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The development and availability of highly effective antiretroviral therapy (ART) for the treatment of HIV infection has transformed the lives of persons with HIV. Combinations of antiretroviral drugs often in the form of a single pill have succeeded in a high percentage of patients in suppressing plasma viremia to below detectable levels by the standard assays. The clinical success of ART in effecting full and sustained suppression of HIV viremia has permitted persons with HIV today to live an approximately normal life expectancy, often with return to normal daily activities.
Despite these transformative therapeutic successes, there has been an increasing focus on pursuing the goal of sustained HIV remission in the absence of life-long dependency on ART. Recognized short-term and uncertain long-term toxicity of antiretroviral drugs, the commonly experienced feeling of “pill fatigue,” stigma associated with taking daily ART, and the costs associated with lifelong ART have provided strong motivation to pursue such a goal.
The major impediment to achieving a sustained ART-free remission is the persistence of an HIV reservoir in an adequately treated patient,1 in which integrated replication-competent HIV provirus persists in a minute fraction of resting CD4+ T cells and potentially other as yet unidentified cell types.2 Virus in these cells has uniformly been resistant to eradication despite years of durable suppression of plasma viremia. Attempts at achieving sustained treatment-induced virologic remission following analytical treatment interruption (ATI) of ART have consistently failed and have invariably been followed by rapid rebound of plasma viremia, usually to the original virologic set point, in almost all patients who were studied.3 These failures have led to the testing of a broad array of interventions in patients with viremia that had been controlled for prolonged periods with ART to determine if viremia could be suppressed following ATI. Two pathways currently are being pursued to achieve a sustained ART-free HIV remission: (1) eradication of the replication-competent HIV reservoir, which is classically referred to as a “cure” and (2) control of plasma viral rebound without eradication of HIV in the absence of ART, which is referred to as “sustained virologic remission.”
Several potential strategies to eradicate HIV from an infected individual have been attempted: (1) latency-reversing agents to deplete HIV reservoirs; (2) modified antibodies and/or effector cells such as CAR-T cells directed at the HIV reservoir; (3) gene editing; and (4) stem cell transplantation.2,4
While studies with latency-reversing agents, used singly and in combination, demonstrated an initial effect on activating latent virus, all of the latency-reversing agents have consistently failed to eradicate the HIV reservoir.2,4 Additional potential strategies to eradicate HIV have included immunotoxic therapy directed at the viral reservoir and gene editing of various molecular targets. In every instance, even when the size of the viral reservoir decreased substantially as measured in the peripheral blood CD4+ T cells, the virus inevitably rebounded when ATI was attempted.2,4
The first stem cell transplantation from a donor homozygous for the CCR5-Δ32 mutation that successfully resulted in eradication of the viral reservoir and an apparent cure was reported in 2009 in a person with HIV (“the Berlin patient”). The patient had acute myelogenous leukemia for which standard chemotherapy failed, prompting the need for a transplant. The patient has had no indication of detectable plasma viremia for more than a decade following discontinuation of ART.2,4 A second person with HIV (“the London patient”) had underlying Hodgkin lymphoma refractory to chemotherapy and in 2016 also received a stem cell transplant from a donor homozygous for the CCR5-Δ32 mutation. This patient has been free of detectable virus for 18 months following ATI.5 These cases demonstrate “proof of concept” that CCR5 represents a promising target for manipulation in attempts at achieving ART-free remission and even cure. However, stem cell transplantation in individuals who do not have an underlying condition apart from HIV infection that requires a transplant is not a feasible approach because of the considerable risks, expense, and lack of scalability to large numbers of patients.
While promising strategies for achieving a classic “cure” by total eradication of replication-competent virus are continuing to be pursued, the complete eradication of HIV in an infected individual remains a substantial major challenge.4 Future research must take into consideration the risk-benefit ratio of these approaches, particularly in individuals whose plasma viremia is well controlled, usually via a single pill containing a combination of antiretroviral drugs with manageable toxicities. Any substitution for this currently effective approach must be of minimal risk, inexpensive, and scalable to large number of patients.
The alternative pathway to achieve a sustained ART-free HIV remission without eradicating the virus requires the control of HIV replication without antiretroviral drugs and is referred to as “sustained virologic remission.” Here again, such approaches must be of low risk to the patient, scalable, and able to at least potentially lead ultimately to induction of durable immune-mediated control of HIV. There are 2 major strategies currently being pursued to achieve ART-free remission in the absence of viral eradication: (1) replacement of daily ART with intermittent or continual non-ART intervention and (2) induction of durable immune-mediated control of HIV without further intervention. The former strategy could be accomplished either by therapeutic vaccination administered as a single intervention or requiring multiple boosts over a period of years. The desired end point would be induction of an HIV-specific immune response that would successfully and durably control viral rebound following ATI. An alternative approach would be passive infusion of a single or preferably a combination of anti-HIV broadly neutralizing antibodies (bNAbs), optimally at intervals of several months, such that antibody therapy would replace the requirement for daily ART or any ART at all.
To date, no therapeutic vaccine candidate studied in a placebo-controlled trial has been successful in achieving durable suppression of HIV replication, including in a randomized, placebo-controlled safety/efficacy trial (NCT01859325) of a therapeutic vaccine that was tested in HIV-infected individuals who initiated ART early in infection.6 It remains to be seen whether a successful therapeutic vaccine approach using more effective candidates aimed at inducing a potent and durable anti-HIV response is attainable.
Recent attention has turned from attempting to induce an effective immune response to passively infusing an already established anti-HIV intervention in the form of anti-HIV bNAbs. Several studies have raised cautious optimism that bNAbs could be infused at intervals optimally of several months and could potentially replace the need for daily ART.2 Future investigations will require selection of those bNAbs that have maximal potency and wider breadth. Similarly, it would be ideal to administer bNAbs intermittently at extended intervals using antibodies with a prolonged half-life. Another strategy that is being pursued is vector-based antibody production in vivo to allow for continual production and release of antibodies.
The approach with the most likely chance of success is the administration of combinations of bNAbs to achieve ART-free remissions. This strategy is based on earlier studies that used individual antiretroviral drugs that targeted distinct and vulnerable phases of the HIV replication cycle. This same principle could be applied to bNAbs, whereby a potential combination of bNAbs could target multiple epitopes on the HIV envelope and result in durable control of HIV infection. In addition, bispecific or trispecific bNAbs directed against 2 or 3 independent HIV-1 envelope determinants, respectively, also can be used.2,4 The ultimate goal of this approach is to develop a regimen, administered every few months, preferably via a subcutaneous route, involving the passive transfer of combinations of bNAbs against multiple HIV epitopes that would replace daily ART.
An alternative strategy to achieving an ART-free HIV remission involves the induction of durable immune-mediated control of virus without the need for continued intervention. This approach is distinct from a typical therapeutic vaccine. In this regard, recent studies have shown that passive infusion of bNAbs during early stages of viral infection in nonhuman primates led to durable suppression of virus replication. This suppression was considered to be very likely mediated by the formation of highly immunogenic immune complexes between the bNAbs and the virus leading to the induction of HIV-specific CD8+ T cells.7 This phenomenon has been referred to as a “vaccinal” effect of the passive transfer of bNAbs in the context of ATI, and this approach is now being actively pursued in clinical trials.
Achieving a sustained, durable ART-free HIV remission by a variety of minimally toxic approaches that are potentially scalable remains an overarching priority in HIV research. Success of such an effort has important implications for the economic costs of lifelong ART in large numbers of patients, medical issues such as drug resistance and/or drug toxicities that are associated with lifelong ART, and the personal and societal stigma associated with the indefinite requirement of ART. Such approaches will require novel and innovative strategies to take advantage of the opportunities and overcome the numerous obstacles currently faced in removing or controlling the persistent replication-competent HIV reservoirs in the absence of ART. Building on the extensive foundation of research in this field and the unprecedented success of combination ART, it is important to continue to explore new pathways to successfully attain an ART-free remission for persons with HIV.
Corresponding Author: Anthony S. Fauci, MD, National Institute of Allergy and Infectious Diseases, National Institutes of Health, 9000 Rockville Pike, Bldg 31, Room 7A03, Bethesda MD 20892 (firstname.lastname@example.org).
Published Online: June 6, 2019. doi:10.1001/jama.2019.5397
Conflict of Interest Disclosures: None reported.
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Chun T, Eisinger RW, Fauci AS. Durable Control of HIV Infection in the Absence of Antiretroviral Therapy: Opportunities and Obstacles. JAMA. Published online June 06, 2019. doi:10.1001/jama.2019.5397
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