In general, it is astonishing how few mutations were observed overall in the 228 patients of the study who have failed therapy. Only 43% of patients had any drug resistance-associated mutation detected. Missing drug pressure due to poor adherence could be a LDN-193189 supply possible explanation for the low prevalence of mutations but it is probably not the major reason because.75% of patients reported to have an excellent adherence. Nevertheless, the prevalence of resistance might be underestimated. Currently used genotypic resistance tests have a population detection limit of only,20%. Additional resistant virus variants might be present at lower levels. The late and rare occurrence of PI/r mutations can be explained by their high genetic barrier compared to NNRTIs. However, the mechanism explaining the lack of resistance to co-administered NRTIs remains unknown. It can be speculated that the two drug classes may have different activities in different anatomical compartments, with regards to free versus cell-cell virus transmissionso that the activity of PI/r might be sufficient to suppress NRTI resistant strains to undetectable levels. It could also be possible that NNRTIs, as they target the same gene as NRTIs, might select for yet unidentified compensatory mutations in the RT connection-, respectively, RNase TWS119 H-domain of the pol gene, subsequently leading to more rapid emergence of NRTI mutations. In theory, the presence of minority variants harboring NNRTI- or NRTI-drug resistant mutations, which have been detected in drug naive HIV-1 infected patients, could have a more severe impact in a regimen that contains a “low genetic barrier” drug rather than a PI/r. This aspect cannot be excluded in the present study.. Poorer adherence in the PI/r-treated group could also possibly explain the differencesbut adherence was excluded as potential bias in a sensitivity analysis. In addition, different NRTI backbones in PI/r- and NNRTI-treated individuals might have influenced our results. To disprove this concern, we performed a sensitivity analysis only including patients with a TDF/FTC backbone and we adjusted the logistic regression for the NRTI backbone. Although our study initially considered 5959 patients who started first-line cART, only 228 individuals qualified for our study. The sample size was too small to compare different treatment regimens in more detail. Unfortunately, sufficient longitudinal resistance data from our patients were not available; otherwise dynamics of evolution of individual drug resistance mutations could have been investigated in more detail. In addition, we cannot exclude that there are resistance associated mutations outside the sequenced region. No phenotypic resistance tests were available that could prove that viruses which do not harbor any mutations are really sensitive to the drugs. In conclusion, PI/r containing cART leads to long-lasting protection of the activity of NRTIs and PI/r despite ongoing viral replication after virological failure. Accumulation of drug resistance mutations against all three drugs of the regimen is slower and less frequent when compared to NNRTI-containing regimens, thus retaining more options for second-line therapy. These findings are of high relevance for settings, which lack the opportunities for regular virological monitoring and where the use of PI/r as first-line therapies should be considered. Inhibiting proteasome function has been demonstrated as a novel therapeutic strategy in multiple disease models like fibrosis, inflammation, ischemia-reperfusion injury and cancer. Proteasome inhibitor bortezomibhas been approved by the United States Food and Drug Administration to treat multiple myeloma.