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New Cure research studies, ART interruptions: biomarkers for viral rebound after interruptions, search for reservoirs where HIV rebounds from; intensified monitoring, safety concerns; patient consent
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Download the PDF here
Download the PDF here
Download the PDF here
Download the PDF here
There are 3 studies in this report. Pdfs for all 3 are attached. Plus a 4th pdf which is the Editorial by Winston et al raising concerns about CNS safety following interruptions, viral rebound, which can cause long tem neurotoxicities.
From Jules: Recently there has been more attention paid to safety for participants in these cure interruption studies, probably because of recent increased scrutiny and concerns raised, in contrast to the earlier days of cure research 4-5 years ago where such safety concerns were dismissed when I would raise it at a meeting or in general it got very much inadequate recognition & attention from all stakeholders in the field of cure research. Out of this comes what is the focus of the paper below by Li et all published 2 yearss ago discussing intensified monitoring of labs every few days after interruption but is now the basis of new interruption study being implemented in recent ACTG study starting; although this is an improvement in safety it does not eliminate safety concerns; what is also important is to have reliable consent which IS a concern, and then there are other cure interruption studies that do NOT have such close monitoring raising the risks on safety concerns. Not all studies have uniform consent, not all researchers have uniform consent, and interruptions & safety implementation varies from study to study, also discussed in these 2 studies......
ART Interruption Associated with HIV in the Brain: "Reseeding CNS during ART Interruption Leading to Intrathecal Immune Activation" - "HIV-1 Viral Escape in Cerebrospinal Fluid of Subjects on Suppressive Antiretroviral Treatment" - (09/18/17)
Cure Studies/ART Interruption & Brain Affects, Vorinostat - (10/13/17)
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1. "The need for treatment interruption studies and biomarker identification in the search for an HIV cure".........from Jules: the other question is do we need biomarkers of viral rebound and are they really meaningful, relevant and predictive; understanding where rebound is coming from, which reservoirs is a 2nd question, do we need to know this too? We do NOT know how large reservoirs are; we do not have any cure therapy that works and finding a functional cure is at very early stages. Can risks for interruptions be avoided? Can they be minimized.....frequent monitoring of interruptions every few days suggested below by Li et al and in recently started ACTG study where monitoring after interruption is every few days, BUT the potential for safety risks persist: "a further adverse outcome, which could be a catastrophic event, is immune reconstitution inflammatory syndromes occurring in the CNS compartment catastrophic event, is immune reconstitution inflammatory syndromes occurring in the CNS compartment. This could occur due to cytokine storms caused by immunotherapeutic agents modifying neuroinflammatory responses, or immune activation following viral rebound and blips caused by HDAC inhibitors (and similar agents) or viral rebounds associated with antiretroviral treatment interruptions". So, proper & adequate consent and is participant capable of grasping this risk in order to provide 'real' consent. [Winston et al, see this Editorial posted today on NATAP website. [HIV cure strategies: response to ignore the central nervous system at your patients' peril', AIDS April, 2017 Winston, Alan; Julie, Fox; Fidler, Sara]
Li, Jonathan Z.a; Smith, Davey M.b; Mellors, John W.c
Role of antiretroviral treatment interruption studies in HIV cure research
The evaluation of new therapies to achieve an antiretroviral therapy (ART)-free remission of HIV infection will require demonstration of efficacy through ART interruption studies. However, there are concerns about stopping ART, including patient safety, selection of HIV drug resistance and increased risk for HIV transmission. In this article, we highlight the importance of identifying biomarkers of ART-free remission for cure research and present an updated approach to treatment interruption that should identify predictive markers while minimizing negative consequences for participants. The proposed approach, termed an intensely monitored antiretroviral pause (MAP), has the potential to accelerate progress towards an HIV cure.
Learning from past treatment interruption studies
Initially, ART interruption studies were performed either to reduce ART exposure with the hope of prolonging the durability of ART regimens and minimizing side effects or as a therapeutic intervention to induce long-term ART-free HIV remission [1]. These studies were spurred by a report published in 1999 of a patient who achieved ART-free HIV remission after several patient-initiated treatment interruptions. To assess the potential benefits of treatment interruption and reduced exposure to antiretrovirals, a large treatment interruption trial, known as the SMART study, was conducted [2]. Unfortunately, the study demonstrated that participants who underwent prolonged treatment interruption had significantly increased risk of opportunistic disease, cardiovascular and other non-AIDS-defining events, and death [2]. As a consequence, treatment interruption strategies were largely abandoned, especially with the advent of better tolerated ART regimens. The results of the SMART study have continued to colour the perceptions of the risks involved in treatment interruption studies despite the SMART study's limited generalizability to newer treatment interruption studies designed to evaluate HIV curative strategies.
There are key aspects of the SMART study that largely contributed to the negative outcomes of treatment interruption and can be avoided when conducting treatment interruptions to evaluate a curative strategy [3]. In the SMART study, participants underwent repeated cycles of prolonged ART interruption with limited monthly postinterruption monitoring. In contrast, treatment interruption studies aimed at understanding viral rebound generally require single, shorter durations of ART interruption and significantly more frequent plasma viral load monitoring after interruption. There are generally two types of ART interruption study designs used today to test potential HIV curative interventions. Over the past decade, the most common study design has a preset duration of ART interruption (e.g. up to 24 weeks of treatment interruption) with the viral load set point, CD4+ cell count or ART reinitiation as the primary efficacy outcomes [4-7], and such studies have generally had an excellent safety record. However, these studies still expose participants to extended periods of viremia, which raise concerns about replenishment of HIV reservoirs, HIV transmission [8], immune damage and clinical risks [9,10]. By contrast, a carefully designed MAP study can minimize potential risks to the participants by using the time to first detectable viremia rebound as the primary outcome. In such a MAP study, participants would be monitored intensively after treatment is stopped, and ART would be restarted as soon as the viremia threshold is reached. A preliminary study of this type has already been conducted by Rothenberger et al. [11] in a small number of individuals treated during chronic infection. In this study, 12 patients underwent a treatment interruption with subsequent three times a week viral load monitoring and restarted ART within 5 days of their plasma viral load becoming detectable. The authors noted no clinical symptoms in any patient and all participants had rapid viral suppression after ART reinitiation [11]. This type of intensive posttreatment interruption study design has also been used in the monitoring of viral rebound after haematopoietic stem cell transplantation [12]. This study design reduces the duration of viremia, especially for individuals whose immune systems are functionally naive to HIV (e.g. those treated during acute infection or have undergone a bone marrow transplant) and are at a greater risk of high-level viremia and acute retroviral syndrome [12,13]. In addition, treatment interruption studies have led to the discovery of posttreatment controllers (PTCs) who exhibit sustained HIV suppression despite the lack of protective human leukocyte antigen (HLA) alleles [14]. Elucidating the mechanisms of viral control in these PTCs may lead to novel approaches for inducing sustained ART-free HIV remission in the general HIV-infected population.
Biomarkers of HIV disease and implications for curative strategies
The identification of biomarkers for HIV disease progression was instrumental in discovering effective ART and improving clinical care. One major advance was the identification that plasma HIV RNA levels predicted the risk of HIV disease progression and that reducing these levels (i.e. viral load) was associated with reduced risk of disease progression [15,16]. Prior to 1997, the approval of ART required reduction in clinical endpoints, including AIDS-defining events and death. These studies typically required thousands of participants and years of follow-up. In 1997, the U.S. Food and Drug Administration (FDA) agreed that plasma HIV RNA could serve as primary endpoints for FDA-registration trials [17]. This change allowed for smaller and shorter trials, improved participant acceptance and significantly accelerated HIV drug development.
As the HIV field increasingly turns towards developing therapies to achieve sustained ART-free HIV remission, biomarkers that can reliably predict meaningful outcomes are once again urgently needed. Therapeutics to achieve a sterilizing or functional HIV cure will require initial validation in treatment interruption trials, but the risks, expense and required duration of the treatment interruptions are obstacles for their use in early-phase clinical studies and a barrier for investment from the pharmaceutical industry. The discovery of virologic, immunologic, host or other biomarkers of the duration of ART-free remission could greatly streamline the allocation of limited resources and avoid the exposure of patients to ineffectual and potentially toxic therapies. In a small MAP study of participants treated during chronic HIV infection, the duration of infection, length of ART suppression and CD4+ cell count nadir were significantly associated with time to viral rebound [11]. In an analysis of SPARTAC trial participants who received ART during primary infection, levels of total HIV DNA were predictive of time to viral rebound during an ART interruption [18]. Finally, a recent pooled analysis of treatment interruption studies from the AIDS Clinical Trials Group demonstrated that the size of the active HIV reservoir, as reflected by cell-associated HIV RNA (CA-RNA) and residual plasma viremia, was predictive of the timing of viral rebound after treatment interruption [19]. These findings suggest that biomarkers can be identified that are predictive of outcome after MAP [20].
Biomarkers currently used to evaluate HIV curative strategies are generally categorized as either reflective of the size of the HIV reservoir [21] or host immune response to HIV. The most commonly used biomarker of HIV reservoir status is cell-associated HIV RNA and it has been used to reflect the efficacy of HIV latency-reversing agents, including the histone deacetylase inhibitors (HDACi) vorinostat [22], romidepsin [23], panobinostat [24], among others [25]. Other commonly used biomarkers of viral persistence include levels of residual plasma viremia [22,24], cell-associated HIV DNA [24,26] and quantitative viral outgrowth assays of infectious virus [27]. Although there is evidence that levels of HIV DNA and RNA may predict viral rebound kinetics after treatment interruption [18,19,28,29], data are very limited for the other HIV reservoir biomarkers, and the optimal HIV reservoir biomarker for the prediction of time to viral rebound off ART is still unclear.
Host immune factors associated with control of viral rebound have been most closely studied in HIV elite controllers, whose viral control is associated with strong HIV-specific T-cell activity [30]. Similarly, HIV-specific T-cell responses have been associated with posttreatment interruption viral load set point in several therapeutic vaccine studies [5,6] and in the spontaneous control of HIV [31]. Other immune factors being evaluated as potential biomarkers of HIV persistence and post-ART viral control include HIV antibody levels, and natural killer cell and dendritic cell profiles. All of these immunologic factors represent potentially promising biomarkers that should be evaluated as predictors of time to rebound during MAP studies.
Given the number and diversity of available biomarkers, the systematic evaluation of the optimal biomarkers to predict post-ART viral rebound kinetics should be a high priority for the field. Although biomarkers are an integral part of drug development programmes, it should be noted that the reliance on biomarkers entails limitations and risks. The most appropriate biomarker may differ by the class of intervention. For example, the optimal biomarker for a latency-reversing agent may differ from that of a therapeutic vaccine or gene-modifying therapy. It is also possible that combinations of biomarkers will be needed to achieve the optimal sensitivity, specificity and predictive value that are unattainable by any one biomarker. It is therefore vital that the validation of potential biomarkers be performed in multiple phases, including preclinical exploratory studies to identify potentially useful markers, retrospective or prospective studies to correlate the biomarker with outcomes, and controlled studies to confirm that changes in the biomarker are associated with improved outcome. These steps were used in the validation of plasma HIV RNA as a surrogate endpoint by showing the correlations between HIV RNA levels and clinical outcome [15], as well as the relationship between HIV RNA suppression and clinical response [16].
Identifying a biomarker that is able to reliably predict time to viral rebound when ART is stopped could greatly accelerate the engagement of industry and other stakeholders in HIV cure efforts. The process of identifying and validating such a biomarker will require some risk to participants who are willing to volunteer to have their ART stopped for this effort. Therefore, such endeavours must proceed with caution and as safely as possible.
Overcoming these challenges will require a multidisciplinary effort with an input from all stakeholders, including academia, industry and regulatory agencies, but these hurdles can be overcome with collaborative and systematic effort as an integral part of the quest for a cure of HIV.
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2. Unite forces to validate biomarkers in the quest for lasting HIV remission......from Jules: without knowing the actual reservoir size do biomarkers of viral rebound matter? At this time we do not have an assay that can measure the full size of the reservoir in a patient, so we do not know real/full reservoir size, although research continues to search for such an assay.
Rokx, Casper; Vella, Stefano; Pantaleo, Guiseppe; Levy, Yves; Boucher, Charles A.B.
We propose an international collaboration to share the datasets of published work, perform meta-analyses, and initiate well designed prospective studies to validate possible biomarkers. Examples of innovative collaborative research projects that result in relevant findings from other research fields are progressively emerging [3], and are also expanding within the HIV research field [1,4]. HIV researchers from various continents have already gathered together to discuss the future management of HIV [5]. These incentives are increasingly applauded by prominent researchers [6,7]. Future collaborative studies should be conducted between trustworthy pioneering researchers who will acknowledge each other's input by relevant coauthorships. Combining knowledge will further shape hypothesis driven studies to fill important knowledge gaps in the HIV cure research. Together, we have a better and unique chance of finding validated biomarkers that will help us to identify patients who can be given a chance to live antiretroviral free lives, outside the spectrum of clinical ATI trials.
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3. Can we avoid treatment interruption studies in the search for an HIV cure?.....from Jules: but are we taking all safety precautions? And do we have rigorous consent and consent forms?
Ghosn, Jadea,b; Delaugerre, Constancec,d,e
AIDS: July 31st, 2015
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http://www.natap.org/2017/HIV/101217_01.htm Cure Studies/ART Interruption & Brain Affects, Vorinostat : "......nine participants presented a compartmentalized HIV RNA rebound within the CSF after interruption of ART, even when sampled within 2 weeks from viral rebound
The median time from ART interruption to viral rebound in blood plasma was 19 days (IQR: 8-31 days), while the median time from ART interruption to viral rebound in CSF supernatant was 30 days (IQR: 16-44 days). The median time from viral rebound to HIV RNA sampling in blood plasma (referred as Time point 1) was 24 days (IQR: 20-87 days), while the median time from viral rebound (within the CSF compartment) to HIV RNA sampling in CSF supernatant (Time point 1) was 14 days (IQR: 4-87 days). Since our study was primarily interested in analyzing viral rebound in CSF, the earliest available time points at which HIV RNA levels were sufficient for sequence analysis were included as Time point 1. Because of the characteristic delay between rebound in blood and CSF, HIV RNA levels in blood had plateaued and were no longer substantially increasing during this time period (see Fig. 1). At Time point 1, median CD4 T cell count was 412 cells/μl [IQR: 397-476] and HIV RNA levels in blood and CSF supernatant were 4.7 log10 (copies/ml) [IQR: 4.2-5.1] and 3.3 log10 (copies/ml) [IQR: 2.7-3.8], respectively. With the exception of participant 34535, we sampled HIV RNA from blood and CSF supernatant for one or more additional time points (referred as Time points 2-5) after a median of 55 days from Time point 1 (IQR: 9-364 days). For participants 34535, 26919 and 25839, plasma and CSF supernatant were available from a time point preceding the initiation of ART."
http://www.natap.org/2017/HIV/091817_01.htm ART Interruption Associated with HIV in the Brain: "Reseeding CNS during ART Interruption Leading to Intrathecal Immune Activation" - "HIV-1 Viral Escape in Cerebrospinal Fluid of Subjects on Suppressive Antiretroviral Treatment"
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As mentioned by Li et al., cART interruption usually yields viral rebound, thus raising concerns about patient safety [18], replenishment of HIV reservoirs [19], selection of HIV drug resistance, and increased risk for HIV transmission [20], especially if treatment interruption duration is long. Li et al. therefore propose an appealing strategy of monitored antiretroviral pause (MAP) using the time to first detectable viremia rebound as the primary outcome. In such a MAP study, participants would be monitored intensively after cART is stopped (i.e. three times a week viral load monitoring), and cART would be restarted as soon as the viremia threshold is reached. They also propose a series of biomarkers to identify the best candidates for such a MAP.
The ideal approach would be to be able to identify markers that would serve as outcomes without the need for cART interruption. In the mean time, to date, the only way to address the search for an HIV cure is through cART interruption. MAP studies design proposed by Li et al. allows for intensive monitoring and strict criteria for cART resumption. One critical point is the risk of viral transmission to the partner(s) during cART interruption. This information is very difficult to collect during trials but should be comprehensively documented and communicated [28]. The study design should also include the active participation of the regular(s) sexual partner(s) to comprehensive counseling and interventions to reduce the risk of HIV transmission, such as a preexposure prophylaxis offer to the negative regular(s) partner(s) [29].
Finally, one should keep in mind the ethical aspect of enrolling patients in these intensive - and sometime aggressive - studies with regards to the current excellent quality of life of PLHIV on well tolerated and less burdensome modern cART.
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