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Efficacy of adding indinavir to previous reverse transcriptase nucleoside analogues in relation to genotypic and
1Retrovirology Laboratory, Foundation irsiCaixa, Badalona, Barcelona, Spain.
Abstract:
We assessed the efficacy of adding indinavir in patients with advanced HIV-1 infection, who were previously exposed to different reverse transcriptase (RT) nucleoside analogues. Twenty-five patients with an initial median CD4 cell count of 20 cells/mm3 (range, 0-80 cells/mm3) were treated with indinavir (800 mg three times per day) for 24 weeks. The median initial viral load was 5.4 log (range, 3.6-6.7 log). Of these patients, 56% (14 of 25) had an initial decrease in viral load of >1 log and sustained response of >0.5 log of HIV-1 RNA from baseline. Twelve of these 14 responder patients (85%) showed a sustained RNA response undetectable by NASBA assay, and no genotypic changes in protease were detected at week 24. In those with a temporary or absent response to indinavir, either resistant viruses or lack of compliance was observed. In compliant patients (15 of 16), relatively small increases in 50% inhibitory concentration (IC50) to indinavir and only two to three amino acid changes were sufficient to produce treatment failure. Phenotypic drug-resistant assays at 24 weeks revealed cross-resistance to ritonavir in all the patient isolates and to saquinavir in one third of the isolates. We observed an initial and persistent response to the addition of indinavir in patients with advanced disease and prolonged antiretroviral treatment. Therapy failure, as defined by increases in viral RNA, was associated with either lack of compliance or the development of low level indinavir-resistant virus. Clinical studies need to be designed to determine to what extent these viruses may respond to other protease inhibitors.
Insights
Adding indinavir showed initial efficacy in advanced HIV-1 patients, with over half achieving viral load reduction. However, treatment failure was linked to indinavir resistance or poor compliance.
Area of Science:
- Virology
- Immunology
- Pharmacology
Background:
- Patients with advanced Human Immunodeficiency Virus type 1 (HIV-1) infection often have prior exposure to nucleoside analogue reverse transcriptase inhibitors.
- Assessing new treatment regimens is crucial for managing advanced HIV-1 disease and overcoming drug resistance.
Purpose of the Study:
- To evaluate the efficacy of adding indinavir to existing antiretroviral therapy in patients with advanced HIV-1 infection.
- To investigate the development of drug resistance and its correlation with treatment outcomes.
Main Methods:
- A 24-week study involving 25 patients with advanced HIV-1 (median CD4 count 20 cells/mm3) treated with indinavir (800 mg TID).
- Viral load and CD4 counts were monitored, alongside genotypic and phenotypic resistance assays for protease inhibitors.
Main Results:
- 56% of patients achieved a significant decrease (>1 log) in HIV-1 RNA viral load, with 85% of responders showing undetectable levels by NASBA assay.
- Treatment failure in compliant patients was associated with low-level indinavir resistance (2-3 amino acid changes) and cross-resistance to ritonavir and saquinavir.
- Lack of compliance was also identified as a factor contributing to treatment failure.
Conclusions:
- Indinavir demonstrated initial efficacy in advanced HIV-1 patients, but resistance development and compliance issues impacted long-term outcomes.
- The emergence of resistant viral strains necessitates further research into the effectiveness of other protease inhibitors in this patient population.