Assessment of Transmitted HIV-1 Drug Resistance Mutations Using Ultra- Deep Pyrosequencing in a Turkish Cohort

Sili, Uluhan; Aksu, Burak; Tekin, Aysun; Hasdemir, Ufuk; Sõyletır, Gũner; Korten, Volkan

doi:10.2174/1570162x16666180910130112

Cited by 6 publications

(5 citation statements)

References 28 publications

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“…Additional articles were identified by experts in the field. We screened out 1330 studies after removing duplicates, and 140 articles were downloaded for full-length screening, of which 39 articles were kept [ 6 , 17 , 24 , 34 , 35 , 36 , 37 , 38 , 39 , 40 , 41 , 42 , 43 , 44 , 45 , 46 , 47 , 48 , 49 , 50 , 51 , 52 , 53 , 54 , 55 , 56 , 57 , 58 , 59 , 60 , 61 , 62 , 63 , 64 , 65 , 66 , 67 , 68 , 69 ].…”

Section: Resultsmentioning

confidence: 99%

HIV-1 Drug Resistance Detected by Next-Generation Sequencing among ART-Naïve Individuals: A Systematic Review and Meta-Analysis

Ouyang,

Yuan,

Zhai

et al. 2024

Viruses

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Background: There are an increasing number of articles focused on the prevalence and clinical impact of pretreatment HIV drug resistance (PDR) detected by Sanger sequencing (SGS). PDR may contribute to the increased likelihood of virologic failure and the emergence of new resistance mutations. As SGS is gradually replaced by next-generation sequencing (NGS), it is necessary to assess the levels of PDR using NGS in ART-naïve patients systematically. NGS can detect the viral variants (low-abundance drug-resistant HIV-1 variants (LA-DRVs)) of virus quasi-species at levels below 20% that SGS may fail to detect. NGS has the potential to optimize current HIV drug resistance surveillance methods and inform future research directions. As the NGS technique has high sensitivity, it is highly likely that the level of pretreatment resistance would be underestimated using conventional techniques. Methods: For the systematic review and meta-analysis, we searched for original studies published in PubMed, Web of Science, Scopus, and Embase before 30 March 2023 that focused exclusively on the application of NGS in the detection of HIV drug resistance. Pooled prevalence estimates were calculated using a random effects model using the ‘meta’ package in R (version 4.2.3). We described drug resistance detected at five thresholds (>1%, 2%, 5%, 10%, and 20% of virus quasi-species). Chi-squared tests were used to analyze differences between the overall prevalence of PDR reported by SGS and NGS. Results: A total of 39 eligible studies were selected. The studies included a total of 15,242 ART-naïve individuals living with HIV. The prevalence of PDR was inversely correlated with the mutation detection threshold. The overall prevalence of PDR was 29.74% at the 1% threshold, 22.43% at the 2% threshold, 15.47% at the 5% threshold, 12.95% at the 10% threshold, and 11.08% at the 20% threshold. The prevalence of PDR to INSTIs was 1.22% (95%CI: 0.58–2.57), which is the lowest among the values for all antiretroviral drugs. The prevalence of LA-DRVs was 9.45%. At the 2% and 20% detection threshold, the prevalence of PDR was 22.43% and 11.08%, respectively. Resistance to PIs and INSTIs increased 5.52-fold and 7.08-fold, respectively, in those with a PDR threshold of 2% compared with those with PDR at 20%. However, resistance to NRTIs and NNRTIs increased 2.50-fold and 2.37-fold, respectively. There was a significant difference between the 2% and 5% threshold for detecting HIV drug resistance. There was no statistically significant difference between the results reported by SGS and NGS when using the 20% threshold for reporting resistance mutations. Conclusion: In this study, we found that next-generation sequencing facilitates a more sensitive detection of HIV-1 drug resistance than SGS. The high prevalence of PDR emphasizes the importance of baseline resistance and assessing the threshold for optimal clinical detection using NGS.

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Section: Resultsmentioning

confidence: 99%

HIV-1 Drug Resistance Detected by Next-Generation Sequencing among ART-Naïve Individuals: A Systematic Review and Meta-Analysis

Ouyang,

Yuan,

Zhai

et al. 2024

Viruses

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“…NGS technologies to test for HIV drug resistance in Turkey is a newly developing area with a very limited amount of data. Sili et al 34 used NGS to study the PR and RT gene regions in 36 HIV‐1‐positive plasma samples, and identified 8.3% ( n = 3) mutations at a frequency of above 20% and 30.6% ( n = 11) mutations at a frequency above 2%. Good technical experience and strong bioinformatics knowledge are critical if NGS technologies are to be used to test ARV drug resistance in Turkey.…”

Section: Discussionmentioning

confidence: 99%

Investigation of drug resistance against protease, reverse transcriptase, and integrase inhibitors by next‐generation sequencing in HIV‐positive patients

Tekin¹,

Gökengin

Onay

et al. 2020

Journal of Medical Virology

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Our aim was to investigate the mutations in protease (PR), reverse transcriptase (RT), and integrase (IN) gene regions in human immunodeficiency virus (HIV) using a single amplicon via next‐generation sequencing (NGS). The study included plasma samples from 49 HIV‐1‐positive patients, which were referred for HIV‐1 drug resistance testing during 2017. A nested polymerase chain reaction (PCR) was performed after the RNA extraction and one‐step reverse transcription stages. The sequencing of the HIV genome in the PR, RT, and IN gene regions was carried out using MiSeq NGS technology. Sanger sequencing (SS) was used to analyze resistance mutations in the PR and RT gene regions using a ViroSeq HIV‐1 Genotyping System. PCR products were analyzed with an ABI3500 GeneticAnalyzer (Applied Biosystems). Resistance mutations detected with NGS at frequencies above 20% were identical to the SS results. Resistance to at least one antiretroviral (ARV) drug was 22.4% (11 of 49) with NGS and 10.2% (5 of 49) with SS. At least one low‐frequency resistance mutation was detected in 18.3% (9 of 49) of the samples. Low‐frequency resistance mutations resulted in virological failure in only one patient. The cost of the analyses was reduced by sample pooling and multiplex analysis using the MiSeq system. This is the first study in Turkey to use NGS technologies for the detection of resistance mutations in all three gene (PR, RT, IN) regions using a single amplicon. Our findings suggest that NGS is more sensitive and cost‐effective than the SS method.

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“…Mutations that result in resistance to ETR and RPV have been observed in HIV isolates from both adults [40,74,117,120,124,125] as well as children and adolescents [64,126], where higher non-adherence may lead to a higher frequency of virologic failure. Drug-resistant strains that have been seen in children have often shown partial susceptibility to ETR and RPV [126].…”

Section: Resistance To Dapysmentioning

confidence: 99%

“…Combinations of NNRTI-resistance mutations have been common among RPV patients in virologic failure[117,126]. HIV-1 RT mutations in the NNRTI-binding site that result in resistance against ETR and/or RPV in certain combinations have included V90I, A98G, L100I/V, K101E/P/Q/R/T, K103N/S, V106A/I, V108I, E138A/G/K/Q/R/S, V179F/I/L/D, Y181C/I/V, Y188H/L, G190A/C/E/Q/S/T/V, H221Y, P225H, F227C/L, and M230I/L (Figure 2)[40,59,61,64,74,117,118,120,121,[124][125][126][127][129][130][131][132][133]. V179F + Y181C + F227C is an example of a combination of mutations that confers high resistance to both ETR and RPV(Table 2)[59].…”

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confidence: 99%

Non-Nucleoside Reverse Transcriptase Inhibitors Join Forces with Integrase Inhibitors to Combat HIV

Himmel¹,

Arnold

2020

Pharmaceuticals

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In the treatment of acquired immune deficiency syndrome (AIDS), the diarylpyrimidine (DAPY) analogs etravirine (ETR) and rilpivirine (RPV) have been widely effective against human immunodeficiency virus (HIV) variants that are resistant to other non-nucleoside reverse transcriptase inhibitors (NNRTIs). With non-inferior or improved efficacy, better safety profiles, and lower doses or pill burdens than other NNRTIs in the clinic, combination therapies including either of these two drugs have led to higher adherence than other NNRTI-containing treatments. In a separate development, HIV integrase strand transfer inhibitors (INSTIs) have shown efficacy in treating AIDS, including raltegravir (RAL), elvitegravir (EVG), cabotegravir (CAB), bictegravir (BIC), and dolutegravir (DTG). Of these, DTG and BIC perform better against a wide range of resistance mutations than other INSTIs. Nevertheless, drug-resistant combinations of mutations have begun to emerge against all DAPYs and INSTIs, attributable in part to non-adherence. New dual therapies that may promote better adherence combine ETR or RPV with an INSTI and have been safer and non-inferior to more traditional triple-drug treatments. Long-acting dual- and triple-therapies combining ETR or RPV with INSTIs are under study and may further improve adherence. Here, highly resistant emergent mutations and efficacy data on these novel treatments are reviewed. Overall, ETR or RPV, in combination with INSTIs, may be treatments of choice as long-term maintenance therapies that optimize efficacy, adherence, and safety.

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Assessment of Transmitted HIV-1 Drug Resistance Mutations Using Ultra- Deep Pyrosequencing in a Turkish Cohort

Abstract: UDPS was used for the first time to assess TDRM in a Turkish HIV cohort and uncovered several mutations hidden within minority variants. UDPS may be preferred to detect PDRMs for avoiding virologic failure with rilpivirine-based ART regimens.

Cited by 6 publications

References 28 publications

HIV-1 Drug Resistance Detected by Next-Generation Sequencing among ART-Naïve Individuals: A Systematic Review and Meta-Analysis

HIV-1 Drug Resistance Detected by Next-Generation Sequencing among ART-Naïve Individuals: A Systematic Review and Meta-Analysis

Investigation of drug resistance against protease, reverse transcriptase, and integrase inhibitors by next‐generation sequencing in HIV‐positive patients

Non-Nucleoside Reverse Transcriptase Inhibitors Join Forces with Integrase Inhibitors to Combat HIV

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