Dissertations / Theses on the topic 'HIV Drug Resistance'
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1
Lalonde, Matthew Scott. "HIV Drug Resistance Polymorphism Analysis Using Ligase Discrimination." Case Western Reserve University School of Graduate Studies / OhioLINK, 2009. http://rave.ohiolink.edu/etdc/view?acc_num=case1244059520.
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Svedhem, Johansson Veronica. "Kinetics of HIV-1 drug resistance mutations in vivo /." Stockholm, 2006. http://diss.kib.ki.se/2006/91-7140-671-9/.
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Lindström, Anna. "Resistance to antiviral drugs in HIV and HBV /." Stockholm, 2005. http://diss.kib.ki.se/2005/91-7140-239-X/.
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Chamberlain, Philip Paul. "Structural mechanisms of drug resistance for HIV reverse transcriptases." Thesis, University of Oxford, 2004. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.403941.
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Beerenwinkel, Niko [Verfasser]. "Computational Analysis of HIV Drug Resistance Data / Niko Beerenwinkel." Aachen : Shaker, 2004. http://d-nb.info/1170545238/34.
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Exner, Natalie Mae. "Surveillance Methods for Monitoring HIV Incidence and Drug Resistance." Thesis, Harvard University, 2014. http://dissertations.umi.com/gsas.harvard:11444.
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Disease surveillance is the continuous collection, analysis, and interpretation of health-related data. Information gained from routine HIV disease surveillance is vital to national program managers deciding to implement new prevention or treatment programs. In this dissertation, we describe methods for estimation of HIV incidence and the prevalence of HIV drug resistance.
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Detsika, Maria G. "Evolution of minority species of HIV harbouring drug resistance." Thesis, University of Liverpool, 2006. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.428256.
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Thao, Vu Phuong. "Transmitted and acquired HIV drug resistance in Viet Nam." Thesis, University of Oxford, 2015. https://ora.ox.ac.uk/objects/uuid:61bd161b-b561-47e1-88b2-86eea11d313f.
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The roll-out of antiretroviral therapy (ART) in Viet Nam along with limited resources for treatment monitoring are expected to be accompanied by the emergence of transmitted and acquired drug resistance. Drug resistance challenges the success of ART program and the efforts to curb the HIV epidemic in Viet Nam. Understanding factors that impact treatment outcome and prevalence and patterns of drug resistance provides imperative information for strategic and effective management. The first part of this thesis aims to study the prevalence and patterns of transmitted drug resistance (TDR) in ART-naïve patients. TDR prevalence was detected in 6.4% of ARV-naïve patients with HIV-associated tuberculous meningitis initiating ART in Ho Chi Minh City (HCMC) from 2005-2007. This rate is lower than that in developed countries and is comparable to TDR rates reported in similar resource-limited countries. Pattern of TDR reflected the standard first-line ART regimens with nucleotide and non-nucleotide reverse transcriptase inhibitors in Viet Nam. The second part of this thesis aims to investigate factors that impact treatment outcome and drug resistance in second-line ART in Viet Nam. In a cohort of adult patients on second-line ART at the Hospital for Tropical Diseases, rate of clinical and/or immunological failure was 18.2% after a median follow up of 29 months. Older age, history of injecting drug use, lower CD4 count at second-line ART initiation, suboptimal ART adherence, and previous protease inhibitor (PI) use independently predicted treatment failure. Prevalence of virological failure (HIV RNA >1000 copies/mL as recommended by the 2013WHO guidelines) in patients who survived and were in active follow up was 9.5%, and high viral load, non-adherence and previous PI use were independent predictors for virological failure to second-line ART. 64% of patients with virological failure carried major PI mutations. Cross-resistance to third-line medications was higher than reported in other studies with cross resistance to ETR, TPV, and DRV of 55%, 45%, and 27% patients, respectively. This information informs selection of appropriate third-line ART regimen for patients failing second-line ART in Viet Nam. In conclusion, the work of this thesis provides important data on TDR in the chronically HIV-infected population in Viet Nam, provides, for the first time, data on treatment outcome to lopinavir-based second-line ART in the presence of extensive NRTI drug resistance, and identifies modifying risk factors to improve treatment outcomes in Viet Nam. Strategies to diagnose treatment failure accurately, to switch therapy timely, and to provide targeted adherence support will improve the outcomes of patients. Continued surveillance of TDR should be performed to assure the effectiveness of ART at the population level. Cost-effectiveness studies should be conducted in order to provide evidence for policy makers to decide whether to apply baseline genotypic testing and viral load monitoring in a resource limited country like Viet Nam. Prospective studies are needed to study the validity of WHO immunological/clinical criteria in defining virological treatment failure in PI-based second-line ART.
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Wang, Qi. "Computational analysis of HIV-1 evolution and drug resistance." Diss., Restricted to subscribing institutions, 2008. http://proquest.umi.com/pqdweb?did=1779690471&sid=1&Fmt=2&clientId=1564&RQT=309&VName=PQD.
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Johansson, Veronica Svedhem. "Kinetics of HIV-1 drug resistance mutations in vivo." Stockholm : Karolinska Institutet, 2006. http://diss.kib.ki.se/2006/91-7140-671-9/thesis.pdf.
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Lin, Kuan-Hung. "Viral Proteases as Drug Targets and the Mechanisms of Drug Resistance: A Dissertation." eScholarship@UMMS, 2016. https://escholarship.umassmed.edu/gsbs_diss/841.
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Viral proteases have been shown to be effective targets of anti-viral therapies for human immunodeficiency virus (HIV) and hepatitis C virus (HCV). However, under the pressure of therapy including protease inhibitors, the virus evolves to select drug resistance mutations both in the protease and substrates. In my thesis study, I aimed to understand the mechanisms of how this protease−substrate co-evolution contributes to drug resistance. Currently, there are no approved drugs against dengue virus (DENV); I investigated substrate recognition by DENV protease and designed cyclic peptides as inhibitors targeting the prime site of dengue protease.
First, I used X-ray crystallography and subsequent structural analysis to investigate the molecular basis of HIV-1 protease and p1-p6 substrate coevolution. I found that co-evolved p1-p6 substrates rescue the HIV-1 I50V protease’s binding activity by forming more van der Waals contacts and hydrogen bonds, and that co-evolution restores the dynamics at the active site for all three mutant substrates.
Next, I used aprotinin as a platform to investigate DENV protease–substrate recognizing pattern, which revealed that the prime side residues significantly modulate substrate affinity to protease and the optimal interactions at each residue position. Based on these results, I designed cyclic peptide inhibitors that target the prime site pocket of DENV protease. Through optimizing the length and sequence, the best inhibitor achieved a 2.9 micromolar Ki value against DENV3 protease. Since dengue protease does not share substrate sequence with human serine proteases, these cyclic peptides can be used as scaffolds for inhibitor design with higher specificity.
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Lin, Kuan-Hung. "Viral Proteases as Drug Targets and the Mechanisms of Drug Resistance: A Dissertation." eScholarship@UMMS, 2009. http://escholarship.umassmed.edu/gsbs_diss/841.
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Viral proteases have been shown to be effective targets of anti-viral therapies for human immunodeficiency virus (HIV) and hepatitis C virus (HCV). However, under the pressure of therapy including protease inhibitors, the virus evolves to select drug resistance mutations both in the protease and substrates. In my thesis study, I aimed to understand the mechanisms of how this protease−substrate co-evolution contributes to drug resistance. Currently, there are no approved drugs against dengue virus (DENV); I investigated substrate recognition by DENV protease and designed cyclic peptides as inhibitors targeting the prime site of dengue protease.
First, I used X-ray crystallography and subsequent structural analysis to investigate the molecular basis of HIV-1 protease and p1-p6 substrate coevolution. I found that co-evolved p1-p6 substrates rescue the HIV-1 I50V protease’s binding activity by forming more van der Waals contacts and hydrogen bonds, and that co-evolution restores the dynamics at the active site for all three mutant substrates.
Next, I used aprotinin as a platform to investigate DENV protease–substrate recognizing pattern, which revealed that the prime side residues significantly modulate substrate affinity to protease and the optimal interactions at each residue position. Based on these results, I designed cyclic peptide inhibitors that target the prime site pocket of DENV protease. Through optimizing the length and sequence, the best inhibitor achieved a 2.9 micromolar Ki value against DENV3 protease. Since dengue protease does not share substrate sequence with human serine proteases, these cyclic peptides can be used as scaffolds for inhibitor design with higher specificity.
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Al, Mazari Ali. "Computational methods for the analysis of HIV drug resistance dynamics." Thesis, The University of Sydney, 2007. http://hdl.handle.net/2123/1907.
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ABSTRACT Despite the extensive quantitative and qualitative knowledge about therapeutic regimens and the molecular biology of HIV/AIDS, the eradication of HIV infection cannot be achieved with available antiretroviral regimens. HIV drug resistance remains the most challenging factor in the application of approved antiretroviral agents. Previous investigations and existing HIV/AIDS models and algorithms have not enabled the development of long-lasting and preventive drug agents. Therefore, the analysis of the dynamics of drug resistance and the development of sophisticated HIV/AIDS analytical algorithms and models are critical for the development of new, potent antiviral agents, and for the greater understanding of the evolutionary behaviours of HIV. This study presents novel computational methods for the analysis of drug-resistance dynamics, including: viral sequences, phenotypic resistance, immunological and virological responses and key clinical data, from HIV-infected patients at Royal Prince Alfred Hospital in Sydney. The lability of immunological and virological responses is analysed in the context of the evolution of antiretroviral drug-resistance mutations. A novel Bayesian algorithm is developed for the detection and classification of neutral and adaptive mutational patterns associated with HIV drug resistance. To simplify and provide insights into the multifactorial interactions between viral populations, immune-system cells, drug resistance and treatment parameters, a Bayesian graphical model of drug-resistance dynamics is developed; the model supports the exploration of the interdependent associations among these dynamics.
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Al, Mazari Ali. "Computational methods for the analysis of HIV drug resistance dynamics." Connect to full text, 2007. http://hdl.handle.net/2123/1907.
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Doctor of Philosophy(PhD)ABSTRACT Despite the extensive quantitative and qualitative knowledge about therapeutic regimens and the molecular biology of HIV/AIDS, the eradication of HIV infection cannot be achieved with available antiretroviral regimens. HIV drug resistance remains the most challenging factor in the application of approved antiretroviral agents. Previous investigations and existing HIV/AIDS models and algorithms have not enabled the development of long-lasting and preventive drug agents. Therefore, the analysis of the dynamics of drug resistance and the development of sophisticated HIV/AIDS analytical algorithms and models are critical for the development of new, potent antiviral agents, and for the greater understanding of the evolutionary behaviours of HIV. This study presents novel computational methods for the analysis of drug-resistance dynamics, including: viral sequences, phenotypic resistance, immunological and virological responses and key clinical data, from HIV-infected patients at Royal Prince Alfred Hospital in Sydney. The lability of immunological and virological responses is analysed in the context of the evolution of antiretroviral drug-resistance mutations. A novel Bayesian algorithm is developed for the detection and classification of neutral and adaptive mutational patterns associated with HIV drug resistance. To simplify and provide insights into the multifactorial interactions between viral populations, immune-system cells, drug resistance and treatment parameters, a Bayesian graphical model of drug-resistance dynamics is developed; the model supports the exploration of the interdependent associations among these dynamics.
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Gill, Vikram Singh. "Populational studies of HIV-1 drug resistance in British Columbia." Thesis, University of British Columbia, 2010. http://hdl.handle.net/2429/21698.
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Objective:
Highly active antiretroviral therapy (HAART) has led to a dramatic decrease in AIDS-related morbidity and mortality, but can be compromised by the development of HIV drug resistance. The objective of this thesis is to explore issues important to the understanding of HIV drug resistance at the populational level in British Columbia, Canada.
Methods:
HIV drug resistance was analyzed via retrospective, observational analyses of the population of HIV-infected individuals receiving treatment through the HIV/AIDS Drug Treatment Program in British Columbia, Canada. Analyses were largely based upon viral protease and reverse transcriptase genotypic sequences obtained from archived plasma samples as well as information in the BC Centre for Excellence in HIV/AIDS’ monitoring and evaluation system.
Results:
One analysis demonstrated a drastic, exponential decrease in the incidence of new cases of HIV-1 drug resistance over time in individuals followed from 1996-2008 that has been concomitant with linear increases in the proportion of individuals with undetectable plasma viral loads. An analysis of the probability of developing resistance, adjusted for several factors, between different initial antiretroviral regimens showed 2.4-fold lower odds of developing HIV drug resistance among individuals initiating HAART with a boosted protease-inhibitor-based regimen versus other common regimens, as well as a decreased likelihood of developing resistance based upon initiating more modern HAART regimens. Finally, a third analysis focussed on specific K65K and K66K silent mutations in HIV reverse transcriptase, which are strongly co-selected with known thymidine analogue mutations, in particular D67N. In steady-state kinetic assays, the presence of these mutations was shown to alleviate replicative pausing and/or dissociation events of HIV-1 reverse transcriptase on RNA reverse transcriptase templates that contained the D67N and K70R mutations.
Conclusion:
Changes in HIV drug resistance have occurred at the populational level in BC over the period of 1996-2008. The superiority of modern HAART regimens in regard to the development of resistance, and overall drastic exponential decreases in the levels of incident drug resistance over time, provide new benchmarks for the analysis of the efficacy of current and future antiretroviral regimens. Furthermore, the identification of novel silent mutations co-selected with therapy exposure may have clinical implications.
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Nguyen, Thuy Thi Vu. "Transmitted antiretroviral drug resistance in a low HIV prevalence setting." Thesis, University of Iowa, 2012. https://ir.uiowa.edu/etd/3360.
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Background: Antiretroviral drug resistance is steadily growing in populations of HIV treatment-naive individuals due to person-to-person transmission. However, Iowa-specific data for transmitted antiretroviral drug resistance-associated mutations prevalence has not been previously reported. We postulate that the prevalence of drug resistance in Iowa does not differ significantly between HIV risk groups.
Methods: Data were collected from electronic medical records and an HIV Program database between 2006 and 2011. Information included age, gender, risk exposure group, viral load, CD4 count, CD4%, and other HIV risk factors and behaviors.
Results: Transmitted drug resistance mutations (TDRM) were not associated with many risk factors, but rapid plasma reagin (RPR) screening for syphilis was significant (p=0.02) and used as a proxy for highest level of sexual risk behavior. RPR was used with minor NRTI and NNRTI along with intravenous drug use in logistic regression to model the likelihood of acquiring TDRM.
Conclusion: Some question the practicality of implementing genotypic ARV resistance testing guidelines because of uncertainty about the prevalence of ARV drug resistance among treatment-naïve patients but harboring resistance mutations puts patients at high risk of failing effective, first-line therapies. Hence, genotypic resistance testing at HIV diagnoses can not only improve disease management but also assist in surveillance.
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Liu, Fengling. "Kinetic and Crystallographic Studies of Drug-Resistant Mutants of HIV-1 Protease: Insights into the Drug Resistance Mechanisms." Digital Archive @ GSU, 2007. http://digitalarchive.gsu.edu/biology_diss/19.
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HIV-1 protease (PR) inhibitors (PIs) are important anti-HIV drugs for the treatment of AIDS and have shown great success in reducing mortality and prolonging the life of HIV-infected individuals. However, the rapid development of drug resistance is one of the major factors causing the reduced effectiveness of PIs. Consequently, various drug resistant mutants of HIV-1 PR have been extensively studied to gain insight into the mechanisms of drug resistance. In this study, the crystal structures, dimer stabilities, and kinetics data have been analyzed for wild type PR and over 10 resistant mutants including PRL24I, PRI32V, PRM46L, PRG48V, PRI50V, PRF53L, PRI54V, PRI54M, PRG73S and PRL90M. These mutations lie in varied structural regions of PR: adjacent to the active site, in the inhibitor binding site, the flap or at protein surface. The enzymatic activity and inhibition were altered in mutant PR to various degrees. Crystal structures of the mutants complexed with a substrate analog inhibitor or drugs indinavir, saquinavir and darunavir were determined at resolutions of 0.84 – 1.50 Å. Each mutant revealed distinct structural changes, which are usually located at the mutated residue, the flap and inhibitor binding sites. Moreover, darunavir was shown to bind to PR at a new site on the flap surface in PRI32V and PRM46L. The existence of this additional inhibitor binding site may explain the high effectiveness of darunavir on drug resistant mutants. Moreover, the unliganded structure PRF53L had a wider separation at the tips of the flaps than in unliganded wild type PR. The absence of flap interactions in PRF53L suggests a novel mechanism for drug resistance. Therefore, this study enhanced our understanding of the role of individual residues in the development of drug resistance and the structural basis of drug resistance mechanisms. Atomic resolution crystal structures are valuable for the design of more potent protease inhibitors to overcome the drug resistance problem.
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Fouche, Desire. "Drug-drug interactions between antiretrovirals and fluconazole in HIV-infected patients." Thesis, Stellenbosch : Stellenbosch University, 2012. http://hdl.handle.net/10019.1/20079.
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Thesis (MScMedSc)--Stellenbosch University, 2012.ENGLISH ABSTRACT: Background: HIV-positive patients have a significantly weakened immune system which makes them highly susceptible for opportunistic infections, requiring additional treatment. Cryptococcal meningitis and oropharyngeal candidiasis are treated with oral fluconazole. A great potential for drug-drug interactions (DDIs) between fluconazole and antiretrovirals (ARVs), efavirenz, nevirapine, and lopinavir/ritonavir, exists due to interference in common metabolic pathways. The outcome may result in the development of adverse drug reactions or drug resistance and treatment failure. Aim: The primary aim of this thesis was to evaluate the effect of fluconazole on the pharmacokinetics of efavirenz, nevirapine and lopinavir/ritonavir in HIV-infected patients diagnosed with cryptococcal meningitis or oropharyngeal candidiasis. Methods: A prospective study was conducted in 80 HIV-positive, treatment experienced adults (≥18 years old) treated in three different outpatient clinics in the Western Cape region. Patients were subdivided according to ARV regimen and the use of fluconazole. A sparse sampling design was used and corresponding ARV serum concentrations were determined by established HPLC and GC methods. Fluconazole serum concentrations were determined by a newly developed HPLC method. Patient characteristics, concomitant medications, clinical test data and ARV serum concentrations were included in a NONMEM generated, onecompartment, open pharmacometric model with first order elimination to detect any drugdrug interactions between fluconazole and the studied ARVs. The secondary outcome was to establish which patient characteristics influence ARV pharmacokinetics. Results: From 80 outpatients, a total of 276 ARV serum samples (137 efavirenz, 67 nevirapine and 72 lopinavir) were collected for pharmacokinetic evaluation. Efavirenz clearance was correlated with race and concomitant use of rifampicin. No significant covariates were established in the nevirapine model. In the lopinavir model, concomitant use of clotrimazole and the antituberculosis combination isoniazid, pyrazinamide and rifampicin were identified as significant covariates. Discussion: No significant effects of fluconazole on the pharmacokinetics of any of the studied ARVs were observed. Varying efavirenz plasma concentrations in different ethnic populations may be due to differences in gene expression particularly CYP2B6. Coloured patients had significantly lower efavirenz serum concentrations (56.8% decrease in clearance), which has not been previously described in the South African context. Although gender was not a significant covariate in the nevirapine model, female patients tended to have higher nevirapine serum concentrations. TB treatment in all patients receiving lopinavir consisted of a combination of isoniazid, pyrazinamide and rifampicin, each with different effects on CYP isoenzymes. The exact contributing factor of each drug in the ultimate decrease in lopinavir clearance (46.4%) can therefore not be established. Conclusions: Given the limitations of the sample size in the present study, no statistical significant effect of fluconazole on the pharmacokinetics of the investigated ARVs could be demonstrated. A retrospective analysis of the data showed various co-factors that influence the pharmacokinetics of the investigated ARVs. This data needs to be confirmed in a prospective study as the identified covariates are appropriate in the management of HIVinfected patients in the South African context.
AFRIKAANSE OPSOMMING: Agtergrond: HIV-positief pasiënte het ‘n aansienlike verswakte immuunstelsel, wat hul hoogs vatbaar tot opportunistiese infeksies maak, en dus, addisionele behandeling benodig. Cryptococcal meningitis en orofaringeale kandidiase word met orale flukonasool behandel. As gevolg van middeling in algemene metaboliese paaie is daar ‘n groot moontlikheid van middel-middel interaksies tussen flukonasool en die antiretrovirale (ARV) middels, efavirenz, nevirapine, en lopinavir/ritonavir. Die uitkomste hiervan mag tot die ontwikkeling van nadelige middel-middel interaksies of middelweerstandigheid en mislukte behandeling lei. Doel: Die primêre doel van hierdie tesis was om die effek van flukonasool op die farmakokinetika van efavirenz, nevirapine en lopinavir/ritonavir in HIV geïnfekteerde pasiënte met gediagnoseerde cryptococcal meningitis en orofaringeale kandidiase te evalueer. Metodes: Die studie was met 80 HIV-positief, behandeling-ervare volwassenes (≥18 jaar) onderneem. Voorafgenoemde was in drie verskillende buitepasiëntklinieke in die Wes-Kaap behandel. Pasiënte was volgens ARV regimen en die gebruik van flukonasool, of dan nie, verder verdeel. ‘n Beperkte steekproef ontwerp was gebruik, en ooreenstemmende ARV serum konsentrasies is deurgevestigde HPLC en GC metodes vasgestel. Flukonasool serum konsentrasies was deur ‘n nuutontwikkelde HPLC metode vasgestel. Pasiëntkenmerke, gepaardgaande medikasie, kliniesetoets data en ARV serum konsentrasies was by ‘n NONMEM genereerde, een-kompartement, oop farmakometriese model met eerste orde eliminasie ingesluit om enige middel interaksies tussen flukonasool en die bestudeerde ARVs op te tel. Die sekondêre uitkomste was om vas te stel watter pasiënt kenmerke ARV farmakokinetika beïnvloed. Resultate:Uit 80 buitepasïente was ‘n totaal van 276 ARV serum monsters (137 efavirenz, 67 nevirapine en 72 lopinavir) vir farmakokinetiese evaluasie gekollekteer. Efavirenz opruiming was met ras gekorreleer asook gepaardgaande gebruik van rifampisien. Geen betekenisvolle ko-variante was in die nevirapine model vasgestel nie. In die lopinavir model het die gepaardgaande gebruik van clotrimazole en die anti-tuberkulose kombinasie isoniazied, pyrazinamied en rifampisien, lopinavir opruiming verminder. Bespreking: In hierdie studie is geen betekenisvolle effekte van flukanosool op die farmakokinetika van enige van die bestudeerde ARVs waargeneem nie. Afwisselende efavirenz plasma konsentrasies in verskillende etniese populasies mag aan verskille in geenuitdrukking, veral CYP2B6, toegeskryf word. Kleurling pasïente het betekenisvolle verlaagde efavirenz serum konsentrasies getoon (56.8% verlaging in opruiming). Hierdie bevinding is nog nooit voorheen in die Suid-Afrikaanse konteks beskryf nie. Alhoewel geslag nie ‘n beduidende ko-variant in die nevirapine model was nie, het vroulike pasïente geneig om hoer nevirapine serum konsentrasies te hê. TB behandeling, in alle pasïente wat lopinavir ontvang het, het uit die volgende kombinasie bestaan: isoniazied, pyrazinamied en rifampisien, elk met hul eie effekte op CYP isoensieme. Die presiese bydra van elke middel in die uiteindelike verlaging (46.4%) in lopinavir opruiming kan dus nie vasgestel word nie. Gevolgtrekking: Gegewe die beperkings van die steekproef in die huidige studie, kon geen statistiese beduidende effek van flukonazool op die farmakokinetika van die betrokke ARVs gedemonstreer word nie. ‘n Retrospektiewe analise van die data het gewys dat verskeidene ko-faktore die farmakokinetika van die betrokke ARVs beïnvloed. Hierdie data moet in ‘n prospektiewe studie bevestig word omdat die geidentifiseerde covariates die bestuur van MIV-positiewe pasiente in die Suid-Afrikaanse konteks te verbeter.
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Smit, Odette. "Early infant HIV diagnosis and characterization of HIV drug resistance in Gauteng, South Africa." Diss., University of Pretoria, 2021. http://hdl.handle.net/2263/79141.
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Despite the high prevalence of the human immunodeficiency virus (HIV) in South African women of reproductive age, the South African (SA) Prevention of Mother-to-Child Transmission (PMTCT) programme has significantly reduced the incidence of new HIV infections in infants from >20% in 2004 to <2% and overall MTCT approximately >5%. The PMTCT programme, however, faces challenges in terms of early infant diagnosis (EID) because of HIV polymerase chain reaction (PCR) indeterminate results as well as HIV drug resistance (HIVDR) secondary to antiretroviral therapy (ART) exposure of mothers and infants. The National Health and Laboratory Services (NHLS) uses the Roche COBAS®AmpliPrep (CAP)/COBAS®TaqMan® (CTM) HIV-1 Qualitative Test (Roche Molecular Systems, Pleasanton, CA) (CAP/CTM) platform as part of EID. Recently, the Roche cobas® 6800/8800 System has been introduced to test HIV viral load and HIV DNA PCR for EID. The platform is already processing samples for HIV viral load; however, verification for HIV DNA PCR for EID with dried blood samples (DBS) is needed, especially for CAP/CTM HIV PCR indeterminate results (Cycle threshold [Ct]>33 with any relative fluorescent intensity [RFI] value or Ct≤33 and RFI <5 on the CAP/CTM, Ct>38 on the Roche cobas® 6800/8800 System). In addition, HIVDR in newly diagnosed infants significantly limits treatment options. Therefore, the current study verified the Roche cobas® 6800/8800 System against the CAP/CTM system for the detection of HIV in EID and determined the HIVDR prevalence and profiles in infants <6 months, and how this affects current SA PMTCT and EID guidelines.
The study comprised 642 DBS samples (235 HIV PCR positive, 193 HIV PCR negative and 214 HIV PCR indeterminate) previously tested on the CAP/CTM assay. Overall, 99.6% (234/235) CAP/CTM HIV PCR positive samples remained positive, while 99.5% (192/193) HIV PCR negative samples remained negative with the Roche cobas® 6800/8800 System. The HIV PCR indeterminate results as detected by the CAP/CTM decreased from 100% (214/214) to 8.4% (18/214) with the Roche cobas® 6800/8800 System. The Roche cobas® 6800/8800 System had a specificity of 99.5% and a sensitivity of 99.6%, but this decreased to 96.3% and 90.8% when HIV PCR indeterminate results were included. The kappa value increased from 0.5, which signifies moderate agreement, to 0.9, which is excellent agreement, when RFI from the CAP/CTM was excluded for result determination. The overall agreement between the two assays, taking only cycle threshold values into account, was 93.8%.
As for HIVDR, mutations were detected in 42.9% (24/56) of infants <6 months. The most common non-nucleoside reverse transcriptase inhibitor (NNRTI) mutation causing high-level resistance was K103N (21.4% [12/56]), followed by Y181C and the NRTI mutation, M184V, both in 8.9% (5/56) of infants. Also, major protease inhibitor (PI) mutations, M46L and V82A were detected in one case each (1.8%).
In conclusion, the performance of the Roche cobas®6800/8800 System was comparable to the CAP/CTM; however, it detected fewer HIV PCR indeterminate results, thus potentially offering conclusive results in a larger proportion of infants. The detection of high levels of the NNRTI mutation, K103N, emphasises the need for constant surveillance since nevirapine is included as part of the SA PMTCT guidelines and the World Health Organization recommends that NNRTIs should be phased-out of as part of PMTCT once the resistance prevalence exceeds 10%.Dissertation (MSc (Medical Virology))--University of Pretoria, 2021.
National Health Laboratory Services Trust and RDP UP
Medical Virology
MSc (Medical Virology)
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Chen, H. K. Jonathan. "Molecular epidemiology of HIV-1 and characterization of drug resistant HIV-1 in Hong Kong." Click to view the E-thesis via HKUTO, 2007. http://sunzi.lib.hku.hk/hkuto/record/B39634401.
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Vu, Phuong Thao. "Transmitted and acquired HIV drug resistence in Vietnam." Thesis, University of Oxford, 2015. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.711876.
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Wilbe, Karin. "Genetic dynamics of HIV-1: recombination, drug resistance and intrahost evolution /." Stockholm, 2004. http://diss.kib.ki.se/2004/91-7349-959-5/.
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Ehteshami, Akbari Maryam. "HIV-1 reverse transcriptase: novel mechanisms of inhibition and drug resistance." Thesis, McGill University, 2011. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=96722.
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The reverse transcriptase (RT) enzyme of human immunodeficiency virus 1 (HIV-1) is an RNA- and DNA-dependent DNA polymerase that also exhibits RNase H activity. The polymerase and RNase H active sites of RT are structurally linked through the connection domain. RT is a major antiretroviral target but the development of viral resistance often leads to therapy failure. Genotyping protocols detect mutations in the polymerase active site that confer resistance to nucleoside analogue RT inhibitors such as zidovudine (AZT). It has been shown however, that mutations outside of this region, such as the N348I substitution in the connection domain, also confer resistance to AZT. Here, we have investigated the mechanism of N348I drug resistance. Our biochemical results have shown that the N348I mutation affects drug susceptibility by reducing nucleic acid substrate binding in the RNase H domain of RT. The N348I mutation also compensates for enzymatic deficits introduced by other resistance-conferring mutations, thus providing a rationale for its selection pattern in vivo.Additionally, we have investigated the mechanism through which INDOPY-1, a newly discovered antiretroviral agent, disrupts RT function. Although INDOPY-1 is not a nucleoside analogue, it can compete with incoming nucleotides and select for mutations at the site of nucleotide binding. Based on these observations, we propose that this antiretroviral agent belongs to a new class of RT inhibitors that we name "Nucleotide-competing RT Inhibitors". Finally, cellular ATP was shown to enhance the potency of INDOPY-1, a property never before seen with any other RT inhibitors. Based on the biochemical properties of this interaction, we propose to describe ATP as an "enhancer" of INDOPY-1-mediated RT inhibition. ATP enhances the binding of INDOPY-1 to RT by "capping" the inhibitor in the polymerase active site.Work presented in this thesis characterizes a novel mechanism of resistance to clinically approved RT inhibitors. It also describes, for the first time, a new class of RT inhibitors that function through a unique mechanism of action.La transcriptase inverse (RT) du VIH-1 est une polymérase d'ADN et d'ARN qui est aussi capable de dégrader l'ARN viral durant la polymérisation. Le domaine de connextion de la RT crée un lien entre le site actif de la polymérase et le site actif d' RNase H de cette enzyme. La RT est une cible majeure de la thérapie contre le SIDA. Mais, à cause du taux de mutation élevé du virus, le développement de résistance aux médicaments est rapide, ce qui engendre la neutralisation des effets avantageux des thérapies antivirales. Les analogues de nucléosides, comme zidovudine (AZT), sont souvent utilisés durant la thérapie anti-SIDA. Les tests génotypiques qui détectent la résistance virale incluent seulement le domaine de la polymérase de la RT. Par contre, il a été démontré que des mutations dans les domaines de la connextion, par example le mutation N348I, peuvent causer la résistance à AZT. Nous avons étudié le mécanisme de résistance à la mutation N348I. Nos resultats biochimiques montrent que N348I a un effet négatif sur l'affinité de l'ARN pour le site actif d'RNase H. Nous montrons aussi que la mutation N348I peut compenser pour des domages causés par d'autres mutations. Ceci peut expliquer l'apparence de cette mutation in vivo. Nous avons aussi étudié le mécanisme d'action d'INDOPY-1, un nouveau agent inhibatoire de la RT. Malgré que l'INDOPY-1 n'est pas un analogue de nucléoside, cet agent peut entrer en compétition avec les nucléotides et les mutations de résistance sont selectionnées dans le site d'association des nucléotides. C'est ainsi que nous avons proposé que l'INDOPY-1 appartient à une nouvelle catégorie d'inhibiteurs que nous nommons «Nucleotide-competing RT inhibitors». Un autre trait caractéristique de l' INDOPY-1 est que sa capacité d'inhibition peut être augmentée par l'ATP cellulaire. Basé sur ceci, nous décrivons l'ATP comme étant le «renforceur» de l'INDOPY-1. Ce mécanisme de renforcement se produit lorsque l'ATP «encapsule» l'INDOPY-1 dans le site actif de la polymérase de la RT.En conclusion, nous avons characterisé un nouveau mécanisme de résistance aux analogues de nucléosides. Nous avons aussi découvert le premier composé d'une nouvelle classe d'agents inhibatoires de la RT.
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Sadiq, S. K. S'ad. "Molecular dynamics simulation studies of drug resistance in HIV-1 protease." Thesis, University College London (University of London), 2008. http://discovery.ucl.ac.uk/1445831/.
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Overcoming the emergence of drug resistance in HIV is a major challenge to the scientific community. We use the established computational method of classical molecular dynamics to investigate the molecular basis of resistance in HIV-1 protease to the inhibitor saquinavir, using the wildtype and the G48V, L90M and G48V7L90M mutant HIV-1 proteases throughout this thesis. Firstly we reveal insights into a G48V mutation-assisted lateral drug escape mechanism from the protease active site. Such a mechanism allows drug escape without the full opening of the flaps of the protease. Furthermore, the mechanism is facilitated by differential drug-protease interactions, induced by mutations that take advantage of the conformational flexibility of the inhibitor. Secondly, we investigate the thermodynamic basis of binding of this set of mutants, using established 'approximate' free energy methods. The absolute and relative free energies of saquinavir binding to this set of proteases are successfully determined using our simulation and free energy analysis protocol and exhibit excellent correlation with experiment. This study is thus a template for an extended study on a larger range of HIV-1 protease-drug combinations. We describe a tool, the 'Binding Affinity Calculator', which has been designed to automate this protocol and which can be routinely applied, using high performance computing and grid technology, to meet the intensive computational demands of such an investigation. The free energy of binding of the NC-pl natural substrate cleaved by the protease is also deter mined. The enhanced flexibility of the substrate over the drug precludes the guarantee of a converged free energy result, even from the 10 ns duration of each simulation. However, qualitative insight into the thermodynamic basis of binding is gleaned as well as the effect of these mutations on the catalytic efficiency of the protease. Furthermore, we combine drug and substrate binding free energies to develop a metric for evaluating the approximate enzymatic fitness of a given mutant protease, computable directly from molecular simulation.
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Rooke, Ronald. "Studies on mechanism of action of AZT and HIV-1 drug resistance." Thesis, McGill University, 1991. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=70202.
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The great adaptability of the Human Immunodeficiency Virus type 1 (HIV-1) and the exclusive use of zidovudine (3$ sp prime$azido-3$ sp prime$deoxythymidine or AZT) in the treatment of AIDS has motivated our search for HIV-1 strains resistant to this drug.Our first attempt at obtaining such strains was made by using an in vitro approach in which a lymphoid cell line, chronically infected with HIV-1, was exposed to various drug concentrations. Although this system has never generated such mutants, we found that the progeny virus population, present in the culture fluids of these chronically infected drug-treated cells lost infectivity. These results suggest a potential post-integrational role for zidovudine, possibly acting at the level of viral assembly or budding.
However, we were successful in isolating zidovudine-resistant HIV-1 strains from the blood of patients undergoing AZT treatment. Our work shows that a minimum of 27 weeks of treatment is necessary for the appearance of the resistant phenotype and that the majority (75%) of patients treated with AZT for more than one year will generate such resistant strains. No correlation between the clinical status of the patients and the occurrence of resistant variants can be drawn from our work. However, in vitro experiments have shown that the resistant isolates are more cytopathic, although less infectious, than the sensitive strains. Reverse transcriptase enzymes from both AZT-resistant and -sensitive strains were virtually identical when their respective enzymatic activities or their affinity for the substrate or the inhibitor were compared. Finally, some zidovudine-resistant isolates demonstrate cross-resistance to other nucleoside analogs with potential clinical applications.
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Wu, Hao, and 吴昊. "Identification of drug resistant mutations in HIV-1 latently infected patients under successful HAART and in CRF_BC variants selected invitro." Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 2011. http://hub.hku.hk/bib/B47149826.
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Wyl, Viktor von. "HIV-1 drug resistance in the Swiss HIV Cohort study : epidemiology and impact on treatment of HIV-infected patients /." Zürich : ETH, 2008. http://e-collection.ethbib.ethz.ch/show?type=diss&nr=17726.
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Schultze, Anna Theresia. "The epidemiology and consequences of HIV drug resistance : analyses of resistance data from European cohort studies." Thesis, University College London (University of London), 2017. http://discovery.ucl.ac.uk/10025819/.
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Although the roll-out of effective combination antiretroviral therapy (cART) has brought great benefits, concerns remain regarding the development of drug resistance. This thesis uses data from the EuroSIDA cohort, the UK Collaborative HIV cohort, the UK HIV Drug Resistance Database, the ViroLAB consortium and the EU-Resist collaboration to describe trends in resistance testing, prevalence and incidence as well as the impact of drug resistance on CD4 count declines both in the presence and absence of ART. My findings show that the proportion of people tested for resistance following virological failure in Europe is low (31.6%) and decreasing. Individuals in Eastern Europe were less likely to receive a resistance test (adjusted odds ratio=0.72, 95% confidence interval=0.55-0.94) compared with individuals in Southern Europe. However, among those who were tested, the proportion with resistance was relatively high (77.9%), indicating a potentially selective approach to resistance testing. Among individuals maintained on a failing treatment regimen with resistance to at least one drug class, I found that CD4 counts declined less steeply among individuals with NRTI resistance, the M184V, D67N or T215Y mutation in the reverse transcriptase, or either the V82A or I54V mutation in the protease. In contrast, CD4 counts declined faster among individuals with NNRTI resistance and those with the V179D or L74I reverse transcriptase mutations. A cluster of mutations, including K103N, was also associated with faster CD4 declines. No class of drug resistance or individual mutation had a large impact on the rate of CD4 decline before the start of cART. These findings have implications for public health policy in Europe aimed at minimizing health disparities, and can be used to provide recommendations for the construction of maintenance therapies for individuals with no other treatment options. Further research into HIV drug resistance is imperative to ensure the continued success of cART.
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Chen, Renxiang. "Studies of HIV-1 mutagenesis during drug therapy and the molecular determinants of HIV-1 variation." Connect to this title online, 2004. http://rave.ohiolink.edu/etdc/view?acc%5Fnum=osu1092663963.
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Thesis (Ph. D.)--Ohio State University, 2004.Document formatted into pages. Includes bibliographical references. Abstract available online via OhioLINK's ETD Center; full text release delayed at author's request until 2005 Aug. 16.
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Ozen, Aysegul. "Structure and Dynamics of Viral Substrate Recognition and Drug Resistance: A Dissertation." eScholarship@UMMS, 2013. https://escholarship.umassmed.edu/gsbs_diss/677.
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Drug resistance is a major problem in quickly evolving diseases, including the human immunodeficiency (HIV) and hepatitis C viral (HCV) infections. The viral proteases (HIV protease and HCV NS3/4A protease) are primary drug targets. At the molecular level, drug resistance reflects a subtle change in the balance of molecular recognition; the drug resistant protease variants are no longer effectively inhibited by the competitive drug molecules but can process the natural substrates with enough efficiency for viral survival. Therefore, the inhibitors that better mimic the natural substrate binding features should result in more robust inhibitors with flat drug resistance profiles. The native substrates adopt a consensus volume when bound to the enzyme, the substrate envelope. The most severe resistance mutations occur at protease residues that are contacted by the inhibitors outside the substrate envelope. To guide the design of robust inhibitors, we investigate the shared and varied properties of substrates with the protein dynamics taken into account to define the dynamic substrate envelope of both viral proteases. The NS3/4A dynamic substrate envelope is compared with inhibitors to detect the structural and dynamic basis of resistance mutation patterns. Comparative analyses of substrates and inhibitors result in a solid list of structural and dynamic features of substrates that are not shared by inhibitors. This study can help guiding the development of novel inhibitors by paying attention to the subtle differences between the binding properties of substrates versus inhibitors.
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Ozen, Aysegul. "Structure and Dynamics of Viral Substrate Recognition and Drug Resistance: A Dissertation." eScholarship@UMMS, 2005. http://escholarship.umassmed.edu/gsbs_diss/677.
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Drug resistance is a major problem in quickly evolving diseases, including the human immunodeficiency (HIV) and hepatitis C viral (HCV) infections. The viral proteases (HIV protease and HCV NS3/4A protease) are primary drug targets. At the molecular level, drug resistance reflects a subtle change in the balance of molecular recognition; the drug resistant protease variants are no longer effectively inhibited by the competitive drug molecules but can process the natural substrates with enough efficiency for viral survival. Therefore, the inhibitors that better mimic the natural substrate binding features should result in more robust inhibitors with flat drug resistance profiles. The native substrates adopt a consensus volume when bound to the enzyme, the substrate envelope. The most severe resistance mutations occur at protease residues that are contacted by the inhibitors outside the substrate envelope. To guide the design of robust inhibitors, we investigate the shared and varied properties of substrates with the protein dynamics taken into account to define the dynamic substrate envelope of both viral proteases. The NS3/4A dynamic substrate envelope is compared with inhibitors to detect the structural and dynamic basis of resistance mutation patterns. Comparative analyses of substrates and inhibitors result in a solid list of structural and dynamic features of substrates that are not shared by inhibitors. This study can help guiding the development of novel inhibitors by paying attention to the subtle differences between the binding properties of substrates versus inhibitors.
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Wright, D. W. "Molecular dynamics simulation of drug resistance in HIV-1 protease and reverse transcriptase." Thesis, University College London (University of London), 2011. http://discovery.ucl.ac.uk/1331997/.
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The emergence of drug resistant strains of HIV represents a major challenge in the treatment of patients who contract the virus. We investigate the use of classical molecular dynamics to give quantitative and qualitative molecular insight into the causes of resistance in the two main drug targets in HIV, protease and reverse transcriptase. We initially establish a simulation and free energy analysis protocol for the study of resistance in protease. Focusing on the binding of the inhibitor lopinavir to a series of six mutants with increasing resistance we demonstrate that ensemble simulations exhibit significantly enhanced thermodynamic sampling over single long simulations. We achieve accurate and converged relative binding free energies, reproducible to within 0.5 kcal mol^-1. The experimentally derived ranking of the systems is reproduced with a correlation coefficient of 0.89 and a mean relative deviation from experiment of 0.9 kcal mol^-1. Our protocol is then applied to investigate a patient derived viral sequence for which contradictory resistance assessments for lopinavir were obtained from existing clinical decision support systems (CDSS). Mutations at only three locations (L10I, A71I/V and L90M) in uenced the ranking. Free energies were computed for HXB2 wildtype sequences incorporating each mutation individually and all possible combinations, along with the full patient sequence. Only in the case of the patient sequence was any resistance observed. This observation suggests an explanation for the discordance found using the CDSS. The effects on drug binding of the mutations at positions 10, 71 and 90 appear to be highly dependent on the background mutations present in the remainder of the sequence. In preparation for the extension of our simulation and free energy protocol to reverse transcriptase the impact of binding both natural DNA substrates and two non nucleoside reverse transcriptase inhibitor (NNRTI) class drugs on the dynamics of reverse transcriptase are investigated. Free energies of both inhibitors (efavirenz and neviripine) are determined which are seen to be independent of the subdomain motions of the protein observed during simulation. Preliminary calculations of the free energies for a set of NNRTI resistant mutants bound to efavirenz are also presented.
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Rudén, Mathilda. "Dependence of HIV drug resistance on the early warning indicator drug stock out, especially in middle-income countries." Thesis, Södertörns högskola, Miljövetenskap, 2017. http://urn.kb.se/resolve?urn=urn:nbn:se:sh:diva-35654.
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Background: HIV drug resistance is presumed to be inevitable due to the error-prone nature of the virus. However, poor adherence to the antiretroviral drugs is proven to be an impending factor for HIV drug resistance development. Of these two explanations, which is the most common reason for HIV drug resistance?Method: A total of 40 published studies about HIV drug resistance, were retrospectively collected in Pubmed (May 2017), from 36 different countries for this paper. From each study was participants, percentage of HIV drug resistance and HIV-1 subtype extracted for analysis. All studies were than classified by either high-income, middle-income or low-income, based on a country income status, defined by the World Bank. HIV drug resistance was tested against: continents, HIV-1 subtypes, number of study participants, income levels, GDP per capita and EWI’s. All statistical analysis was performed in R: The R project for statistical computing.Result: This paper show, that HIV drug resistance primarily is caused by poor adherence which is closely associated with drug stock out. Highest HIV drug resistance levels was found in middle-income countries. However, number of participants enrolled per study was important for the outcome and this indicates that HIV drug resistance would be higher in low-income countries if larger studied had been carried out in these settings. This means that there is a large unrecorded prevalence of HIV drug resistance in low-income countries.
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Chen, H. K. Jonathan, and 陳漢坤. "Molecular epidemiology of HIV-1 and characterization of drug resistantHIV-1 in Hong Kong." Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 2007. http://hub.hku.hk/bib/B39634401.
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Gupta, R. K. "HIV-1 drug resistance and investigation of Tetherin-Vpu as a potential therapeutic target." Thesis, University College London (University of London), 2011. http://discovery.ucl.ac.uk/1306714/.
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The Red Queen hypothesis elegantly reflects virus-host interactions whereby alternate switching in selective advantage occurs between host and parasite. HIV has a prolific ability to generate genetic diversity, contributing to viral persistence. This property presents serious challenges to sustained treatment with antiviral drugs on a global scale. In resource poor settings where viral monitoring is not currently feasible, the possibility of more widespread resistance exists. In this thesis I demonstrate using meta-analysis that lack of viral load monitoring in the first year of antiretroviral treatment is associated with higher prevalence of resistance in patients with viral failure. A second meta-analysis suggests that use of boosted protease inhibitors as first line therapy is associated with lower prevalence of resistance mutations compared to non-nucleoside reverse transcriptase inhibitors, therefore potentially limiting the emergence of resistant HIV strains. The use of Pis in such areas might, however, be complicated by our findings that certain viruses circulating in resource poor regions (not previously exposed to PIs) have reduced PI susceptibility due to gag polymorphism, highlighting the plasticity of HIV. The continual evolution of drug resistance means that further research into alternative targets is required. Such targets may include host factor-virus interactions. The mammalian restriction factor BST-2/tetherin is counteracted by HIV-1 using its Vpu protein. We show that tetherin has been under positive selection in primates. Furthermore tetherin can be rendered almost insensitive to Vpu by a single positively selected substitution, revealing this as a potentially important drug target, and suggesting tetherin's evolution has been shaped by viruses. Intriguingly, most SIV do not encode Vpu, and I show that the envelope protein of SIVtan is able to counteract tetherin by intracellular sequestration. Pharmacological blockade of Vpu-tetherin interactions should be investigated, although we have highlighted a potential mechanism for virus escape through gain of function by envelope.
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Ragland, Debra A. "The Structural Basis for the Interdependence of Drug Resistance in the HIV-1 Protease." eScholarship@UMMS, 2012. http://escholarship.umassmed.edu/gsbs_diss/879.
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The human immunodeficiency virus type 1 (HIV-1) protease (PR) is a critical drug target as it is responsible for virion maturation. Mutations within the active site (1°) of the PR directly interfere with inhibitor binding while mutations distal to the active site (2°) to restore enzymatic fitness. Increasing mutation number is not directly proportional to the severity of resistance, suggesting that resistance is not simply additive but that it is interdependent. The interdependency of both primary and secondary mutations to drive protease inhibitor (PI) resistance is grossly understudied.
To structurally and dynamically characterize the direct role of secondary mutations in drug resistance, I selected a panel of single-site mutant protease crystal structures complexed with the PI darunavir (DRV). From these studies, I developed a network hypothesis that explains how mutations outside the active site are able to perpetuate changes to the active site of the protease to disrupt inhibitor binding.
I then expanded the panel to include highly mutated multi-drug resistant variants. To elucidate the interdependency between primary and secondary mutations I used statistical and machine-learning techniques to determine which specific mutations underlie the perturbations of key inter-molecular interactions. From these studies, I have determined that mutations distal to the active site are able to perturb the global PR hydrogen bonding patterns, while primary and secondary mutations cooperatively perturb hydrophobic contacts between the PR and DRV. Discerning and exploiting the mechanisms that underlie drug resistance in viral targets could proactively ameliorate both current treatment and inhibitor design for HIV-1 targets.
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Martin, A. S. "Investigating the development and evolution of drug resistance in the HIV-1 pol gene." Thesis, University College London (University of London), 2013. http://discovery.ucl.ac.uk/1413952/.
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The prognosis of those infected with HIV-1 has improved significantly since the introduction of highly active antiretroviral therapy (HAART). This has led to complete suppression of HIV-1 replication and reduction of viraemia to undetectable levels. Initially HAART comprised of three classes of drugs, namely nucleoside reverse transcriptase inhibitors (NRTIs), non-nucleoside reverse transcriptase inhibitors (NNRTIs) and protease inhibitors (PIs), which target two important viral enzymes. Until recently, patients developing highly drug-resistant HIV-1 have had limited therapy options. This has changed in the last few years with the development and approval for use of second-generation NNRTIs and PIs, and three new classes of drugs including integrase strand transfer inhibitors (INSTIs). This means that patients undergoing INSTI-containing salvage therapy are taking drugs targeting all three HIV-1 pol genes; protease (PR), RT and IN. However, little data is available on the evolution, interaction and linkage of drug resistance mutations throughout the pol gene. In this study, we developed a single genome sequencing assay of the full-length HIV-1 pol gene and used it to investigate the development and linkage of drug resistance mutations in sequential samples from two patients failing INSTI-containing salvage therapy. Different phylogenetic methods were used to explore the evolution and dynamics of drug resistance mutations in the full-length HIV-1 pol gene. Furthermore, we examined the effect of co-evolved PR and RT on the susceptibility of patient-derived viruses to INSTIs and viral replicative fitness. Our data indicate that the development of drug resistance mutations in IN is complex and is a fine balance between attaining high levels of drug resistance and decent replicative fitness. This is to a degree influenced by mutations in other regions of the HIV-1 pol gene. Taken together, the data suggests that larger regions of patient-derived HIV-1 genome should be examined in order to get a good understanding of HIV-1 drug susceptibility.
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Ragland, Debra A. "The Structural Basis for the Interdependence of Drug Resistance in the HIV-1 Protease." eScholarship@UMMS, 2016. https://escholarship.umassmed.edu/gsbs_diss/879.
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The human immunodeficiency virus type 1 (HIV-1) protease (PR) is a critical drug target as it is responsible for virion maturation. Mutations within the active site (1°) of the PR directly interfere with inhibitor binding while mutations distal to the active site (2°) to restore enzymatic fitness. Increasing mutation number is not directly proportional to the severity of resistance, suggesting that resistance is not simply additive but that it is interdependent. The interdependency of both primary and secondary mutations to drive protease inhibitor (PI) resistance is grossly understudied.
To structurally and dynamically characterize the direct role of secondary mutations in drug resistance, I selected a panel of single-site mutant protease crystal structures complexed with the PI darunavir (DRV). From these studies, I developed a network hypothesis that explains how mutations outside the active site are able to perpetuate changes to the active site of the protease to disrupt inhibitor binding.
I then expanded the panel to include highly mutated multi-drug resistant variants. To elucidate the interdependency between primary and secondary mutations I used statistical and machine-learning techniques to determine which specific mutations underlie the perturbations of key inter-molecular interactions. From these studies, I have determined that mutations distal to the active site are able to perturb the global PR hydrogen bonding patterns, while primary and secondary mutations cooperatively perturb hydrophobic contacts between the PR and DRV. Discerning and exploiting the mechanisms that underlie drug resistance in viral targets could proactively ameliorate both current treatment and inhibitor design for HIV-1 targets.
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Chang, Max W. "Computational structure-based methods to anticipate HIV drug resistance evolution and accelerate inhibitor discovery." Diss., Connect to a 24 p. preview or request complete full text in PDF format. Access restricted to UC campuses, 2008. http://wwwlib.umi.com/cr/ucsd/fullcit?p3315120.
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3315Thesis (Ph. D.)--University of California, San Diego, 2008.Title from first page of PDF file (viewed August 4, 2008). Available via ProQuest Digital Dissertations. Vita. Includes bibliographical references (p. 128-139).
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Rylander, Andreas, and Liam Persson. "Modelling the Impact of Drug Resistance on Treatment as Prevention as an HIV Control Strategy." Thesis, KTH, Matematisk statistik, 2019. http://urn.kb.se/resolve?urn=urn:nbn:se:kth:diva-254237.
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Uganda is using a strategy called treatment as prevention where as many individuals as possible that are infected with HIV receive treatment. As a result, the number of newly infected individuals has decreased significantly. However, there is a discussion about a potential problem regarding transmitted drug resistance. This work aims to investigate if this in fact will be a problem in the future, and to estimate the costs for different scenarios. Through developing a population-based mathematical model that describes transmission dynamics of HIV in Uganda, stochastic simulations are made for different conditions. Through analysing our simulations, we can see that Uganda may have to change their approach to HIV treatment.För att minska smittoriskerna av HIV nyttjar Uganda en strategi som syftar till att behandla så många smittade personer som möjligt. Detta har lett till en signifikant minskning av antalet smittade personer. Det har dock uppstått en diskussion angående om läkemedels-resistent smitta kan komma att utgöra ett problem. Detta arbete syftar till att undersöka om detta kan utgöra ett problem i framtiden samt till att uppskatta de kostnader som kan uppstå i olika typer av scenarion. Under olika förutsättningar genomförs stokastiska simuleringar med hjälp av en matematisk populationsmodell framtagen för att beskriva spridningen av HIV i Uganda. Genom att analysera resultaten från olika simuleringar dras slutsatsen att Uganda kan behöva omvärdera sitt tillvägagångssätt gällande behandling av HIV.
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Lopes, Carmen Andréa Freitas. "Prevalência de mutações do HIV-1 e avaliação de subtipos virais em falha terapêutica no estado do Pará." reponame:Biblioteca Digital de Teses e Dissertações da UFRGS, 2014. http://hdl.handle.net/10183/127189.
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Introdução: Resistência aos antirretrovirais pode limitar opções de tratamento, principalmente em pacientes com acúmulo de falhas terapêuticas, o que pode comprometer resultados clínicos. Objetivos: caracterizar o perfil de mutações na transcriptase reversa e protease do HIV-1 de pacientes em falha ao tratamento. Secundariamente, avaliar associação entre mutações e número de falhas terapêuticas, associação entre mutações e subtipos do HIV-1 e apresentar a evolução temporal da prevalência dos subtipos do HIV-1, no estado do Pará, ao Norte do Brasil. Método: Estudo transversal, no qual se avaliam genotipagens, entre janeiro de 2004 a dezembro de 2013, com dados obtidos de formulário de solicitação do exame padronizado pela RENAGENO e de impressos dos resultados, ambos arquivados em quatro serviços de atendimento especializados. Foram incluídos os testes realizados por laboratório da RENAGENO, em maiores de 18 anos, e o primeiro exame daqueles que o realizaram em mais de um momento, totalizando 377 amostras. As mutações são descritas de acordo com o banco de dados de resistência do HIV da Universidade de Stanford (http://hivdb.stanford.edu), estimam-se suas prevalências e avaliam-se mutações de resistência de acordo com o número de falhas no momento da genotipagem, bem como diferenças de mutações entre subtipos B e não-B do HIV-1. Resultados: A mutação M184V foi a mais prevalente (80,1%), seguida da K130N (40,6%) e TAM. Em pacientes multiexperimentados previamente à genotipagem, resistência a ZDV, d4T e TDF foi associada às mutações M41L, D67N, V118I, L210W, K219Q e T69D; bem como resistência a todos os IP/r associou-se às mutações principais M46I, V82A, L90M, I54V, I84V, M46L e L76V. O subtipo B é o predominante no Pará (90,7%) e diferenças de prevalência de mutações entre subtipos ocorreram entre as mutações L63P e A71T versus subtipo B, enquanto as mutações L76V, M36I, K20R, L10V, L89M e F53L associaram-se ao subtipo não-B. Conclusão: A seleção de mutações de resistência do HIV-1 relacionada aos antirretrovirais é similar ao descrito em literatura. O acúmulo de falhas ao tratamento favorece a emergência de mutações, o que reforça o monitoramento de falha virológica, seguida de genotipagem para minimizar o impacto de resistência. Estudos adicionais de epidemiologia molecular são necessários para avaliar melhor a questão da prevalência de subtipos de HIV-1 no estado e possíveis associações com mutações de resistência do HIV-1.Introduction: Resistance to antiretroviral treatment can limit treatment options, especially in patients with accumulation of therapeutic failures, which may compromise clinical outcomes. Objectives: characterizing the profile of mutations in the protease and reverse transcriptase of HIV-1 patients in the treatment failure. Secondarily to evaluate the association between mutations and the number of treatment failures, association between mutations and subtypes of HIV-1 and present the temporal evolution of the prevalence of subtypes of HIV-1 in the state of Pará in northern Brazil. Method: cross-sectional study in which genotyping is evaluated between January, 2004 and December, 2013 with data obtained from the standardized application form for the examination RENAGENO and printed the results, both filed in four specialty care services. We included those by laboratory RENAGENO in 18 years and the first examination in those who underwent more than one time, totaling 377 samples. Mutations are described according to the database of HIV resistance at Stanford University (http://hivdb.stanford.edu), estimated their prevalence and resistance is evaluated according to the number of failures at the time of genotyping as well as differences between mutations and subtype B and non-B HIV-1. Results: The M184V mutation was the most prevalent (80.1%), followed by K130N (40.6%) and TAM. In patients who received at least three treatments prior to genotyping, resistance to ZDV, d4T and TDF was associated with mutations M41L, D67N, V118I, L210W, K219Q and T69D; well as resistance to all PI / r was associated with the major mutations M46I, V82A, L90M, I54V, I84V M46L and L76V. HIV-1 subtype B was the most prevalent (90.7%) and there were differences between subtypes B versus mutations: L63P and A71T were more frequent in the subtype B, whereas mutations L76V, K20R, L10V, L89M and F53L were in non-B subtypes. Conclusion: The selection of resistance mutations in HIV-1 related to antiretroviral is similar to that described in the literature. The accumulation of failures to treatment favors the emergence of mutations, reinforcing the monitoring and evaluation of virologic failure by genotyping to minimize the impact resistance. Additional molecular epidemiological studies are needed to better assess the issue of prevalence of subtypes of HIV-1 in the state and possible associations with resistance mutations in HIV-1.
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Singh, Y., and M. Mars. "A pilot study to integrate HIV drug resistance gold standard interpretation algorithms using neural networks." Journal for New Generation Sciences, Vol 11, Issue 2: Central University of Technology, Free State, Bloemfontein, 2013. http://hdl.handle.net/11462/639.
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Published ArticleThere are several HIV drug resistant interpretation algorithms which produce different resistance measures even if applied to the same resistance profile. This discrepancy leads to confusion in the mind of the physician when choosing the best ARV therapy.
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Kyeyune, Fred. "DECIPHERING THE GENOTYPIC HIV DRUG RESISTANCE IN A COHORT OF UGANDAN PATIENTS FAILING ANTIRETROVIRAL THERAPY." Case Western Reserve University School of Graduate Studies / OhioLINK, 2016. http://rave.ohiolink.edu/etdc/view?acc_num=case1459554730.
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Pugach, Pavel. "The evolutionary response of the HIV-1 ENV complex to selection pressures in vitro /." Access full-text from WCMC:, 2007. http://proquest.umi.com/pqdweb?did=1428842531&sid=4&Fmt=2&clientId=8424&RQT=309&VName=PQD.
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Lockbaum, Gordon J. "Molecular Mechanisms of Resistance and Structure-Based Drug Design in Homodimeric Viral Proteases." eScholarship@UMMS, 2020. https://escholarship.umassmed.edu/gsbs_diss/1072.
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Drug resistance is a global health threat costing society billions of dollars and impacting millions of lives each year. Current drug design strategies are inadequate because they focus on disrupting target activity and not restricting the evolutionary pathways to resistance. Improved strategies would exploit the structural and dynamic changes in the enzyme–inhibitor system integrating data from many inhibitors and variants.
Using HIV-1 protease as a model system, I aimed to elucidate the underlying resistance mechanisms, characterize conserved protease-inhibitor interactions, and generate more robust inhibitors by applying these insights. For primary mechanisms of resistance, comparing interactions at the protease–inhibitor interface showed how specific modifications affected potency. For mutations distal to the active site, molecular dynamics simulations were necessary to elucidate how changes propagated to reduce inhibitor binding. These insights informed inhibitor design to improve potency against highly resistant variants by optimizing hydrogen bonding. A series of hybrid inhibitors was also designed that showed excellent potency by combining key moieties of multiple FDA-approved inhibitors. I characterized the structural basis for alterations in binding affinity in HIV-1 protease both from mutations and inhibitors.
I applied these strategies to HTLV-1 protease, a potential drug target. I identified the HIV-1 inhibitor darunavir as a viable scaffold and evaluated analogues, leading to a low-nanomolar compound with potential for optimization. Hopefully, insights from this thesis will lead to the development of potent HTLV-1 protease inhibitors. More broadly, these inhibitor design strategies are applicable to other rapidly evolving targets, thereby reducing drug resistance rates in the future.
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Slaughter, Alison Paige. "Mechanism of action of allosteric HIV-1 integrase inhibitors." The Ohio State University, 2015. http://rave.ohiolink.edu/etdc/view?acc_num=osu1428684473.
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Ngilirabanga, Jean Baptiste. "Selected antiretroviral and anti-tuberculosis drug combinations by non-covalent bonding." University of Western Cape, 2021. http://hdl.handle.net/11394/8332.
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Doctor Pharmaceuticae - DPharmTreatment of the human immunodeficiency virus (HIV) and tuberculosis (TB) infections have become very complicated due to the advent of drug resistance. Drug combinations offer an alternative approach to reducing the emergence of drug resistance. Pharmaceutical co-crystals have provided the pharmaceutical industry with the ability to optimise the physicochemical properties of active pharmaceutical ingredients (APIs) while preserving the biological activity. Pharmaceutical co-crystals are formed between APIs and suitable co-formers that are biologically safe or even a second or third API.
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Shiningavamwe, Andreas Ndafudifwa. "Drug mutation patterns and risk factors associated with patients failing first-line antiretroviral therapy regimen in Oshikoto and Oshana regions, Namibia." University of the Western Cape, 2015. http://hdl.handle.net/11394/4997.
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Magister Public Health - MPHHIV/AIDS is a major health problem in Namibia with HIV prevalence estimated at 18.2% among pregnant women. Antiretroviral therapy (ART) was introduced in the public sector in 2003 and ART roll out was expanded throughout the country in the subsequent years. There are 221 ART sites in Namibia which include 34 district hospitals and 187 outreach service points. Currently there are 127,486 patients registered on ART in Namibia. However, there have been cases of patients experiencing treatment failure. The treatment failure can give rise to the emergence of HIV drug resistance. Genotyping information from patients with treatment failure can be valuable for tracking the dominant mutations conferring HIV drug resistance. However, HIV genotyping is not routinely available in Namibia due to cost. It is essential to determine the risk factors associated with development of HIV drug resistance so that these factors can be addressed. The aim of the current study was to describe HIV drug resistance mutations and the risk factors associated with HIV drug resistance among patients failing first- line ART regimen in Oshikoto and Oshana regions in Namibia. The case-control study design was used to collect data from cases who were being suspected of treatment failure to the first–line regimen in Oshikoto and Oshana regions in Namibia. The demographic, clinical and genotype information was collected from patient records. Out of 168 cases, 97 cases were eligible for this study and were matched with 105 controls. The mean age was 44.8 (±13.2) years for controls and 43.3 (±13.3) years for cases. Cases from Oshana and Oshikoto regions harboured 63% and 71% respectively for nucleoside reverse transcriptase inhibitors mutations with the dominant mutation being M184V/I. Sixty-eight percent (68%) and 76% respectively harboured mutations for non-nucleoside reverse transcriptase inhibitors with dominant mutation being K103N. Missed appointments, initiating inappropriate first-line regimen and adverse events or side effects were identified as risk factors for virological failure with odd ratios (OR) of 21.58 (95% CI 6.50 -71.59); 11.70 (95% CI 1.69 - 80.99) and 7.17 (95% CI 1.89 -27.22) respectively. Patients failing the first-line regimen need to be genotyped to assess the development of HIV drug resistance. The patients initiating ART should be educated on impacts of missing clinical appointments and adverse events of the drugs in order to prevent the emergence of drug resistance.
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Belay, Belay Tessema. "Molecular epidemiology and drug resistance of Mycobacterium tuberculosis among HIV positive and HIV negative tuberculosis patients in Amhara region, Northwest Ethiopia." Doctoral thesis, Universitätsbibliothek Leipzig, 2012. http://nbn-resolving.de/urn:nbn:de:bsz:15-qucosa-91937.
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Tuberculosis is a major public health problem in Ethiopia. The aims of this study were (i) to investigate the recovery rate of M. tuberculosis from smear positive single morning sputum specimens subjected to long-term storage at -20°C, (ii) to assess the level and risk factors for first- and second-line anti-TB drug resistance, (iii) to evaluate the performance of the GenoType®MTBDRplus and GenoType®MTBDRsl assays for drug susceptibility testing compared to the BacT/ALERT 3D system as reference method, (iv) to analyze the frequency of gene mutations associated with resistance to isoniazid (INH), rifampicin (RMP) and ethambutol (EMB) among M. tuberculosis isolates, and (v) to study the population structure and transmission dynamics of M. tuberculosis isolates from patients in Amhara region, Northwest Ethiopia. The median specimen storage time was 132 days. Of 319 specimens, 90.0% were culture positive. The length of time of sputum storage had no significant effect on the recovery rate of M. tuberculosis. Of 260 M. tuberculosis isolates, 15.8% were resistant to at least one first-line drug, 5.0% were multidrug resistant (MDR) and 3.5% were resistant to all first-line drugs. Any resistance to INH, RMP, streptomycin (STM), EMB and pyrazinamide (PZA) was 13.8%, 5.8%, 10.0%, 7.3% and 4.6%, respectively. All isolates were susceptible to second-line drugs. The GenoType®MTBDRplus assay had a sensitivity of 92% and specificity of 99% to detect INH resistance, and 100% sensitivity and specificity to detect RMP resistance and MDR. The GenoType®MTBDRsl assay had a sensitivity of 42% and specificity of 100% to detect EMB resistance. According to the molecular methods, mutations conferring resistance to INH, RMP, or EMB were detected in 13.5%, 5.8%, and 3.1% of the isolates, respectively, while mutation conferring MDR was present in 5.0% of the isolates. Of 244 M. tuberculosis isolates, 59.0% were classified as known lineages; Dehli/CAS (38.9%), Haarlem (8.6%), Ural (3.3%), LAM (3.3%), TUR (2.0%), X-type (1.2%), S-type (0.8%), Beijing (0.4%) and Uganda II (0.4%) lineage. Interestingly, 31.6% of the isolates were grouped in to four previously undefined phylogenetic lineages and were named as Ethiopia_3 (13.1%), Ethiopia_1 (7.8%), Ethiopia_H37Rv like (7.0%) and Ethiopia_2 (3.7%) lineages. The remaining 9.4% of the isolates could not be assigned to the known or new lineages. Overall, 45.1% of the isolates were grouped in clusters, indicating high rate of recent transmission. Similarly, 66.7% of MDR strains were grouped in clusters.
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Hill, Alison Lynn. "Dynamics of HIV treatment and social contagion." Thesis, Harvard University, 2013. http://dissertations.umi.com/gsas.harvard:10814.
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Modern-day management of infectious diseases is critically linked to the use of mathematical models to understand and predict dynamics at many levels, from the mechanisms of pathogenesis to the patterns of population-wide transmission and evolution. This thesis describes the development and application of mathematical techniques for HIV infection and dynamics on social networks. Treatment of HIV infection has improved dramatically in the past few decades but is still limited by the development of drug resistance and the inability of current therapies to completely eradicate the virus from an individual. We begin with a synthesis of the important evolutionary principles governing the HIV epidemic, emphasizing the role of modeling. We then describe a modeling framework to study the emergence of drug-resistant HIV within a patient. Our model integrates laboratory data and patient behavior, with the goal of predicting outcomes of clinical trials. Current results demonstrate how pharmacologic properties of antiretroviral drugs affect selection for drug resistance, and can explain drug-class-specific resistance risks. Thirdly, we describe models for a new class of drugs that aim to eliminate cells with latent viral infection. We provide estimates for the required efficacy of these drugs and describe the potential challenges of future clinical trials. Finally, models and mechanisms for understanding viral dynamics are increasingly finding applications outside traditional virology. They can be used to study the dynamics of behaviors, to help predict and intervene in their spread. We describe techniques for applying infectious disease models to social contagion, drawing on techniques for network epidemiology. We use this framework to interpret data on the interpersonal spread of health-related behaviors.