High Detection Rate of HIV Drug Resistance Mutations among Patients Who Fail Combined Antiretroviral Therapy in Manaus, Brazil

Chaves, Yury Oliveira; Pereira, Flávio Ribeiro; Pinheiro, Rebeca de Souza; Batista, Diego Rafael Lima; Balieiro, Antônio Alcirley da Silva; Lacerda, Marcus Vinícius Guimarães; Nogueira, Paulo Afonso; Guimarães, Monick Lindenmeyer

doi:10.1155/2021/5567332

Cited by 3 publications

(6 citation statements)

References 52 publications

(81 reference statements)

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“…Previous studies demonstrate that the expanding HIV-1 subtype B epidemic in the Northern Brazilian state of Amazonas was driven by both pandemic (B PAN ) and non-pandemic (B CAR ) viral variants ( Cabello et al, 2015 ; Divino et al, 2016 ; Arantes et al, 2019 ; Crispim et al, 2019 ; Chaves et al, 2021 ; Gräf et al, 2021 ), thus creating a great opportunity to compare the epidemic dynamics of both subtype B forms spreading in the same population. This study revealed that the B PAN and B CAR epidemics in Amazonas have been shaped by different evolutionary histories, but displayed very similar transmissibility and expansion dynamics at most recent times.…”

Section: Discussionmentioning

confidence: 99%

“…In this study, we used a total of 1,272 HIV-1 subtype B pol sequences (nucleotides 2,253–3,275 of reference strain HXB2) from Amazonas state sampled between 2009 and 2018 that were either available at the Los Alamos HIV Database 1 by March 2021 or were recently published ( Chaves et al, 2021 ; Gräf et al, 2021 ) and made available in GenBank 2 . Only one sequence per subject was selected.…”

Section: Methodsmentioning

confidence: 99%

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Dissemination Dynamics of HIV-1 Subtype B Pandemic and Non-pandemic Lineages Circulating in Amazonas, Brazil

et al. 2022

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The HIV-1 epidemic in the Amazonas state, as in most of Brazil, is dominated by subtype B. The state, nonetheless, is singular for its significant co-circulation of the variants BCAR, which can mostly be found in the Caribbean region, and BPAN, a clade that emerged in the United States and aggregates almost the totality of subtype B infections world-wide. The Amazonian HIV-1 epidemic provides a unique scenario to compare the epidemic potential of BPAN and BCAR clades spreading in the same population. To reconstruct the spatiotemporal dynamic and demographic history of both subtype B lineages circulating in Amazonas, we analyzed 1,272 HIV-1 pol sequences sampled in that state between 2009 and 2018. Our phylogeographic analyses revealed that while most BCAR infections resulted from a single successful founder event that took place in the Amazonas state around the late 1970s, most BPAN infections resulted from the expansion of multiple clusters seeded in the state since the late 1980s. Our data support the existence of at least four large clusters of the pandemic form in Amazonas, two of them nested in Brazil’s largest known subtype B cluster (BBR–I), and two others resulting from new introductions detected here. The reconstruction of the demographic history of the most prevalent BPAN (n = 4) and BCAR (n = 1) clades identified in Amazonas revealed that all clades displayed a continuous expansion [effective reproductive number (Re) > 1] until most recent times. During the period of co-circulation from the late 1990s onward, the Re of Amazonian BPAN and BCAR clusters behaved quite alike, fluctuating between 2.0 and 3.0. These findings support that the BCAR and BPAN variants circulating in the Brazilian state of Amazonas displayed different evolutionary histories, but similar epidemic trajectories and transmissibility over the last two decades, which is consistent with the notion that both subtype B variants display comparable epidemic potential. Our findings also revealed that despite significant advances in the treatment of HIV infections in the Amazonas state, BCAR and BPAN variants continue to expand and show no signs of the epidemic stabilization observed in other parts of the country.

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Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Dissemination Dynamics of HIV-1 Subtype B Pandemic and Non-pandemic Lineages Circulating in Amazonas, Brazil

et al. 2022

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“…The mean viral load upon TL + D failure was 3.61 log10 copies/mL for individuals with no INRAMs, compared to 3.62 log 10 copies/mL among individuals with any INRAM. The difference between presence or absence of an integrase INRAM is not statistically signi cant (Wilcoxon rank-sum test, W = 790.5, p = 0.514).…”

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confidence: 91%

“…Starting in January 2017, the recommended rst-line regimen in Brazil is the xed-dose combination of generic tenofovir 300 mg plus lamivudine 300 mg, associated with 50 mg of the INSTI dolutegravir (DTG), a regimen known as TL + D. DTG is a second-generation INSTI with a high genetic barrier and few drug-drug interactions [8,9]. In addition, in clinical trials and large-scale public health rollout programs, mutations in the integrase gene associated with antiretroviral resistance have rarely been described after virologic failure to rst line DTG-containing regimens [2,9,10].…”

Section: Introductionmentioning

confidence: 99%

Dolutegravir-Associated Resistance Mutations after first-line treatment failure in Brazil

Diaz

Hunter

Camargo

et al. 2022

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Background: Since January 2017, the recommended first-line antiretroviral regimen in Brazil is the fixed-dose combination of tenofovir plus lamivudine, with dolutegravir (TL+D). According to the literature, integrase resistance-associated mutations (INRAMs) are rarely found upon virologic failure to first-line dolutegravir plus two nucleoside reverse transcriptase inhibitors. Methods: HIV Sanger sequences of the pol gene were generated from plasma of patients with confirmed virologic failure to first-line TL+D in the Brazilian public health system before December 31, 2018. Results: 113 individuals were included in the analysis. Major INRAMs were detected in six patients (5.31%), four with R263K, one with G118R, one with E138A. Four patients with major INRAMs also had the K70E and M184V mutations in the RT gene. 16(14.2%) additional individuals presented minor INRAMs, and three (2.7%) patients had both major and minor INRAMS. 13 (11.5%) patients also presented mutations in the RT gene selected by tenofovir and lamivudine, including four with both the K70E and M184V mutations and four with only M184V. The polymorphic integrase mutations L101I and T124A, which are in the in vitro pathway for integrase inhibitor resistance, were found in 48 and 19 patients respectively. Mutations not related to TL+D, thus probable transmitted resistance mutations (TDR), were present in 28 patients (24.8%): 25 (22.1%) to nucleoside reverse transcriptase inhibitors, 19 (16.8%) to non-nucleoside reverse transcriptase inhibitors, and 6 (5.31%) to protease inhibitors. Conclusions: In marked contrast to previous reports, we report a relatively high frequency of INRAMs among selected patients failing first-line TL+D in the public health system in Brazil. Possible reasons for this discrepancy include delays in detecting virologic failure, patients inadvertently on dolutegravir monotherapy, TDR, and/or infecting subtype.

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“…Starting in January 2017, the recommended first-line regimen in Brazil is the fixed-dose combination of generic tenofovir 300 mg plus lamivudine 300 mg, associated with 50 mg of the INSTI dolutegravir (DTG), a regimen known as TL + D. DTG is a second-generation INSTI with a high genetic barrier to resistance and few drug-drug interactions [ 8 , 9 ]. In addition, in clinical trials and large-scale public health rollout programs, mutations in the integrase gene associated with antiretroviral resistance have rarely been described after virologic failure to first-line DTG-containing regimens [ 2 , 9 , 10 ].…”

Section: Introductionmentioning

confidence: 99%

Dolutegravir-associated resistance mutations after first-line treatment failure in Brazil

et al. 2023

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Background Since January 2017, the recommended first-line antiretroviral regimen in Brazil is the fixed-dose combination of tenofovir plus lamivudine with dolutegravir (TL + D). According to the literature, integrase resistance-associated mutations (INRAMs) are rarely found upon virologic failure to first-line dolutegravir plus two nucleoside reverse transcriptase inhibitors. We evaluated the HIV antiretroviral genotypic resistance profile of patients referred for genotyping in the public health system who failed first-line TL + D after at least six months of therapy on or before December 31, 2018. Methods HIV Sanger sequences of the pol gene were generated from plasma of patients with confirmed virologic failure to first-line TL + D in the Brazilian public health system before December 31, 2018. Results One hundred thirteen individuals were included in the analysis. Major INRAMs were detected in seven patients (6.19%), four with R263K, one with G118R, one with E138A, and one with G140R. Four patients with major INRAMs also had the K70E and M184V mutations in the RT gene. Sixteen (14.2%) additional individuals presented minor INRAMs, and five (4,42%) patients had both major and minor INRAMS. Thirteen (11.5%) patients also presented mutations in the RT gene selected by tenofovir and lamivudine, including four with both the K70E and M184V mutations and four with only M184V. The integrase mutations L101I and T124A, which are in the in vitro pathway for integrase inhibitor resistance, were found in 48 and 19 patients, respectively. Mutations not related to TL + D, thus probable transmitted resistance mutations (TDR), were present in 28 patients (24.8%): 25 (22.1%) to nucleoside reverse transcriptase inhibitors, 19 (16.8%) to non-nucleoside reverse transcriptase inhibitors, and 6 (5.31%) to protease inhibitors. Conclusions In marked contrast to previous reports, we report a relatively high frequency of INRAMs among selected patients failing first-line TL + D in the public health system in Brazil. Possible reasons for this discrepancy include delays in detecting virologic failure, patients inadvertently on dolutegravir monotherapy, TDR, and/or infecting subtype.

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High Detection Rate of HIV Drug Resistance Mutations among Patients Who Fail Combined Antiretroviral Therapy in Manaus, Brazil

Cited by 3 publications

References 52 publications

Dissemination Dynamics of HIV-1 Subtype B Pandemic and Non-pandemic Lineages Circulating in Amazonas, Brazil

Dissemination Dynamics of HIV-1 Subtype B Pandemic and Non-pandemic Lineages Circulating in Amazonas, Brazil

Dolutegravir-Associated Resistance Mutations after first-line treatment failure in Brazil

Dolutegravir-associated resistance mutations after first-line treatment failure in Brazil

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