Analytical treatment interruption in chronic HIV-1 infection: time and magnitude of viral rebound in adults with 10 years of undetectable viral load and low HIV-DNA (APACHE study)

2019 ◽  
Vol 74 (7) ◽  
pp. 2039-2046 ◽  
Author(s):  
Antonella Castagna ◽  
Camilla Muccini ◽  
Laura Galli ◽  
Alba Bigoloni ◽  
Andrea Poli ◽  
...  
Keyword(s):  
Viral Load ◽  
Undetectable Viral Load ◽  
Treatment Interruption ◽  
Viral Reservoir ◽  
Viral Rebound ◽  
Analytical Treatment ◽  
Hiv Rna ◽  
Hiv Dna ◽  
Acute Retroviral Syndrome ◽  
Hiv 1

AbstractObjectivesDespite the fact that there are individuals who have chronic HIV infection, few studies have investigated ART interruption in this setting. The aim of this study was to evaluate the ability to spontaneously control viral replication during analytical treatment interruption (ATI) in adults with chronic HIV-1 infection, on ART, with suppressed viraemia for >10 years and with a low reservoir.Patients and methodsThis was a prospective, open-label, single-arm, non-randomized, proof-of-concept study (NCT03198325) of subjects with chronic HIV-1 infection, HIV-RNA <50 copies/mL for ≥10 years, without residual viraemia for ≥5 years, CD4+ >500 cells/mm3, HIV-DNA <100 copies/106 PBMCs and without comorbidities or AIDS-defining diseases. Enrolled patients were strictly monitored. The ART regimen in use at ATI was resumed in the case of confirmed viral rebound (CVR, two consecutive HIV-RNA >50 copies/mL). Results are reported as median (IQR).ResultsNine patients underwent ATI. All participants experienced CVR [4.84 (IQR: 3.47–6.47) HIV-RNA log10 copies/mL] after ATI at a median time of 21 days (range 14–56) and restarted ART. After ART resumption, all the subjects achieved HIV-RNA <50 copies/mL in a median of 88 days (range 15–197). No serious adverse event occurred; one subject experienced acute retroviral syndrome. No significant correlation between baseline factors and time to viral rebound was observed, while the magnitude of viral rebound was significantly associated with pre-ART HIV-1 RNA (Spearman r = 0.786, P = 0.036), nadir CD4+ (Spearman r = −0.800, P = 0.010), baseline CD4+ (Spearman r = −0.667, P = 0.049) and years with undetectable viral load (Spearman r = −0.717, P = 0.030).ConclusionsDespite a long period of HIV viral load suppression and a low viral reservoir, early and consistent viral rebound was observed during ATI in all subjects.

scholarly journals Evaluating predictive markers for viral rebound and safety assessment in blood and lumbar fluid during HIV-1 treatment interruption

2020 ◽  
Vol 75 (5) ◽  
pp. 1311-1320
Author(s):  
Marie-Angélique De Scheerder ◽  
Clarissa Van Hecke ◽  
Henrik Zetterberg ◽  
Dietmar Fuchs ◽  
Nele De Langhe ◽  
...  
Keyword(s):  
Immune Activation ◽  
Neuronal Injury ◽  
Treatment Interruption ◽  
Viral Reservoir ◽  
Viral Rebound ◽  
Analytical Treatment ◽  
Neurofilament Light Chain ◽  
Rna Transcripts ◽  
Hiv 1 ◽  
Potential Biomarkers

Abstract Background Validated biomarkers to evaluate HIV-1 cure strategies are currently lacking, therefore requiring analytical treatment interruption (ATI) in study participants. Little is known about the safety of ATI and its long-term impact on patient health. Objectives ATI safety was assessed and potential biomarkers predicting viral rebound were evaluated. Methods PBMCs, plasma and CSF were collected from 11 HIV-1-positive individuals at four different timepoints during ATI (NCT02641756). Total and integrated HIV-1 DNA, cell-associated (CA) HIV-1 RNA transcripts and restriction factor (RF) expression were measured by PCR-based assays. Markers of neuroinflammation and neuronal injury [neurofilament light chain (NFL) and YKL-40 protein] were measured in CSF. Additionally, neopterin, tryptophan and kynurenine were measured, both in plasma and CSF, as markers of immune activation. Results Total HIV-1 DNA, integrated HIV-1 DNA and CA viral RNA transcripts did not differ pre- and post-ATI. Similarly, no significant NFL or YKL-40 increases in CSF were observed between baseline and viral rebound. Furthermore, markers of immune activation did not increase during ATI. Interestingly, the RFs SLFN11 and APOBEC3G increased after ATI before viral rebound. Similarly, Tat-Rev transcripts were increased preceding viral rebound after interruption. Conclusions ATI did not increase viral reservoir size and it did not reveal signs of increased neuronal injury or inflammation, suggesting that these well-monitored ATIs are safe. Elevation of Tat-Rev transcription and induced expression of the RFs SLFN11 and APOBEC3G after ATI, prior to viral rebound, indicates that these factors could be used as potential biomarkers predicting viral rebound.

scholarly journals Characterization of Intact Proviruses in Blood and Lymph Node from HIV-Infected Individuals Undergoing Analytical Treatment Interruption

2019 ◽  
Vol 93 (8) ◽  
Author(s):  
Line K. Vibholm ◽  
Julio C. C. Lorenzi ◽  
Joy A. Pai ◽  
Yehuda Z. Cohen ◽  
Thiago Y. Oliveira ◽  
...  
Keyword(s):  
T Cells ◽  
Lymph Node ◽  
Treatment Interruption ◽  
Latent Reservoir ◽  
Lymphoid Tissues ◽  
Viral Rebound ◽  
Analytical Treatment ◽  
Latent Hiv ◽  
Hiv 1

ABSTRACT 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.

scholarly journals HIV-DNA undetectability during chronic HIV infection: frequency and predictive factors

2020 ◽  
Vol 75 (10) ◽  
pp. 2994-2997
Author(s):  
Silvia Nozza ◽  
Laura Galli ◽  
Nicola Gianotti ◽  
Mariarita Parisi ◽  
Andrea Poli ◽  
...  
Keyword(s):  
Predictive Factors ◽  
Undetectable Viral Load ◽  
People Living With Hiv ◽  
Infection Frequency ◽  
Hiv Diagnosis ◽  
Cross Sectional ◽  
Infected People ◽  
Hiv Rna ◽  
Hiv Dna ◽  
Hiv 1

Abstract Background HIV-DNA is a marker of HIV reservoirs. Objectives of the study were to determine prevalence of HIV-DNA &lt; 100 copies/106 PBMCs in blood and to identify factors associated with this in a cohort of HIV-1-infected subjects treated with ART and with undetectable viral load (VL). Methods This was a cross-sectional study on chronic HIV-1-infected people living with HIV (PLWH) followed up at the Department of Infectious Diseases of San Raffaele Scientific Institute on current ART without change for 12 months, with available pre-ART HIV-RNA and with undetectable VL for ≥12 months. HIV-DNA was amplified and quantified by real-time PCR (ABI Prism 7900); limit of detectability was 100 copies/106 PBMCs. Logistic regression was used to identify predictive factors for HIV-DNA &lt; 100 copies/106 PBMCs. Results Four hundred and sixty-eight PLWH were considered in the analyses, 119 (25%) with HIV-DNA &lt; 100 copies/106 PBMCs. At multivariate analysis, we found that PLWH with lower zenith HIV-RNA, higher nadir CD4 and a shorter time between HIV diagnosis and ART start were more likely to have HIV-DNA &lt; 100 copies/106 PBMCs, after adjustment for age, gender, calendar year of ART start, type of current ART regimen, percentage time spent with undetectable VL since ART start, current CD4 and CD4/CD8 ratio. Conclusions In our chronic PLWH on virological suppression for 4 years, the prevalence of HIV-DNA &lt; 100  copies/106 PBMCs was found to be 25%. Lower zenith HIV-RNA, shorter time between HIV diagnosis and starting ART and higher CD4 nadir were independently associated with low HIV-DNA.

scholarly journals Anti-HIV-1 ADCC Antibodies following Latency Reversal and Treatment Interruption

2017 ◽  
Vol 91 (15) ◽  
Author(s):  
Wen Shi Lee ◽  
Anne B. Kristensen ◽  
Thomas A. Rasmussen ◽  
Martin Tolstrup ◽  
Lars Østergaard ◽  
...  
Keyword(s):  
Antiretroviral Therapy ◽  
Treatment Interruption ◽  
Viral Rebound ◽  
Analytical Treatment ◽  
Antigenic Stimulus ◽  
Latently Infected ◽  
Infected Cells ◽  
Functional Antibodies ◽  
Hiv 1 ◽  
Reversing Agents

ABSTRACT There is growing interest in utilizing antibody-dependent cellular cytotoxicity (ADCC) to eliminate infected cells following reactivation from HIV-1 latency. A potential barrier is that HIV-1-specific ADCC antibodies decline in patients on long-term antiretroviral therapy (ART) and may not be sufficient to eliminate reactivated latently infected cells. It is not known whether reactivation from latency with latency-reversing agents (LRAs) could provide sufficient antigenic stimulus to boost HIV-1-specific ADCC. We found that treatment with the LRA panobinostat or a short analytical treatment interruption (ATI), 21 to 59 days, was not sufficient to stimulate an increase in ADCC-competent antibodies, despite viral rebound in all subjects who underwent the short ATI. In contrast, a longer ATI, 2 to 12 months, among subjects enrolled in the Strategies for Management of Antiretroviral Therapy (SMART) trial robustly boosted HIV-1 gp120-specific Fc receptor-binding antibodies and ADCC against HIV-1-infected cells in vitro. These results show that there is a lag between viral recrudescence and the boosting of ADCC antibodies, which has implications for strategies toward eliminating latently infected cells. IMPORTANCE The “shock and kill” HIV-1 cure strategy aims to reactivate HIV-1 expression in latently infected cells and subsequently eliminate the reactivated cells through immune-mediated killing. Several latency reversing agents (LRAs) have been examined in vivo, but LRAs alone have not been able to achieve HIV-1 remission and prevent viral rebound following analytical treatment interruption (ATI). In this study, we examined whether LRA treatment or ATI can provide sufficient antigenic stimulus to boost HIV-1-specific functional antibodies that can eliminate HIV-1-infected cells. Our study has implications for the antigenic stimulus required for antilatency strategies and/or therapeutic vaccines to boost functional antibodies and assist in eliminating the latent reservoir.

scholarly journals Models of SIV rebound after treatment interruption that involve multiple reactivation events

2020 ◽  
Author(s):  
Christiaan H. van Dorp ◽  
Jessica M. Conway ◽  
James B. Whitney ◽  
Dan H. Barouch ◽  
Alan S. Perelson
Keyword(s):  
Growth Rate ◽  
Viral Load ◽  
Antiretroviral Therapy ◽  
Treatment Interruption ◽  
Latent Reservoir ◽  
Viral Rebound ◽  
Viral Growth ◽  
Art Initiation ◽  
Reactivation Event ◽  
Hiv 1

AbstractIn order to assess the efficacy of novel HIV-1 treatments leading to a functional cure, the time to viral rebound is frequently used as a surrogate endpoint. The longer the time to viral rebound, the more efficacious the therapy. In support of such an approach, mathematical models serve as a connection between the size of the latent reservoir and the time to HIV-1 rebound after treatment interruption. The simplest of such models assumes that a single successful latent cell reactivation event leads to observable viremia after a period of exponential viral growth. Here we consider a generalization developed by Pinkevych et al. and Hill et al. of this simple model in which multiple reactivation events can occur, each contributing to the exponential growth of the viral load. We formalize and improve the previous derivation of the dynamics predicted by this model, and use the model to estimate relevant biological parameters from SIV rebound data. We confirm a previously described effect of very early antiretroviral therapy (ART) initiation on the rate of recrudescence and the viral load growth rate after treatment interruption. We find that every day ART initiation is delayed results in a 39% increase in the recrudescence rate, and a 11% decrease of the viral growth rate. We show that when viral rebound occurs early relative to the viral load doubling time, a model with multiple successful reactivation events fits the data better than a model with only a single successful reactivation event.Author SummaryHIV-1 persists during suppressive antiretroviral therapy (ART) due to a reservoir of latently infected cells. When ART is stopped, HIV generally rebounds within a few weeks. However, there is a small fraction of patients that do not rebound over a period of months or years. A variety of treatments are being tested for their ability to reduce the size of the latent reservoir, to induce effective immune responses against the virus, or to prevent or prolong the time to viral rebound after ART interruption. These novel treatments are typically first tested in SIV infected macaques, and the efficacy of the treatment assessed by interrupting ART and measuring the time to viral rebound. Here, we develop and test a mathematical and statistical model that describes the process of viral rebound. The model can be used for statistical inference of the efficacy of newly developed treatments. Importantly, the model takes into account that multiple recrudescence events can precede rebound. We test the model using data from early treated SIV infected macaques.

scholarly journals Reverse Transcriptase Mutations in HIV-1 Infected Patients Treated with Two Nucleoside Analogues: The Smart Study

2002 ◽  
Vol 15 (2) ◽  
pp. 129-139 ◽  
Author(s):  
N. Gianotti ◽  
M. Setti ◽  
P.E. Manconi ◽  
F. Leoncini ◽  
F. Chiodo ◽  
...  
Keyword(s):  
Viral Load ◽  
Reverse Transcriptase ◽  
Undetectable Viral Load ◽  
Clinical Failure ◽  
Detectable Viral Load ◽  
Hiv Rna ◽  
Smart Study ◽  
Independent Variable ◽  
One Year ◽  
Hiv 1

Resistance to nucleoside reverse transcriptase inhibitors (NRTIs) was studied in 527 HIV-1-infected patients, 342 responder and 185 non-responder to two NRTIs. Responders were followed for one year to assess the incidence of clinical failure. The prevalence of the 215Y/F substitution was higher among non-responder, compared to responder patients (33.7% vs. 17%, P = 0.0005), whereas the prevalence of the 184V and of the 70R mutations was comparable between these two groups. The 74V substitution was never observed and the 75T mutation was detected in only two subjects non-responder to a stavudine including regimen. Reduced susceptibility to didanosine or stavudine was infrequent. Reduced susceptibility to zidovudine was observed in 25% of individuals failing a zidovudine including regimen, whereas reduced susceptibility to lamivudine was detected in all subjects failing a lamivudine including regimen. In the prospective analysis, patients with undetectable viral load at enrollment had a lower incidence of failure rate over one year compared to those with detectable HIV-RNA at entry (P < 0.0001). A detectable viral load at enrollment was the only independent variable that predicted clinical failure over one year (P < 0.0001).

scholarly journals Impact of Analytical Treatment Interruption on Burden and Diversification of HIV Peripheral Reservoir: A Pilot Study

Viruses ◽  
2021 ◽  
Vol 13 (7) ◽  
pp. 1403
Author(s):  
Rossana Scutari ◽  
Valentino Costabile ◽  
Laura Galli ◽  
Maria Concetta Bellocchi ◽  
Luca Carioti ◽  
...  
Keyword(s):  
Pilot Study ◽  
Dna Sequences ◽  
Viral Reservoir ◽  
P Value ◽  
Residual Viremia ◽  
Analytical Treatment ◽  
Time Points ◽  
Hiv Dna ◽  
Study Results ◽  
Hiv 1

Background: If analytical antiretroviral-treatment (ART) interruption (ATI) might significantly impact quantitative or qualitative peripheral-total HIV-DNA is still debated. Methods: Six chronically HIV-1 infected patients enrolled in APACHE-study were analysed for peripheral-total HIV-DNA and residual viremia, major-resistance-mutations (MRMs) and C2-V3-C3 evolution at pre-ATI (T1), during ATI (T2) and at achievement of virological success after ART-resumption (post-ATI, T3). These data were obtained at three comparable time-points in five chronically HIV-1 infected patients on suppressive ART for ≥1 year, enrolled in MODAt-study. Results: At T1, APACHE and MODAt individuals had similar peripheral-total HIV-DNA and residual viremia (p = 0.792 and 0.662, respectively), and no significant changes for these parameters were observed between T1 and T3 in both groups. At T1, 4/6 APACHE and 2/5 MODAt carried HIV-DNA MRMs. MRMs disappeared at T3 in 3/4 APACHE. All disappearing MRMs were characterized by T1 intra-patient prevalence <80%, and mainly occurred in APOBEC3-related sites. All MRMs persisted over-time in the 2 MODAt. C2-V3-C3 genetic-distance significantly changed from T1 to T3 in APACHE individuals (+0.36[0.11–0.41], p = 0.04), while no significant changes were found in MODAt. Accordingly, maximum likelihood trees (bootstrap > 70%) and genealogical sorting indices (GSI > 0.50 with p-value < 0.05) showed that T1 C2-V3-C3 DNA sequences were distinct from T2 and T3 viruses in 4/6 APACHE. Virus populations at all three time-points were highly interspersed in MODAt. Conclusions: This pilot study indicates that short ATI does not alter peripheral-total HIV-DNA burden and residual viremia, but in some cases could cause a genetic diversification of peripheral viral reservoir in term of both MRMs rearrangement and viral evolution.

scholarly journals Transient viral replication during analytical treatment interruptions in SIV infected macaques can alter the rebound-competent viral reservoir

2021 ◽  
Vol 17 (6) ◽  
pp. e1009686
Author(s):  
Taina T. Immonen ◽  
Christine M. Fennessey ◽  
Leslie Lipkey ◽  
Abigail Thorpe ◽  
Gregory Q. Del Prete ◽  
...  
Keyword(s):  
Antiretroviral Therapy ◽  
Viral Replication ◽  
Rhesus Macaques ◽  
Treatment Strategies ◽  
Viral Reservoir ◽  
Virus Population ◽  
Analytical Treatment ◽  
Treatment Interruptions ◽  
The Impact ◽  
Hiv 1

Analytical treatment interruptions (ATIs) of antiretroviral therapy (ART) play a central role in evaluating the efficacy of HIV-1 treatment strategies targeting virus that persists despite ART. However, it remains unclear if ATIs alter the rebound-competent viral reservoir (RCVR), the virus population that persists during ART and from which viral recrudescence originates after ART discontinuation. To assess the impact of ATIs on the RCVR, we used a barcode sequence tagged SIV to track individual viral lineages through a series of ATIs in Rhesus macaques. We demonstrate that transient replication of individual rebounding lineages during an ATI can lead to their enrichment in the RCVR, increasing their probability of reactivating again after treatment discontinuation. These data establish that the RCVR can be altered by uncontrolled replication during ATI.

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