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Article ; Online: Comparison of HIV drug resistance profiles across HIV-1 subtypes A and D for patients receiving a tenofovir-based and zidovudine-based first line regimens in Uganda.

Ayitewala, Alisen / Kyeyune, Fred / Ainembabazi, Pamela / Nabulime, Eva / Kato, Charles Drago / Nankya, Immaculate

2020 Volume 17, Issue 1, Page(s) 2

Abstract: Background: Resistance to antiretroviral drugs is a major challenge among Human Immunodeficiency Virus (HIV) positive patients receiving antiretroviral therapy (ART). Mutations that arise as a result of this are diverse across the various drugs, drug ... ...

Abstract	Background: Resistance to antiretroviral drugs is a major challenge among Human Immunodeficiency Virus (HIV) positive patients receiving antiretroviral therapy (ART). Mutations that arise as a result of this are diverse across the various drugs, drug classes, drug regimens and subtypes. In Uganda, there is a paucity of information on how these mutations differ among the different drug regimens and the predominant HIV-1 subtypes. The purpose of this study was to determine mutation profile differences between first-line drug regimens: TDF/3TC/EFV and AZT/3TC/EFV and HIV-1 subtypes: A and D in Uganda. The study also investigated the potential usage of rilpivirine, doravirine and etravirine in patients who failed treatment on efavirenz. Methods: A retrospective study was conducted on 182 archived plasma samples obtained from patients who were experiencing virological failure between 2006 and 2017 at five Joint Clinical Research Center (JCRC) sites in Uganda. Sanger sequencing of the Reverse Transcriptase (RT) gene from codons 1-300 was done. Mutation scores were generated using the Stanford University HIV Drug Resistance Database. A Chi-square test was used to determine the association between drug resistance mutations (DRMs) and drug regimens or HIV-1 subtypes. Results: The prevalence of DRMs was 84.6% among patients failing a first-line efavirenz (EFV)-based regimen. The most prevalent Nucleoside Reverse Transcriptase Inhibitor (NRTI) mutations were M184V/I (67.3%), K219/Q/E (22.6%) and K65R (21.1%). While K103N (50.8%) and G190A/S/E/G (29.1%) were the most prevalent Non-Nucleoside Reverse Transcriptase Inhibitor (NNTRI) mutations. As expected, discriminatory DRMs such as K65R, L74I, and Y115F were noted in Tenofovir (TDF) containing regimens while the Thymidine Analogue Mutations (TAMs) L210W and T215 mutations were in Zidovudine (AZT)-based regimens. No significant difference (p = 0.336) was found for overall DRMs between HIV-1 subtypes A and D. Among the patients who had resistance to EFV, 37 (23.6%) were susceptible to newer NNRTIs such as Rilpivirine and Etravirine. Conclusion: Accumulation of DRMs between AZT/3TC/EFV and TDF/3TC/EFV is comparable but individual mutations that confer resistance to particular drugs should be considered at virological failure. Having either HIV-1 subtype A or D is not associated with the acquisition of DRMs, therefore HIV diversity should not determine the choice of treatment. Rilpivirine, etravirine and doravirine had minimal benefits for patients who failed on efavirenz.
MeSH term(s)	Adolescent ; Adult ; Anti-HIV Agents/therapeutic use ; Drug Resistance, Multiple, Viral/genetics ; Female ; HIV Infections/drug therapy ; HIV-1/classification ; HIV-1/drug effects ; HIV-1/genetics ; Humans ; Male ; Mutation ; Retrospective Studies ; Tenofovir/therapeutic use ; Treatment Failure ; Uganda ; Young Adult ; Zidovudine/therapeutic use
Chemical Substances	Anti-HIV Agents ; Zidovudine (4B9XT59T7S) ; Tenofovir (99YXE507IL)
Language	English
Publishing date	2020-01-31
Publishing country	England
Document type	Comparative Study ; Journal Article ; Multicenter Study
ZDB-ID	2173450-1
ISSN	1742-6405 ; 1742-6405
ISSN (online)	1742-6405
ISSN	1742-6405
DOI	10.1186/s12981-020-0258-7
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Article ; Online: Reduced and highly diverse peripheral HIV-1 reservoir in virally suppressed patients infected with non-B HIV-1 strains in Uganda.

Joussef-Piña, Samira / Nankya, Immaculate / Nalukwago, Sophie / Baseke, Joy / Rwambuya, Sandra / Winner, Dane / Kyeyune, Fred / Chervenak, Keith / Thiel, Bonnie / Asaad, Robert / Dobrowolski, Curtis / Luttge, Benjamin / Lawley, Blair / Kityo, Cissy M / Boom, W Henry / Karn, Jonathan / Quiñones-Mateu, Miguel E

Retrovirology

2022 Volume 19, Issue 1, Page(s) 1

Abstract: Background: Our understanding of the peripheral human immunodeficiency virus type 1 (HIV-1) reservoir is strongly biased towards subtype B HIV-1 strains, with only limited information available from patients infected with non-B HIV-1 subtypes, which are ...

Abstract	Background: Our understanding of the peripheral human immunodeficiency virus type 1 (HIV-1) reservoir is strongly biased towards subtype B HIV-1 strains, with only limited information available from patients infected with non-B HIV-1 subtypes, which are the predominant viruses seen in low- and middle-income countries (LMIC) in Africa and Asia. Results: In this study, blood samples were obtained from well-suppressed ART-experienced HIV-1 patients monitored in Uganda (n = 62) or the U.S. (n = 50), with plasma HIV-1 loads < 50 copies/ml and CD4 Conclusions: The smaller, but more diverse, peripheral HIV-1 reservoir in Ugandan patients might be associated with viral (e.g., non-B subtype with higher cytopathicity) and/or host (e.g., higher incidence of co-infections or co-morbidities leading to less clonal expansion) factors. This highlights the need to understand reservoir dynamics in diverse populations as part of ongoing efforts to find a functional cure for HIV-1 infection in LMICs.
MeSH term(s)	Adult ; Anti-Retroviral Agents/therapeutic use ; CD4-Positive T-Lymphocytes ; HIV Infections ; HIV-1/genetics ; Humans ; Proviruses/genetics ; Uganda/epidemiology ; Viral Load
Chemical Substances	Anti-Retroviral Agents
Language	English
Publishing date	2022-01-15
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	2142602-8
ISSN	1742-4690 ; 1742-4690
ISSN (online)	1742-4690
ISSN	1742-4690
DOI	10.1186/s12977-022-00587-3
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Article ; Online: High-level resistance to bictegravir and cabotegravir in subtype A- and D-infected HIV-1 patients failing raltegravir with multiple resistance mutations.

Ndashimye, Emmanuel / Li, Yue / Reyes, Paul S / Avino, Mariano / Olabode, Abayomi S / Kityo, Cissy M / Kyeyune, Fred / Nankya, Immaculate / Quiñones-Mateu, Miguel E / Barr, Stephen D / Arts, Eric J

The Journal of antimicrobial chemotherapy

2021 Volume 76, Issue 11, Page(s) 2965–2974

Abstract: Objectives: The second-generation integrase strand transfer inhibitor (INSTI) bictegravir is becoming accessible in low- and middle-income countries (LMICs), and another INSTI, cabotegravir, has recently been approved as a long-acting injectable. Data ... ...

Abstract	Objectives: The second-generation integrase strand transfer inhibitor (INSTI) bictegravir is becoming accessible in low- and middle-income countries (LMICs), and another INSTI, cabotegravir, has recently been approved as a long-acting injectable. Data on bictegravir and cabotegravir susceptibility in raltegravir-experienced HIV-1 subtype A- and D-infected patients carrying drug resistance mutations (DRMs) remain very scarce in LMICs. Patients and methods: HIV-1 integrase (IN)-recombinant viruses from eight patients failing raltegravir-based third-line therapy in Uganda were genotypically and phenotypically tested for susceptibility to bictegravir and cabotegravir. Ability of these viruses to integrate into human genomes was assessed in MT-4 cells. Results: HIV-1 IN-recombinant viruses harbouring single primary mutations (N155H or Y143R/S) or in combination with secondary INSTI mutations (T97A, M50I, L74IM, E157Q, G163R or V151I) were susceptible to both bictegravir and cabotegravir. However, combinations of primary INSTI-resistance mutations such as E138A/G140A/G163R/Q148R or E138K/G140A/S147G/Q148K led to decreased susceptibility to both cabotegravir (fold change in EC50 values from 429 to 1000×) and bictegravir (60 to 100×), exhibiting a high degree of cross-resistance. However, these same IN-recombinant viruses showed impaired integration capacity (14% to 48%) relative to the WT HIV-1 NL4-3 strain in the absence of drug. Conclusions: Though not currently widely accessible in most LMICs, bictegravir and cabotegravir offer a valid alternative to HIV-infected individuals harbouring subtype A and D HIV-1 variants with reduced susceptibility to first-generation INSTIs but previous exposure to raltegravir may reduce efficacy, more so with cabotegravir.
MeSH term(s)	Amides ; Drug Resistance, Viral ; HIV Infections/drug therapy ; HIV Integrase/genetics ; HIV Integrase Inhibitors/pharmacology ; HIV Integrase Inhibitors/therapeutic use ; HIV-1/genetics ; Heterocyclic Compounds, 3-Ring ; Humans ; Mutation ; Piperazines ; Pyridones/pharmacology ; Raltegravir Potassium/pharmacology ; Raltegravir Potassium/therapeutic use
Chemical Substances	Amides ; HIV Integrase Inhibitors ; Heterocyclic Compounds, 3-Ring ; Piperazines ; Pyridones ; Raltegravir Potassium (43Y000U234) ; bictegravir (8GB79LOJ07) ; HIV Integrase (EC 2.7.7.-) ; cabotegravir (HMH0132Z1Q)
Language	English
Publishing date	2021-08-27
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	191709-2
ISSN	1460-2091 ; 0305-7453
ISSN (online)	1460-2091
ISSN	0305-7453
DOI	10.1093/jac/dkab276
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Article ; Online: First-line HIV treatment failures in non-B subtypes and recombinants: a cross-sectional analysis of multiple populations in Uganda.

Poon, Art F Y / Ndashimye, Emmanuel / Avino, Mariano / Gibson, Richard / Kityo, Cissy / Kyeyune, Fred / Nankya, Immaculate / Quiñones-Mateu, Miguel E / Arts, Eric J

AIDS research and therapy

2019 Volume 16, Issue 1, Page(s) 3

Abstract: Background: Our understanding of HIV-1 and antiretroviral treatment (ART) is strongly biased towards subtype B, the predominant subtype in North America and western Europe. Efforts to characterize the response to first-line treatments in other HIV-1 ... ...

Abstract	Background: Our understanding of HIV-1 and antiretroviral treatment (ART) is strongly biased towards subtype B, the predominant subtype in North America and western Europe. Efforts to characterize the response to first-line treatments in other HIV-1 subtypes have been hindered by the availability of large study cohorts in resource-limited settings. To maximize our statistical power, we combined HIV-1 sequence and clinical data from every available study population associated with the Joint Clinical Research Centre (JCRC) in Uganda. These records were combined with contemporaneous ART-naive records from Uganda in the Stanford HIVdb database. Methods: Treatment failures were defined by the presence of HIV genotype records with sample collection dates after the ART start dates in the JCRC database. Drug resistances were predicted by the Stanford HIVdb algorithm, and HIV subtype classification and recombination detection was performed with SCUEAL. We used Bayesian network analysis to evaluate associations between drug exposures and subtypes, and binomial regression for associations with recombination. Results: This is the largest database of first-line treatment failures ([Formula: see text]) in Uganda to date, with a predicted statistical power of 80% to detect subtype associations at an odds ratio of [Formula: see text]. In the subset where drug regimen data were available, we observed that use of 3TC was associated with a higher rate of first line treatment failure, whereas regimens containing AZT and TDF were associated with reduced rates of failure. In the complete database, we found limited evidence of associations between HIV-1 subtypes and treatment failure, with the exception of a significantly lower frequency of failures among A/D recombinants that comprised about 7% of the population. First-line treatment failure was significantly associated with reduced numbers of recombination breakpoints across subtypes. Conclusions: Expanding access to first-line ART should confer the anticipated public health benefits in Uganda, despite known differences in the pathogenesis of HIV-1 subtypes. Furthermore, the impact of ART may actually be enhanced by frequent inter-subtype recombination in this region.
MeSH term(s)	Adolescent ; Adult ; Anti-Retroviral Agents/therapeutic use ; Bayes Theorem ; Cohort Studies ; Cross-Sectional Studies ; Drug Resistance, Viral ; Female ; Genotype ; HIV Infections/drug therapy ; HIV Infections/virology ; HIV Seropositivity ; HIV-1/classification ; HIV-1/drug effects ; HIV-1/genetics ; Humans ; Male ; Recombination, Genetic ; Sequence Analysis, DNA ; Treatment Failure ; Uganda ; Young Adult
Chemical Substances	Anti-Retroviral Agents
Language	English
Publishing date	2019-01-22
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ISSN	1742-6405
ISSN (online)	1742-6405
DOI	10.1186/s12981-019-0218-2
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Article ; Online: Accumulation of integrase strand transfer inhibitor resistance mutations confers high-level resistance to dolutegravir in non-B subtype HIV-1 strains from patients failing raltegravir in Uganda.

Ndashimye, Emmanuel / Avino, Mariano / Olabode, Abayomi S / Poon, Art F Y / Gibson, Richard M / Li, Yue / Meadows, Adam / Tan, Christine / Reyes, Paul S / Kityo, Cissy M / Kyeyune, Fred / Nankya, Immaculate / Quiñones-Mateu, Miguel E / Arts, Eric J

The Journal of antimicrobial chemotherapy

2020 Volume 75, Issue 12, Page(s) 3525–3533

Abstract: Background: Increasing first-line treatment failures in low- and middle-income countries (LMICs) have led to increased use of integrase strand transfer inhibitors (INSTIs) such as dolutegravir. However, HIV-1 susceptibility to INSTIs in LMICs, ... ...

Abstract	Background: Increasing first-line treatment failures in low- and middle-income countries (LMICs) have led to increased use of integrase strand transfer inhibitors (INSTIs) such as dolutegravir. However, HIV-1 susceptibility to INSTIs in LMICs, especially with previous raltegravir exposure, is poorly understood due to infrequent reporting of INSTI failures and testing for INSTI drug resistance mutations (DRMs). Methods: A total of 51 non-subtype B HIV-1 infected patients failing third-line (raltegravir-based) therapy in Uganda were initially selected for the study. DRMs were detected using Sanger and deep sequencing. HIV integrase genes of 13 patients were cloned and replication capacities (RCs) and phenotypic susceptibilities to dolutegravir, raltegravir and elvitegravir were determined with TZM-bl cells. Spearman's correlation coefficient was used to determine cross-resistance between INSTIs. Results: INSTI DRMs were detected in 47% of patients. HIV integrase-recombinant virus carrying one primary INSTI DRM (N155H or Y143R/S) was susceptible to dolutegravir but highly resistant to raltegravir and elvitegravir (>50-fold change). Two patients, one with E138A/G140A/Q148R/G163R and one with E138K/G140A/S147G/Q148K, displayed the highest reported resistance to raltegravir, elvitegravir and even dolutegravir. The former multi-DRM virus had WT RC whereas the latter had lower RCs than WT. Conclusions: In HIV-1 subtype A- and D-infected patients failing raltegravir and harbouring INSTI DRMs, there is high-level resistance to elvitegravir and raltegravir. More routine monitoring of INSTI treatment may be advised in LMICs, considering that multiple INSTI DRMs may have accumulated during prolonged exposure to raltegravir during virological failure, leading to high-level INSTI resistance, including dolutegravir resistance.
MeSH term(s)	Drug Resistance, Viral ; HIV Infections/drug therapy ; HIV Integrase/genetics ; HIV Integrase Inhibitors/pharmacology ; HIV Integrase Inhibitors/therapeutic use ; HIV-1/genetics ; Heterocyclic Compounds, 3-Ring ; Humans ; Mutation ; Oxazines ; Piperazines/therapeutic use ; Pyridones ; Raltegravir Potassium/pharmacology ; Raltegravir Potassium/therapeutic use ; Uganda
Chemical Substances	HIV Integrase Inhibitors ; Heterocyclic Compounds, 3-Ring ; Oxazines ; Piperazines ; Pyridones ; Raltegravir Potassium (43Y000U234) ; dolutegravir (DKO1W9H7M1) ; HIV Integrase (EC 2.7.7.-)
Language	English
Publishing date	2020-08-27
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	191709-2
ISSN	1460-2091 ; 0305-7453
ISSN (online)	1460-2091
ISSN	0305-7453
DOI	10.1093/jac/dkaa355
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Article ; Online: Absence of HIV-1 Drug Resistance Mutations Supports the Use of Dolutegravir in Uganda.

Ndashimye, Emmanuel / Avino, Mariano / Kyeyune, Fred / Nankya, Immaculate / Gibson, Richard M / Nabulime, Eva / Poon, Art F Y / Kityo, Cissy / Mugyenyi, Peter / Quiñones-Mateu, Miguel E / Arts, Eric J

AIDS research and human retroviruses

2018 Volume 34, Issue 5, Page(s) 404–414

Abstract: To screen for drug resistance and possible treatment with Dolutegravir (DTG) in treatment-naive patients and those experiencing virologic failure during first-, second-, and third-line combined antiretroviral therapy (cART) in Uganda. Samples from 417 ... ...

Abstract	To screen for drug resistance and possible treatment with Dolutegravir (DTG) in treatment-naive patients and those experiencing virologic failure during first-, second-, and third-line combined antiretroviral therapy (cART) in Uganda. Samples from 417 patients in Uganda were analyzed for predicted drug resistance upon failing a first- (N = 158), second- (N = 121), or third-line [all 51 involving Raltegravir (RAL)] treatment regimen. HIV-1 pol gene was amplified and sequenced from plasma samples. Drug susceptibility was interpreted using the Stanford HIV database algorithm and SCUEAL was used for HIV-1 subtyping. Frequency of resistance to nucleoside reverse transcriptase inhibitors (NRTIs) (95%) and non-NRTI (NNRTI, 96%) was high in first-line treatment failures. Despite lack of NNRTI-based treatment for years, NNRTI resistance remained stable in 55% of patients failing second-line or third-line treatment, and was also at 10% in treatment-naive Ugandans. DTG resistance (n = 366) was not observed in treatment-naive individuals or individuals failing first- and second-line cART, and only found in two patients failing third-line cART, while 47% of the latter had RAL- and Elvitegravir-resistant HIV-1. Secondary mutations associated with DTG resistance were found in 2%-10% of patients failing third-line cART. Of 14 drugs currently available for cART in Uganda, resistance was readily observed to all antiretroviral drugs (except for DTG) in Ugandan patients failing first-, second-, or even third-line treatment regimens. The high NNRTI resistance in first-line treatment in Uganda even among treatment-naive patients calls for the use of DTG to reach the UNAIDS 90:90:90 goals.
MeSH term(s)	Drug Resistance, Viral ; Female ; Genotype ; HIV Infections/drug therapy ; HIV Infections/virology ; HIV Integrase Inhibitors/pharmacology ; HIV Integrase Inhibitors/therapeutic use ; HIV-1/drug effects ; HIV-1/genetics ; Heterocyclic Compounds, 3-Ring/pharmacology ; Heterocyclic Compounds, 3-Ring/therapeutic use ; Humans ; Male ; Mutation, Missense ; Retrospective Studies ; Sequence Analysis, DNA ; Uganda ; pol Gene Products, Human Immunodeficiency Virus/genetics
Chemical Substances	HIV Integrase Inhibitors ; Heterocyclic Compounds, 3-Ring ; pol Gene Products, Human Immunodeficiency Virus ; dolutegravir (DKO1W9H7M1)
Language	English
Publishing date	2018-02-26
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	639130-8
ISSN	1931-8405 ; 0889-2229
ISSN (online)	1931-8405
ISSN	0889-2229
DOI	10.1089/AID.2017.0205
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Article: Defining the fitness of HIV-1 isolates with dual/mixed co-receptor usage.

Nankya, Immaculate L / Tebit, Denis M / Abraha, Awet / Kyeyune, Fred / Gibson, Richard / Jegede, Oyebisi / Nickel, Gabrielle / Arts, Eric J

AIDS research and therapy

2015 Volume 12, Page(s) 34

Abstract: Background: CCR5-using (r5) HIV-1 predominates during asymptomatic disease followed by occasional emergence of CXCR4-using (x4) or dual tropic (r5x4) virus. We examined the contribution of the x4 and r5 components to replicative fitness of HIV-1 ... ...

Abstract	Background: CCR5-using (r5) HIV-1 predominates during asymptomatic disease followed by occasional emergence of CXCR4-using (x4) or dual tropic (r5x4) virus. We examined the contribution of the x4 and r5 components to replicative fitness of HIV-1 isolates. Methods: Dual tropic r5x4 viruses were predicted from average HIV-1 env sequences of two primary subtype C HIV-1 isolates (C19 and C27) and from two patient plasma samples (B12 and B19). Chimeric Env viruses with an NL4-3 backbone were constructed from the B12 and B19 env sequences. To determine replicative fitness, these primary and chimeric dual tropic HIV-1 were then competed against HIV-1 reference isolates in U87.CD4 cells expressing CXCR4 or CCR5 or in PBMCs ± entry inhibitors. Contribution of the x4 and r5 clones within the quasispecies of these chimeric or primary HIV-1 isolates were then compared to the frequency of x4, r5, and dual tropic clones within the quasispecies as predicted by phenotypic assays, clonal sequencing, and 454 deep sequencing. Results: In the primary HIV-1 isolates (C19 and C27), subtype C dual tropic clones dominated over x4 clones while pure r5 clones were absent. In two subtype B chimeric viruses (B12 and B19), r5 clones were >100-fold more abundant than x4 or r5/x4 clones. The dual tropic C19 and C27 HIV-1 isolates outcompeted r5 primary HIV-1 isolates, B2 and C3 in PBMCs. When AMD3100 was added or when only U87.CD4.CCR5 cells were used, the B2 and C3 reference viruses now out-competed the r5 component of the dual tropic C19 and C27. In contrast, the same replicative fitness was observed with dualtropic B12 and B19 HIV-1 isolates relative to x4 HIV-1 A8 and E6 or the r5 B2 and C3 viruses, even when the r5 or x4 component was inhibited by maraviroc (or AMD3100) or in U87.CD4.CXCR4 (or CCR5) cells. Conclusions: In the dual tropic HIV-1 isolates, the x4 replicative fitness is higher than r5 clones but the x4 or x4/r5 clones are typically at low frequency in the intrapatient virus population. Ex vivo HIV propagation promotes outgrowth of the x4 clones and provides an over-estimate of x4 dominance in replicative fitness within dual tropic viruses.
Language	English
Publishing date	2015
Publishing country	England
Document type	Journal Article
ISSN	1742-6405
ISSN	1742-6405
DOI	10.1186/s12981-015-0066-7
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Article ; Online: Sensitive detection of HIV-1 resistance to Zidovudine and impact on treatment outcomes in low- to middle-income countries.

Gibson, Richard M / Nickel, Gabrielle / Crawford, Michael / Kyeyune, Fred / Venner, Colin / Nankya, Immaculate / Nabulime, Eva / Ndashimye, Emmanuel / Poon, Art F Y / Salata, Robert A / Kityo, Cissy / Mugyenyi, Peter / Quiñones-Mateu, Miguel E / Arts, Eric J

Infectious diseases of poverty

2017 Volume 6, Issue 1, Page(s) 163

Abstract: Background: Thymidine analogs, namely AZT (Zidovudine or Retrovir™) and d4T (Stavudine or Zerit™) are antiretroviral drugs still employed in over 75% of first line combination antiretroviral therapy (cART) in Kampala, Uganda despite aversion to ... ...

Abstract	Background: Thymidine analogs, namely AZT (Zidovudine or Retrovir™) and d4T (Stavudine or Zerit™) are antiretroviral drugs still employed in over 75% of first line combination antiretroviral therapy (cART) in Kampala, Uganda despite aversion to prescribing these drugs for cART in high income countries due in part to adverse events. For this study, we explored how the continued use of these thymidine analogs in cART could impact emergence of drug resistance and impact on future treatment success in Uganda, a low-income country. Methods: We examined the drug resistance genotypes by Sanger sequencing of 262 HIV-infected patients failing a first line combined antiretroviral treatment containing either AZT or d4T, which represents approximately 5% of the patients at the Joint Clinical Research Center receiving a AZT or d4T containing treatment. Next generation sequencing (DEEPGEN™HIV) and multiplex oligonucleotide ligation assays (AfriPOLA) were then performed on a subset of patient samples to detect low frequency drug resistant mutations. CD4 cell counts, viral RNA loads, and treatment changes were analyzed in a cohort of treatment success and failures. Results: Over 80% of patients failing first line AZT/d4T-containing cART had predicted drug resistance to 3TC (Lamivudine) and non-nucleoside RT inhibitors (NNRTIs) in the treatment regimen but only 45% had resistance AZT/d4T associated resistance mutations (TAMs). TAMs were however detected at low frequency within the patients HIV quasispecies (1-20%) in 21 of 34 individuals who were failing first-line AZT-containing cART and lacked TAMs by Sanger. Due to lack of TAMs by Sanger, AZT was typically maintained in second-line therapies and these patients had a low frequency of subsequent virologic success. Conclusions: Our findings suggest that continued use of AZT and d4T in first-line treatment in low-to-middle income countries may lead to misdiagnosis of HIV-1 drug resistance and possibly enhance a succession of second- and third-line treatment failures.
MeSH term(s)	Adolescent ; Adult ; Anti-HIV Agents/pharmacology ; Anti-HIV Agents/therapeutic use ; CD4 Lymphocyte Count ; Child ; Child, Preschool ; Cohort Studies ; Drug Resistance, Viral ; Female ; HIV Infections/drug therapy ; HIV-1/drug effects ; Humans ; Male ; Middle Aged ; Treatment Failure ; Treatment Outcome ; Uganda ; Viral Load ; Young Adult ; Zidovudine/pharmacology ; Zidovudine/therapeutic use
Chemical Substances	Anti-HIV Agents ; Zidovudine (4B9XT59T7S)
Language	English
Publishing date	2017-12-04
Publishing country	England
Document type	Journal Article
ZDB-ID	2689396-4
ISSN	2049-9957 ; 2049-9957
ISSN (online)	2049-9957
ISSN	2049-9957
DOI	10.1186/s40249-017-0377-0
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Article ; Online: HIV-1 strains belonging to large phylogenetic clusters show accelerated escape from integrase inhibitors in cell culture compared with viral isolates from singleton/small clusters.

Brenner, Bluma G / Ibanescu, Ruxandra-Ilinca / Oliveira, Maureen / Roger, Michel / Hardy, Isabelle / Routy, Jean-Pierre / Kyeyune, Fred / Quiñones-Mateu, Miguel E / Wainberg, Mark A

The Journal of antimicrobial chemotherapy

2017 Volume 72, Issue 8, Page(s) 2171–2183

Abstract: Objectives: Viral phylogenetics revealed two patterns of HIV-1 spread among MSM in Quebec. While most HIV-1 strains ( n = 2011) were associated with singleton/small clusters (cluster size 1-4), 30 viral lineages formed large networks (cluster size 20- ...

Abstract	Objectives: Viral phylogenetics revealed two patterns of HIV-1 spread among MSM in Quebec. While most HIV-1 strains ( n = 2011) were associated with singleton/small clusters (cluster size 1-4), 30 viral lineages formed large networks (cluster size 20-140), contributing to 42% of diagnoses between 2011 and 2015. Herein, tissue culture selections ascertained if large cluster lineages possessed higher replicative fitness than singleton/small cluster isolates, allowing for viral escape from integrase inhibitors. Methods: Primary HIV-1 isolates from large 20+ cluster ( n = 11) or singleton/small cluster ( n = 6) networks were passaged in vitro in escalating concentrations of dolutegravir, elvitegravir and lamivudine for 24-36 weeks. Sanger and deep sequencing assessed genotypic changes under selective drug pressure. Results: Large cluster HIV-1 isolates selected for resistance to dolutegravir, elvitegravir and lamivudine faster than HIV-1 strains forming small clusters. With dolutegravir, large cluster HIV-1 variants acquired solitary R263K ( n = 7), S153Y ( n = 1) or H51Y ( n = 1) mutations as the dominant quasi-species within 8-12 weeks as compared with small cluster lineages where R263K ( n = 1/6), S153Y (1/6) or WT species (4/6) were observed after 24 weeks. Interestingly, dolutegravir-associated mutations compromised viral replicative fitness, precluding escalations in concentrations beyond 5-10 nM. With elvitegravir, large cluster variants more rapidly acquired first mutations (T66I, A92G, N155H or S147G) by week 8 followed by sequential accumulation of multiple mutations leading to viral escape (>10 μM) by week 24. Conclusions: Further studies are needed to understand virological features of large cluster viruses that may favour their transmissibility, replicative competence and potential to escape selective antiretroviral drug pressure.
MeSH term(s)	Cluster Analysis ; Drug Resistance, Viral ; Genotype ; HIV Infections/virology ; HIV Integrase Inhibitors/pharmacology ; HIV-1/classification ; HIV-1/drug effects ; HIV-1/genetics ; HIV-1/isolation & purification ; Humans ; Mutation ; Phylogeny ; Quebec ; Selection, Genetic ; Serial Passage ; Virus Cultivation
Chemical Substances	HIV Integrase Inhibitors
Language	English
Publishing date	2017-02-25
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	191709-2
ISSN	1460-2091 ; 0305-7453
ISSN (online)	1460-2091
ISSN	0305-7453
DOI	10.1093/jac/dkx118
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article ; Online: Higher sequence diversity in the vaginal tract than in blood at early HIV-1 infection.

Klein, Katja / Nickel, Gabrielle / Nankya, Immaculate / Kyeyune, Fred / Demers, Korey / Ndashimye, Emmanuel / Kwok, Cynthia / Chen, Pai-Lien / Rwambuya, Sandra / Poon, Art / Munjoma, Marshall / Chipato, Tsungai / Byamugisha, Josaphat / Mugyenyi, Peter / Salata, Robert A / Morrison, Charles S / Arts, Eric J

PLoS pathogens

2018 Volume 14, Issue 1, Page(s) e1006754

Abstract: In the majority of cases, human immunodeficiency virus type 1 (HIV-1) infection is transmitted through sexual intercourse. A single founder virus in the blood of the newly infected donor emerges from a genetic bottleneck, while in rarer instances ... ...

Abstract	In the majority of cases, human immunodeficiency virus type 1 (HIV-1) infection is transmitted through sexual intercourse. A single founder virus in the blood of the newly infected donor emerges from a genetic bottleneck, while in rarer instances multiple viruses are responsible for systemic infection. We sought to characterize the sequence diversity at early infection, between two distinct anatomical sites; the female reproductive tract vs. systemic compartment. We recruited 72 women from Uganda and Zimbabwe within seven months of HIV-1 infection. Using next generation deep sequencing, we analyzed the total genetic diversity within the C2-V3-C3 envelope region of HIV-1 isolated from the female genital tract at early infection and compared this to the diversity of HIV-1 in plasma. We then compared intra-patient viral diversity in matched cervical and blood samples with three or seven months post infection. Genetic analysis of the C2-V3-C3 region of HIV-1 env revealed that early HIV-1 isolates within blood displayed a more homogeneous genotype (mean 1.67 clones, range 1-5 clones) than clones in the female genital tract (mean 5.7 clones, range 3-10 clones) (p<0.0001). The higher env diversity observed within the genital tract compared to plasma was independent of HIV-1 subtype (A, C and D). Our analysis of early mucosal infections in women revealed high HIV-1 diversity in the vaginal tract but few transmitted clones in the blood. These novel in vivo finding suggest a possible mucosal sieve effect, leading to the establishment of a homogenous systemic infection.
MeSH term(s)	Base Sequence ; Cervix Uteri/virology ; Cohort Studies ; Female ; Genetic Variation ; HIV Infections/virology ; HIV Seropositivity/blood ; HIV Seropositivity/virology ; HIV-1/genetics ; HIV-1/isolation & purification ; High-Throughput Nucleotide Sequencing ; Humans ; Longitudinal Studies ; RNA, Viral/blood ; RNA, Viral/chemistry ; RNA, Viral/isolation & purification ; Reproductive Tract Infections/blood ; Reproductive Tract Infections/virology ; Uganda ; Vagina/virology ; Viral Load ; Viremia/blood ; Viremia/virology ; Zimbabwe ; env Gene Products, Human Immunodeficiency Virus/chemistry ; env Gene Products, Human Immunodeficiency Virus/genetics
Chemical Substances	RNA, Viral ; env Gene Products, Human Immunodeficiency Virus
Language	English
Publishing date	2018-01-18
Publishing country	United States
Document type	Comparative Study ; Journal Article ; Multicenter Study ; Research Support, N.I.H., Extramural
ZDB-ID	2205412-1
ISSN	1553-7374 ; 1553-7366
ISSN (online)	1553-7374
ISSN	1553-7366
DOI	10.1371/journal.ppat.1006754
Database	MEDical Literature Analysis and Retrieval System OnLINE

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