Pre-treatment and acquired HIV drug resistance in Dar es Salaam, Tanzania in the era of tenofovir and routine viral load monitoring

2019 ◽  
Vol 74 (10) ◽  
pp. 3016-3020 ◽  
Author(s):  
Godfrey Barabona ◽  
Macdonald Mahiti ◽  
Salim Masoud ◽  
Peter Mbelele ◽  
Amina Shaban Mgunya ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Progressive Increase ◽  
Dar Es Salaam ◽  
Antiretroviral Drugs ◽  
Hiv Treatment ◽  
Resistance Mutations ◽  
Genetic Barrier ◽  
Hiv Drug Resistance ◽  
Pre Treatment ◽  
Treat All

Abstract Objectives We investigated the prevalence and patterns of pre-treatment and acquired HIV drug resistance mutations (DRMs) in Tanzania as a ‘treat all’ strategy, virological monitoring and the progressive increase in usage of tenofovir are being implemented in HIV treatment programmes. Methods Viral RNA was isolated from plasma of 60 ART-naive and 166 treated-but-viraemic (>400 copies/mL) HIV-1-infected adults attending a care and treatment clinic at Muhimbili National Hospital, Dar es Salaam, Tanzania, between June and October 2017. Viral genes encoding protease and reverse transcriptase were amplified by PCR and directly sequenced. Results Viral genotyping of successfully amplified samples revealed pre-treatment DRMs in 14/47 (29.8%) ART-naive subjects. Of these, 7/47 (14.9%) harboured mutations that confer high-level resistance to at least one drug of the default first-line regimen. In treated-but-viraemic subjects, DRMs were found in 100/111 (90%), where DRMs against NNRTI, NRTI and PI were observed in 95/100 (95%), 92/100 (92%) and 13/100 (13%), respectively. Tenofovir-resistance mutations K65R and K70G/E or ≥3 thymidine analogue resistance mutations including M41L and L210W were found in 18/36 (50%) subjects on a tenofovir-containing regimen at failure. Four patients harboured multiple DRMs, which can confer resistance to all available ART regimens in Tanzania. Conclusions Taken together, pre-treatment and acquired DRMs were highly prevalent, which represents a major risk for the efficacy of ART programmes in Tanzania. Availability of a newer generation of antiretroviral drugs with a higher genetic barrier to resistance and robust treatment monitoring is warranted for effective and sustainable HIV treatment.

scholarly journals Barcoding analysis of HIV drug resistance mutations using Oxford Nanopore MinION (ONT) sequencing

2017 ◽  
Author(s):  
Claudia Gonzalez ◽  
Jessica Gondola ◽  
Alma Y Ortiz ◽  
Juan M Castillo ◽  
Juan M Pascale ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Reverse Transcriptase ◽  
Treatment Resistance ◽  
Resistance Mutations ◽  
Reverse Transcriptase Inhibitors ◽  
Nucleoside Reverse Transcriptase Inhibitors ◽  
Hiv Drug Resistance ◽  
Drug Resistance Mutations ◽  
Oxford Nanopore ◽  
Pre Treatment

ABSTRACTDetermination of HIV drug resistance (HIVDR) is becoming an integral baseline HIV evaluation for newly infected subjects, as the level of pre-treatment resistance is increasing worldwide. Until now, the gold standard for monitoring ART mutations is the Sanger sequencing method, however, next-generation sequencing technologies (NGS) because high-throughput capability, are gaining attention as a method for detection of HIVDR. In the present work, we evaluated the use of the Oxford Nanopore Technologies (ONT) MinION as an alternative method for detection of drug resistance mutations in pre-treatment HIV positive subjects.We evaluate 36 samples taken during November 2016 from treatment naïve subjects with age greater than 18 years old, who went to the lab for their first HIV monitoring. To evaluate the agreement between Sanger and MinION generated sequences, we aligned the sequences (∼1200bp) with muscle v. 3.8.31. Then we counted the differences and calculated the p-distance of the obtained sequences, comparing paired sequences and grouping Sanger and MinION obtained sequences. The percentage of similarity among each sequence was also evaluated.All samples were submitted to the Standford University HIV drug resistance database (HIVdb version 8.4). Then we compared the resistance predictions obtained from the sequences generated by Sanger and MinION methods.Results: The median of available pores was 1314 for the first run, 1215 for the second run, and 536 for the third run. After 3 hours with SQK-NSK007 a total of 18803 2D reads were base-called and in 16577 reads (88%) a barcode was detected.Comparing the nucleotide differences of each sample, we observed that 23 (74%) samples had identical sequence, for the other samples the percentage of identity among each analyzed sequence was greater than 95%. A good positive predictive value (100%) in the estimation of drug resistance mutations in the groups of protease inhibitors (PI), nucleoside reverse transcriptase inhibitors (NRTIs), and non-nucleoside reverse transcriptase inhibitors (NNRTIs).We present an approach for the analysis of HIV reads generated with MinION ONT, further studies are guaranteed before the application of this methodology in clinical settings to assess its suitability for HIVDR testing.

scholarly journals Challenging conventional wisdom on the evolution of resistance to multi-drug HIV treatment: Lessons from data and modeling

2019 ◽  
Author(s):  
Alison Feder ◽  
Kristin Harper ◽  
Pleuni S. Pennings
Keyword(s):  
Drug Resistance ◽  
Standard Of Care ◽  
Compartment Model ◽  
Antiretroviral Drugs ◽  
Hiv Treatment ◽  
Current Standard ◽  
Hiv Drug Resistance ◽  
Resistance Evolution ◽  
Single Drug ◽  
Evolution Of Resistance

AbstractUnder the current standard of care, individuals with HIV take three antiretroviral drugs simultaneously. Triple-drug combination therapies limit HIV drug resistance evolution, because viruses resistant to a subset of the cocktail are suppressed by the remainder of the drugs and should not complete replication and spread. Despite this, reanalysis of HIV genetic data shortly after triple drug therapies became available (1990s and 2000s) reveals ongoing drug resistance in patients on three-drug therapies. In disagreement with expected patterns of evolution in three-drug therapy-treated HIV populations, resistance usually evolves one mutation at a time in a semi-predictable order. We argue here that these surprising observations can be explained using a model that divides the human body into compartments (for example, the gut, lymph nodes and brain). If one drug reaches a compartment that the other two drugs cannot, this creates a single-drug compartment that can select for single-drug resistant viruses. Such viruses can potentially become resistant to additional drugs, if they migrate to another compartment where a second drug is present, and so on. In addition to a compartment model, for some drug combinations, an alternative model of time-heterogeneity due to short half-lives combined with sub-optimal adherence could also explain the observations. We discuss how these lessons from HIV drug resistance evolution may be useful for other systems.

HIV-1 Resistance to Antiretroviral Drugs

2019 ◽  
pp. 245-256
Author(s):  
Tamara Bininashvili ◽  
Quentin Doperalski ◽  
Naiel Nassar
Keyword(s):  
Drug Resistance ◽  
Significant Role ◽  
Antiretroviral Drugs ◽  
Cross Resistance ◽  
Previous Exposure ◽  
Resistance Mutations ◽  
Hiv Drug Resistance ◽  
Drug Resistance Mutations ◽  
Resistance Patterns ◽  
Hiv 1

Discuss the different HIV drug resistance mutations and cross-resistance patterns in each class of HIV medication. In recent years, newer HIV medications have been introduced, and several studies have identified resistance mutations associated with the newer medications. • Previous exposure to antiretroviral (ARV) medications has a significant role in the development of drug resistance, especially in patients who are noncompliant with medications....

scholarly journals HIV Drug Resistance Mutations Detection by Next-Generation Sequencing during Antiretroviral Therapy Interruption in China

Pathogens ◽  
2021 ◽  
Vol 10 (3) ◽  
pp. 264
Author(s):  
Miaomiao Li ◽  
Shujia Liang ◽  
Chao Zhou ◽  
Min Chen ◽  
Shu Liang ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Next Generation Sequencing ◽  
Antiretroviral Therapy ◽  
Detection Threshold ◽  
Next Generation ◽  
Resistance Mutations ◽  
Hiv Drug Resistance ◽  
Drug Resistance Mutations ◽  
Therapy Interruption ◽  
Generation Sequencing

Patients with antiretroviral therapy interruption have a high risk of virological failure when re-initiating antiretroviral therapy (ART), especially those with HIV drug resistance. Next-generation sequencing may provide close scrutiny on their minority drug resistance variant. A cross-sectional study was conducted in patients with ART interruption in five regions in China in 2016. Through Sanger and next-generation sequencing in parallel, HIV drug resistance was genotyped on their plasma samples. Rates of HIV drug resistance were compared by the McNemar tests. In total, 174 patients were included in this study, with a median 12 (interquartile range (IQR), 6–24) months of ART interruption. Most (86.2%) of them had received efavirenz (EFV)/nevirapine (NVP)-based first-line therapy for a median 16 (IQR, 7–26) months before ART interruption. Sixty-one (35.1%) patients had CRF07_BC HIV-1 strains, 58 (33.3%) CRF08_BC and 35 (20.1%) CRF01_AE. Thirty-four (19.5%) of the 174 patients were detected to harbor HIV drug-resistant variants on Sanger sequencing. Thirty-six (20.7%), 37 (21.3%), 42 (24.1%), 79 (45.4%) and 139 (79.9) patients were identified to have HIV drug resistance by next-generation sequencing at 20% (v.s. Sanger, p = 0.317), 10% (v.s. Sanger, p = 0.180), 5% (v.s. Sanger, p = 0.011), 2% (v.s. Sanger, p < 0.001) and 1% (v.s. Sanger, p < 0.001) of detection thresholds, respectively. K65R was the most common minority mutation, of 95.1% (58/61) and 93.1% (54/58) in CRF07_BC and CRF08_BC, respectively, when compared with 5.7% (2/35) in CRF01_AE (p < 0.001). In 49 patients that followed-up a median 10 months later, HIV drug resistance mutations at >20% frequency such as K103N, M184VI and P225H still existed, but with decreased frequencies. The prevalence of HIV drug resistance in ART interruption was higher than 15% in the survey. Next-generation sequencing was able to detect more minority drug resistance variants than Sanger. There was a sharp increase in minority drug resistance variants when the detection threshold was below 5%.

scholarly journals Analysis of Low-Frequency Mutations Associated with Drug Resistance to Raltegravir before Antiretroviral Treatment

2010 ◽  
Vol 55 (3) ◽  
pp. 1114-1119 ◽  
Author(s):  
Jia Liu ◽  
Michael D. Miller ◽  
Robert M. Danovich ◽  
Nathan Vandergrift ◽  
Fangping Cai ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Treatment Failure ◽  
Low Frequency ◽  
Hiv Treatment ◽  
Viral Population ◽  
Virologic Suppression ◽  
Resistance Mutations ◽  
The Difference ◽  
Allele Specific Sequencing ◽  
Hiv 1

ABSTRACTRaltegravir is highly efficacious in the treatment of HIV-1 infection. The prevalence and impact on virologic outcome of low-frequency resistant mutations among HIV-1-infected patients not previously treated with raltegravir have not been fully established. Samples from HIV treatment-experienced patients entering a clinical trial of raltegravir treatment were analyzed using a parallel allele-specific sequencing (PASS) assay that assessed six primary and six secondary integrase mutations. Patients who achieved and sustained virologic suppression (success patients,n= 36) and those who experienced virologic rebound (failure patients,n= 35) were compared. Patients who experienced treatment failure had twice as many raltegravir-associated resistance mutations prior to initiating treatment as those who achieved sustained virologic success, but the difference was not statistically significant. The frequency of nearly all detected resistance mutations was less than 1% of viral population, and the frequencies of mutations between the success and failure groups were similar. Expansion of pre-existing mutations (one primary and five secondary) was observed in 16 treatment failure patients in whom minority resistant mutations were detected at baseline, suggesting that they might play a role in the development of drug resistance. Two or more mutations were found in 13 patients (18.3%), but multiple mutations were not present in any single viral genome by linkage analysis. Our study demonstrates that low-frequency primary RAL-resistant mutations were uncommon, while minority secondary RAL-resistant mutations were more frequently detected in patients naïve to raltegravir. Additional studies in larger populations are warranted to fully understand the clinical implications of these mutations.

scholarly journals Antiretroviral Resistance and Pregnancy Characteristics of Women with Perinatal and Nonperinatal HIV Infection

2016 ◽  
Vol 2016 ◽  
pp. 1-8 ◽  
Author(s):  
Gweneth B. Lazenby ◽  
Okeoma Mmeje ◽  
Barbra M. Fisher ◽  
Adriana Weinberg ◽  
Erika K. Aaron ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Hiv Infection ◽  
Univariate Analysis ◽  
Categorical Variables ◽  
Continuous Variables ◽  
Resistance Mutations ◽  
Hiv Drug Resistance ◽  
Fourfold Increase ◽  
Perinatal Hiv ◽  
Adverse Pregnancy

Objective. To compare HIV drug resistance in pregnant women with perinatal HIV (PHIV) and those with nonperinatal HIV (NPHIV) infection.Methods. We conducted a multisite cohort study of PHIV and NPHIV women from 2000 to 2014. Sample size was calculated to identify a fourfold increase in antiretroviral (ARV) drug resistance in PHIV women. Continuous variables were compared using Student’st-test and Wilcoxon rank-sum tests. Categorical variables were compared usingχ2and Fisher’s exact tests. Univariate analysis was used to determine factors associated with antiretroviral drug resistance.Results. Forty-one PHIV and 41 NPHIV participants were included. Women with PHIV were more likely to have drug resistance than those with NPHIV ((55% versus 17%,p=0.03), OR 6.0 (95% CI 1.0–34.8),p=0.05), including multiclass resistance (15% versus 0,p=0.03), and they were more likely to receive nonstandard ARVs during pregnancy (27% versus 5%,p=0.01). PHIV and NPHIV women had similar rates of preterm birth (11% versus 28%,p=0.08) and cesarean delivery (47% versus 46%,p=0.9). Two infants born to a single NPHIV woman acquired HIV infection.Conclusions. PHIV women have a high frequency of HIV drug resistance mutations, leading to nonstandard ARVs use during pregnancy. Despite nonstandard ARV use during pregnancy, PHIV women did not experience increased rates of adverse pregnancy outcomes.

scholarly journals Using machine learning and big data to explore the drug resistance landscape in HIV

2021 ◽  
Author(s):  
Luc Blassel ◽  
Anna Tostevin ◽  
Christian Julian Villabona-Arenas ◽  
Martine Peeters ◽  
Stephane Hue ◽  
...  
Keyword(s):  
Machine Learning ◽  
Drug Resistance ◽  
Reverse Transcriptase ◽  
Prediction Accuracy ◽  
Sequence Data ◽  
Transcriptase Inhibitor ◽  
Binary Representation ◽  
Resistance Mutations ◽  
Genetic Barrier ◽  
The Uk

Drug resistance mutations (DRMs) appear in HIV under treatment pressure. DRMs are commonly transmitted to naive patients. The standard approach to reveal new DRMs is to test for significant frequency differences of mutations between treated and naive patients. However, we then consider each mutation individually and cannot hope to study interactions between several mutations. Here, we aim to leverage the ever-growing quantity of high-quality sequence data and machine learning methods to study such interactions (i.e. epistasis), as well as try to find new DRMs. We trained classifiers to discriminate between Reverse Transcriptase Inhibitor (RTI)-experienced and RTI-naive samples on a large HIV-1 reverse transcriptase (RT) sequence dataset from the UK (n ≈ 55; 000), using all observed mutations as binary representation features. To assess the robustness of our findings, our classifiers were evaluated on independent data sets, both from the UK and Africa. Important representation features for each classifier were then extracted as potential DRMs. To find novel DRMs, we repeated this process by removing either features or samples associated to known DRMs. When keeping all known resistance signal, we detected sufficiently prevalent known DRMs, thus validating the approach. When removing features corresponding to known DRMs, our classifiers retained some prediction accuracy, and six new mutations significantly associated with resistance were identified. These six mutations have a low genetic barrier, are correlated to known DRMs, and are spatially close to either the RT active site or the regulatory binding pocket. When removing both known DRM features and sequences containing at least one known DRM, our classifiers lose all prediction accuracy. These results likely indicate that all mutations directly conferring resistance have been found, and that our newly discovered DRMs are accessory or compensatory mutations. Moreover, we did not find any significant signal of epistasis, beyond the standard resistance scheme associating major DRMs to auxiliary mutations.

scholarly journals More effective drugs lead to harder selective sweeps in the evolution of drug resistance in HIV-1

eLife ◽  
2016 ◽  
Vol 5 ◽  
Author(s):  
Alison F Feder ◽  
Soo-Yon Rhee ◽  
Susan P Holmes ◽  
Robert W Shafer ◽  
Dmitri A Petrov ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Hiv Treatment ◽  
Adaptive Mutation ◽  
Selective Sweeps ◽  
Resistance Mutations ◽  
Consensus Sequences ◽  
Adaptive Mutations ◽  
Slow Evolution ◽  
Effective Drugs ◽  
Hiv 1

In the early days of HIV treatment, drug resistance occurred rapidly and predictably in all patients, but under modern treatments, resistance arises slowly, if at all. The probability of resistance should be controlled by the rate of generation of resistance mutations. If many adaptive mutations arise simultaneously, then adaptation proceeds by soft selective sweeps in which multiple adaptive mutations spread concomitantly, but if adaptive mutations occur rarely in the population, then a single adaptive mutation should spread alone in a hard selective sweep. Here, we use 6717 HIV-1 consensus sequences from patients treated with first-line therapies between 1989 and 2013 to confirm that the transition from fast to slow evolution of drug resistance was indeed accompanied with the expected transition from soft to hard selective sweeps. This suggests more generally that evolution proceeds via hard sweeps if resistance is unlikely and via soft sweeps if it is likely.

The Continuous Surveillance of InSTI resistance could be an important Public Health Tool in the Fight against HIV Infection

2021 ◽  
Vol 19 ◽  
Author(s):  
Giuseppa Visalli ◽  
Alessio Facciolà ◽  
Maria Giovanna Costanzo ◽  
Angela Di Pietro
Keyword(s):  
Drug Resistance ◽  
Hiv Infection ◽  
Hiv Treatment ◽  
Large Cohort ◽  
University Hospital ◽  
Hiv Positive ◽  
Percentage Increase ◽  
Resistance Mutations ◽  
Hiv Test ◽  
Resistance Tests

Aims: To evaluate the frequency of the InSTIs mutations in a large cohort of HIV-infected people. Background: The Highly Active Anti-Retroviral Therapy (HAART) allow turning HIV infection from a fatal disease to a chronic infection and Integrase Strand Transfer Inhibitors (InSTIs) represent the cornerstone of this treatment. However, the spread of HIV-1 drug resistance mutations represents an emerging threat to the long-term success of HIV treatment programs. Objectives: To evaluate the trend of the HIV drug resistance to InSTIs in a large cohort of HIV-positive people in order to assess the risk represented by these subjects in the spread of the HIV infection to the community. Methods: A cross-sectional study was conducted analysing all the InSTIs resistance tests performed in HIV positive subjects in the period 2017-2019 by the HIV Laboratory of the University Hospital "Gaetano Martino" of Messina, Italy. Results: In 2017-2019, 252 InSTIs resistance tests were performed of which 59 (23.4%), 88 (34.9%) and 105 (41.7%) respectively in the three considered years. Overall, 28 (11.1%) samples showed resistance to at least one of the four InSTIs. We observed a significant percentage increase of 95% about the resistance to all the four drugs. Conclusion: Because the InSTI resistance is not rare, a continuous surveillance can represent nowadays, together with an incessant health education and a wide offer of the HIV test, the most important tool in the fight against HIV infection.

Sign in / Sign up

Export Citation Format

Share Document