repeated the indinavir dosing and blood plasma level measurements. The effect on indinavir levels was seen by comparing the two measurements-- without St. John's wort, vs. with.

The overall blood levels were decreased by an average of 57% when St. John's wort was being used. And the critical trough levels--the lowest levels, just before the next dose of indinavir 8 hours later--were estimated to decrease by 80% (this decrease was estimated instead of measured, because only 5 hours, not 8 hours, of blood measurements were taken).

More information about the study (even more than in the published article) is available at but subscription or registration is necessary. Also, the February 12 issue has a report of two cases of organ transplant rejection which appear to have been caused by reduced cyclosporin levels due to St. John's wort--and several letters discussing pros and cons of St. John's wort, which does have mainstream medical support for use as an antidepressant. (One letter notes that the herbal product contains many potentially active chemicals, and it is not known whether the active ingredient which may work as an antidepressant is the same ingredient which causes the drug interactions--meaning that it might be possible to develop a formulation which separates the two effects.)

Nothing in the new findings suggests any problem with St. John's wort itself, except for patients who are taking medications with which it may interact.

The FDA sent the following advisory:
"FDA Advisory, February 10, 2000
"Risk of Drug Interactions with St. John's Wort and Indinavir and Other Drugs

"Dear Health Care Professional:

"The Food and Drug Administration would like to inform you about results from a study conducted by The National Institutes of Health (NIH) that showed a significant drug interaction between St John's wort (hypericum perforatum), an herbal product sold as a dietary supplement, and indinavir, a protease inhibitor used to treat HIV infection. In this study, concomitant administration of St. John's wort and indinavir substantially decreased indinavir plasma concentrations, potentially due to induction of the cytochrome P450 metabolic pathway. For additional information on this study please refer to the February 12, 2000 LANCET publication (Piscitelli, et al).

"Indinavir and other antiretroviral agents

"At this time, pharmacokinetic data are available only for concomitant administration of indinavir with St. John's wort. However, based on these results, it is expected that St John's wort may significantly decrease blood concentrations of all of the currently marketed HIV protease inhibitors (PIs) and possibly other drugs (to varying degrees) that are similarly metabolized, including the nonnucleoside reverse transcriptase inhibitors (NNRTIs). Consequently, concomitant use of St John's wort with PIs or NNRTIs is not recommended because this may result in suboptimal antiretroviral drug concentrations, leading to loss of virologic response and development of resistance or class cross-resistance.

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AIDS Treatment News Interview: Dr. Keith Henry, M.D.
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"Because herbal products are widely used in the United States and are available in various forms such as combination products and teas, it is important that health care professionals ask patients about concomitant use of products that could contain St. John's wort (hypericum perforatum).

"In addition, FDA is working closely with drug manufacturers to ensure that product labeling of antiretrovirals is revised to highlight the potential for drug interactions with St. John's wort.

"Other drugs
"Based on this study and reports in the medical literature, St. John's wort appears to be an inducer of an important metabolic pathway, cytochrome P450. As many prescription drugs used to treat conditions such as heart disease, depression, seizures, certain cancers or to prevent conditions such as transplant rejection or pregnancy (oral contraceptives) are metabolized via this pathway, health care providers should alert patients about these potential drug interactions to prevent loss of therapeutic effect of any drug metabolized via the cytochrome P450 pathway.

"All health care professionals are encouraged to report any serious adverse event associated with the concomitant use of prescription drugs and St. John's wort products to the FDA's MedWatch program at 1-800-FDA-1088 (fax 1-800-FDA-0178)."

1. Piscitelli SC, Burstein AH, Chaitt D, Alfaro RM, and Falloon J. Indinavir concentrations and St. John's wort. The Lancet, February 12, 2000; volume 355, pages 547-548.
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