Being Alive Newsletter - February 1999
Walt Senterfitt
After years of waiting, hopes soaring then ebbing, we have another new drug to choose as we begin 1999-Glaxo Wellcome's abacavir, formerly known as 1592, and trade named Ziagen. The FDA announced the accelerated approval of Ziagen on December 18. Accelerated approval is the process by which medications for HIV and other life-threatening conditions are approved more rapidly than usual, on the basis of limited information as to effectiveness, and subject to confirmation or reversal after more studies are completed and data accrue from use in the community.
Ziagen is a member of the nucleoside analog reverse transcriptase inhibitors (NRTIs) class, along with drugs such as AZT (Retrovir), ddI (Videx), or d4T (Zerit). It interferes with the translation of hiv's genetic material that is necessary for HIV to implant itself in a T-cell. As with all other antiretroviral drugs, it must be used in combination with other antiretroviral drugs, two or more other drugs usually. If not, HIV mutations resistant to this drug will rapidly emerge in one's body and eventually flood one's immune system.
An attractive feature of Ziagen is that it may be taken just twice a day and without regard to food-with or without food makes no difference in its absorption by the body.
It was approved on the basis of three medium-sized studies of six months each. Two of them demonstrated that abacavir+AZT+3TC (or Ziagen + Combivir) is more effective in lowering viral load than AZT+3TC is alone. The other study, albeit not conclusively, indicated that its use in this same 3-drug combination may be as effective (even better for some) as AZT+3TC+indinavir (Combivir + Crixivan). In addition to these clinical trials, more than 11,000 people have used Ziagen through expanded access mechanisms, and numerous providers and patients have reported success incorporating Ziagen into various treatment combinations.
This drug has been hyped by some in the community as a wonder drug during its years of development (remember those screaming headlines on the front covers of the San Francisco AIDS Foundation's newsletter Beta?). Its success in practice has been less dramatic than its promise portended. Though it was most eagerly awaited by those whose options were running out of other treatment options, it unsurprisingly seems more effective in those who are treatment naïve or have had previous experience with fewer rather than more other drugs. There is considerable cross-resistance between Ziagen on the one hand and Combivir on the other, meaning that those who have virus resistant to Combivir to start with may experience little benefit from adding Ziagen.
Abacavir can cause a serious side effect, called a hypersensitivity reaction, in three to five percent of patients taking it. This reaction usually (but not always) occurs within two to six weeks of starting the drug. It is characterized by symptoms like fevers, malaise, severe fatigue, nausea, vomiting and sometimes a rash. This reaction almost always goes away within two days of stopping the drug, but if the drug is later restarted after the reaction, it can cause a much more serious recurrence that begins rapidly and can be fatal within a day. Never start Ziagen again after stopping because of a hypersensitivity reaction! It is very important that persons taking this drug as well as medical and auxiliary health care providers understand the symptoms and cautions very clearly. At present, there is no way known to predict who will and who will not have this reaction.
Here are excerpts from the cautionary short "talk paper" the FDA released the same day it announced Ziagen's approval:
"December 18, 1998. FDA approved today abacavir (trade name Ziagen) for the treatment of HIV-1 infection in adults and children. The following can be used to answer questions:
"A potentially fatal hypersensitivity, or allergic reaction, has been associated with the use of Ziagen in at least five percent of patients. Symptoms of this reaction may include skin rash, fever, nausea, abdominal pain and severe tiredness.
"A written list of the hypersensitivity symptoms is printed on a warning card and is provided along with a Medication Guide to patients by pharmacists. Anyone who experiences a hypersensitivity reaction must stop taking the medicine and call their health care provider immediately. Ziagen should not be taken again after a reaction occurs because more severe symptoms will arise within hours and may include life-threatening low blood pressure or death.
"An abacavir hypersensitivity reaction registry has been established-physicians should register patients developing symptoms of hypersensitivity by calling 800.270.0425.
"All NRTIs can cause lactic acidosis-a fatal metabolic disturbance that causes an abnormal buildup of lactic acid-symptoms can include an enlarged liver.
"Additional reported side effects of abacavir include nausea, vomiting, fatigue, headache, diarrhea and loss of appetite."
The recommended dose for adolescents and adults is one 300 mg pill twice a day for a total daily dose of 600 mg. The recommended dose for children (who should be at least three months old) is 8 mg/kg taken twice a day. In a study of its use in treating HIV dementia, a higher dose is being used-600 mg twice a day, for a total of 1200 mg.
Abacavir does have interactions with a number of other drugs, so each person starting it should be sure to discuss these possibilities with providers. Fortunately, it does not seem to interact with protease inhibitors. However, many patients may be affected by its interaction with alcohol. It is metabolized by the same pathway as is alcohol, and it may raise alcohol levels in the blood. Studies are ongoing currently to see how widespread and how significant this effect is. Other studies are looking at interaction with oral ganciclovir (Cytovene), Bactrim or Septra and methadone.
There are so many gaps in our knowledge of this drug that it is impossible to give specific advice on who it is best suited for, in combination with what. For one thing, there is no evidence yet on the long-term effectiveness of the drug among persons who do respond to it initially. For another, the comparisons in the clinical trials all involved AZT+3TC (Combivir). This is no surprise since Glaxo makes all these drugs, and the company hopes to position the combination of Ziagen/Combivir attractively in the market-two pills twice a day, eat what you want, save protease inhibitors and NNRTIs for later.
Not a bad concept, but we have as yet no conclusive data comparing this combination head-to-head over time with alternatives. One of the three trials used in FDA approval, comparing Crixivan with Combivir to Ziagen with Combivir, is a useful comparison but the results are inconclusive. Some other trials failed to show significant benefit for abacavir. Though tests in animals showed that abacavir crosses the "blood brain barrier" well and thus should be helpful against HIV in the brain, clinical trials have not yet demonstrated that it is effective against dementia in practice.
For these reasons, the patient representative on the FDA panel that considered Glaxo's application, Jeff Bloom, voted symbolically against its approval (the patient representative vote does not count). Though he caught a lot of flack for doing so, he based his vote on the scarcity of information, especially in comparisons with current standard-of-care combinations (which the two-drug AZT+3TC arm in the two main clinical trials is not). He thought that approval now might do more harm than good, because a person's first antiviral combination is so important. The voting members decided to go with accelerated approval by a 7­2 vote, but even some of the supporters said they wished that more supporting data were available.
Glaxo priced the drug somewhat lower than expected, about $3450 a year wholesale or $4500 a year retail. It is already covered under California's ADAP program.
It is good to have another weapon in our arsenal. Many people with HIV will no doubt benefit. However, we must demand careful and rapid attention to research on the unanswered questions. It is especially critical to discover the mechanisms of the hypersensitivity reaction so that we might know how to predict or prevent it and to conduct head-to-head comparisons of Ziagen combinations with other standard-of-care combinations so that we can learn how best to use this new tool.
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