• New Treatments and Targets
  Authored by Roy Gulick (New York, U.S.A.)
  Abstract PL3.1

In this presentation, Dr. Roy (Trip) Gulick of Cornell University, New York City, presented an overview of new drug development in the field of HIV. The major reasons for new drug development are the following:

1. Previously approved drugs frequently involve complex dosing regimens and many of the drugs in current practice have varying degrees of toxicity. This has led to problems of adherence to complex antiviral regimens.

2. Resistance has developed against all currently approved drugs; this may reflect problems of adherence but is also a consequence of low-level viral replication (and, hence, mutations), even in cases of good adherence.

3. Treatment failure (rising viral loads, declining CD4 counts, accompanied by mutations in the current targets of approved antiviral therapy, i.e., reverse transcriptase and protease) may be eventually seen in as many as 60 percent of patients.

4. Currently approved HIV drugs are all expensive and there is a need for cheaper products, particularly for developing countries.

For these reasons, newer drugs and combinations are urgently needed. In his summary, Dr. Gulick spoke about novel compounds that block HIV entry into cells by attacking the fusion process, a promising development, and mentioned that at least one such compound, T-20 (enfuvirtide, Fuzeon), may be close to being approved. He also spoke of a need to enhance the pharmacokinetic properties of antiretroviral drugs.

He discussed a number of novel nucleoside and non-nucleoside antagonists of reverse transcriptase (RT), that may remain active against viral isolates shown to be resistant to previously approved members of these drug classes. In some cases, this may be due to the fact that these newer compounds select preferentially for different mutations than their predecessors. Hence, a distinct mutational profile may enable their use in salvage regimens after initial failures. The same rationale applies, of course, to protease inhibitors (PIs), and several of these seem far along in regard to study in clinical trials research (e.g., atazanavir [BMS-232623, Zrivada] and tipranavir [PNU-140690]).

New agents currently being developed include other inhibitors of viral entry that act by blocking interactions between gp120 and the CD4 receptor and/or interactions with chemokine receptors (the Schering C and D compounds), and antagonists of the viral integrase enzyme (Merck and Shinogi/GSK).

Scientists are also hard at work at identifying other targets for future drug development. These include the viral vif, rev and tat proteins and the RNaseH enzyme that is associated with reverse transcriptase activity.

Consideration of where we are in regards to current management of HIV disease needs to factor into account that new drug development is ongoing and will never be at a standstill. Physicians must sometimes make treatment decisions for failing patients based on short-term considerations, while hoping that new drugs will arrive on the scene to provide longer-term success.