New abacavir data open door to a better treatment paradigm
Simple regimen with high potency makes for winning combination
Adding Glaxo Wellcome's experimental drug abacavir to the combivir two-drugs-in-one combo can provide results as good as those seen with protease inhibitors, yet it is easy to take and has few side effects or drug interactions, according to data Glaxo Wellcome presented at the 12th World AIDS Conference in Geneva.
"I think after Geneva there is going to be much discussion about treatment guidelines, and abacavir is going to change the way that looks," says Neal Graham, MD, Glaxo Wellcome's director for HIV programs for the United States. "We could be entering a new paradigm in terms of sparing whole classes of drugs and still getting a simple regimen with lots of potency."
Abacavir (ABC) is a nucleoside reverse transcriptase inhibitor developed by Glaxo Wellcome as an investigational treatment for HIV and is currently being studied in Phase III trials in adults and children. Two of those studies were presented at the conference, along with long-term, follow-up data on the drug reaching out to 72 weeks.
For the first time, Graham says, three drugs in the same class have effectively reduced viral load in treatment-naive patients to levels that have been seen only in those on protease inhibitors.
"The data are fairly provocative because the early promise of the drug has been held up," he says. "We are seeing very good viral load responses with combivir and abacavir together."
Compared to similar trials that combined a protease inhibitor with AZT and 3TC (the two drugs contained in combivir), the abacavir- combivir regimen data "look nearly identical," Graham says.
Intent-to-treat results from 16 weeks of treatment in 210 patients who were previously untreated and had CD4 levels higher than 100 showed that 75% of subjects had plasma HIV RNA levels below 400 copies, compared to 35% for those on combivir alone. The company presented only viral load data, as other end points were not unblinded yet. The results were particularly strong for patients with high viral loads. Approximately 67% of those who had viral loads over 100,000 copies (12 of 18 patients) had undetectable levels of virus (below 400 copies) at 16 weeks, compared to only 13% (2 of 16) of those taking combivir alone.
While the 16-week data are impressive, some researchers have withheld judgment until seeing longer follow-up. The company presented data from a small cohort of 50 patients who were part of a trial comparing AZT, 3TC, and ABC to ABC and a protease inhibitor. After 72 weeks of treatment, 70% of the patients on the AZT-3TC-ABC regimen have viral loads under 400 copies, while 55% have below 50 copies.
"It really looks more and more that we can meet and match a protease inhibitor-containing regimen," Graham tells AIDS Alert. "The beauty of combivir and abacavir is that it looks like you can get protease-inhibitor-like potency and not have to use a non-nucleoside or a protease inhibitor. And if you do have a problem, you have two classes of drugs which you haven't touched and with no cross-resistance."
So far, abacavir has been studied with each of the approved protease inhibitors as well. Other data presented at the conference showed that abacavir plus a protease inhibitor is a powerful combination that not only gets virus to undetectable levels, but works well in helping the immune system to reconstitute.
Indeed, for patients who want to hit hard and hit early, the abacavir-protease inhibitor combination is highly attractive because it is so much more potent then other nucleoside reverse transcriptase inhibitors, Graham notes. The drug has not gone head to head with nevirapine, a non-nucleoside reverse transcriptase inhibitor that also has strong potency, at least in the short term.
Four pills a day
Noting that abacavir is three times more potent than AZT and more than twice as strong as 3TC, Graham says the abacavir-combivir combination has the potential to change the way treatment is initiated because it is such a simple, compact regimen.
A regimen with abacavir provides dosing of two tablets a day with no food or water restrictions. With combivir also dosed at two pills a day, the triple-drug regimen adds up to only four pills a day. Indeed, one reason Graham suspects patients have done so well on the combination after 72 weeks is that it is easier to adhere to than other triple-drug regimens.
Later this summer, Glaxo Wellcome will begin randomizing patients to either an adherence education course or a standard of care as a way of systematically examining how compliance can be improved further. Called "Tools for Health Empowerment," the course has 11 education modules based on group-learning theory where patients and home caregivers are taught about issues as divergent as empowerment and pathogenesis. The company hopes to be able to offer the course to AIDS service organizations and community groups as well as to physicians, Graham notes, adding that it can be used for other treatment regimens, too.
High potency. Few pills. No serious drug interactions or side effects. Abacavir sounds like an ideal drug, but there is at least one area of concern. While toxicity data on more than 8,000 patients indicate that the drug has few side effects (there was no increase in adverse events in the abacavir-combivir regimen vs. combivir alone), up to 3% of patients have experienced hypersensitivity to the drug, Graham notes.
Before the phenomenon was well-characterized, hypersensitivity was severe enough that at least six patients were hospitalized. Although the patients recovered, one patient in France died from complications that may have been directly related to the drug, he explains.
In all cases, the patients were rechallenged with the drug, which is believed to have caused the severe reactions. The French patient rechallenged himself without medical care, Graham notes.
The company has worked hard to understand the problem and educate patients and providers on how to detect it, Graham says. "Physicians have done a good job recognizing and dealing with it and have not had much trouble differentiating it from other issues,"Graham says.
The reaction is characterized by fever, followed by other systemic symptoms, typically nausea, diarrhea, and rash. Fever is the most defining characteristic. The best way to differentiate the reaction is by giving the patient an additional dose, which is not harmful and will cause a heightened reaction within a few hours, Graham says. So far, abacavir has shown none of the more common side effects from protease inhibitors, such as liver toxicity, peripheral neuropathy, kidney stones, and fat redistribution.
The latter side effect has become a growing concern for patients taking protease inhibitors. One published study and two journal letters have described in these patients the frequency of fat wasting and redistribution, or peripheral lipodystrophy, as it is called. The problem of fat wasting and redistribution has caused a significant number of patients to stop taking the drugs, researchers report.
In the journal AIDS, researchers from Australia reported cases of lipodystrophy in 41 patients on indinavir and 25 patients on ritonavir-saquinavir in a study of nearly 200 HIV-positive men.1 The frequency of this condition increased with prolonged treatment with the drugs. The median time to lipodystrophy was 10 months in these patients, with the interval being shorter for patients on ritonavir-saquinavir than in those patients on indinavir.
The authors conclude that more long-term study is needed to determine whether fat depletion is associated with significant morbidity, and note that treatments for the condition need to be explored. In a letter to Lancet, the authors noted that the concern is greatest among patients in early treatment, where protease inhibitors have not yet shown a survival benefit. The frequency could become greater with long-term therapy, they conclude.2
Rebecca Wurtz, MD, a hospital epidemiologist at Evanston (IL) Hospital, also told in a recent letter to Lancet of two cases of women on protease inhibitors who had abnormal fat distribution. One of the women developed a small buffalo hump, while the other had muscle wasting in the arms.2
References
1. Carr A, Samaras K, Burton S, et al. A syndrome of peripheral lipodystrophy, hyperlipidaemia and insulin resistance in patients receiving HIV protease inhibitors. AIDS 1998; 12:F51-F58.
2. Wurtz R, Carr A, Samaras K. Abnormal fat distribution and use of protease inhibitors. Lancet 1998; 351:1,735.
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