AIDS Trestment News
A Call for More Cautious Antiretroviral Treatmentby John S. James
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 that 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: http://www.acponline.org./journals/annals/15feb00/henry.htm.
St. John's Wort Warning: Do Not Combine with Protease Inhibitors, NNRTIsby John S. James
So far, St. John's wort has only been tested for interaction with the protease inhibitor indinavir (Crixivan®). 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 www.thelancet.com 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 cyclosporine 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 that may work as an antidepressant is the same ingredient that causes the drug interactions -- meaning that it might be possible to develop a formulation that 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 this month:
"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 non-nucleoside 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.
"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.
"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)."
New Guidelines for HIV Treatment; Resistance Testing Now Recommended
"This report recommends that care should be supervised by an expert, and makes recommendations for laboratory monitoring including plasma HIV RNA, CD4+ T-cell counts and HIV drug-resistance testing. The report also provides guidelines for antiretroviral therapy, including when to start treatment, what drugs to initiate, when to change therapy, and therapeutic options when changing therapy. Special considerations are provided for adolescents and pregnant women. As with treatment of other chronic conditions, therapeutic decisions require a mutual understanding between the patient and the health care provider regarding the benefits and risks of treatment. Antiretroviral regimens are complex, have major side effects, pose difficulty with adherence, and carry serious potential consequences from the development of viral resistance due to non-adherence to the drug regimen or suboptimal levels of antiretroviral agents. Patient education and involvement in therapeutic decisions is important for all medical conditions, but is considered especially critical for HIV infection and its treatment."[from the Summary, page 2]
A major change in these guidelines is that viral resistance testing is recommended -- in case of virologic failure during antiretroviral therapy, or of less than optimal suppression of viral load after starting therapy. Resistance testing should also be considered in acute HIV infection (but treatment should begin immediately, not wait for the results of the test).
But resistance testing is not generally recommended before starting treatment of chronic infection -- or after discontinuation of antiretroviral drugs -- because when the drugs are absent, the resistant virus is likely to become a minor species that is missed by the test but ready to come back quickly when the drugs are started again. Also, resistance testing is not recommended when viral load is under 1,000 copies/mL, because current tests are unreliable when the viral load is very low.
These guidelines (which are 100 pages of text, including the tables and references) were developed by a panel of experts convened by the U.S. Department of Health and Human Services, and the Henry J. Kaiser Family Foundation. There is a list of major changes, showing where this version differs from the previous one.
Note: Similar but not identical HIV treatment guidelines, from a different panel (convened by the International AIDS Society-USA), were published January 19 in JAMA, (Journal of the American Medical Association). They are available at http://jama.ama-assn.org/issues/v283n3/full/jst90023.html.
HIV Resistance-Testing Information on Web
A Web site for physicians provides brief articles on resistance testing, ask-the-experts questions and answers, tables showing which mutations affect which drugs, a glossary, and other background information. "Designed to deliver important new research findings to the practicing clinician, each feature article contains pertinent background information and an emphasis on practical implications." Next month, a review of drug-resistance information from the recent Retroviruses conference will be added.
Article topics include new drugs in development, changing FDA requirements for approval of new resistance tests and of new drugs, and reports from the 3rd International Workshop on HIV Drug Resistance, San Diego, 1999. See especially the Best of Site page.
This site is funded through the UCLA Clinical AIDS Research and Education (CARE) Center, and is made possible by an unrestricted educational grant from Roche Pharmaceuticals. It is available at: http://www.hivresistance.com.
Abacavir Warning: Certain Respiratory Symptoms Can Indicate Hypersensitivity Reaction
This risk of hypersensitivity to abacavir has long been known. But recently the FDA and Glaxo Wellcome changed the warning in the official labeling to point out that respiratory symptoms may be part of the hypersensitivity reaction. Shortness of breath has always been in the description; now cough and sore throat have been added. This is because some cases of hypersensitivity to abacavir were initially diagnosed as pneumonia, bronchitis, or respiratory tract illness.
Patients using abacavir who suspect they may have the hypersensitivity reaction need to contact their physician immediately. If this reaction occurs, the drug must be stopped. But the cost of stopping unnecessarily because of a false diagnosis of hypersensitivity reaction is that an important option will be lost. Therefore, when patients have symptoms suggestive of a hypersensitivity reaction, a careful evaluation by the health care provider is important.
Below is the January, 2000 letter sent by Glaxo Wellcome to health care professionals, warning them of the need to consider certain respiratory symptoms along with other symptoms in evaluating a patient for the diagnosis of hypersensitivity to abacavir.
Also, the complete labeling for the drug, including the new information about the hypersensitivity reaction, is available at: http://www.glaxowellcome.com/pi/ziagen.pdf.
"Letter to Health Care Professionals GlaxoWellcome January 2000
"Important Drug Warning
"Re: Fatal Hypersensitivity Reactions, Respiratory Symptoms, and Ziagen® (abacavir sulfate)
"Dear Health Care Provider:
"Glaxo Wellcome Inc. would like to bring to your attention a revised Warning in the labeling for Ziagen (abacavir sulfate) about fatal hypersensitivity reactions to abacavir in patients presenting with respiratory symptoms. Ziagen is a nucleoside analogue reverse transcriptase inhibitor indicated for use in combination with other antiretroviral drugs for the treatment of HIV-1 infection.
"Since its approval in December 1998, the labeling for Ziagen has included a Warning and description of fatal hypersensitivity reactions to Ziagen. Although presentations vary markedly between patients, frequently occurring features of these hypersensitivity reactions are fever, rash, gastrointestinal symptoms (nausea, vomiting, diarrhea, or abdominal pain), and fatigue or malaise. While respiratory symptoms have been recognized as part of the hypersensitivity reaction in some patients, recent information underscores their importance.
"Fatalities in patients treated with Ziagen who developed hypersensitivity reactions in which the initial presentation included respiratory symptoms of dyspnea, cough, or pharyngitis have been reported. Deaths have been reported in patients receiving Ziagen who were initially diagnosed with an acute respiratory disease (pneumonia, bronchitis, or flu-like illness) and who were later recognized to have had a hypersensitivity reaction to abacavir that included respiratory symptoms. A delay in diagnosis of hypersensitivity can result in Ziagen being continued or re-introduced, leading to more severe hypersensitivity reactions, including life-threatening hypotension and death.
"Review of reports of hypersensitivity in patients receiving Ziagen indicates that respiratory symptoms (including cough, dyspnea, and pharyngitis) have occurred in approximately 20% of patients who have had hypersensitivity reactions. In contrast to some allergic reactions, wheezing or bronchospasm have occurred only infrequently in patients with hypersensitivity reactions to Ziagen.
"The diagnosis of hypersensitivity reaction should be carefully considered for patients presenting with symptoms of acute respiratory diseases and other symptoms associated with hypersensitivity to abacavir, even if alternative respiratory diagnoses (pneumonia, bronchitis, pharyngitis, or flu-like illness) are possible. If the clinical presentation of an acute illness cannot be clearly differentiated from a hypersensitivity reaction, Ziagen must be permanently discontinued. Ziagen should not be restarted following a hypersensitivity reaction because more severe symptoms will recur within hours and may include life-threatening hypotension and death.
"This updated warning about fatal hypersensitivity reactions to abacavir in patients presenting with respiratory symptoms is now included in the revised labeling for Ziagen. In addition, this revised warning is reflected in the Patient Medication Guide and Warning Card and should be discussed with patients treated with Ziagen.
"This information is provided to help you in the management of patients prescribed Ziagen Tablets or Ziagen Oral Solution. Please take the time to read the enclosed revised package insert, including the revised warning below (in bold), for additional product information and other risks associated with the recommended use of Ziagen.
"Fatal hypersensitivity reactions have been associated with therapy with Ziagen. Patients developing signs or symptoms of hypersensitivity (which include fever; skin rash; fatigue; gastrointestinal symptoms such as nausea, vomiting, diarrhea, or abdominal pain; and respiratory symptoms such as pharyngitis, dyspnea, or cough) should discontinue Ziagen as soon as hypersensitivity reaction is suspected. Ziagen should not be restarted following a hypersensitivity reaction because more severe symptoms will recur within hours and may include life-threatening hypotension and death (see Warnings, precautions: Information for Patients, and Adverse Reactions).
"Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of nucleoside analogues alone or in combination, including Ziagen and other antiretrovirals (see Warnings).
"Ziagen in combination with other antiretroviral agents is indicated for the treatment of HIV-1 infection. This indication is based on analyses of surrogate markers in controlled studies of up to 24 weeks in duration. At present, there are no results from controlled trials evaluating long-term suppression of HIV RNA or disease progression with Ziagen.
"Although hypersensitivity reaction is described in the package insert for Ziagen, you can assist us in continuing to monitor the safety of Ziagen products by reporting all cases of hypersensitivity reaction occurring in patients treated with Ziagen to the Abacavir Hypersensitivity Reaction Registry at Glaxo Wellcome at 1-800-270-0425 or to the FDA MedWatch program by telephone at 1-800-FDA-1088, via fax at 1-800-FDA-0178, or by mail at MedWatch HF-2, FDA, 5600 Fishers Lane, Rockville, MD 20857.
"We appreciate the opportunity to provide this information to facilitate the care of your patients. Any questions from health care professionals may be directed to our Drug Information Department at 1-800-334-0089. Thank you."
Copyright 2000 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.