An apparent paradox: resistance mutations in HIV-1 DNA predict improved virological responses to antiretroviral therapy

2019 ◽  
Vol 74 (10) ◽  
pp. 3011-3015 ◽  
Author(s):  
Anna Maria Geretti ◽  
Adam Abdullahi ◽  
Olga Mafotsing Fopoussi ◽  
Laura Bonnett ◽  
Victoire Fokom Defo ◽  
...  
Keyword(s):  
Viral Load ◽  
Virological Failure ◽  
Dna Sequences ◽  
Sub Saharan Africa ◽  
Resistance Mutations ◽  
First Line ◽  
Second Line Therapy ◽  
Apparent Paradox ◽  
Sub Saharan ◽  
Hiv 1

Abstract Background In sub-Saharan Africa, detecting resistance-associated mutations (RAMs) at failure of first-line ART with two NRTIs plus an NNRTI predicts improved virological responses to second-line therapy with two NRTIs plus a ritonavir-boosted PI (PI/r). This indicates residual NRTI activity in the presence of RAMs, although additional factors may contribute to the effect. Objectives The aim of this study was to investigate the influence of pre-existing RAMs on the outcomes of maintenance monotherapy with ritonavir-boosted darunavir within a randomized trial in Cameroon. Methods RAMs were detected in HIV-1 DNA using PBMCs collected at initiation of darunavir/ritonavir monotherapy. Adherence was assessed by pill count and visual analogue scale (VAS). Predictors of virological failure (confirmed or last available viral load >400 copies/mL) were explored by logistic regression analysis. Trial name = MANET (NCT02155101). Results After NNRTI-based therapy, participants (n = 81) had received PI/r-based therapy for a median of 3.2 years and had a confirmed viral load <60 copies/mL and a median CD4 count of 466 cells/mm3. NRTI and NNRTI RAMs were detected in 39/60 (65.0%) and 41/60 (68.3%) HIV-1 DNA sequences, respectively. Over 48 weeks of monotherapy, 16/81 (19.8%) patients experienced virological failure. After adjusting for age, HIV-1 DNA load, adherence by VAS and RAM status, virological failure was less likely with higher VAS-measured adherence (adjusted OR 0.04, 95% CI 0.01–0.37; P = 0.004) and detectable HIV-1 DNA RAMs (adjusted OR 0.15, 95% CI 0.03–0.82; P = 0.028). Conclusions Pre-existing NRTI and NNRTI RAMs are associated with improved virological responses to NRTI-sparing ART in sub-Saharan Africa, indicating a predictive effect that is independent of residual NRTI activity.

scholarly journals Accumulation of HIV-1 drug resistance after continued virological failure on first-line ART in adults and children in sub-Saharan Africa

2016 ◽  
Vol 71 (10) ◽  
pp. 2918-2927 ◽  
Author(s):  
T. Sonia Boender ◽  
Cissy M. Kityo ◽  
Ragna S. Boerma ◽  
Raph L. Hamers ◽  
Pascale Ondoa ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Virological Failure ◽  
Sub Saharan Africa ◽  
First Line ◽  
Adults And Children ◽  
Sub Saharan ◽  
Hiv 1

scholarly journals Characterization of HIV-1 near Full-Length Proviral Genome Quasispecies from Patients with Undetectable Viral Load Undergoing First-Line HAART Therapy

2017 ◽  
Author(s):  
Brunna M. Alves ◽  
Juliana D. Siqueira ◽  
Marianne M. Garrido ◽  
Ornella M. Botelho ◽  
Isabel M. Prellwitz ◽  
...  
Keyword(s):  
Viral Load ◽  
Highly Active Antiretroviral Therapy ◽  
Treatment Success ◽  
Undetectable Viral Load ◽  
Hiv Treatment ◽  
Full Length ◽  
Resistance Mutations ◽  
First Line ◽  
Subtype B ◽  
Hiv 1

Increased access to highly active antiretroviral therapy (HAART) by HIV+ individuals has become a reality worldwide. In Brazil, ART currently reaches over half of the HIV-infected subjects. In the context of a remarkable HIV-1 genetic variability, highly related variants, called quasispecies, are generated. HIV quasispecies generated during infection can influence virus persistence and pathogenicity, representing a challenge to treatment. However, the clinical relevance of minority quasispecies is still uncertain. For this study, we have determined the archived proviral sequences, viral subtype and drug resistance mutations from a cohort of HIV+ patients with undetectable viral load undergoing HAART as first-line therapy using next-generation sequencing for near full-length virus genome (NFLG) assembly. HIV-1 consensus sequences representing NFLG were obtained for eleven patients, while for another twelve varying genome coverage rates were obtained. Phylogenetic analysis showed the predominance of subtype B (83%; 19/23). Considering the minority variants, 18 patients carried archived virus harboring at least one mutation conferring antiretroviral resistance; for six patients, the mutations correlated with the current ARVs used. These data highlight the importance of monitoring HIV minority drug resistant variants and their clinical impact, to guide future regimen switches and improve HIV treatment success.

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.

Scale-up of antiretroviral treatment in sub-Saharan Africa is accompanied by increasing HIV-1 drug resistance mutations in drug-naive patients

AIDS ◽  
2011 ◽  
Vol 25 (17) ◽  
pp. 2183-2188 ◽  
Author(s):  
Avelin F. Aghokeng ◽  
Charles Kouanfack ◽  
Christian Laurent ◽  
Eugenie Ebong ◽  
Arrah Atem-Tambe ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Antiretroviral Treatment ◽  
Scale Up ◽  
Sub Saharan Africa ◽  
Resistance Mutations ◽  
Drug Resistance Mutations ◽  
Drug Naïve ◽  
Sub Saharan ◽  
Hiv 1

scholarly journals Rapid accumulation of HIV-1 thymidine analogue mutations and phenotypic impact following prolonged viral failure on zidovudine-based first-line ART in sub-Saharan Africa

2017 ◽  
Vol 72 (5) ◽  
pp. 1450-1455 ◽  
Author(s):  
Ruth L. Goodall ◽  
David T. Dunn ◽  
Peter Nkurunziza ◽  
Lincoln Mugarura ◽  
Theresa Pattery ◽  
...  
Keyword(s):  
Sub Saharan Africa ◽  
First Line ◽  
Thymidine Analogue ◽  
Rapid Accumulation ◽  
Sub Saharan ◽  
Hiv 1

scholarly journals High HIV-1 Virological Failure and Drug Resistance among Adult Patients Receiving First-Line ART for At least 12 Months at a Decentralized Urban HIV Clinic Setting in Senegal before the Test-and-Treat

2021 ◽  
Vol 14 ◽  
pp. 117863372110145
Author(s):  
Aristid Ekollo Mbange ◽  
Abou Abdallah Malick Diouara ◽  
Halimatou Diop-Ndiaye ◽  
Ndèye Aminata Diaw Diouf ◽  
Ndèye Fatou Ngom-Ngueye ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Virological Failure ◽  
Sub Saharan Africa ◽  
Treatment Center ◽  
First Line ◽  
Hiv Diagnosis ◽  
Saint Louis ◽  
Test And Treat ◽  
Adherence Support ◽  
Hiv 1

Background: The feasibility of antiretroviral therapy (ART) monitoring remains problematic in decentralized HIV clinic settings of sub-Saharan Africa. We assessed the rates and correlates of HIV-1 virological failure (VF) and drug resistance (DR) in 2 pre-test-and-treat urban clinic settings of Senegal. Methods: Consenting HIV-1-infected adults (⩾18 years) receiving first-line ART for ⩾12 months were cross-sectionally enrolled between January and March 2015, at the referral outpatient treatment center of Dakar (n = 151) and decentralized regional hospital of Saint-Louis (n = 127). In the 12 months preceding plasma specimens’ collection patients at Saint-Louis had no viral load (VL) testing. Significant predictors of VF (VL ⩾ 1000 copies/ml) and DR (clinically relevant mutations) were determined using binomial logistic regression in R software. Results: Of the 278 adults on EFV-/NVP-based regimens, 32 (11.5% [95%CI: 8.0-15.9]) experienced VF. Failing and non-failing patients had comparable median time [interquartile] on ART (69.5 [23.0-89.5] vs 64.0 [34.0-99.0] months; P = .46, Mann–Whitney U-test). Of the 27 viraemic isolates successfully genotyped, 20 (74.1%) carried DR mutations; most frequent were M184VI (55.6%), K103N (37.1%), thymidine analog mutations (29.6%), Y181CY (22.2%). The pattern of mutations did not always correspond to the ongoing treatment. The adjusted odds of VF was significantly associated with the decentralized clinic site ( P < .001) and CD4 < 350 cells/mm3 ( P < .006). Strong correlates of DR also included Saint-Louis ( P < .009), CD4 < 350 cells/mm3 ( P <. 001), and nevirapine-based therapies (comparator: efavirenz-based therapies; P < .027). In stratification analyses by site, higher rate of VF at Saint-Louis (20.5% [95%CI: 13.8-28.5] vs 4.0% [95%CI: 1.5-8.5] in Dakar) was associated with nevirapine-based therapies (OR = 3.34 [1.07-11.75], P = .038), self-reported missing doses (OR = 3.30 [1.13-10.24], P = .029), and medical appointments (OR = 2.91 [1.05-8.47], P = .039) in the last 1 and 12 months(s), respectively. The higher rate of DR at Saint-Louis (12.9% [95%CI: 7.6-20.1] vs 2.7% [95%CI: 0.7-6.7] in Dakar) was associated with nevirapine-based therapies (OR = 5.13 [1.12-37.35], P = .035). Conclusion: At decentralized urban settings, there is need for enhanced virological monitoring and adherence support. HIV programs in Senegal should intensify early HIV diagnosis for effective test-and-treat. These interventions, in addition to the superiority of efavirenz-based therapies provide a favorable framework for transitioning to the recommended potent drug dolutegravir, thereby ensuring its long-term use.

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