scholarly journals HIV-1 second-line failure and drug resistance at high-level and low-level viremia in Western Kenya

AIDS ◽  
2018 ◽  
Vol 32 (17) ◽  
pp. 2485-2496 ◽  
Author(s):  
Rami Kantor ◽  
Allison DeLong ◽  
Leeann Schreier ◽  
Marissa Reitsma ◽  
Emanuel Kemboi ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Second Line ◽  
Western Kenya ◽  
Low Level ◽  
High Level ◽  
Hiv 1

Extensive drug resistance during low-level HIV viraemia while taking NNRTI-based ART supports lowering the viral load threshold for regimen switch in resource-limited settings: a pre-planned analysis from the SESOTHO trial

2021 ◽  
Author(s):  
Jennifer Anne Brown ◽  
Alain Amstutz ◽  
Bienvenu Lengo Nsakala ◽  
Ulrike Seeburg ◽  
Fiona Vanobberghen ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Viral Load ◽  
Second Line ◽  
Who Guidelines ◽  
Sequencing Data ◽  
First Line ◽  
Low Level ◽  
First Line Therapy ◽  
High Level ◽  
Hiv 1

Abstract Objectives WHO guidelines on ART define the HIV-1 viral load (VL) threshold for treatment failure at 1000 copies/mL. The Switch Either near Suppression Or THOusand (SESOTHO) trial, conducted in Lesotho from 2017 to 2020, found that patients with persistent viraemia below this threshold (100–999 copies/mL) benefit from switching to second-line ART. This pre-planned nested study assesses the prevalence of resistance-associated mutations (RAMs) in SESOTHO trial participants. Methods The SESOTHO trial [registered at ClinicalTrials.gov (NCT03088241)] enrolled 80 persons taking NNRTI-based first-line ART with low-level HIV-1 viraemia (100–999 copies/mL) and randomized them (1:1) to switch to a PI-based second-line regimen (switch) or continue on first-line therapy (control). We sequenced relevant regions of the viral pol gene using plasma samples obtained at enrolment and 36 weeks. RAMs were classified with the Stanford HIV Drug Resistance Database. Results Sequencing data were obtained for 37/80 (46%) participants at baseline and 26/48 (54%) participants without viral suppression to <50 copies/mL at 36 weeks (21 control participants and 5 switch participants). At baseline, 31/37 (84%) participants harboured high-level resistance to at least two drugs of their current regimen. At 36 weeks, 17/21 (81%) control participants harboured resistance to at least two drugs of their current regimen, while no PI-associated resistance was detected in the 5 switch participants with ongoing viraemia. Conclusions Among persons with low-level viraemia while taking NNRTI-based first-line ART enrolled in the SESOTHO trial, the majority harboured HIV-1 with RAMs that necessitate ART modification. These findings support lowering the VL threshold triggering a switch to second-line ART in future WHO guidelines.

Characteristics of drug resistance in HIV-1 CRF55_01B from ART-experienced patients in Guangdong, China

2020 ◽  
Vol 75 (7) ◽  
pp. 1925-1931 ◽  
Author(s):  
Yun Lan ◽  
Ruolei Xin ◽  
Weiping Cai ◽  
Xizi Deng ◽  
Linghua Li ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Drug Susceptibility ◽  
Public Health Issue ◽  
Resistance Mutations ◽  
Acquired Drug Resistance ◽  
Low Level ◽  
High Level ◽  
Hiv 1 ◽  
Level Resistance ◽  
Epidemiological Information

Abstract Background HIV-1 acquired drug resistance (ADR) has become a critical clinical and public health issue. Recently, HIV-1 CRF55_01B has been found more frequently in the MSM population. Objective To investigate the characteristics of HIV-1 drug resistance mutations (DRMs) and the extent of changes in drug susceptibility among ART-experienced CRF55_01B-infected adults of Guangdong. Methods ADR was tested for immediately in CRF55_01B-infected patients with virological failure. Demographic and epidemiological information was collected. DRMs and antiretroviral susceptibility were interpreted using the Stanford University HIV Drug Resistance Database HIVdb program. Results Overall, 162 (4.78%) CRF55_01B isolates were identified from 2013 to 2018. Among DRMs, M184V (43.83%) was the most frequent NRTI DRM, followed by K65R (23.46%), and V179E (98.77%) was the most frequent NNRTI DRM, followed by K103N (47.53%) and Y181C (14.81%). According to the HIVdb program, 79.01% of the CRF55_01B-infected patients carried mutations conferring low-level or higher drug resistance to any of the three classes of ART drugs. Among PI DRMs, only one mutation affording low-level resistance to nelfinavir was found (0.62%). Among NRTI DRMs, a high proportion of high-level resistance to lamivudine (58.64%) and emtricitabine (58.02%) was found. As regards NNRTIs, more than 75% of patients carried efavirenz and nevirapine DRMs. The percentages of high-level resistance were 70.99%, 63.58%, 22.22%, 17.90% and 4.32% for nevirapine, efavirenz, rilpivirine, doravirine and etravirine, respectively. Conclusions High frequencies of DRMs and resistance were observed among CRF55_01B-infected patients failing ART in Guangdong, and interventions may be considered to minimize ecological contributions to ART.

scholarly journals Mechanism of Darunavir (DRV)’s High Genetic Barrier to HIV-1 Resistance: A Key V32I Substitution in Protease Rarely Occurs, but Once It Occurs, It Predisposes HIV-1 To Develop DRV Resistance

mBio ◽  
2018 ◽  
Vol 9 (2) ◽  
Author(s):  
Manabu Aoki ◽  
Debananda Das ◽  
Hironori Hayashi ◽  
Hiromi Aoki-Ogata ◽  
Yuki Takamatsu ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Amino Acid ◽  
Critical Role ◽  
Viral Fitness ◽  
Single Amino Acid ◽  
Amino Acid Substitutions ◽  
Wild Type ◽  
Genetic Barrier ◽  
High Level ◽  
Hiv 1

ABSTRACTDarunavir (DRV) has bimodal activity against HIV-1 protease, enzymatic inhibition and protease dimerization inhibition, and has an extremely high genetic barrier against development of drug resistance. We previously generated a highly DRV-resistant HIV-1 variant (HIVDRVRP51). We also reported that four amino acid substitutions (V32I, L33F, I54M, and I84V) identified in the protease of HIVDRVRP51are largely responsible for its high-level resistance to DRV. Here, we attempted to elucidate the role of each of the four amino acid substitutions in the development of DRV resistance. We found that V32I is a key substitution, which rarely occurs, but once it occurs, it predisposes HIV-1 to develop high-level DRV resistance. When two infectious recombinant HIV-1 clones carrying I54M and I84V (rHIVI54Mand rHIVI84V, respectively) were selected in the presence of DRV, V32I emerged, and the virus rapidly developed high-level DRV resistance. rHIVV32Ialso developed high-level DRV resistance. However, wild-type HIVNL4-3(rHIVWT) failed to acquire V32I and did not develop DRV resistance. Compared to rHIVWT, rHIVV32Iwas highly susceptible to DRV and had significantly reduced fitness, explaining why V32I did not emerge upon selection of rHIVWTwith DRV. When the only substitution is at residue 32, structural analysis revealed much stronger van der Waals interactions between DRV and I-32 than between DRV and V-32. These results suggest that V32I is a critical amino acid substitution in multiple pathways toward HIV-1’s DRV resistance development and elucidate, at least in part, a mechanism of DRV’s high genetic barrier to development of drug resistance. The results also show that attention should be paid to the initiation or continuation of DRV-containing regimens in people with HIV-1 containing the V32I substitution.IMPORTANCEDarunavir (DRV) is the only protease inhibitor (PI) recommended as a first-line therapeutic and represents the most widely used PI for treating HIV-1-infected individuals. DRV possesses a high genetic barrier to development of HIV-1’s drug resistance. However, the mechanism(s) of the DRV’s high genetic barrier remains unclear. Here, we show that the preexistence of certain single amino acid substitutions such as V32I, I54M, A71V, and I84V in HIV-1 protease facilitates the development of high-level DRV resistance. Interestingly, allin vitro-selected highly DRV-resistant HIV-1 variants acquired V32I but never emerged in wild-type HIV (HIVWT), and V32I itself rendered HIV-1 more sensitive to DRV and reduced viral fitness compared to HIVWT, strongly suggesting that the emergence of V32I plays a critical role in the development of HIV-1’s resistance to DRV. Our results would be of benefit in the treatment of HIV-1-infected patients receiving DRV-containing regimens.

scholarly journals Switch to second-line versus continued first-line antiretroviral therapy for patients with low-level HIV-1 viremia: An open-label randomized controlled trial in Lesotho

PLoS Medicine ◽  
2020 ◽  
Vol 17 (9) ◽  
pp. e1003325
Author(s):  
Alain Amstutz ◽  
Bienvenu Lengo Nsakala ◽  
Fiona Vanobberghen ◽  
Josephine Muhairwe ◽  
Tracy Renée Glass ◽  
...  
Keyword(s):  
Randomized Controlled Trial ◽  
Antiretroviral Therapy ◽  
Controlled Trial ◽  
Second Line ◽  
First Line ◽  
Open Label ◽  
Low Level ◽  
Randomized Controlled ◽  
Hiv 1

scholarly journals Antiretroviral Drug Resistance in HIV‐1‐Infected Patients with Low‐Level Viremia

2010 ◽  
Vol 201 (9) ◽  
pp. 1303-1307 ◽  
Author(s):  
Nicola E. Mackie ◽  
Andrew N. Phillips ◽  
Steve Kaye ◽  
Clare Booth ◽  
Anna‐Maria Geretti
Keyword(s):  
Drug Resistance ◽  
Low Level ◽  
Antiretroviral Drug Resistance ◽  
Antiretroviral Drug ◽  
Hiv 1

scholarly journals Factors associated with high-risk low-level viremia leading to virologic failure: 16-year retrospective study of a Chinese antiretroviral therapy cohort

2019 ◽  
Author(s):  
Tong Zhang ◽  
Haibo Ding ◽  
Minghui An ◽  
Xiaonan Wang ◽  
Wen Tian ◽  
...  
Keyword(s):  
Antiretroviral Therapy ◽  
High Risk ◽  
Virologic Failure ◽  
Baseline Viral Load ◽  
Factors Associated ◽  
Low Level ◽  
Subtype B ◽  
High Level ◽  
Hiv 1

Abstract Background: Low level viremia (LLV) often occurs during antiretroviral therapy (ART) against HIV-1. However, its impact on virologic failure (VF) is controversial because of non-uniform definitions of LLV and VF. Methods: A long-term first line regimen ART cohort from 2002–2018 from Shenyang, northeast China, was retrospectively studied. All participants were followed up every 3 to 6 months to evaluate the treatment effect. The high-risk LLV subgroups leading to VF (with strict standards) were explored with Cox proportional hazards model and linear mixed-effect model. The association factors of high-risk LLV were further explored using multivariate logistic regression analyses. Results: A total of 2155 HIV-1 infected participants were included; of these, 38.8% showed LLV. Both high level LLV (HLLV) and any other level LLV coupled with high level blip (HBL) showed higher risk of VF (hazards ratios, HRHLLV=5.93, and HRHBL=2.84, p<0.01 respectively). Moreover, HR increased with prolonged duration of LLV. Independent factors associated with high-risk LLV included the zenith baseline viral load (VL) above 6 log copies/ml (aOR=3.49, p=0.002), nadir baseline CD4+T cell counts below 200 cells/ml (aOR=1.78, p=0.011), Manchu (aOR=2.03, p=0.003), ART over 60 months (aOR=1.81, p=0.004), AZT+3TC+NVP (aOR=2.26, p<0.001) or DDI-based regimen (aOR=9.96, p<0.001), and subtype B’ infection (aOR=8.22, p=0.001). Conclusions: In case of VF with strict standards, high-risk LLV leading to VF includes VL above 400 copies/ml, occurring at least once. Serious laboratory indicators or advanced stage of infection, long term ART and subtype B’ infection might also predict the occurrence of high-risk LLV.

scholarly journals Factors associated with high-risk low-level viremia leading to virologic failure: 16-year retrospective study of a Chinese antiretroviral therapy cohort

2020 ◽  
Author(s):  
Tong Zhang ◽  
Haibo Ding ◽  
Minghui An ◽  
Xiaonan Wang ◽  
Wen Tian ◽  
...  
Keyword(s):  
Antiretroviral Therapy ◽  
High Risk ◽  
Virologic Failure ◽  
Baseline Viral Load ◽  
Factors Associated ◽  
Low Level ◽  
Subtype B ◽  
High Level ◽  
Hiv 1

Abstract Background: Low level viremia (LLV) often occurs during antiretroviral therapy (ART) against HIV-1. However, whether LLV increases the risk of virologic failure (VF) is controversial because of the non-uniform definitions of LLV and VF. Methods: A long-term first line regimen ART cohort from 2002–2018 from Shenyang, northeast China, was retrospectively studied. All participants were followed up every 3 to 6 months to evaluate the treatment effect. The high-risk LLV subgroups leading to VF (with strict standards) were explored with Cox proportional hazards model and linear mixed-effect model. The association factors of high-risk LLV were further explored using multivariate logistic regression analyses. Results: A total of 2155 HIV-1 infected participants were included; of these, 38.7% showed LLV. Both high level LLV (HLLV) and any other level LLV coupled with high level blip (HLB) showed higher risk of VF (hazards ratios, HRHLLV=5.93, and HRHLB=2.84, p<0.05 respectively). Moreover, HR increased with prolonged duration of LLV. Independent factors associated with high-risk LLV included the zenith baseline viral load (VL) above 6 log copies/ml (aOR=3.49, p=0.002), nadir baseline CD4+T cell counts below 200 cells/mm3 (aOR=1.78, p=0.011), Manchu (aOR=2.03, p=0.003), ART over 60 months (aOR=1.81, p=0.004), AZT+3TC+NVP (aOR=2.26, p<0.001) or DDI-based regimen (aOR=9.96, p=0.002), and subtype B’ infection (aOR=8.22, p=0.001). Conclusions: In case of VF with strict standards, high-risk LLV leading to VF includes VL above 400 copies/ml, occurring at least once. Serious laboratory indicators or advanced stage of infection, long term ART and subtype B’ infection might also predict the occurrence of high-risk LLV.

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