Interferon alfa therapy: toward an improved treatment for HIV infection.

Highly active antiretroviral therapy (HAART) is an expensive, lifelong treatment for human immunodeficiency virus (HIV) infection that is associated with significant toxicity. Despite advances in treatment, there remains a need for novel therapies for HIV infection. One strategy is to achieve a functional cure, in which treatment can be safely stopped despite the presence of residual virus, by finding approaches that enhance the immune response to HIV. Such a therapy would require boosting a patient’s immune system to suppress viral replication below clinically relevant levels, thereby eliminating the need for HAART. A sterilizing cure, by contrast, is one in which all functional HIV genomes within the body are eliminated. Latent HIV genomes represent a major barrier to a sterilizing cure because these genomes do not produce viral proteins and thus cannot be eliminated by the immune system or by current therapies [1]. In this issue, Azzoni and colleagues assessed the potential of pegylated (Peg) interferon alfa-2a to suppress HIV replication [2]. In what could be a first step towards a functional cure, they found that Peg–interferon alfa-2a permitted a subset of subjects to maintain low viral loads for 12–24 weeks in the absence of HAART. Furthermore, they found that in patients with a favorable virologic response to Peg interferon alfa-2a, levels of HIV provirus in peripheral blood mononuclear cells (PBMCs) were reduced. This finding suggests that Peg– interferon alfa-2a may eliminate latent HIV genomes, a possibility that would shed light on the search for a sterilizing as well as a functional cure for HIV. Interferon alfa is used clinically for the treatment of hepatitis B and C virus infections, and several studies have assessed the capacity of this cytokine to limit HIV replication in vivo [3–9]. Multiple studies confirm that interferon alfa can reduce viral load and delay disease progression in viremic patients [3, 5–11]. However, interferon alfa’s potential to suppress viremia in patients with wellcontrolled viral loads is less clear. Recently, one study subjected HAARTtreated patients with a viral load of <400 copies/mL for at least 6 months and a CD4 T-cell count of >350 cells/μL to a series of three 4-week structured treatment interruptions (STIs), during which they received interferon alfa therapy or no treatment [4]. Treatment was then suspended until the end of the trial. Interferon alfa administration was observed to significantly blunt the viral load rebound during the 4-week STI phase, but it did not prolong the time to treatment resumption after treatment was suspended. This study also noted that interferon alfa was deleterious in patients with a low nadir CD4 T-cell count [4]. This issue’s study by Azzoni et al is the first to show an effect of Peg–interferon alfa-2a treatment on viral load rebound during a multimonth interval of treatment interruption and the first to identify an effect of Peg–interferon alfa2a on the HIV proviral reservoir [2]. In this study, the authors recruited 23 HAART-treated, HIV-positive patients with HIV plasma RNA levels of <50 copies/mL [2]. All subjects received Peg– interferon alfa-2a therapy in addition to HAART for 5 weeks; then HAART but not Peg–interferon alfa-2a therapy was interrupted for 12–24 weeks [2]. Viral suppression was maintained through week 12 of treatment interruption in 45% of patients and through week 24 in 30% of patients; in both cases, the proportion of patients with suppressed viral loads was significantly greater than expected on the basis of data from historical controls [2]. The authors comment that the higher level of suppression observed in this study compared with Received and accepted 5 September 2012; electronically published 26 October 2012. Correspondence: Kathleen L. Collins, MD, PhD, Department of Internal Medicine, University of Michigan, Ann Arbor, 3510 MSRB1, 1150 W Medical Center Dr, Ann Arbor, MI, 48109 ([email protected]). The Journal of Infectious Diseases 2013;207:201–3 © The Author 2012. Published by Oxford University Press on behalf of the Infectious Diseases Society of America. All rights reserved. For Permissions, please e-mail: journals. [email protected]. DOI: 10.1093/infdis/jis667