Commonly Transmitted HIV-1 Drug Resistance Mutations in Reverse-Transcriptase and Protease in Antiretroviral Treatment–Naive Patients and Response to Regimens Containing Tenofovir Disoproxil Fumarate or Tenofovir Alafenamide

Background: The World Health Organization (WHO) recommends the surveillance of transmitted drug resistance mutations (TDRMs) to ensure the effectiveness and sustainability of HIV treatment programs. Objective: Our aim was to determine the TDRMs and evaluate the distribution of HIV-1 subtypes using and compared next-generation sequencing (NGS) and Sanger-based sequencing (SBS) in a cohort of 44 antiretroviral treatment-naïve patients. Methods: All samples that were referred to the microbiology laboratory for HIV drug resistance analysis between December 2016 and February 2018 were included in the study. After exclusions, 44 treatment-naive adult patients with a viral load of >1000 copies/mL were analyzed. DNA sequencing for reverse transcriptase and protease regions was performed using both DeepChek ABL single round kit and Sanger-based ViroSeq HIV-1 Genotyping System. The mutations and HIV-1 subtypes were analyzed using the Stanford HIVdb version 8.6.1 Genotypic Resistance software, and TDRMs were assessed using the WHO surveillance drug-resistance mutation database. HIV-1 subtypes were confirmed by constructing a maximum-likelihood phylogenetic tree using Los Alamos IQ-Tree software. Results: NGS identified nucleos(t)ide reverse transcriptase inhibitor (NRTI)-TDRMs in 9.1% of the patients, non-nucleos(t)ide reverse transcriptase inhibitor (NNRTI)-TDRMs in 6.8% of the patients, and protease inhibitor (PI)-TDRMs in 18.2% of the patients at a detection threshold of ≥1%. Using SBS, 2.3% and 6.8% of the patients were found to have NRTI- and NNRTI-TDRMs, respectively, but no major PI mutations were detected. M41L, L74I, K65R, M184V, and M184I related to NRTI, K103N to NNRTI, and N83D, M46I, I84V, V82A, L24I, L90M, I54V to the PI sites were identified using NGS. Most mutations were found in low-abundance (frequency range: 1.0% - 4.7%) HIV-1 variants, except M41L and K103N. The subtypes of the isolates were found as follows; 61.4% subtype B, 18.2% subtype B/CRF02_AG recombinant, 13.6% subtype A, 4.5% CRF43_02G, and 2.3% CRF02_AG. All TDRMs, except K65R, were detected in HIV-1 subtype B isolates.. Conclusion: The high diversity of protease site TDRMs in the minority HIV-1 variants and prevalence of CRFs were remarkable in this study. All minority HIV-1 variants were missed by conventional sequencing. TDRM prevalence among minority variants appears to be decreasing over time at our center.

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PREVALENCE AND STRUCTURE OF HIV-1 DRUG RESISTANCE AMONG TREATMENT NAÏVE PATIENTS SINCE THE INTRODUCTION OF ANTIRETROVIRAL THERAPY IN THE RUSSIAN FEDERATION

HIV Infection and Immunosuppressive Disorders ◽

10.22328/2077-9828-2019-11-2-75-83 ◽

2019 ◽

Vol 11 (2) ◽

pp. 75-83 ◽

Cited By ~ 2

Author(s):

A. A. Kirichenko ◽

D. E. Kireev ◽

A. E. Lopatukhin ◽

A. V. Murzakova ◽

I. A. Lapovok ◽

...

Keyword(s):

Drug Resistance ◽

Reverse Transcriptase ◽

Russian Federation ◽

Antiretroviral Drugs ◽

Transmitted Drug Resistance ◽

Resistance Mutations ◽

Drug Resistance Mutations ◽

Treatment Naïve ◽

The Russian Federation ◽

Hiv 1

Aim: to analyze the prevalence, structure of drug resistance and drug resistance mutations in the protease and reverse transcriptase genes of HIV-1 among treatment naïve patients.Materials and methods. We analyzed protease and reverse transcriptase sequences from 1560 treatment naïve HIV-infected patients from all Federal Districts of the Russian Federation with the first positive immune blot during 1998–2017. Sequences were analyzed for the presence of drug resistance mutations and predicted drug resistance to antiretroviral drugs using two algorithms — Stanford HIVDR Database (HIVdb) and the 2009 SDRM list (CPR).Results. The prevalence of drug resistance mutations was 11,1%. More often the prevalence of drug resistance was found for non-nucleoside reverse transcriptase inhibitor drugs (rilpivirine, nevirapine, efavirenz). The prevalence of transmitted drug resistance associated with mutations from the SDRM list was 5,3%, which is classified by the WHO as a moderate level. However, it should be noted that since the large-scale use of antiretroviral drugs in the Russian Federation, there has been a trend towards a gradual increase in the level of the transmitted drug resistance, and in 2016 it has already reached 6,1%.Conclusion. The results demonstrate the need for regular surveillance of the prevalence of HIV drug resistance to antiretroviral drugs among treatment naïve patients in the Russian Federation.

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Identifications of drug resistance mutations among antiretroviral treatment naive HIV-1 patients in Peninsular Malaysia

Asian Pacific Journal of Tropical Medicine ◽

10.1016/j.apjtm.2016.12.005 ◽

2017 ◽

Vol 10 (1) ◽

pp. 75-78

Author(s):

Rozainanee Mohd Zain ◽

Nabila Ibrahim ◽

Suriani Ismail ◽

Jeyanthi Suppiah ◽

Nor Aziyah Mat Rahim ◽

...

Keyword(s):

Drug Resistance ◽

Antiretroviral Treatment ◽

Peninsular Malaysia ◽

Resistance Mutations ◽

Drug Resistance Mutations ◽

Treatment Naïve ◽

Hiv 1

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Minority HIV-1 Drug Resistance Mutations Are Present in Antiretroviral Treatment–Naïve Populations and Associate with Reduced Treatment Efficacy

PLoS Medicine ◽

10.1371/journal.pmed.0050158 ◽

2008 ◽

Vol 5 (7) ◽

pp. e158 ◽

Cited By ~ 266

Author(s):

Jeffrey A Johnson ◽

Jin-Fen Li ◽

Xierong Wei ◽

Jonathan Lipscomb ◽

David Irlbeck ◽

...

Keyword(s):

Drug Resistance ◽

Treatment Efficacy ◽

Antiretroviral Treatment ◽

Resistance Mutations ◽

Drug Resistance Mutations ◽

Treatment Naïve ◽

Hiv 1

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Drug Resistance Mutations to Protease and Reverse Transcriptase Inhibitors in Treatment Naive HIV-1 Clade C Infected Individuals from Mumbai, India

International Journal of Virology ◽

10.3923/ijv.2011.13.23 ◽

2010 ◽

Vol 7 (1) ◽

pp. 13-23 ◽

Cited By ~ 2

Author(s):

P.D. Potdar ◽

B.S. Daswani ◽

N.J. Rane

Keyword(s):

Drug Resistance ◽

Reverse Transcriptase ◽

Resistance Mutations ◽

Reverse Transcriptase Inhibitors ◽

Drug Resistance Mutations ◽

Clade C ◽

Treatment Naïve ◽

Hiv 1

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Silent mutations at codons 65 and 66 in reverse transcriptase alleviate indel formation and restore fitness in subtype B HIV-1 containing D67N and K70R drug resistance mutations

Nucleic Acids Research ◽

10.1093/nar/gkv128 ◽

2015 ◽

Vol 43 (6) ◽

pp. 3256-3271 ◽

Cited By ~ 6

Author(s):

Sushama Telwatte ◽

Anna C. Hearps ◽

Adam Johnson ◽

Catherine F. Latham ◽

Katie Moore ◽

...

Keyword(s):

Drug Resistance ◽

Reverse Transcriptase ◽

Resistance Mutations ◽

Drug Resistance Mutations ◽

Subtype B ◽

Hiv 1

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Low-Frequency Drug Resistance in HIV-Infected Ugandans on Antiretroviral Treatment Is Associated with Regimen Failure

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.00038-16 ◽

2016 ◽

Vol 60 (6) ◽

pp. 3380-3397 ◽

Cited By ~ 26

Author(s):

Fred Kyeyune ◽

Richard M. Gibson ◽

Immaculate Nankya ◽

Colin Venner ◽

Samar Metha ◽

...

Keyword(s):

Drug Resistance ◽

Treatment Failure ◽

Sanger Sequencing ◽

Antiretroviral Treatment ◽

Low Frequency ◽

Drug Resistant ◽

Viral Quasispecies ◽

Resistance Mutations ◽

Drug Resistance Mutations ◽

Hiv 1

Most patients failing antiretroviral treatment in Uganda continue to fail their treatment regimen even if a dominant drug-resistant HIV-1 genotype is not detected. In a recent retrospective study, we observed that approximately 30% of HIV-infected individuals in the Joint Clinical Research Centre (Kampala, Uganda) experienced virologic failure with a susceptible HIV-1 genotype based on standard Sanger sequencing. Selection of minority drug-resistant HIV-1 variants (not detectable by Sanger sequencing) under antiretroviral therapy pressure can lead to a shift in the viral quasispecies distribution, becoming dominant members of the virus population and eventually causing treatment failure. Here, we used a novel HIV-1 genotyping assay based on deep sequencing (DeepGen) to quantify low-level drug-resistant HIV-1 variants in 33 patients failing a first-line antiretroviral treatment regimen in the absence of drug-resistant mutations, as screened by standard population-based Sanger sequencing. Using this sensitive assay, we observed that 64% (21/33) of these individuals had low-frequency (or minority) drug-resistant variants in the intrapatient HIV-1 population, which correlated with treatment failure. Moreover, the presence of these minority HIV-1 variants was associated with higher intrapatient HIV-1 diversity, suggesting a dynamic selection or fading of drug-resistant HIV-1 variants from the viral quasispecies in the presence or absence of drug pressure, respectively. This study identified low-frequency HIV drug resistance mutations by deep sequencing in Ugandan patients failing antiretroviral treatment but lacking dominant drug resistance mutations as determined by Sanger sequencing methods. We showed that these low-abundance drug-resistant viruses could have significant consequences for clinical outcomes, especially if treatment is not modified based on a susceptible HIV-1 genotype by Sanger sequencing. Therefore, we propose to make clinical decisions using more sensitive methods to detect minority HIV-1 variants.

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