RESUMO
BACKGROUND: Inflammation is associated with end-organ disease and mortality for people with human immunodeficiency virus (PWH). Ruxolitinib, a Jak 1/2 inhibitor, reduces systemic inflammation for individuals without human immunodeficiency virus (HIV) and HIV reservoir markers ex vivo. The goal of this trial was to determine safety and efficacy of ruxolitinib for PWH on antiretroviral therapy (ART). METHODS: AIDS Clinical Trials Group (ACTG) A5336 was an open-label, multisite, randomized controlled trial (RCT). Participants were randomly assigned (2:1) using centralized software to ruxolitinib (10 mg twice daily) plus stable ART for 5 weeks vs ART alone, stratified by efavirenz use. Eligible participants were suppressed on ART for ≥2 years, without comorbidities, and had >350 CD4+ T cells/µL. Primary endpoints were premature discontinuation, safety events, and change in plasma interleukin 6 (IL-6). Secondary endpoints included other measures of inflammation/immune activation and HIV reservoir. RESULTS: Sixty participants were enrolled from 16 May 2016 to 10 January 2018. Primary safety events occurred in 2.5% (1 participant) for ruxolitinib and 0% for controls (Pâ =â .67). Three participants (7.5%) prematurely discontinued ruxolitinib. By week 5, differences in IL-6 (mean fold change [FC], 0.93 vs 1.10; Pâ =â .18) and soluble CD14 (mean FC, 0.96 vs 1.08; relative FC, 0.96 [90% confidence interval {CI}, .90-1.02]) levels for ruxolitinib vs controls was observed. Ruxolitinib reduced CD4+ T cells expressing HLA-DR/CD38 (mean difference, -0.34% [90% CI, -.66% to -.12%]) and Bcl-2 (mean difference, -3.30% [90% CI, -4.72% to -1.87%]). CONCLUSIONS: In this RCT of healthy, virologically suppressed PWH on ART, ruxolitinib was well-tolerated. Baseline IL-6 levels were normal and showed no significant reduction. Ruxolitinib significantly decreased markers of immune activation and cell survival. Future studies of Jak inhibitors should target PWH with residual inflammation despite suppressive ART. CLINICAL TRIALS REGISTRATION: NCT02475655.
Assuntos
Infecções por HIV , Pirimidinas , Adulto , HIV , Humanos , Nitrilas/uso terapêutico , Pirazóis , Pirimidinas/uso terapêuticoRESUMO
BACKGROUND: Despite low plasma human immunodeficiency virus (HIV) RNA, HIV controllers have evidence of viral replication and elevated inflammation. We assessed the effect of antiretroviral therapy (ART) on HIV suppression, immune activation, and quality of life (QoL). METHODS: A5308 was a prospective, open-label study of rilpivirine/emtricitabine/tenofovir disoproxil fumarate in ART-naive HIV controllers (N = 35), defined as having HIV RNA <500 copies/mL for ≥12 months. The primary outcome measured change in %CD38+HLA-DR+ CD8+ T cells. Residual plasma viremia was measured using the integrase single-copy assay. QoL was measured using the EQ-5D questionnaire. Outcomes were evaluated using repeated measures general estimating equations models. RESULTS: Before ART, HIV controllers with undetectable residual viremia <0.6 HIV-1 RNA copies/mL had higher CD4+ counts and lower levels of T-cell activation than those with detectable residual viremia. ART use was effective in further increasing the proportion of individuals with undetectable residual viremia (pre-ART vs after 24-48 weeks of ART: 19% vs 94%, P < .001). Significant declines were observed in the %CD38+HLA-DR+CD8+ T cells at 24-48 (-4.0%, P = .001) and 72-96 (-7.2%, P < .001) weeks after ART initiation. ART use resulted in decreases of several cellular markers of immune exhaustion and in a modest but significant improvement in self-reported QoL. There were no significant changes in CD4+ counts or HIV DNA. CONCLUSIONS: ART in HIV controllers reduces T-cell activation and improves markers of immune exhaustion. These results support the possible clinical benefits of ART in this population.
Assuntos
Infecções por HIV , HIV-1 , Contagem de Linfócito CD4 , Linfócitos T CD4-Positivos , Linfócitos T CD8-Positivos , Infecções por HIV/tratamento farmacológico , Humanos , Ativação Linfocitária , Estudos Prospectivos , Qualidade de Vida , Carga ViralRESUMO
BACKGROUND: The discovery of potent and broadly neutralizing antibodies (bNAbs) against human immunodeficiency virus (HIV) has made passive immunization a potential strategy for the prevention and treatment of HIV infection. We sought to determine whether passive administration of VRC01, a bNAb targeting the HIV CD4-binding site, can safely prevent or delay plasma viral rebound after the discontinuation of antiretroviral therapy (ART). METHODS: We conducted two open-label trials (AIDS Clinical Trials Group [ACTG] A5340 and National Institutes of Health [NIH] 15-I-0140) of the safety, side-effect profile, pharmacokinetic properties, and antiviral activity of VRC01 in persons with HIV infection who were undergoing interruption of ART. RESULTS: A total of 24 participants were enrolled, and one serious alcohol-related adverse event occurred. Viral rebound occurred despite plasma VRC01 concentrations greater than 50 µg per milliliter. The median time to rebound was 4 weeks in the A5340 trial and 5.6 weeks in the NIH trial. Study participants were more likely than historical controls to have viral suppression at week 4 (38% vs. 13%, P=0.04 by a two-sided Fisher's exact test in the A5340 trial; and 80% vs. 13%, P<0.001 by a two-sided Fisher's exact test in the NIH trial) but the difference was not significant at week 8. Analyses of virus populations before ART as well as before and after ART interruption showed that VRC01 exerted pressure on rebounding virus, resulting in restriction of recrudescent viruses and selection for preexisting and emerging antibody neutralization-resistant virus. CONCLUSIONS: VRC01 slightly delayed plasma viral rebound in the trial participants, as compared with historical controls, but it did not maintain viral suppression by week 8. In the small number of participants enrolled in these trials, no safety concerns were identified with passive immunization with a single bNAb (VRC01). (Funded by the National Institute of Allergy and Infectious Diseases and others; ACTG A5340 and NIH 15-I-0140 ClinicalTrials.gov numbers, NCT02463227 and NCT02471326 .).
Assuntos
Anticorpos Monoclonais/uso terapêutico , Anticorpos Neutralizantes/uso terapêutico , Infecções por HIV/tratamento farmacológico , HIV/isolamento & purificação , Viremia/prevenção & controle , Adulto , Idoso , Anticorpos Monoclonais/efeitos adversos , Anticorpos Monoclonais/farmacocinética , Anticorpos Neutralizantes/efeitos adversos , Anticorpos Amplamente Neutralizantes , Feminino , HIV/genética , Anticorpos Anti-HIV , Infecções por HIV/virologia , Estudo Historicamente Controlado , Humanos , Masculino , Pessoa de Meia-Idade , Filogenia , RNA Viral/sangue , Carga ViralRESUMO
Background: Reversing immune exhaustion with an anti-PD-L1 antibody may improve human immunodeficiency virus type 1 (HIV-1)-specific immunity and increase clearance of HIV-1-expressing cells. Methods: We conducted a phase I, randomized, double-blind, placebo-controlled, dose-escalating study of BMS-936559, including HIV-1-infected adults aged >18 to <70 years on suppressive antiretroviral therapy with CD4+ counts >350 cells/µL and detectable plasma HIV-1 RNA by single-copy assay. Data on single infusions of BMS-936559 (0.3 mg/kg) versus placebo are described. The primary outcomes were safety defined as any grade 3 or greater or immune-related adverse event (AE) and the change in HIV-1 Gag-specific CD8+ T cell responses from baseline to day 28 after infusion. Results: Eight men enrolled: 6 received 0.3 mg/kg of BMS-936559, and 2 received placebo infusions. There were no BMS-936559-related grade 3 or greater AEs. In 1 participant, asymptomatic hypophysitis (a protocol-defined immune-related AE) was identified 266 days after BMS-936559 infusion; it resolved over time. The mean percentage of HIV-1 Gag-specific CD8+ T cells expressing interferon γ increased from baseline (0.09%) through day 28 (0.20%; P = .14), driven by substantial increases in 2 participants who received BMS-936559. Conclusions: In this first evaluation of an immunologic checkpoint inhibitor in healthy HIV-1-infected persons, single low-dose BMS-936559 infusions appeared to enhance HIV-1-specific immunity in a subset of participants. Clinical Trials Registration: NCT02028403.
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Antirretrovirais/uso terapêutico , Anticorpos Monoclonais/uso terapêutico , Antígeno B7-H1/antagonistas & inibidores , Infecções por HIV/tratamento farmacológico , Adulto , Linfócitos T CD8-Positivos , Infecções por HIV/imunologia , Infecções por HIV/virologia , HIV-1 , Humanos , Masculino , Pessoa de Meia-IdadeRESUMO
UNLABELLED: Abnormal levels of inflammation are associated with cardiovascular disease and mortality in human immunodeficiency virus (HIV)-infected patients. Microbial translocation, which may cause inflammation, is decreased by sevelamer in patients undergoing hemodialysis. In this single-arm study, we evaluated the effects of 8 weeks of sevelamer therapy on 36 HIV-infected subjects who were not receiving antiretroviral therapy. Sevelamer did not significantly change markers of microbial translocation, inflammation, or T-cell activation. During sevelamer treatment, however, levels of soluble tissue factor, low-density lipoprotein (LDL) cholesterol, and oxidized LDL cholesterol decreased significantly, whereas D-dimer levels increased. Thus, in this study population, sevelamer did not reduce microbial translocation but may have yielded cardiovascular benefits. CLINICAL TRIALS REGISTRATION: NCT 01543958.
Assuntos
Translocação Bacteriana , Fármacos Cardiovasculares/uso terapêutico , LDL-Colesterol/sangue , Infecções por HIV/complicações , Lipoproteínas LDL/sangue , Poliaminas/uso terapêutico , Tromboplastina/análise , Adulto , Doenças Cardiovasculares/prevenção & controle , Infecções por HIV/tratamento farmacológico , Humanos , Receptores de Lipopolissacarídeos/sangue , Lipopolissacarídeos/sangue , Masculino , Pessoa de Meia-Idade , Sevelamer , Resultado do Tratamento , Adulto JovemRESUMO
Background: T cells in people with human immunodeficiency virus (HIV) demonstrate an exhausted phenotype, and HIV-specific CD4+ T cells expressing programmed cell death 1 (PD-1) are enriched for latent HIV, making antibody to PD-1 a potential strategy to target the latent reservoir. Methods: This was a phase 1/2, randomized (4:1), double-blind, placebo-controlled study in adults with suppressed HIV on antiretroviral therapy with CD4+ counts ≥350 cells/µL who received 2 infusions of cemiplimab versus placebo. The primary outcome was safety, defined as any grade 3 or higher adverse event (AE) or any immune-related AE (irAE). Changes in HIV-1-specific polyfunctional CD4+ and CD8+ T-cell responses were evaluated. Results: Five men were enrolled (median CD4+ count, 911â cells/µL; median age, 51 years); 2 received 1 dose of cemiplimab, 2 received 2 doses, and 1 received placebo. One participant had a probable irAE (thyroiditis, grade 2); another had a possible irAE (hepatitis, grade 3), both after a single low-dose (0.3 mg/kg) infusion. The Safety Monitoring Committee recommended no further enrollment or infusions. All 4 cemiplimab recipients were followed for 48 weeks. No other cemiplimab-related serious AEs, irAEs, or grade 3 or higher AEs occurred. One 2-dose recipient of cemiplimab had a 6.2-fold increase in polyfunctional, Gag-specific CD8+ T-cell frequency with supportive increases in plasma HIV RNA and decreases in total HIV DNA. Conclusions: One of 4 participants exhibited increased HIV-1-specific T-cell responses and transiently increased HIV-1 expression following 2 cemiplimab infusions. The occurrence of irAEs after a single, low dose may limit translating the promising therapeutic results of cemiplimab for cancer to immunotherapeutic and latency reversal strategies for HIV. Clinical Trials Registration. NCT03787095.
RESUMO
Combination antiretroviral therapy (cART) has resulted in tremendous gains in survival among HIV-infected patients, but as a group those who achieve undetectable viral loads on cART experience a greater degree of immune activation and inflammation than the general population. HIV-infected patients continue to experience premature immune senescence with earlier and more frequent non-AIDS events compared to HIV-uninfected individuals. Chronic immune activation during suppressive cART derives from a variety of sources mediated by cytokines, chemokines, coagulation, microbial translocation, immune regulators and T(effector) cell activation abnormalities, among others. Current investigational strategies to control immune activation target potential causes of persistently heightened immune activation during cART such as microbial translocation, co-infections, and comorbidities or mediators along a common final pathway. Although several interventions have shown promise in vitro or in preliminary clinical trials, no intervention has sufficient evidence for routine use, making control of immune activation during cART an unmet need.
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Antirretrovirais/uso terapêutico , Infecções por HIV/tratamento farmacológico , Infecções por HIV/imunologia , Imunidade Inata , Ativação Linfocitária/imunologia , Linfócitos T CD4-Positivos/imunologia , Doença Crônica , Coinfecção , Quimioterapia Combinada/métodos , Humanos , Imunidade Inata/efeitos dos fármacos , Ativação Linfocitária/efeitos dos fármacos , Replicação Viral/efeitos dos fármacosRESUMO
Ruxolitinib is a US Food and Drug Administration-approved orally administered Janus kinase (1/2) inhibitor that reduces cytokine-induced inflammation. As part of a randomized, phase 2, open-label trial, ruxolitinib (10 mg twice daily) was administered to HIV-positive, virologically suppressed individuals (33 men, 7 women) on antiretroviral therapy (ART) for 5 weeks. Herein, we report the population PK subsequently determined from this study. Plasma concentrations of ruxolitinib (294 samples) and antiretroviral agents were measured at week 1 (N = 39 participants) and week 4 or 5 (N = 37). Ruxolitinib PK was adequately described with a 2-compartment model with first-order absorption and elimination with distribution volumes normalized to mean body weight (91.5 kg) and a separate typical clearance for participants administered efavirenz (a known cytochrome P450 3A4 inducer). Participants administered an ART regimen with efavirenz had an elevated typical apparent oral clearance versus the integrase inhibitor regimen group (22.5 vs 12.9 L/hr; N = 14 vs 25). Post hoc predicted apparent oral clearance was likewise more variable and higher (P < .0001) in those administered efavirenz. There was an ≈25% variation in ruxolitinib plasma exposures between week 1 and week 4/5. ART plasma concentrations resembled those from PK studies without ruxolitinib. Therefore, integrase inhibitor-based ART regimens may be preferred over efavirenz-based regimens when ruxolitinib is administered to HIV-positive individuals.
Assuntos
Alcinos/farmacologia , Antirretrovirais/uso terapêutico , Benzoxazinas/farmacologia , Ciclopropanos/farmacologia , Indutores do Citocromo P-450 CYP3A/farmacologia , Infecções por HIV/tratamento farmacológico , Nitrilas/farmacocinética , Pirazóis/farmacocinética , Pirimidinas/farmacocinética , Adulto , Antirretrovirais/farmacocinética , Peso Corporal , Interações Medicamentosas , Feminino , Humanos , Janus Quinases/antagonistas & inibidores , Masculino , Taxa de Depuração Metabólica , Pessoa de Meia-Idade , Nitrilas/administração & dosagem , Pirazóis/administração & dosagem , Pirimidinas/administração & dosagemRESUMO
WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT: * Maraviroc is a CCR5 receptor antagonist, while raltegravir is a HIV-1 integrase inhibitor. * Based on the known metabolic pathways (CYP3A4 for maraviroc and UGT1A1 for raltegravir), interaction between the two drugs is unlikely. However, unexpected interactions have been reported for other antiretroviral drugs. * As both these drugs are likely to be used in combination, this study evaluated the pharmacokinetic interaction between them. WHAT THIS STUDY ADDS: * Relative to individual monotherapy, co-administration resulted in a 20% and 33% decrease in mean C(max), and 14% and 37% decrease in mean AUC of maraviroc and raltegravir, respectively. * Co-administration was generally safe and well tolerated in healthy subjects. * These changes are not likely to be clinically relevant, thus no dose adjustment is necessary. AIMS: To assess the two-way pharmacokinetic interaction between maraviroc and raltegravir. METHODS: In this open-label, multiple-dose, fixed-sequence study, 18 healthy, human immunodeficiency virus (HIV)-seronegative subjects received the following: days 1-3 raltegravir 400 mg q12h, days 4-5 washout, days 6-11 maraviroc 300 mg q12h, and days 12-14 raltegravir 400 mg q12h + maraviroc 300 mg q12h. Serial 12-h blood samples were collected on days 3 (raltegravir), 11 (maraviroc) and 14 (raltegravir + maraviroc). Plasma samples were assayed by validated liquid chromatography tandem mass spectrometry assays. Test/reference ratios and 95% confidence intervals (CIs) were determined for pharmacokinetic parameters. RESULTS: For maraviroc, the test/reference % ratio (95% CI) for AUC(tau) was 85.8 (78.7, 93.5), for C(max) was 79.5 (64.8, 97.5) and for C(min) was 90.3 (84.2, 96.9). For raltegravir, the test/reference % ratio (95% CI) for AUC(tau) was 63.3 (41.0, 97.6), for C(max) was 66.8 (37.1, 120.0) and for C(min) was 72.4 (55.1, 95.2). In all subjects, maraviroc average concentrations (AUC(tau) divided by 12) were >100 ng ml(-1), the threshold value below which there is an increased risk of virological failure. Based on clinical experience for raltegravir, mean C(min) decreases >60% are considered to be clinically relevant for short-term activity; however, in the present study mean changes were only 28% and thus not considered to be of clinical relevance. CONCLUSIONS: Co-administration of maraviroc and raltegravir decreased systemic exposure of both drugs; however, these are not likely to be clinically relevant. Safety and efficacy studies may help in understanding the role of this combination in the treatment of HIV infection.
Assuntos
Cicloexanos/farmacocinética , Inibidores da Fusão de HIV/farmacocinética , Pirrolidinonas/farmacocinética , Triazóis/farmacocinética , Adulto , Área Sob a Curva , Cromatografia Líquida , Relação Dose-Resposta a Droga , Interações Medicamentosas , Quimioterapia Combinada , Feminino , Infecções por HIV/tratamento farmacológico , Soronegatividade para HIV , Humanos , Masculino , Maraviroc , Pessoa de Meia-Idade , Raltegravir Potássico , Espectrometria de Massas em TandemRESUMO
Plasmacytoid dendritic cells (pDCs) are robust producers of IFNα and one of the first immune cells to respond to SIV infection. To elucidate responses to early HIV-1 replication, we studied blood pDCs in 29 HIV-infected participants who initiated antiretroviral therapy during acute infection and underwent analytic treatment interruption (ATI). We observed an increased frequency of partially activated pDCs in the blood before detection of HIV RNA. Concurrent with peak pDC frequency, we detected a transient decline in the ability of pDCs to produce IFNα in vitro, which correlated with decreased phosphorylation of IFN regulatory factory 7 (IRF7) and NF-κB. The levels of phosphorylated IRF7 and NF-κB inversely correlated with plasma IFNα2 levels, implying that pDCs were refractory to in vitro stimulation after IFNα production in vivo. After ATI, decreased expression of IFN genes in pDCs inversely correlated with the time to viral detection, suggesting that pDC IFN loss is part of an effective early immune response. These data from a limited cohort provide a critical first step in understanding the earliest immune response to HIV-1 and suggest that changes in blood pDC frequency and function can be used as an indicator of viral replication before detectable plasma viremia.
Assuntos
Células Dendríticas/imunologia , Infecções por HIV/imunologia , HIV-1/fisiologia , Viremia/imunologia , Replicação Viral/imunologia , Adulto , Células Dendríticas/patologia , Feminino , Infecções por HIV/patologia , Infecções por HIV/terapia , Humanos , Fator Regulador 7 de Interferon/imunologia , Interferon-alfa/imunologia , Masculino , NF-kappa B/imunologia , Viremia/patologia , Viremia/terapiaRESUMO
The National Institute of Allergy and Infectious Diseases (NIAID) organised the Strategies for an HIV Cure 2018 meeting focused on research to develop innovative strategies for eradicating or achieving long-term remission of HIV infection. The purpose was to bring together researchers studying HIV persistence and cure strategies, including the six National Institutes of Health (NIH)-funded Martin Delaney Collaboratories for HIV Cure Research (MDCs), as well as industry and community partners, to share scientific results and stimulate active discussion among all stakeholders about the merits of various approaches under investigation. These discussions were intended to stimulate new collaborations and ideas for future research. The meeting covered a comprehensive range of topics spanning basic and translational research, drug discovery and development, and clinical research. Aside from the oral presentations described here, the meeting also included 130 poster presentations. Each of the three days of presentations is available for viewing via the NIH VideoCast website at: https://videocast.nih.gov/PastEvents.asp.
RESUMO
BACKGROUND: HIV-1-specific broadly neutralising antibodies such as VRC01 could promote HIV remission by halting viral replication and clearing infected cells. We investigated whether VRC01 could promote sustained viral control off antiretroviral therapy (ART) in adults who initiated ART during acute HIV infection. METHODS: We did a randomised, double-blind, placebo-controlled trial at the Thai Red Cross AIDS Research Centre in Bangkok, Thailand. Eligible participants were aged 20-50 years, had initiated ART during acute infection (ie, Fiebig stages I-III), had been taking ART for more than 24 months, had fewer than 50 HIV-1 RNA copies per mL on three consecutive measurements, had more than 400 CD4 cells per µL, had fewer than ten copies of integrated HIV-1 DNA per 106 peripheral blood mononuclear cells, and were in generally good health. Eligible participants were randomly assigned (3:1) based on computer-generated lists with a blocking factor of 4 to receive VRC01 (40 mg/kg) or placebo (saline) intravenously every 3 weeks for up to 24 weeks during analytic interruption of ART, followed by continued observation off all therapies. Randomisation was stratified by Fiebig stage (I vs II vs III) at HIV diagnosis. Participants were monitored closely and resumed ART if 1000 or more HIV-1 RNA copies were detected per mL of plasma. The primary outcomes were the frequency of serious adverse events and the proportion of participants with fewer than 50 HIV-1 RNA copies per mL 24 weeks after treatment interruption. Efficacy analyses included all participants who received at least one full dose of study product, and safety analyses included all participants exposed to any study product. The trial was registered with ClinicalTrials.gov, number NCT02664415. This trial is completed. FINDINGS: Between Aug 8, 2016, and Jan 9, 2017, 19 men were randomly assigned, 14 to the VRC01 group and five to the placebo group. One participant in the VRC01 group received a partial infusion without undergoing treatment interruption. The other 18 participants all received at least one full study infusion and underwent ART interruption. No serious adverse events were reported in either group. Only one participant in the VRC01 group achieved the primary efficacy endpoint of viral suppression 24 weeks after ART interruption. The other 17 restarted ART because of a confirmed recording of 1000 or more HIV-1 RNA copies per mL before 24 weeks. INTERPRETATION: VRC01 monotherapy in individuals who initiated ART during acute HIV infection was well tolerated but did not significantly increase the number of participants with viral suppression 24 weeks after ART interruption. Further development of VRC01 and other immunotherapies for HIV will probably occur as part of combination regimens that include several treatments directed against unique therapeutic targets. FUNDING: US Department of the Army, US National Institutes of Health, and the Thai Red Cross AIDS Research Centre.
Assuntos
Anticorpos Monoclonais/efeitos dos fármacos , Anticorpos Amplamente Neutralizantes/efeitos dos fármacos , Anticorpos Anti-HIV/efeitos dos fármacos , Infecções por HIV/tratamento farmacológico , HIV-1/imunologia , Adulto , Anticorpos Monoclonais/imunologia , Anticorpos Monoclonais/farmacologia , Anticorpos Neutralizantes/imunologia , Anticorpos Neutralizantes/uso terapêutico , Anticorpos Antivirais/imunologia , Anticorpos Antivirais/uso terapêutico , Terapia Antirretroviral de Alta Atividade , Anticorpos Amplamente Neutralizantes/imunologia , Anticorpos Amplamente Neutralizantes/farmacologia , Contagem de Linfócito CD4 , Linfócitos T CD4-Positivos , Feminino , Anticorpos Anti-HIV/imunologia , Anticorpos Anti-HIV/farmacologia , Infecções por HIV/imunologia , Infecções por HIV/virologia , Humanos , Masculino , Pessoa de Meia-Idade , Resultado do Tratamento , Carga Viral , Adulto JovemRESUMO
Analytical antiretroviral treatment interruption (ATI) is an important feature of HIV research, seeking to achieve sustained viral suppression in the absence of antiretroviral therapy (ART) when the goal is to measure effects of novel therapeutic interventions on time to viral load rebound or altered viral setpoint. Trials with ATIs also intend to determine host, virological, and immunological markers that are predictive of sustained viral control off ART. Although ATI is increasingly incorporated into proof-of-concept trials, no consensus has been reached on strategies to maximise its utility and minimise its risks. In addition, differences in ATI trial designs hinder the ability to compare efficacy and safety of interventions across trials. Therefore, we held a meeting of stakeholders from many interest groups, including scientists, clinicians, ethicists, social scientists, regulators, people living with HIV, and advocacy groups, to discuss the main challenges concerning ATI studies and to formulate recommendations with an emphasis on strategies for risk mitigation and monitoring, ART resumption criteria, and ethical considerations. In this Review, we present the major points of discussion and consensus views achieved with the goal of informing the conduct of ATIs to maximise the knowledge gained and minimise the risk to participants in clinical HIV research.
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Antirretrovirais/administração & dosagem , Infecções por HIV/tratamento farmacológico , Suspensão de Tratamento/normas , Humanos , Resposta Viral Sustentada , Carga ViralRESUMO
BACKGROUND: The effect of a brief analytical treatment interruption (ATI) on the HIV-1 latent reservoir of individuals who initiate antiretroviral therapy (ART) during chronic infection is unknown. METHODS: We evaluated the impact of transient viremia on the latent reservoir in participants who underwent an ATI and at least 6 months of subsequent viral suppression in a clinical trial testing the effect of passive infusion of the broadly neutralizing Ab VRC01 during ATI. RESULTS: Measures of total HIV-1 DNA, cell-associated RNA, and infectious units per million cells (IUPM) (measured by quantitative viral outgrowth assay [QVOA]) were not statistically different before or after ATI. Phylogenetic analyses of HIV-1 env sequences from QVOA and proviral DNA demonstrated little change in the composition of the virus populations comprising the pre- and post-ATI reservoir. Expanded clones were common in both QVOA and proviral DNA sequences. The frequency of clonal populations differed significantly between QVOA viruses, proviral DNA sequences, and the viruses that reactivated in vivo. CONCLUSIONS: The results indicate that transient viremia from ATI does not substantially alter measures of the latent reservoir, that clonal expansion is prevalent within the latent reservoir, and that characterization of latent viruses that can reactivate in vivo remains challenging. TRIAL REGISTRATION: ClinicalTrials.gov NCT02463227FUNDING. Funding was provided by the NIH.
Assuntos
Antirretrovirais/administração & dosagem , Infecções por HIV/tratamento farmacológico , Infecções por HIV/virologia , HIV-1 , Adulto , Anticorpos Monoclonais/administração & dosagem , Anticorpos Amplamente Neutralizantes , Linfócitos T CD4-Positivos/efeitos dos fármacos , Linfócitos T CD4-Positivos/virologia , DNA Viral/sangue , DNA Viral/genética , Esquema de Medicação , Genes env , Variação Genética/efeitos dos fármacos , Anticorpos Anti-HIV , Proteína gp160 do Envelope de HIV/genética , HIV-1/classificação , HIV-1/efeitos dos fármacos , HIV-1/genética , Humanos , Masculino , Pessoa de Meia-Idade , Filogenia , Provírus/classificação , Provírus/efeitos dos fármacos , Provírus/genética , Carga Viral/efeitos dos fármacos , Viremia/tratamento farmacológico , Viremia/virologia , Latência Viral/efeitos dos fármacos , Latência Viral/genéticaRESUMO
Over the past several years there has been intense activity directed at the possibility of achieving remission or eradication of HIV infection. Current assays for the measurement of latent HIV are insufficient to demonstrate complete clearance of replication-competent HIV. Therefore, the ultimate test for assessing whether investigational interventions have resulted in HIV remission or eradication is to interrupt standard antiretroviral therapy (ART) in a carefully controlled clinical trial setting. These procedures, known as analytic treatment interruptions (ATIs), raise important scientific and ethical questions. The lack of definitive assays for measuring viral reservoirs not only makes research on HIV remission or cure challenging, it also affects the ability to assess risks from ATIs themselves. In spite of these challenges, basic ethical criteria can be met with careful study design and close monitoring. In this brief report we outline ethical standards for HIV cure research involving ATIs. These criteria should be revisited as the science evolves.
Assuntos
Infecções por HIV/tratamento farmacológico , Inibidores de Checkpoint Imunológico/efeitos adversos , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Contagem de Linfócito CD4 , Método Duplo-Cego , Infecções por HIV/imunologia , Humanos , Masculino , Pessoa de Meia-Idade , PlacebosRESUMO
Despite effective antiretroviral therapy (ART) and undetectable HIV RNA in the plasma, latent replication-competent HIV persists indefinitely in long-lived cells. Cessation of ART results in rebound of HIV from these persistent reservoirs. While this was thought to be an insurmountable obstacle to viral eradication, recent cases suggest otherwise. To date one patient has been "cured" of HIV and several others have been able to interrupt ART without viral rebound for prolonged periods. These events have sparked renewed interest in developing strategies that will allow eradication of HIV in infected individuals. We review the current knowledge of HIV latency and the viral reservoir, describe the potential utility of emerging cancer therapeutics in HIV cure research with an emphasis on pathways implicated in reservoir persistence, and outline opportunities and challenges in the context of the current clinical trial and regulatory environment.
Assuntos
Fármacos Anti-HIV/uso terapêutico , Antineoplásicos/uso terapêutico , Infecções por HIV/tratamento farmacológico , Fármacos Anti-HIV/farmacologia , Antineoplásicos/farmacologia , HIV/efeitos dos fármacos , HIV/isolamento & purificação , Infecções por HIV/virologia , Humanos , Neoplasias/tratamento farmacológicoRESUMO
Passive immunization with HIV-1-neutralizing monoclonal antibodies (mAbs) is being considered for prevention and treatment of HIV-1 infection. As therapeutic agents, mAbs could be used to suppress active virus replication, maintain suppression induced by antiretroviral therapy (ART), and/or decrease the size of the persistent virus reservoir. We assessed the impact of VRC01, a potent human mAb targeting the HIV-1 CD4 binding site, on ART-treated and untreated HIV-1-infected subjects. Among six ART-treated individuals with undetectable plasma viremia, two infusions of VRC01 did not reduce the peripheral blood cell-associated virus reservoir measured 4 weeks after the second infusion. In contrast, six of eight ART-untreated, viremic subjects infused with a single dose of VRC01 experienced a 1.1 to 1.8 log10 reduction in plasma viremia. The two subjects with minimal responses to VRC01 were found to have predominantly VRC01-resistant virus before treatment. Notably, two subjects with plasma virus load <1000 copies/ml demonstrated virus suppression to undetectable levels for over 20 days until VRC01 levels declined. Among the remaining four subjects with baseline virus loads between 3000 and 30,000 copies, viremia was only partially suppressed by mAb infusion, and we observed strong selection pressure for the outgrowth of less neutralization-sensitive viruses. In summary, a single infusion of mAb VRC01 significantly decreased plasma viremia and preferentially suppressed neutralization-sensitive virus strains. These data demonstrate the virological effect of this neutralizing antibody and highlight the need for combination strategies to maintain virus suppression.
Assuntos
Anticorpos Neutralizantes/administração & dosagem , Anticorpos Neutralizantes/imunologia , Infecções por HIV/imunologia , Infecções por HIV/virologia , HIV-1/imunologia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Terapia Antirretroviral de Alta Atividade , Linfócitos T CD4-Positivos/imunologia , Doença Crônica , Anticorpos Anti-HIV/sangue , Infecções por HIV/sangue , Infecções por HIV/tratamento farmacológico , Humanos , Cinética , Pessoa de Meia-Idade , Carga Viral/imunologia , Adulto JovemRESUMO
OBJECTIVE: We tested the hypothesis that the gastrointestinal tolerance of a new infant formula equals or exceeds the tolerance of other milk-based infant formulas and compared the tolerance of this new formula with that of human milk. METHODS: This prospective, phase IV, open-label study was conducted in 17 countries. Healthy, full-term infants, 28 to 98 d old, were enrolled on their current feeding (no treatment assigned). Feeding regimens included human milk (HM), a new infant formula (NF; Similac Advance), other infant formula (OF), HM + NF, and HM + OF. Data for stool frequency, stool consistency, and gastrointestinal symptoms were collected in study diaries for 2 wk. RESULTS: Gastrointestinal tolerance was evaluated in 6999 infants: 979 (14.0%) received HM, 1695 (24.2%) received HM + NF, 635 (9.1%) received HM + OF, 2677 (38.2%) received NF, and 1013 (14.5%) received OF. Infants fed HM had softer and more frequent stools than did those who received NF, HM + NF, or OF (P < 0.001). Infants fed NF had softer and more frequent stools than did those fed OF (P < 0.001), including those fed Enfalac or S-26 (P < 0.001). Regurgitation (P < 0.001) and colic (P = 0.006) were more frequent with OF than with NF. All feeding regimens were well tolerated and only 3.5% of subjects experienced adverse events. CONCLUSIONS: This global study demonstrated that stools of infants fed NF are softer and more frequent than stools from infants fed OF and are closer to those of breast-fed infants. Infants consuming NF also experienced less regurgitation and colic than did infants in other feeding groups.
Assuntos
Sistema Digestório/efeitos dos fármacos , Alimentos Infantis/efeitos adversos , Animais , Cólica/epidemiologia , Cólica/etiologia , Constipação Intestinal/epidemiologia , Constipação Intestinal/etiologia , Fezes/química , Feminino , Refluxo Gastroesofágico/epidemiologia , Refluxo Gastroesofágico/etiologia , Humanos , Lactente , Alimentos Infantis/análise , Fenômenos Fisiológicos da Nutrição do Lactente , Recém-Nascido , Cooperação Internacional , Masculino , Leite/efeitos adversos , Leite Humano/metabolismo , Estudos Prospectivos , SegurançaRESUMO
OBJECTIVE: The objective was to measure the total potentially available nucleosides (TPAN) in breast milk from Asian women. METHODS: One hundred sixty milk samples were collected from 135 healthy, lactating women in Hong Kong, the Philippines, and Singapore at four stages of lactation: colostrum (1 to 3 days postpartum), transitional (7 to 10 days postpartum), early mature (28 to 35 days postpartum), and late mature (90 to 100 days postpartum). Samples were pooled by site and stage of lactation before analysis. RESULTS: The mean TPAN concentration was 203 microM/L (69.4 mg/L corrected for recovery). Average TPAN concentrations were 171.9 microM/L in colostrum, 208.1 microM/L in transitional milk, 221.6 microM/L in early mature milk, and 210.6 microM/L in late mature milk, with no notable differences between countries. The major sources of nucleosides were RNA (43.3% of TPAN) and free nucleotides (39.9% of TPAN). The average percentages of cytidine, uridine, guanosine, and adenosine monophosphates were 44.5%, 23.1%, 16.5%, and 16.1% of TPAN, respectively. The sources of nucleosides and percentages of nucleotide bases were similar for all stages of lactation. Over 91% of the TPAN was present in the non-cellular component except in colostrum. CONCLUSIONS: The average TPAN level in Asian women is similar to that in European and American women, and free nucleotides in human milk represent less than half of the TPAN.