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The International AIDS Society convened a multidisciplinary committee of experts to provide guidance and key considerations for the safe management of clinical trials involving people living with HIV during the SARS-CoV-2 pandemic. It is not guidance for the design of prevention studies for people at risk of HIV acquisition, nor for the programmatic delivery of antiretroviral therapy.
The risks and benefits of performing any clinical trial must be carefully evaluated on an ongoing basis. The massive disruption to society caused by SARS-CoV-2 and the COVID-19 pandemic has only heightened the need to regularly reconsider how best to implement a clinical trial. This document aims to provide a framework on considerations to optimally perform studies (Table 1).
The pandemic remains highly dynamic. It is expected that with the emergence of effective prevention and treatment strategies, the risk to people with HIV in clinical trials will decline over time. Uncertainty exists, however, about how well these strategies will be implemented globally, particularly for marginalized populations, many of whom are at high risk of reduced address to ART and/or disease progression.
Also, more contagious and potentially more pathogenic SARS-CoV-2 variants are emerging and these might reduce the effectiveness of current prevention and treatment strategies. It is hence reasonable to assume that SARS-CoV-2 will persist and continue to pose challenges to conducting clinical research in people with HIV. Guidelines regarding how best to implement HIV treatment studies will accordingly also evolve. With this document, we hope to provide a flexible approach that should remain viable and relevant even as the nature of the pandemic continues to evolve.
In January 2020, a novel coronavirus, the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), was identified as the causative agent of COVID-19 disease . The World Health Organization (WHO) declared SARS-CoV-2 infection a pandemic on 11 March 2020 . At the time of writing, there have been an estimated 110 million confirmed cases of COVID 19, including over 2.4 million deaths globally , with an estimated infection fatality ratio approaching 1% [3-5].
SARS-CoV-2 transmission is predominantly through respiratory droplets and airborne particles spread during close contact . Infection with SARS-CoV-2 can result in a spectrum of clinical presentations, from asymptomatic infection and mild respiratory illness to severe respiratory distress and death [7-9]. Severe COVID-19 has been associated with many risk factors, including older age (>60 years), male gender and the presence of co-morbidities (such as cardiovascular disease, renal disease, hypertension, diabetes, obesity, ongoing cancer and recent organ recipients) . Other important risk factors for more severe disease are poverty, poor housing and being a member of ethnic minority populations . Many of these risk factors are over-represented among people living with HIV.
Evidence suggests that people living with HIV on successful antiretroviral therapy (ART) may be at an increased risk of COVID-19 acquisition, although the interplay of socioeconomic status and therefore exposure may well confound these studies [10,11]. While some studies show that people living with HIV are not at increased risk of more severe COVID-19, in certain settings, such as South Africa, this is not always the case [10,12,13]. A systematic review of 23 articles found that HIV may not be an individual risk factor, but people living with HIV and with co-morbidities had an increased risk of severe outcomes [14-16]. For people living with HIV with severe immunosuppression or uncontrolled HIV viraemia, fatality rates for COVID-19 remain uncertain [15,17,18]. More recent studies suggest that among those with HIV, people who had a low CD4+ T cell count nadir prior to ART compared to those with higher nadirs had a higher risk of complications from COVID-19 .
While there is a hypothetical concern that some people living with HIV may develop suboptimal responses to COVID-19 vaccines [20,21], this is as yet unconfirmed, and preliminary data among people living with HIV on successful ART with CD4 counts >350 suggests that this may not be the case . Given these trends, it is important for researchers to carefully consider the pros and cons of any research programme that might put people living with HIV at high risk for COVID-19 or at increased risk of a sub-optimal response to a COVID-19 vaccine.
It is important to consider the risks and benefits of conducting versus deferring clinical trials in people living with HIV. As it is likely that SARS-CoV-2 infection will become endemic and persist in some manner for years, the consensus reached was that the development of novel treatment and cure strategies for HIV must continue.
Once HIV trials are deemed safe to resume or open on the local level, we recommend that all study stakeholders carefully consider whether the potential risks to the study participants are acceptable. Importantly, whenever possible, the case for ongoing research should be discussed with and supported by the community.
We recommend that each study is reviewed and evaluated on a case-by-case basis, dependent on the type of intervention planned, background prevalence and incidence of SARS-CoV-2, as well as access and uptake of a safe and effective SARS-CoV-2 preventative vaccine. Each clinical trial should have a current COVID-19 risk mitigation plan, clearly outlined in all study-related material and participant information sheets, including a plan for COVID-19 vaccines. The COVID-19 issues will require robust informed consent to ensure that study participants are aware of the implications of acquiring COVID-19 during the research. The balance of the preservation of trial scientific integrity in order to retain the capacity to generate mean
There are currently ten vaccines approved under either emergency use or full approval in many parts of the world [23,24]. These include mRNA, viral vector, protein and killed vaccines. Some Phase 3 studies have included people living with HIV, but the numbers have been small. Therefore, an accurate assessment of safety and efficacy of each vaccine in the context of people living with HIV remains unknown. In a Phase 3 study of an adjuvanted protein vaccine (Novavax) in South Africa, 6% of participants were people living with HIV. Although the efficacy rates in this population were not reported, there was substantial improvement in efficacy rates when people living with HIV were excluded from the analysis .
Current recommendations are for people living with HIV on ART to receive a COVID-19 vaccine, with no specific preference for an individual vaccine, although this may well change as further data emerge. In people living with HIV not on ART, current US recommendations are to initiate ART and once on stable ART with a controlled viral load, COVID-19 vaccination is recommended.
Access and equity to SARS-CoV-2 vaccines: There are major disparities in who acquires SARS-CoV-2 and disease severity once infected. There are also disparities in people’s ability to access treatment and prevention for COVID-19. Given that many of these same trends exist in terms of people living with HIV, the overall burden of SARS-CoV-2 will likely prove to be much higher globally on those with HIV than those without HIV. Currently 80% of COVID-19 vaccines have been purchased by 11 countries, predominantly high income countries. COVID-19 vaccine programs have not even started in many countries with the highest prevalence of HIV .
Timing of vaccines during the conduct of a clinical trial: Timing of vaccination must be considered prior to resuming clinical research in people living with HIV. Ensuring the safety and well-being of study participants and staff while maintaining maximal scientific integrity is key. We recommend obtaining a SARS-CoV-2 and vaccination history at every visit.
For analytical treatment interruption (ATI) interventional studies, if a SARS-CoV-2 vaccination is available in the country of research, full vaccination a minimum of 4 weeks before ATI in ATI interventional studies is recommended. This is to avoid any confounding of immunogenic effects from the vaccine with the intervention in question or the risk of inducing viral replication during an ATI. However, should a SARS-CoV-2 vaccine become available during an HIV trial protocol, the study protocol should be modified to allow for vaccination. Specifically, efforts should be made to pause the study to allow vaccination to be done as safely as possible. Ideally, no immunotherapy or interruption in ART would occur until four weeks after administration of the complete vaccine regimen.
Participation in Phase 3 COVID-19 studies had different requirements for receipt of influenza vaccines, but most guidelines now recommend a separation of two weeks between COVID-19 and influenza vaccines. Given the experimental nature of interventions, specifically in cure research, and the potential adverse effects of an ATI, we recommend here a longer separation between intervention and/or ATI and receipt of a COVID-19 vaccine of 4 weeks.
Due to the addition of a potential confounding factor, additional immunological monitoring on the vaccine effect should be considered.
Vaccination hesitancy may be a barrier to restarting clinical research in people living with HIV. Community engagement is key to providing education on the importance of vaccination to reduce the risk of COVID-19 infection. The risks and benefits of study enrolment and/or continuing in a study for a participant not willing to receive an available COVID-19 vaccine must be carefully assessed. For trials where such a risk-benefit assessment indicates it is appropriate to proceed, there must be a robust informed consent process that explicitly includes information about the increased risks of enrolment in a trial with increased risks of COVID-19 exposure.
Risk and proposed mitigation strategies are presented in Table 2.
There remain several additional unknown aspects of the interaction between HIV and SARS-CoV-2 infection that may be incorporated into future mitigation strategies as data becomes available. These include:
The COVID-19 pandemic has shown that a rapid response to a global public health challenge is possible. The response has been remarkable, both in financial and human terms; however, it has significantly disrupted ongoing and planned clinical research efforts. As a result, the IAS established an international steering group to define the primary needs, identify key questions and advise on how best to address these. Members also set the agenda for an online consultation and help identify participants for the consultation. Two online consultations were held, on 9 and 17 December 2020. A summary document was circulated for comments to a larger group of 40 international stakeholders and led to the development of this document.
Figure 1 presents an overview of the issues identified for discussion and/or inclusion in the guidance. The steering group brings together diverse stakeholders involved in clinical research. The group met virtually to discuss the broad approach. A position statement was drafted and approved by all participants. This same panel will be assembled again to update the guidelines if substantial changes in the pandemic emerge.
The authors would like to thank the contributors to the online consultation: Pedro Cahn, Kara Chew, Carlos del Rio, Rajesh Gandhi, Nagalingesawaran Kumarasamy, Jillian Lau, James McMahon, Cristina Mussini, Jean-Pierre Routy, Ole Sogaard, Jeremy Sugarman, Jeff Taylor, Fu-Sheng Wang.
Local community SARS-CoV-2 incidence levels and mobility restrictions should be taken into account before HIV study enrolment. ‘If local infection rates increase, pausing a study that requires in person study visits, may be necessary’.
The risk of SARS-CoV-2 acquisition should be mitigated by: (1) the provision of personal protective equipment (PPE) for study participants, all research and clinical staff and community partners, as needed; (2) the frequency of in-person study visits where feasible; and (3) the use of remote study visits, electronic consent and study records where feasible and permissible.
Exclusion of active SARS-CoV-2 infection through the offer of SARS-CoV-2 PCR or antigen testing for all study participants, before enrolment, at least 72 hours prior to any investigational drug dosing and at regular intervals throughout the trial period is recommended. The need for and frequency of SARS-CoV-2 testing will be dependent on local incidence patterns. Deferral of study enrolment until proven SARS-CoV-2 negative or no longer deemed infectious, based on local guidelines, can be considered for any potential participant initially testing SARS-CoV-2 positive.
A negative SARS-CoV-2 PCR or antigen test result should be confirmed immediately prior to any planned analytical antiretroviral treatment interruptions ATI or the administration of any immunotherapy that might conceivably put a person at high risk of COVID-related morbidity.
Access to an available SARS-CoV-2 vaccine is recommended before recruitment into an HIV study. Ideally, this vaccine will have some proven efficacy in people living with HIV. Where a vaccine is available, deferral of trial entry until four weeks after the last vaccination, when optimal immunogenicity and protection are anticipated, is recommended. This is particularly relevant for trials that include immunotherapies and/or analytical antiretroviral treatment interruptions (ATI).
If a SARS-CoV-2 vaccine becomes available during the trial, then whenever possible, immunotherapy that could potentially interfere with an optimal vaccine response or the initiation of an ATI should be deferred until four weeks after the last vaccine dose. The vaccine should be offered to any study participants already enrolled into the protocol.
Careful evaluation must be applied to any study of interventions that could compromise immune function (for example, immune activators, immune modulators, latency-reversing agents and therapeutic HIV vaccines) that could adversely impact the natural history of COVID-19 and/or response to a COVID-19 vaccine.
Suggested mitigation approach
Recommendations within the HIV study protocol must take into account local epidemic and context.
Robust risk mitigation strategies must be embedded within the study protocol.
Studies must be flexible and, if possible, have contingencies planned so that the study might be paused in case of local increases in new infections (or in response to local lockdowns). All protocols should have flexibility to scale up risk mitigation based on community transmission.
Study teams should engage with external primary care physicians and/or HIV clinicians who can provide advice on local epidemiological knowledge and build individual care plans.
Safety monitoring committees or other external advisory bodies should be in place prior to opening the study. The committee members should be tasked with making recommendations regarding continuing, pausing or halting the study based on local conditions in relation to COVID-19.
Challenges to trial integrity
Concerns regarding COVID-19 will make all studies more challenging to enrol. Funders and other stakeholders may need to modify expectations.
Modifying studies as conditions mandate will result in protocol violations and hence may affect scientific integrity; this risk to the study should be included whenever an investigator, funder or regulator chooses to conduct any clinical trial during a pandemic.
Eligibility criteria might have to be modified. Specifically, those who are at high risk for COVID-19-related morbidity might be excluded. Risk factors include advanced age, diabetes mellitus and obesity. High-risk participants might need more intensive counselling during the conduct of the study.
Stricter eligibility criteria will limit enrolment and make any study more challenging to conduct. The results may be less generalizable.
The informed consent process should include a discussion on: (1) elevated risk of acquiring SARS-CoV-2 during study visits; and (2) the potential risk of immunotherapies, treatment interruptions and other interventions.
Participants may have to be re-consented at key time points in the study (e.g., prior to ATI) or as new knowledge on HIV and COVID-19 emerges.
When feasible, participants may be given the option of opting out of specific procedures (e.g., tissue biopsies) and interventions (e.g., ATI) if the study integrity can be maintained.
There may be challenges to trial recruitment and challenges to study outcome measures.
Efforts should now be routinely made to limit participant visits to any healthcare system; virtual visits (telemedicine) should be used whenever possible.
Online consent and electronic patient portals should be considered.
The number of visits to the primary research centre for viral load measurement might be reduced, including those taken during any planned ATI. Alternative strategies for testing (e.g., local home visits by phlebotomy teams, at-home self-testing of viral load) should be implemented when possible.
Resources should be provided to ensure that participants use the safest forms of transportation available. To avoid public transportation, parking and taxi vouchers might be used.
Pre-visit telephone health screening (e.g., symptom assessment) and on-site health screening (e.g., temperature checks) should be used.
Reduced visits and reliance on telemedicine (virtual visits) will reduce the quality of the data, make rigorous laboratory monitoring more challenging, and reduce the number of biologic specimens that might be used to advance the science.
Regular SARS-CoV-2 testing should be offered throughout the study based on a testing algorithm. The frequency of testing should be dependent on the type of study intervention and symptom development. Testing should be offered to all symptomatic patients.
The mechanism of action of curative interventions (i.e., immune modulators) should be reviewed with the trial sponsor. This should address whether the intended intervention could modify the immune response to SARS-CoV-2 and imply a higher risk of severe COVID-19.
Plans should be in place to help manage the care of any participant who tests positive while the study is being carried out.
If a person is diagnosed with acute SARS-CoV-2 infection, all procedures will have to be delayed. Immunotherapies and other potentially risky interventions (including ATIs) should be deferred. If a person acquires SARS-CoV-2 during an ATI, ART should be resumed.
Clinical studies will have to provide appropriate resources so that all participants can access accurate SARS-CoV-2 PCR or antigen testing.
If a vaccine becomes available during the trial period, the protocol should be modified to allow for safe vaccination.
A vaccination history should be taken at each study visit.
Full vaccination at least 14-28 days before ATI is recommended, if available, to avoid immunogenic interference with study questions.
Clinical studies will have to provide appropriate resources so that all participants can access accurate SARS-CoV-2 PCR or antigen testing.
The pausing or rescheduling of procedures to allow for vaccination will result in protocol deviations and could affect the integrity of the study. Prospective plans to account for any contingencies should be in place before a study is initiated.
The Peter Doherty Institute for Infection and Immunity, The University of Melbourne and Royal Melbourne Hospital, Melbourne, Australia.
University of California, San Francisco (UCSF), San Francisco, USA.
IrsiCaixa AIDS Research Institute, HUGTIP, Badalona, Spain.
Imperial College London, London, UK.
University of the Witwatersrand, Johannesburg, South Africa.
Fundação Oswaldo Cruz. Rio de Janeiro, Brazil.
AVAC, Lilongwe, Malawi.
i-Base, London, UK.
Kirby Institute, Sidney, Australia.
International AIDS Society