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Ronald J Bosch - One of the best experts on this subject based on the ideXlab platform.
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analytical Treatment Interruption in hiv trials statistical and study design considerations
Current Hiv\ aids Reports, 2021Co-Authors: Lu Zheng, Camlin Tierney, Ronald J BoschAbstract:Analytical Treatment Interruption (ATI) remains an essential component in clinical studies investigating novel agents or combination Treatment strategies aiming to induce HIV Treatment-free remission or long-term viral control. We provide an overview on key study design aspects of ATI trials from the perspective of statisticians. ATI trial designs have evolved towards shorter Treatment Interruption phases and more frequent viral load monitoring aiming to reduce prolonged viremia risks. Criteria for ART resumption have evolved as well. Common outcome measures in modern ATI trials include time to viral rebound, viral control, and viral set point. Design of the ATI component in HIV clinical trials is driven by the scientific question and the mechanism of action of the intervention being investigated.
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comparison of empirical and dynamic models for hiv viral load rebound after Treatment Interruption
Statistical Communications in Infectious Diseases, 2020Co-Authors: Ante Bing, Ronald J Bosch, Melanie Prague, Alison L Hill, Victor Degruttola, Rui WangAbstract:Objective To compare empirical and mechanistic modeling approaches for describing HIV-1 RNA viral load trajectories after antiretroviral Treatment Interruption and for identifying factors that predict features of viral rebound process. Methods We apply and compare two modeling approaches in analysis of data from 346 participants in six AIDS Clinical Trial Group studies. From each separate analysis, we identify predictors for viral set points and delay in rebound. Our empirical model postulates a parametric functional form whose parameters represent different features of the viral rebound process, such as rate of rise and viral load set point. The viral dynamics model augments standard HIV dynamics models-a class of mathematical models based on differential equations describing biological mechanisms-by including reactivation of latently infected cells and adaptive immune response. We use Monolix, which makes use of a Stochastic Approximation of the Expectation-Maximization algorithm, to fit non-linear mixed effects models incorporating observations that were below the assay limit of quantification. Results Among the 346 participants, the median age at Treatment Interruption was 42. Ninety-three percent of participants were male and sixty-five percent, white non-Hispanic. Both models provided a reasonable fit to the data and can accommodate atypical viral load trajectories. The median set points obtained from two approaches were similar: 4.44 log10 copies/mL from the empirical model and 4.59 log10 copies/mL from the viral dynamics model. Both models revealed that higher nadir CD4 cell counts and ART initiation during acute/recent phase were associated with lower viral set points and identified receiving a non-nucleoside reverse transcriptase inhibitor (NNRTI)-based pre-ATI regimen as a predictor for a delay in rebound. Conclusion Although based on different sets of assumptions, both models lead to similar conclusions regarding features of viral rebound process.
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a flexible nonlinear mixed effects model for hiv viral load rebound after Treatment Interruption
Statistics in Medicine, 2020Co-Authors: Rui Wang, Ronald J Bosch, Ante Bing, Cathy Wang, Victor DegruttolaAbstract:Characterization of HIV viral rebound after the discontinuation of antiretroviral therapy is central to HIV cure research. We propose a parametric nonlinear mixed effects model for the viral rebound trajectory, which often has a rapid rise to a peak value followed by a decrease to a viral load set point. We choose a flexible functional form that captures the shapes of viral rebound trajectories and can also provide biological insights regarding the rebound process. Each parameter can incorporate a random effect to allow for variation in parameters across individuals. Key features of viral rebound trajectories such as viral set points are represented by the parameters in the model, which facilitates assessment of intervention effects and identification of important preTreatment Interruption predictors for these features. We employ a stochastic expectation-maximization (StEM) algorithm to incorporate HIV-1 RNA values that are below the lower limit of assay quantification. We evaluate the performance of our model in simulation studies and apply the proposed model to longitudinal HIV-1 viral load data from five AIDS Clinical Trials Group Treatment Interruption studies.
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circulating cd30 cd4 t cells increase before human immunodeficiency virus rebound after analytical antiretroviral Treatment Interruption
The Journal of Infectious Diseases, 2020Co-Authors: Cecilia A Prator, Ronald J Bosch, Cassandra Thanh, Shreya Kumar, Tony Pan, Michael J Peluso, Norman G Jones, Jeffrey M Milush, Sonia Bakkour, Mars StoneAbstract:BACKGROUND Identification of nonviral markers of human immunodeficiency virus (HIV) infection that increase before viral rebound during analytical Treatment Interruption (ATI) may affect HIV persistence research. We previously showed that HIV ribonucleic acid (RNA) is enriched in CD30+CD4+ T cells in many individuals. Here, we studied CD30+CD4+ T-cell dynamics before ATI, during ATI (before detectable plasma RNA), and after HIV rebound. METHODS Peripheral blood mononuclear cells from 23 participants collected longitudinally from 5 Adult AIDS Clinical Trials Group studies incorporating ATI were included in this study. Flow cytometric characterization of expression of CD30 and markers of T-cell activation and exhaustion were performed along with HIV-1 RNA and deoxyribonucleic acid quantification and measurement of soluble plasma CD30 and CD30 ligand. RESULTS The percentage of CD4+ T cells expressing CD30 significantly increased from pre-ATI to postInterruption time points before detectible viremia (1.65 mean relative increase, P = .005). Seventy-seven percent of participants experienced an increase in CD30+ cells before viral rebound. In contrast, there were no significant differences between pre-ATI and postInterruption pre-rebound time points in percentages of lymphocytes expressing CD69, CD38/HLA-DR, or PD-1 until after HIV recrudescence. CONCLUSIONS CD30 may be a surrogate marker of early replication or viral transcriptional activity before detection by routine peripheral blood sampling.
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Impact of HLA Class I Alleles on Timing of HIV Rebound After Antiretroviral Treatment Interruption.
Pathogens & immunity, 2017Co-Authors: You Jeong Park, Ronald J Bosch, Daniel R Kuritzkes, John W. Mellors, Behzad Etemad, Hayat Ahmed, Vivek Naranbhai, Evgenia Aga, Michael F. Para, Rajesh T. GandhiAbstract:Identifying host determinants associated with HIV reservoir size and viral rebound timing after an analytic Treatment Interruption (ATI) is an important step in the search for an HIV functional cure. A pooled analysis of 103 participants from four AIDS Clinical Trials Group ATI studies to identify the association between HLA class I alleles with HIV reservoir size and viral rebound timing. Total HIV DNA and cell-associated HIV RNA (CA-RNA) were quantified in pre-ATI peripheral blood mononuclear cell samples, and residual plasma viremia was measured using the single-copy assay. HLA class I typing was performed and we generated an odds ratio (OR) of predicted HLA effect on HIV viremia control for each individual and compared this with time to viral rebound, and levels of HIV DNA and CA-RNA. There was no significant association between the HLA ORs and levels of HIV DNA or CA-RNA, but carriage of protective HLA-B alleles (lower OR scores) was associated with delayed viral rebound ( P= 0.02). Higher OR scores at the HLA-C locus were associated with longer duration of ART Treatment ( P= 0.01) and this trend was also seen with the combined OR score ( P= 0.007). Individuals with protective HLA-B alleles had delayed viral rebound after Treatment Interruption that was not explained by differences in baseline reservoir size. The results indicate the vital role of cellular host immunity in preventing HIV rebound and the importance of taking into account the HLA status of study participants being evaluated in HIV cure trials.
Thiago Y Oliveira - One of the best experts on this subject based on the ideXlab platform.
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Characterization of Intact Proviruses in Blood and Lymph Node from HIV-Infected Individuals Undergoing Analytical Treatment Interruption.
Journal of virology, 2019Co-Authors: Line K Vibholm, Julio C C Lorenzi, Joy A Pai, Yehuda Z Cohen, Thiago Y Oliveira, John P Barton, Marco Garcia Noceda, Yuria Ablanedo-terrazas, Perla M Del Rio EstradaAbstract:The role of lymphoid tissue as a potential source of HIV-1 rebound following Interruption of antiretroviral therapy (ART) is uncertain. To address this issue, we compared the latent viruses obtained from CD4+ T cells in peripheral blood and lymph nodes to viruses emerging during Treatment Interruption. Latent viruses were characterized by sequencing near-full-length (NFL) proviral DNA and env from viral outgrowth assays (VOAs). Five HIV-1-infected individuals on ART were studied, four of whom participated in a clinical trial of a TLR9 agonist that included an analytical Treatment Interruption. We found that 98% of intact or replication-competent clonal sequences overlapped between blood and lymph node. In contrast, there was no overlap between 205 latent reservoir and 125 rebound sequences in the four individuals who underwent Treatment Interruption. However, rebound viruses could be accounted for by recombination. The data suggest that CD4+ T cells carrying latent viruses circulate between blood and lymphoid tissues in individuals on ART and support the idea that recombination may play a role in the emergence of rebound viremia.IMPORTANCE HIV-1 persists as a latent infection in CD4+ T cells that can be found in lymphoid tissues in infected individuals during ART. However, the importance of this tissue reservoir and its contribution to viral rebound upon ART Interruption are not clear. In this study, we sought to compare latent HIV-1 from blood and lymph node CD4+ T cells from five HIV-1-infected individuals. Further, we analyzed the contribution of lymph node viruses to viral rebound. We observed that the frequencies of intact proviruses were the same in blood and lymph node. Moreover, expanded clones of T cells bearing identical proviruses were found in blood and lymph node. These latent reservoir sequences did not appear to be the direct origin of rebound virus. Instead, latent proviruses were found to contribute to the rebound compartment by recombination.
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relationship between intact hiv 1 proviruses in circulating cd4 t cells and rebound viruses emerging during Treatment Interruption
Proceedings of the National Academy of Sciences of the United States of America, 2018Co-Authors: Chinglan Lu, Julio C C Lorenzi, Yehuda Z Cohen, Thiago Y Oliveira, John P Barton, Lilian Nogueira, Pilar Mendoza, Henning Gruell, Lillian B Cohn, Florian KleinAbstract:Combination antiretroviral therapy controls but does not cure HIV-1 infection because a small fraction of cells harbor latent viruses that can produce rebound viremia when therapy is interrupted. The circulating latent virus reservoir has been documented by a variety of methods, most prominently by viral outgrowth assays (VOAs) in which CD4+ T cells are activated to produce virus in vitro, or more recently by amplifying proviral near full-length (NFL) sequences from DNA. Analysis of samples obtained in clinical studies in which individuals underwent analytical Treatment Interruption (ATI), showed little if any overlap between circulating latent viruses obtained from outgrowth cultures and rebound viruses from plasma. To determine whether intact proviruses amplified from DNA are more closely related to rebound viruses than those obtained from VOAs, we assayed 12 individuals who underwent ATI after infusion of a combination of two monoclonal anti–HIV-1 antibodies. A total of 435 intact proviruses obtained by NFL sequencing were compared with 650 latent viruses from VOAs and 246 plasma rebound viruses. Although, intact NFL and outgrowth culture sequences showed similar levels of stability and diversity with 39% overlap, the size of the reservoir estimated from NFL sequencing was larger than and did not correlate with VOAs. Finally, intact proviruses documented by NFL sequencing showed no sequence overlap with rebound viruses; however, they appear to contribute to recombinant viruses found in plasma during rebound.
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characterization of intact proviruses in blood and lymph node from hiv infected individuals undergoing analytical Treatment Interruption
bioRxiv, 2018Co-Authors: Line K Vibholm, Julio C C Lorenzi, Joy A Pai, Yehuda Z Cohen, Thiago Y Oliveira, John P Barton, Marco Garcia Noceda, Yuria Ablanedoterrazas, Perla M Del Rio Estrada, Gustavo ReyesteranAbstract:The role of lymphoid tissue as a potential source of HIV-1 rebound following Interruption of antiretroviral therapy is uncertain. To address this issue, we compared the latent viruses obtained from CD4+ T cells in peripheral blood and lymph nodes to viruses emerging during Treatment Interruption. Latent viruses were characterized by sequencing near full-length (NFL) proviral DNA, and env from viral outgrowth cultures (VOAs). 5 HIV-1 infected individuals on antiretroviral therapy (ART) were studied, 4 of whom participated in a clinical trial that included an analytical Treatment Interruption. Intact or replication competent clonal sequences from blood and lymph node overlapped. In contrast, there was no overlap between 205 latent reservoir and 125 rebound sequences in the 4 individuals who underwent Treatment Interruption. However, rebound viruses could be accounted for by recombination. The data suggest that CD4+ T cells carrying latent viruses circulate between blood and lymphoid tissues in individuals on ART and support the idea that recombination may play a role in the emergence of rebound viremia. Clinical Trial Registration ID #NCT02443935.
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hiv 1 antibody 3bnc117 suppresses viral rebound in humans during Treatment Interruption
Nature, 2016Co-Authors: Julio C C Lorenzi, Johannes F Scheid, Joshua A Horwitz, Yotam Baron, Edward F Kreider, Anna Feldmann, Malte Braunschweig, Lilian Nogueira, Thiago Y OliveiraAbstract:Interruption of combination antiretroviral therapy in HIV-1-infected individuals leads to rapid viral rebound. Here we report the results of a phase IIa open label clinical trial evaluating 3BNC117,a broad and potent neutralizing antibody against the CD4 binding site of the HIV-1 Env protein, during analytical Treatment Interruption in 13 HIV-1-infected individuals. Participants with 3BNC117-sensitive virus outgrowth cultures were enrolled. Results show that two or four 30 mg kg(-1) 3BNC117 infusions,separated by 3 or 2 weeks, respectively, are generally well tolerated.Infusions are associated with a delay in viral rebound of 5-9 weeks after two infusions, and up to 19 weeks after four infusions, or an average of 6.7 and 9.9 weeks, respectively, compared with 2.6 weeks for historical controls (P < 0.00001). Rebound viruses arise predominantly from a single provirus. In most individuals,emerging viruses show increased resistance, indicating escape.However, 30% of participants remained suppressed until antibody concentrations waned below 20 μg ml(-1), and the viruses emerging in all but one of these individuals showed no apparent resistance to 3BCN117, suggesting failure to escape over a period of 9-19 weeks.We conclude that the administration of 3BNC117 exerts strong selective pressure on HIV-1 emerging from latent reservoirs during analytical Treatment Interruption in humans.
Lambert Assoumou - One of the best experts on this subject based on the ideXlab platform.
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Treatment Interruption in chronically hiv infected patients with an ultralow hiv reservoir
AIDS, 2016Co-Authors: Ruxandra Calin, Lambert Assoumou, Roland Tubiana, Vincent Calvez, Chiraz Hamimi, Sidonie Lambertniclot, Guislaine Carcelain, Jonathan Bellet, Yasmine Dudoit, Dominique CostagliolaAbstract:OBJECTIVES To investigate the potential for combination antiretroviral therapy (cART)-free remission following analytic Treatment Interruption (ATI) in chronically HIV-infected patients with ultralow cell-associated DNA. METHODS Pilot study of patients (pts) with plasma viral load (pVL) less than 50 copies/ml for more than 2 years on cART, CD4 above 500 cells/μl, CD4/CD8 above 0.9, CD4 nadir above 300 cells/μl and HIV-DNA below 100 copies/10 peripheral blood mononuclear cells (PBMCs), undergoing Treatment Interruption. Ultrasensitive pVL, CD4 cell count, triplicate HIV-DNA were measured at D0, W2, W4, and every 4 weeks off-ART until W48 and at W4, W12 and W24 after ART resumption (RxR). RxR occurred in case of pVL rebound above 400 copies/ml or CD4 above 400 cells or HIV-related clinical event. The primary endpoint was the percentage of patients who did not reach RxR criteria at W24. Individuals were to be enrolled in three cohorts of five. Enrolment in cohort 2 began if at least one of five patients from cohort 1 remained in success at W8. Cohort 3 did not start. RESULTS Ten patients were enrolled, with median (range) CD4 1118 cells/μl (608-1494), CD4/CD8 2.1 (1.4-2.6), HIV-DNA 66 copies/10 PBMC (<66-66) at screening, viral suppression of 4.9 years (2.9-8.3), CD4 nadir 495 cells/μl (330-739). One patient remained off-ART up to W48. Viral rebound occurred in nine of 10 patients at W2 (2 patients), W4 (6 patients) and W12 (one patient). pVL was resuppressed on cART at W4 (8 patients) and W12 (one patient). HIV DNA returned to baseline values within a median of 12 weeks following RxR. CONCLUSION In a highly selected population of 10 patients with chronic HIV infection, an excellent immune status, durable virological suppression and ultralow reservoir, the success rate of ATI was 10% (95% confidence interval 0.3-44.5%) and nine of 10 patients had prompt rebound of plasma viremia. Resumption of ART led to return to baseline cell-associated total DNA.
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a low hiv dna level in peripheral blood mononuclear cells at antiretroviral Treatment Interruption predicts a higher probability of maintaining viral control
AIDS, 2015Co-Authors: Lambert Assoumou, Aurelie Melard, Christine Rouzioux, Christophe Piketty, Laurence Weiss, Marianne Burgard, Pierremarie Girard, Dominique CostagliolaAbstract:OBJECTIVE The main aim of this study was to determine whether HIV replication can be controlled following Interruption of Treatment started early in the course of infection (CD4 >350 cells/μl and viral load <50 000 copies/ml), but not during the primary infection. METHODS Patients enrolled in a multicenter trial of Treatment Interruption (ANRS 116 SALTO) with CD4 above 450 cells/μl and viral load below 400 copies/ml at Treatment Interruption were selected for this second analysis. We determined the proportion of patients whose plasma HIV-RNA load remained below 400 copies/ml during the first 12 months of Treatment Interruption, and baseline factors predictive of time to loss of viral control. Viral load rebound was defined as two successive values above 400 copies/ml, or as one value above 400 copies/ml, followed by Treatment resumption. RESULTS We studied 95 patients with a median CD4 nadir of 382 cells/μl (340-492). At Treatment Interruption, the median CD4 cell count and HIV-DNA load were 813/μl (695-988) and 206 copies/10 peripheral blood mononuclear cells (PBMCs) (53-556). Twelve months after Treatment Interruption, seven patients still had viral load below 400 copies/ml (Kaplan-Meier estimate 7.5%, 95% confidence interval 3.7-14.6), and four of them still had viral load below 400 copies/ml at 36 months. A multivariable Cox proportional-hazards model showed that time to loss of viral control was more shorter in patients with HIV-DNA at least 150 copies/10 PBMCs at Treatment Interruption (hazard ratio 2.1, 95% confidence interval 1.3-3.3, P = 0.002) than in those with HIV-DNA below 150 copies/10 PBMCs. CONCLUSION Patients who have low HIV-DNA levels at antiretroviral Treatment Interruption are more likely to maintain viral control for long periods.
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a high hiv dna level in pbmcs at antiretroviral Treatment Interruption predicts a shorter time to Treatment resumption independently of the cd4 nadir
Journal of Medical Virology, 2010Co-Authors: Christophe Piketty, Aurelie Melard, Jeanmichel Ragnaud, Laurence Weiss, Michele Bentata, Lambert Assoumou, Marianne Burgard, Christine RouziouxAbstract:This study aimed to evaluate the safety of antiretroviral Treatment Interruption (TI) in HIV-infected patients who started Treatment based on earlier guidelines, and to identify baseline factors predictive of the time to reach fixed criteria for Treatment resumption. Prospective, open-label, multicenter trial. Patients were eligible if they had a CD4 cell count >350/mm3 and plasma HIV RNA 450/mm3 and stable plasma HIV RNA <5,000 copies/ml for at least 6 months prior to enrolment. The criteria for ART resumption were a CD4 cell count <300/mm3 and/or a CDC stage B or C event. 116 patients had received ART for a median of 5.3 years. The median CD4 cell count and plasma HIV RNA values at inclusion were 809/mm3 and 2.6 log copies/ml, respectively. Median HIV DNA load at inclusion was 2.3 log copies/106 peripheral blood mononuclear cells (PBMCs). Thirty-six months after TI, 63.9% of the patients had not yet reached the criteria for ART resumption, and 55.9% of patients had not resumed ART. In Cox multivariable analysis, a high HIV DNA level at TI, a low CD4 nadir, and pre-existing AIDS status were the only significant risk factors for reaching the criteria for ART resumption (hazards ratio: 2.15 (1.02–4.53), 4.59 (1.22–17.24), and 5.74 (1.60–20.56), respectively). Patients who started ART with a CD4 cell count above 350/mm3 were able to interrupt Treatment for long periods without a high absolute risk of either AIDS or severe non-AIDS morbidity/mortality. A high PBMC HIV DNA level at TI was a strong predictor for more rapid Treatment resumption. J. Med. Virol. 82:1819–1828, 2010. © 2010 Wiley-Liss, Inc.
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a high hiv dna level in pbmcs at antiretroviral Treatment Interruption predicts a shorter time to Treatment resumption independently of the cd4 nadir
Journal of Medical Virology, 2010Co-Authors: Christophe Piketty, Aurelie Melard, Jeanmichel Ragnaud, Laurence Weiss, Michele Bentata, Lambert Assoumou, Marianne Burgard, Pierremarie Girard, Christine RouziouxAbstract:This study aimed to evaluate the safety of antiretroviral Treatment Interruption (TI) in HIV-infected patients who started Treatment based on earlier guidelines, and to identify baseline factors predictive of the time to reach fixed criteria for Treatment resumption. Prospective, open-label, multicenter trial. Patients were eligible if they had a CD4 cell count >350/mm(3) and plasma HIV RNA 450/mm(3) and stable plasma HIV RNA <5,000 copies/ml for at least 6 months prior to enrollment. The criteria for ART resumption were a CD4 cell count <300/mm(3) and/or a CDC stage B or C event. 116 patients had received ART for a median of 5.3 years. The median CD4 cell count and plasma HIV RNA values at inclusion were 809/mm(3) and 2.6 log copies/ml, respectively. Median HIV DNA load at inclusion was 2.3 log copies/10(6) peripheral blood mononuclear cells (PBMCs). Thirty-six months after TI, 63.9% of the patients had not yet reached the criteria for ART resumption, and 55.9% of patients had not resumed ART. In Cox multivariable analysis, a high HIV DNA level at TI, a low CD4 nadir, and pre-existing AIDS status were the only significant risk factors for reaching the criteria for ART resumption (hazards ratio: 2.15 (1.02-4.53), 4.59 (1.22-17.24), and 5.74 (1.60-20.56), respectively). Patients who started ART with a CD4 cell count above 350/mm(3) were able to interrupt Treatment for long periods without a high absolute risk of either AIDS or severe non-AIDS morbidity/mortality. A high PBMC HIV DNA level at TI was a strong predictor for more rapid Treatment resumption.
Julio C C Lorenzi - One of the best experts on this subject based on the ideXlab platform.
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Characterization of Intact Proviruses in Blood and Lymph Node from HIV-Infected Individuals Undergoing Analytical Treatment Interruption.
Journal of virology, 2019Co-Authors: Line K Vibholm, Julio C C Lorenzi, Joy A Pai, Yehuda Z Cohen, Thiago Y Oliveira, John P Barton, Marco Garcia Noceda, Yuria Ablanedo-terrazas, Perla M Del Rio EstradaAbstract:The role of lymphoid tissue as a potential source of HIV-1 rebound following Interruption of antiretroviral therapy (ART) is uncertain. To address this issue, we compared the latent viruses obtained from CD4+ T cells in peripheral blood and lymph nodes to viruses emerging during Treatment Interruption. Latent viruses were characterized by sequencing near-full-length (NFL) proviral DNA and env from viral outgrowth assays (VOAs). Five HIV-1-infected individuals on ART were studied, four of whom participated in a clinical trial of a TLR9 agonist that included an analytical Treatment Interruption. We found that 98% of intact or replication-competent clonal sequences overlapped between blood and lymph node. In contrast, there was no overlap between 205 latent reservoir and 125 rebound sequences in the four individuals who underwent Treatment Interruption. However, rebound viruses could be accounted for by recombination. The data suggest that CD4+ T cells carrying latent viruses circulate between blood and lymphoid tissues in individuals on ART and support the idea that recombination may play a role in the emergence of rebound viremia.IMPORTANCE HIV-1 persists as a latent infection in CD4+ T cells that can be found in lymphoid tissues in infected individuals during ART. However, the importance of this tissue reservoir and its contribution to viral rebound upon ART Interruption are not clear. In this study, we sought to compare latent HIV-1 from blood and lymph node CD4+ T cells from five HIV-1-infected individuals. Further, we analyzed the contribution of lymph node viruses to viral rebound. We observed that the frequencies of intact proviruses were the same in blood and lymph node. Moreover, expanded clones of T cells bearing identical proviruses were found in blood and lymph node. These latent reservoir sequences did not appear to be the direct origin of rebound virus. Instead, latent proviruses were found to contribute to the rebound compartment by recombination.
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relationship between intact hiv 1 proviruses in circulating cd4 t cells and rebound viruses emerging during Treatment Interruption
Proceedings of the National Academy of Sciences of the United States of America, 2018Co-Authors: Chinglan Lu, Julio C C Lorenzi, Yehuda Z Cohen, Thiago Y Oliveira, John P Barton, Lilian Nogueira, Pilar Mendoza, Henning Gruell, Lillian B Cohn, Florian KleinAbstract:Combination antiretroviral therapy controls but does not cure HIV-1 infection because a small fraction of cells harbor latent viruses that can produce rebound viremia when therapy is interrupted. The circulating latent virus reservoir has been documented by a variety of methods, most prominently by viral outgrowth assays (VOAs) in which CD4+ T cells are activated to produce virus in vitro, or more recently by amplifying proviral near full-length (NFL) sequences from DNA. Analysis of samples obtained in clinical studies in which individuals underwent analytical Treatment Interruption (ATI), showed little if any overlap between circulating latent viruses obtained from outgrowth cultures and rebound viruses from plasma. To determine whether intact proviruses amplified from DNA are more closely related to rebound viruses than those obtained from VOAs, we assayed 12 individuals who underwent ATI after infusion of a combination of two monoclonal anti–HIV-1 antibodies. A total of 435 intact proviruses obtained by NFL sequencing were compared with 650 latent viruses from VOAs and 246 plasma rebound viruses. Although, intact NFL and outgrowth culture sequences showed similar levels of stability and diversity with 39% overlap, the size of the reservoir estimated from NFL sequencing was larger than and did not correlate with VOAs. Finally, intact proviruses documented by NFL sequencing showed no sequence overlap with rebound viruses; however, they appear to contribute to recombinant viruses found in plasma during rebound.
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characterization of intact proviruses in blood and lymph node from hiv infected individuals undergoing analytical Treatment Interruption
bioRxiv, 2018Co-Authors: Line K Vibholm, Julio C C Lorenzi, Joy A Pai, Yehuda Z Cohen, Thiago Y Oliveira, John P Barton, Marco Garcia Noceda, Yuria Ablanedoterrazas, Perla M Del Rio Estrada, Gustavo ReyesteranAbstract:The role of lymphoid tissue as a potential source of HIV-1 rebound following Interruption of antiretroviral therapy is uncertain. To address this issue, we compared the latent viruses obtained from CD4+ T cells in peripheral blood and lymph nodes to viruses emerging during Treatment Interruption. Latent viruses were characterized by sequencing near full-length (NFL) proviral DNA, and env from viral outgrowth cultures (VOAs). 5 HIV-1 infected individuals on antiretroviral therapy (ART) were studied, 4 of whom participated in a clinical trial that included an analytical Treatment Interruption. Intact or replication competent clonal sequences from blood and lymph node overlapped. In contrast, there was no overlap between 205 latent reservoir and 125 rebound sequences in the 4 individuals who underwent Treatment Interruption. However, rebound viruses could be accounted for by recombination. The data suggest that CD4+ T cells carrying latent viruses circulate between blood and lymphoid tissues in individuals on ART and support the idea that recombination may play a role in the emergence of rebound viremia. Clinical Trial Registration ID #NCT02443935.
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hiv 1 antibody 3bnc117 suppresses viral rebound in humans during Treatment Interruption
Nature, 2016Co-Authors: Julio C C Lorenzi, Johannes F Scheid, Joshua A Horwitz, Yotam Baron, Edward F Kreider, Anna Feldmann, Malte Braunschweig, Lilian Nogueira, Thiago Y OliveiraAbstract:Interruption of combination antiretroviral therapy in HIV-1-infected individuals leads to rapid viral rebound. Here we report the results of a phase IIa open label clinical trial evaluating 3BNC117,a broad and potent neutralizing antibody against the CD4 binding site of the HIV-1 Env protein, during analytical Treatment Interruption in 13 HIV-1-infected individuals. Participants with 3BNC117-sensitive virus outgrowth cultures were enrolled. Results show that two or four 30 mg kg(-1) 3BNC117 infusions,separated by 3 or 2 weeks, respectively, are generally well tolerated.Infusions are associated with a delay in viral rebound of 5-9 weeks after two infusions, and up to 19 weeks after four infusions, or an average of 6.7 and 9.9 weeks, respectively, compared with 2.6 weeks for historical controls (P < 0.00001). Rebound viruses arise predominantly from a single provirus. In most individuals,emerging viruses show increased resistance, indicating escape.However, 30% of participants remained suppressed until antibody concentrations waned below 20 μg ml(-1), and the viruses emerging in all but one of these individuals showed no apparent resistance to 3BCN117, suggesting failure to escape over a period of 9-19 weeks.We conclude that the administration of 3BNC117 exerts strong selective pressure on HIV-1 emerging from latent reservoirs during analytical Treatment Interruption in humans.
Dominique Costagliola - One of the best experts on this subject based on the ideXlab platform.
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Treatment Interruption in chronically hiv infected patients with an ultralow hiv reservoir
AIDS, 2016Co-Authors: Ruxandra Calin, Lambert Assoumou, Roland Tubiana, Vincent Calvez, Chiraz Hamimi, Sidonie Lambertniclot, Guislaine Carcelain, Jonathan Bellet, Yasmine Dudoit, Dominique CostagliolaAbstract:OBJECTIVES To investigate the potential for combination antiretroviral therapy (cART)-free remission following analytic Treatment Interruption (ATI) in chronically HIV-infected patients with ultralow cell-associated DNA. METHODS Pilot study of patients (pts) with plasma viral load (pVL) less than 50 copies/ml for more than 2 years on cART, CD4 above 500 cells/μl, CD4/CD8 above 0.9, CD4 nadir above 300 cells/μl and HIV-DNA below 100 copies/10 peripheral blood mononuclear cells (PBMCs), undergoing Treatment Interruption. Ultrasensitive pVL, CD4 cell count, triplicate HIV-DNA were measured at D0, W2, W4, and every 4 weeks off-ART until W48 and at W4, W12 and W24 after ART resumption (RxR). RxR occurred in case of pVL rebound above 400 copies/ml or CD4 above 400 cells or HIV-related clinical event. The primary endpoint was the percentage of patients who did not reach RxR criteria at W24. Individuals were to be enrolled in three cohorts of five. Enrolment in cohort 2 began if at least one of five patients from cohort 1 remained in success at W8. Cohort 3 did not start. RESULTS Ten patients were enrolled, with median (range) CD4 1118 cells/μl (608-1494), CD4/CD8 2.1 (1.4-2.6), HIV-DNA 66 copies/10 PBMC (<66-66) at screening, viral suppression of 4.9 years (2.9-8.3), CD4 nadir 495 cells/μl (330-739). One patient remained off-ART up to W48. Viral rebound occurred in nine of 10 patients at W2 (2 patients), W4 (6 patients) and W12 (one patient). pVL was resuppressed on cART at W4 (8 patients) and W12 (one patient). HIV DNA returned to baseline values within a median of 12 weeks following RxR. CONCLUSION In a highly selected population of 10 patients with chronic HIV infection, an excellent immune status, durable virological suppression and ultralow reservoir, the success rate of ATI was 10% (95% confidence interval 0.3-44.5%) and nine of 10 patients had prompt rebound of plasma viremia. Resumption of ART led to return to baseline cell-associated total DNA.
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a low hiv dna level in peripheral blood mononuclear cells at antiretroviral Treatment Interruption predicts a higher probability of maintaining viral control
AIDS, 2015Co-Authors: Lambert Assoumou, Aurelie Melard, Christine Rouzioux, Christophe Piketty, Laurence Weiss, Marianne Burgard, Pierremarie Girard, Dominique CostagliolaAbstract:OBJECTIVE The main aim of this study was to determine whether HIV replication can be controlled following Interruption of Treatment started early in the course of infection (CD4 >350 cells/μl and viral load <50 000 copies/ml), but not during the primary infection. METHODS Patients enrolled in a multicenter trial of Treatment Interruption (ANRS 116 SALTO) with CD4 above 450 cells/μl and viral load below 400 copies/ml at Treatment Interruption were selected for this second analysis. We determined the proportion of patients whose plasma HIV-RNA load remained below 400 copies/ml during the first 12 months of Treatment Interruption, and baseline factors predictive of time to loss of viral control. Viral load rebound was defined as two successive values above 400 copies/ml, or as one value above 400 copies/ml, followed by Treatment resumption. RESULTS We studied 95 patients with a median CD4 nadir of 382 cells/μl (340-492). At Treatment Interruption, the median CD4 cell count and HIV-DNA load were 813/μl (695-988) and 206 copies/10 peripheral blood mononuclear cells (PBMCs) (53-556). Twelve months after Treatment Interruption, seven patients still had viral load below 400 copies/ml (Kaplan-Meier estimate 7.5%, 95% confidence interval 3.7-14.6), and four of them still had viral load below 400 copies/ml at 36 months. A multivariable Cox proportional-hazards model showed that time to loss of viral control was more shorter in patients with HIV-DNA at least 150 copies/10 PBMCs at Treatment Interruption (hazard ratio 2.1, 95% confidence interval 1.3-3.3, P = 0.002) than in those with HIV-DNA below 150 copies/10 PBMCs. CONCLUSION Patients who have low HIV-DNA levels at antiretroviral Treatment Interruption are more likely to maintain viral control for long periods.
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prolonged valproic acid Treatment does not reduce the size of latent hiv reservoir
AIDS, 2008Co-Authors: Nathalie Sagotlerolle, Marielaure Chaix, Dominique Costagliola, Aurelia Lamine, Faroudy Boufassa, Jeanpaul Aboulker, Cecile Goujard, Coralie Paller, Jeanfrancois Delfraissy, Olivier LambotteAbstract:Objective To investigate the impact of prolonged valproic acid Treatment on the HIV reservoir in patients on highly active antiretroviral therapy. Design In a single-center pilot study, the size of the HIV reservoir of 11 patients receiving valproic acid for seizures for more than 2 years was compared with 13 matched patients. In addition, the outcome of patients receiving valproic acid in the French clinical trials of scheduled Treatment Interruption was recorded. Methods Total and integrated HIV-1 DNA in, respectively, peripheral blood mononuclear cells and CD4 T cells of the patients were quantified by real-time PCR methods. The frequency of CD4 T cells carrying replication-competent virus was estimated by a quantitative limiting-dilution assay in which virus growth was detected by RT-PCR in culture supernatants of activated CD4 T cells. Clinical charts of the patients included in scheduled Treatment Interruption trials receiving valproic acid were reviewed. Results Total and integrated HIV DNA were logarithmically more abundant than cells carrying replication-competent virus, but there was no significant difference in these three parameters between the two groups of matched patients. Three patients receiving valproic acid were included in scheduled Treatment Interruption trials. The rebound of viral replication was similar to that of the other patients of the trials. Conclusion Long-term valproic acid therapy seems to be insufficient to reduce the size of the HIV-1 reservoir.
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no benefit of a structured Treatment Interruption based on genotypic resistance in heavily pretreated hiv infected patients
AIDS, 2005Co-Authors: Jade Ghosn, Stephanie Dominguez, Gilles Peytavin, Marc Wirden, Nadine Ktorza, Hocine Aitmohand, Luminita Schneider, Francois Bricaire, Vincent Calvez, Dominique CostagliolaAbstract:Objective: To evaluate the potential benefits of a tailored antiretroviral Treatment Interruption with duration based on the observed reversion of resistance mutations. Methods: In this open single-arm pilot study, 23 patients with multiple Treatment failure interrupted therapy and underwent longitudinal genotypic resistance testing. Salvage gigatherapy was started when resistance mutations to at least two antiretroviral drug classes reverted. The primary endpoint was a fall in viral load by > 1 log 10 copies/ml after 12 weeks of salvage therapy. Results: Baseline median viral load was 5.14 log copies/ml and CD4 cell count 43 x 10 6 cells/I. Genotypic resistance testing showed a median of six, two and nine resistance mutations to nucleoside analogue reverse transcriptase inhibitors, non-nucleoside analogue reverse transcriptase inhibitors and protease inhibitors, respectively; viral strains were susceptible to no more than one drug in 17/23 patients. The median duration of Treatment Interruption was 24 weeks (range, 12-37), leading to median changes from baseline of + 0.54 log 10 copies/ml and -30 x 10 6 cells/I. At the end of Treatment Interruption, plasma HIV was susceptible to at least three drugs in 16/23 patients. After 12 weeks of salvage multitherapy, only one patient had a decrease in viral load >1 log copies/ml. All baseline resistance mutations recurred after Treatment resumption. AIDS-defining events occurred in two-thirds of patients during the study period. Conclusion: In HIV-infected patients with multiple failures and no therapeutic options at baseline, significant reversion of resistance mutations after prolonged Treatment Interruption failed to restore antiviral efficacy of a salvage regimen and was clinically deleterious.
