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Recommendations [listed just below] for analytical antiretroviral treatment interruptions in HIV research trials-report of a consensus meeting
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Download the PDF here
Download the PDF here
Boris Julg, Lynda Dee, Jintanat Ananworanich, Dan H Barouch, Katharine Bar, Marina Caskey, Donn J Colby, Liza Dawson, Krista L Dong, Karine Dubé, Joseph Eron, John Frater, Rajesh T Gandhi, Romas Geleziunas, Philip Goulder, George J Hanna, Richard Jefferys, Rowena Johnston, Daniel Kuritzkes, Jonathan Z Li, Udom Likhitwonnawut, Jan van Lunzen, Javier Martinez-Picado, Veronica Miller, Luis J Montaner, Douglas F Nixon, David Palm, Giuseppe Pantaleo, Holly Peay, Deborah Persaud, Jessica Salzwedel, Karl Salzwedel, Timothy Schacker, Virginia Sheikh, Ole S. Søgaard, Serena Spudich, Kathryn Stephenson, Jeremy Sugarman, Jeff Taylor, Pablo Tebas, Caroline T Tiemessen, Randall Tressler, Carol D Weiss, Lu Zheng, Merlin L Robb, Nelson L Michael, John W Mellors, Steven G Deeks, Bruce D Walker
These recommendations are NOT ENFORCEABLE,
?? Will These Recommendation Be Enforced, Will Informed Consent Address ALL These Recommendations & Warn Potential Study Participants of All These Risks?
from Jules: why did it take all these years to discuss ethics, & find these limitations & concerns for patients considering ATIs. For years we have been conducting cure search without many of these considerations by researchers & potential patient study participant. The mention of Informed consent in this paper - will Informed Consent now REQUIRE full warning & discussion of ALL the risks outlined in this study????......"the establishment of an eclectic advisory group, such as the one described in this Review, that can regularly revisit and recommend changes in the approach to ATIs in HIV research studies should accelerate the evaluation of strategies that seek ART-free viral control while minimising risk to research participants."
Paper Excerpts: More importantly, researchers should determine criteria for whether an intervention has achieved predefined goals (eg, stipulating that a therapeutic vaccine induces immune responses above a prespecified threshold) before subjecting participants to an ATI. In general, the group agreed that ATIs should not be used in the absence of supporting data simply to generate hypotheses.....The group agreed that no single population was best for all ATIs. There was consensus that ATI studies, which are largely experimental, should focus on otherwise healthy individuals with well controlled HIV who do not have substantial or serious comorbidities. Because experimental studies can involve relatively long ATIs, high viraemia, or both, investigators should seek participants who are expected to have a functional immune system, and who can probably tolerate a period of high viraemia or any viraemia occasioned by infrequent viral load monitoring....Therefore, an agreement that participants in ATI studies should have stable CD4 counts of equal or greater than 500 cells per μL was reached. However, support was also given for allowing CD4 counts of equal to or greater than 350 cells per μL
Here are a few bullets I excerpted from the Discussion I consider important followed by a lis of Recommended Inclusions & Exclusions & Monitoring and Restart criteria.
DOES THIS MEAN LIVER EVALUATION/SCREENING WILL BE UTILIZED??????, Fibroscan? how to screen is debatable?
• Patients with non-infectious liver disease (including advanced non-alcoholic fatty liver and advanced non-alcoholic steatohepatitis), should be excluded if evidence of substantial fibrosis (fibrosis score ≥F2) or cirrhosis determined by histology, imaging, or non-invasive measurements, is found.
• Overall, the potential for neurological and CNS problems during acute or sustained viraemia are real, but poorly defined, risks of ATIs. Previous experience with cerebrospinal fluid monitoring during prolonged ART interruption indicated rebound of HIV RNA accompanied by elevations in biomarkers of intrathecal inflammation and neuronal injury by approximately 20 days after ATI.18, 19, 20 However, the clinical consequences of these changes are unknown.
• Several conditions and populations were considered to define strict exclusion criteria for ATIs: active co-infection, cancer, neurological concerns, ART resistance, cardiovascular disease, history of AIDS defining illness and CD4 nadir, pregnancy, renal and liver disease, risk of HIV transmission to sexual partners of ATI study participants, and paediatric populations.
• Achieving and ensuring informed consent can be very challenging, and the individual engagement of the research team member(s) and the potential participant is essential for supporting informed consent in early phase clinical trials. There was consensus that trial investigators need to ensure that participants understand the risks involved with ATI studies [including as discussed in this paper above CNS viral escape imitations & risks].....An important distinction was noted between participants who are misinformed (eg, those who do not understand the intent of the research) versus participants who display therapeutic optimism (eg, those who understand the intent of the research but are unrealistically optimistic about obtaining the best outcome).
• Possible viral load-based restart criteria were also discussed. There was some support for 12-16 weeks of uncontrolled viraemia as an acceptable limit in studies for which a stable viral setpoint is a primary endpoint. Another proposed limit was to tolerate a viral load of 1000 copies per mL or more for 4 weeks. Overall, the consensus was that no universal values for duration or peak of viraemia should be used as restart criteria but that, when setting limits, duration of viraemia might be more important than the amount of viraemia.
• participants should be monitored weekly for 12 weeks, and testing frequency might be decreased to every other week thereafter, with the option of resuming weekly monitoring if necessary (eg, when rebound of viraemia occurs; appendix p 6).
• There was a consensus on the fact that researchers should also examine participants' psychosocial tolerance for longer ATIs, particularly because the research field moves towards less restrictive ATIs and prolonged periods of viraemia. Cohort studies of people with acute HIV infection in Thailand have successfully integrated decision-making assessments in HIV remission protocols with ATIs. Overall, the consensus was that research protocols should include formal monitoring of both perceived health and non-health associated benefits, and also perceived risks, such as anxiety related to being off ART, stress related to becoming viraemic, and fear of transmitting HIV to sexual partners.
Additional or more stringent criteria might be required based on known toxicities of the study drug(s) or expected risks of the study intervention(s). Inclusion and exclusion criteria, monitoring, and antiretroviral therapy (ART) restart criteria might differ in children depending on age. ART=antiretroviral therapy. *Baseline CD4 counts of ≥350 cells per μL might be considered.
Based on FDA-approved HIV RNA quantification assay.‡ Latent tuberculosis infection discussed in the text. §Other malignancies discussed in the text. ¶Defined as single key mutations or an accumulation of minor mutations that result in resistance to entire respective drug classes. ||Symptoms include, but are not limited to, unintentional weight loss
(>5-10% of the pre-ATI bodyweight), otherwise unexplained persistent fever (>100·4°F/38°C), persistent night sweats, persistent diarrhoea, oral candidiasis and generalised lymphadenopathy. **Largely dependent on the CD4 entry criteria; a sufficiently large delta between the entry value versus CD4 measurement for ART resumption should be ensured.
12-16 weeks of uncontrolled viraemia, with HIV RNA of more than 100 000 copies per mL; it might be acceptable in studies in which a stable viral set point is a primary endpoint.
Summary
Analytical antiretroviral treatment interruption (ATI) is an important feature of HIV research, seeking to achieve sustained viral suppression in the absence of antiretroviral therapy (ART) when the goal is to measure effects of novel therapeutic interventions on time to viral load rebound or altered viral setpoint. Trials with ATIs also intend to determine host, virological, and immunological markers that are predictive of sustained viral control off ART. Although ATI is increasingly incorporated into proof-of-concept trials, no consensus has been reached on strategies to maximise its utility and minimise its risks. In addition, differences in ATI trial designs hinder the ability to compare efficacy and safety of interventions across trials. Therefore, we held a meeting of stakeholders from many interest groups, including scientists, clinicians, ethicists, social scientists, regulators, people living with HIV, and advocacy groups, to discuss the main challenges concerning ATI studies and to formulate recommendations with an emphasis on strategies for risk mitigation and monitoring, ART resumption criteria, and ethical considerations. In this Review, we present the major points of discussion and consensus views achieved with the goal of informing the conduct of ATIs to maximise the knowledge gained and minimise the risk to participants in clinical HIV research.
from Jules: why did it take all these years to discuss ethics, & find these limitations & concerns for patients considering ATIs. For years we have been conducting cure search without many of these considerations by researchers & potential patient study participant. The mention of Informed consent in this paper - will Informed Consent now REQUIRE full warning & discussion of ALL the risks outlined in this stud????
Conclusion
In summary, ATIs are not yet irreplaceable for assessing the efficacy of interventions aimed at inducing HIV suppression in the absence of ART. Guidance on how to operationalise ATI studies to maximise scientific return but minimise participant's risk is crucial. The recommendations and consensus viewpoints summarised in this Review are thought to be a step forward in building consensus about how best to implement ATIs, taking scientific, clinical, and ethical aspects, and expectations into consideration. With the field rapidly evolving and with new data emerging, the establishment of an eclectic advisory group, such as the one described in this Review, that can regularly revisit and recommend changes in the approach to ATIs in HIV research studies should accelerate the evaluation of strategies that seek ART-free viral control while minimising risk to research participants.
Background
Despite the success of modern antiretroviral therapy (ART) in limiting HIV replication, HIV infection remains a chronic disease that long-term ART alone will probably never eliminate. Thus, efforts to eradicate HIV infection, or at least induce a state of ART-free viral suppression, are being vigorously pursued. To ultimately validate promising strategies, analytical antiretroviral therapy interruptions (ATI) appear to be necessary until a promising biomarker that robustly predicts post-treatment viral control emerges; therefore, so far, ATIs are irreplaceable. Despite the important role of ATIs in HIV research, clinical trial designs that include ATIs have been quite heterogeneous, hindering the ability to compare efficacy and safety of interventions and ATIs across trials. Therefore, on July 9, 2018, we convened a forum at the Ragon Institute of MGH, MIT and Harvard in Cambridge, Massachusetts, USA, to assess the scientific value, risks, benefits, and methods of ATIs, including the ethical and community perspectives of these approaches. Our goal was to formulate recommendations for the conduct of ATIs in a manner that maximises the knowledge gained and minimises the risk to trial participants. This Review summarises the major points of discussion (panel) and any consensus viewpoints that were achieved. It is expected that this meeting is the beginning of an ongoing discussion on how to conduct ATIs that will continue to evolve to reflect the ever-changing clinical and scientific landscape.
Excerpted from DISCUSSION in paper
Overall, the potential for neurological and CNS problems during acute or sustained viraemia are real, but poorly defined, risks of ATIs. Previous experience with cerebrospinal fluid monitoring during prolonged ART interruption indicated rebound of HIV RNA accompanied by elevations in biomarkers of intrathecal inflammation and neuronal injury by approximately 20 days after ATI.18, 19, 20
However, the clinical consequences of these changes are unknown. Thus far, the risk for a neurological adverse event in the context of ATI appear low, although aseptic meningitis as a sign of acute retroviral syndrome has been reported.16, 21
In general, patients with a history of HIV-associated dementia or progressive multifocal leukoencephalopathy should be excluded. HIV-associated dementia is associated with neuroinflammation, neuronal injury, and a high burden of HIV replication in the CNS that is typically genetically compartmentalised with respect to the blood, suggesting a CNS cellular source.22, 23
These pathologies are improved by ART.24
However, residual low-grade intrathecal immune activation and HIV RNA detection in the CNS despite suppression in the plasma suggest that the brain is a site of HIV persistence, which might be vulnerable to further injury or development of local ART resistance with CSF escape during recrudescence of viral replication and inflammation.25, 26
Progressive multifocal leukoencephalopathy is a frequently fatal disorder caused by CNS infection with the John Cunningham virus for which an effective antiviral therapy is not yet available.27
Immune competence is essential for John Cunningham virus control and irreversible brain injury persists in individuals who survive progressive multifocal leukoencephalopathy.
The potential emergence of new drug-resistance mutations is of concern. Drug resistance might occur during the interruption phase or when ART is resumed. Specifically, stopping ART regimens containing antiretrovirals with different serum half-lives, which results, for example, in delayed wash-out of non-nucleoside reverse-transcriptase inhibitors (NNRTIs) among other drugs, poses a risk for the development of drug resistance. The treatment of study participants on such regimens should be switched to short-acting antiretrovirals (eg, switching NNRTIs to integrase inhibitors) before an ATI. Although one study7 reported no evidence of new antiretroviral drug resistance mutations within intact sequences of HIV proviral DNA following reinitiation of ART, one patient in a different study16 developed the K103N mutation during ART reinitiation due to adherence issues caused by an acute retroviral syndrome. Based on these observations, the consensus was that studies should only enrol individuals who have multiple alternative ART options available in case their current treatment becomes less effective. Excluding individuals who have resistance to two or more classes of drugs (defined as single key mutations or an accumulation of minor mutations that result in resistance to entire respective drug classes) was also supported (appendix p 3).
The group reached a consensus that all potential study participants should be screened for signs and symptoms of cardiovascular disease before taking part in an ATI study. If findings on initial screening raised concern, additional testing for cardiovascular disease should be done before enrolment. Individuals with a known cardiovascular event or at high risk of an event (eg, Atherosclerotic Cardiovascular Disease Score >15%) should be excluded.
Approximately two-thirds of meeting participants concluded that anyone with a history of AIDS-defining illness according to Centers for Diseases Control and Prevention criteria should be excluded (appendix p 3)
the general consensus was that individuals with a lifetime CD4 nadir of less than 200 cells per μL should be excluded, regardless of whether they are on stable treatment with higher CD4 T-cell counts. Moreover, there was some support within the group that a lifetime CD4 nadir of less than 350 cells per μL should be considered to be an exclusion criterion while we are still in the early stages of conducting ATI studies. Overall, there was also consensus that investigators should carefully consider the context of their study when choosing a CD4 nadir cutoff.
Patients with non-infectious liver disease (including advanced non-alcoholic fatty liver and advanced non-alcoholic steatohepatitis), should be excluded if evidence of substantial fibrosis (fibrosis score ≥F2) or cirrhosis determined by histology, imaging, or non-invasive measurements, is found [from Jules: except no one screens n HIV for fibrosis & fatty liver in HIV but HCV-negative people, re we going to start screening????? will researchers incorporate screening??? a fibroscan??
Methods
41 experts on HIV research (adult and paediatric clinicians; virologists and immunologists; bioethicists; patient advocates; statisticians; social scientists; and representatives of regulatory authorities and funding agencies [US Food and Drug Administration, US National Institutes of Health, and AmfAR]) and industry from Denmark, South Africa, Spain, Switzerland, Thailand, the UK and the USA, participated by invitation from the scientific committee (BJ, LD, JA, DHB, MLR, NLM, JWM, SGD, and BDW). Main challenges concerning ATI studies were identified before the meeting, including establishing strategies for risk mitigation, monitoring and ART resumption criteria, and evaluating ethical considerations. Four panels were established to prepare and present expert opinions on assigned topics and to formulate a set of questions for which opinion of the larger group was considered crucial. Panel presentations were followed by an open group discussion and concluded with an electronic, anonymous poll on selected questions. A manuscript detailing recommendations was prepared by the scientific committee and then circulated to the larger group for review and revision. The recommendations presented in this manuscript are largely based on expert opinions given the paucity of clinical evidence specific to ATIs and the limited availability of randomised controlled trials. The references used in this document were identified by literature search focusing on reported clinical studies, including observational, cohort, or interventional studies in which ART was temporarily interrupted with predetermined restart criteria. We have adhered to the policies for protection of human subjects as prescribed in AR-70-25.
How do we ensure informed consent and avoid unreasonable expectations?
Achieving and ensuring informed consent can be very challenging, and the individual engagement of the research team member(s) and the potential participant is essential for supporting informed consent in early phase clinical trials. There was consensus that trial investigators need to ensure that participants understand the risks involved with ATI studies. In addition to potential physical risks, informed consent documents should address potential social, financial, and psychological risks. This process also includes informing the participant about potential stress or worry associated with re-experiencing detectable viraemia or fear of transmitting HIV. There was some support for testing the participants' knowledge of the study after informed consent to ensure that potential participants understand the procedures and risks involved in trial participation. Evidence from a study in Thailand
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suggests that close relationships between clinical trial teams and participants has facilitated an improved understanding of the study and required procedures. As a result of these close relationships, most participants reported feeling that they had made an active and informed choice to participate at the conclusion of the study. An important distinction was noted between participants who are misinformed (eg, those who do not understand the intent of the research) versus participants who display therapeutic optimism (eg, those who understand the intent of the research but are unrealistically optimistic about obtaining the best outcome).
Conclusion
In summary, ATIs are not yet irreplaceable for assessing the efficacy of interventions aimed at inducing HIV suppression in the absence of ART. Guidance on how to operationalise ATI studies to maximise scientific return but minimise participant's risk is crucial. The recommendations and consensus viewpoints summarised in this Review are thought to be a step forward in building consensus about how best to implement ATIs, taking scientific, clinical, and ethical aspects, and expectations into consideration. With the field rapidly evolving and with new data emerging, the establishment of an eclectic advisory group, such as the one described in this Review, that can regularly revisit and recommend changes in the approach to ATIs in HIV research studies should accelerate the evaluation of strategies that seek ART-free viral control while minimising risk to research participants.
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