New drugs garner interest; but inhibitors lose shine
New drugs garner interest; but inhibitors lose shine
New options being recommended
As increased reports of adherence and toxicity problems have dampened remarkable gains in protease inhibitor therapy, researchers at the 12th Worlds AIDS Conference presented a strong case for offering patients alternative options using two promising candidates from a different class of drugs. And while the conference lacked the hyped-up treatment breakthroughs that marked this gathering two years ago, dramatic decreases in adult mortality and mother-to-child transmission underscored the scope of benefits gained since the Vancouver meeting.
"There isn't any loss of enthusiasm for what is being accomplished in care," John Bartlett, MD, chief of infectious diseases at Johns Hopkins University in Baltimore, tells AIDS Alert. "The CDC surveillance data are very convincing in terms of reductions in mortality and opportunistic infections."
Although the 75% decline in AIDS mortality and morbidity seen in the United States over the past three years isn't shared by many countries, researchers reported significant drops in cases of mothers transmitting the virus to infants in those countries where zidovudine preventive therapy is available. Indeed, by combining AZT prophylaxis with cesarean section, transmission was nearly eliminated in a study of women in France, reports Lynn Moffenson, MD, assistant chief of the maternal and child health branch at the National Institute of Child and Human Development in Bethesda, MD.
Among 902 mothers undergoing AZT therapy at a Paris hospital, those who delivered vaginally had a 6.6% transmission rate, compared to 0.8% for those who underwent emergency cesarean. Although cesarean section is not a viable HIV prevention method in those developing countries where AIDS prevalence is greatest, she noted that the findings, along with the recently reported success of short-course AZT preventive therapy, indicate that most transmission occurs at or near the time of birth.
More treatment options available
News of antiretroviral treatment options presented here took on added significance in light of the increased prevalence of drug resistance seen in patients on protease inhibitors. How much of this phenomenon is due to poor adherence to regimens or to treatment failures is not clear. However, researchers presented compelling data showing that other options are needed as patients face the prospect of extended therapy now that it is clear that virus cannot be completely eradicated as hoped.
Against that backdrop, follow-up studies were presented on two investigational drugs: abacavir, a nucleoside reverse transcriptase inhibitor manufactured by Glaxo Wellcome in London, England, and efavirenz, a non-nucleoside reverse transcriptase inhibitor made by DuPont Pharmaceuticals in Wilmington, DE.
Comparable results have been seen when efavirenz is combined with two other antiretroviral drugs. The drug suppressed HIV RNA levels to below quantifiable levels (less than 400 copies) in a greater percentage of patients than did a standard regimen containing a protease inhibitor, DuPont researchers reported.
In combination with AZT and 3TC, efavirenz suppressed HIV through 24 weeks more effectively than AZT, 3TC, and indinavir in 450 primarily antiretroviral-naive patients. Schlomo Straszewski, MD, director of the outpatient clinic for HIV-infected patients at Johann Wolfgang Goethe University in Frankfurt, reported at the conference that significantly fewer patients taking efavirenz dropped out of the study, possibly reflecting better tolerance of the drug and its once-daily dosing regimen.
While Bartlett put both abacavir and efavirenz at the top of the list of exciting new drugs, he and other top AIDS experts cautioned that long-term results are lacking and resistance could develop more rapidly when treatment is limited to only one class of drug.
"People here are saying three nukes are not going to do it [provide long-term suppression] - you need another point of attack," he said. "For some patients it may be preferable, but not for the majority."
Another potentially powerful treatment offering fewer pills is the combination of the non-nucleoside reverse transcriptase inhibitor nevirapine (Viramune) with stavudine (d4T) and didanosine (ddI). The treatment combination is a twice-daily regimen requiring only seven to eight pills per day, and has no cross-resistance with protease inhibitors, researchers noted. In one study presented at the conference, 54% of patients (13 of 24) who had detectable virus at baseline achieved undetectable viral load during the 26-week study period. Researchers from Vancouver underscored the long-term potency of nevirapine, showing that patients had maintained viral suppression and stabilized CD4 counts for nearly three years on a combination of nevirapine, ddI, and AZT.
"For patients experiencing difficulties with protease inhibitors, changing to this more convenient but still effective regimen [nevirapine, d4T, and ddI] is a very attractive option," Cathy Pell, MD, a researcher at Taylor Square Private Clinic in Sydney, Australia, said at the conference.
Another drug that has gained interest is hydroxyurea, an agent used since the 1960s primarily for leukemia and sickle cell anemia, and which works against HIV by inhibiting a cellular enzyme the virus needs to replicate. Promising results on several combinations with the agent were presented at the conference, including a triple-drug regimen with didanosine (ddI) and stavudine (d4T).
"Hydroxyurea is an attractive option in combination therapy to treat HIV because it prevents viral rebound for a long period of time," said Franco Lori, MD, an Italian AIDS researcher who was the first to experiment with the drug in HIV treatment.
Noting that a third drug may be needed that also targets actively replicating target cells, Lori presented data on the combination of hydroxyurea, ddI, and the protease inhibitor indinavir in 11 patients with primary HIV infection. In all patients, virus became undetectable (less than 50 copies) and remained undetectable throughout 78 weeks of treatment.
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