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Introduction: Understanding the clinical potency of latency-reversing agents (LRAs) on the HIV-1 reservoir is useful to deploy future strategies. This systematic review evaluated the effects of LRAs in human intervention studies., Methods: A literature search was performed using medical databases focusing on studies with adults living with HIV-1 receiving LRAs. Eligibility criteria required participants from prospective clinical studies, a studied compound hypothesised as LRA, and reactivation or tolerability assessments. Relevant demographical data, LRA reactivation capacity, reservoir size, and adverse events were extracted. A study quality assessment with analysis of bias was performed by RoB 2 and ROBINS-I tools. The primary endpoints were HIV-1 reservoir reactivation after LRA treatment quantified by cell-associated unspliced HIV-1 RNA, and LRA tolerability defined by adverse events. Secondary outcomes were reservoir size and the effect of LRAs on analytical treatment interruption (ATI) duration., Results: After excluding duplicates, 5182 publications were screened. In total 45 publications fulfilled eligibility criteria including 26 intervention studies and 16 randomised trials. The risk of bias was evaluated as high. Chromatin modulators were the main investigated LRA class in 24 studies. Participants were mostly males (90.1%). Where reported, HIV-1 subtype B was most frequently observed. Reactivation after LRA treatment occurred in 78% of studies and was observed with nearly all chromatin modulators. When measured, reactivation mostly occurred within 24 h after treatment initiation. Combination LRA strategies have been infrequently studied and were without synergistic reactivation. Adverse events, where reported, were mostly low grade, yet occurred frequently. Seven studies had individuals who discontinued LRAs for related adverse events. The reservoir size was assessed by HIV-1 DNA in 80% of studies. A small decrease in reservoir was observed in three studies on immune checkpoint inhibitors and the histone deacetylase inhibitors romidepsin and chidamide. No clear effect of LRAs on ATI duration was observed., Conclusion: This systematic review provides a summary of the reactivation of LRAs used in current clinical trials whilst highlighting the importance of pharmacovigilance. Highly heterogeneous study designs and underrepresentation of relevant patient groups are to be considered when interpreting these results. The observed reactivation did not lead to cure or a significant reduction in the size of the reservoir. Finding more effective LRAs by including well-designed studies are needed to define the required reactivation level to reduce the HIV-1 reservoir., Competing Interests: The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: KSH received travel and conference compensation from Gilead. CR received unrestricted grants for investigator initiated research, advisory board participants, and travel compensation from ViiV and Gilead. All other authors declare no potential competing interests., (© 2023 The Authors.)

Background: People who initiate antiretroviral therapy (ART) during acute HIV infection are potential candidates for HIV cure-related clinical trials, as early ART reduces the size of the HIV reservoir. These trials, which may include ART interruption (ATI), might involve potential risks. We explored knowledge and perception of HIV cure and willingness to participate in cure-related trials among participants of the Netherlands Cohort Study on Acute HIV infection (NOVA study), who started antiretroviral therapy immediately after diagnosis of acute HIV infection., Methods: We conducted 20 in-depth qualitative interviews with NOVA study participants between October-December 2018. Data were analyzed thematically, using inductive and iterative coding techniques., Findings: Most participants had limited knowledge of HIV cure and understood HIV cure as complete eradication of HIV from their bodies. HIV cure was considered important to most participants, mostly due to the stigma surrounding HIV. More than half would consider undergoing brief ATI during trial participation, but only one person considered extended ATI. Viral rebound and increased infectiousness during ATI were perceived as large concerns. Participants remained hopeful of being cured during trial participation, even though they were informed that no personal medical benefit was to be expected., Interpretation: Our results highlight the need for thorough informed consent procedures with assessment of comprehension and exploration of personal motives prior to enrollment in cure-related trials. Researchers might need to moderate their expectations about how many participants will enroll in a trial with extended ATI., Competing Interests: The authors declare the following financial interests/personal relationships which may be considered as potential competing interests. The authors have no financial or proprietary interests in any material discussed in this article. GdB received honoraria to her institution for scientific advisory board participations for 10.13039/100005564Gilead Sciences and speaker fees from 10.13039/100005564Gilead Sciences. PR received grants from ViiV Healthcare, 10.13039/100005564Gilead Sciences and 10.13039/100004334Merck and participated in a Data Safety Monitoring Board, the honoraria are paid to the institution. CR received grants from Gilead, ViiV, Merck and JJ and payments or honoraria from Gilead and ViiV for viral education., (© 2022 The Authors.)

We felt the urgency to launch the EU2Cure Consortium to support research and find a cure for the human immunodeficiency virus (HIV) infection through intensified collaboration within Europe. This consortium is open to stakeholders on cure in Europe from academia and the community to connect. The aim of this consortium is to intensify the research collaboration amongst European HIV cure groups and the community and facilitate interactions with other academic and community cure consortia, private parties, and policy makers. Our main aim is to create a European research agenda, data sharing, and development of best practice for clinical and translational science to achieve breakthroughs with clinically feasible HIV cure strategies. This consortium should also enable setting up collaborative studies accessible to a broader group of people living with HIV. Besides reservoir studies, we have identified three overlapping scientific interests in the consortium that provide a starting point for further research within a European network: developing "shock and kill" cure strategies, defining HIV cure biomarkers, and connecting cure cohorts. This strategy should aid stakeholders to sustain progress in HIV cure research regardless of coincidental global health or political crises., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have influenced the work reported in this paper., (© 2021 The Author(s).)

Objective: Little is known about willingness among people living with HIV (PLHIV) to participate in HIV cure research in the Netherlands. We compared results of a cross-sectional questionnaire assessing hypothetical willingness to actual willingness among PLHIV to take part in a clinical HIV cure trial., Methods: Between March and June 2018, PLHIV visiting the outpatient clinic of a university hospital in the Netherlands were asked to complete a questionnaire about HIV cure research. Results were compared to the number of PLHIV willing to take part in an actual HIV cure study at the same center during an overlapping time period., Results: In total, 165 participants, predominantly male (80%) from Western European countries (61%) completed the questionnaire. The majority would participate in cure research (n ​= ​111, 67%). Separately, actual willingness among PLHIV to participate in an HIV cure study was addressed in 312 cases. Apart from gender (96% male), baseline characteristics were comparable. Less than half expressed actual willingness to participate in the study (n ​= ​135, 43%)., Conclusions: Hypothetical willingness to participate in cure-related research was high among PLHIV who completed the questionnaire. Actual willingness among eligible PLHIV to take part in an HIV cure study was much lower. Our findings show that questionnaires may overestimate willingness to participate in HIV cure trials and indicate that reasons for refusal in actual research should be further explored., Competing Interests: There are no conflicts of interest., (© 2020 The Author(s).)

The Second European Round Table on the Future Management of HIV took place in Barcelona, 10-11 October 2014 and focused on the HIV-1 reservoir, strategies for HIV cure and primary HIV infection (PHI). Important issues in the HIV-1 reservoir research field are the validity of reservoir measurement techniques and the potential of new drugs to target latently infected cells. Current HIV-1 cure concepts are based on theoretical assumptions of biologically plausible mechanisms, supported by several clinical observations. Three main potential strategies are under investigation in order to achieve a sterilising cure or maintain HIV-1 remission: latency reversal resulting in antigen expression and viral cytolysis or immune targeted cell-death; immunological control of the reservoir; or replacement of the complete autologous haematopoietic and lymphoid stem-cell repertoire by transplantation. An interesting opportunity for restricting the size of the reservoir entails the early initiation of antiretroviral treatment (ART) during PHI. In terms of the reservoir, early treatment limits its size, alters its composition, and restricts the genetic variability of integrated proviral HIV-1 DNA. The challenges ahead involve the identification of patients undergoing seroconversion to HIV-1 and the prompt initiation of treatment. How the seemingly beneficial impact of early treatment will make cure more feasible, and whether the positive effects of the cure efforts outweigh the potentially negative impact of life-long ART, are important aspects of future collaborative research prospects.