The Body Covers: The 39th Annual Meeting of the Interscience Conference on Antimicrobial Agents and Chemotherapy
Managing HIV Disease for Life --
New Issues Challenges, and Opportunities
September 26, 1999
This talk reviewed the significant number of new agents now in Phases I-III, with an eye towards defining the potential niche for each product in future regimens. Overall, there is still a need for new agents, and the criteria for identifying promising agents includes the following characteristics:Abstract: Improving Existing Drugs and Designing Better Compounds
There are five NRTIs that were reviewed. They include:
FTC: Known now as emtricitabine, developed by Triangle. It is a fluorinated nucleoside analogue, with in vitro activity against HIV and Hepatitis B virus. It appears to be more potent than lamivudine, and is given once daily at a dose of 200 milligrams. The side effect profile appears minimal, but the resistance profile is similar to lamivudine.
f-ddA: Known as lodenosine, developed by US Bioscience. It is a purine nucleoside analogue, and can be taken without regard to food intake. Little in vitro cross resistance is seen with other NRTI's so far, and it retains potency even in the presence of HIV with the 151M mutation conferring cross resistance to most of the current NRTI's. In a small study presented at ICAAC 99, the combination of stavudine, indinavir and f-ddA was shown to result in a 1.8 log reduction in viral load in four weeks, and was generally well tolerated.
d-OTC: Another cytosine analogue with good CNS penetration. Monotherapy studies showed a 1.3 log drop in 7 days, and PK analysis showed a half life of 14 hours, allowing QD dosing. It is active against AZT and 3TC resistant virus in animal models.
DAPD/DXG: the second guanosine analogue (after abacavir), DXG is the active metabolite. It has significant activity against common AZT and 3TC resistance mutations.
In addition to new agents, there are improvements being made to current agents. Four studies have tested didanosine given once daily, and compared it to results when using it in the standard BID schedule. The most recent study was presented at ICAAC by Dr. Gathe, and used a new 200 mg. tablet dosed as two tablets given once a day, in combination with stavudine and nelfinavir. At week 24 there was similar viral suppression with 79% below 400 copies, compared with 73% who were on ZDV, 3TC, and nelfinavir. Further, there were similar or less adverse events noted on a study which compared QD to BID ddI given with stavudine (Mobley, AIDS 1999, 13 F87). Of note, there was less diarrhea with the QD schedule, with 9% reporting diarrhea, as compared with 21% on the BID arm. While the 200mg. tablet is under active development, there is a newer form of ddI also in development, with an enteric coated capsule formulation. As the capsule passes through the stomach and releases its contents in the small intestine, there is no need for buffer, simplifying the amount of medication taken, as well as reducing any side effects attributed to the buffer.
Seven new protease inhibitors were reviewed by Dr. Gathe.
ABT-378: This agent, coformulated with ritonavir, has received a great deal of attention for several reasons. First, it maintains activity against isolates that have mutations associated with all of the currently used agents, and clinical data confirm that it shows activity against these isolates. Further, the drug is well tolerated, with loose stools as the most frequent adverse event noted. An impressive 89% of antiviral naïve patients had a viral load below 50 copies at week 24 in the first study done with this agent, and a second cohort results confirm similar response rates.
Tipranavir: This nonpeptidic PI has in vitro activity against HIV isolates that show resistance to any of the available agents. Further, the 48V and 90M mutations seems with many agents results in hypersensitivity to this agent. However, there is cross resistance seen in the presence of some of the substitutions at position 82 and 84. It has in vitro synergy with compounds in each of the other classes. Initial dosing was at a somewhat cumbersome 1500 mg TID, but studies are ongoing to explore its combination with ritonavir to simplify the schedule and dose required. Initial clinical trial results reported over a one log reduction in patients with preexisting PI resistance when added as a single agent.
AG 1776: This against shows activity against strains with multiple mutations currently seen with other PI's, and has in vitro synergy with ritonavir, indinavir and nelfinavir. Clinical data are expected next year.
L-756,423: This PI is structurally similar to indinavir, and in combination with it may overcome indinavir resistant strains due to an increase in serum levels of the compound. It appears to have PK supporting QD dosing.
BMS 232632: This compounds has an in vitro resistance pattern that suggests that there is some cross resistance from indinavir and ritonavir, while amprenavir, nelfinavir and saquinavir resistant strains remains sensitive to this agent. In addition, virus resistant to this compound remain sensitive to saquinavir. PK data suggest the possibility of QD dosing, and phase II data are expected next year.
MKC-442: Clinical data were presented at ICAAC about this compound, developed by Triangle. It is given at a BID schedule, with no food restrictions. Side effects similar to other compounds in this class have been reported, including a rash, and CNS disturbances noted. In vitro data suggest that the K103N mutation may arise on this compound.
AG-1549: This agent has an interesting in vitro resistance profile, in that virus with one mutation at K103N was fully sensitive to this compound, although more than 2 of the common NNRTI mutations do result in reduced susceptibility.
DMP-961/963: The two compounds show greater activity against K103N mutations than do current compounds, and it has a very long half life in animal studies.
Adefovir: This compound is familiar to many clinicians as multiple studies have been presented over the past few years. These studies demonstrate the favorable characteristics of QD dosing, and enhanced activity in the presence of the 184V mutation in the RT gene. Because of its urinary excretion, there is a concern for proximal renal tubular dysfunction reported, although dose reductions to 60 mg. have decreased the incidence of this problem at 48 weeks while maintaining similar antiviral activity.
Tenofovir (PMPA): This agent is also dosed QD, and had favorable clinical trial results presented in both antiviral naïve and RT experienced patients. Maximal viral load drops nearing one log are reported when used as a single agent, and the activity appears to be maintained even when added to an existing regimen. Renal dysfunction has not been a problem in studies done so far.
Other agents reviewed briefly include T-20, the first active fusion inhibitor. Initial results from a four week dose finding study demonstrated over 1 log drops in viral load in the first few weeks, although there was some rebound seen within the first month. However, follow up results using this combination in patients with multiply resistant virus suggested the potential for improved durability, and there were few adverse events noted despite the subcutaneous administration.
Finally, Dr. Gathe summarized the likelihood that there would be at least one new agent in at least one of the current classes of agents, and perhaps even a new class available in the future. The need to use these agents in combinations was urged, so as to minimize the historically observed loss of potency when each of these agents gets wide use as soon as it introduced.
Authored by: Joseph Gathe, M.D., Clinical Instructor, Baylor College of Medicine, Houston, Texas
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