Research Initiative Treatment Action (RITA!); Vol 5, No. 2 April 1999
Paul Simmons, RN, ACRN
On December 18, 1998, the U.S. Food and Drug Administration approved the 15th agent for the treatment of HIV infection. Abacavir (uh-BACK-ah-veer) sulfate, brand named Ziagen (z-EYE-uh-jen), received accelerated approval based on data from three short-term Phase III studies.
A long-awaited and much ballyhooed therapy, abacavir's annual price of $3,540 has met with the praise of some activists.1
Abacavir is a nucleoside analogue reverse transcriptase inhibitor (NARTI). It is the most powerful drug in its class and one of the most powerful antiretrovirals available. GlaxoWellcome, the same company that makes zidovudine (Retrovir) and lamivudine (Epivir), manufactures the drug. Abacavir is indicated—in combination with other antiretrovirals—for the treatment of HIV infection.
Abacavir is supplied in tablet and solution forms. The tablets are yellow, capsule-shaped, film-coated and imprinted with "GX623" on one side. The solution is clear in appearance, yellow in color and strawberry-banana in flavor.2
The tablets should be stored at a room temperature of 68º to 77ºF; the solution should be kept at room temperature or refrigerated, but not frozen.3
Each tablet is equivalent to 300 mg. of abacavir. The appropriate dose of abacavir for adults is 300 mgmdash;or 1 tabletmdash;twice daily.
Abacavir may be taken with or without food.
The side effects mostly commonly associated with abacavir therapy include nausea, vomiting, fatigue, headache, diarrhea and loss of appetite. The most serious side effect, however, is a hypersensitivity reaction that occurs in approximately 5% of those receiving abacavir therapy.
Symptoms of abacavir hypersensitivity usually appear within the first 6 weeks of treatment and include a skin rash or two or more of the following sets of symptoms:
Patients who believe they are experiencing abacavir hypersensitivity should stop taking the drug and call their physician immediately. Those who experience hypersensitivity to abacavir must never take the drug again. Any effort to rechallenge can produce life-threatening symptoms. [Please also refer to the updated Abacavir warning from January 2000, which includes shortness of breath, cough, or sore throat as important warning signs of Abacavir hypersensitivity].
A family of liver enzymes known as P450 isoforms metabolizes several antiretrovirals, including the protease inhibitors (PIs) and non-nucleoside reverse transcriptase inhibitors (NNRTIs). Since many other commonly prescribed drugs are also metabolized through these pathways, PIs and NNRTIs can produce significant interactions with a number of medications. Abacavir, however, is not significantly metabolized by P450 isoforms. It is therefore unlikely that clinically relevant drug interactions will occur between abacavir and drugs metabolized by P450 pathways.
As with any antiretroviral, HIV can develop resistance to abacavir.4 Among other considerations, resistance to anti-HIV therapy is associated with poor adherence to treatment on the part of the patient and inappropriate prescribing practices on the part of the physician.
Patients who have used and developed resistance to several nucleoside analogs—in other words, zidovudine, lamivudine, didanosine (Videx) and stavudine (Zerit)—are unlikely to reduce their viral load with the use of abacavir. On the other hand, patients who have used and developed resistance to only two nucleosides may see significant reductions in viral load when abacavir is combined with other drugs.5
In a Glaxo-sponsored expanded access program, which provided the drug to patients with advanced disease and few treatment options, abacavir produced a 0.5 log reduction in viral load for only 1 in 4 patients.6
Inasmuch as different enzymes and binding sites are involved, cross-resistance between abacavir and protease inhibitors or non-nucleoside reverse transcriptase inhibitors is unlikely.
In a pivotal study of abacavir,7 a team of Glaxo investigatorsmdash;lead by Margaret Fischl of Miami—unethically randomized 86 patients to a substandard regimen of zidovudine and lamivudine alone and another 87 to a combination of abacavir, zidovudine and lamivudine.8
Subjects were required to be naive to antiretroviral therapy. The median baseline viral load among the study participants was approximately 38,000 copies, while the median baseline CD4 count was approximately 450 cells.
At the end of the first 16 weeks of study, which were double-blind, approximately 80%9 of the subjects in the three-drug arm had an undetectable viral load (less than 400 copies). Unsurprisingly, less than 40% of the subjects in the straw-man comparison arm had undetectable plasma viremia. By week 48, approximately 60% of the triple therapy subjects still had undetectable viral loads; however, participants with a baseline viral load of less than 100,000 copies were much less likely than other subjects to achieve undetectable viremia with the use of abacavir.
It is worth noting that at week 16, despite an inferior virologic response, subjects in the zidovudine/lamivudine arm had appreciably higher CD4 T cell increases than those in the abacavir-containing group. Specifically, the median CD4 T cell rise in the two-drug group was over 100 cells while participants in the three-drug arm had a median CD4 increase of less than 50 cells. By week 48, differences in CD4 T cell count between the groups had leveled out, with both sets of patients picking up a median of approximately 150 cells.
Glaxo reports that only 6% of the subjects assigned to the three-drug group withdrew from study for adverse events.
In Glaxo study CNA2007—dubbed by Treatment Issues as "the most ambitious salvage therapy trial to date"10 —101 subjects with heavy treatment experience were given a regimen of efavirenz (Sustiva), amprenavir (Agenerase) and abacavir. (Most of the study participants had taken 3 PIs and 5 NRTIs.) After 16 weeks of treatment, only 1 in 4 subjects had an undetectable viral load (less than 400 copies). Among the participants who had prior NNRTI experience and baseline plasma viremia greater than 40,000 copies, only 7% had an undetectable viral load at week 16.
For those who have been heavily treated with other nucleoside analogs, the introduction of Ziagen brand abacavir ismdash;at bestmdash;of no consequence andmdash;at worstmdash;a disappointment.
Furthermore, Glaxo has not elucidated the optimal clinical use of abacavir, and the wisdom of treating patients with the nucleoside-only regimen the company pursued in its pivotal study is unknown. The drug's unimpressive anti-HIV effect in patients with high baseline viral loads and its concomitant failure to produce short-term, significant rises in CD4 T cell count should caution physicians about the use of this agent as initial therapy in patients with advanced disease. However, for patients with limited or no NRTI experience, this latest addition to the anti-HIV armamentarium offers a potent, convenient and generally well-tolerated choice.
1 Delaney, Martin. GlaxoWellcome press release, December 1, 1998.
2 Ziagen package insert, GlaxoWellcome.
3 Ibid.
4 Point mutations associated with abacavir resistance include M184V, L74V, Y115F and K65R. M184V and L74V are the mutations most frequently recovered from clinical isolates.
5 Baseline phenotypic resistance to abacavir of 4 fold or less is associated with viral load reductions of up to 2 logs. Baseline resistance of 4-7 fold may still allow viral load decreases of as much 1.5 logs. Resistance of 7 fold or greater yields no measurable change in viral load.
6 Levin, Jules. NATAP Reports, March 3, 1998.
7 CNA3003.
8 In 1997, when this study began, three-drug therapy was the standard of care.
9 Percentage based on intent-to-treat analysis.
10 Gilden, Dave. Salvage therapy: still more intuition than data, Treatment Issues, 13:1, 9.
Accelerated approval: the abbreviated process under which the FDA grants conditional approval to a new drug.
Rechallenge: administration of a drug to a patient from whom the drug was previously withdrawn, usually for reason of toxicity.
P450 isoforms: pathways in the liver through which drugs are metabolized.
Pivotal study: a study on which the success or failure or a drug hinges. Results of a pivotal study are presented to the FDA when the company seeks marketing approval.
Double-blind: a kind of clinical study in which neither the physician nor the patient knows until after the study is over whether the patient received the treatment or a sugar pill. This type of study is done to avoid influencing the results with the bias or preconceptions of the physician or patient.
Plasma viremia: the amount of virus in the blood plasma.
Intent-to-treat analysis: a method of analysis in which all trial participants are counted in the results, even if they discontinued the drug. Contrast with on-treatment analysis that includes only those patients who remained on the drug.
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Copyright © 1999 - Research Initiative Treatment Action (RITA!). Reproduced with permission. RITA! is published by The Center for AIDS. Contact Thomas Gegeny, MS, ELS, Editor, RITA! for permission to reproduce RITA!. tom@centerforaids.org. http://www.centerforaids.org
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