HIV-1 non-B resistance mutations and natural polymorphisms to integrase strand transfer inhibitors in recently diagnosed patients in Gabon, Central Africa.
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ABSTRACT:
SUBMITTER: Engone-Ondo JD
PROVIDER: S-EPMC9244210 | biostudies-literature | 2022 Jun
REPOSITORIES: biostudies-literature
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HIV-1 non-B resistance mutations and natural polymorphisms to integrase strand transfer inhibitors in recently diagnosed patients in Gabon, Central Africa.
Engone-Ondo Jéordy D JD Bignoumba Michelle M Boundzanga Moussavou Pamela P Gafou Amahani A Diane Abdoulaye A Yangawagou Leslie Monica LM Kassa Kassa Roland Fabrice RF Onanga Richard R Mouinga-Ondémé Augustin A Aghokeng Avelin F AF
The Journal of antimicrobial chemotherapy 20220601 7
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Project description:With the widespread use of Integrase strand transfer inhibitors (INSTIs), surveillance of HIV-1 pretreatment drug resistance is critical in optimizing antiretroviral treatment efficacy. However, despite the introduction of these drugs, data concerning their resistance mutations (RMs) is still limited in Ethiopia. Thus, this study aimed to assess INSTI RMs and polymorphisms at the gene locus coding for Integrase (IN) among viral isolates from ART-naive HIV-1 infected Ethiopian population. This was a cross-sectional study involving isolation of HIV-1 from plasma of 49 newly diagnosed drug-naive HIV-1 infected individuals in Addis-Ababa during the period between June to December 2018. The IN region covering the first 263 codons of blood samples was amplified and sequenced using an in-house assay. INSTIs RMs were examined using calibrated population resistance tool version 8.0 from Stanford HIV drug resistance database while both REGA version 3 online HIV-1 subtyping tool and the jumping profile Hidden Markov Model from GOBICS were used to examine HIV-1 genetic diversity. Among the 49 study participants, 1 (1/49; 2%) harbored a major INSTIs RM (R263K). In addition, blood specimens from 14 (14/49; 28.5%) patients had accessory mutations. Among these, the M50I accessory mutation was observed in a highest frequency (13/49; 28.3%) followed by L74I (1/49; 2%), S119R (1/49; 2%), and S230N (1/49; 2%). Concerning HIV-1 subtype distribution, all the entire study subjects were detected to harbor HIV-1C strain as per the IN gene analysis. This study showed that the level of primary HIV-1 drug resistance to INSTIs is still low in Ethiopia reflecting the cumulative natural occurrence of these mutations in the absence of selective drug pressure and supports the use of INSTIs in the country. However, continues monitoring of drug resistance should be enhanced since the virus potentially develop resistance to this drug classes as time goes by.
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Project description:There has been no systematic review of the prevalence of transmitted integrase strand transfer inhibitor (INSTI) resistance. We systematically searched the English-language PubMed database and GenBank to identify studies published since 2010 reporting 50 or more INSTI-naive HIV-1-infected adults undergoing integrase genotyping. We extracted data related to country, sample year, specimen type, sequencing method, and subtype. For studies with sequences in GenBank, we determined the prevalence of three categories of INSTI-associated resistance mutations: (1) nonpolymorphic INSTI-selected drug resistance mutations (DRMs) that we refer to as surveillance DRMs; (2) rarely selected nonpolymorphic INSTI-associated DRMs; and (3) common polymorphic accessory INSTI-selected DRMs. A total of 103 studies met inclusion criteria including 75 studies in GenBank containing integrase sequences from 16,481 INSTI-naive persons. The median sample year was 2013 (interquartile range: 2008-2014). The prevalence of INSTI surveillance DRMs, rarely selected DRMs, and common polymorphic accessory INSTI-selected DRMs were 0.5%, 0.8%, and 6.2%, respectively. There was no association between the presence of nonpolymorphic surveillance DRM and region, sample year, or subtype. Two surveillance DRMs, E138K and R263K occurred in 0.15% and 0.10% of naive sequences, respectively. Several lines of evidence suggested that the 0.5% prevalence of surveillance DRMs partly reflects the cumulative natural occurrence of these mutations in the absence of selective drug pressure. There was an unexplained temporal increase in the proportion of sequences with polymorphic accessory mutations. The prevalence of INSTI-associated surveillance DRMs is low even in regions where INSTIs have been a major component of antiretroviral therapy for several years. The presence of INSTI-associated surveillance DRMs in INSTI-naive persons likely results from actual cases of transmitted INSTI resistance and from a low background level reflecting the cumulative rare natural occurrence of several nonpolymorphic mutations.
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Project description:HIV drug resistance has been one of the major obstacles to HIV eradication and has contributed to the need for the constant development of new antiretroviral drugs over the past 25 years. With the recent approval of dolutegravir for human therapy by the U.S. Food and Drug Administration, health practitioners may soon have access to three integrase strand transfer inhibitors to treat individuals living with HIV. Here, we review the use of raltegravir, elvitegravir, and dolutegravir for use in first- and second-line HIV treatment regimens and the issue of HIV resistance against integrase inhibitors.
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Project description:IntroductionThe widespread adoption of integrase strand transfer inhibitors (INSTIs) has led to the emergence of INSTI-associated drug-resistance mutations. This cross-sectional study conducted a comprehensive national survey to investigate the prevalence of pretreatment drug resistance (PDR) to INSTIs among newly diagnosed human immunodeficiency virus (HIV) individuals in China.MethodsThe study enrolled 10,654 individuals from 31 provincial-level administrative divisions between 2018 and 2023. All participants underwent integrase region genotypic resistance testing. PDR to INSTIs was analyzed using the Stanford HIV drug resistance database, and molecular transmission networks were constructed using HIV-TRACE.ResultsThe overall PDR prevalence of INSTIs was 0.95%. The predominant major and accessory mutations identified were E138K/A (n=19) and G163R/K (n=29), respectively. Multivariable logistic regression analysis revealed that age ≥50 years [adjusted odds ratio (aOR)=1.87, 95% confidence interval (CI): 1.03, 3.42] and HIV subtype B (aOR=3.87, 95% CI: 1.97, 7.58) were significant risk factors for PDR. Molecular network analysis showed that 1,257 (26.0%) CRF07_BC sequences formed 432 transmission clusters, while 811 (27.6%) CRF01_AE sequences were associated with 335 clusters. The identified drug-resistance mutations included E138K/A, R263K, Y143H, G163R/K, E157Q, and T97A.ConclusionsThe current prevalence of PDR to INSTIs in China remains low. However, given the increasingly widespread use of INSTIs, continuous surveillance of drug resistance emergence and transmission patterns is essential.
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Project description:Integrase Strand Transfer Inhibitors (INSTIs) are currently used as the most effective therapy in the treatment of human immunodeficiency virus (HIV) infections. Raltegravir (RAL) and Elvitegravir (EVG), the first generation of INSTIs used successfully in clinical treatment, are susceptible to the emergence of viral resistance and have a high rate of cross-resistance. To counteract these resistant mutants, second-generation INSTI drugs have been developed: Dolutegravir (DTG), Cabotegravir (CAB), and Bictegravir (BIC). However, HIV is also able to develop resistance mechanisms against the second-generation of INSTIs. This review describes the mode of action of INSTIs and then summarizes and evaluates some typical resistance mutations, such as substitution and insertion mutations. The role of unintegrated viral DNA is also discussed as a new pathway involved in conferring resistance to INSTIs. This allows us to have a more detailed understanding of HIV resistance to these inhibitors, which may contribute to the development of new INSTIs in the future.
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Project description:Integrase (IN) strand transfer inhibitors (INSTIs) are recent compounds in the antiretroviral arsenal used against HIV. INSTIs work by blocking retroviral integration; an essential step in the viral lifecycle that is catalyzed by the virally encoded IN protein within a nucleoprotein assembly called an intasome. Recent structures of lentiviral intasomes from simian immunodeficiency virus (SIV) and HIV have clarified the INSTI binding modes within the intasome active sites and helped elucidate an important mechanism of viral resistance. The structures provide an accurate depiction of interactions of intasomes and INSTIs to be leveraged for structure-based drug design. Here, we review these recent structural findings and contrast with earlier studies on prototype foamy virus intasomes. We also present and discuss examples of the latest chemical compounds that show promising inhibitory potential as INSTI candidates.
| S-EPMC7429322 | biostudies-literature
Project description:IntroductionSub-Saharan African countries are introducing integrase strand transfer inhibitors (INSTIs) in their ART programmes as the preferred first-line regimen, and dolutegravir is the INSTI of choice due to its potency, tolerability and high genetic barrier to resistance. Dolutegravir was introduced into the first-line ART regimen in Tanzania in 2019. However, there is a paucity of data on the occurrence of mutations in HIV lineages circulating in Tanzania. This study aimed to determine the prevalence of INSTI primary resistance mutations in Tanzanian patients exposed to ART but not INSTIs.MethodsPlasma samples from 50 INSTI-naive patients failing first- or second-line ART [median (IQR) age: 40 (21.93-46.41) years; 68% women] were subjected to Sanger sequencing of the HIV integrase gene. Participants had been on ART for a median (IQR) duration of 7.32 (4.73-9.29) years, with 80% and 20% failing first- and second-line ART, respectively.ResultsNo major INSTI mutations were found, but 2 (4%) participants had the accessory mutation T97A. Using the REGA HIV-1 subtyping tool, HIV subtype A1 (53.1%) was found to be dominant, followed by subtypes C (30.6%) and D (16.3%).ConclusionsThis study found no current evidence for transmitted resistance against INSTIs among unexposed patients failing ART and supports the scale-up of INSTI-based regimens. However, the presence of accessory mutations calls for the surveillance of INSTI resistance mutations to ensure that the anticipated long-term desired outcomes are achieved.
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