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From bedside to bench and back : future options for antiretroviral drugs in non-B HIV-1 subtypes
Thesis (DMed)--Stellenbosch University, 2020.
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Stellenbosch : Stellenbosch University
2020
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| _version_ | 1867614017709670400 |
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| access_status_str | Open Access |
| author | Njenda, Duncan Tazvinzwa |
| author2 | Engelbrecht, Susan |
| author_browse | Engelbrecht, Susan Njenda, Duncan Tazvinzwa |
| author_facet | Engelbrecht, Susan Njenda, Duncan Tazvinzwa |
| author_sort | Njenda, Duncan Tazvinzwa |
| collection | Thesis |
| dc_rights_str_mv | Stellenbosch University |
| description | Thesis (DMed)--Stellenbosch University, 2020. |
| format | Thesis |
| id | oai:scholar.sun.ac.za:10019.1/109087 |
| institution | Stellenbosch University (South Africa) |
| language | en_ZA |
| last_indexed | 2026-06-10T12:45:21.489Z |
| license_str | Other — see source repository |
| provenance_str_mv | Harvested via OAI-PMH from SUNScholar — Stellenbosch University Repository |
| publishDate | 2020 |
| publishDateRange | 2020 |
| publishDateSort | 2020 |
| publisher | Stellenbosch : Stellenbosch University |
| publisherStr | Stellenbosch : Stellenbosch University |
| record_format | dspace |
| source_str | SUNScholar — Stellenbosch University Repository |
| spelling | oai:scholar.sun.ac.za:10019.1/109087 From bedside to bench and back : future options for antiretroviral drugs in non-B HIV-1 subtypes Njenda, Duncan Tazvinzwa Engelbrecht, Susan Jacobs, Graeme Brendon Neogi, Ujjwal Sonnerborg, Anders Spetz, Anna-Lena Stellenbosch University. Faculty of Medicine and Health Sciences. Dept. of Pathology: Medical Virology. HIV-1 drug resistance Non-B subtype Protease inhibitor UCTD ARV (Viruses) --Drugs Thesis (DMed)--Stellenbosch University, 2020. Introduction: HIV-1 drug resistance remains a burden in low- and middle-income countries (LMIC). Regardless of the advances in antiretroviral (ARV) therapy, there is an increase in the trend of acquired and pre-treatment drug resistance mutations (DRM) in LMIC affected by HIV-1 non-B subtypes. The overall aim of this thesis is to understand the potential subtype-specific differences in viral fitness and drug susceptibility against the drugs that target different stages of viral replication that includes, protease-mediated cleavage and maturation (Paper I), reverse transcription (Paper II) and integration (Paper III). Methods:The thesis presents cross-sectional drug resistance data from predominantly HIV-1 non-B subtypes. It also includes virological drug sensitivity and enzyme-based in vitro assay results of recombinant viruses derived from predominantly HIV-1 non-B and few HIV-1B infected patients. The following areas were investigated: a) the role that HIV-1 subtype C (HIV-1C) gag-p6 gene could play in response to proteaseInhibitors PIs in the absence of known PI primary mutations (Paper I). b) Ex vivo potency of the newer drug 4’-Ethynyl-2’-Fluoro-2’ deoxyadenosine (EFdA),first and second generation non-nucleoside reverse transcriptase inhibitors (NNRTIs)and Tenofovir alafenamide(TAF) against diverse HIV-1 subtypes (Paper III). c)Ex vivo potency of Integrase strand transfer inhibitors (INSTIs) against diverse HIV-1subtypes as well as genotypic resistance data comparing INSTI naïve and INSTI-experienced patients. Results: In paper I, the study showed an increase in viral fitness for HIV-1C viruses carrying the PYxE insertion in gag-p6 when compared to the wild-type (WT) HIV-1C viruses. Furthermore, some PYxE-carrying viruses had low sensitivity to LPV and (TAF) when tested in drug sensitivity assays. Clinical data analysis showed a higher pre-therapy viral load and a decrease in CD4+ T-cell counts for patients harboring PYxE-carrying viruses when compared to WT. Paper II. demonstrated that EFdA has a high inhibitory potential independent of HIV-1 subtype and high antiviral activity against resistant viruses. However, HIV-1C viruses had a significantly reduced susceptibility to NNRTIs, specifically Rilpivirine and Etravirine. In paper III, the drug susceptibility of INSTIs results indicated that INSTIs such as Dolutegravir (DRV), Bictegravir (BIC) and Cabotegravir (CAB) inhibited non-B subtypes significantly as compared to HIV-1B subtypes. Conclusion: Inferences can be made from the results to suggests that subtype-specific differences play an essential role in influencing the ARV susceptibility which could further impact the treatment efficacy in sub-optimal adherence. To reduce the trend of increasing DRMs in non-B HIV-1 subtypes which are mainly dominating in LMICs, adherence support and viral load monitoring should be prioritized. A rapid adaptation of INSTIs and newer drugs that have long-acting potential is encouraged. However, pre-clinical studies and clinical trials that are mainly restricted to the HIV-1B enrolled patients, should be inclusive of non-HIV-1B infected patients before the massive roll-out of INSTIs and newer drugs continues in non-HIV-1B dominated settings. Inleiding: weerstand teen HIV-1 is steeds 'n las in lande met lae en middelinkomste (LMIC). Ongeag die vooruitgang in antiretrovirale (ARV) terapie, is daar 'n toename in die neiging tot verkrygde en voorbehandelde geneesmiddelweerstandsmutasies (DRM) in LMIC wat beïnvloed word deur HIV-1 nie-B-subtipes. Die oorhoofse doel van hierdie tesis is om die potensiële subtipes-spesifieke verskille in virale fiksheid en geneesmiddelgevoeligheid te verstaanteenoor die medisyne wat verskillende fases van virale replikasie teiken, wat proteasemedieerde splyting en volwassenheid insluit (Vraestel I), omgekeerde transkripsie (Vraestel II ) en integrasie (Vraestel III)Metodes: Die tesis bied dwarsdeursnit-gegewensweerstandigheidsdata van hoofsaaklik HIV-1 nie-B-subtipes. Dit bevat ook virologiese sensitiwiteit vir die geneesmiddels en in vitro gebaseerde in-vitro-ondersoekresultate van rekombinante virusse afgelei van hoofsaaklik HIV-1 nie-B-en min HIV-1B-geïnfekteerde pasiënte. Die volgende gebiede is ondersoek:a)die rol wat HIV-1 subtipe C (HIV-1C) gag-p6 geen kan speel in eaksie op protease-remmers PI's in die afwesigheid van bekende PI primêre mutasies (Vraestel I).b)Die potensiaal vanex vivo van die nuwer geneesmiddel 4'-Ethynyl-2'-Fluoro-2 'deoxyadenosine (EFdA), eerste en tweede generasie omgekeerde transkriptase-remmers (NNRTI's) en Tenofovir alafenamide (TAF) teen diverse HIV-1 subtipes (Vraestel II)c)Ex vivo-sterkte van Integrase-streng-oordrag-remmers (INSTI's) teen diverse HIV-1 subtipes, asook genotipiese weerstandsdata wat INSTI-naïef en INSTI-ervare pasiënte vergelyk.(Vraestel III)Resultate: In vraestel I het die studie 'n toename in die virale fiksheid vir HIV-1C-virusse wat die PYxE-invoeging in gag-p6dra, vergelyk met die wilde-tipe (WT) HIV-1C-virusse. Verder het sommige PYxE-draende virusse 'n lae sensitiwiteit vir LPV en (TAF) gehad toe hulle in medisyne-senisitiwiteitsondersoeke getoets is. Kliniese data-ontleding hetgetoon dat 'n hoër virale lading voor die terapie en 'n afname in CD4 + T-seltellings was vir pasiënte wat PYxE-draende virusse bevat in vergelyking met WT. Vraestel II. aangetoon dat EFdA 'n hoë remmende potensiaal het, onafhanklik van HIV-1-subtipe en 'n hoë antivirale aktiwiteit teen weerstandige virusse. HIV-1C-virusse het egter 'n aansienlike verminderde vatbaarheid vir NNRTI's, spesifiek Rilpivirine en Etravirine, gehad. In vraestel IIIhet die geneesmiddelgevoeligheid van INSTIs-resultate aangedui dat INSTI's soos Dolutegravir (DRV), Bictegravir (BIC) en Cabotegravir (CAB) nie-B-subtipes beduidend belemmer het in vergelyking met die subtipes HIV-1B.Gevolgtrekking:Uit die resultate kan afleidings gemaak word om aan te dui dat subtipespesifieke verskille 'n wesenlike rol speel in die beïnvloeding van die ARV-vatbaarheid, wat die effektiwiteit van die behandeling in sub-optimale nakoming verder kan beïnvloed. Om die neiging tot toenemende DRM's in nie-B HIV-1 subtipes te verminder, wat hoofsaaklik in LMIC's oorheers, moet aanhegtingsondersteuning en moniteringvan virale ladings geprioritiseer word. 'N Vinnige aanpassing van INSTI's en nuwer medisyne wat langwerkende potensiaal het, word aangemoedig. Voor-kliniese studies en kliniese toetse wat hoofsaaklik beperk is tot die HIV-1B-ingeskrewe pasiënte, moet egter nie-HIV-1B-geïnfekteerde pasiënte insluit voordat die massiewe implementering van INSTI's en nuwer medisyne in nie-HIV-1B voortduur. gedomineerde instellings Doctoral 2020-07-30T10:44:29Z 2021-01-31T19:34:48Z 2020-07-30T10:44:29Z 2021-01-31T19:34:48Z 2020-12 Thesis http://hdl.handle.net/10019.1/109087 en_ZA Stellenbosch University 89 pages application/pdf Stellenbosch : Stellenbosch University |
| spellingShingle | HIV-1 drug resistance Non-B subtype Protease inhibitor UCTD ARV (Viruses) --Drugs Njenda, Duncan Tazvinzwa From bedside to bench and back : future options for antiretroviral drugs in non-B HIV-1 subtypes |
| title | From bedside to bench and back : future options for antiretroviral drugs in non-B HIV-1 subtypes |
| title_full | From bedside to bench and back : future options for antiretroviral drugs in non-B HIV-1 subtypes |
| title_fullStr | From bedside to bench and back : future options for antiretroviral drugs in non-B HIV-1 subtypes |
| title_full_unstemmed | From bedside to bench and back : future options for antiretroviral drugs in non-B HIV-1 subtypes |
| title_short | From bedside to bench and back : future options for antiretroviral drugs in non-B HIV-1 subtypes |
| title_sort | from bedside to bench and back future options for antiretroviral drugs in non b hiv 1 subtypes |
| topic | HIV-1 drug resistance Non-B subtype Protease inhibitor UCTD ARV (Viruses) --Drugs |
| url | http://hdl.handle.net/10019.1/109087 |
| work_keys_str_mv | AT njendaduncantazvinzwa frombedsidetobenchandbackfutureoptionsforantiretroviraldrugsinnonbhiv1subtypes |