AIDSWEEKLY Plus, Monday, 24 February 1997
Daniel J. DeNoon, Senior Editor
Why look for new anti-HIV drugs when media reports have declared that the advent of triple-drug combinations signals the end of AIDS?
The answer, in a nutshell, is that the complex dosages, toxicities, and drug interactions of these treatments make them hard for patients to take and difficult for doctors to prescribe.
But new drugs under development - and new combinations including existing drugs - hold the promise of improved, individualized treatment strategies.
"There is reason for hope amid the hype," said long-time AIDS clinician Ann Collier of the University of Washington, Seattle.
Collier discussed the status of antiretroviral therapy in an address to the Fourth Conference on Retroviruses and Opportunistic Infections, held January 22-26, 1997, in Washington, D.C.
She provided a checklist of desirable characteristics for the next generation of antiretroviral therapies:
It is not necessary for all new drugs to satisfy each or all of the above requirements. "But if new agents don't have at least one, or hopefully several of these attributes, it is unlikely that they will be useful or gain widespread use," Collier warned.
She noted that for at least the next several years, most combination antiretroviral strategies will include reverse transcriptase inhibitors (RTIs).
Among the most promising of the new RTIs is the prodrug of the nucleoside analog carbovir, dubbed 1592U89 by manufacturer Glaxo/Wellcome. Collier noted that some 150 patients have been treated with the drug.
"The key point to note is a marked anti-HIV effect regardless of dose with a median decrease in HIV RNA of 1.5 to 2 logs," she said. "These preliminary data are certainly impressive for a nucleoside RTI. The pharmacokinetic properties and CNS [central nervous system] penetration make this compound a high interest for future combinations."
One such combination already under clinical study is the combination of 1592U89 with the new experimental protease inhibitor 141W94 (a.k.a. VX-478 -- see the accompanying article in this issue).
Another promising nucleoside is the uracil-based HEPT derivative known as MKC-442, licensed from the Mitsubishi Kasei Corp. by Triangle Pharmaceuticals, Durham, North Carolina.
MKC-442 is a potent drug with a remarkably long half-life, permitting twice-daily administration (see AIDS Weekly Plus, February 3, 1997).
A third nucleoside of note is the adenine analog adefovir dipivoxil, previously called bis-POM-PMEA by manufacturer Gilead Sciences Inc., Foster City, California.
"[Its] convenient dosing schedule and tolerability suggest a potential role as part of combination regimens," Collier said.
But existing nucleosides are still going strong. Collier noted that didanosine (ddI) and stavudine (d4T) achieve potent anti-HIV effects in combination, and that the two drugs appear to act synergistically in combination with hydroxyurea.
She also noted that non-nucleoside RTIs are proving more useful than had previously been thought possible. New NNRTIs include loviride (the (alpha)-APA derivative originally known as R 89439; Janssen Research Foundation, Beerse, Belgium) and DMP-266 (the benzoxazinone L-743,726; Merck).
"If additional data [on DMP-266] continue to describe activity and show tolerance, it will certainly be of interest for other combinations," Collier said.
She pointed to new studies showing that there may be a future role for the existing NNRTI nevirapine, which, in combination with zidovudine (AZT) and ddI, yields potent and long-lasting decreases in viral load and increased CD4 counts.
As impressive as the current crop of protease inhibitors are, new agents provide tantalizing hints of improved efficacy, pharmacokinetics, and/or tolerability.
The new Abbott drug ABT-378 is highly potent in vitro even in the presence of human serum, which tends to bind most HIV protease inhibitors. Moreover, very small doses of ritonavir markedly increase plasma levels of ABT-378.
"Certainly this has potentially great interest in the clinical setting," Collier said. "The data from the upcoming Phase I studies merit close attention."
Early results from trials of the protease inhibitor 141W94 (formerly VX-478) have generated strong tolerability, pharmacokinetic, and bioavailability data.
"The preliminary results and b.i.d. regimen certainly suggest a promising role for this agent in combination with other antiretrovirals," Collier said.
The Agouron protease inhibitor nelfinavir (AG1343) is now becoming available.
Collier said that the drug cannot be co-administered with rifampin or trefinadine, but noted that three clinical studies enrolling some 700 patients demonstrate that the drug can be effective.
"These data demonstrate that nelfinavir-containing regimens do have potent anti-HIV effects for at least 24 weeks - in particular the triple combination - and suggest that this compound will be a useful addition to the anti-HIV armamentarium," she said.
Other types of new drugs that inhibit neither HIV protease nor reverse transcriptase are in earlier stages of development. These have a wide array of targets: cell binding; cell fusion, HIV integrase, gag, and mRNA; nucleocapsids; nucleotide reductase; and zinc-finger motifs.
"The wide range of approaches under serious investigation is a testimony to scientific creativity," Collier said. "Caution is clearly in order until these concepts have demonstrated activity in humans, but the diversity of approaches is certainly encouraging and exciting."
Future anti-HIV strategies, Collier predicted, will build on the new AIDS treatment paradigm calling for the use of powerful drugs as standard therapy.
"What's clear to all of us is that potent combinations - which in early 1997 means regimens containing three agents - achieve better HIV suppression for longer than dual regimens," she said. "But there is no magic in the number 'triple': already the use of four-agent therapies is under investigation. We can also conceive in the future that two- drug regimens may be developed at some point which are as potent as our current three-drug regimens."
Collier suggested that, given the great interpatient differences in HIV disease, there may never be a single standard drug regimen.
"We need to get better at individualizing our treatments," she said. "Each patient is an individual and we now have sensitive measures of disease activity to help us. That said, we're all aware that the number of combinations which could be used will only increase as new drugs are added to our armamentarium."
Choosing a combination from this growing list must be based on consideration of potency; synergy or additivity, or at least not consistent in-vitro antagonism; non-overlapping resistance patterns; dissimilar toxicities; inclusion of agents with CNS activity; and, perhaps most importantly, "regimens that humans can take without devoting their lives to alarm clocks on their watches."
The choice of drugs will be strongly determined by which of three treatment strategies are pursued: 1) eradication, employing intensive combination treatment for a defined period in an effort to cure HIV infection; 2) lifelong suppressive therapy, employing combination therapy that can provide maximum HIV suppression for a patient's lifetime. Such treatment would be altered as needed to deal with drug- resistant HIV strains that might emerge. The third strategy is remission-inducing therapy, in which aggressive treatment would be given for a defined period and then gradually reduced to a less intense regimen intended to maintain extremely low viral load.
"Each of these strategies is being studied and no one, even with a crystal ball, knows which strategy will ultimately be best," Collier said.
She reminded her audience of a statement attributed to Voltaire: "Perfection is attained by slow degrees. She requires the hand of time."
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