Tesis doctoral de Roger Paredes Deiros
This doctoral thesis by compendium of publications addresses the clinical relevance of minority hiv-1 variants harboring resistance mutations. The first publication presents a systematic evaluation of allele-specific polymerase chain reaction (aspcr) as a tool to detect low-frequency viral variants harboring resistance mutations in the reverse transcriptase (m184v, m184i) and protease (d30n)-coding regions of pol, as well as in env (v38a). In the second publication, we use this technique alongside others to characterize with high resolution the decay dynamics of m184v mutants in subjects infected with multidrug-resistant hiv-1 who interrupt treatment with reverse transcriptase inhibitors and continue protease inhibitors. This study shows that aspcr can be used to estimate the fitness of particular allelic variants in vivo and helps to improve our understanding of quasispecies dynamics in the presence and absence of therapy. The third publication shows how detection of low-frequency mutants can be applied to the surveillance of primary antiretroviral resistance, increasing the prevalence of resistance mutations by 2 to 3-fold relative to using bulk sequencing of plasma viruses. In the fourth publication, we show that antiretroviral naí¯ve hiv-1-infected pregnant women frequently select resistance mutations to drugs with low-genetic barrier during pregnancy-limited antiretroviral therapy; again, the frequency of resistance mutations increases more than two-fold using the aspcr assay. These findings have important clinical implications, given that women selecting resistance mutations during pregnancy-limited antiretroviral therapy may be more likely to fail postpartum antiretroviral therapy. In the fifth publication we demonstrate that pre-existing minority variants harboring resistance to non-nucleoside reverse transcriptase inhibitors more than triple the risk of virological failure to first-line efavirenz-based antiretroviral therapy, even in drug-adherent subjects. In summary, this work demonstrates that minority hiv-1 resistant variants, which are often missed by standard viral population sequencing assays, do modify antiretroviral therapy outcomes and therefore are of major clinical importance.
Datos académicos de la tesis doctoral «Clinical implications of minority hiv-1 resistant variants«
- Título de la tesis: Clinical implications of minority hiv-1 resistant variants
- Autor: Roger Paredes Deiros
- Universidad: Autónoma de barcelona
- Fecha de lectura de la tesis: 24/03/2009
Dirección y tribunal
- Director de la tesis
- Daniel Robert Kuritzkes
- Tribunal
- Presidente del tribunal: josep María Gatell artigas
- francesc Vidal marsal (vocal)
- (vocal)
- (vocal)