Antiretroviral Therapy
(Part XXIV)

Over the past year, viral resistance to antiretroviral agents has emerged as the dominant issue facing clinicians and patients. It is therefore not surprising that the annual resistance meeting has evolved to be one of the most important and eagerly awaited scientific conferences of the year. This year, to maintain an informal "workshop" environment, attendance was limited to approximately 200 scientists. Many representatives from academia, industry, advocacy groups, and the media were unable to attend.

This report will highlight some of the key presentations, focusing on presentations that have direct clinical implications or provide novel insights into drug resistance. As an introduction, this report begins with a brief review of resistance assays and mutation patterns associated with each of the 11 currently available agents.

Contents:

HIV-1 Resistance: A Primer

• Phenotypic assays
• Genotypic assays
• Mutations associated with resistance to antiretroviral drugs

• Virological outcomes in ACTG 320, a randomized, placebo controlled trial of indinavir in combination with two nucleosides
• Nelfinavir resistance: significance of pre-existing natural polymorphisms
• Resistance after long-term saquinavir therapy
• Indinavir resistance following saquinavir therapy
• Acquisition of mutations associated with reduced susceptibility to saquinavir (hard gel capsules)
• Acquisition of mutations to saquinavir soft gel capsule
• Nelfinavir and indinavir therapy following failure to saquinavir
• Viral resistance to the combination of ritonavir and saquinavir
• Drug resistance genotypes from plasma virus of HIV-infected patients failing combination drug therapy
• Genotypic analysis of HIV-1 protease from patients failing highly active anti-retroviral therapy

• Validation of HIV-1 RNA and CD4 count as surrogate markers in the CEASAR trial
• Detection of HIV-1 RNA in the plasma of patients in whom HIV-1 RNA is undetectable using commercial assays
• The durability of response to protease inhibitor therapy is predicted by viral load
• Genotypic or phenotypic susceptibility testing may not predict clinical responses to indinavir.

• Continued evolution of HIV-1 during combination therapy despite levels of HIV-1 < 500 copies/ml
• Emergence of drug resistance in different tissue compartments after 1 year of potent antiretroviral therapy
• Evidence for prevention of new HIV-1 infection cycles in patients treated with indinavir plus zidovudine plus lamivudine

• Drug resistance during indinavir therapy is caused by mutations in the protease gene and in its gag substrate cleavage sites
• A unique mechanism for zidovudine-resistance
• Pathways for zidovudine/lamivudine dual resistance
• Cross-resistance to HIV-1 protease inhibitors in vitro
• HIV genotypic variation in plasma and vaginal lavages