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

Goodall, Ruth L. , Dunn, David T., Nkurunziza, Peter, Mugarura, Lincoln, Pattery, Theresa, Munderi, Paula, Kityo, Cissy, Gilks, Charles, Kaleebu, Pontiano, Pillay, Deenan, Gupta, Ravindra K. and DART Virology Group (2017) 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. Journal of Antimicrobial Chemotherapy, 72 5: 1450-1455. doi:10.1093/jac/dkw583


Author Goodall, Ruth L.
Dunn, David T.
Nkurunziza, Peter
Mugarura, Lincoln
Pattery, Theresa
Munderi, Paula
Kityo, Cissy
Gilks, Charles
Kaleebu, Pontiano
Pillay, Deenan
Gupta, Ravindra K.
DART Virology Group
Title 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
Journal name Journal of Antimicrobial Chemotherapy   Check publisher's open access policy
ISSN 1460-2091
0305-7453
Publication date 2017-02-04
Sub-type Article (original research)
DOI 10.1093/jac/dkw583
Open Access Status Not yet assessed
Volume 72
Issue 5
Start page 1450
End page 1455
Total pages 6
Place of publication Oxford, United Kingdom
Publisher Oxford University Press
Language eng
Subject 3004 Pharmacology
2736 Pharmacology (medical)
2725 Infectious Diseases
Abstract Background: Lack of viral load monitoring of ART is known to be associated with slower switch from a failing regimen and thereby higher prevalence of MDR HIV-1. Many countries have continued to use thymidine analogue drugs despite recommendations to use tenofovir in combination with a cytosine analogue and NNRTI as firstline ART. The effect of accumulated thymidine analogue mutations (TAMs) on phenotypic resistance over time has been poorly characterized in the African setting. Patients and methods: A retrospective analysis of individuals with ongoing viral failure between weeks 48 and 96 in the NORA (Nevirapine OR Abacavir) study was conducted. We analysed 36 genotype pairs from weeks 48 and 96 of first-line ART (14 treated with zidovudine/lamivudine/nevirapine and 22 treated with zidovudine/lamivudine/abacavir). Phenotypic drug resistance was assessed using the Antivirogram assay (v. 2.5.01, Janssen Diagnostics). Results: At 96 weeks, extensive TAMs (≥ 3 mutations) were present in 50% and 73% of nevirapine- and abacavirtreated patients, respectively. The mean (SE) number of TAMs accumulating between week 48 and week 96 was 1.50 (0.37) in nevirapine-treated participants and 1.82 (0.26) in abacavir-treated participants. Overall, zidovudine susceptibility of viruses was reduced between week 48 [geometric mean fold change (FC) 1.3] and week 96 (3.4, P=0.01). There was a small reduction in tenofovir susceptibility (FC 0.7 and 1.0, respectively, P=0.18). Conclusions: Ongoing viral failure with zidovudine-containing first-line ART is associated with rapidly increasing drug resistance that could be mitigated with effective viral load monitoring.
Formatted abstract
Background: Lack of viral load monitoring of ART is known to be associated with slower switch from a failing regimen and thereby higher prevalence of MDR HIV-1. Many countries have continued to use thymidine analogue drugs despite recommendations to use tenofovir in combination with a cytosine analogue and NNRTI as first-line ART. The effect of accumulated thymidine analogue mutations (TAMs) on phenotypic resistance over time has been poorly characterized in the African setting.
Patients and methods: A retrospective analysis of individuals with ongoing viral failure between weeks 48 and 96 in the NORA (Nevirapine OR Abacavir) study was conducted. We analysed 36 genotype pairs from weeks 48 and 96 of first-line ART (14 treated with zidovudine/lamivudine/nevirapine and 22 treated with zidovudine/lamivudine/abacavir). Phenotypic drug resistance was assessed using the Antivirogram assay (v. 2.5.01, Janssen Diagnostics).
Results: At 96 weeks, extensive TAMs (≥3 mutations) were present in 50% and 73% of nevirapine- and abacavir-treated patients, respectively. The mean (SE) number of TAMs accumulating between week 48 and week 96 was 1.50 (0.37) in nevirapine-treated participants and 1.82 (0.26) in abacavir-treated participants. Overall, zidovudine susceptibility of viruses was reduced between week 48 [geometric mean fold change (FC) 1.3] and week 96 (3.4, P = 0.01). There was a small reduction in tenofovir susceptibility (FC 0.7 and 1.0, respectively, P = 0.18).
Conclusions: Ongoing viral failure with zidovudine-containing first-line ART is associated with rapidly increasing drug resistance that could be mitigated with effective viral load monitoring.
Keyword Phenotype
Abacavir
Mutation
Drug resistance
Africa south of the Sahara
Q-Index Code C1
Q-Index Status Provisional Code
Grant ID WT108082AIA
Institutional Status UQ

Document type: Journal Article
Sub-type: Article (original research)
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