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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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Infecções por HIV , Inibidores da Transcriptase Reversa , Humanos , Brasil , Inibidores da Transcriptase Reversa/farmacologia , Inibidores da Transcriptase Reversa/uso terapêutico , Lamivudina/farmacologia , Lamivudina/uso terapêutico , Mutação , Antirretrovirais , Tenofovir , Falha de Tratamento , Infecções por HIV/tratamento farmacológicoRESUMO
This study describes human immunodeficiency virus 1 (HIV-1) prevalence, associated factors, viral genetic diversity, transmitted drug resistance (TDR), and acquired drug resistance mutations (DRM) among a population of 522 men who have sex with men (MSM) recruited by the respondent-driven sampling (RDS) method, in Goiânia city, the capital of the State of Goiás, Central-Western Brazil. All serum samples were tested using a four-generation enzyme-linked immunosorbent assay (ELISA), and reactive samples were confirmed by immunoblotting. Plasma RNA or proviral DNA was extracted, and partial polymerase (pol) gene including the protease/reverse transcriptase (PR/RT) region was amplified and sequenced. HIV-1 subtypes were identified by phylogenetic inference and by bootscan analysis. The time and location of the ancestral strains that originated the transmission clusters were estimated by a Bayesian phylogeographic approach. TDR and DRM were identified using the Stanford databases. Overall, HIV-1 prevalence was 17.6% (95% CI: 12.6-23.5). Self-declared black skin color, receptive anal intercourse, sex with drug user partner, and history of sexually transmitted infections were factors associated with HIV-1 infection. Of 105 HIV-1-positive samples, 78 (74.3%) were sequenced and subtyped as B (65.4%), F1 (20.5%), C (3.8%), and BF1 (10.3%). Most HIV-1 subtype B sequences (67%; 34 out of 51) branched within 12 monophyletic clusters of variable sizes, which probably arose in the State of Goiás between the 1980s and 2010s. Most subtype F1 sequences (n = 14, 88%) branched in a single monophyletic cluster that probably arose in Goiás around the late 1990s. Among 78 samples sequenced, three were from patients under antiretroviral therapy (ART); two presented DRM. Among 75 ART-naïve patients, TDR was identified in 13 (17.3%; CI 95%: 9.6-27.8). Resistance mutations to non-nucleoside reverse transcriptase inhibitors (NNRTI) predominated (14.7%), followed by nucleoside reverse transcriptase inhibitor (NRTI) mutations (5.3%) and protease inhibitor (PI) mutations (1.3%). This study shows a high prevalence of HIV-1 associated with sexual risk behaviors, high rate of TDR, and high genetic diversity driven by the local expansion of different subtype B and F1 strains. These findings can contribute to the understanding about the dissemination and epidemiological and molecular characteristics of HIV-1 among the population of MSM living away from the epicenter of epidemics in Brazil.
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We aimed to characterize HIV-1 molecular epidemiology and transmission clusters among heterosexual (HET) and men who have sex with men (MSM) individuals, as well as transmitted drug resistance mutations (TDRM) in Central-Western Brazil. This cross-sectional survey was conducted among 190 antiretroviral naïve HIV-1 infected individuals. Proviral DNA was extracted, and nested PCR amplified partial polymerase gene (PR/RT). After sequencing, subtypes were assigned, and the sequences were analyzed for the occurrence of possible transmission networks. Calibrated Population Resistance (CPR) tool from Stanford HIV Database was used to investigate the presence of TDRM. Among 150 individuals whose samples were successfully sequenced, the most prevalent HIV-1 subtype was B, followed by recombinant forms. The occurrence of twenty transmission clusters composed by at least two sequences was verified, suggesting the existence of transmission clusters among individuals from the same or distinct sexual orientations. Intermediate level of TDRM (12%) was found in the study population, and almost half of the subjects with TDRM had more than one resistance mutation. No correlations between sexual orientation and the presence of TDRM, HIV-1 subtypes/recombinants forms were verified. Taken together, the necessity of the continuous monitoring of the TDRM to verify the importance of pre-genotyping and to delineate future strategies in primary antiretroviral therapy. Likewise, the knowledge of the HIV-1 transmission networks in Brazil would allow the implementation of effective HIV-1 prevention strategies in local settings.
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ABSTRACT Itajaí is a port city in southern Brazil with one of the highest incidence and mortality rates from AIDS in the country. The prevalence and incidence of HIV infection were investigated in 1085 of 3196 new HIV-1 infection cases evaluated in the counseling and testing center of Itajaí from January 2002 to August 2008. Recent infections were assessed using the BED(tm), and polregion sequencing was performed in 76 samples. The prevalence ranged from 3.08% to 6.17% among women and from 10.26% to 17.36% among men. A total of 17% of infections were classified as recent, with annual incidence varying from 1.6% to 4.8 per 100 patient/year among women and from 2.05% to 8.5 per 100 patient/year among men. Pol sequences were obtained from 38 randomly recent infections selected individuals: 71% were infected by subtype C, 24% B, 2% D, and 2% F1. Among 38 subjects with established infection, 76% were subtype C, and 24% B. Transmitted drug resistance was detected in 18.4% of recent infection subjects (7.8% to nucleoside analog reverse-transcriptase inhibitors, 5.2% to non-nucleoside reverse-transcriptase inhibitors, and 5.2% protease inhibitors) and 5.2% of subjects with established infection had nucleoside analog reverse-transcriptase inhibitors resistance. The high prevalence and incidence of HIV infection in this region is unprecedented in studies involving cases evaluated in the counseling and testing centers in Brazil.
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Adolescente , Adulto , Idoso , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Masculino , Pessoa de Meia-Idade , Aconselhamento/estatística & dados numéricos , Infecções por HIV/epidemiologia , Distribuição por Idade , Brasil/epidemiologia , Genótipo , HIV-1 , Incidência , Prevalência , Estudos Retrospectivos , Distribuição por SexoRESUMO
Itajaí is a port city in southern Brazil with one of the highest incidence and mortality rates from AIDS in the country. The prevalence and incidence of HIV infection were investigated in 1085 of 3196 new HIV-1 infection cases evaluated in the counseling and testing center of Itajaí from January 2002 to August 2008. Recent infections were assessed using the BED™, and pol region sequencing was performed in 76 samples. The prevalence ranged from 3.08% to 6.17% among women and from 10.26% to 17.36% among men. A total of 17% of infections were classified as recent, with annual incidence varying from 1.6% to 4.8 per 100 patient/year among women and from 2.05% to 8.5 per 100 patient/year among men. Pol sequences were obtained from 38 randomly recent infections selected individuals: 71% were infected by subtype C, 24% B, 2% D, and 2% F1. Among 38 subjects with established infection, 76% were subtype C, and 24% B. Transmitted drug resistance was detected in 18.4% of recent infection subjects (7.8% to nucleoside analog reverse-transcriptase inhibitors, 5.2% to non-nucleoside reverse-transcriptase inhibitors, and 5.2% protease inhibitors) and 5.2% of subjects with established infection had nucleoside analog reverse-transcriptase inhibitors resistance. The high prevalence and incidence of HIV infection in this region is unprecedented in studies involving cases evaluated in the counseling and testing centers in Brazil.
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Aconselhamento/estatística & dados numéricos , Infecções por HIV/epidemiologia , Adolescente , Adulto , Distribuição por Idade , Idoso , Brasil/epidemiologia , Criança , Pré-Escolar , Feminino , Genótipo , HIV-1 , Humanos , Incidência , Lactente , Masculino , Pessoa de Meia-Idade , Prevalência , Estudos Retrospectivos , Distribuição por SexoRESUMO
HIV-1 transmitted-drug-resistance and genetic diversity are dynamic and may differ in distinct locations/risk groups. In Brazil, increased AIDS incidence and related mortality have been detected in the Northeast region, differently from the epicenter in the Southeast. This cross-sectional study describes transmitted-dru- resistance and HIV-1 subtypes in protease/PR and reverse transcriptase/RT regions among antiretroviral naïve patients from Piauí State, Northeast Brazil. Among 96 patients recruited 89 (92.7%) had HIV-1 PR/RT regions sequenced: 44 females and 45 males, 22 self-declared as men who have sex with men. Transmitted-drug-resistance was investigated by CPR tool (Stanford HIV-1 Drug Resistance/SDRM). HIV-1 subtypes were assigned by REGA and phylogenetic inference. Overall, transmitted-drug-resistance rate was 11.2% (10/89; CI 95%: 5.8-19.1%); 22.7% among men who have sex with men (5/22; CI 95%: 8.8-43.4%), 10% in heterosexual men (2/20; CI 95%: 1.7-29.3%) and 6.8% in women (3/44; CI 95%: 1.8-17.4%). Singleton mutations to protease-inhibitor/PI, nucleoside-reverse-transcriptase-inhibitor/NRTI or non-nucleoside-reverse-transcriptase-inhibitor/NNRTI predominated (8/10): PI mutations (M46L, V82F, L90M); NRTI mutations (M41L, D67N) and NNRTI mutations (K103N/S). Dual class resistance mutations to NRTI and NNRTI were observed: T215L (NRTI), Y188L (NNRTI) and T215N (NRTI), F227L (NNRTI). Subtype B prevailed (86.6%; 77/89), followed by subtype F1 (1.1%, 1/89) and subtype C (1.1%, 1/89). B/F1 and B/C intersubtype recombinants represented 11.2% (10/89). In Piauí State extensive testing of incidence and transmitted-drug-resistance in all populations with risk behaviors may help control AIDS epidemic locally.
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Transmissão de Doença Infecciosa , Farmacorresistência Viral , Variação Genética , Infecções por HIV/transmissão , Infecções por HIV/virologia , HIV-1/efeitos dos fármacos , HIV-1/genética , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Brasil/epidemiologia , Estudos Transversais , Feminino , Genótipo , Infecções por HIV/epidemiologia , Protease de HIV/genética , Transcriptase Reversa do HIV/genética , HIV-1/isolamento & purificação , Humanos , Masculino , Pessoa de Meia-Idade , Mutação de Sentido Incorreto , Filogenia , Prevalência , Análise de Sequência de DNA , Adulto JovemRESUMO
INTRODUCTION: In Brazil, the use of antiretrovirals is widespread: more than 260,000 individuals are currently undergoing treatment. We conducted a survey targeting antiretroviral-naïve individuals who were initiating antiretroviral therapy (ART) according to local guidelines. This survey covered five Brazilian regions. METHODS: The HIV Threshold Survey methodology (HIV-THS) of the World Health Organization was utilized, and subjects were selected from seven highly populated cities representative of all Brazilian macro-regions. Dried blood spots (DBS) were collected on SS903 collection cards and were transported by regular mail at room temperature to a single central laboratory for genotyping. RESULTS: We analysed samples from 329 individuals initiating highly active antiretroviral therapy (HAART), 39 (11.8%) of whom were harbouring transmitted drug resistance (TDR). The mean CD4+ T cell count was 253 cells/µL, and the mean viral load was 142,044 copies/mL. The regional prevalence of resistance was 17.0% in the Northeast, 12.8% in the Southeast, 10.6% in the Central region, 8.5% in the North and 8.5% in the South. The inhibitor-specific TDR prevalence was 6.9% for nucleoside reverse transcriptase inhibitors, 4.9% for non-nucleoside reverse transcriptase inhibitors and 3.9% for protease inhibitors; 3.6% of individuals presented resistance to more than one class of inhibitors. Overall, there were trends towards higher prevalences of subtype C towards the South and subtype F towards the North. Of the DBS samples collected, 9.3% failed to provide reliable results. DISCUSSION: We identified variable TDR prevalence, ranging from intermediate to high levels, among individuals in whom HIV disease progressed, thus implying that resistance testing before initiating ART could be effective in Brazil. Our results also indicate that the use of DBS might be especially valuable for providing access to testing in resource-limited and remote settings.
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Farmacorresistência Viral , Infecções por HIV/virologia , HIV-1/efeitos dos fármacos , HIV-1/genética , Adolescente , Adulto , Idoso , Sangue/virologia , Brasil , DNA Viral/genética , Dessecação/métodos , Feminino , Genótipo , Técnicas de Genotipagem , Infecções por HIV/epidemiologia , HIV-1/isolamento & purificação , Humanos , Masculino , Pessoa de Meia-Idade , Prevalência , Manejo de Espécimes/métodos , Adulto JovemRESUMO
El Salvador harbours one of the largest Central American human immunodeficiency virus (HIV) epidemics, but few studies have analysed it in depth. Here, we describe the presence of transmitted drug resistance (TDR) and HIV variants in the HIV-infected adult population in El Salvador. Dried blood spots from 119 HIV-infected antiretroviral-naive adults attended in El Salvador were collected in 2011. The TDR was assessed according to the list recommended by the WHO. HIV-1 variants were described using phylogeny. Pol sequences could be amplified in 88 patients (50.6% men), with a mean age of 35 years. Almost all (96.7%) were infected with HIV through sexual practice and 58.7% were recently diagnosed. The mean CD4(+) count was 474 cells/mm(3) and 43.1% and 15.5% of patients showed moderate (<500 CD4 cells) or severe (<200) immune suppression, respectively. HIV-1 viral load was >100 000 copies/mL in 24.7% of patients and <2000 copies/mL in 9.1%. Five samples (5.7%) harboured any TDR mutation: 2.3% for nucleoside reverse transcriptase inhibitor (NRTI) and non-nucleoside reverse transcriptase inhibitor (NNRTI), and 1.4% for protease inhibitor (PI). All showed only one TDR single-class resistance mutation: M184I (two cases) for NRTI, K101E and K103N for NNRTI and L23I for PI. All viruses excepting one (URF_BG) belonged to subtype B. No phylogenetic TDR networks were found. In conclusion, we report a TDR prevalence of 5.7% in El Salvador, lower than in other Central American studies. Periodical studies are essential to monitor and prevent TDR emergence in low-income and middle-income regions. Also, more efforts are needed to promote early diagnosis and prevention of infection in El Salvador.
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Farmacorresistência Viral/genética , Infecções por HIV/epidemiologia , Infecções por HIV/transmissão , HIV-1/genética , Produtos do Gene pol do Vírus da Imunodeficiência Humana/genética , Adolescente , Adulto , Idoso , Fármacos Anti-HIV/uso terapêutico , Estudos de Coortes , Teste em Amostras de Sangue Seco , El Salvador/epidemiologia , Feminino , Variação Genética , Infecções por HIV/tratamento farmacológico , Infecções por HIV/virologia , HIV-1/imunologia , Humanos , Lamivudina/uso terapêutico , Masculino , Pessoa de Meia-Idade , Dados de Sequência Molecular , Filogenia , Pobreza/prevenção & controle , Adulto JovemRESUMO
The presence of transmitted human immunodeficiency virus (HIV)-1 drug-resistance (TDR) at the time of antiretroviral therapy initiation is associated with failure to achieve viral load (VL) suppression. Here, we report TDR surveillance in a specific population of men who have sex with men (MSM) in Belo Horizonte, Brazil. In this study, the rate of TDR was evaluated in 64 HIV-infected individuals from a cohort of MSM between 1996-June 2012. Fifty-four percent had a documented recent HIV infection, with a seroconversion time of less than 12 months. The median CD4+T lymphocyte count and VL were 531 cells/mm3and 17,746 copies/mL, respectively. Considering the surveillance drug resistance mutation criteria, nine (14.1%) patients presented TDR, of which three (4.7%), five (7.8%) and four (6.2%) had protease inhibitors, resistant against nucleos(t)ide transcriptase inhibitors and against non-nucleoside reverse-transcriptase inhibitors mutations, respectively. Two of the patients had multi-drug-resistant HIV-1. The most prevalent viral subtype was B (44, 68.8%), followed by subtype F (11, 17.2%). This study shows that TDR may vary according to the population studied and it may be higher in clusters of MSM.