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    • In the studies referenced above the majority of subjects

    2018-11-07

    In the studies referenced above, the majority of subjects were non-black (66% in (Ribaudo et al., 2010) and 80% in (Lubomirov et al., 2011)), yet the greatest increase in EFV use is likely in populations that are of broader ethnicity, thus it is of importance to determine whether SNP analysis is associated with EFV discontinuation in mixed ethnicity populations. We therefore sought to determine if pharmacogenetic testing of select SNPs in CYP2B6, CYP2A6, and CYP3A4 would be associated with premature treatment discontinuation of virologically suppressive, EFV-containing ART regimens in a multi-national, mixed ethnicity cohort of patients with a long duration of follow up.
    Materials and Methods
    Results 1134 participants were identified as meeting inclusion criteria, whereas 1204 participants did not. Of these, 761 (67%) participants had DNA of sufficient quantity and quality to perform the genotyping assay. After genotyping, 3 participants were excluded due to uninterpretable assay results. Thus, the analyses in this report are based on a total of 758 patients (See Fig. 1 for flow diagram). Of the 758 patients, 131 (17%) were ART naïve and initiated EFV as their first regimen and 315 (42%) were ART experienced who switched to EFV from another regimen. Eighty (11%) participants were ART naïve and initiated nevirapine (NVP) and 232 (31%) participants were ART experienced who switched to atazanavir (ATV) from another regimen. The characteristics of these patients at the time their cART regimen was initiated are summarized in Supplemental Tables 1 and 2. Of interest, 24% of all patients were black, which is a am580 known to have a greater incidence of premature cART discontinuation (Ribaudo et al., 2013).
    Discussion EFV-based regimens are recommended as first-line and command a substantial market share of current ART use; yet as EFV is now off patent and generic versions are available at lower cost, it is likely that the use of EFV containing regimens will increase in resource limited settings where cost of medications has prohibited widespread access to therapy. However EFV discontinuation rates for non-virologic reasons (i.e., for reasons other than viral resistance) can reach as high as 20% and therefore being able to a priori discriminate those who are more likely to tolerate EFV based therapy is of great global health importance. Herein we demonstrate in a multiethnic population, individuals with loss or decrease of function alleles for 2 or more EFV metabolizing enzymes, including CYP2B6, are at ~2-fold increased risk of premature discontinuation of EFV, irrespective of race or any other factor. As EFV becomes a more affordable and widespread option for HIV care, a pharmacogenetic test that accurately discriminates those patients who will discontinue EFV for ADE reasons could be an important addition to the clinician\'s decision tools for selecting cART regimens for individual patients. HLA-B*5701 testing to predict abacavir hypersensitivity significantly influenced the care of HIV, by allowing the safe use of a medication that had life threatening ADE potential. Notably, the frequency of the highest genetic risk score in the present study (5.3%) is similar to the reported frequency of HLA-B*5701 (Orkin et al., 2010). Being able to determine who will tolerate EFV may enhance the ability of patients who take EFV to tolerate EFV, lower risk of developing NNRTI resistance due to missed doses, and reduced morbidity due to ADEs. Each of these predictions is testable and warrants further study. This may lead to cost savings through less work and school absences, less need to switch cART regimens and incur the additional expense and inconvenience of doctor visits and lab tests needed to initiate and monitor a therapy change. This may not necessarily be the case though; the rate per 100 person years for stopping EFV (including ART experienced and naïve combined) in our study was 23.3. The corresponding rate for stopping NVP was 35.3; however, better tolerated agents are available now, including integrase inhibitors, which could be used instead of EFV or NVP. An alternative strategy could be reducing EFV dose. Evidence supporting reduced dosing for EFV is found in the ENCORE1 trial where reduced dose EFV (400mg) was non-inferior to 600mg EFV for virologic suppression, and study-drug related ADEs (Puls et al., 2014); it would be of great interest to stratify such an analysis by genetic risk score.