A belated response to Ariella. Just my opinion, but I wonder if 1592 will be widely used as "an option for those whose virus has grown resistant to protease inhibitors" due to a potentially life threatening side effect as well as cross resistance issues. exchange2000.com
According to an older article in Treatment Action News, Nov. 97, thebody.com
Glaxo reported that "In the experience to date with the experimental antiretroviral, Abacavir (1592U89), about 3% of patients have developed a systemic hypersensitivity reaction. Initially this reaction is usually not severe and will go away by itself within a couple days of stopping the drug. But if it does occur, the patient must not try the drug again; if they do, a serious and potentially life-threatening condition can develop within hours.
The initial reaction usually begins from a few days to four weeks after starting Abacavir. At first there is low-grade fever, nausea (with or without vomiting), and malaise (not feeling well, as with the flu); these symptoms build up over a few days. There is usually a rash, although sometimes it is not noticed by the patient. As soon as the fever and flu-like symptoms occur, the drug must be stopped, or the symptoms will become increasingly severe. After discontinuation the symptoms will disappear rapidly, and there seems to be no further problem, as long as the patient never tries the drug again.
But when Abacavir has been tried again, high fever, severe nausea and vomiting, and rash (not severe) have developed within hours. In four of these cases there was life- threatening low blood pressure. These patients were hospitalized with intensive care. No deaths had occurred at the time of this article.
According to Glaxo, the problem appears to be entirely manageable by recognizing the small percentage of patients who cannot tolerate Abacavir and must stop using it permanently. Glaxo is planning research to determine the mechanism of action of the hypersensitivity, which currently is unknown. At this time there is no way to predict which patients are likely to develop it. About 2,000 people have taken Abacavir so far, and the drug's overall safety appears to be good. Clinical trials continue to accrue patients and the Abacavir development program continues unchanged (comments written in November 1997).
Glaxo Wellcome is educating physicians, researchers, and volunteers in clinical trials about Abacavir hypersensitivity; information has also been shared with the FDA. Anyone suspecting that they have developed hypersensitivity to Abacavir should speak with their investigator or physician immediately.
Dr. Deeks and Dr Schouten, in summary articles of the 5th Retro conference in February, commented on the hypersensitivity issue, and reported that one patient has died and 5 were hospitalized.
hivinsite.ucsf.edu
(Section on Abacavir (1592U89- Dr. Deeks)
thebody.com
Section 5: Antiretroviral Chemotherapy I (Dr. Schouten)
From Dr. Schouten's summary:
Dr. John Mellors presented a study of 1592, an RTI in combination with five different protease inhibitors at the retro conference. 80 patients were randomized into groups that received Abacavir (300mg every 12 hours) in combination with either Indinavir (Crixivan), Ritonavir (Norvir), Saquinavir (Fortovase), Nelfinavir (Viracept) or the new protease inhibitor, 141W94 (1200mg every 12 hours). The drugs performed well with 50-85% of the participants below 400 copies of the virus at 16 weeks, and 40-70% below 50 copies at 16 weeks (Dr. Mellors noted that the arm containing saquinavir produced inferior results). Some participants developed a rash from Abacavir (2-5%) that was seen 3-42 days after beginning therapy. It is important not to re-start Abacavir after discontinuing the drug (re-challenging) because of the development of a rash. Five people were hospitalized and one person died after they were re-challenged with Abacavir.
Dr. Deeks comments: "Abacavir, a potent nucleoside reverse transcriptase, appears to be very effective when used in combination with a protease inhibitor. The acute hypersensitivity reaction associated with Abacavir is potentially severe: clinicians must be very familiar with this drug and the management of adverse events prior to prescribing it." Abacavir is available in expanded access for patients with HIV dementia, due to it's superior ability to cross the blood-brain barrier.
As far as cross-resistance, early study results suggested as much as a 2 log reduction in plasma HIV RNA when treatment na‹ve patients were treated with 1592. Data recently presented by Dr. David Hardy to an investigator's meeting sponsored by Glaxo-Wellcome, however, suggests that heavily pre-treated patients may not benefit from 1592. While patients pre-treated with ddI or d4T experienced relatively normal reductions in plasma HIV RNA (about 1.5 log) after twelve weeks of 1592 treatment, patients with extensive AZT or AZT+3TC double nucleoside therapy were much less responsive: after twelve weeks of therapy, patients with more than a year of prior AZT treatment had only a .05 log reduction while patients with extensive AZT+3TC therapy had only a 0.05 log reduction. Since the lion's share of the traditional expanded access population will have received loads of prior AZT (and invariably 3TC too), it is unlikely that they will receive much benefit from 1592 -- at least based on the results from this study: from article titled "1592U89 (Abacavir): efficacy & resistance data"
natap.org in section on Drug Development.
New web site of National AIDS Treatment Advocacy Project
An abstract by Palmer et al, "Highly Drug-Resistant HIV-1 Isolates are Cross Resistant to Many of the Current Compounds in Clinical Development" found that most of the new drugs in clinical development already show
resistance, including 1592 and Vertex' protease inhibitor VX478, that is in Phase III clinical trials (Abstract 405).
Palmer et al tested isolates containing mutations common to reverse
transcriptase inhibitors and protease inhibitors and found that many of the
new drugs in clinical development were resistant to these common mutations
In other words, 1592 and VX478 were already resistant to this isolate, which contained mutations commonly found in other reverse transcriptase inhibitors and protease inhibitors.
.
1. 1592U89 and F-ddA and PFA were highly resistant to the
MNR - multinucleoside-resistant isolate; (with mutations-75L,77L,116Y,151M)
PMEA and PMPA were partially susceptible, and HBY 097 was completely
susceptible to this MNR.
2. The MDR isolate contained 7 RT inhibitors mutations and 7 protease
inhibitor mutations. MDR isolates were resistant to
1592U89, FddA, VX-478 were resistant to this MDR.
PMEA< PMPA< HBY 097, and SD-146 were sensitive to this MDR.]
The authors propose that new drugs be assessed for activity against highly
drug-resistant pre-clinically, to develop better salvage therapies.
As far as the hypersensitivity reaction that has occurred in Abacavir (1592), it is no longer a "serious and potentially life-threatening condition" if one patient has already died. And if my impression is correct, it is not always easy for the patient or physician to tell if this hypersensitivity reaction has occurred, as the rash may not even be noticed.
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