Long-term virological outcomes, failure and acquired resistance in a large cohort of Ugandan children

2019 ◽  
Vol 74 (10) ◽  
pp. 3035-3043
Author(s):  
M H W Huibers ◽  
C Kityo ◽  
R S Boerma ◽  
E Kaudha ◽  
K C E Sigaloff ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Viral Suppression ◽  
Acquired Resistance ◽  
Close Monitoring ◽  
Resistance Mutations ◽  
Second Line Therapy ◽  
Drug Resistance Mutations ◽  
Virological Outcomes ◽  
Susceptibility Score

Abstract Objectives To evaluate long-term virological failure (VF) and drug resistance among HIV-infected Ugandan children on first-line ART. Methods In a multicentre prospective cohort study, viral load (VL) and drug resistance mutations (DRMs) were investigated at baseline and 6 monthly intervals in children (age ≤ 12 years). VF (two consecutive VLs >1000 copies/mL or death after 6 months of ART) was defined as early VF (0–24 months of ART) or late VF (25–48 months of ART). An active regimen was defined as partially active if the genotypic susceptibility score (GSS) was <3. Results Between 2010 and 2011, 316 children were enrolled. Viral suppression was achieved in 75.8%, 71.5%, 72.6% and 69.2% at 12, 24, 36 and 48 months. VF occurred in 111/286 (38.8%), of which 67.6% was early and 32.4% late VF. Early VF was associated with a partially active regimen at baseline (OR 6.0, 95% CI 1.9–18.5), poor adherence (OR 3.1, 95% CI 1.3–7.4) and immunodeficiency (OR 3.3, 95% CI 1.1–10.2). Late VF was associated with age >3 years (OR 2.5, 95% CI 1.0–6.6) and WHO stage 3/4 (OR 4.2, 95% CI 1.4–13.4). Acquired DRMs were detected in 27.0% before 24 months, versus 14.4% after 24 months (P < 0.001). A total of 92.2% of the children with early VF, versus 56.2% with late VF, had a partially active regimen (P < 0.001). Conclusions VF rates were high, occurred predominantly in the first 24 months and appeared to increase again in year four. Risk factors and patterns of early VF/DRMs were different from those of late VF/DRMs. Virological control may improve by close monitoring and prompt switching to second-line therapy in the first 24 months. Late VF may be prevented by early start of ART.

scholarly journals Pre-treatment minority HIV-1 drug resistance mutations and long term virological outcomes: is prediction possible?

2016 ◽  
Vol 13 (1) ◽  
Author(s):  
M. L. Mzingwane ◽  
C. T. Tiemessen ◽  
K. L. Richter ◽  
S. H. Mayaphi ◽  
G. Hunt ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Resistance Mutations ◽  
Drug Resistance Mutations ◽  
Virological Outcomes ◽  
Pre Treatment ◽  
Hiv 1

scholarly journals Engagement in Care, Viral Suppression, Drug Resistance, and Reasons for Nonengagement After Home-Based Same-Day Antiretroviral Therapy Initiation in Lesotho: A Two-Year Follow-up of the CASCADE Trial

2019 ◽  
Vol 71 (10) ◽  
pp. 2608-2614 ◽  
Author(s):  
Alain Amstutz ◽  
Jennifer Anne Brown ◽  
Isaac Ringera ◽  
Josephine Muhairwe ◽  
Thabo Ishmael Lejone ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Antiretroviral Therapy ◽  
Viral Suppression ◽  
Human Immunodeficiency Virus Testing ◽  
Long Term Results ◽  
Absolute Difference ◽  
Engagement In Care ◽  
Resistance Mutations ◽  
Home Based

Abstract Background The CASCADE trial showed that compared with usual care (UC), offering same-day (SD) antiretroviral therapy (ART) during home-based human immunodeficiency virus testing improved engagement in care and viral suppression 12 months after diagnosis. However, questions remain regarding long-term outcomes and the risk of propagating drug resistance. Methods After completion of the primary endpoint at 12 months, participants not in care in both arms were traced and encouraged to access care. At 24 months, the following outcomes were assessed in both arms: engagement in care, viral suppression, and reasons for nonengagement. Furthermore, we explored the acquisition of drug resistance mutations (DRMs) among SD arm nonlinkers. Results At 24 months, 64% (88/137) in the SD arm vs 59% (81/137) in the UC arm were in care (absolute difference [AD], 5%; 95% confidence interval [CI], −6 to16; P = .38) and 57% (78/137) vs 54% (74/137) had documented viral suppression (AD, 3%; 95% CI, −9 to 15; P = .28). Among 36 participants alive and not in care at 24 months with ascertained status, the majority rejected contact with the health system or were unwilling to take ART. Among 8 interviewed SD arm nonlinkers, 6 had not initiated ART upon enrollment, and no acquired DRMs were detected. Two had taken the initial 30-day ART supply and acquired DRMs. Conclusions SD ART resulted in higher rates of engagement in care and viral suppression at 12 months but not at 24 months. Leveling off between both arms was driven by linkage beyond 12 months in the UC arm. We did not observe compensatory long-term disengagement in the SD arm. These long-term results endorse SD ART initiation policies. Clinical Trials Registration NCT02692027.

scholarly journals The development of drug resistance mutations K103N Y181C and G190A in long term Nevirapine-containing antiviral therapy

2014 ◽  
Vol 11 (1) ◽  
pp. 36 ◽  
Author(s):  
Yuncong Wang ◽  
Hui Xing ◽  
Lingjie Liao ◽  
Zhe Wang ◽  
Bin Su ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Antiviral Therapy ◽  
Resistance Mutations ◽  
Drug Resistance Mutations

scholarly journals Natural polymorphisms in HIV-1 CRF01_AE strain and profile of acquired drug resistance mutations in a long-term combination treatment cohort in northeastern China

2019 ◽  
Author(s):  
Zesong Sun ◽  
Jinming Ouyang ◽  
Bin Zhao ◽  
Minghui An ◽  
Lin Wang ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Deep Sequencing ◽  
Northeastern China ◽  
Wilcoxon Test ◽  
Resistance Mutations ◽  
Drug Resistance Mutations ◽  
Z Value ◽  
Hiv 1 ◽  
Time Point

Abstract Background: The impacts of genetic polymorphisms on drug resistance mutations (DRMs) among various HIV-1 subtypes have long been debated. In this study, we aimed to analyze the natural polymorphisms and acquired DRM profile in HIV-1 CRF01_AE-infected patients in a large first-line antiretroviral therapy (ART) cohort in northeastern China. Methods: The natural polymorphisms of CRF01_AE were analyzed in 2034 patients from a long-term ART cohort in northeastern China. The polymorphisms in 105 treatment failure (TF) patients were compared with those in 1148 treatment success (TS) patients. The acquired DRM profile of 42 patients who experienced TF with tenofovir/lamivudine/efavirenz (TDF/3TC/EFV) treatment was analyzed by comparing the mutations at TF time point to those at baseline. The Stanford HIVdb algorithm was used to interpret the DRMs. Binomial distribution, McNemar test, Wilcoxon test and CorMut package were used to analyze the mutation rates and co-variation. Deep sequencing was used to analyze the evolutionary dynamics of co-variation. Results: Before ART, there were significantly more natural polymorphisms of 31 sites on reverse transcriptase (RT) in CRF01_AE than subtype B HIV-1 (|Z value|≥3), including five known drug resistance-associated sites (238, 118, 179, 103, and 40). However, only the polymorphism at site 75 was associated with TF (|Z value|≥3). The mutation rate at 14 sites increased significantly at TF time point compared to baseline, with the most common DRMs comprising G190S/C, K65R, K101E/N/Q, M184V/I, and V179D/I/A/T/E, ranging from 66.7% to 45.2%. Moreover, two unknown mutations (V75L and L228R) increased by 19.0% and 11.9% respectively, and they were under positive selection (Ka/Ks>1, log odds ratio [LOD]>2) and were associated with several other DRMs (cKa/Ks>1, LOD>2). Deep sequencing of longitudinal plasma samples showed that L228R occurred simultaneously or followed the appearance of Y181C. Conclusion: The high levels of natural polymorphisms in CRF01_AE had little impact on treatment outcomes. The findings regarding potential new CRF01_AE-specific minor DRMs indicate the need for more studies on the drug resistance phenotype of CRF01_AE.

scholarly journals Natural polymorphisms in HIV-1 CRF01_AE strain and profile of acquired drug resistance mutations in a long-term combination treatment cohort in northeastern China

2019 ◽  
Author(s):  
Zesong Sun ◽  
Jinming Ouyang ◽  
Bin Zhao ◽  
Minghui An ◽  
Lin Wang ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Deep Sequencing ◽  
Evolutionary Dynamics ◽  
Northeastern China ◽  
Resistance Mutations ◽  
Drug Resistance Mutations ◽  
Subtype B ◽  
Z Value ◽  
Hiv 1

Abstract Background The impacts of genetic polymorphisms on drug resistance mutations (DRMs) among various HIV-1 subtypes have long been debated. In this study, we aimed to analyze the natural polymorphisms and acquired DRM profile in HIV-1 CRF01_AE-infected patients in a large Tenofovir/Lamivudine/Efavirenz (TDF/3TC/EFV) first-line antiretroviral therapy (ART) cohort in northeastern China.Methods The natural polymorphisms of CRF01_AE were analyzed in 2034 patients from a long-term ART cohort in northeastern China. The polymorphisms in 105 treatment failure (TF) patients were compared with those in 1148 treatment success (TS) patients. The acquired DRM profile of 42 patients who experienced TF with TDF/3TC/EFV treatment was analyzed by comparing the mutations at TF to those at baseline. The Stanford HIVdb algorithm was used to interpret the DRMs. Binomial distribution, McNemar test, and CorMut package were used to analyze the mutation rates and co-variation. Deep sequencing was used to analyze the evolutionary dynamics of co-variation.Results Before ART, the natural polymorphisms of 31 sites on reverse transcriptase (RT) were significantly higher in CRF01_AE than subtype B HIV-1 (|Z value|≥3), including five known drug resistance-associated sites (238, 118, 179, 103, and 40). However, only the polymorphism at site 75 was associated with TF (|Z value|≥3). The mutation rate at 14 sites increased significantly at TF compared to baseline, with the most common DRMs comprising G190S/C, K65R, K101E/N/Q, M184V/I, and V179D/I/A/T/E, ranging from 66.7% to 45.2%. Moreover, two unknown mutations (V75L and L228R) increased by 19.0% and 11.9% respectively, and they were under positive selection (Ka/Ks>1, log odds ratio [LOD]>2) and were associated with several other DRMs (cKa/Ks>1, LOD>2). Deep sequencing of longitudinal plasma samples showed that L228R occurred simultaneously or followed the appearance of Y181C.Conclusion The high levels of polymorphisms in CRF01_AE had little impact on treatment outcomes. The findings regarding potential new CRF01_AE-specific minor DRMs indicate the need for more studies on the drug resistance phenotype of CRF01_AE.

scholarly journals Profiling the Landscape of Drug Resistance Mutations in Neosubstrates to Molecular Glue Degraders

2021 ◽  
Author(s):  
Pallavi M Gosavi ◽  
Kevin C Ngan ◽  
Megan Yeo ◽  
Cindy Su ◽  
Jiaming Li ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Drug Discovery ◽  
Cell Survival ◽  
Protein Degradation ◽  
Ternary Complex ◽  
Acquired Resistance ◽  
Resistance Mechanisms ◽  
Sequence Conservation ◽  
Resistance Mutations ◽  
Drug Resistance Mutations

Targeted protein degradation (TPD) holds immense promise for drug discovery but mechanisms of acquired resistance to degraders remain to be fully identified. Here we used CRISPR-suppressor scanning to identify mechanistic classes of drug resistance mutations to molecular glue degraders in GSPT1 and RBM39, neosubstrates targeted by E3 ligase substrate receptors cereblon and DCAF15, respectively. While many mutations directly alter the ternary complex heterodimerization surface, distal resistance sites were also identified. Several distal mutations in RBM39 led to modest decreases in degradation yet can enable cell survival, underscoring how small differences in degradation can lead to resistance. Integrative analysis of resistance sites across GSPT1 and RBM39 revealed varying levels of sequence conservation and mutational constraint that control the emergence of different resistance mechanisms, highlighting that many regions co-opted by TPD are inessential. Altogether, our study identifies common resistance mechanisms for molecular glue degraders and outlines a general approach to survey neosubstrate requirements necessary for effective degradation.

scholarly journals Acquired HIV drug resistance mutations on first-line antiretroviral therapy in Southern Africa: Bayesian evidence synthesis

2020 ◽  
Author(s):  
Anthony Hauser ◽  
Fardo Goldstein ◽  
Martina L. Reichmuth ◽  
Roger Kouyos ◽  
Nicola Low ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Antiretroviral Therapy ◽  
Reverse Transcriptase ◽  
Southern Africa ◽  
Evidence Synthesis ◽  
Resistance Mutations ◽  
First Line ◽  
Nnrti Resistance ◽  
Drug Resistance Mutations

Background: Until 2019, first-line antiretroviral therapy (ART) in Southern Africa consisted of one non-nucleoside reverse transcriptase inhibitor (NNRTI) and two nucleoside reverse transcriptase inhibitors (NRTI). As a response to the increasing level of NNRTI resistance, these drugs are being replaced by dolutegravir (DTG), an integrase inhibitor with a high barrier to resistance. Patients failing an NNRTI-based regimen might therefore start DTG-based therapy with preexisting NRTI resistance, potentially jeopardizing the long-term success of DTG-based ART. We performed a systematic review and meta-analysis to quantify the prevalence of NRTI drug resistance mutations (DRMs) in patients failing NNRTI-based ART in Southern Africa. Methods: We searched several bibliographic databases, including Embase and Medline, from inception to May 2019 to identify studies reporting NRTI DRMs observed among adult HIV-positive patients experiencing virological failure on first-line NNRTI-based regimens in countries of Southern Africa. After screening titles and abstracts, two independent reviewers assessed full manuscripts of potentially eligible studies and extracted data. We developed a hierarchical logistic meta-regression model to synthesize the effect of different ART regimen on the emergence of NRTI and NNRTI DRMs across studies, accounting for ART duration and study-specific effects. Analyses were performed in a Bayesian framework using the rstan package in R.Results: Of 7,579 studies, 3,247 were duplicates and 4,135 were excluded after initial screening. After assessing 194 full-texts, we included 15 studies with 17 study samples and 2,432 individuals from South Africa (13 studies), Mozambique (1), Botswana (1), Lesotho (1) and Zambia (1). We analyzed the dynamics of nine NRTI DRMs by ART regimen. Baseline levels of DRMs were low, ranging from 0.2% to 7.8%. The use of emtricitabine/lamivudine was associated with development of high levels of the M184V/I mutation (1.2% at baseline vs. 64% after 3 years on treatment). When emtricitabine/lamivudine was combined with tenofovir disoproxil fumarate, a substantial increase in the K65R mutation (0.8% at baseline vs. 69.5% after 3 years) was observed. We also analyzed the dynamics of seven NNRTI DRMs after 3 years. With a prevalence of 45.6% after 3 years of efavirenz, K103 was the most prevalent NNRTI resistance mutation, followed by V106 (35.5% after 3 years of efavirenz) and Y181 (14.7% after 3 years of nevirapine).Interpretation: In patients failing first-line ART in Southern Africa, the prevalence of NRTI DRM is high, suggesting that a substantial proportion of patients failing NNRTI-based regimen will switch to DTG-based regimen with non-working NRTIs. This could potentially impair the long-term efficacy of DTG-introduction in Southern Africa.

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