Conference updates show promising drug data
Conference updates show promising drug data
New combinations, easier regimens provide options
A trial of dual-protease inhibitor therapy shows that ritonavir plus saquinavir suppresses HIV RNA within the central nervous system. It also shows that the experimental non-nucleoside reverse transcriptase inhibitor, DMP 266, combined with another protease inhibitor, crixivan, also can suppress virus to undetectable levels in blood, according to data presented at the 37th Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC) in Toronto.
In a late-breaking session, Abbott Laboratories of Abbott Park, IL, announced the results of an ongoing trial of 141 patients receiving different treatments of its drug ritonavir (Norvir), combined with Hoffmann-La Roche’s saquinavir mesylate (Invirase). Of patients who reached 48 weeks of therapy, nearly 90% had undetectable plasma HIV RNA (less than 200 copies). For 13 patients treated for 60 weeks, the virus was analyzed in their central nervous system, a potential reservoir for HIV. All but one were shown to have undetectable virus (less than 400 copies) there.
"These data suggest that the combination of Norvir/Invirase reduces the virus harbored in the central nervous system," says Charles Farthing, MD, medical director of the AIDS Healthcare Foundation in Los Angeles and an investigator in the study.
The regimen was generally well-tolerated, the companies note. The most common adverse reactions were tingling around the mouth, diarrhea, fatigue, and nausea.
Also presented in a late-breaking session were data on ritonavir taken by children in combination with stavudine (D4T) or with zidovudine (AZT) and lamivudine (3TC). Data on 162 children, whose median age was 7 years, showed that 61% of those taking ritonavir and D4T had undetectable HIV RNA at 12 weeks, compared to only 14% for those taking AZT and 3TC without the protease inhibitor. As a result, the treatment arm without ritonavir was closed.
In another dual-protease inhibitor combination, Abbott announced that ritonavir causes an increase of indinavir blood levels. A preliminary study of four combinations of ritonavir and indinavir at reduced doses showed that standard indinavir dosing was achieved, suggesting that twice-daily dosing of both drugs may be possible.
Abbott also presented data on its next-generation protease inhibitor, ABT-378, in combination with ritonavir. Because its in vitro potency is 10 times greater than ritonavir, only a single daily dose was given to the study’s 48 patients, and was found to be well-tolerated. A single-dose protease inhibitor would have the added benefit of increasing drug compliance, researchers noted.
New NNRTI shows promise
DuPont Merck Pharmaceutical Co. of Wilmington, DE, presented Phase III results at ICAAC on its new non-nucleoside reserve transcriptase inhibitor (NNRTI), DMP 266 (efavirenz). In data reported at 48 weeks, 88% of the 59 patients receiving a combination of DMP 266 and indinavir achieved HIV RNA levels (less than 400 copies, while CD4 counts increased an average of 245 cells. No increase in side effects for treatments containing DMP 266 over indinavir alone were reported.
A combination of DMP 266 and another protease inhibitor, nelfinavir (Viracept), resulted in an increase of approximately 15% in nelfinavir blood levels. "These data indicate that once-daily efavirenz and nelfinavir at regular doses may be a promising combination and such clinical trials are under way," said Nancy Ruiz, MD, medical director of virology at DuPont Merck.
The company also reported that analysis of cerebrospinal fluid in three patients taking 200 mg of the drug once daily showed measurable levels of DMP 266. Also, the drug appears to retain its activity against nucleoside analog- resistant mutants.
Another study, presented at the 35th Meeting of the Infectious Disease Society of America in San Francisco showed that an investigational soft gel formulation of saquinavir (Fortovase) has nearly 10 times the drug exposure of the current hard gel formulation (Invirase).
When used in combination with AZT and 3TC, the protease inhibitor reduced viral load below detectable limits (400 copies) in 77% of patients, and increased CD4 counts by 143 cells at 12 weeks, researchers noted.
The study enrolled 41 treatment-naive patients with more than 10,000 copies of HIV-RNA and CD4 counts greater than 100. They received 1200 mg of fortovase three times daily. The drug was well-tolerated by most patients. The most frequent adverse reactions were diarrhea, nausea, and headache. After 12 weeks, only two patients had to withdraw because of side effects.
Results from ongoing trials of triple-drug combinations were recently published in the New England Journal of Medicine. Researchers for the study (ACTG 320) report that a combination of indinavir and two nucleoside analogues (zidovudine and lamivudine) "significantly slows the progression of HIV-1 disease" in patients with CD4 counts of 200 or lower, as compared to treatment with zidovudine and lamivudine alone.1 The study enrolled 1,156 subjects who had previously been treated with zidovudine, but had not taken lamivudine or protease inhibitors. Only 6% of the patients on triple-drug therapy progressed to AIDS or death, vs. 11% in the two-drug group. Mortality in the three-drug group was 1.4%, compared to 3.1% in the zidovudine and lamivudine group.
Ronald Mitsuyasu, MD, an AIDS specialist at UCLA who helped lead the trial, noted that triple combination therapy was superior to the two-drug combination in both subgroups of the study those with advanced AIDS (CD4 counts less than 50), and those with CD4 counts between 51 and 200.
"It is clear that well-tolerated therapies of ever-increasing potency, such as the indinavir-containing arm of this study, are preferred for people with advanced HIV disease," he noted.
In a second study published in the same issue of the Journal, researchers reported that a combination of indinavir, zidovudine, and lamivudine significantly reduced levels of HIV RNA in HIV-infected patients who had previously taken zidovudine.2
The double-blind study randomly assigned 97 HIV-positive patients with CD4 counts between 50 and 400 and at least 20,000 copies of HIV RNA per milliliter to either 800 mg of indinavir every eight hours; 200 mg of zidovudine every eight hours, plus 150 mg of lamivudine two times a day; or all three drugs. A combination of the three drugs produced the best response, reducing HIV RNA levels to under 500 copies per milliliter in 90% of the triple-drug recipients within the first 24 weeks. In that same time period, only 43% of the indinavir-only patients and none of the zidovudine-lamivudine recipients had HIV RNA levels under 500.
References
1. Hammer S, Squires K, Hughes M, et al. A controlled trial of two nucleoside analogues plus indinavir in persons with HIV infection and CD4 cell counts of 200 per cubic millimeter or less. N Engl J Med 1997; 337:725-733.
2. Gulick R, Mellors J, Havlir D, et al. Treatment with indinavir, zidovudine, and lamivudine in adults with HIV infection and prior antiretroviral therapy. N Engl J Med 1997; 337:734-739.
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