Daniel Kuritzkes

..This review summarizes recent information on antiretroviral drug resistance...

..This heterogeneity makes it difficult to draw general conclusions about the relationship between patterns of CCR5 antagonist resistance and the use of specific CCR5 domains for entry...

..We sought to compare clearance rates of plasma human immunodeficiency virus type 1 (HIV-1) RNA in men and women starting triple-nucleoside-based versus efavirenz (EFV)-based regimens...

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..Because "archived" resistant HIV may emerge quickly once treatment is initiated, we need to keep this in mind when selecting initial therapy...

..We wished to determine the safety and anti-human immunodeficiency virus (HIV) type 1 activity of single doses of TNX-355, a humanized IgG4 anti-CD4 monoclonal antibody with potent activity against HIV-1 in vitro, in HIV-infected subjects...

..This randomized study shows that TAMs accumulate at similar rates during treatment with ZDV or d4T, but the specific pattern of mutations may differ somewhat in patients treated with these thymidine analogues...

..27 [95% confidence interval], 1.15-4.49; P = .018). These results support resistance testing before starting antiretroviral therapy...

..Resistance may be overcome by pharmacological enhancement of plasma PI levels, but newer drugs that are active against PI-resistant viruses are needed...

..To provide an overview of HIV-1 entry inhibitors, with a focus on chemokine receptor antagonists...

..The TRUGENE HIV-1 Genotyping Kit and OpenGene DNA Sequencing System consistently generate highly accurate sequence data when tested with IMC-derived HIV and patient samples...

..5 +/- 2.4% overall platform performance (n = 9 devices). This integrated platform has potential for point-of-care testing (POCT) to rapidly capture, image and count specific cell types from unprocessed whole blood...

..It is concluded with 95% confidence that phase 1 viral decay differences between exon 26 TT and CC groups are unlikely to exceed 18%...

..These findings provide evidence that increased HIV-1 replication during filgrastim treatment was associated with activation of HIV-1 variants that, before filgrastim treatment, were minor components of the plasma quasi species...

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

..Sequences from the Stanford HIV RT and Protease Sequence Database showed that these mutations were more common in HIV-1 isolates from patients treated with zidovudine and lamivudine than in patients not treated with these drugs...

..Pregnancy-limited antiretroviral therapy (PLAT) drastically reduces HIV-1 transmission to the newborn, but may select for antiretroviral drug resistance mutations in mothers...

..HIV-specific CD4+ T-cell immunity was detected in most subjects with low-level and undetectable viremia and may have a role in controlling viremia in the setting of partial suppression...

..There were no significant differences among subgroups with respect to treatment responses. These results demonstrate the potency of efavirenz-containing regimens across a spectrum of pretreatment VLs and CD4 counts...

..Quantification of future drug options as an outcome of antiretroviral therapy trials may complement traditional clinical, virologic, and immunologic end points, thereby providing novel insights...

..The clinical relevance of detecting minority drug-resistant human immunodeficiency virus type 1 (HIV-1) variants is uncertain...

..Peripartum administration of single-dose nevirapine reduces mother-to-child transmission of human immunodeficiency virus type 1 (HIV-1) but selects for nevirapine-resistant virus...

..clinicaltrials.gov NCT00125099)..

..We also hope to inform the field regarding issues in choosing composite versus virological endpoints as well as other key considerations in trial design and monitoring...

..Available data suggest that lamivudine contributes to partial viral suppression, despite the presence of M184V mutations and high-level phenotypic lamivudine resistance...

..Analyzing viral fitness can provide important insights into the role of polymorphisms in drug resistance...

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

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..We report on a child initiated on this regimen, during concurrent TB treatment, who promptly developed an adverse reaction, virologic failure and dual-class antiretroviral drug resistance, compromising subsequent salvage ART...

..1 to 0.4%. These technologies should help define the impact of low-frequency drug-resistant mutants on response to antiretroviral therapy...

..These results help explain why T215Y but not T215F usually emerges as the first major TAM, as well as the clustering of L210W with TAM-1 mutations and T215F with TAM-2 mutations...

..Resulting sequence data were highly accurate compared to a "home brew" assay and clonal sequence analysis...

..However, there are no quantitative analyses supporting this hypothesis...

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..Pretreatment V3 loop sequences reemerged following VCV discontinuation, implying that VCV resistance has associated fitness costs...

..91 versus -0.57 log(10) copies/mL at week 24, respectively. Results suggest that the enhanced-sensitivity assay is a better screening tool for determining patient eligibility for CCR5 antagonist therapy...

..Greater V3 diversity was observed post-selection. This previously unreported degree of V3 loop sequence diversity has implications for viral pathogenesis, vaccine design, and the optimal use of HIV-1 CCR5 antagonists...

..These results show that Delta70 enhances resistance to certain purine and pyrimidine analogues and contributes to multinucleoside resistance in the appropriate viral genetic background...

..Subsequently, ENF was readministered for 4 weeks as "pulse intensification."..

..In contrast to observations when all drugs are interrupted, loss of resistance during enfuvirtide interruption is most likely due to ongoing viral evolution (and back-mutation), rather than emergence of an archived virus...

..A variety of methods are available to determine HIV-1 co-receptor usage, commonly referred to as viral tropism. This article reviews recent data on phenotypic and genotypic assays of HIV-1 tropism...

..We further address the substantial impact PEPfAR has achieved in general and more specifically toward improving maternal and child health and why continued PEPfAR investment remains essential...

..As the roll out of antiretroviral therapy continues in developing countries, drug resistance monitoring for both subtype B and non-subtype B strains of HIV will become increasingly important...

..Limitations of resistance testing remain, and more study is needed to refine optimal use and interpretation...

..However, there is a need for additional trials to better define the role resistance testing may play in developing management approaches to mitigate or minimize emergence of resistant HIV...

..After a lag phase of variable duration, wild-type variants emerged due to continued evolution of pol and back mutation rather than through emergence of an archived wild-type variant...

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..Further studies are needed to determine whether the reduced fitness of ENF-resistant viruses alters their pathogenicity in vivo...

..This assay provides a sensitive, efficient and relatively low-cost approach suitable for use by research laboratories for assessing HIV-1 coreceptor usage of plasma samples...

..Lower plasma efavirenz clearance is associated with a cytochrome P450 2B6 gene (CYP2B6) polymorphism (516G-->T) that is more frequent among African American individuals than among European American individuals...

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..In addition, ASPCR can be used to assess the dynamics of mutant populations in the viral quasispecies in response to changing selection pressures, allowing inferences on viral fitness in vivo through mathematical modeling...

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..These results implicate the nature of the HLA-viral peptide interaction as the major factor modulating durable control of HIV infection...

..The growing complexity of the HIV-1 resistance spectrum calls for more sophisticated testing and clinical expertise, in addition to more effective drugs...

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..Concordance with the Trofile assay was good, but assays using replicating viruses did not increase substantially the ability to detect the presence of CXCR4-using virus...

..Children with expansions were not more likely to have increased numbers of CD8(+) T cells, a finding consistent with the possibility that the CD8(+) TCR repertoire has limited diversity...

..These findings correspond well with the clinical trials data and help explain the temporal pattern of RAL resistance evolution...

..No one approach can be recommended for all patients, because the pattern of drug resistance and other factors such as regimen complexity, toxicities, and disease stage must be taken into account...

..This article summarizes a presentation on HIV resistance made by Daniel R. Kuritzkes, MD, at an International AIDS Society-USA Continuing Medical Education course in San Francisco in May 2007...

..Pilot studies of orally bioavailable small-molecule CCR5 inhibitors in HIV-1-infected subjects have provided proof of concept for this novel drug class; phase III safety and efficacy trials are under way...

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..We examined the relationships of plasma leptin and adiponectin levels to fat distribution and insulin sensitivity in the HIV lipodystrophy syndrome...

..The integrated platform points a promising direction for point-of-care testing (POCT) to rapidly capture, image and count subpopulations of cells from blood samples in an automated matter...

..This on-chip HIV capture and imaging platform creates new avenues for point-of-care diagnostics and monitoring applications of infectious diseases...

..Human DNA banks must allow future analyses while addressing confidentiality, ethical, and regulatory issues...

..These results suggest that the E138K and M184I/V mutations are mutually compensatory and may explain the frequent occurrence of E138K/M184I after the virologic failure of rilpivirine-, lamivudine-, and emtricitabine-containing regimens...

..The T-20 vs. Optimized Regimen Only Study 1 (TORO 1) was a randomized, open-label, phase 3 study of enfuvirtide (T-20), a human immunodeficiency virus type 1 (HIV-1) fusion inhibitor...

..The clinical significance of incomplete reconstitution of CD4 lymphocyte number, phenotype, and proliferative function in HIV-1 infection remains to be determined...

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..This integrated assay system for the detection of HIV-1 drug resistance mutations has a high degree of accuracy and reproducibility in several laboratories...

..65, P < 0.0001). However, our results suggest that the preexistence of secondary mutations in protease genetic background may have implications in HIV-1 fitness evolution and virologic response to antiretroviral therapy...

..We are happy to feature the latest edition in this issue of Topics in HIV Medicine. It is our hope that addressing these issues will help guide your treatment strategy decisions regarding resistance testing...

..Although enfuvirtide resistance mutations are associated with significant fitness defects in vivo, the clinical significance of these mutations remains undefined...

..Nucleoside analogue reverse transcriptase inhibitors may have continued ARV activity despite long durations of partially suppressive therapy and the presence of resistant HIV-1...

..Amdoxovir (2,6-diaminopurine dioxolane; DAPD) is a nucleoside reverse transcriptase inhibitor (NRTI) of human immunodeficiency virus-1 (HIV-1) with activity against wild-type and NRTI-resistant viruses...

..The successful development of new NRTIs will depend upon a thorough appreciation of these many and complex issues, not only among those involved in the design of clinical studies, but also those contributing to their review and conduct...

..A number of amino acid substitutions, particularly minor mutations, represent polymorphisms that in isolation may not reflect prior drug selective pressure or reduced drug susceptibility...

..Three-drug antiretroviral regimens are standard of care for initial treatment of human immunodeficiency virus 1 (HIV-1) infection, but a 4-drug regimen could improve antiretroviral activity and be more effective than a 3-drug regimen...

..We sought to determine how much agreement exists within a group of experts in the interpretation of complex genotypes...

..But their combinations in viral dynamic modeling significantly predicted virologic response. The HIV dynamic modeling can appropriately capture complicated nonlinear relationships and interactions among multiple covariates...

..A number of amino acid substitutions, particularly minor mutations, represent polymorphisms that in isolation may not reflect prior drug selective pressure or reduced drug susceptibility...

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..Chemokine coreceptor use impacts both the natural history of human immunodeficiency virus type 1 (HIV-1) disease and the potential use of a new class of antiretroviral agents, the CCR5 inhibitors...

..To assess metabolic changes after initiation of protease inhibitor (PI)-sparing regimens in antiretroviral-naive patients...

..Drugs that have been approved by the US Food and Drug Administration (FDA) or available through expanded access protocols are included...

..Therefore, evolution of episomal viral cDNAs is a valid surrogate of ongoing viral replication in HIV-1-infected individuals...

..Little is known about how commonly used dual-NRTI regimens affect the intracellular levels of NRTI-TPs, the active form of these drugs. This study investigates the effect of dual-NRTI therapy in intracellular NRTI-TP levels...

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..In conclusion, these data demonstrate durable efficacy and safety of ENF over 96 weeks and that early use of ENF in combination with other agents for the treatment of antiretroviral-experienced HIV-infected subjects is beneficial...

..Clinical stability has been observed with continued antiretroviral therapy (ART) in the setting of partial virological suppression. The optimal time to switch treatment in patients with low but detectable HIV-1 RNA is not known...

..This research program provides a framework within which the applicant can mentor beginning clinical investigators in patient-oriented research focused on these critical issues in HIV-1 medicine. ..

..Results of these studies will provide a deeper understanding of the molecular, virologic, and clinical consequences ofT-20 resistance, and may help guide the use of T-20 in salvage therapy. ..

..administrative component ..

..This research program provides a framework within which the applicant can mentor beginning clinical investigators in patient-oriented research focused on critical issues in HIV-1 medicine. ..

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..This research program provides a framework within which the applicant can mentor beginning clinical investigators in patient-oriented research focused on critical issues in HIV-1 medicine. ..

..Better understanding of the virologic, genetic, and biochemical aspects of AZT/3TC dual resistance will help direct therapy and may lead to better therapeutic strategies in the future. ..

..coli expression vectors and purified to near homogeneity. Mechanistic studies with reconstituted p66/p51 heterodimers will be performed using synthetic homopolymeric, as well as native heteromeric, RNA templates. ..

..Results of these studies will provide a deeper understanding of the molecular, virologic, and clinical consequences ofT-20 resistance, and may help guide the use of T-20 in salvage therapy. ..

..This research program provides a framework within which the applicant can mentor beginning clinical investigators in patient-oriented research focused on critical issues in HIV-1 medicine. ..