scholarly journals Virological outcome measures during analytical treatment interruptions in chronic HIV-1 infected patients

2019 ◽  
Author(s):  
Csaba Fehér ◽  
Lorna Leal ◽  
Montserrat Plana ◽  
Nuria Climent ◽  
Alberto Crespo Guardo ◽  
...  
Keyword(s):  
Outcome Measures ◽  
Surrogate Marker ◽  
Confounding Factors ◽  
Hiv Cure ◽  
Analytical Treatment ◽  
Set Point ◽  
Delta Set ◽  
Treatment Interruptions ◽  
Virological Outcome ◽  
Hiv 1

Abstract Background Analytical treatment interruptions (ATI) are essential in research on HIV cure. However, the heterogeneity of virological outcome measures used in different trials hinders the interpretation of the efficacy of different strategies. Methods A retrospective analysis of viral load (VL) evolution in 334 ATI episodes in chronic HIV-1 infected patients collected from 11 prospective studies. Quantitative [baseline VL, set point, delta set point, VL and delta VL at given weeks after ATI, peak VL, delta peak VL, and area under the rebound curve], and temporal parameters [time to rebound (TtR), set point, peak, and certain absolute and relative VL thresholds] were described. Pairwise correlations between parameters were analyzed, and potential confounding factors (sex, age, time of known HIV infection, time on ART, and immunological interventions) were evaluated. Results Set point was lower than baseline VL (median delta set point -0.26. p< 0.001). This difference was >1 log10 copies/mL in 13.9% of the cases. Median TtR was 2 weeks; no patients had undetectable VL at week 12. Median time to set point was 8 weeks: by week 12, 97.4% of the patients had reached the set point. TtR and baseline VL were correlated with most temporal and quantitative parameters. The variables independently associated with TtR were baseline VL and the use of immunological interventions. Conclusions TtR could be an optimal surrogate marker of response in HIV cure strategies. Our results underline the importance of taking into account baseline VL and other confounding factors in the design and interpretation of these studies.

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.

scholarly journals Acceptability, motivation and the prospect of cure for people living with HIV and their healthcare providers in HIV cure-focused treatment interruption studies

2020 ◽  
Vol 17 (1) ◽  
Author(s):  
Jillian S. Y. Lau ◽  
Miranda Z. Smith ◽  
Brent Allan ◽  
Cipriano Martinez ◽  
Jennifer Power ◽  
...  
Keyword(s):  
Descriptive Analysis ◽  
Healthcare Providers ◽  
Treatment Interruption ◽  
People Living With Hiv ◽  
Hiv Cure ◽  
Educational Strategies ◽  
Analytical Treatment ◽  
Clinical Endpoints ◽  
Treatment Interruptions ◽  
Living With Hiv

Abstract Background Analytical treatment interruptions (ATI) are commonly used clinical endpoints to assess interventions aimed at curing HIV or achieving antiretroviral therapy (ART)-free HIV remission. Understanding the acceptability of ATI amongst people living with HIV (PLHIV) and their HIV healthcare providers (HHP) is limited. Methods Two online surveys for PLHIV and HHP assessed awareness and acceptability of ATI, and understanding of the prospect for HIV cure in the future. Responses were collected from July 2017–January 2018. A descriptive analysis was performed and similar questions across the two surveys were compared using χ squared test. Results 442 PLHIV and 144 HHP completed the survey. 105/400 (26%) PLHIV had ever interrupted ART, 8% of which were in a clinical trial. Altruistic motivations were drivers of participation of PLHIV in cure related research. 81/135 (60%) HHP would support their patients wishing to enrol in an HIV cure-focused trial, but fewer would promote and allow such participation (25% and 31% respectively). Compared to HHP, PLHIV were more likely to believe that an HIV cure would be achievable within 10 years (55% vs. 19%, p < 0.001), had less awareness of ATI (46% vs. 62%, p < 0.001) and were less likely to have had experience of either participation or enrolment in an ATI study (5% vs. 18%, p < 0.001) Conclusion PLHIV were more optimistic about the potential for HIV cure. HHP had more direct experience with HIV cure-focused studies. Educational strategies are required for both groups to increase understanding around ATIs in HIV cure research but should be tailored specifically to each group.

scholarly journals Modest de novo Reactivation of Single HIV-1 Proviruses in Peripheral CD4+ T Cells by Romidepsin

2021 ◽  
Vol 1 ◽  
Author(s):  
Kathrine Kjær ◽  
Steffen Leth ◽  
Christina V. Konrad ◽  
Jesper D. Gunst ◽  
Rasmus Nymann ◽  
...  
Keyword(s):  
Clinical Trials ◽  
T Cells ◽  
De Novo ◽  
Viral Rna ◽  
Viral Reservoir ◽  
Latent Reservoir ◽  
Host Immune System ◽  
Analytical Treatment ◽  
Treatment Interruptions ◽  
Hiv 1

A cure for human immunodeficiency virus (HIV-1) is restricted by the continued presence of a latent reservoir of memory CD4+ T cells with proviruses integrated into their DNA despite suppressive antiretroviral therapy (ART). A predominant strategy currently pursued in HIV-1 cure-related research is the “kick and kill” approach, where latency reversal agents (LRAs) are used to reactivate transcription from integrated proviruses. The premise of this approach is that “kicking” latent virus out of hiding allows the host immune system to recognize and kill infected cells. Clinical trials investigating the efficacy of LRAs, such as romidepsin, have shown that these interventions do induce transient spikes in viral RNA in HIV-1-infected individuals. However, since these trials failed to significantly reduce viral reservoir size or significantly delay time to viral rebound during analytical treatment interruptions, it is questioned how much each individual latent provirus is actually “kicked” to produce viral transcripts and/or proteins by the LRA. Here, we developed sensitive and specific digital droplet PCR-based assays with single-provirus level resolution. Combining these assays allowed us to interrogate the level of viral RNA transcripts from single proviruses in individuals on suppressive ART with or without concomitant romidepsin treatment. Small numbers of proviruses in peripheral blood memory CD4+ T cells were triggered to become marginally transcriptionally active upon romidepsin treatment. These novel assays can be applied retrospectively and prospectively in HIV-1 cure-related clinical trials to gain crucial insights into LRA efficacy at the single provirus level.

scholarly journals How Unavoidable Are Analytical Treatment Interruptions in HIV Cure–Related Studies?

2019 ◽  
Vol 220 (Supplement_1) ◽  
pp. S24-S26 ◽  
Author(s):  
David M Margolis ◽  
Steven G Deeks
Keyword(s):  
Clinical Trial ◽  
Human Immunodeficiency Virus ◽  
Antiretroviral Therapy ◽  
Virus Infection ◽  
Human Immunodeficiency Virus Infection ◽  
Outcome Measure ◽  
Hiv Cure ◽  
Analytical Treatment ◽  
Treatment Interruptions ◽  
Immunodeficiency Virus

Abstract In this discussion, 2 established researchers and clinical trialists debate their opposing views on the utility, benefits, and risks of the use of analytical interruption of antiretroviral therapy as a clinical trial end point and outcome measure in human studies seeking to induce remission of or eradicate human immunodeficiency virus infection.

scholarly journals Acceptability, motivation and the prospect of cure for people living with HIV and their healthcare providers in HIV cure-focused treatment interruption studies

2020 ◽  
Author(s):  
Jillian SY Lau ◽  
Miranda Z Smith ◽  
Brent Allan ◽  
Cipriano Martinez ◽  
Jennifer Power ◽  
...  
Keyword(s):  
Descriptive Analysis ◽  
Healthcare Providers ◽  
Treatment Interruption ◽  
People Living With Hiv ◽  
Hiv Cure ◽  
Educational Strategies ◽  
Analytical Treatment ◽  
Clinical Endpoints ◽  
Treatment Interruptions ◽  
Living With Hiv

Abstract Background Analytical treatment interruptions (ATI) are commonly used clinical endpoints to assess interventions aimed at curing HIV or achieving antiretroviral therapy (ART)-free HIV remission. Understanding the acceptability of ATI amongst people living with HIV (PLHIV) and their HIV healthcare providers (HHP) is limited. Methods Two online surveys for PLHIV and HHP assessed awareness and acceptability of ATI, and understanding of the prospect for HIV cure in the future. Responses were collected from July 2017-January 2018. A descriptive analysis was performed and similar questions across the two surveys were compared using χ squared test. Results 442 PLHIV and 144 HHP completed the survey. 105/400 (26%) PLHIV had ever interrupted ART, 8% of which were in a clinical trial. Altruistic motivations were drivers of participation of PLHIV in cure related research. 81/135 (60%) HHP would support their patients wishing to enrol in an HIV cure-focused trial, but fewer would promote and allow such participation (25% and 31% respectively). Compared to HHP, PLHIV were more likely to believe that an HIV cure would be achievable within 10 years (55% vs 19%, p<0.001), had less awareness of ATI (46% vs 62%,p<0.001) and were less likely to have had experience of either participation or enrolment in an ATI study (5% vs 18%,p<0.001) Conclusion PLHIV were more optimistic about the potential for HIV cure. HHP had more direct experience with HIV cure-focused studies. Educational strategies are required for both groups to increase understanding around ATIs in HIV cure research but should be tailored specifically to each group.

Systematic Review and Meta-analysis of Treatment Interruptions in Human Immunodeficiency Virus (HIV) Type 1–infected Patients Receiving Antiretroviral Therapy: Implications for Future HIV Cure Trials

2019 ◽  
Author(s):  
Melanie Stecher ◽  
Annika Claßen ◽  
Florian Klein ◽  
Clara Lehmann ◽  
Henning Gruell ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
Antiretroviral Therapy ◽  
Current Evidence ◽  
P Value ◽  
Analytical Treatment ◽  
Treatment Interruptions ◽  
Immunodeficiency Virus ◽  
Hiv 1

AbstractBackgroundSafety and tolerability of analytical treatment interruptions (ATIs) as a vital part of human immunodeficiency virus type 1 (HIV-1) cure studies are discussed. We analyzed current evidence for the occurrence of adverse events (AEs) during TIs.MethodsOur analysis included studies that reported on AEs in HIV-1–infected patients undergoing TIs. All interventional and observational studies were reviewed, and results were extracted based on predefined criteria. The proportion of AEs was pooled using random-effects models. Metaregression was used to explore the influence of baseline CD4+ T-cell count, viral load, study type, previous time on combined antiretroviral therapy, and follow-up interval during TIs.ResultsWe identified 1048 studies, of which 22 studies including 7104 individuals fulfilled the defined selection criteria. Included studies had sample sizes between 6 and 5472 participants, with durations of TI cycles ranging from 7 days to 27 months. The intervals of HIV-1-RNA testing varied from 2 days to 3 months during TIs. The overall proportion of AEs during TIs >4 weeks was 3% (95% confidence interval [CI], 0%–7%) and was lower in studies with follow-up intervals ≤14 days (0%; 95% CI, 0%–1%) than in studies with wider follow-up intervals (6%; 95% CI, 2%–13%; P value for interaction = .01).ConclusionsWe found moderate-quality evidence indicating that studies with narrow follow-up intervals did not show a substantial increase in AEs during TIs. Our findings indicate that ATI may be a safe strategy as part of HIV-1 cure trials by closely monitoring for HIV-1 rebound.

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