scholarly journals HIV-1 Subtype C Drug Resistance Mutations in Heavily Treated Patients Failing Integrase Strand Transfer Inhibitor-Based Regimens in Botswana

Viruses ◽  
2021 ◽  
Vol 13 (4) ◽  
pp. 594
Author(s):  
Kaelo K. Seatla ◽  
Dorcas Maruapula ◽  
Wonderful T. Choga ◽  
Tshenolo Ntsipe ◽  
Nametso Mathiba ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Virologic Failure ◽  
Resistance Testing ◽  
Strand Transfer ◽  
Resistance Mutations ◽  
Subtype C ◽  
Genotypic Resistance Testing ◽  
Transfer Inhibitor ◽  
Integrase Strand Transfer Inhibitor ◽  
Hiv 1

There are limited real-world mutational and virological outcomes data of treatment-experienced persons diagnosed with HIV-1 subtype C (HIV-1 C) who are failing Integrase Strand Transfer Inhibitor-based regimens. Requisition forms sent for HIV-1 genotypic resistance testing (GRT) between May 2015 and September 2019 were reviewed and participants experiencing virologic failure while on dolutegravir (DTG) or raltegravir (RAL) cART at sampling recruited. Sanger sequencing of the HIV-1 Pol gene was performed from residual plasma samples and drug resistance mutational (DRM) analysis performed using the Stanford University HIV drug resistance database. 40 HIV-1C integrase sequences were generated from 34 individuals, 24 of whom were on DTG cART, three on RAL cART and seven on an unknown (DTG or RAL)-anchored cART at time of GRT. 11/34 (32%) individuals had DRMs to DTG and other integrase inhibitors. 7/11 (64%) patients had exposure to a RAL-based cART at the time of sampling. Out of the 11 individuals with DRMs, one (9%) had 2-class, 6 (55%) had 3-class, and 4 (36%) had 4-class multidrug-resistant HIV-1C. 7/11 individuals (64%) are currently virologically suppressed. Of the four individuals not virologically suppressed, three had extensive DRMs involving 4-classes of ARV drugs and one individual has demised. Resistance to DTG occurs more often in patients exposed to RAL cART. Individuals with 4-class DRMs plus integrase T97 and E157Q mutations appear to have worse outcomes. There is a need for frequent VL monitoring and GRT amongst treatment-experienced HIV-1C diagnosed individuals.

Prevalence of integrase strand transfer inhibitor resistance mutations in antiretroviral-naive HIV-1-infected individuals in Cameroon

2020 ◽  
Vol 76 (1) ◽  
pp. 124-129
Author(s):  
Benjamin M Wenk ◽  
Herbert A Mbunkah ◽  
Ndi N Nsanwe ◽  
Eyongetah T Mbu ◽  
Lydia M Besong ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Universal Primers ◽  
Polymorphism Analysis ◽  
Strand Transfer ◽  
Resistance Mutations ◽  
Transfer Inhibitor ◽  
Study Sites ◽  
Inhibitor Resistance ◽  
The Impact ◽  
Hiv 1

Abstract Objectives In Cameroon, the integrase (IN) strand transfer inhibitor (INSTI) dolutegravir was recently introduced for the treatment of HIV-1 infection. Since pretreatment HIV-1 drug resistance can jeopardize the success of ART, and considering the high heterogeneity of circulating HIV-1 subtypes in Cameroon, we investigated the prevalence of pretreatment HIV-1 resistance to INSTIs. Methods Fingerprick dried blood spot samples were collected from 339 newly diagnosed HIV-1-infected individuals between 2015 and 2016 in four hospitals in Cameroon. Universal primers were designed to amplify the HIV-1 IN region from amino acid 1 to 276. Amplicons were sequenced with Illumina next-generation sequencing and analysed with the Polymorphism Analysis Sequencing (PASeq) platform, using the Stanford HIV Drug Resistance Database to interpret HIV-1 drug resistance mutations (DRMs). Results The amplification/sequencing success rate was 75.2% with 255/339 sequences obtained. Applying a cut-off of 1%, major DRMs to INSTIs were detected in 13 (5.1%) individuals, but only 1 individual harboured an INSTI DRM (E92G) at a nucleotide frequency ≥15%. However, 140/255 (54.9%) individuals harboured polymorphic accessory INSTI DRMs, mainly at high frequencies. In line with that observation, HIV-1 subtype diversity among individuals was high. Conclusions Pretreatment HIV-1 resistance to INSTIs was low in the study sites, which supports the use of INSTIs in Cameroon. Nevertheless, further studies are necessary to assess the impact of polymorphic accessory INSTI DRMs on INSTI-based ART regimens.

scholarly journals Detectable viral load among HIV -1 positive pregnant women on ART (Option B +) in northern Tanzania: Baseline results from the HIVDR study

2021 ◽  
Vol 3 (1) ◽  
pp. 44-50
Author(s):  
Nicholaus Steven Mazuguni ◽  
Festo Mazuguni ◽  
Eva Prosper Muro
Keyword(s):  
Drug Resistance ◽  
Viral Load ◽  
Virological Failure ◽  
Virologic Failure ◽  
Resistance Mutation ◽  
Resistance Testing ◽  
Resistance Mutations ◽  
Drug Resistance Mutations ◽  
Hiv 1 ◽  
Level Resistance

Introduction: In Tanzania, the Ministry of Health, Community Development, Gender, Elderly and Children (MoHCDEC) has implemented the Option B+ as one of the strategies to facilitate achievement of elimination of mother to child transmission of HIV. To prevent emergence of drug resistance mutations early identification of option B+ failure is critical. The emergence of drug resistance mutation and subsequent treatment failure poses a major concern for HIV program in low- and middle-income resource settings where treatment options are limited. Methodology: We recruited treatment naïve, treatment experienced HIV-1 positive pregnant women and those who had prophylaxis in their previous pregnancy in Kilimanjaro, northern Tanzania August 2016 to February 2017. Whole blood (2ml) for biochemistry, viral load and drug resistance testing were taken at baseline. ARV drug resistance testing was done on women with VL ≥ 1000 copies/ml. We used descriptive statistic and logistic regression to determine the strength of association between virologic outcome (virologic failure) and independent predictors. Results: One hundred and forty eight (148) pregnant HIV-positive women were enrolled in the study with mean age of 29.82 years (SD=6.17) from August, 2016 to February, 2017. Virologic failure was demonstrated in 34 (23%) with viral load   ≥ 1,000 copies/ml. Genotyping results were available from 26 women, mutations associated with ARV resistance were detected in 23.1% (n = 6/26). Among the six women with ARV resistance mutation 4(66.7%) had high level resistance and 2(33.3%) had low level resistance. Among the 26 samples genotyped 15(58%) viruses were subtype A, while eight were subtype C (31%) and three subtypes D (11%). The most dominant drug resistance mutations against the reverse transcriptase inhibitors for the women with high level resistance were K103N, Y188L, D67N, K70R, M184V, T215F, K219EQ, and the low-level resistance was E138A. The older age was associated with virological failure compared to those who were < 20 year of age. Conclusion: Viral load testing should be done on women who were already on antiretroviral treatment on their first antenatal visit to ensure early detection of virological failure and enable clinicians to take an appropriate course of action on their management. Educational intervention on adherence should be targeted at an early stage to women with virological failure during pregnancy to reduce the emergence of HIV-1 drug resistance mutations.

scholarly journals Zero prevalence of primary drug resistance-associated mutations to protease inhibitors in HIV-1 drug-naive patients in and around Aligarh, India

2014 ◽  
Vol 8 (01) ◽  
pp. 079-085 ◽  
Author(s):  
Mohd Azam ◽  
Abida Malik ◽  
Meher Rizvi ◽  
Arvind Rai
Keyword(s):  
Drug Resistance ◽  
Protease Inhibitors ◽  
Resistance Testing ◽  
Protease Gene ◽  
Resistance Mutations ◽  
Subtype C ◽  
Primary Resistance ◽  
Primary Drug Resistance ◽  
Treatment Naïve ◽  
Hiv 1

Introduction: This study aimed to evaluate the prevalence of resistance mutations in the protease gene of HIV-1 strains isolated from north Indian antiretroviral (ARV) treatment-naive patients and to assess the phylogenetic relatedness of these strains with known HIV-1 strains. Methodology: Fifty-four HIV-1 strains isolated from treatment-naive patients (n = 54) were included in this study. Resistance genotyping for the protease gene was performed using semi-nested PCR and DNA sequencing. The sequences were aligned (ClustalW) and a phylogenetic tree was built (MEGA 4 software). Drug resistance (DR) pattern was analyzed using the Stanford HIV-DR database and the IAS-USA mutation list. For subtyping purposes, all the nucleotide sequences were submitted to the REGA HIV-1 subtyping tool version 2.0l. Results: All the strains (100%) were found to belong to the C subtype and to harbor at least two secondary mutations in the protease gene. The most frequent mutations were H69K and I93L (52 of 52 strains), followed by I15V (80.7%), L19I (69.2%), M36I (67.3%), R41K (94.2%), L63P (61.5%), and L89M (82.7%). Conclusion: This study confirms that HIV-1 subtype C predominates in northern India. Protease secondary mutations associated with drug resistance to protease inhibitors (PIs) were present with high frequency in the HIV-1 C subtype strains isolated from north Indian ARV treatment-naive patients, but no primary resistance mutations were found in this region. We suggest that resistance testing in HIV-1 infected patients should ideally be performed before the initiation of therapy to tailor the treatment for the individual to achieve the optimal therapeutic outcome

scholarly journals Protease Inhibitor Resistance Is Uncommon in HIV-1 Subtype C Infected Patients on Failing Second-Line Lopinavir/r-Containing Antiretroviral Therapy in South Africa

2011 ◽  
Vol 2011 ◽  
pp. 1-5 ◽  
Author(s):  
Carole L. Wallis ◽  
John W. Mellors ◽  
Willem D. F. Venter ◽  
Ian Sanne ◽  
Wendy Stevens
Keyword(s):  
South Africa ◽  
Drug Resistance ◽  
Protease Inhibitor ◽  
Virologic Failure ◽  
Second Line ◽  
Resistance Mutations ◽  
Subtype C ◽  
Resistance Patterns ◽  
Main Barrier ◽  
Hiv 1

Limited data exist on HIV-1 drug resistance patterns in South Africa following second-line protease-inhibitor containing regimen failure. This study examined drug resistance patterns emerging in 75 HIV-1 infected adults experiencing virologic failure on a second-line regimen containing 2 NRTI and lopinavir/ritonavir. Ninety six percent of patients (n=72) were infected with HIV-1 subtype C, two patients were infected with HIV-1 subtype D and one with HIV-1 subtype A1. Thirty nine percent (n=29) of patients had no resistance mutations in protease or reverse transcriptase suggesting that medication non-adherence was a major factor contributing to failure. Major lopinavir resistance mutations were infrequent (5 of 75; 7%), indicating that drug resistance is not the main barrier to future viral suppression.

scholarly journals Prevalence of Human Immunodeficiency Virus-1 Integrase Strand Transfer Inhibitor Resistance in British Columbia, Canada Between 2009 and 2016: A Longitudinal Analysis

2019 ◽  
Vol 6 (3) ◽  
Author(s):  
Kimia Kamelian ◽  
Katherine J Lepik ◽  
William Chau ◽  
Benita Yip ◽  
Wendy W Zhang ◽  
...  
Keyword(s):  
British Columbia ◽  
Human Immunodeficiency Virus ◽  
Drug Resistance ◽  
Strand Transfer ◽  
Resistance Mutations ◽  
Immunodeficiency Virus ◽  
Transfer Inhibitor ◽  
Inhibitor Resistance ◽  
Integrase Strand Transfer Inhibitor ◽  
Human Immunodeficiency Virus 1

AbstractBackgroundIntegrase strand transfer inhibitors (INSTIs) are highly efficacious and well tolerated antiretrovirals with fewer adverse side-effects relative to other classes of antiretrovirals. The use of INSTIs raltegravir, elvitegravir, and dolutegravir has increased dramatically over recent years. However, there is limited information about the evolution and prevalence of INSTI resistance mutations in clinical human immunodeficiency virus populations.MethodsHuman immunodeficiency virus-1-positive individuals ≥19 years were included if they received ≥1 dispensed prescription of antiretroviral therapy (ART) in British Columbia between 2009 and 2016 (N = 9358). Physician-ordered drug resistance tests were analyzed and protease inhibitor (PI), reverse-transcriptase inhibitor (RT), and INSTI resistance were defined as having ≥1 sample with a combined, cumulative score ≥30 by Stanford HIV Drug Resistance Algorithm version 7.0.1.ResultsAlthough most ART-treated individuals were tested for PI and RT resistance, INSTI resistance testing lagged behind the uptake of INSTIs among INSTI-treated individuals (11% in 2009; 34% in 2016). The prevalence of INSTI resistance was relatively low, but it increased from 1 to 7 per 1000 ART-treated individuals between 2009 and 2016 (P &lt; .0001, R2 = 0.98). Integrase strand transfer inhibitor resistance mutations increased at integrase codons 66, 97, 140, 148, 155, and 263.ConclusionsThe prevalence of INSTI resistance remains low compared with PI and RT resistance in ART-treated populations but is expanding with increased INSTI use.

scholarly journals Virologic failure after 48 weeks of raltegravir-based regimen in low HIV-1 incidence setting

2020 ◽  
Vol 28 ◽  
pp. 204020662092790
Author(s):  
Wassim Chehadeh ◽  
Osama Albaksami ◽  
Shaikhah Al-Shammari
Keyword(s):  
Salvage Therapy ◽  
Virologic Failure ◽  
Strand Transfer ◽  
Adherence To Treatment ◽  
First Line ◽  
Transfer Inhibitor ◽  
High Level ◽  
Integrase Strand Transfer Inhibitor ◽  
Hiv 1 ◽  
Level Resistance

Background With the advent of next generation integrase strand transfer inhibitors, the rates of virologic failure in treated subjects are expected to decrease. In this study, we analyzed the mutation patterns leading to virologic failure before and after starting integrase strand transfer inhibitor-based regimen as first-line or salvage therapy. Methods Between 2016 and 2019, blood samples were received from 258 patients with HIV-1 infection. Plasma HIV-1 RNA concentrations, and pol gene sequences were determined at baseline, and 16–48 weeks of treatment with integrase strand transfer inhibitor-based regimen. Only patients who did not achieve viral suppression at 48 weeks of integrase strand transfer inhibitor-based treatment were eligible for the current study. Results Virologic failure was observed in seven patients on raltegravir-based regimen. All patients with virologic failure but one were infected with CRF01_AE virus subtype. Raltegravir based-regimen was offered as first-line therapy for four patients, and as salvage therapy for three patients. M184V mutation associated with high level resistance to lamivudine and emtricitabine was detected in six out of seven patients. Primary mutations (Y143C, N155H, T66I, G118R, E138K) conferring high level resistance to raltegravir were detected in only three patients. Pre-existing polymorphic integrase mutation (T97A) was detected in two patients. Furthermore, two patients reported low adherence to treatment. Conclusions Emergence of primary mutations in the integrase gene can account for virologic failure in less than half of patients on raltegravir-based regimen. Low adherence to treatment, pre-existing accessory mutations, and resistance to reverse transcriptase inhibitors may have some role in virologic outcome.

scholarly journals HIV-1 Drug Resistance Mutations: Potential Applications for Point-of-Care Genotypic Resistance Testing

PLoS ONE ◽  
2015 ◽  
Vol 10 (12) ◽  
pp. e0145772 ◽  
Author(s):  
Soo-Yon Rhee ◽  
Michael R. Jordan ◽  
Elliot Raizes ◽  
Arlene Chua ◽  
Neil Parkin ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Point Of Care ◽  
Resistance Testing ◽  
Resistance Mutations ◽  
Genotypic Resistance ◽  
Drug Resistance Mutations ◽  
Genotypic Resistance Testing ◽  
Potential Applications ◽  
Hiv 1

scholarly journals A2 Phylogenetic investigation of transmitted HIV-1 drug resistance mutations in Denmark, 2009–17

2019 ◽  
Vol 5 (Supplement_1) ◽  
Author(s):  
J Fonager ◽  
T K Fischer
Keyword(s):  
Drug Resistance ◽  
Resistance Testing ◽  
Transmitted Drug Resistance ◽  
Newly Diagnosed ◽  
Resistance Mutations ◽  
Sequence Alignments ◽  
Drug Resistance Mutations ◽  
Subtype B ◽  
Genotypic Resistance Testing ◽  
Hiv 1

Abstract Transmission of HIV-1 resistance mutations among therapy-naïve patients impairs the efficiency of antiretroviral therapy (ART). Therefore, genotypic resistance testing of patients is recommended at baseline, as this both allows for the selection of the correct ART regimen and for surveillance of transmitted drug resistance mutations (TDRM) among therapy naive HIV-1 patients. In Denmark, the occurrence of TDRM in newly diagnosed and therapy naïve HIV-1 patients is monitored through the SERO project. Here, we investigated if the prevalence of TDRM differed between patients within and outside of phylogenetically identified transmission clusters. Samples from 1,227 newly diagnosed HIV-1 patients were sent along with epidemiological information to the Virological Surveillance and Research group at Statens Serum Institut. HIV-1 RNA extraction, RT-PCR and Sanger sequencing of the pol gene was performed using an in-house assay. The sequences were analyzed using BioNumerics v. 6.6 and manually checked for the presence of mixed mutations and analyzed for mutations using the HIVDB 8.4 algorithm implemented at the Stanford database. Sequence alignments were performed in Mafft, and phylogenetic analysis was performed using Mega 6.0 using the Maximum likelihood general time reversible model with 100 bootstrap replicates. Clusters were identified with ClusterPicker at default settings (cluster support = 90%, genetic distance 4.5%). Active clusters contained newly diagnosed patients from the 2015 to 2017 period. HIV-1 sequences from 588 patients belonged to one of 154 clusters, and sequences from 639 patients did not belong to a cluster. Patients in clusters were significantly more likely to be men who have sex with men and subtype B and significantly less likely to be late presenters (Fisher’s test P < 0.05). The TDRM prevalence was significantly higher for patients outside of clusters than within clusters, 16.6 per cent versus 12.1 per cent, respectively (Fisher’s test P < 0.05); however, no significant differences were found in the TDRM prevalence between the 75 active and 79 inactive clusters, nor between small (<3 patients) and large (≥3 patients) clusters. E138A, V179D, and K103N were the three most prevalent TDRMs for both patient groups, whereas M41L differed between them. In Denmark, the TDRM prevalence is lower within clusters than outside, indicating that TDRM cases are either imported and/or belong to yet unidentified clusters.

scholarly journals Integrase strand transfer inhibitor (INSTI)-resistance mutations for the surveillance of transmitted HIV-1 drug resistance

2019 ◽  
Author(s):  
Philip L Tzou ◽  
Soo-Yon Rhee ◽  
Diane Descamps ◽  
Dana S Clutter ◽  
Bradley Hare ◽  
...  
Keyword(s):  
Drug Resistance ◽  
First Generation ◽  
Strand Transfer ◽  
Resistance Mutations ◽  
In Vitro Susceptibility ◽  
Rare Mutations ◽  
Subtype B ◽  
Transfer Inhibitor ◽  
Hiv 1

Abstract Background Integrase strand transfer inhibitors (INSTIs) are expected to be widely adopted globally, requiring surveillance of resistance emergence and transmission. Objectives We therefore sought to develop a standardized list of INSTI-resistance mutations suitable for the surveillance of transmitted INSTI resistance. Methods To characterize the suitability of the INSTI-resistance mutations for transmitted HIV-1 drug resistance (TDR) surveillance, we classified them according to their presence on published expert lists, conservation in INSTI-naive persons, frequency in INSTI-treated persons and contribution to reduced in vitro susceptibility. Mutation prevalences were determined using integrase sequences from 17 302 INSTI-naive and 2450 INSTI-treated persons; 53.3% of the INSTI-naive sequences and 20.0% of INSTI-treated sequences were from non-B subtypes. Approximately 10% of sequences were from persons who received dolutegravir alone or a first-generation INSTI followed by dolutegravir. Results Fifty-nine previously recognized (or established) INSTI-resistance mutations were present on one or more of four published expert lists. They were classified into three main non-overlapping groups: 29 relatively common non-polymorphic mutations, occurring in five or more individuals and significantly selected by INSTI treatment; 8 polymorphic mutations; and 22 rare mutations. Among the 29 relatively common INSTI-selected mutations, 24 emerged as candidates for inclusion on a list of INSTI surveillance drug-resistance mutations: T66A/I/K, E92G/Q, G118R, F121Y, E138A/K/T, G140A/C/S, Y143C/H/R/S, S147G, Q148H/R/K, N155H, S230R and R263K. Conclusions A set of 24 non-polymorphic INSTI-selected mutations is likely to be useful for quantifying INSTI-associated TDR. This list may require updating as more sequences become available from INSTI-experienced persons infected with HIV-1 non-subtype B viruses and/or receiving dolutegravir.

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