Sexual Transmission of an HIV-1 Variant Resistant to Multiple Reverse-Transcriptase and Protease Inhibitors

Hecht, Frederick M.; Grant, Robert M.; Petropoulos, Christos J.; Dillon, Beth; Chesney, Margaret A.; Tian, Huan; Hellmann, Nicholas S.; Bandrapalli, Nirmala I.; Digilio, Laura; Branson, Bernard M.; Kahn, James O.

doi:10.1056/nejm199807303390504

Cited by 421 publications

(192 citation statements)

References 32 publications

Supporting

Mentioning

180

Contrasting

Unclassified

Order By: Relevance

“…Adaptation by HIV Pr to current therapeutics is emerging and spreading, with transmission of multi-drug-resistant virus reported (47). JE-2147 is a second-generation inhibitor, with improved potency against HIV Pr and a drug resistance profile different from those of the currently available therapeutics (8).…”

Section: Resultsmentioning

confidence: 99%

Anisotropic Dynamics of the JE-2147−HIV Protease Complex: Drug Resistance and Thermodynamic Binding Mode Examined in a 1.09 Å Structure^,

et al. 2002

View full text Add to dashboard Cite

The structure of HIV protease (HIV Pr) bound to JE-2147 (also named AG1776 or is determined here to 1.09 Å resolution. This highest-resolution structure for HIV Pr allows refinement of anisotropic displacement parameters (ADPs) for all atoms. Clustering based on the directional information in ADPs defines two sets of subdomains such that within each set, subdomains undergo similar anisotropic motion. These sets are (a) the core of monomer A grouped with both substrate-binding flaps and (b) the core of monomer B coupled to both catalytic aspartates (25A/B). The four-stranded -sheet (1-4 A/B and 95-99 A/B) that forms a significant part of the dimer interface exhibits large anisotropic amplitudes that differ from those of the other sets of subdomains. JE-2147 is shown here to be a picomolar inhibitor (K i ) 41 ( 18 pM). The structure is used to interpret the mechanism of association of JE-2147, a secondgeneration inhibitor for which binding is enthalpically driven, with respect to first-generation inhibitors for which binding is predominantly entropically driven [Velazquez-Campoy, A., et al. (2001) Arch. Biochem. Biophys. 390, 169-175]. Relative to the entropically driven inhibitor complexes, the JE-2147-HIV Pr complex exhibits an ∼0.5 Å movement of the substrate flaps in toward the substrate, suggesting a more compatible enthalpically driven association. Domains of the protease identified by clustering of ADPs also suggest a model of enthalpy-entropy compensation for all HIV Pr inhibitors in which dynamic coupling of the flaps is offset by an increased level of motion of the -sheet domain of the dimer interface (1-4 A/B and 95-99 A/B).

show abstract

Section: Resultsmentioning

confidence: 99%

Anisotropic Dynamics of the JE-2147−HIV Protease Complex: Drug Resistance and Thermodynamic Binding Mode Examined in a 1.09 Å Structure^,

et al. 2002

View full text Add to dashboard Cite

show abstract

“…17 Near-perfect adherence levels of > 95% are required to optimise the outcomes of highly active antiretroviral therapy (HAART), such as minimised drug resistance, slowed disease progression, decreased hospitalisation and delayed death. [18][19][20][21] At the beginning of the national ART programme implementation in South Africa, patients were screened to establish their ability to adhere to therapy prior to enrolment. Later, pressures to scale up the ART programme made this screening less stringent.…”

Section: Introductionmentioning

confidence: 99%

Adherence to antiretroviral therapy, virologic failure and workload at the Rustenburg Provincial Hospital

Chabikuli

Datonye

Nachega

et al. 2010

South African Family Practice

View full text Add to dashboard Cite

SA Fam Pract 2010;52(4):350-355Background: Adherence to antiretroviral therapy (ART) is a strong predictor of progression to AIDS and death. It remains the most important potentially alterable factor that determines treatment outcomes. Methods:The study is a cross-sectional survey of self-reported adherence to ART and associated factors. The clinic had a tenfold increase in patient enrolment and a ninefold decline in staff-to-patient ratio, and the proportion of patients lost to follow-up doubled in the preceding four years.Conclusion: Adherence to ART was poor. The capacity of the clinic to manage patients adequately has declined significantly. Decentralisation of ART services to primary health care facilities should be considered.Peer reviewed.

show abstract

“…There is, however, an increasing inclination to consider socioeconomic condition (as assessed through income, level of education, job and housing conditions) as having a poor predictive power, except in cases of extreme poverty 9,14 . For instance, the study conducted in several Brazilian states found an association between a very low educational level and non-adherence 25 .…”

mentioning

confidence: 99%

Risk-factors for non-adherence to antiretroviral therapy

Silva

Ximenes

Filho

et al. 2009

Rev. Inst. Med. trop. S. Paulo

View full text Add to dashboard Cite

SUMMARYCross-sectional study analyzed as case-control to identify risk factors for non-adherence to antiretroviral therapy. We studied 412 out-clinics HIV infected subjects of three public hospitals of Recife, Pernambuco. The objective was to examine the association between non-adherence to the antiretroviral therapy and biological, social-behavior and demographics and economic factors, factors related to the disease and/or treatment, factors related to life habits and depression symptoms. Variables significantly associated with non-adherence to antiretroviral therapy were: time elapsed since HIV diagnosis (p = 0.002), daily dose (p = 0.046), use of alcohol (p = 0.030) and past drug use (p = 0.048), and borderline p-values were found for educational level (p = 0.093) and family monthly income (p = 0.08). In the multivariable analysis, the factors that remained in the final model were family monthly income, time period with HIV infection and use of alcohol. No association was observed between non-adherence to antiretroviral therapy and gender, age, sexual orientation, marital status, educational level and place of residence.Based on our results and the local situation we suggest: assessment of social needs; training of partners and/or families on supporting adherence, creation of "adherence groups" to motivate and to reassure patients on the benefits of treatment; counseling and/or psychotherapy for alcohol drinkers.

show abstract

Sexual Transmission of an HIV-1 Variant Resistant to Multiple Reverse-Transcriptase and Protease Inhibitors

Cited by 421 publications

References 32 publications

Anisotropic Dynamics of the JE-2147−HIV Protease Complex: Drug Resistance and Thermodynamic Binding Mode Examined in a 1.09 Å Structure^,

Anisotropic Dynamics of the JE-2147−HIV Protease Complex: Drug Resistance and Thermodynamic Binding Mode Examined in a 1.09 Å Structure^,

Adherence to antiretroviral therapy, virologic failure and workload at the Rustenburg Provincial Hospital

Risk-factors for non-adherence to antiretroviral therapy

Contact Info

Product

Resources

About

Sexual Transmission of an HIV-1 Variant Resistant to Multiple Reverse-Transcriptase and Protease Inhibitors

Cited by 421 publications

References 32 publications

Anisotropic Dynamics of the JE-2147−HIV Protease Complex: Drug Resistance and Thermodynamic Binding Mode Examined in a 1.09 Å Structure,

Anisotropic Dynamics of the JE-2147−HIV Protease Complex: Drug Resistance and Thermodynamic Binding Mode Examined in a 1.09 Å Structure,

Adherence to antiretroviral therapy, virologic failure and workload at the Rustenburg Provincial Hospital

Risk-factors for non-adherence to antiretroviral therapy

Contact Info

Product

Resources

About

Anisotropic Dynamics of the JE-2147−HIV Protease Complex: Drug Resistance and Thermodynamic Binding Mode Examined in a 1.09 Å Structure^,

Anisotropic Dynamics of the JE-2147−HIV Protease Complex: Drug Resistance and Thermodynamic Binding Mode Examined in a 1.09 Å Structure^,