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The discovery and deployment of antiretroviral therapy (ART) for human immunodeficiency virus (HIV) infection is one of the most extraordinary achievements in recent biomedical history. Between 1996 and 2012, ART averted an estimated 6.6 million AIDS-related deaths worldwide.1 For HIV-infected individuals with access to ART, life expectancy at diagnosis now approximates that of uninfected individuals—a remarkable feat. These extraordinary successes, however, are tempered by the necessity of lifelong drug therapy. Many patients struggle with adherence in the face of competing priorities, both within the clinical context (comorbidities) and beyond (food insecurity, housing, substance abuse, and other challenges). The drugs can cause health issues in the form of cumulative toxicities. Nations and health systems struggle to find the resources needed to provide long-term therapy. The challenges of resistance and drug-drug interactions add considerable complexity to the provision of care.
Recognizing the challenges inherent to lifelong ART, the medical, public health, and activist communities have sought alternatives, and the prospect of a cure for HIV has attracted increased scientific attention and funding during the past several years. In considering approaches for these investments, it is important to explicitly define an “HIV cure,” because the definition dictates the direction and goal of the research effort. It is also important to distinguish between discovery and implementation and to avoid overpromising and creating false hope, particularly when the research effort is still in the discovery stage.
One widely accepted definition of a cure is the indefinite or permanent absence of disease following the cessation of therapy. The crux of this definition lies in the meaning of “indefinite” or “permanent,” as informed by previous experience with other diseases. For example, experience with acute bacterial pneumonia has taught clinicians that a cure can be declared within days to weeks following cessation of antibiotic therapy. In contrast, for many cancers, the disease-free time necessary to declare a cure varies widely, from immediately following surgical removal to several years or even decades following surgery, chemotherapy, or both, depending on the cancer in question. These end points are based on experience with large cohorts of cured patients. With HIV, such extensive experience is not available and still needs to be accumulated—if indeed a true cure is possible.
Although the time of the end point remains uncertain, so too do the feasibility of the goals of cure research: (1) viral eradication, in which all traces of virus are gone, including the latent, replication-competent viral DNA integrated into human cells (“viral reservoirs”) and (2) sustained virologic remission, in which viral replication as manifested by viremia remains controlled following cessation of daily ART. Each goal is being pursued in early-stage research and some evidence of feasibility has been established, albeit under special and relatively unique circumstances.
The prospect of viral eradication has garnered attention in recent years, after an adult male referred to as “The Berlin Patient” was cured of HIV following allogeneic hematopoietic stem cell transplantation (HSCT), a risky procedure with a high mortality rate. Importantly, the patient had been diagnosed with acute myelogenous leukemia and required both extensive pretransplant conditioning therapy (aimed at eliminating his own immune cells) and HSCT to cure the malignancy. Therefore, it was leukemia, not HIV infection, that tipped the risk-benefit evaluation in favor of HSCT. In addition, the transplant donor cells were “resistant” to HIV, carrying a homozygous mutation in the CCR5 gene, which encodes the coreceptor used by most strains of HIV to enter human cells. Therefore, after ablation of the patient’s immune cells and replacement with resistant cells, residual HIV lacked targets for self-propagation and viral rebound.2 Today, 5 years after transplantation, the patient takes no ART and remains free of detectable virus.
The excitement generated by this case has been tempered in recent months after a failure to replicate the results in 2 similar HIV-infected patients who received a less aggressive conditioning regimen and HSCT using cells from donors without the homozygous CCR5 gene deletion. Ongoing research seeks to duplicate the results in the Berlin patient without the need for HSCT. In this regard, patients are receiving autologous cells that have been treated ex vivo to modify the CCR5 gene; cells are then grown in culture and infused back into the patients.3 Other approaches, including attempts to “flush out” and eliminate HIV reservoirs, have thus far been unsuccessful.4 At this point, all eradication approaches remain in the early discovery stage, and it is too soon to predict their likelihood of success.
Alternative approaches aim for a sustained virologic remission, whereby viral replication is completely suppressed or kept at very low levels in the absence of daily ART. These approaches have progressed from the discovery phase to the early feasibility and implementation phases as they build on concepts that suggest that early treatment can limit or avert creation of permanent viral reservoirs. Several recent examples seem particularly promising. First, the infant referred to as the “Mississippi Baby,” who was born to an HIV-infected mother who had received neither prenatal nor perinatal ART, began receiving full antiretroviral treatment at age 30 hours. It was later determined that the infant was infected, and ART was continued through age 18 months, at which point the child was lost to follow-up. At age 23 months the child was again seen in clinic and had no detectable virus in the blood, despite not taking ART for the previous 5 months, and had no HIV-specific antibodies. These results persisted for a total of 27 months without therapy. However, at age 46 months, the child experienced unequivocal viral rebound (consecutive plasma viral load measurements of 16 750 HIV RNA copies/mL and 10 564 copies/mL). Although a permanent cure was not achieved, the infant’s early treatment led to a markedly sustained virologic remission. In light of these new findings, researchers must now work to better understand what enabled the child to remain off treatment for more than 2 years without detectable virus or measurable immunologic response and what might be done to extend the period of sustained HIV remission in the absence of ART.5,6
The applicability of this case to adults with HIV infection may be limited because, in contrast to the Mississippi baby, the overwhelming majority of infected adults present to care and are started on ART months to years after initial infection. Perhaps the closest adult analogies to the Mississippi baby are the patients of the VISCONTI cohort, in which adult men began receiving ART 1 to 2 months after infection. Fourteen patients were able to discontinue therapy while controlling viral replication at low levels.7 Other approaches to maintaining a sustained virologic remission include harnessing the immune system to block viral rebound by, for example, infusing antibodies or viral vectors with gene inserts that produce antibodies designed to neutralize virus, or using therapeutic vaccines to control viral replication following cessation of ART.8,9 These approaches have shown promise in animal models, and human studies are under way or imminent. Although such regimens will not eradicate all traces of virus, they might allow individuals to discontinue daily ART.
These sustained virologic remissions observed both in an infant and in acutely infected adults argue strongly that early entry into and successful retention in the HIV care continuum (the steps from a person learning his or her HIV status to accessing care to achieving suppression of HIV while receiving ART) likely will be an essential element of an aspirational pathway toward viral eradication or sustained virologic remission for many more patients. However, the smooth transition from early diagnosis through virologic suppression continues to elude most patients in resource-rich and resource-poor settings alike. Even with further efforts to close the gaps in the care continuum, it is essential to remain realistic about the extraordinary challenges posed by finding a cure for HIV infection and the feasibility of its widespread implementation. To reach individuals living with HIV around the world, a curative regimen must be effective, simple, safe, and scalable.
In summary, although an HIV cure remains within the uncertain realm of discovery, recent advances give cause for hope. While continuing to support and accelerate cure research, the global AIDS community must intensify its efforts to diagnose HIV-infected individuals and enter and retain them in an effective care continuum. These efforts have already saved millions of lives in the absence of a cure, and health systems that facilitate early initiation of therapy and sustained adherence will be a critical component of any overall cure effort.
Corresponding Author: Anthony S. Fauci, MD, National Institute of Allergy and Infectious Diseases, Bethesda, MD 20892-2520 (firstname.lastname@example.org).
Conflict of Interest Disclosures: All authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest and none were reported.
Correction: This article was updated online on July 19, 2014, to provide new information not available when the article went to press.
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