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OBJECTIVES: The main objective of this analysis was to evaluate the impact of pre-existing drug resistance by next-generation sequencing (NGS) on the risk of treatment failure (TF) of first-line regimens in participants enrolled in the START study. METHODS: Stored plasma from participants with entry HIV RNA >1000 copies/mL were analysed using NGS (llumina MiSeq). Pre-existing drug resistance was defined using the mutations considered by the Stanford HIV Drug Resistance Database (HIVDB v8.6) to calculate the genotypic susceptibility score (GSS, estimating the number of active drugs) for the first-line regimen at the detection threshold windows of >20%, >5%, and >2% of the viral population. Survival analysis was conducted to evaluate the association between the GSS and risk of TF (viral load >200 copies/mL plus treatment change). RESULTS: Baseline NGS data were available for 1380 antiretroviral therapy (ART)-naïve participants enrolled over 2009-2013. First-line ART included a non-nucleoside reverse transcriptase inhibitor (NNRTI) in 976 (71%), a boosted protease inhibitor in 297 (22%), or an integrase strand transfer inhibitor in 107 (8%). The proportions of participants with GSS <3 were 7% for >20%, 10% for >5%, and 17% for the >2% thresholds, respectively. The adjusted hazard ratio of TF associated with a GSS of 0-2.75 versus 3 in the subset of participants with mutations detected at the >2% threshold was 1.66 (95% confidence interval 1.01-2.74; p = 0.05) and 2.32 (95% confidence interval 1.32-4.09; p = 0.003) after restricting the analysis to participants who started an NNRTI-based regimen. CONCLUSIONS: Up to 17% of participants initiated ART with a GSS <3 on the basis of NGS data. Minority variants were predictive of TF, especially for participants starting NNRTI-based regimens.
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Fármacos Anti-VIH , Infecciones por VIH , Seropositividad para VIH , VIH-1 , Humanos , Infecciones por VIH/epidemiología , VIH-1/genética , Fármacos Anti-VIH/farmacología , Fármacos Anti-VIH/uso terapéutico , Inhibidores de la Transcriptasa Inversa/uso terapéutico , Seropositividad para VIH/tratamiento farmacológico , Secuenciación de Nucleótidos de Alto Rendimiento , Carga Viral , Farmacorresistencia Viral/genéticaRESUMEN
The historic academic affiliation program between the U.S. Department of Veterans Affairs and academic medical centers recently marked its 75th anniversary. The partnership has dramatically influenced medical education, research, and clinical care in the United States. In commemorating the anniversary, this article highlights areas in medicine that the partnership has influenced. The authors provide examples from their own experiences of particularly effective collaborations and describe some of the limitations they have encountered. Looking toward the future, they highlight other areas in which collaboration may be particularly effective.
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Educación Médica , Veteranos , Centros Médicos Académicos , Hospitales de Veteranos , Humanos , Estados Unidos , United States Department of Veterans AffairsRESUMEN
In the phase 3 BRIGHTE study in heavily treatment-experienced adults with multidrug-resistant HIV-1, fostemsavir plus optimized background therapy (OBT) resulted in sustained rates of virologic suppression through 96 weeks. HIV-1 RNA <40 copies/mL was achieved in 163/272 (60%) Randomized Cohort (RC) participants (with 1 or 2 remaining approved fully active antiretrovirals) and 37/99 (37%) Non-randomized Cohort (NRC) participants (with 0 fully active antiretrovirals). Here we report genotypic and phenotypic analyses of HIV-1 samples from 63/272 (23%) RC participants and 49/99 (49%) NRC participants who met protocol-defined virologic failure (PDVF) criteria through Week 96. The incidence of PDVF was as expected in this difficult-to-treat patient population and, among RC participants, was comparable regardless of the presence of predefined gp120 amino acid substitutions that potentially influence phenotypic susceptibility to temsavir (S375H/I/M/N/T, M426L, M434I, M475I) or baseline temsavir 50% inhibitory concentration fold change (IC50 FC). The incidence of PDVF was lower among participants with higher overall susceptibility score to newly used antiretrovirals (OSS-new), indicating that OSS-new may be a preferred predictor of virologic outcome in heavily treatment-experienced individuals. Predefined gp120 substitutions, most commonly M426L or S375N, were emergent on treatment in 24/50 (48%) RC and 33/44 (75%) NRC participants with PDVF, with related increases in temsavir IC50 FC. In BRIGHTE, PDVF was not consistently associated with treatment-emergent genotypic or phenotypic changes in susceptibility to temsavir or to antiretrovirals in the initial OBT. Further research will be needed to identify which factors are most likely to contribute to virologic failure in this heavily treatment-experienced population (ClinicalTrials.gov, NCT02362503).
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Fármacos Anti-VIH , Farmacorresistencia Viral Múltiple , Infecciones por VIH , VIH-1 , Organofosfatos , Piperazinas , Adulto , Fármacos Anti-VIH/uso terapéutico , Farmacorresistencia Viral Múltiple/genética , Infecciones por VIH/tratamiento farmacológico , VIH-1/genética , Humanos , Organofosfatos/uso terapéutico , Piperazinas/uso terapéuticoRESUMEN
PURPOSE OF REVIEW: Fostemsavir is a recently Food and Drug Administration-approved HIV-1 attachment inhibitor that binds to HIV-1 gp120 and prevents viral attachment to the cellular CD4 receptor. Here, we review the pharmacology, efficacy, tolerability, and resistance profile of fostemsavir. RECENT FINDINGS: Fostemsavir is well tolerated and maintains virologic activity in individuals harboring multidrug-resistant HIV-1. In conjunction with optimal background therapy, a majority of heavily treatment-experienced clinical trial participants treated with fostemsavir achieved virologic suppression. SUMMARY: The approval of fostemsavir represents an important advance for individuals harboring multidrug resistant HIV-1 due to its novel mechanism of action and lack of cross-resistance to other antiretrovirals. Further study will better define the role of resistance testing for fostemsavir and fostemsavir's potential role outside of salvage therapy in heavily treatment-experienced individuals.
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Fármacos Anti-VIH , Infecciones por VIH , VIH-1 , Fármacos Anti-VIH/farmacología , Fármacos Anti-VIH/uso terapéutico , Infecciones por VIH/tratamiento farmacológico , VIH-1/genética , Humanos , Organofosfatos , PiperazinasRESUMEN
OBJECTIVE: Persistence of the viral reservoir is the main barrier to curing HIV. Initiation of ART during acute HIV infection can limit the size and diversity of the reservoir. In depth characterization of the reservoir in individuals who initiate ART during acute infection will be critical for clinical trial design and cure strategies. METHODS: Four cohorts with participants who initiated ART during acute infection or during chronic infection were enrolled in a cross-sectional, noninterventional study. Viral reservoir was evaluated by the Intact Proviral DNA Assay (IPDA), the Total HIV DNA Assay (THDA) and the Quantitative Viral Outgrowth Assay (QVOA). Viral diversity and susceptibility to V3-glycan bNAbs were determined by genotyping of the viral envelope gene. RESULTS: Participants who initiated ART during the acute Fiebig I-IV stages had lower level of total HIV DNA than participants who initiated ART during chronic infection whereas no difference was observed in intact HIV DNA or outgrowth virus. Participants who initiated ART during Fiebig I-IV also had lower viral diversity and appeared to have higher susceptibility to bNAbs than participants initiating ART during chronic infection. CONCLUSION: Individuals initiating ART during Fiebig I-IV had small viral reservoirs, low viral diversity, and high susceptibility to bNAbs, and would be an optimal target population for proof-of-concept HIV cure trials.
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Infecciones por VIH , VIH-1 , Antirretrovirales/uso terapéutico , Anticuerpos ampliamente neutralizantes , Estudios Transversales , VIH-1/genética , Humanos , Carga ViralRESUMEN
OBJECTIVES: The aim of this study was to understand how demographic and treatment-related factors impact responses to fostemsavir-based regimens. DESIGN: BRIGHTE is an ongoing phase 3 study evaluating twice-daily fostemsavir 600âmg and optimized background therapy (OBT) in heavily treatment-experienced individuals failing antiretroviral therapy with limited treatment options (Randomized Cohort 1-2 and Nonrandomized Cohort 0 fully active antiretroviral classes). METHODS: Virologic response rates (HIV-1 RNA <40âcopies/ml, Snapshot analysis) and CD4+ T-cell count increases in the Randomized Cohort were analysed by prespecified baseline characteristics (age, race, sex, region, HIV-1 RNA, CD4+ T-cell count) and viral susceptibility to OBT. Safety results were analysed by baseline characteristics for combined cohorts (post hoc). RESULTS: In the Randomized Cohort, virologic response rates increased between Weeks 24 and 96 across most subgroups. Virologic response rates over time were most clearly associated with overall susceptibility scores for new OBT agents (OSS-new). CD4+ T-cell count increases were comparable across subgroups. Participants with baseline CD4+ T-cell counts less than 20âcells/µl had a mean increase of 240âcells/µl. In the safety population, more participants with baseline CD4+ T-cell counts less than 20 vs. at least 200âcells/µl had grade 3/4 adverse events [53/107 (50%) vs. 24/96 (25%)], serious adverse events [58/107 (54%) vs. 25/96 (26%)] and deaths [16/107 (15%) vs. 2/96 (2%)]. There were no safety differences by other subgroups. CONCLUSION: Week 96 results for BRIGHTE demonstrate comparable rates of virologic and immunologic response (Randomized Cohort) and safety (combined cohorts) across subgroups. OSS-new is an important consideration when constructing optimized antiretroviral regimens for heavily treatment-experienced individuals with limited remaining treatment options.
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Fármacos Anti-VIH , Infecciones por VIH , VIH-1 , Adulto , Fármacos Anti-VIH/uso terapéutico , Recuento de Linfocito CD4 , Infecciones por VIH/tratamiento farmacológico , Humanos , Organofosfatos , Piperazinas , Resultado del Tratamiento , Carga ViralRESUMEN
Introduction: For those with heavily treatment experienced (HTE) HIV-1 and virologic failure, therapeutic options are limited. A variety of barriers such as drug resistance, side effects, past intolerance, and administration inability contribute to the need for novel drug classes in this population.Areas Covered: Herein, we review the pharmacology, clinical efficacy, and safety profile of fostemsavir, a first in its class attachment inhibitor recently FDA approved for use.Expert Opinion: Fostemsavir is a well-tolerated oral medication with relatively few drug-drug interactions. Clinical trial data demonstrates virologic and notable immunologic response in conjunction with optimal background therapy in HTE persons living with HIV. Fostemsavir exhibits no cross-resistance with other ARV classes and thus is an important advancement for patients harboring drug-resistant HIV. Further study will be needed to determine outstanding clinical questions such as the role of drug resistance testing and fostemsavir use outside of the HTE population.
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Fármacos Anti-VIH/administración & dosificación , Infecciones por VIH/tratamiento farmacológico , Organofosfatos/administración & dosificación , Piperazinas/administración & dosificación , Administración Oral , Fármacos Anti-VIH/efectos adversos , Fármacos Anti-VIH/farmacología , Farmacorresistencia Viral , Infecciones por VIH/virología , VIH-1/aislamiento & purificación , Humanos , Organofosfatos/efectos adversos , Organofosfatos/farmacología , Piperazinas/efectos adversos , Piperazinas/farmacologíaRESUMEN
BACKGROUND: Fostemsavir, a prodrug of the first-in-class attachment inhibitor, temsavir, is indicated for heavily treatment-experienced individuals with multidrug-resistant HIV-1. We previously reported superior efficacy of fostemsavir versus placebo in the randomised cohort of the BRIGHTE study after 8-day functional monotherapy (primary endpoint); here we report planned interim analyses through week 96. METHODS: BRIGHTE (NCT02362503) is an ongoing multicentre, two-cohort, phase 3 trial, done at 108 centres in 22 countries. We enrolled heavily treatment-experienced adults (≥18 years) failing antiretroviral therapy (HIV-1 RNA ≥400 copies per mL) into two cohorts: the randomised cohort, in which patients with one or two fully active antiretrovirals remaining received oral fostemsavir (600 mg twice a day) or placebo in combination with their failing regimen for 8 days, followed by fostemsavir plus optimised background therapy; or the non-randomised cohort, in which patients with no remaining antiretroviral options received oral fostemsavir (600 mg twice a day) plus optimised background therapy from day 1. Endpoints for the week 96 interim analyses included the proportions of participants with plasma HIV-1 RNA of less than 40 copies per mL, changes from baseline in CD4 cell counts, and the frequency of adverse events, adverse events leading to discontinuation, and deaths. The intention-to-treat exposed population and the safety population both included all participants who received at least one dose of study treatment. The response rates (proportion of participants with HIV-1 RNA <40 copies per mL) in the intention-to-treat exposed population were calculated via snapshot analysis at weeks 24, 48, and 96. FINDINGS: Between Feb 23, 2015, and Aug 11, 2016, 371 participants were enrolled and treated, of which 272 participants were in the randomised cohort and 99 in the non-randomised cohort. 320 (86%) of 371 reported a history of AIDS. In the randomised cohort, rates of virological suppression (HIV-1 RNA <40 copies per mL) increased from 53% (144 of 272) at week 24 to 60% (163 of 272) at week 96. Response rates in the non-randomised cohort were 37% (37 of 99) at week 24 and week 96. Mean increases in CD4 counts from baseline at week 96 were 205 cells per µL (SD 191) in the randomised cohort and 119 cells per µL (202) in the non-randomised cohort. Mean CD4/CD8 ratio increased from 0·20 at baseline to 0·44 at week 96 in the randomised cohort. Few adverse events led to discontinuation (26 [7%] of 371). 12 (4%) of 272 people in the randomised cohort and 17 (17%) of 99 in the non-randomised cohort died; the median baseline CD4 count for participants who died was 11 cells per µL. INTERPRETATION: In heavily treatment-experienced individuals with advanced HIV-1 disease and limited treatment options, fostemsavir-based antiretroviral regimens were generally well tolerated and showed a distinctive trend of increasing virological and immunological response rates through 96 weeks; these findings support fostemsavir as a treatment option for this vulnerable population. FUNDING: ViiV Healthcare.
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Inhibidores de Fusión de VIH/administración & dosificación , Infecciones por VIH/tratamiento farmacológico , VIH-1/efectos de los fármacos , Organofosfatos/administración & dosificación , Piperazinas/administración & dosificación , Adulto , Fármacos Anti-VIH/administración & dosificación , Recuento de Linfocito CD4 , Farmacorresistencia Viral Múltiple , Femenino , Proteína gp120 de Envoltorio del VIH/genética , Infecciones por VIH/inmunología , Infecciones por VIH/virología , VIH-1/fisiología , Humanos , Masculino , Persona de Mediana Edad , Mutación , Profármacos/administración & dosificación , Seguridad , Resultado del Tratamiento , Carga Viral/efectos de los fármacosRESUMEN
BACKGROUND: The global pandemic of Severe Acute Respiratory Syndrome-Related Coronavirus 2 (SARS-CoV2) has resulted in unprecedented challenges for healthcare systems. One barrier to widespread testing has been a paucity of traditional respiratory viral swab collection kits relative to the demand. Whether other sample collection kits, such as widely available MRSA nasal swabs can be used to detect SARS-CoV-2 is unknown. METHODS: We compared simultaneous nasal MRSA swabs (COPAN ESwabs ® 480C flocked nasal swab in 1mL of liquid Amies medium) and virals wabs (BD H192(07) flexible mini-tip flocked nasopharyngeal swabs in 3mL Universal Transport Medium) for SARS-CoV-2 PCR testing using Simplexa COVID-19 Direct assay on patients over a 4-day period. When the results were discordant, the viral swab sample was run again on the Cepheid Xpert Xpress ® SARS-CoV-2 assay. RESULTS: Of the 81 included samples, there were 19 positives and 62 negatives in viral media and 18 positives and 63 negative in the MRSA swabs. Amongst all included samples, there was concordance between the COPAN ESwabs ® 480C and the viral swabs in 78 (96.3%). CONCLUSION: We found a high rate of concordance in test results between COPAN ESwabs ® 480C in Amies solution and BD H192(07) nasopharyngeal swabs in in 3 mL of Universal Viral Transport medium viral media. Clinicians and laboratories should feel better informed and assured using COPAN ESwabs ® 480C to help in the diagnosis of COVID-19.
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Betacoronavirus/genética , Infecciones por Coronavirus/diagnóstico , Staphylococcus aureus Resistente a Meticilina/genética , Neumonía Viral/diagnóstico , Manejo de Especímenes/métodos , Betacoronavirus/aislamiento & purificación , COVID-19 , Infecciones por Coronavirus/virología , Humanos , Staphylococcus aureus Resistente a Meticilina/aislamiento & purificación , Nasofaringe/microbiología , Nasofaringe/virología , Pandemias , Neumonía Viral/virología , Estabilidad del ARN , ARN Bacteriano/análisis , ARN Bacteriano/metabolismo , ARN Viral/análisis , ARN Viral/metabolismo , Reacción en Cadena en Tiempo Real de la Polimerasa , SARS-CoV-2RESUMEN
BACKGROUND: Among some patients with human immunodeficiency virus type 1 (HIV-1) infection who have undergone multiple antiretroviral therapies and have limited options for treatment, new classes of antiretroviral drugs with novel mechanisms of action are needed. Fostemsavir is the prodrug of temsavir, a first-in-class investigational HIV-1 attachment inhibitor. METHODS: In this ongoing phase 3 trial in 23 countries, we enrolled patients with multidrug-resistant HIV-1 infection in two cohorts, according to their remaining treatment options. In the first cohort, we assigned (in a 3:1 ratio) patients who had the option of using at least one fully active, approved antiretroviral drug in at least one but no more than two antiretroviral classes to add either fostemsavir (at a dose of 600 mg twice daily) or placebo to their failing regimen for 8 days, followed by open-label fostemsavir plus optimized background therapy (randomized cohort). In the second cohort, patients who had no remaining antiretroviral options were started on open-label fostemsavir plus optimized background therapy on day 1 (nonrandomized cohort). The primary end point was the mean change in the HIV-1 RNA level from day 1 through day 8 in the randomized cohort. RESULTS: A total of 371 patients were treated, including 272 in the randomized cohort and 99 in the nonrandomized cohort. At day 8, the mean decrease in the HIV-1 RNA level was 0.79 log10 copies per milliliter in the fostemsavir group and 0.17 log10 copies in the placebo group (P<0.001). At week 48, a virologic response (HIV-1 RNA level, <40 copies per milliliter) had occurred in 54% of the patients in the randomized cohort and in 38% of those in the nonrandomized cohort; the mean increase in the CD4+ T-cell count was 139 cells per cubic millimeter and 64 cells per cubic millimeter, respectively. Adverse events led to the discontinuation of fostemsavir in 7% of the patients. In the randomized cohort, glycoprotein 120 (gp120) substitutions were found in 20 of 47 patients (43%) with virologic failure. CONCLUSIONS: In patients with multidrug-resistant HIV-1 infection with limited therapy options, those who received fostemsavir had a significantly greater decrease in the HIV-1 RNA level than those who received placebo during the first 8 days. Efficacy was sustained through 48 weeks. (Funded by Bristol-Myers Squibb and GSK/ViiV Healthcare; BRIGHTE ClinicalTrials.gov number, NCT02362503.).
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Antirretrovirales/uso terapéutico , Infecciones por VIH/tratamiento farmacológico , VIH-1 , Organofosfatos/uso terapéutico , Piperazinas/uso terapéutico , Adulto , Anciano , Recuento de Linfocito CD4 , Farmacorresistencia Viral Múltiple , Quimioterapia Combinada , Femenino , VIH-1/genética , Humanos , Masculino , Persona de Mediana Edad , Profármacos/uso terapéutico , ARN Viral/sangre , Carga Viral/efectos de los fármacosRESUMEN
Hepatitis C virus (HCV) infections are more common among US veterans receiving care through Veterans Affairs (VA) Medical Centers than among the general population. Historically, HCV therapies had lower efficacy rates in VA patients, possibly due to common comorbidities such as psychiatric disorders and substance abuse. The direct-acting antivirals ombitasvir/paritaprevir/ritonavir and dasabuvir (OBV/PTV/r+DSV)±ribavirin (RBV) are approved in the US for HCV genotype 1 (GT1)-infected adults with or without cirrhosis. This study prospectively evaluated the safety and efficacy of OBV/PTV/r+DSV±RBV in VA patients with HCV GT1 infection. TOPAZ-VA was a phase 3b, open-label trial. Adult US veterans with HCV GT1 infection, without cirrhosis or with compensated cirrhosis, were eligible for enrollment. Patients with GT1a infection received OBV/PTV/r +DSV+RBV for 12 weeks or 24 weeks (for those with cirrhosis); GT1b-infected patients without cirrhosis received OBV/PTV/r +DSV for 12 weeks; those with cirrhosis received OBV/PTV/r +DSV with RBV. The primary endpoint was sustained virologic response at posttreatment week 12 (SVR12); safety was also assessed. Ninety-nine patients were enrolled at 10 sites from May through November 2015. The majority were male (96%), white (60%), and with GT1a infection (68%); 49% reported ongoing psychiatric disorders. Overall, 94% (93/99) achieved SVR12; three patients had a virologic failure. The most common AEs were fatigue (28%), headache (20%), and nausea (15%); six patients discontinued treatment due to AEs. In US veterans with HCV GT1 infection, OBV/PTV/r +DSV±RBV yielded a 94% overall SVR12 rate and was well tolerated. The presence of psychiatric disorders and/or injection drug use did not impact efficacy.
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OBJECTIVE: Very-low-level viremia (VLLV) is a relatively new concept in the realm of human immunodeficiency virus (HIV) care. Newer generation assays are now able to detect plasma HIV RNA Viral Load (VL) levels as low as 20 copies/mL. The authors characterized patients with VLLV (VL between 20 and 50 copies/mL) in order to identify possible risk factors associated with virologic failure and poor clinical outcomes. METHODS: The authors reviewed 119 consecutive charts of patients with VLLV. Sociodemographic data were extracted and viral load and CD4 counts were trended over a 12 month period (February 2013-February 2014). Regression analysis was used to assess the role of different factors on virologic failure at 1 year. RESULTS: Of the study participants with evaluable data (n = 100), the median age was 53 years (interquartile range: 43-57.5), 67% were nonwhite, 34% were women, 58% were smokers, 47% were alcoholics, 58% had a history of intravenous drug use, and 40% were coinfected with hepatitis C virus. More than half of the participants had 3 or more comorbidities and their HIV pill burden was high (more than 2 pills daily). After 12 months, 65 participants achieved undetectable viral load levels, whereas 15 experienced virologic failure (2 consecutive viral loads > 50 copies/mL) and the remaining 20 had persistent VLLV. In the virologic failure group, there was a predominance of white males (66%) with a significant number of comorbidities and pill burden. Univariate logistic regression suggested that there was a difference between the failure versus nonfailure groups in terms of race, ethnicity, and alcohol use. Multivariate regression with virological failure as the outcome suggested a trend only in terms of participant's alcohol use. CONCLUSION: Most patients with initial VLLV (70%) achieved virologic suppression at 1 year with no antiretroviral therapy changes. Thus, VLLV does not necessarily predict virologic failure and should not prompt more frequent clinic visits or antiretroviral regimen changes. Further research is needed in order to determine the predictors of virologic failure in this subset of patients and the clinicians' attitude toward VLLV.
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Infecciones por VIH/virología , Viremia/virología , Adulto , Fármacos Anti-VIH/uso terapéutico , Recuento de Linfocito CD4 , Femenino , Infecciones por VIH/tratamiento farmacológico , Infecciones por VIH/inmunología , VIH-1/efectos de los fármacos , VIH-1/genética , VIH-1/fisiología , Humanos , Masculino , Persona de Mediana Edad , Carga Viral/efectos de los fármacos , Viremia/tratamiento farmacológico , Viremia/inmunologíaRESUMEN
OBJECTIVE: Determine HIV drug resistance mutations (DRMs) prevalence at low and high levels in ART-experienced patients experiencing virologic failure (VF). METHODS: 29 subjects from 18 counties in Hunan Province that experienced VF were evaluated for the prevalence of DRMs (Stanford DRMs with an algorithm value ≥15, include low-, intermediate and high-level resistance) by both Sanger sequencing (SS) and deep sequencing (DS) to 1% frequency levels. RESULTS: DS was performed on samples from 29 ART-experienced subjects; the median viral load 4.95×10(4) c/ml; 82.76% subtype CRF01_AE. 58 DRMs were detected by DS. 18 DRMs were detected by SS. Of the 58 mutations detected by DS, 40 were at levels <20% frequency (26 NNRTI, 12 NRTI and 2 PI) and the majority of these 95.00% (38/40) were not detected by standard genotyping. Of these 40 low-level DRMs, 16 (40%) were detected at frequency levels of 1-4% and 24 (60%) at levels of 5-19%. SS detected 15 of 17 (88.24%) DRMs at levels ≥ 20% that were detected by DS. The only variable associated with the detection of DRMs by DS was ART adherence (missed doses in the prior 7 days); all patients that reported missing a dose in the last 7 days had DRMs detected by DS. CONCLUSIONS: DS of VF samples from treatment experienced subjects infected with primarily AE subtype frequently identified Stanford HIVdb NRTI and NNRTI resistance mutations with an algorithm value 15. Low frequency level resistant variants detected by DS were frequently missed by standard genotyping in VF specimens from antiretroviral-experienced subjects.
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Farmacorresistencia Viral , Infecciones por VIH/virología , VIH-1/efectos de los fármacos , VIH-1/genética , Mutación , Adulto , Anciano , Terapia Antirretroviral Altamente Activa , China , Femenino , Infecciones por VIH/diagnóstico , Infecciones por VIH/tratamiento farmacológico , Infecciones por VIH/epidemiología , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Incidencia , Masculino , Cumplimiento de la Medicación , Persona de Mediana Edad , Prevalencia , Factores de Riesgo , Insuficiencia del Tratamiento , Carga Viral , Adulto JovenRESUMEN
UNLABELLED: Elite controllers (ECs) are a rare group of HIV seropositive individuals who are able to control viral replication without antiretroviral therapy. The mechanisms responsible for this phenotype, however, have not been fully elucidated. In this study, we examined CD4(+) T cell resistance to HIV in a cohort of elite controllers and explored transcriptional signatures associated with cellular resistance. We demonstrate that a subgroup of elite controllers possess CD4(+) T cells that are specifically resistant to R5-tropic HIV while remaining fully susceptible to X4-tropic and vesicular stomatitis virus G (VSV-G)-pseudotyped viruses. Transcriptome analysis revealed 17 genes that were differentially regulated in resistant elite controllers relative to healthy controls. Notably, the genes encoding macrophage inflammatory protein 1α (MIP-1α), CCL3 and CCL3L1, were found to be upregulated. The MIP-1α, MIP-1ß, and RANTES chemokines are natural ligands of CCR5 and are known to interfere with HIV replication. For three elite controllers, we observed increased production of MIP-1α and/or MIP-1ß at the protein level. The supernatant from resistant EC cells contained MIP-1α and MIP-1ß and was sufficient to confer R5-tropic resistance to susceptible CD4(+) T cells. Additionally, this effect was reversed by using inhibitory anti-MIP antibodies. These results suggest that the T cells of these particular elite controllers may be naturally resistant to HIV infection by blocking R5-tropic viral entry. IMPORTANCE: HIV is a pandemic health problem, and the majority of seropositive individuals will eventually progress to AIDS unless antiretroviral therapy (ART) is administered. However, rare patients, termed elite controllers, have a natural ability to control HIV infection in the absence of ART, but the mechanisms by which they achieve this phenotype have not been fully explored. This paper identifies one mechanism that may contribute to this natural resistance: some elite controllers have CD4(+) T cells that produce high levels of MIP chemokines, which block R5-tropic HIV entry. This mechanism could potentially be exploited to achieve a therapeutic effect in other HIV-seropositive individuals.
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Infecciones por VIH/inmunología , Sobrevivientes de VIH a Largo Plazo , VIH-1 , Proteínas Inflamatorias de Macrófagos/sangre , Adulto , Anciano , Linfocitos T CD4-Positivos/inmunología , Linfocitos T CD4-Positivos/virología , Estudios de Casos y Controles , Quimiocina CCL3/sangre , Quimiocina CCL3/genética , Quimiocina CCL4/sangre , Quimiocina CCL4/genética , Quimiocina CCL5/sangre , Quimiocina CCL5/genética , Quimiocinas CC/sangre , Quimiocinas CC/genética , Estudios de Cohortes , Femenino , Dosificación de Gen , Infecciones por VIH/genética , Infecciones por VIH/virología , VIH-1/inmunología , VIH-1/patogenicidad , Interacciones Huésped-Patógeno , Humanos , Proteínas Inflamatorias de Macrófagos/genética , Masculino , Persona de Mediana Edad , ARN Mensajero/sangre , ARN Mensajero/genética , Receptores CCR5/sangre , Receptores CXCR4/sangre , Regulación hacia ArribaRESUMEN
BACKGROUND: Limited data exist comparing viral quasispecies between cerebrospinal fluid (CSF) and plasma compartments during primary HIV infection. Deep sequencing is a new method to examine the HIV plasma and CSF quasispecies. METHODS: In this pilot study, deep sequencing of protease (PR) and reverse transcriptase (RT) was performed in plasma and CSF from participants during primary HIV infection. Estimated mutational load was calculated by mutant variant frequency multiplied by HIV-RNA level. RESULTS: Paired plasma and CSF samples were studied from five antiretroviral therapy-naïve male participants with median 109 days post estimated transmission, age 32 years, CD4 cell count 580 cells/µL, HIV-RNA 5.18 log10 copies/mL in plasma and 3.67 log10 copies/mL in CSF. Plasma samples averaged 7,124 reads of PR and 2,448 reads of RT, whereas CSF samples averaged 7,082 and 2,792 reads, respectively. A distinct drug-resistance pattern with linked mutations present at significant levels (5-10%) was detected in one participant in CSF. Other low abundance variants (>0.2%) were detected in plasma and CSF of four out of five participants. CONCLUSIONS: Deep sequencing of CSF HIV is technically possible with sufficient HIV-RNA levels. Differences between the quasispecies in the two compartments detected in one participant, which were present with a high mutational load in CSF at an estimated 3.6 months after HIV infection, suggest that early CNS compartmentalisation may be revealed by sensitive deep-sequencing methods. The presence of distinct low abundance (<1%) resistance variants in plasma and CSF of three other subjects may be significant, but further investigation is needed.
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PURPOSE OF REVIEW: The review discusses new technologies for the sensitive detection of HIV drug resistance, with a focus on applications in antiretroviral treatment (ART)-naïve populations. RECENT FINDINGS: Conventional sequencing is well established for detecting HIV drug resistance in routine care and guides optimal treatment selection in patients starting ART. Access to conventional sequencing is nearly universal in Western countries, but remains limited in Asia, Latin America, and Africa. Technological advances now allow detection of resistance with greatly improved sensitivity compared with conventional sequencing, variably increasing the yield of resistance testing in ART-naïve populations. There is strong cumulative evidence from retrospective studies that sensitive detection of resistant mutants in baseline plasma samples lacking resistance by conventional sequencing more than doubles the risk of virological failure after starting efavirenz-based or nevirapine-based ART. SUMMARY: Sensitive resistance testing methods are mainly confined to research applications and in this context have provided great insight into the dynamics of drug resistance development, persistence, and transmission. Adoption in care settings is becoming increasingly possible, although important challenges remain. Platforms for diagnostic use must undergo technical improvements to ensure good performance and ease of use, and clinical validation is required to ensure utility.
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Fármacos Anti-VIH/metabolismo , ADN Viral/aislamiento & purificación , Farmacorresistencia Viral/genética , Infecciones por VIH/tratamiento farmacológico , Mutación/genética , ARN Viral/aislamiento & purificación , Análisis de Secuencia de ADN/métodos , Terapia Antirretroviral Altamente Activa , ADN Viral/genética , Técnicas de Genotipaje/economía , Infecciones por VIH/genética , VIH-1/efectos de los fármacos , Asignación de Recursos para la Atención de Salud/economía , Humanos , Tamizaje Masivo/economía , Datos de Secuencia Molecular , ARN Viral/genética , Sensibilidad y Especificidad , Análisis de Secuencia de ADN/economíaRESUMEN
Low-frequency HIV variants possessing resistance mutations against nonnucleoside reverse transcriptase inhibitors (NNRTI), especially at HIV reverse transcriptase (RT) amino acid (aa) positions K103 and Y181, have been shown to adversely affect treatment response. Therapeutic failure correlates with both the mutant viral variant frequency and the mutational load. We determined the prevalence of NNRTI resistance mutations at several RT aa positions in viruses from 204 antiretroviral (ARV)-naïve HIV-infected individuals using deep sequencing, and examined the relationship between mutant variant frequency and mutational load for those variants. Deep sequencing to ≥0.4% levels found variants with major NNRTI-resistance mutations having a Stanford-HIVdb algorithm value ≥30 for efavirenz and/or nevirapine in 52/204 (25.5%) ARV-naïve HIV-infected persons. Eighteen different major NNRTI mutations were identified at 11 different positions, with the majority of variants being at frequency >1%. The frequency of these variants correlated strongly with the mutational load, but this correlation weakened at low frequencies. Deep sequencing detected additional major NNRTI-resistant viral variants in treatment-naïve HIV-infected individuals. Our study suggests the significance of screening for mutations at all RT aa positions (in addition to K103 and Y181) to estimate the true burden of pre-treatment NNRTI-resistance. An important finding was that variants at low frequency had a wide range of mutational loads (>100-fold) suggesting that frequency alone may underestimate the impact of specific NNRTI-resistant variants. We recommend further evaluation of all low-frequency NNRTI-drug resistant variants with special attention given to the impact of mutational loads of these variants on treatment outcomes.
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Fármacos Anti-VIH/farmacología , Farmacorresistencia Viral/genética , Infecciones por VIH/virología , VIH-1/genética , Mutación , Inhibidores de la Transcriptasa Inversa/farmacología , Fármacos Anti-VIH/uso terapéutico , Infecciones por VIH/tratamiento farmacológico , Humanos , Tasa de Mutación , Inhibidores de la Transcriptasa Inversa/uso terapéuticoRESUMEN
BACKGROUND: There are few data on the prevalence of WHO transmitted drug resistance mutations (TDRs) that could affect treatment responses to first line antiretroviral therapy (ART) in Hunan Province, China. OBJECTIVE: Determine the prevalence of WHO NRTI/NNRTI/PI TDRs in ART-naïve subjects in Hunan Province by deep sequencing. METHODS: ART-naïve subjects diagnosed in Hunan between 2010-2011 were evaluated by deep sequencing for low-frequency HIV variants possessing WHO TDRs to 1% levels. Mutations were scored using the HIVdb.stanford.edu algorithm to infer drug susceptibility. RESULTS: Deep sequencing was performed on samples from 90 ART-naïve subjects; 83.3% were AE subtype. All subjects had advanced disease (average CD4 count 134 cells/mm3). Overall 25.6%(23/90) of subjects had HIV with major WHO NRTI/NNRTI TDRs by deep sequencing at a variant frequency level ≥ 1%; 16.7%(15/90) had NRTI TDR and 12.2%(11/90) had a major NNRTI TDR. The majority of NRTI/NNRTI mutations were identified at variant levels <5%. Mutations were analyzed by HIVdb.stanford.edu and 7.8% of subjects had variants with high-level nevirapine resistance; 4.4% had high-level NRTI resistance. Deep sequencing identified 24(27.6%) subjects with variants possessing either a PI TDR or hivdb.stanford.edu PI mutation (algorithm value ≥ 15). 17(19.5%) had PI TDRs at levels >1%. CONCLUSIONS: ART-naïve subjects from Hunan Province China infected predominantly with subtype AE frequently possessed HIV variants with WHO NRTI/NNRTI TDRs by deep sequencing that would affect the first line ART used in the region. Specific mutations conferring nevirapine high-level resistance were identified in 7.8% of subjects. The majority of TDRs detected were at variant levels <5% likely due to subjects having advanced chronic disease at the time of testing. PI TDRs were identified frequently, but were found in isolation and at low variant frequency. As PI/r use is infrequent in Hunan, the existence of PI mutations likely represent AE subtype natural polymorphism at low variant level frequency.
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Farmacorresistencia Viral , Infecciones por VIH/epidemiología , Infecciones por VIH/virología , VIH-1/genética , Mutación , Adulto , Anciano , Fármacos Anti-VIH/farmacología , Recuento de Linfocito CD4 , Femenino , Genotipo , Infecciones por VIH/inmunología , Infecciones por VIH/transmisión , VIH-1/efectos de los fármacos , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Masculino , Persona de Mediana Edad , Prevalencia , Carga Viral , Adulto JovenRESUMEN
Human immunodeficiency virus (HIV) exhibits remarkable diversity in its genomic makeup and exists in any given individual as a complex distribution of closely related but nonidentical genomes called a viral quasispecies, which is subject to genetic variation, competition, and selection. This viral diversity clinically manifests as a selection of mutant variants based on viral fitness in treatment-naive individuals and based on drug-selective pressure in those on antiretroviral therapy (ART). The current standard-of-care ART consists of a combination of antiretroviral agents, which ensures maximal viral suppression while preventing the emergence of drug-resistant HIV variants. Unfortunately, transmission of drug-resistant HIV does occur, affecting 5% to >20% of newly infected individuals. To optimize therapy, clinicians rely on viral genotypic information obtained from conventional population sequencing-based assays, which cannot reliably detect viral variants that constitute <20% of the circulating viral quasispecies. These low-frequency variants can be detected by highly sensitive genotyping methods collectively grouped under the moniker of deep sequencing. Low-frequency variants have been correlated to treatment failures and HIV transmission, and detection of these variants is helping to inform strategies for vaccine development. Here, we discuss the molecular virology of HIV, viral heterogeneity, drug-resistance mutations, and the application of deep sequencing technologies in research and the clinical care of HIV-infected individuals.
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Genoma Viral , Infecciones por VIH/genética , VIH/genética , Secuenciación de Nucleótidos de Alto Rendimiento , Farmacorresistencia Viral/genética , VIH/química , VIH/patogenicidad , Infecciones por VIH/tratamiento farmacológico , Infecciones por VIH/epidemiología , Infecciones por VIH/transmisión , Infecciones por VIH/virología , Humanos , MutaciónRESUMEN
The role of financial incentives in HIV care is not well studied. We conducted a single-site study of monetary incentives for viral load suppression, using each patient as his own control. The incentive size ($100/quarter) was designed to be cost-neutral, offsetting estimated downstream costs averted through reduced HIV transmission. Feasibility outcomes were clinic workflow, patient acceptability, and patient comprehension. Although the study was not powered for effectiveness, we also analyzed viral load suppression. Of 80 eligible patients, 77 consented, and 69 had 12 month follow-up. Feasibility outcomes showed minimal impact on patient workflow, near-unanimous patient acceptability, and satisfactory patient comprehension. Among individuals with detectable viral loads pre-intervention, the proportion of undetectable viral load tests increased from 57 to 69 % before versus after the intervention. It is feasible to use financial incentives to reward ART adherence, and to specify the incentive by requiring cost-neutrality and targeting biological outcomes.