Is it time to abandon single intervention cure trials?

Only one person in the world has been cured of HIV. The Berlin patient was transplanted with CCR5-negative and HIV-resistant stem cells for cancer that eradicated his HIV. Reported in 2009, the case renewed interest in the search for a cure. But what has happened in the ensuing years? In 2013, apparent HIV remission (ie, undetectable plasma viral load in the absence of antiretroviral therapy or ART) in the two Boston patients transplanted with HIV-permissive CCR5-positive stem cells for cancer and the Mississippi baby treated with ART extremely early in life were met with disappointments when HIV subsequently reappeared in all three. Studies with latency-reversing agents to reactivate hidden viruses universally failed to deplete HIV proviral DNA suffi ciently and to eliminate infected cells. The VISCONTI cohort of adults in HIV remission for longer than 10 years remains unique, but it has reinforced the relevance of early ART in HIV cure research. No therapeutic HIV vaccine trials in human beings have produced the substantial benefi ts needed to eliminate HIV-infected cells, although vaccines recently studied in animals show potential. Broadly neutralising antibodies can lower HIV viral load, nonetheless are not believed to target latently infected cells. Gene editing and cell-based therapies that modify stem cells to become resistant to HIV or have better killing ability are promising, but have inherent risks and scalability issues. Much progress has been made in understanding the mechanisms of HIV persistence, immune destruction and immune activation. These investigations highlight the extent to which HIV has mastered immune evasion to stay hidden in diverse cell types and tissues. The limits to tissue sampling and technology to assess HIV reservoirs hinder quantifi cation of the eff ects of interventions on HIV persistence in people. The key question now is how can we make signifi cant gains in HIV cure research in the next 5 years? On the basis of experience from current studies, single therapies would be unlikely to lead to long-term HIV remission. Combination therapies are far more promising, but researchers continue to struggle to identify what these combinations would be. This brings us to the vital question: what are the best pathways to combination cure? The usual approach would be to start with single therapy trials in animal models for safety and potency endpoints, and then to proceed to trials in people to determine safety before moving to effi cacy trials. Each step takes years and is then repeated when compounds are put into combinations. With such a process, an HIV cure remains too far in the future. How can we innovate our way to combination cure? We argue that now is the time to move directly from in vitro studies to combination therapy trials in animals and then people. Concerns over having less information about investigational drugs when they are not studied individually could be lessened by use of animal models to investigate the mechanisms and understand successes and failures. Animal models aff ord opportunities to test activity of interventions, to investigate biomarkers, and to do extensive tissue studies. Combinations could be carefully selected on the basis of extensive in vitro and existing animal and human data and animal and human studies could run in parallel (fi gure). Each regimen could have two or more compounds with multimodal targeting of HIV. An example is one or more latency reversing compounds plus immunotherapeutic agents that provide passive humoral and active cellular immunity against the virally infected cells. Another includes gene-editing therapy to make cells resistant to the virus plus immunotoxins to target already infected cells in tissues and peripheral blood. Combinations that are safe are selected to proceed in animal effi cacy and phase 1 human safety studies simultaneously. Once information from these