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1.
Pan Afr Med J ; 33: 222, 2019.
Artigo em Francês | MEDLINE | ID: mdl-31692792

RESUMO

Introduction: HIV-2, endemic in West Africa, has a natural resistance to non-nucleoside reverse transcriptase inhibitors (NNRTIs) which makes it difficult to treat it in developing countries. Methods: We conducted a descriptive, longitudinal, prospective study over the period November 2005-June 2017. Virologic failure has been defined as any viral load greater than 50 copies/ml after 6 months of ARV treatment administered twice. Assays for detecting drug-resistance mutations was performed in the protease-coding region and in the reverse transcriptase-coding region. Results: Data from a total of 110 patients were collected. The patients had a median age of 46 years (ranging from 18 to 67) with a sex-ratio F/M of 2.54. At inclusion, viral load could be assessed in 44% of cases with a median of 935cp/ml (ranging from 17 to 144038). Antiretroviral regimen consisted of a combination of 2 NRTIs and 1IP in 94% of cases. The median follow-up was 1200 days (ranging from 1 to 3840); 94 then 76 patients completed their 12-month and 24-month assessments respectively. At 24-month follow-up, 39 patients had virologic failure, reflecting a prevalence of 39% estimated at 33% at 12-month follow-up and at 11% at 24-month follow-up; NRTIs resistance was observed in 45% of patients, IP resistance in 41% of patients while multi-NRTIs resistance and multi-IP resistance in 30% of patients. Conclusion: Currently, there is an urgent need to make available the new therapeutic classes of ARV for second line ART for patients living with HIV-2 with therapeutic failure in resource-limited settings.


Assuntos
Infecções por HIV/tratamento farmacológico , Inibidores da Protease de HIV/administração & dosagem , HIV-2/isolamento & purificação , Inibidores da Transcriptase Reversa/administração & dosagem , Adolescente , Adulto , Idoso , Farmacorresistência Viral/genética , Quimioterapia Combinada , Feminino , Seguimentos , Infecções por HIV/epidemiologia , Infecções por HIV/virologia , Inibidores da Protease de HIV/farmacologia , HIV-2/efeitos dos fármacos , HIV-2/genética , Humanos , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Inibidores da Transcriptase Reversa/farmacologia , Senegal/epidemiologia , Carga Viral , Adulto Jovem
2.
Medicine (Baltimore) ; 98(43): e17585, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31651864

RESUMO

This study sought to examine the human immunodeficiency virus type 1 (HIV-1) genetic diversity on drug resistance among men who have sex with men (MSM) with virologic failure in antiretroviral therapy (ART), and investigate linking-associated factors for genetic transmission networks.Seven hundred and thirty-four HIV-positive MSM with virologic failure in ART were recruited into our study from 2011 to 2017. HIV-1 pol gene sequences were used for phylogenetic and genotypic drug resistance analyses. The drug resistance mutations were determined using the Stanford University HIV Drug Resistance Database. The genetic transmission networks were analyzed for CRF01_AE and CRF07_BC sequences by the genetic distance-based method.Of 734 subjects, 372 (50.68%) showed drug resistance, in which CRF01_AE and CRF07_BC were the predominating subtypes. Drug resistance more frequently occurred in non-nucleoside reverse transcriptase inhibitors (NNRTIs) treatment (48.64%), and followed by nucleoside reverse transcriptase inhibitors (NRTIs) (36.51%) and PIs (4.03%). The most common drug resistance-associated mutations in protease inhibitors (PIs), NRTIs and NNRTIs were K20I/R, M184V/I and K103N/KN, respectively. For 283CRF01_AE sequences, 64 (22.61%) fell into clusters at a genetic distance of 0.011, resulting in 17 clusters ranging in size from 2 to 16 individuals. For 230 CRF07_BC sequences, 66 (28.69%) were connected to at least one other sequence with 0.005 genetic distances, resulting in 8 clusters ranging in size from 2 to 52 individuals. Individuals who showed drug resistance to ART were less likely to fall into clusters than those who did not. The genetic linkage was robust by the exclusion of sites associated with drug resistance.CRF01_AE and CRF07_BC were the main strains among MSM with virologic failure in ART, and the drug resistance more frequently occurred in NNRTIs, followed by NRTIs and PIs. Genetic transmission networks revealed a complexity of transmission pattern, suggesting early-diagnosis and in-time intervention among MSM.


Assuntos
Fármacos Anti-HIV/efeitos adversos , Farmacorresistência Viral/genética , Infecções por HIV/tratamento farmacológico , HIV-1/genética , Inibidores da Transcriptase Reversa/efeitos adversos , Adolescente , Adulto , China , Homossexualidade Masculina , Humanos , Masculino , Minorias Sexuais e de Gênero/estatística & dados numéricos , Falha de Tratamento , Adulto Jovem
3.
Zhonghua Liu Xing Bing Xue Za Zhi ; 40(8): 982-987, 2019 Aug 10.
Artigo em Chinês | MEDLINE | ID: mdl-31484265

RESUMO

Objective: To understand the distribution of HIV-1 genotypes and the status of drug resistance among people living with HIV who had prepared to initiate antiretroviral therapy (ART) in Dehong Dai and Jingpo autonomous prefecture (Dehong). Methods: A total of 170 adults with HIV were recruited in Dehong from January to June 2017, before initiating ART. HIV-1 pol genes were amplified and used to analyze the HIV-1 genotypes and drug resistance. Results: A total of 147 samples were successfully sequenced. Based on the phylogenetic analysis, 12 HIV-1 genotypes were found among the subjects, including three predominant genotypes such as subtype C (29.9%, 44/147), unique recombinant forms (URFs) (27.2%, 40/147) and CRF01_AE (19.7%, 29/147). Circulating recombinant forms (CRFs) which were newly identified in this area in recent years were also found among these subjects, including CRF62_BC, CRF64_BC, CRF86_BC and CRF96_cpx. The distribution of HIV-1 genotypes between heterosexual transmission or intravenous drug use, showed statistical difference. Surveillance drug resistance mutations (SDRMs) were found among 8.8% (13/147) of the subjects. Proportion of drug resistant strains among injecting drug users (25.0%, 8/32) was higher than that among those heterosexual transmitted individuals (4.6%, 5/109, χ(2)=10.166, P=0.002). Conclusions: Among people living with HIV-1 who had prepared to initiate ART, their HIV-1 genetics were highly complicated, with moderate prevalence rate of HIV-1 drug-resistant strains.


Assuntos
Fármacos Anti-HIV/uso terapêutico , Farmacorresistência Viral/genética , Infecções por HIV/tratamento farmacológico , Infecções por HIV/virologia , HIV-1/genética , Adulto , Análise do Polimorfismo de Comprimento de Fragmentos Amplificados , Fármacos Anti-HIV/farmacologia , Terapia Antirretroviral de Alta Atividade , China/epidemiologia , Genes pol , Genótipo , Infecções por HIV/epidemiologia , HIV-1/efeitos dos fármacos , Humanos , Filogenia
4.
BMC Bioinformatics ; 20(1): 410, 2019 Jul 30.
Artigo em Inglês | MEDLINE | ID: mdl-31362714

RESUMO

BACKGROUND: Antiretroviral drugs are a very effective therapy against HIV infection. However, the high mutation rate of HIV permits the emergence of variants that can be resistant to the drug treatment. Predicting drug resistance to previously unobserved variants is therefore very important for an optimum medical treatment. In this paper, we propose the use of weighted categorical kernel functions to predict drug resistance from virus sequence data. These kernel functions are very simple to implement and are able to take into account HIV data particularities, such as allele mixtures, and to weigh the different importance of each protein residue, as it is known that not all positions contribute equally to the resistance. RESULTS: We analyzed 21 drugs of four classes: protease inhibitors (PI), integrase inhibitors (INI), nucleoside reverse transcriptase inhibitors (NRTI) and non-nucleoside reverse transcriptase inhibitors (NNRTI). We compared two categorical kernel functions, Overlap and Jaccard, against two well-known noncategorical kernel functions (Linear and RBF) and Random Forest (RF). Weighted versions of these kernels were also considered, where the weights were obtained from the RF decrease in node impurity. The Jaccard kernel was the best method, either in its weighted or unweighted form, for 20 out of the 21 drugs. CONCLUSIONS: Results show that kernels that take into account both the categorical nature of the data and the presence of mixtures consistently result in the best prediction model. The advantage of including weights depended on the protein targeted by the drug. In the case of reverse transcriptase, weights based in the relative importance of each position clearly increased the prediction performance, while the improvement in the protease was much smaller. This seems to be related to the distribution of weights, as measured by the Gini index. All methods described, together with documentation and examples, are freely available at https://bitbucket.org/elies_ramon/catkern.


Assuntos
Algoritmos , Biologia Computacional/métodos , Farmacorresistência Viral/genética , HIV-1/genética , Fármacos Anti-HIV/farmacologia , Farmacorresistência Viral/efeitos dos fármacos , Infecções por HIV/virologia , HIV-1/efeitos dos fármacos , HIV-1/isolamento & purificação , Humanos , Modelos Lineares , Análise de Componente Principal
5.
BMC Infect Dis ; 19(1): 741, 2019 Aug 23.
Artigo em Inglês | MEDLINE | ID: mdl-31443633

RESUMO

BACKGROUND: The use of fixed combination antiretroviral therapy with a low genetic barrier for the treatment of patients infected with human immunodeficiency virus (HIV) may affect the local HIV transmitted drug resistance (TDR) pattern. The present study aimed to investigate changes in the prevalence of HIV TDR following the implementation of a fixed regimen of HIV treatment in Taiwan in 2012. METHODS: TDR was measured in antiretroviral treatment-naïve HIV-1-infected individuals who participated in voluntary counseling and testing between 2007 and 2015 in southern Taiwan. Antiretroviral resistance mutations were interpreted using the HIVdb program from the Stanford University HIV Drug Resistance Database. RESULTS: Sequences were obtained from 377 consecutive individuals between 2007 and 2015. The overall prevalence rates of TDR HIV among the study population from 2007 to 2011 and 2012-2015 were 10.6 and 7.9%, respectively. Among the detected mutations, K103 N and V179D + K103R were more frequently observed after 2012. Four HIV-infected patients with K103 N variants were detected after 2012, and 4 of the 5 patients with V179D + K103R variants were found after 2012. No significant differences were observed in the TDRs among nucleoside reverse transcriptase inhibitors (NRTIs), non-NRTIs (NNRTIs), protease inhibitors, multiple drug resistance, and any drug resistance between period 1 (2007-2011) and period 2 (2012-2015). CONCLUSIONS: A fixed treatment regimen with zidovudine/lamivudine + efavirenz or nevirapine as first-line therapy for treatment-naïve patients infected with HIV did not significantly increase the TDR during the 4-year follow-up period. Due to the increase in NNRTI resistance associated with mutations after 2012, a longer follow-up period and larger sample size are needed in future studies.


Assuntos
Farmacorresistência Viral/genética , Infecções por HIV/tratamento farmacológico , HIV-1/efeitos dos fármacos , HIV-1/genética , Mutação , Adulto , Fármacos Anti-HIV/uso terapêutico , Terapia Antirretroviral de Alta Atividade , Benzoxazinas/uso terapêutico , Combinação de Medicamentos , Farmacorresistência Viral/efeitos dos fármacos , Feminino , Infecções por HIV/epidemiologia , Infecções por HIV/virologia , Humanos , Lamivudina/uso terapêutico , Masculino , Nevirapina/uso terapêutico , Prevalência , Inibidores da Transcriptase Reversa/uso terapêutico , Taiwan/epidemiologia , Zidovudina/uso terapêutico
7.
BMC Infect Dis ; 19(1): 601, 2019 Jul 10.
Artigo em Inglês | MEDLINE | ID: mdl-31291899

RESUMO

BACKGROUND: Despite effective antiretroviral therapy developed over the last decade, HIV infection remains a major worldwide public health problem. Recently, a promising preventive treatment has been made available for HIV prophylaxis, PrEP for pre-ExPosure Prophylaxis. Indeed, it was shown to significantly reduce the risk of HIV infection in patients exposed to high risk of infection such as men having sex with men (MSM), heterosexuals and people who inject drugs. Several issues pertaining to PrEP remain uncertain including short and long-term adverse events, drug resistance, risk compensation and resurgence of other sexually transmitted infections. CASE PRESENTATION: We report a case of a 52-year-old MSM eligible for PrEP as he was exposed to a high risk of HIV infection, presented no clinical symptoms of HIV primary infection and was seronegative for HIV. PrEP therapy was then initiated with fixed association of emtricitabine-tenofovir disoproxil. One month later, HIV tests using two different assays were positive, despite perfect compliance reported by the patient and confirmed by plasma drug level. A retrospective search for plasma viral RNA in the blood sample before PrEP initiation turned out positive. Genotyping and treatment sensitivity performed on sample after one month of PrEP showed a virus resistance to lamivudine and emtricitabine. Similar cases in the literature and pivotal studies have reported HIV infections in patients initiating or undergoing PrEP. These patients where either infected but still seronegative, displaying no clinical symptoms upon enrollment, or became infected during PrEP. Reasons are mainly poor compliance to treatment, resistance to PrEP, and lack of diagnosis before PrEP. Guidelines advocate safe sex behavior before initiation, search for clinical signs of HIV primary infection and two different serologic tests performed with one-month interval. DISCUSSION AND CONCLUSIONS: Our patient newly HIV infected received PrEP as he was still seronegative. Current recommendations fail to screen recently HIV infected, but still seronegative patients who are initiating PrEP. This issue raises strong concerns regarding the lack of adequate selection for eligibility to PrEP and may contribute to exposing partners to HIV infection and select viral mutations. Infection risk could be minimized by search for plasma viral HIV RNA at pre-inclusion, at least for patients suspected of unsafe behaviors such as non-respect of the non-exposure period before PrEP initiation.


Assuntos
Fármacos Anti-HIV/uso terapêutico , Infecções por HIV/prevenção & controle , Guias de Prática Clínica como Assunto/normas , Profilaxia Pré-Exposição/normas , Fármacos Anti-HIV/efeitos adversos , Fármacos Anti-HIV/farmacologia , Farmacorresistência Viral/efeitos dos fármacos , Farmacorresistência Viral/genética , Infecções por HIV/sangue , Infecções por HIV/diagnóstico , Homossexualidade Masculina , Humanos , Masculino , Pessoa de Meia-Idade , RNA Viral/sangue , RNA Viral/genética
8.
Virol J ; 16(1): 87, 2019 07 02.
Artigo em Inglês | MEDLINE | ID: mdl-31266524

RESUMO

BACKGROUND: Human infection with avian influenza H7N9 virus was first reported in 2013. Since the fifth epidemic, a highly pathogenic avian influenza (HPAI) H7N9 virus has emerged and caused 33 human infections. Several potential NAI resistance sites have been found in human cases. However, the drug susceptibility and replication ability of HPAI H7N9 virus with such substitutions have not yet been studied. METHODS: Thirty-three HPAI H7N9 virus strains were isolated from human cases in China, and then sequences were analyzed to identify potential NAI resistance sites. Recombinant influenza viruses were generated to evaluate the effect of NA amino acid substitutions on NAI (oseltamivir or zanamivir) susceptibility and viral replication efficiency in MDCK cells. RESULTS: Four potential NAI resistance sites, R292 K, E119V, A246T or H274Y, were screened. All four substitutions conferred either reduced or highly reduced susceptibility to oseltamivir or zanamivir. 292 K not only highly reduced the susceptibility of HPAI H7N9 to oseltamivir but also induced an increase in the IC50 of zanamivir. 119 V or 274Y conferred reduced susceptibility of HPAI H7N9 to oseltamivir. Additionally, 246 T conferred reduced susceptibility to zanamivir. All tested NAI-resistant viruses were capable of replication in MDCK cells. The virus yields of rg006-NA292K were lower than those of rg006-NA292R at 24, 48, 72 and 96 h postinfection (P<0.05). Rg006-NA119V, rg006-NA246T or rg006-NA274Y showed comparable replication capacity to wild-type virus (except for rg006-NA274Y at 96 h, P<0.05). CONCLUSIONS: All 4 amino acid substitutions (R292 K, E119V, A246T or H274Y) in NA reduced the susceptibility of HPAI H7N9 to NAIs. The NAI-resistant mutations in HPAI H7N9, in most cases, did not reduce the replication ability of the virus in mammalian cells. Special attention needs to be paid to these mutations, and the development of new anti-H7N9 drugs is of great importance.


Assuntos
Antivirais/farmacologia , Inibidores Enzimáticos/farmacologia , Subtipo H7N9 do Vírus da Influenza A/efeitos dos fármacos , Subtipo H7N9 do Vírus da Influenza A/genética , Influenza Humana/virologia , Replicação Viral/efeitos dos fármacos , Substituição de Aminoácidos , Animais , Galinhas , Cães , Farmacorresistência Viral/genética , Humanos , Subtipo H7N9 do Vírus da Influenza A/fisiologia , Influenza Aviária , Células Madin Darby de Rim Canino , Neuraminidase/antagonistas & inibidores , Oseltamivir/farmacologia , Zanamivir/farmacologia
9.
BMC Infect Dis ; 19(1): 669, 2019 Jul 29.
Artigo em Inglês | MEDLINE | ID: mdl-31357947

RESUMO

BACKGROUND: As a gateway for HIV-1 in China, Yunnan has experienced dramatic changes in HIV-1 epidemics, during which HIV-1 genotypes have become complex. To track dynamic changes in HIV-1 genotypes, an HIV-1 molecular epidemiological study was implemented in the recently infected population in Yunnan. METHODS: From 6,357 HIV-1-positive samples diagnosed during the first half of 2015 in Yunnan, 586 samples were identified as recent infections with BED-capture enzyme immunoassay (CEIA) and were subjected to phylogenetic analyses. Spatial scanning analyses for the main HIV-1 genotypes were also performed. RESULTS: Among the 439 specimens successfully genotyped, more than ten genotypes were detected, including CRF08_BC (45.3%), CRF07_BC (19.4%), unique recombinant forms (URFs) (18.2%), CRF01_AE (11.4%), subtype C (2.1%), CRF85_BC (1.1%), CRF55_01B (0.9%), subtype B (0.5%), CRF64_BC (0.5%), CRF59_01B (0.2%), CRF83_cpx (0.2%) and CRF87_cpx (0.2%). Females, Chinese, heterosexual contact and intravenous drug injection were significantly associated with CRF08_BC infection; homosexual contact was significantly associated with CRF01_AE and CRF07_BC infection; males and non-Chinese had a higher risk of URF infection than females. Among all HIV-1 genotypes, the geographic coverage of CRF08_BC was the largest. For CRF08_BC, CRF07_BC, URFs and CRF01_AE, spatial clusters were detected. The two CRF08_BC clusters and one URF cluster were associated with heterosexual transmission, and two of CRF01_AE clusters were associated with homosexual transmission. Transmitted drug resistance (TDR)-associated mutations were detected in 2.4% of individuals. CONCLUSIONS: The diversity of HIV-1 genotypes increased in recent infections because of a long-term HIV-1 epidemic in Yunnan. The predominant HIV-1 strains showed distinct demographic characteristics and formed spatial clusters. These findings improved our understanding of the evolution of HIV-1 in Yunnan and provided information for further HIV-1 control and prevention.


Assuntos
Farmacorresistência Viral/genética , Epidemias , Variação Genética , Infecções por HIV/virologia , HIV-1/genética , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , China/epidemiologia , Feminino , Genótipo , Infecções por HIV/epidemiologia , HIV-1/classificação , Heterossexualidade , Homossexualidade , Humanos , Masculino , Pessoa de Meia-Idade , Mutação , Filogenia , Análise Espacial , Adulto Jovem
10.
BMC Infect Dis ; 19(1): 569, 2019 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-31262272

RESUMO

BACKGROUND: Antiretroviral therapy (ART) was rolled-out in Ethiopia in 2005, but there are no reports on outcome of ART and human immunodeficiency virus drug resistance (HIVDR) at national level. We described acquired drug resistance mutations in pol gene and performed a viral genome wide association study in virologic treatment failure patients who started first line ART during 2009-2011 in the first large countrywide HIV cohort in Ethiopia. METHODS: The outcome of tenofovir (TDF)- and zidovudine (ZDV)-based ART was defined in 874 ART naïve patients using the on-treatment (OT) and intention-to-treat (ITT) analyses. Genotypic resistance testing was done in patients failing ART (> 1000 copies/ml) at month 6 and 12. Near full-length genome sequencing (NFLG) was used to assess amino acid changes in HIV-1 gag, pol, vif, vpr, tat, vpu, and nef genes between paired baseline and month 6 samples. RESULTS: High failure rates were found in ITT analysis at month 6 and 12 (23.3%; 33.9% respectively). Major nucleoside and non-nucleoside reverse transcriptase (NRTI/NNRTI) drug resistance mutations were detected in most failure patients at month 6 (36/47; 77%) and month 12 (20/30; 67%). A high rate of K65R was identified only in TDF treated patients (35.7%; 50.0%, respectively). No significant difference was found in failure rate or extent of HIVDR between TDF- and ZDV- treated patients. All target regions of interest for HIVDR were described by NFLG in 16 patients tested before initiation of ART and at month 6. CONCLUSION: In this first Ethiopian national cohort, a high degree of HIVDR was seen among ART failure patients, independent on whether TDF- or ZDV was given. However, the major reason to ART failure was lost-to-follow-up rather than virologic failure. Our NFLG assay covered all relevant target genes for antiretrovirals and is an attractive alternative for HIVDR surveillance.


Assuntos
Fármacos Anti-HIV/uso terapêutico , Farmacorresistência Viral/genética , Infecções por HIV/virologia , HIV-1/genética , Mutação , Adulto , Estudos de Coortes , Farmacorresistência Viral/efeitos dos fármacos , Etiópia , Feminino , Estudo de Associação Genômica Ampla , Genótipo , Infecções por HIV/tratamento farmacológico , Integrase de HIV/genética , HIV-1/efeitos dos fármacos , Humanos , Masculino , Inibidores da Transcriptase Reversa/uso terapêutico , Tenofovir/uso terapêutico , Falha de Tratamento , Zidovudina/uso terapêutico
11.
BMC Infect Dis ; 19(1): 562, 2019 Jun 27.
Artigo em Inglês | MEDLINE | ID: mdl-31248372

RESUMO

BACKGROUND: The proportion of older HIV-1 infected people in China has increased rapidly in recent years. Elucidation of the transmission characteristics of this high-risk population subgroup is helpful for the development of tailored interventions. METHODS: A phylogenetic analysis was performed that uses available HIV-1 pol sequences amplified with nested RT-PCR from plasma samples of all newly diagnosed participants spanning from October 2017 to September 2018 in Fuyang, Anhui Province. Transmission clusters were identified as two or more sequences that shared a corresponding node with an aLRT-SH value ≥90 in the maximum-likelihood phylogenetic tree and had an overall mean genetic distance of ≤1.5%. A local transmission cluster was defined as a cluster that had more than 80% of its sequences from Fuyang. The role of older people in local HIV-1 transmission was determined using an integration of molecular and demographic data. RESULTS: Of 362 available sequences, 14 subtypes, and 28 local transmission clusters were identified. It was found that the proportion of older people in the local transmission cluster (69/77, 89.61%) was much higher than that of younger people (46/114, 40.35%) (χ2 test, P < 0.001). In the pretreatment drug resistance analysis, the proportion of sequences with PDRMs in the local transmission cluster was not significantly different between the older people group (57.14%, 4/7) and non-old-aged group (11.11%, 1/9) (Fisher's exact test, P > 0.05). CONCLUSION: By combining phylogenetic analyses with demographic data, more detailed information was provided about the local transmission structure in Fuyang. These findings suggested that older people play an important role in local transmission, and more tailored interventions for this population subgroup are urgently needed.


Assuntos
Infecções por HIV/diagnóstico , HIV-1/classificação , Adulto , Idoso , Antirretrovirais/uso terapêutico , China/epidemiologia , Farmacorresistência Viral/genética , Feminino , Genótipo , Infecções por HIV/tratamento farmacológico , Infecções por HIV/epidemiologia , Infecções por HIV/transmissão , HIV-1/genética , HIV-1/isolamento & purificação , Humanos , Masculino , Pessoa de Meia-Idade , Filogenia , Reação em Cadeia da Polimerase , RNA Viral/isolamento & purificação , RNA Viral/metabolismo
12.
Zhonghua Liu Xing Bing Xue Za Zhi ; 40(6): 648-653, 2019 Jun 10.
Artigo em Chinês | MEDLINE | ID: mdl-31238613

RESUMO

Objective: To explore HIV-1 drug resistance and influencing factors among people living with HIV/AIDS before antiretroviral therapy in Liangshan Yi Autonomous Prefecture (Liangshan). Methods: Between January 1 and June 30, in both 2017 and 2018, a cross-sectional survey was conducted in Liangshan HIV-1 pol sequences were gathered and analyzed according to WHO Guidelines on HIV drug resistance surveillance of 2014. Both HyPhy 2.2.4 and Cytoscape 3.6.1 software were used to analyze the drug resistant strains of HIV-1 transmission network. Results: A total of 464 people living with HIV/AIDS was recruited. The proportion of HIV-1 CRF07_BC subtype was 88.6% (411/464), with HIV-1 drug resistance rate was 9.9% (46/464). The HIV-1 drug resistance rates of non-nucleoside reverse transcriptase inhibitors (NNRTI), nucleoside reverse transcriptase inhibitors(NRTI) and protease inhibitors (PI) were 6.7% (31/464), 1.9% (9/464) and 0.4% (2/464) respectively. New recombinant strains of HIV-1 URF_01BC subtype was independently clustered according to the drug resistant mutation sites. Results from the multivariate logistic analysis showed that injected drug users group had higher risk on HIV-1 drug resistance (aOR=3.03, 95%CI:1.40-6.54) than heterosexual group among people living with HIV/AIDS. Conclusions: HIV-1 drug resistance rate had already been in a high level before antiretroviral therapy was in place. The newly identified recombinant strains of HIV-1 URF_01BC subtype were independently clustered according to the drug resistant mutation sites. It was necessary to strengthen the prevention of the HIV-1 drug resistant strains transmission.


Assuntos
Fármacos Anti-HIV/uso terapêutico , Farmacorresistência Viral/genética , Infecções por HIV/tratamento farmacológico , Infecções por HIV/virologia , HIV-1/efeitos dos fármacos , HIV-1/genética , China/epidemiologia , Estudos Transversais , Infecções por HIV/epidemiologia , HIV-1/isolamento & purificação , Humanos , Mutação , Análise de Sequência de DNA , Carga Viral
13.
Gastroenterology ; 157(3): 692-704.e9, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31078622

RESUMO

BACKGROUND & AIMS: Sofosbuvir is a frequently used pan-genotype inhibitor of hepatitis C virus (HCV) polymerase. This drug eliminates most chronic HCV infections, and resistance-associated substitutions in the polymerase are rare. However, HCV genotype 3 responds slightly less well to sofosbuvir-based therapies than other genotypes. We collected data from England's National Health Service Early Access Program to search for virus factors associated with sofosbuvir treatment failure. METHODS: We collected patient serum samples and used the capture-fusion assay to assess viral sensitivity to sofosbuvir in 14 HCV genotype 3 samples. We identified polymorphisms associated with reduced response and created modified forms of HCV and replicons containing the substitutions of interest and tested their sensitivity to sofosbuvir and ribavirin. We examined the effects of these polymorphisms by performing logistic regression multivariate analysis on their association with sustained virologic response in a separate cohort of 411 patients with chronic HCV genotype 3 infection who had been treated with sofosbuvir and ribavirin, with or without pegylated interferon. RESULTS: We identified a substitution in the HCV genotype 3a NS5b polymerase at amino acid 150 (alanine [A] to valine [V]), V at position 150 was observed in 42% of patients) with a reduced response to sofosbuvir in virus replication assays. In patients treated with sofosbuvir-containing regimens, the A150V variant was associated with a reduced response to treatment with sofosbuvir and ribavirin, with or without pegylated interferon. In 326 patients with V at position 150, 71% achieved an sustained virologic response compared to 88% with A at position 150. In cells, V at position 150 reduced the response to sofosbuvir 7-fold. We found that another rare substitution, glutamic acid (E) at position 206, significantly reduced the response to sofosbuvir (8.34-fold reduction); the combinations of V at position 150 and E at position 206 reduced the virus response to sofosbuvir 35.77-fold. Additionally, in a single patient, we identified 5 rare polymorphisms that reduced sensitivity to sofosbuvir our cell system. CONCLUSIONS: A common polymorphism, V at position 150 in the HCV genotype 3a NS5b polymerase, combined with other variants, reduces the virus response to sofosbuvir. Clinically, infection with HCV genotype 3 containing this variant reduces odds of sustained virologic response. In addition, we identified rare combinations of variants in HCV genotype 3 that reduce response to sofosbuvir.


Assuntos
Antivirais/uso terapêutico , Farmacorresistência Viral , Hepacivirus/efeitos dos fármacos , Hepatite C Crônica/tratamento farmacológico , Mutação , Polimorfismo Genético , Sofosbuvir/uso terapêutico , Proteínas não Estruturais Virais/antagonistas & inibidores , Substituição de Aminoácidos , Antivirais/efeitos adversos , Linhagem Celular Tumoral , Relação Dose-Resposta a Droga , Farmacorresistência Viral/genética , Quimioterapia Combinada , Genótipo , Hepacivirus/enzimologia , Hepacivirus/genética , Hepatite C Crônica/diagnóstico , Hepatite C Crônica/virologia , Humanos , Fenótipo , Sofosbuvir/efeitos adversos , Resposta Viral Sustentada , Fatores de Tempo , Resultado do Tratamento , Proteínas não Estruturais Virais/genética , Proteínas não Estruturais Virais/metabolismo
14.
Nat Commun ; 10(1): 2005, 2019 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-31043606

RESUMO

A long-acting injectable formulation of the HIV integrase inhibitor cabotegravir (CAB-LA) is currently in clinical development for PrEP. Although the long plasma half-life of CAB-LA is an important attribute for PrEP, it also raises concerns about drug resistance emergence if someone becomes infected with HIV, or if PrEP is initiated during undiagnosed acute infection. Here we use a macaque model of SHIV infection to model risks of drug resistance to CAB-LA PrEP. Six macaques infected with SHIV received CAB-LA before seroconversion. We show integrase mutations G118R, E92G/Q, or G140R in plasma from 3/6 macaques as early as day 57, and identify G118R and E92Q in viruses from vaginal and rectal fluids. G118R and G140R confer > 800-fold resistance to CAB and cross-resistance to all licensed integrase inhibitors. Our results emphasize the need for appropriate HIV testing strategies before and possibly shortly after initiating CAB LA PrEP to exclude acute infection.


Assuntos
Farmacorresistência Viral/genética , Infecções por HIV/prevenção & controle , Inibidores de Integrase de HIV/farmacologia , Profilaxia Pré-Exposição/métodos , Piridonas/farmacologia , Síndrome de Imunodeficiência Adquirida dos Símios/prevenção & controle , Doença Aguda , Animais , Modelos Animais de Doenças , Farmacorresistência Viral/efeitos dos fármacos , Feminino , Células HEK293 , Infecções por HIV/sangue , Infecções por HIV/imunologia , Infecções por HIV/virologia , Integrase de HIV/genética , Inibidores de Integrase de HIV/sangue , Inibidores de Integrase de HIV/uso terapêutico , HIV-1/efeitos dos fármacos , HIV-1/genética , Meia-Vida , Humanos , Macaca , Masculino , Piridonas/sangue , Piridonas/uso terapêutico , Soroconversão , Síndrome de Imunodeficiência Adquirida dos Símios/sangue , Síndrome de Imunodeficiência Adquirida dos Símios/imunologia , Síndrome de Imunodeficiência Adquirida dos Símios/virologia , Vírus da Imunodeficiência Símia/efeitos dos fármacos , Vírus da Imunodeficiência Símia/genética , Vírus da Imunodeficiência Símia/imunologia , Fatores de Tempo
15.
Mikrobiyol Bul ; 53(2): 144-155, 2019 Apr.
Artigo em Turco | MEDLINE | ID: mdl-31130119

RESUMO

Chronic hepatitis B (CHB) is an important public health problem affecting over 240 million people all around the world. The aim of the treatment in chronic hepatitis B is to prevent progression to cirrhosis and liver cancer. Interferons (standard and peginterferon) (Peg-IFN) and nucleoside/nucleotide analogues (NAs) are widely used in the treatment of CHB. The use of long-term therapy can however result in drug resistant mutations, which can lead to treatment failure. In patients with chronic hepatitis B, in addition to primary drug resistance mutations in the pol gene, compensatory mutations were reported. The genom of HBV polymerase (pol) gene overlaps with the envelope (S) gene. Nucleoside/nucleotide analogue (NA) resistance mutations in the pol gene of HBV, either from selection of primary or secondary resistance mutations, typically result in changes in HBsAg. Recent studies have conferred a new acronym for these HBV pol/S gene overlap mutants; ADAPVEMs, for antiviral drug-associated potential vaccine-escape mutants. The aim of this study was to investigate clinically and epidemiologically significant HBV pol/S gene mutations in NA treated CHB patients. In the study, a total of 100 patients who received nucleoside/nucleotide analogue therapy for one year or more were included. The levels of HBV DNA from serum samples were detected by the commercial real-time PCR assay and the mutations of pol/S genes by direct sequencing. Sixteen samples with low HBV DNA levels (> 200 IU/ml) could not be interpreted by sequencing due to insufficient amplification. Of the remaining 84 patients that could be sequenced HBV pol gene of HBV, 53 (63.09%) were males and 31 (36.91%) were women and the mean age was 47 ± 14.99 years (range: 20-67). Primary/secondary drug mutations (rtM204I/V, rtI169S, rtL180M, rtT184L, rtA194V, rtM204I/rtL91I, rtQ149K, rtQ215H/S, rtN238D) were detected in 38 (45.2%) of the patients. Because of the HBV pol/S gene overlapping, in 27 patients immun-selected amino acid substitutions (sI110L, sT127P, sS114A, sT123A), in nine patients HBIg selected escape mutants (sP120R, sT123N, sE164D, sY134F, sQ129H, sT118A, sP127K), in seven patients vaccine escape mutants (sT126I, sP120S, sG145A, s S193L) and in one patient misdiagnosis of HBsAg (sT131I) were detected. In addition, antiviral drug-associated potential vaccine-escape mutants were detected in 13 (15.4%) patients. In patients with chronic HBV, NAs including commonly used lamivudine were observed to have the potential for ADAPVEM to emerge during treatment. It was concluded that after determination of antiviral drug resistance and ADAPVEMs replanning of treatment should be done in the NA treatment of patients with CHB.


Assuntos
Antivirais , Farmacorresistência Viral , Produtos do Gene pol , Vírus da Hepatite B , Hepatite B Crônica , Mutação , Proteínas do Envelope Viral , Adulto , Idoso , Antivirais/uso terapêutico , Farmacorresistência Viral/genética , Feminino , Produtos do Gene pol/genética , Antígenos de Superfície da Hepatite B/metabolismo , Vírus da Hepatite B/genética , Hepatite B Crônica/tratamento farmacológico , Hepatite B Crônica/virologia , Humanos , Lamivudina/uso terapêutico , Masculino , Pessoa de Meia-Idade , Mutação/genética , Nucleotídeos/uso terapêutico , Proteínas do Envelope Viral/genética , Adulto Jovem
16.
Mikrobiyol Bul ; 53(2): 156-169, 2019 Apr.
Artigo em Turco | MEDLINE | ID: mdl-31130120

RESUMO

HBV is a DNA virus and the causative agent of hepatitis B infection. Hepatitis B is a contagious disease and is still a major health problem all over the world. When the infection become chronic, it may cause serious diseases such as fibrosis, cirrhosis and/or hepatocellular carcinoma. Interferon/pegylated interferon by intravenous route and nucleoside/nucleotide (NA) analogues such as lamivudine, adefovir, entecavir, telbivudine and tenofovir given by oral route are used in the treatment. Antivirals given by oral route are mostly preferred in the treatment. However, because of the replication strategy and biological properties of HBV, mutations that cause antiviral resistance against these drugs can occur at different rates, although they can vary from drug to drug over time. It is possible that drug resistant virus may transmit from patient to healthy individuals. Therefore, there is a possibility of infection with drug-resistant HBV before treatment. Antiviral resistance mutations are divided into four categories; i) Nucleos(t)ide analog resistance (NAr)-related mutations, ii) primary drug resistance mutations, iii) secondary/compensatory mutations, iv) putative antiviral resistance mutations and pre-treatment variations. Recent studies have focused particularly on putative mutations and pre-treatment variations. The aim of this study was to better understanding of the antiviral resistance profiles of chronic hepatitis B (CHB) patients treated and untreated with NA, and help to prevent unnecessary drug use, minimize the side effects and economic damages. A total of 124 patients who have received nucleoside analog (NA) drug treatments (n= 72) and patients without NA treatment (n= 52) were included in the study. Viral DNA was isolated from the plasma samples of the patients. A DNA fragment, which is 551 bp, was amplified and sequenced including the binding side of all nucleoside analogs containing the B, C and D domains located in the reverse transcriptase region in the HBV genome. Different types of mutations were detected in 13 (18.05%) of 72 treated patients and in 18 (34.61%) of 52 untreated patients (p< 0.05). Primary drug resistance mutations such as rtI169T, rtA181T/V, rtT184A/C/F/G/I/L/M/S, rtA194T, rtS202C/G/I, rtM204I/V/S, rtN236T, rt M250I/L/V and rtV173L were not detected in any of the patient samples. However, potential drug resistance mutations such as rtR164R, rtG165D/A, rtG172Q, rtS176N, rtF178V, rtA181G, rtS185N/G/C, rtV207M, rtQ215H/S, rtL231V, rtI233K, rtN238S, rtV253T, rtC256G/S and rtI266R/V were detected in untreated patient samples in B, C, D and D domains of reverse transcriptase region. Our results have suggested that the detection of pretreatment variations could be helpful for choosing the correct antiviral drug for the better treatment management.


Assuntos
Farmacorresistência Viral , Vírus da Hepatite B , Hepatite B Crônica , Antivirais/farmacologia , Farmacorresistência Viral/genética , Vírus da Hepatite B/efeitos dos fármacos , Vírus da Hepatite B/genética , Hepatite B Crônica/tratamento farmacológico , Hepatite B Crônica/virologia , Humanos , Mutação , Inibidores da Transcriptase Reversa/farmacologia
17.
Can J Gastroenterol Hepatol ; 2019: 4029541, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30941326

RESUMO

Background and Aim: The development of interferon- (IFN-) free regimens substantially improved efficacy of treatment for HCV, but despite excellent effectiveness the failures still occur. The aim of our study was to evaluate the efficacy of retreatment with genotype specific direct acting antivirals- (DAA-) based regimens in nonresponders to previous IFN-free therapy. Materials and Methods: Analysed population consisted of 31 nonresponders to IFN-free regimen, which received second IFN-free rescue therapy, selected from 6228 patients included in a national database EpiTer-2. Results: Age and gender distribution were similar, whereas proportion of genotype 1b was slightly higher and genotype 4 lower in the whole population compared to studied one. Patients included in the study demonstrated much more advanced fibrosis. Primary therapy was discontinued in 12 patients, which were recognized as failures due to nonvirologic reason, whereas virologic reason of therapeutic failure was recognized in 19 patients which completed therapy. Overall sustained virologic response (SVR) rate was 81% and 86% in intent-to-treat (ITT) and modified ITT analysis, respectively (74% and 78% in virologic failures, 92% and 100% in nonvirologic failures). Resistance-associated substitutions (RAS) testing was carried out in 8 patients from the group of completed primary therapy and three of them had potential risk for failure of rescue therapy due to NS5A association, while two of them achieved SVR. Conclusions: We demonstrated moderate effectiveness of genotype specific rescue therapy in failures due to virologic reason and high in those who discontinued primary therapy. Therefore rescue therapy with genotype specific regimens should be considered always if more potent regimens are not available.


Assuntos
Antivirais/uso terapêutico , Hepacivirus/genética , Hepatite C Crônica/tratamento farmacológico , Cirrose Hepática/tratamento farmacológico , Adulto , Idoso , Farmacorresistência Viral/genética , Feminino , Genótipo , Hepatite C Crônica/patologia , Hepatite C Crônica/virologia , Humanos , Cirrose Hepática/patologia , Cirrose Hepática/virologia , Masculino , Pessoa de Meia-Idade , Retratamento , Estudos Retrospectivos , Resposta Viral Sustentada , Falha de Tratamento , Proteínas não Estruturais Virais/genética , Adulto Jovem
19.
BMC Infect Dis ; 19(1): 313, 2019 Apr 08.
Artigo em Inglês | MEDLINE | ID: mdl-30961560

RESUMO

BACKGROUND: Genetic variability and liability to develop drug-resistant mutations are the main characteristics of HIV-1, which can not only increase the risk of antiretroviral treatment (ART) failure, but also can lead to the spread of resistant strains. We aim to investigate the distribution of HIV-1 genotypes and prevalence of pretreatment drug resistance (PDR) in ART-naïve HIV-1 infected patients in Shanghai China. METHODS: A cross-sectional study was performed among the newly diagnosed ART-naive HIV-1 infected patients during the period from January 2017 to November 2017 in Shanghai Public Health Clinical Center. The target fragment of 1316 bp in the pol gene spanning the reverse transcriptase and protease regions was amplified using a nested polymerase chain reaction. HIV-1 genotypes were determined by phylogenetic analysis, and PDR associated mutations were determined according to Stanford University HIV Drug Resistance Database ( http://hivdb.stanford.edu/ ). RESULTS: We successfully amplified pol gene sequences from blood samples of 317 patients, of whom 95.3% were male, and 68.8% were men who have sex with men. The median age was 33 years; and the median CD4 count was 275 cells/µL. The predominant HIV-1 genotype was circulating recombinant form (CRF) 01_AE (53.0%, 168/317), followed by CRF07_BC (29.7%, 94/317), B (7.6%, 24/317), CRF08_BC (1.9%, 6/317), CRF55_01B (1.9%, 6/317), CRF 59_01B (0.9%, 3/317). In addition, 5% (16/317) HIV-1 strains were identified as other subtypes or CRFs/URFs (unique recombinant forms). The overall prevalence of PDR was 17.4% (55/317). PDR frequency to non-nucleoside reverse transcriptase inhibitor (NNRTI, 16.4%) was much higher than that to nucleoside reverse transcriptase inhibitor (NRTI, 4.7%) and protease inhibitor (PI, 0.6%). The most common HIV-1 mutation pattern for NNRTI and NRTI were V179D/E (10.1%, 32/317) and M184 V (2.8%, 9/317), respectively. About half (49.1%, 27/55) of the HIV-1 strains with mutation presented as potential low-level resistant to NNRTI attributed to V179D/E. CONCLUSION: The distribution of HIV-1 genotypes in Shanghai China is diverse and complex. The high prevalence of PDR highlights the significance of baseline HIV-1 drug resistance testing. Non-NNRTI-containing regimen may be the preferred initial therapy for newly diagnosed HIV-1 patients in Shanghai in the absence of PDR test results.


Assuntos
Fármacos Anti-HIV/uso terapêutico , Farmacorresistência Viral/genética , Infecções por HIV/virologia , HIV-1/genética , Adulto , Idoso , China/epidemiologia , Estudos Transversais , Farmacorresistência Viral/efeitos dos fármacos , Feminino , Genes pol , Variação Genética , Genótipo , Infecções por HIV/tratamento farmacológico , Infecções por HIV/epidemiologia , HIV-1/efeitos dos fármacos , Homossexualidade Masculina , Humanos , Masculino , Pessoa de Meia-Idade , Mutação , Filogenia , Prevalência
20.
Int J STD AIDS ; 30(5): 453-459, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30999831

RESUMO

Patient's gender may impact pharmacokinetics and play a role in viral suppression. Existing literature has focused on treatment-naïve patients and produced inconclusive results, often implicating differences in adherence as the driver of gender-based outcome differences. The present analysis assessed whether viral suppression on third-line HIV treatment among a closely followed population differs by gender. A retrospective cohort study of patients on third-line HIV treatment was initiated at the HIV Advanced Treatment Centre in Lusaka, Zambia between January 2012 and December 2015. The association between gender and viral suppression was assessed using log binomial regression adjusted for core drug, number of drug mutations, and baseline viral load. Of the 80 included patients (56% female; median age: 40 years), 50 (62%) were virally suppressed at six months. After adjustment, females were less likely to be virologically suppressed at six months on third-line treatment compared to male HIV patients (relative risk 0.82, 95% confidence interval: 0.56, 1.20). Our data suggest that women were less likely to be suppressed following six months of third-line therapy compared to men; however, the difference was not statistically significant. Larger studies are needed to determine whether women are at increased risk of viral failure on third-line therapy compared to men.


Assuntos
Fármacos Anti-HIV/uso terapêutico , Terapia Antirretroviral de Alta Atividade/métodos , Infecções por HIV/tratamento farmacológico , HIV-1/efeitos dos fármacos , Carga Viral/efeitos dos fármacos , Adulto , Contagem de Linfócito CD4 , Farmacorresistência Viral/genética , Feminino , Infecções por HIV/epidemiologia , Infecções por HIV/virologia , HIV-1/genética , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Fatores Sexuais , Resultado do Tratamento , Zâmbia/epidemiologia
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