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Highlights of the 9th edition of the Conference on HIV Persistence During Therapy, 10-13 December 2019, Miami, USA - ATI Risks, Functional Not Sterilizing Cure the Goal
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"Overall, the potential for neurological and CNS problems during acute or sustained viraemia are real, but poorly defined, risks of ATIs.
A full sterilising cure does not seem to be in our immediate reach, however therapeutic approaches aiming at a functional cure (where the virus will be maintained below a certain threshold and both morbidity or secondary transmission will not occur) are the focus of current approaches.
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......Monitoring of participants' psychosocial experiences during ATIs is crucial.
This assessment would involve participants' motivations, needs, concerns, and perceptions throughout the study. 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.
Resuming ART at the time of rebound or setting restart criteria too stringently might prevent potential complications of an ATI, but will also reduce the capacity to test the effectiveness of many interventions that aim to work through an immunological mechanisms and, consequently, might prevent the identification of virological controllers
There was consensus that cure should not be used in titles and the informed consent processes. Most ATI studies are early stage trials and are not designed to lead to a potential cure. Thus, the use of cure is misleading."
http://viruseradication.com/journal-details/Highlights_of_the_
9th_edition_of_the_
Conference_on_HIV_Persistence_During_Therapy,_10-13_December_2019,_Miami,_USA/
To be able to expect long-lasting virus remission, interventions should mimic elite or post-treatment controllers with an RNA plasma viral load below the level of detection and persisting at least for 1 year in order to be clinically meaningful and economically sound.
Furthermore, to assess the clinical value of these cure strategies, ART interruption remains the only read-out to evaluate viral control after ART discontinuation. Therefore, consensus on the mitigation of these risks following ART interruption requested for the participants and their sexual partners has to be optimised [ 56 ]. To this end, identification of inflammatory biomarkers that can predict viral rebound has become a research priority to further reduce risk of participating in cure research clinical trials [ 57 , 58 ]. Several innovative functional cure strategies have been presented this year.
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
In addition, the occurrence of AIDS-defining illnesses is, in most cases, linked to a CD4 nadir, which by itself is a criterion for determining eligibility. Therefore, 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, 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.
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. There was a strong consensus that patients with chronic hepatitis B virus infection, detectable hepatitis B surface antigen or hepatitis B virus DNA, active hepatitis C virus infection, or detectable hepatitis C virus RNA should be strictly excluded.....
https://www.thelancet.com/journals/lanhiv/article/PIIS2352-3018(19)30052-9/fulltext
The group reached a consensus that individuals who have been fully treated for and cured of hepatitis C or who have cleared the virus naturally, and have documented undetectable plasma hepatitis C virus RNA, do not need to be excluded. Other co-infections, for example Mycobacterium tuberculosis, need to be considered, specifically given the high prevalence of M tuberculosis infection among people with HIV in certain geographic locations.....
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.
The association between cardiovascular risk and ATI is debatable. Although some investigators strictly exclude individuals with any cardiovascular risk or history, others might allow certain cases, such as individuals who have a distant history of disease and who have been treated and stable for many years. 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
Although HIV transmission is among the greatest risks during an ATI, participants undergoing ATIs might also face legal and even criminal charges should they transmit HIV while off ART.28
Thus, HIV transmission must be vigilantly prevented for the safety of both partners and participants. Therefore, a consensus was reached that, at a minimum, participants must be clearly and comprehensively counselled on transmission risks. The majority of the meeting participants thought that having HIV-negative sexual partners who are not accessing pre-exposure or post-exposure prophylaxis should not in itself be an exclusion criterion for a potential participant of an ATI study
What is considered adequate monitoring during the ATI phase?
The consensus was that, in most circumstances, once weekly monitoring is a reasonable frequency. Although more frequent testing might be desired from a clinical and scientific perspective, it is necessary to consider the very real burden this frequency presents to participants and monitoring frequency must be balanced against participant retention, especially in studies lasting 6-12 months. It was agreed that the early weeks of ATI warrant the most thorough testing. Specifically, 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). The rationale for frequent monitoring in the initial 12 weeks is based on the observation that the majority of individuals rebound during this time.29, 30
Frequent early testing is thus crucial to detect rebound with precision. Nevertheless, it was noted that less frequent monitoring in later weeks could also result in undetected viraemia.
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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