Hepatitis C Resistance-Associated Substitutions Among People Who Inject Drugs Treated With Direct-Acting Antiviral-Containing Regimens.

BACKGROUND: Resistance-associated substitutions (RASs) to HCV direct-acting antivirals (DAAs) can contribute to virologic failure and limit retreatment options. People who inject drugs (PWID) are at highest risk for transmission of resistant virus. We report on RASs at baseline and after virologic failure in DAA-naive and protease inhibitor-experienced PWID. METHODS: We sequenced the NS3/4A, NS5A, and NS5B regions from 150 PWID with genotype 1 (GT1) viruses; 128 (85.3%) GT1a, 22 (14.7%) GT1b. RESULTS: Among the 139 (92.7%) DAA-naive PWID, 85 of 139 (61.2%) had baseline RASs-67 of 139 (48.2%) in NS3 (predominantly Q80K/L); 25 of 139 (18.0%) in NS5A; and 8 of 139 (5.8%) in NS5B. Of the 11 protease inhibitor-experienced participants, 9 had baseline NS3 RASs (V36L N = 1, Q80K N = 9) and 4 had baseline NS5A RASs (M28V N = 2, H58P N = 1, A92T N = 1). Among the 11 participants who had posttreatment samples with detectable virus (7 treatment failures, 1 late relapse, 3 reinfections), 1 sofosbuvir/ledipasvir failure had a baseline H58P. Two sofosbuvir/ledipasvir-treated participants developed new NS5A mutations (Q30H, Y93H, L31M/V). Otherwise, no RASs were detected. CONCLUSIONS: Our results demonstrate RAS prevalence among DAA-naive PWID is comparable to that in the general population. Only 2 of 150 (1.3%) in our longitudinal cohort developed treatment-emergent RASs. Concern for transmission of resistant virus may therefore be minimal.

Short Communication: Trends in Transmitted Drug Resistance in Treatment-Naive HIV Patients in Korea.

Transmitted drug resistance (TDR) in treatment-naive HIV patients can contribute to failure of initial antiretroviral therapy. In Korea, there has been a gradual increase in TDR, but the recent increase in the use of integrase strand transfer inhibitors (INSTIs) could affect TDR trends and INSTI resistance mutations. We evaluated the patterns of TDR in newly diagnosed HIV patients over time from 2011 to 2019. We analyzed the genotypic resistance of strains in 336 patients and sequenced the integrase gene in 71 among 336 subjects. The overall prevalence of TDR was 5.9% (20 of 336 patients), and it showed a tendency to increase over time (5.1% in 2011-2013, 6.1% in 2014-2016, and 7.2% in 2017-2019; p = .3018). Furthermore, non-nucleoside reverse transcriptase inhibitor resistance showed a marginally significant increase over time (1.45% in 2011-2013, 3.48% in 2014-2016, and 6.02% in 2017-2019; p = .0505). Regarding transmitted INSTI resistance mutation, there were no major INSTI resistance mutations but several accessory INSTI resistance mutations and predominant natural polymorphisms. This study shows several significant changes in TDR and suggests the importance of continuous surveillance of TDR and genetic variation in the integrase region.

Evaluation of Genotypic Antiviral Resistance Testing as an Alternative to Phenotypic Testing in a Patient with DOCK8 Deficiency and Severe HSV-1 Disease.

Antiviral resistance frequently complicates the treatment of herpes simplex virus (HSV) infections in immunocompromised patients. Here we present the case of an adolescent boy with dedicator of cytokinesis 8 (DOCK8) deficiency, who experienced recurrent infections with resistant HSV-1. We used both phenotypic and genotypic methodologies to characterize the resistance profile of HSV-1 in the patient and conclude that genotypic testing outperformed phenotypic testing. We also present the first analysis of intrahost HSV-1 evolution in an immunocompromised patient. While HSV-1 can remain static in an immunocompetent individual for decades, the virus from this patient rapidly acquired genetic changes throughout its genome. Finally, we document a likely case of transmitted resistance in HSV-1 between the patient and his brother, who also has DOCK8 deficiency. This event demonstrates that resistant HSV-1 is transmissible among immunocompromised persons.

Integrase Strand Transfer Inhibitor Resistance Mutations in Antiretroviral Therapy-Naive and Treatment-Experienced HIV Patients in South Korea.

Updated guidelines for the treatment of antiretroviral therapy (ART)-negative patients with HIV recommend integrase strand transfer inhibitor (INSTI)-based regimens. HIV patients are tested for resistance to antiretrovirals, and the reported prevalence of transmitted INSTI resistance remains rare worldwide. However, no data related to INSTI resistance in Korean HIV patients have been reported. We aimed to determine the prevalence of INSTI resistance-related mutations in South Korea. We subjected both ART-naive (n = 58) and ART-experienced Korean HIV patients (n = 41) to genotypic resistance analysis and determined a prevalence of INSTI major resistance mutations of 3.4% (n = 2) among ART-naive patients and 22.0% (n = 9) among ART-experienced patients. In the former group, both major INSTI resistance cases involved the nonpolymorphic E92Q mutation in the integrase strand. Our findings suggest that INSTI resistance testing should be included in the standard resistance screening protocols for Korean HIV patients.

Canary in the Coal Mine? Transmitted Mutations Conferring Resistance to All Integrase Strand Transfer Inhibitors in a Treatment-Naive Patient.

Transmitted drug resistance to the integrase strand transfer inhibitor (INSTI) class of antiretrovirals is very rare. We present a case of a treatment-naive female patient with human immunodeficiency virus harboring resistance to all INSTIs, including bictegravir and dolutegravir.

Evolution of HIV-1 transmitted drug resistance in Italy in the 2007-2014 period: A weighted analysis.

BACKGROUND: Recent studies suggest that transmitted drug resistance (TDR) may be decreasing in latest years, likely because of the reduced frequency of acquired resistance. However, specific risk factors, geographical areas and special HIV-infected populations may be disproportionally affected by TDR. OBJECTIVES: Correlates of TDR and time trends were evaluated from 2007 to 2014. STUDY DESIGN: We evaluated the genotypic results of 2155 naïve patients enrolled in the I.Co.N.A cohort at 23 clinical Centers in Italy between 2007 and 2014. A weighted analysis was performed to account for the patients enrolled in the cohort in each clinical Centre at each biennium (total number of patients: 3737). RESULTS: Overall prevalence of TDR was 10.7%. Independent predictors of TDR were sexual risk factor (OR 2.315, p = 0.020) and non-Italian geographical origin (OR 1.57, p = 0.038). The weighted prevalence of TDR was 10.5% with a stable proportion over calendar years. Generally, TDR prevalence was numerically higher, although not significantly, in clinical Centers of metropolitan areas with more than 3 millions of residents as compared to others (11.3% vs. 9.2%). The difference in TDR prevalence between these Centers decreased in more recent years. CONCLUSIONS: A stable frequency of TDR was observed during the most recent years in Italy, with opposite and converging trends in large metropolitan areas as compared to the rest of the country, suggesting a more homogeneous spread of TDR across the country in latest years. Concerns remain for sexual route of infection and non-Italian origin, reinforcing the need for specific prevention strategies prioritizing specific populations.

Commonly Transmitted HIV-1 Drug Resistance Mutations in Reverse-Transcriptase and Protease in Antiretroviral Treatment-Naive Patients and Response to Regimens Containing Tenofovir Disoproxil Fumarate or Tenofovir Alafenamide.

Background: The presence of transmitted drug resistance mutations (TDRMs) in antiretroviral treatment (ART)-naive patients can adversely affect the outcome of ART. Methods: Resistance testing was conducted in 6704 ART-naive subjects predominantly from the United States and Europe in 9 clinical studies conducted by Gilead Sciences from 2000 to 2013. Results: The presence of TDRMs increased during this period (from 5.2% to 11.4%), primarily driven by an increase in nonnucleoside reverse-transcriptase (RT) inhibitor (NNRTI) resistance mutations (from 0.3% to 7.1%), particularly K103N/S (increase from 0.3% to 5.3%). Nucleoside/nucleotide RT inhibitor mutations were found in 3.1% of patients. Only 1 patient had K65R (0.01%) and 7 had M184V/I (0.1%), despite high use of tenofovir disoproxil fumarate (TDF), emtricitabine, and lamivudine and potential transmission of resistance to these drugs. At least 1 thymidine-analogue mutations was present in 2.7% of patients with 0.07% harboring T215Y/F and 2.7% harboring T215 revertant mutations (T215rev). Patients with the combination of M41L + L210W + T215rev showed full human immunodeficiency virus RNA suppression while receiving a TDF- or tenofovir alafenamide-containing regimen. Conclusions: There was an overall increase of TDRMs among patients enrolling in clinical trials from 2000 through 2013, driven primarily by an increase in NNRTI resistance. However, the presence of common TDRMs, including thymidine-analogue mutations/T215rev, showed no impact on response to TDF- or tenofovir alafenamide-containing regimens.

The trend of transmitted drug resistance in newly diagnosed antiretroviral-naive HIV/AIDS patients during 1999-2012 in South Korea.

BACKGROUND: The use of antiretroviral drugs has reduced the mortality and morbidity of patients with HIV/AIDS. More than 20 antiretroviral drugs have been used in patients with HIV/AIDS since zidovudine was first introduced in 1991 in South Korea. OBJECTIVES: To investigate and estimate the annual prevalence of transmitted drug resistance and drug-resistant variants of HIV-1 in newly diagnosed antiretroviral-naive patients in South Korea during 1999-2012. STUDY DESIGN: Plasma specimens were collected from 928 antiretroviral-naive patients during 1999-2012. Mutations in the protease and reverse transcriptase sections of the HIV-1 pol gene were identified using the Stanford HIV Drug Resistance Database (Stanford DB). RESULTS: Among 928 HIV-1 isolates from antiretroviral-naive patients, 45 (4.8%) showed 'intermediate' or 'resistant' drug resistance. The predicted prevalence of drug resistance among isolates was 2.2%, 2.7%, and 0.3% for resistance to nucleoside reverse transcriptase inhibitors, non-nucleoside reverse transcriptase inhibitors, and protease inhibitors, respectively. CONCLUSIONS: There was no significant increase in the prevalence of drug resistance among antiretroviral-naive patients infected with HIV-1 during 1999-2012 in South Korea, although there was a slight increase during 2009-2012. The emergence of drug-resistant variants will continue to be monitored by national surveys.

Avaliação da prevalência de resistência transmitida aos antirretrovirais em indivíduos infectados pelo HIV-1 em Salvador- Bahia / Prevalence of transmitted resistance to antiretroviraldrugs in patients infected with HIV-1 in Salvador, Bahia. Luiz Carl

Avaliar a prevalência de resistência transmitida aos antirretrovirais em indivíduos infectados pelo HIV-1 em acompanhamento clínico e laboratorial na cidade de Salvador-Bahia. Estudo descritivo de corte transversal com amostragem de conveniência composto por 121 pacientes infectados pelo HIV-1, com 18 anos de idade ou mais, virgens de tratamento antirretrovial e que fazem coletas de exame para quantificação das Subpopulações Linfocitárias e da carga viral sérica do HIV-1 no Laboratório de Retrovírus do Hospital Universitário Professor Edgard Santos ou no Centro Especializado em Diagnóstico, Assistência e Pesquisa (CEDAP). Os pacientes foram entrevistados para preenchimento de um questionário epidémiologico e consentiram na utilização do excedente de sangue para realização do sequenciamento do gene pol do HIV-1 contendo parte da Transcriptase e da Protease para análise das mutações de resistência aos antirretrovirais e a caracterização genotípica, análise de recombinações e estudo da história evolutiva viral. Entre os 103 pacientes 66% são do sexo masculino, a mediana de idade e do tempo estimado do diagnóstico do HIV-1 são respectivamente de 35 anos e 29 meses. A principal categoria de exposição relatada foi a sexual com 88,3%, seguida por 3% com acidentes com perfurocortantes e 1% uso de drogas intravenosas. A mediana da contagem dos Linfócitos TCD4+ foi de 438 cel/mm3 e de 4,4 log10. Na análise de Mutação de Resistência à Fármacos (DRM) atráves da ferramenta de Calibração da População com Resistência (CPR) observamos uma prevalência global de 6,8%, 3 (2,9%)...

To evaluate the prevalence of transmitted resistance to antiretroviral drugs in patients infected with HIV- 1 assisted in the city of Salvador, Bahia. A descriptive crosssectional study with 121 patients with 18 years of age or older, chronic or recent diagnosis of HIV -1, antirretrovial naïve and make collections for examination and quantification of lymphocyte subpopulations serum viral load of HIV -1 in the Retrovirus Laboratory, Hospital Universitário Professor Edgard Santos or in Centro Especializado em Diagnóstico, Assistência e Pesquisa (CEDAP). Patients were interviewed to fill an epidemiological questionnaire and consented to the use of drawed blood to be sequenced of the transcriptase and protease region of the pol gene of HIV - 1 for analysis of antiretroviral resistance mutations and subtype viral. Of the 121 patients, 104 sequences for phylogenetic analysis and transmitted resistance were obtained, 18 individuals were excluded due quality or amplification problems. Among 103 patients 66% were male, the median age and the estimated time of diagnosis of HIV -1 were respectively 35 and 29 months. The main category of reported exposure was sexual with 88.3%, followed by 3% with Occupational Exposure and 1% use of Intravenous Drugs. The median CD4 + lymphocyte count was 438 cells/mm3 and 4.4 log10. The analysis of Drug Resistance Mutation (DRM) by Calibrating Population Resistance tool (CPR) has a global prevalence of 6.8%, distributed: 2.9%...

Genetic diversity and primary resistance among HIV-1-positive patients from Maringá, Paraná, Brazil / Diversidade genética e resistência primária entre pacientes HIV-1-positivos de Maringá, Paraná, Brasil

The objective of this study is to identify subtypes of Human Immunodeficiency Virus type 1 (HIV-1) and to analyze the presence of mutations associated to antiretroviral resistance in the protease (PR) and reverse transcriptase (RT) regions from 48 HIV-1 positive treatment naïve patients from an outpatient clinic in Maringá, Paraná, Brazil. Sequencing was conducted using PR, partial RT and group-specific antigen gene (gag) nested PCR products from retrotranscribed RNA. Transmitted resistance was determined according to the Surveillance Drug Resistance Mutation List (SDRM) algorithm. Phylogenetic and SimPlot analysis of concatenated genetic segments classified sequences as subtype B 19/48 (39.6%), subtype C 12/48 (25%), subtype F 4/48 (8.3%), with 13/48 (27.1%) recombinant forms. Most recombinant forms were B mosaics (B/F 12.5%, B/C 10.4%), with one C/F (2.1%) and one complex B/C/F mosaic (2.1%). Low levels of transmitted resistance were found in this study, 2/48 (2.1% to NRTIs and 2.1% for PI). This preliminary data may subsidize the monitoring of the HIV evolution in the region.

O objetivo foi identificar subtipos do Vírus da Imunodeficiência Humana tipo-1 (HIV-1) e analisar a presença de mutações/polimorfismos nas regiões da protease (PR) e transcriptase reversa (TR) de 48 pacientes virgens de tratamento atendidos no município de Maringá, Paraná, Brasil. O sequenciamento foi conduzido usando produtos de nested PCR dos genes da PR, TR parcial e group-specific antigen gene (gag) de RNA retrotranscrito. A interpretação da resistência transmitida foi realizada segundo o algoritmo Surveillance Drug Resistance Mutation List (SDRM). As análises filogenética e SimPlot dos segmentos concatenados classificaram as sequências como subtipo B 19/48 (39,6%), subtipo C 12/48 (25%), subtipo F 4/48 (8,3%), com 13/48 (27,1%) formas recombinantes. A maioria das formas recombinantes era mosaicos B (B/F 12,5%, B/C 10,4%), com um C/F (2,1%) e um mosaico complexo B/C/F (2,1%). A prevalência de resistência transmitida foi de 4,2% (2,1% para ITRN e 2,1% para IP). Baixos níveis de resistência transmitida foram encontrados nesse estudo, 2/48 (2,1% para INTR e 2,1% para IP). Esses achados, embora preliminares, podem contribuir no monitoramento da epidemia de HIV na região.