viral drug resistance

..With appropriate analysis, ultra-deep pyrosequencing is a promising method for characterizing genetic diversity and detecting minor yet clinically relevant variants in biological samples with complex genetic populations...

..Minor (i.e., <20% prevalence) drug-resistant human immunodeficiency virus (HIV) variants may go undetected, yet be clinically important...

..We used sensitive and simple tests to investigate evidence of transmitted drug resistance in antiretroviral drug-naïve persons and assess the clinical implications of minority drug-resistant variants...

..The alternative regimen of lopinavir-ritonavir plus efavirenz may prevent toxic effects associated with NRTIs...

..The updated SDRM list has 93 mutations including 34 NRTI-resistance mutations at 15 RT positions, 19 NNRTI-resistance mutations at 10 RT positions, and 40 PI-resistance mutations at 18 protease positions...

..We identified predictors of viral failure and documented genotypic mutations in a subset of patients with viral failure after 12 months on antiretroviral therapy (ART)...

..Early surveillance data suggest that the prevalence of oseltamivir resistance among A(H1N1) viruses will most likely be higher during the 2008-2009 season...

..Tenofovir disoproxil fumarate (DF) is a once-daily nucleotide analogue reverse transcriptase inhibitor...

..The aim of this study was to characterize adefovir resistance in a patient who developed clinical and virologic evidence of breakthrough during a 96-week course of treatment...

..Our analysis suggests that it may be possible to exploit the size and location of the group-1 cavity to develop new anti-influenza drugs...

....

..Therefore, we evaluated the possible role of minority quasispecies of drug-resistant human immunodeficiency virus type 1, which are undetectable at baseline by population sequencing, with regard to early virological failure...

..In conclusion, 48 weeks of adefovir dipivoxil resulted in significant improvements in virologic, biochemical, and clinical parameters in CHB patients pre- and post-LT with lamivudine-resistant HBV...

..Thus, there is a need to standardize nomenclature relating to hepatitis B antiviral resistance, and to define genotypic, phenotypic, and clinical resistance to NA therapy...

..7) and H1N1 (ref. 8) viruses with neuraminidases carrying these mutations, our results indicate that it would be prudent for pandemic stockpiles of oseltamivir to be augmented by additional antiviral drugs, including zanamivir...

..As antiretroviral regimens for the treatment of HIV infection improve, trials providing data on long-term follow-up are increasingly important...

..We assessed whether this risk could be overcome by adefovir-lamivudine combination therapy...

..The replication capacity of both mutants, in particular that of the His274Tyr virus, was impaired when compared with the wild-type virus in vitro...

..The prevalence of resistance was assessed among patients from KwaZulu Natal, South Africa, following failure of their first highly active antiretroviral therapy (HAART) regimen...

..The ability of these viruses to sustain their fitness and spread among persons should be considered when shaping future strategies for treating and preventing seasonal and pandemic influenza...

..However, other factors, such as entropy compensation and solvent anchoring, might also be exploited for improved drug design...

..The need to preserve NAb resistance may therefore be a constraint upon how escape from CCR5 inhibitors occurs in vivo...

..High usage of the neuraminidase inhibitor (NAI) oseltamivir in Japan since 2003 led the Neuraminidase Inhibitor Susceptibility Network to assess the susceptibility of community isolates of influenza viruses to oseltamivir and zanamivir...

..We investigated the clinical relevance of the detection of majority and minority-resistant variants in an observational study in antiretroviral therapy naive, recently infected patients...

....

..Taken together, these findings demonstrate that HIV-1 infection in Cyprus is being replenished by a continuous influx of new strains from many countries, establishing an ever-evolving and polyphyletic infection in the island...

..These findings offer insights into the effect of PIR mutations on the evolution of BVM resistance in PI-experienced patients...

....

..However, continued vigilance, especially of emerging avian H5N1 strains, combined with careful, systematic laboratory-based monitoring, is essential...

..These findings support the idea that minority viral populations with distinct resistance genotypes, although undetectable by standard genotyping, can contribute to the failure of salvage regimens...

..This hypothesis was further corroborated by the observation that a high concentration of maraviroc blocks the activity of aplaviroc against maraviroc-resistant virus...

..These findings suggest that drug therapy for poxviruses may be complicated by drug resistance but that treatment of the infection with currently known compounds is possible...

..Drug-resistance mutations are predicted to counter the effect of drug binding by either increasing the hydrophilicity of the pore or weakening helix-helix packing, thus facilitating channel opening...

..Altogether, these results account for the predominance of G140S/Q148H mutants in clinical trials using Raltegravir...

..Patients with YMDD variants losing clinical response with a significant increase in the HBV DNA and ALT levels may require additional therapy...

..The frequency of variants with decreased sensitivity to the NAIs did not increase significantly during this period, but continued surveillance is required, especially in regions with higher NAI use...

..Owing to capacity constraints, standard patient care, treatment initiation and follow up are based on World Health Organization (WHO) clinical staging and do not provide laboratory monitoring to assess treatment failure...

..A single dose of nevirapine during labor reduces perinatal transmission of human immunodeficiency virus type 1 (HIV-1) but often leads to viral nevirapine resistance mutations in mothers and infants...

..Substitutions selected under treatment were observed at positions corresponding to HIV-1 resistance mutations as well as at positions of currently unknown impact on HIV-1...

..Further, the clinical implications of low-abundance drug-resistant variants at time of virologic failure are unknown...

..A method has been developed to estimate a fitness landscape experienced by HIV-1 under treatment selective pressure as a function of the genotypic sequence thereby also estimating the genetic barrier to resistance...

..We analyzed NVP resistance in HIV-infected Ugandan infants who received either SD NVP or extended NVP prophylaxis...

..Our finding reveals that sequence analysis of the transmembrane domain of M2 protein may not adequately identify all drug-resistant variants...

..Protease (PR) cleavage site (CS) mutations could compensate for impaired replication capacity of drug-resistant viruses...

..Furthermore, children can be a source of viral transmission, even after 5 days of treatment with oseltamivir...

..Although resistant viruses fade to undetectable levels in plasma, they may persist as stably integrated proviruses within the latent reservoir in resting CD4(+) T cells, potentially complicating future treatment...

..The findings reported here may stimulate and encourage new strategies for developing effective drugs against influenza A, particularly in dealing with the drug-resistant problems...

..In the light of emerging resistance, close monitoring and understanding of the nature and dynamics of resistance mutations in newly emerging strains should be a priority...

..All together, these results define at the molecular level how nucleoside-resistant viruses can be driven to reduced viral fitness...

..Characterization of the phenotypic and clinical significance of these common patterns may lead to improved treatment recommendations for a large proportion of patients for whom antiretroviral therapy is failing...

..Successful therapy heavily relies on the expertise of the clinician...

..To describe current practice in testing for transmitted antiretroviral drug resistance (TDR) and the prevalence of TDR in a large UK HIV-1 cohort...

..Better knowledge of the quantitative dynamics of the immune response during influenza infections will be crucial to further improve the results...

....

....

..These data argue for testing all drug-naive patients and are of relevance when guidelines for management of postexposure prophylaxis and first-line therapy are updated...

....

..We used the WHO's HIVDR threshold survey method to assess transmitted HIVDR in three antenatal clinic (ANC) sites along the corridor between the two most populous cities in Swaziland, where ART was introduced in 2003...

..Here, we review how mathematical models have been used to provide insights into the emerging threat of antiviral resistance. We focus mainly on the problem of drug resistance to HIV...

..To determine the underlying biochemical mechanisms responsible for the diminished viral replicative capacity associated with K65R/M184V-containing viruses...

..4A protease inhibitor, has shown strong antiviral activity in phase 1 clinical studies. Because of high levels of HCV replication and the low fidelity of HCV polymerase, selection of resistant isolates during therapy may occur...

....

..This study examined whether, in the context of a first-line abacavir/lamivudine highly active antiretroviral therapy (HAART) regimen, K65R might occur as a minority population where L74V was detected at virological failure...

..There are few data on the selection of resistance by ritonavir-boosted saquinavir (SQV/r), particularly in antiretroviral (ARV)-naive patients...

..Women previously exposed to ART for PMTCT who will start HIV treatment should have genotypic resistance testing performed...

....

....

....

..Despite the presence of different mutations, the viral variants were still susceptible to other RTIs and PIs that are currently not available in Tunisia. Thus, alternative therapeutic options exist but are not yet accessible...

..Dried blood spots (DBS) are a convenient alternative to plasma for drug resistance testing in resource-limited settings. We investigated the correlation between resistance genotypes generated from DBS and plasma...

..The objective of this study was to determine the impact of the emergence of drug-resistance mutations on survival among persons initiating HAART...

..These findings support the use of resistance testing in HIV-infected inmates who must begin antiretroviral therapy, given the high rate of primary resistance to drugs frequently included in the initial treatment regimens...

..CONCLUSIONS: In patients with advanced resistance, treatment simplification prevented resurgence of wild-type HIV, reduced drug burden, but failed to stabilize progression of the immune deficiency...

..To study the antiviral efficacy and the mutations selected by a triple therapy with zidovudine (AZT), lamivudine (3TC) and tenofovir disoproxil fumarate (TDF)...

..Viral populations defined by 103K/N and 184M/V as linked or single mutations in the HIV-1 reverse transcriptase gene were investigated in plasma samples and compared with previous findings in the CD45RO(+)T cell compartment...

....

..However, such programs will not produce comparable estimates unless a standardized list of drug-resistance mutations is used to define transmitted resistance...

..In conclusion, the assay permits the quantitation of the level of resistance of clinical HIV-1 isolates to PR and RT inhibitors...

..This strategy may be beneficially applied in the treatment of children in Africa, where thymidine analog + lamivudine-based regimen became available recently but further options are limited...

....

..Therefore, treatment intensification in those patients without resistance, or a selective substitution of nucleosides in those with resistance limited to these compounds, might be justified...

..The findings suggest, immunological recovery notwithstanding, virological failure is independent of drug-resistant mutations and consequent possible changes in viral fitness...

..Further studies are needed to elucidate the precise regions that are essential for these characteristics...

..Thus, drug monitoring may be useful to assess treatment adherence and risk of drug resistance in early virological failures. This information may be crucial for choosing the most appropriate rescue intervention...

..Switching from d4T/ddI to ZDV/3TC may be associated with a higher incidence of four or more NAM. Thus, suboptimal and dual NRTI therapy is not recommended for global application...

..To determine whether HIV-1 replicates locally in the female genital tract during therapy, and to study whether endocervix is the dominant source of virus in cervicovaginal lavage fluid...

..New formulations of amprenavir, together with boosted regimens, may enhance the activity in the presence of protease inhibitor-resistant virus...

..62 vs. 80.32% for VG). Rule-based algorithms can reliably interpret genotypic data obtained from most heavily pretreated patients. However, occasional genotypic patterns may be erroneously interpreted without resistance phenotyping...

..55-fold higher in patients with the M184V/I mutation than in patients without detectable mutation (P=0.007). CONCLUSIONS: The M184V/I mutation is frequently selected during repeated treatment interruptions...

..To identify predictors of the virological response to antiretroviral therapy in patients in whom initial therapy has failed...

..We conclude that in the presence of suboptimal ART, sexually transmitted infections may enhance the spread of drug-resistant HIV-1...

..It may be important to routinely test for resistance in newly infected cases to improve the choice of drugs for treatment because the virus may revert and resistant forms can become latent...

....

..Further studies should clarify whether this is true for other drugs of the nucleoside analogues class...

..M184V/I mutation is associated with high-level phenotypic resistance to lamivudine (3TC). The aim of the present analysis was to correlate the time of appearance/disappearance of M184V/I with duration of 3TC treatment...

..In contrast, resistance among pre-treated patients has increased; resistance to all three drug families having been recognized in nearly a quarter of patients...

..A continuous surveillance of the circulation of ARV drug-resistant viruses must be organized to guide ARV treatment strategies and policies...

..The clinical significance of the polymorphisms associated with reduced susceptibility to NNRTIs remains to be clarified...

..CONCLUSIONS: Our data confirm the association among individual pharmacokinetic parameters, genotype pattern and virological response to NFV-containing regimens...

..The' study will determine: 1) the incidence and prevalence of resistant CMV; 2) risk factors for the development of resistant CMV (e.g. duration of anti-CMV therapy); and 3) the relationship between viral resistance and clinical outcome...

....

..b>Viral drug resistance is a continuum; a certain fold-change in virus susceptibility does not necessitate a drug will be inactive ..

..motifs associated with NCI, and to study the relationship to viral subtype and the relationship of viral drug resistance in different compartments to NCI...

....

..A combination of genetic, virological, biochemical, and crystallographic approaches will be initiated. Efforts to discover new agents that exploit this interaction (and to understand their mechanisms) will also begin. ..

....

..ARV therapy is expected to dramatically increase in developing countries, and viral drug resistance evolution will inevitably take place...

..Antiviral effects will be correlated with the kinetics of drug entry into the CSF. ..

..Non-adherence results in poor response to therapy, viral drug resistance, cross-resistance and the spread of drug-resistant viral strains...

..A combination of genetic, virological, biochemical, and crystallographic approaches will be initiated. Efforts to discover new agents that exploit this interaction (and to understand their mechanisms) will also begin. ..

..efficiently, and by doing so, it will help develop anti- HIV therapeutics that are both less susceptible to current clinically significant resistance mutations as well as more refractory to the development of viral drug resistance.

..efficiently, and by doing so, it will help develop anti- HIV therapeutics that are both less susceptible to current clinically significant resistance mutations as well as more refractory to the development of viral drug resistance.

..efficiently, and by doing so, it will help develop anti- HIV therapeutics that are both less susceptible to current clinically significant resistance mutations as well as more refractory to the development of viral drug resistance.

..Future plans are to test the drugs and strategies in our SHIV/rhesus macaque models for mucosal membrane transmission and AIDS. ..

..W. Lawrence Drew (UCSF) and from Dr. Alejo Erice (University of Minnesota). ..

....

..This research integrates organic synthesis, protein-ligand x-ray crystallography, molecular modeling and in-depth virus and cell-biological studies to design the next generation of HIV-1 protease inhibitors. ..

....