PubMed · 16078811
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Carol M Dunckley. 2005. Julius.. https://doi.org/10.1002/chp.18
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BACKGROUND: HIV proviral sequencing overcomes the limit of plasma viral load requirement by detecting all the 'archived mutations', but the clinical relevance remains to be evaluated. METHODS: We included 25 participants with available proviral sequences (both intact and defective sequences available) and utilized the genotypic sensitivity score (GSS) to evaluate the level of resistance in their provirus and plasma virus. Defective sequences were further categorized as sequences with and without hypermutations. Personalized GSS score and total GSS score were calculated to evaluate the level of resistance to a whole panel of antiretroviral therapies and to certain antiretroviral therapy that a participant was using. The rate of sequences with drug resistance mutations (DRMs) within each sequence compartment (intact, defective and plasma viral sequences) was calculated for each participant. RESULTS: Defective proviral sequences harbored more DRMs than other sequence compartments, with a median DRM rate of 0.25 compared with intact sequences (0.0, P = 0.014) and plasma sequences (0.095, P = 0.30). Defective sequences with hypermutations were the major source of DRMs, with a median DRM rate of 1.0 compared with defective sequences without hypermutations (0.042, P < 0.001). Certain Apolipoprotein B Editing Complex 3-related DRMs including reverse transcriptase gene mutations M184I, E138K, M230I, G190E and protease gene mutations M46I, D30N were enriched in hypermutated sequences but not in intact sequences or plasma sequences. All the hypermutated sequences had premature stop codons due to Apolipoprotein B Editing Complex 3. CONCLUSION: Proviral sequencing may overestimate DRMs as a result of hypermutations. Removing hypermutated sequences is essential in the interpretation of proviral drug resistance testing.
We consider the application of instrumental variable techniques in a longitudinal clinical trial in paediatric HIV/AIDS, with a substantial degree of non-compliance to randomized treatment (Nelfinavir versus placebo) and with left censoring of the outcome variable (HIV RNA concentration). We consider in detail the assumptions and implications behind the inclusion and exclusion of interactions between randomized arm and baseline covariates in modelling actual treatment received, and between treatment and baseline covariates in modelling outcome. Estimated treatment effects were sensitive to inclusion of interactions, and we show how such sensitivity can be explored and explained.
Many AIDS patients in China who received free-of-charge antiretroviral therapeutics, including nucleoside reverse transcriptase inhibitors (NRTIs) and nonnucleoside reverse transcriptase inhibitors (NNRTIs), showed significant life improvement. Increasing numbers of patients, however, are experiencing antiretroviral therapy failure due to the emergence of drug-resistant viruses. The aim of this study was to investigate the genotypic and phenotypic drug resistance patterns of HIV-1 subtype B' variants, which are prevalent in China, in order to rationally design more efficient anti-HIV-1 regimens for future treatment of AIDS patients. 13 out of 16 patients (81%) who were treated with two NRTIs (ddI, and d4T or AZT) and one NNRTI (NVP) exhibited high resistance to NVP, 8 of them with a >1,000 IC50 fold increase. Five codons (101, 103, 108, 181, and 190) were involved in the NVP-resistant mutations, and K103N and Y181C mutations were predominant in these isolates. Fifteen isolates were resistant to at least one of the NRTIs, with high resistance to AZT (>10 IC50 fold increase) and intermediate resistance to d4T or ddI (approximately 4 IC50 fold increase). More than 10 codons were involved in the NRTI-resistant mutation and located in two regions (M41-V75 and T215-K219) of the reverse transcriptase. Concordance between the genotype and phenotype patterns for both NRTIs and NNRTI were detected in a majority of the isolates, suggesting that phenotypic resistance is predictable from genotyping assays, which are faster and less expensive than phenotypic assay. Because NVP and AZT can induce high resistances in these patients, these two drugs should be replaced with others more effective NNRTIs and NRTIs.