Gut-associated phages are hypothesized to alter the abundance and activity of their bacterial hosts, contributing to human health and disease. Although temperate phages constitute a significant fraction of the gut virome, the effects of lysogenic infection are underexplored. We report that the temperate phage, Bacteroides phage BV01, broadly alters its host's transcriptome, the prominent human gut symbiont Bacteroides vulgatus. This alteration occurs through phage-induced repression of a tryptophan-rich sensory protein (TspO) and represses bile acid deconjugation. Because microbially modified bile acids are important signals for the mammalian host, this is a mechanism by which a phage may influence mammalian phenotypes. Furthermore, BV01 and its relatives in the proposed phage family Salyersviridae are ubiquitous in human gut metagenomes, infecting a broad range of Bacteroides hosts. These results demonstrate the complexity of phage-bacteria-mammal relationships and emphasize a need to better understand the role of temperate phages in the gut microbiome.

A growing body of research is beginning to elucidate reasons people living with HIV (PLWHIV) might prefer oral daily antiretroviral treatment (ART) compared with emerging long-acting ART (LA-ART) or HIV remission strategies under investigation. Our objective is to provide qualitative insights into the reasons why PLWHIV might prefer one of these HIV control therapies over others. From May to August 2018, we implemented a semistructured cross-sectional survey of PLWHIV in the United States to better understand patient preferences around various HIV treatment and remission options. Using free text, respondents were asked to explain why they preferred one HIV control option over the other two. We analyzed responses to the open-ended survey questions on reasons for preferring oral daily ART versus LA-ART versus HIV remission strategies using conventional content analysis. The results showed that PLWHIV preferred oral daily ART because of its familiarity and known safety and efficacy profile, whereas those who preferred LA-ART would value the convenience it offers. Finally, HIV remission strategies would be preferred to avoid taking ART altogether. The qualitative results provide insights into reasons why PLWHIV in the United States might prefer oral daily ART versus novel therapies. More importantly, they provide information to better align HIV virological control strategies with end-user perspectives. To make informed choices around evolving HIV therapeutics, PLWHIV and HIV care providers would benefit from decision tools to better assess options and trade-offs. More research is needed on how best to effectively support PLWHIV and HIV care providers in shared decision-making.

Analytic treatment interruptions (ATIs) are currently the standard for assessing the impact of experimental interventions aimed at inducing sustained antiretroviral therapy (ART)-free remission in trials related to HIV cure. ATIs are associated with substantial risk to both study participants and their sexual partner(s). Two documented HIV transmissions occurring in the context of ATIs have been recently reported, but recommendations for mitigating the risk of such events during ATIs are limited. We outline a practical approach to risk mitigation during ATI studies and describe strategies we are utilising in an upcoming clinical trial that may be applicable to other centres.

Background

Background: Analytical treatment interruptions (ATIs) in HIV cure-related research can result in trial participants becoming viremic with HIV, placing HIV-negative sexual partners at elevated risk of acquiring HIV.

Objective

Objective:Our study aimed to generate ethical and practical considerations for designing and implementing appropriate risk mitigation strategies to reduce unintended HIV transmission events during ATIs.

Methods

Methods: We conducted 21 in-depth interviews with five types of informants: bioethicists, community members, biomedical HIV cure researchers, socio-behavioral scientists/epidemiologists, and HIV care providers. We used conventional content analysis to analyze the data and generate considerations.

Results

Results: Key findings include: 1) Ethical permissibility of ATI trials depends on due diligence and informed consent to mitigate risks to participants and their sexual partners; 2) Participants should receive adequate support and/or counseling if they choose to disclose ATI participation to their partners; 3) Measures to protect sexual partners of trial participants from HIV transmission during ATIs should include referral to and/or provision of pre-exposure prophylaxis, as well as other available means of preventing HIV transmission; 4) There is uncertainty regarding the appropriate management of emerging sexually transmitted infections during ATI trials and possible protection measures for multiple and/or anonymous partners of ATI trial participants.

Conclusion

Conclusion: While there is no way to completely eliminate the risk of HIV transmission to sexual partners during ATIs, HIV cure trialists and sponsors should consider the ethical concerns related to the sexual partners of ATI participants. Doing so is essential to ensuring the welfare of participants, their partners and the trustworthiness of research.

Introduction

The impact of colchicine on hospitalized patients with Coronavirus disease-19 (COVID-19) related cardiac injury is unknown.

Materials and methods

In this multicenter randomized controlled open-label clinical trial, we randomized hospitalized adult patients with documented COVID-19 and evidence of cardiac injury in a 1:1 ratio to either colchicine 0.6 mg po twice daily for 30 days plus standard of care or standard of care alone. Cardiac injury was defined as elevated cardiac biomarkers, new arrhythmia, new/worsened left ventricular dysfunction, or new pericardial effusion. The primary endpoint was the composite of all-cause mortality, need for mechanical ventilation, or need for mechanical circulatory support (MCS) at 90 days. Key secondary endpoints included the individual components of the primary endpoint and change in and at least 2-grade reduction in the World Health Organization (WHO) Ordinal Scale at 30 days. The trial is registered with clinicaltrials.gov (NCT04355143).

Results

We enrolled 93 patients, 48 patients in the colchicine arm and 45 in the control arm. There was no significant difference in the primary outcome between the colchicine and control arms (19 vs. 15%, p = 0.78), nor in the individual components of all-cause mortality (17 vs. 15%, p = 1.0) and need for mechanical ventilation (8 vs. 5%, p = 0.68); no patients in either group required MCS. The change in (-1.8 ± 2.4 vs. -1.2 ± 2.0, p = 0.12) and at least 2-grade reduction (75 vs. 75%, p = 1.0) in the WHO ordinal scale was also similar between groups.

Conclusion

Patients hospitalized with COVID-19 and evidence of cardiac injury did not benefit from colchicine therapy.

Background

Most HIV cure-related studies involve interrupting antiretroviral treatment to assess the efficacy of pharmacologic interventions - also known as analytical treatment interruptions (ATIs). ATIs imply the risk of passing HIV to sexual partners due to the loss of undetectable HIV status. There has been a notable lack of attention paid to perceptions of ATIs among racial, ethnic, sex and gender minorities, and HIV serodifferent couples. These populations are among those most impacted by HIV in the United States. Future HIV cure research paradigms should equitably include considerations from these groups.

Methods

From August - October 2020, we conducted in-depth interviews with 10 racial, ethnic, sex, and gender minority HIV serodifferent couples in geographically diverse regions of the United States to understand their perspectives about ATIs and partner protection measures to prevent secondary HIV transmissions because of participation in ATI studies. We used framework analysis to analyze the qualitative data.

Results

Of the 10 couples recruited, four identified as a gay couple, two as a gay and bisexual couple, two as a heterosexual couple, one as a gay and queer couple, and one as a queer couple. We found that HIV serodifferent couples in our study viewed ATIs as contradicting HIV treatment adherence messages. Couples expressed discomfort around ATIs in HIV cure research. They were concerned with the return of HIV detectability and worried ATIs might result in secondary HIV transmission. Participants were strongly in favor of using a range of partner protection measures during ATIs that included PrEP, HIV risk reduction counseling, and alternatives for penetrative sex practices. Couples also recommended that sex partners be consulted or involved as part of ATI trials.

Conclusions

Our findings highlight new potential opportunities and strategies to mitigate risk of HIV transmission during ATIs among key groups historically under-represented in HIV cure research. Findings also underscore the relational aspects of ATI trials. We provide preliminary considerations for planning ATI trials with diverse HIV serodifferent partners. Future studies should continue to explore these issues among other types of partnerships, cultures, and socio-cultural settings.

There are two concurrent and novel major research pathways toward strategies for HIV control: (1) long-acting antiretroviral therapy (ART) formulations and (2) research aimed at conferring sustained ART-free HIV remission, considered a step toward an HIV cure. The importance of perspectives from people living with HIV on the development of new modalities is high, but data are lacking. We administered an online survey in which respondents selected their likelihood of participation or nonparticipation in HIV cure/remission research based on potential risks and perceived benefits of these new modalities. We also tested the correlation between perceptions of potential risks and benefits with preferences of virologic control strategies and/or responses to scenario choices, while controlling for respondent characteristics. Of the 282 eligible respondents, 42% would be willing to switch from oral daily ART to long-acting ART injectables or implantables taken at 6-month intervals, and 24% to a hypothetical ART-free remission strategy. We found statistically significant gender differences in perceptions of risk and preferences of HIV control strategies, and possible psychosocial factors that could mediate willingness to switch to novel HIV treatment or remission options. Our study yielded data on possible desirable product characteristics for future HIV treatment and remission options. Findings also revealed differences in motivations and preferences across gender and other sociodemographic characteristics that may be actionable as part of research recruitment efforts. The diversity of participant perspectives reveals the need to provide a variety of therapeutic options to people living with HIV and to acknowledge their diverse experiential expertise when developing novel HIV therapies.

Introduction

The question of what motivates people to participate in research is particularly salient in the HIV field. While participation in HIV research was driven by survival in the 1980's and early 1990's, access to novel therapies became the primary motivator with the advent of combination antiretroviral therapy (cART) in the late 1990s. In the HIV cure-related research context, the concept of altruism has remained insufficiently studied.

Methods

We conducted a scoping review to better contextualize and understand how altruism is or could be operationalized in HIV cure-related research. We drew from the fields of altruism in general, clinical research, cancer, and HIV clinical research-including the HIV prevention, treatment, and cure-related research fields.

Discussion

Altruism as a key motivating factor for participation in clinical research has often been intertwined with the desire for personal benefit. The cancer field informs us that reasons for participation usually are multi-faceted and complex. The HIV prevention field offers ways to organize altruism-either by the types of benefits achieved (e.g., societal versus personal), or the origin of the values that motivate research participation. The HIV treatment literature reveals the critical role of clinical interactions in fostering altruism. There remains a dearth of in-depth knowledge regarding reasons surrounding research participation and the types of altruism displayed in HIV cure-related clinical research.

Conclusion

Lessons learned from various research fields can guide questions which will inform the assessment of altruism in future HIV cure-related research.

There are two concurrent and novel major research pathways toward strategies for HIV control: (1) long-acting antiretroviral therapy (ART) formulations and (2) research aimed at conferring sustained ART-free HIV remission, considered a step toward an HIV cure. The importance of perspectives from people living with HIV on the development of new modalities is high, but data are lacking. We administered an online survey in which respondents selected their likelihood of participation or nonparticipation in HIV cure/remission research based on potential risks and perceived benefits of these new modalities. We also tested the correlation between perceptions of potential risks and benefits with preferences of virologic control strategies and/or responses to scenario choices, while controlling for respondent characteristics. Of the 282 eligible respondents, 42% would be willing to switch from oral daily ART to long-acting ART injectables or implantables taken at 6-month intervals, and 24% to a hypothetical ART-free remission strategy. We found statistically significant gender differences in perceptions of risk and preferences of HIV control strategies, and possible psychosocial factors that could mediate willingness to switch to novel HIV treatment or remission options. Our study yielded data on possible desirable product characteristics for future HIV treatment and remission options. Findings also revealed differences in motivations and preferences across gender and other sociodemographic characteristics that may be actionable as part of research recruitment efforts. The diversity of participant perspectives reveals the need to provide a variety of therapeutic options to people living with HIV and to acknowledge their diverse experiential expertise when developing novel HIV therapies.

Despite disproportionate incidence and prevalence of HIV among transgender individuals, cisgender women, and racial and ethnic minority groups, all remain underrepresented in HIV cure research. As HIV cure trials are scaled up, there is emerging research on ways to mitigate risks of HIV acquisition for sexual partners of analytical treatment interruption (ATI) trial participants. As such, it is imperative that HIV cure researchers consider the implications of implementing ATIs in populations that are disproportionately affected by HIV, but largely underrepresented in trials to date. In this qualitative study, we sought to derive triangulated perspectives on the social and ethical implications regarding ATIs and partner protection strategies during ATIs among under-represented populations. We conducted 21 in-depth interviews with 5 types of informants: bioethicists, community members [people living with HIV (PLWH) and their advocates], biomedical HIV cure researchers, sociobehavioral scientists, and HIV care providers. We analyzed the data using conventional content analysis and reduced the data to important considerations for implementing ATI trials in diverse communities and settings. Our study revealed the following key themes: (1) attention must be paid to gender and power dynamics in ATI trials; (2) ATI trials should be designed and implemented through the lenses of intersectionality and equity frameworks; (3) ATI trials may have both positive and negative effects on stigma for PLWH and their partners; and (4) partnership dynamics should be considered when designing ATI protocols. Our study generated actionable considerations that could be implemented in ATI trials to promote their acceptability to communities that have been underrepresented in HIV cure research to date. Research teams must invest in robust community and stakeholder engagement to define best practices. Paying attention to representation and equity will also promote better and more equitable implementation of HIV cure strategies once these become ready for rollout.