The Body Covers: The 1st International AIDS Society Conference on HIV Pathogenesis and Treatment
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Antiretrovirals: What's Next? (Abstract IL10)
Speaker: Doug Richman
Authored by Richman, D.; University of California, San Diego, CA, USA
Given the success of antiretroviral therapy overall in prolonging life, HIV specialists have begun to shift their attention to treatments that have a favorable balance of both potency as well as optimal freedom from longer term side effects. It is now clearer that treatment has the chance to be successful not just for months but for years and perhaps decades. Thus, steps needed to allow people to live on our medications requires we focus on issues of improved convenience, short and longer term toxicity, increased potency, as well as medications that allow options if viral rebound occurs. If antiviral activity and toxicity can be separated, it is critical that this be the focus of new drug development. However, since there is a lack of clarity regarding the mechanisms of at least some of the most troubling toxicities, it is impossible to do lab screening to avoid such side effects. This is true for the major side effect concerns such as increases in cholesterol, increases in blood sugar, and lipodystrophy. Thus, initial testing must be vigilant to define the early signs of such side effects.
Sometimes -- just through luck -- medications are identified that do not have side effects otherwise common for their class of medications. This is the case for a protease inhibitor under development by BMS, now called atazanavir (formerly 232632). This protease inhibitor has shown promise given that it is taken just once daily, and shows potency similar to what is seen with nelfinavir. However, the issue of cholesterol increases seen with many of the current protease inhibitors is not seen with this drug, based on data from two studies. In addition, this agent retains activity after there is resistance to others, although studies to define its success in this regard are still awaited. Phase III studies are currently being launched in several sites around the world.
Dr. Richman briefly reviewed a number of agents currently in the earliest phases of testing, with a discussion of the salient features that make the product distinct:
DAPD: this nucleoside, under development by Triangle, shows enormous potency in the face of resistance to ZDV (AZT) and 3TC (Epivir).
DuPont 681/684: These two new protease inhibitors show retained activity against virus that is resistant to currently used protease inhibitors based on test tube work.
Tibotec 120: This non-nucleoside, now in phase I, shows activity similar to other non-nucleosides such as nevirapine and efavirenz, and in test tubes shows retained activity to HIV even after there is resistance to the current non-nucleosides.
Further behind in development are agents to target enzymes that are as yet not targeted by currently marketed agents. These include:
Schering "C" or "D": These agents target CCR5, a co-receptor on cells that is necessary for viral entry. Both appear to be active, and phase I testing of the former has restarted.
Integrase inhibitors: under development by Merck, there are agents that -- in test tubes -- appear to interfere with the steps required by HIV to integrate itself into cellular DNA. Phase I testing is anticipated to begin sometime in the next year if current plans continue to suggest this is acceptable to do.
Zinc finger inhibitors: There is a step in the HIV life cycle that is critical for assembly of HIV, and requires a zinc-containing enzyme; thus, agents that are active by interfering with these enzymes are being developed. To date, there appear to be compounds that have acceptable activity while at the same time showing acceptable toxicity in cell culture studies.
While there are a number of compounds in active development, there is generalized concern that the industry is beginning to show signs of decreased interest in pursuing the development of compounds for HIV infection. This is alarming to many in the field, since it is clear that we are far from finished in defining a series of treatments that meet the criteria spelled out at the beginning of the talk; hopefully these agents reviewed here, plus others, will help us be closer to that challenge.
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