CE: Alpana; QCO/280107; Total nos of Pages: 9; QCO 280107 REVIEW CURRENT OPINION Advancing the HIV cure agenda: the next 5 years John Thornhill a,b,c, Sarah Fidlera,b,c,Ã, and John Fraterb,d,e,f,Ã Purpose of review To explore how ethical considerations, improved diagnostics and data from clinical trials might see the lowering of some of the barriers blocking a cure for HIV infection over the next 5 years. Recent findings Despite the recent well publicized but eventually disappointing case reports, there remains only one successful HIV cure, the ‘Berlin patient’. We will review the data suggesting that more potent agents might achieve in-vivo viral activation and explore the tantalizing phenomenon of ‘posttreatment control’ following treatment in primary HIV infection. We will also explore how new assays and novel interventions might move the field forward. Summary There is a need for new agents that can be safely tested to impact the viral reservoir, a more meaningful understanding of how to assay patient samples, and research into mechanisms behind how the reservoir is established and impacted by therapy. With HIVþve individuals responding so well to antiretroviral therapy, new trials must be tested hand-in-hand with guidance from patient representatives, especially with respect to determining the acceptable risk. The road to a cure is going to be difficult, but it is vital that inevitable disappointments do not detract from the final goal, which remains worth striving for. Keywords cure, eradication, HIV, latency, reservoir INTRODUCTION the reservoir incorporates numerous assays and The last 5 years has seen increased interest, invest- read-outs – a consensus will be needed. Once ment and engagement in a cure for HIV infection measured, we need to decide whether the drugs becoming a reality [1]. However, despite significant we have to hand, like the histone deacetylase inhibi- scientific and clinical advances, a number of key tors (HDACis), show genuine promise or are just questions remain unanswered and new hurdles have useful as proof of concept for the currently undis- arisen. This review will consider the long-term issues covered agents that may follow. Will monotherapy that may be important for the field to move forward. be adequate or will a second intervention be The prognosis for people living with HIV on required, for example, in the form of immunother- suppressive antiretroviral therapy (ART) is now apy, as in the ‘Kick and Kill’ [4] approach? And, excellent [2]. Accordingly, for those in the field of lastly, what other approaches might enter the arena HIV cure to test unproven and potentially toxic over the next 5 years, and how might technologies interventions [3] or stop successful therapy (especi- ally in the context of the effectiveness of ART to aDivision of Medicine, Wright Fleming Institute, Imperial College, London, prevent onward viral transmission), there needs to bCollaborative HIV Eradication of Reservoirs: UK BRC (CHERUB), be caution. We will evaluate the ethical concerns cImperial National Institute of Health Research Biomedical Research d that need to be considered when researching inter- Centre, London, Nuffield Department of Clinical Medicine, Peter Med- awar Building for Pathogen Research, eInstitute for Emerging Infections, ventions aimed at HIV cure in otherwise healthy The Oxford Martin School and fOxford National Institute of Health people living with HIV on ART. Research Biomedical Research Centre, Oxford, UK A better understanding of the biology and Correspondence to John Frater, Nuffield Department of Clinical Medi- pathogenesis of HIV will assist the design of inter- cine, Peter Medawar Building for Pathogen Research, Oxford, OX1 3SY, ventions aimed at HIV cure. For example, the obser- UK. E-mail: [email protected] vation of posttreatment control (PTC) in which ÃSarah Fidler and John Frater contributed equally to the writing of this some patients stopping ART show no sign of virae- article. mic relapse needs to be further clarified, including Curr Opin Infect Dis 2015, 28:000–000 the mechanisms and predictive markers. Measuring DOI:10.1097/QCO.0000000000000123 0951-7375 ß 2015 Wolters Kluwer Health | Lippincott Williams & Wilkins www.co-infectiousdiseases.com Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited. CE: Alpana; QCO/280107; Total nos of Pages: 9; QCO 280107 HIV infections and AIDS HIV Association and the Collaborative HIV Eradica- KEY POINTS tion of Reservoirs: UK BRC (CHERUB) collaboration As new interventions aimed at curing HIV move into [12] are excellent examples of this, with over 800 clinical trials, it is vital that research is planned and respondents and the results to be presented in late conducted in conjunction with the patient groups. 2014. Posttreatment control remains an exciting area of cure research, although much more data are needed. Is cure research a peccadillo of wealthier An algorithm of biomarkers to help identify individuals nations or can it have global impact? who could stop therapy to test for cure or virological A scalable, affordable solution for all people living remission is an important target. with HIV must be the goal of any cure strategy, A cure for HIV is likely to comprise a cocktail of particularly in resource-limited regions where the interventions and may involve significant toxicity. burden of HIV disease is greatest. In view of region- specific priorities, any diversion of funding from HIV prevention, vaccine development or ART roll- out must also be balanced appropriately. As – at least and knowledge from other fields be applied to cur- initially – most cure-related research is unlikely to ing HIV? Underpinning all of these issues is a need impact the vast majority of individuals living with for the field to agree on the definitions of the con- HIV, for example, in the sub-Saharan Africa, it is cepts of ‘latency’, the ‘reservoir’ and even ‘cure’. For vital that key priorities are not overlooked. How- example, latency might be considered as a state of ever, this should not replace the need for proof-of- transcriptional silence with no (or rare) viral trans- concept research, much of which will be conducted cripts and no virion production. The extent to where resources are available, and which might then which a latent cell can be activated to produce a be scaled up into more comprehensive studies. replication-competent virus varies, and ongoing basic research is still needed to understand these processes and the reversibility of latency. Is it safe or ethical to stop antiretroviral therapy? The only true test of HIV cure is to stop therapy and ETHICAL CONSIDERATIONS assay for the return of viraemia. However, the safety In light of the excellent prognosis for HIVþve indi- of this remains contentious. Not only might the viduals on ART, potential ethical implications need return of viral replication be pathogenic and risk to be considered when proposing any new trials onward transmission, but also it remains unclear as or interventions. to the extent to which rebound viraemia after treat- ment interruption might replenish the reservoir to such an extent that the participant may not be Investigating a healthy population eligible for further interventions for a prolonged Research into curing HIV infection engenders a period. One of the difficulties is the lack of predic- number of important ethical considerations [5,6]. tive assays that could identify individuals prior to Life expectancy for people living with HIV and viral rebound [13], which could also potentially receiving ART approaches that of the general popu- increase the risk of onward viral transmission. The lation [2,7]. This is despite potential lifelong ART- only safe option therefore for individuals enrolling related toxicities and the increased inflammation into cure approach trials with treatment interrup- and immune activation observed for individuals on tion is to include very frequent viral load testing. suppressive therapy [8–10]. With this in mind, any How frequently viral load needs to be checked and clinical trials of potentially toxic interventions for how long after treatment interruption is assessing HIV cure must have strict safety and unknown, although it is clear that when viraemia acceptability safeguards in place. Furthermore, full returns it can do so abruptly and to high levels [13]. and transparent engagement with community and With these uncertainties in mind, significant coun- industry partners as well as policy makers in the selling of these risks and monitoring for rebound design of such trials will be paramount [11]. For will be needed in any stopping protocol. example, garnering opinion from those living with The data are mixed. In the SMART study, treat- HIV will help set the boundaries for what interven- ment interruption caused a significant increase in tions and trials might be considered acceptable – the risk of all-cause mortality amongst those in the questionnaires such as that run across the UK in discontinuation arm compared with controls who conjunction with Public Health England, the British remained on suppressive therapy [14]. The mean 2 www.co-infectiousdiseases.com Volume 28 Number 00 Month 2015 Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited. CE: Alpana; QCO/280107; Total nos of Pages: 9; QCO 280107 Advancing the HIV cure agenda Thornhill et al. length of treatment interruption in SMART was insights they may provide for a scalable approach to 16.8 months, as restarting ART was guided primarily cure, particularly in the setting of changing WHO by CD4 T-cell count, rather than viral load as it ART initiation guidelines [20,21]. would be for a cure-based intervention. Although After treatment interruption, it is expected that SMART is widely cited as the counter-argument to most patients will experience rebound viraemia stopping ART, trials of treatment interruption in soon (within 12 weeks) off ART; however, in the primary infection have not revealed the same degree SPARTAC trial, there was evidence for a correlation of risk.