Resistance, drug failure, and disease progression

Area of Science:

• Virology
• Immunology
• Pharmacology

Background:

• The clinical significance of reduced in vitro susceptibility of HIV to antiretroviral agents, particularly nucleoside analogs like zidovudine, remains challenging to define.
• Conversely, the virological significance of resistance to non-nucleoside reverse transcriptase inhibitors (NNRTIs) like nevirapine is well-established.

Purpose of the Study:

• To elucidate the clinical significance of HIV drug resistance, particularly in relation to antiretroviral therapy (ART) and disease progression.
• To investigate the prognostic value of specific HIV drug resistance mutations and biological phenotypes in patients undergoing treatment.

Main Methods:

• Analysis of clinical trial data (ACTG 116B/117) examining the relationship between prior zidovudine therapy duration and switching to didanosine.
• Preliminary analysis of resistant HIV strains isolated from patients to identify correlations between resistance, biological phenotype, and clinical progression.

Main Results:

• High-level resistance to zidovudine was identified as a significant poor prognostic factor, associated with a threefold higher relative hazard of progression.
• No direct relationship was found between the duration of prior zidovudine therapy and the benefit of switching to didanosine.
• Emergence of nevirapine resistance is rapid, though high dosages may retain activity against resistant strains.

Conclusions:

• Acquisition of HIV strains with high-level zidovudine resistance portends a worse clinical outcome.
• Currently, viral resistance and biological phenotype are not sufficiently informative for guiding individual patient management in HIV therapy.