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Yvette Delph Comments On the Future of HIV/AIDS Research

Summer 2001

Yvette Delph: Antiviral Project Director for Treatment Action Group

In the 20 years since AIDS was first described, HIV has been identified as the causative agent, tests for HIV have been developed, three classes of antiretroviral drugs (ARDs) have been licensed, and much has been learned about the effects of HIV disease and the drugs used to treat it. Even more needs to be learned. There is still no cure. Current ARDs cause major and sometimes fatal side effects, they need to be taken for life and their effectiveness against HIV is compromised within months in many people. And an effective vaccine is a very long way off.

There is a great need for new classes of ARDs that are effective against new HIV targets. The last new class of agents to reach the market, the non-nucleoside reverse transcriptase inhibitors (NNRTIs), was first licensed in the US in June 1996. There are some new drug classes in the pipeline. Hopefully they will provide effective ways of combating HIV, especially HIV that is resistant to current ARDs. These new drug classes include:

    Entry Inhibitors
      Attachment inhibitors
      • PRO 542
      • CXCR4 co-receptor inhibitors
        • bicyclams (AMD-3100)
        • polyphemusins (T22)
      • CCR5 co-receptor inhibitors
        • SC-351125
        • PRO 140
        • TAK 779
        • SCH-D
      Fusion inhibitors
      • T-20
      • T-1249
      • d-peptides
      • 5-helix
    Integrase Inhibitors
      Diketo acids
      • L-708,906
      • L-731,988
    Viral Capsid Formation and Assembly Inhibitors
      glycyl-prolyl-glycine amide (GPG-NH2)

There are other potential new targets in the HIV infection and replication cycle, which also offer the hope of novel, effective drugs against HIV. These include:

  • DC-SIGN inhibitors
  • Uncoating inhibitors
  • Maturation inhibitors
  • Zinc finger inhibitors
  • Inhibitors of HIV regulatory proteins (nef, rev, tat, vif, vpr)

Another important area of research is in the area of therapeutic drug monitoring (TDM). It is difficult to predict the blood levels of the current ARDs even when taken as prescribed and, because they are so prone to the development of both resistance and toxicity, it is postulated that adjusting drug dosages based on monitoring of drug levels may increase efficacy and decrease toxicity. Studies are underway involving TDM of protease inhibitors and NNRTIs. Initial results are conflicting but promising. TDM of nucleoside reverse transcriptase inhibitors (NRTIs) is not feasible at this time, as intracellular levels of nucleoside triphosphates would need to be measured.

Other areas of research which require greater attention and resources are: the effects of gender, ethnic, racial and age differences as well as co-morbidities (like hepatitis, diabetes, and cardiovascular disease) on HIV disease, its treatment and care. As the prevalence of multidrug resistant (MDR) HIV increases, options and strategies for salvage therapy are an increasing and urgent need. In general, pharmaceutical companies have not been willing to cooperate in studying investigational agents together in highly treatment-experienced persons. This is a disgrace that needs to be remedied urgently.

Structured intermittent therapy (SIT) is being studied for varying therapeutic strategies, including: as an immune stimulant (auto vaccination); for management of MDR; and for reduction of toxicity. SIT research deserves to be closely followed -- especially as a possible way to decrease toxicity, for which it seems to hold the most promise.

There is also a great need for well-designed, systematic research into the long-term (more than five years) effectiveness and toxicity of ARDs. Questions like when to start antiretroviral therapy (ART), what to start with, and when and how to change ART remain unanswered. Effective mechanisms for detecting known as well as unknown long-term toxicities of ARDs need to be developed and implemented.

There is much that remains to be answered about HIV treatment. It is imperative that adequate resources be dedicated and, even more important, the political will mustered to address these issues with the necessary urgency.

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This article was provided by AIDS Community Research Initiative of America. It is a part of the publication CRIA Update. Visit ACRIA's website to find out more about their activities, publications and services.