Editorial Commentary: Universal Antiretroviral Therapy for HIV Infection?

Abstract

Human immunodeficiency virus (HIV) still infects more people per year than existing health systems are able to initiate and maintain on antiretroviral therapy. Therefore, the development of effective HIV population prevention strategies remains a high priority. There is no immediate promise for an effective HIV vaccine, risk behavior change has been difficult to implement, and biomedical prevention measures lack effectiveness due to inconsistent use. In contrast, antiretroviral therapy (ART) can benefit the infected individual and under clinical trial conditions has been shown to reduce transmission [1]. The use of ART as both treatment and prevention is now a well-established concept, which has been widely welcomed as the “missing link” that will curb HIV incidence [2]. However, a disconnect exists between the individual and transmission benefits of ART. Persons with advanced HIV disease (reflected by having a CD4 lymphocyte count <250 cells/μL), have clear benefit, documented by several randomized controlled trials (reviewed in [3]). Conversely, the target populations for transmission benefit are those with high CD4 counts, in whom observational studies have shown inconsistent or no clinical benefit (reviewed in [4]). Additional biological plausibility for early treatment has been the observation that untreated HIV infection activates host inflammatory processes associated with organ disease and cancers and that ART partly (but not completely) reverts immune activation. However, no specific anti-inflammatory intervention has been demonstrated to reduce the risk of these adverse outcomes, and changes in inflammatory biomarker levels have not been validated surrogates for clinical benefits of ART. Therefore, whether inflammation is causally involved in the pathogenesis of these events or merely an epiphenomena to the underlying pathology remains to be identified in HIV as it does in the general population. The uncertainties relating to net benefit of early ART are reflected in disparities between treatment guidelines. Guidelines based on consensus “expert opinion” recommend that all HIV-positive persons, as a matter of principle, should be started on ART [5, 6], and those based on available direct evidence [7–9] (including the 2010 World Health Organization guidelines) are more conservative. Unfortunately, consensus among experts can be prescient or subsequently shown to be incorrect. For example, 10 years ago, expert opinion was that ART could be used intermittently, but the SMART (Strategies for Management of Antiretroviral Therapy) trial demonstrated definitively that this view was wrong [10]. Gallant et al, in this issue of Clinical Infectious Diseases [11], highlight reasons why the recommendations of the US guidelines are not necessarily generalizable to other settings. They highlight a fundamental ethical obligation of clinicians to benefit patients while not causing harm. They note that although the individual benefits of early ART remain undefined in resource-limited settings, the risks associated with early ART may be higher. Cost constraints in resourcelimited settings limit the available ART repertoire, resulting in frequent use of older, cheaper drugs with poor adverse event profiles. In a setting where only stavudine-based ART regimens are available, for example, starting ART at a high CD4 count of 650 cells/μL would less likely maintain health than deferring to a more conservative threshold of 250–350 cells/μL. Lack of laboratory monitoring may also potentially increase risk by delayed recognition of toxicity. Tenofovir, which is included in most currently recommended ART regimens, may adversely affect kidney and bone physiology [12, 13]. Emerging reports of more severe renal diseases in settings without access to laboratory monitoring raise Received 30 May 2013; accepted 1 June 2013; electronically published 11 June 2013. Correspondence: Jens D. Lundgren, MD, DMSc, Department of Infectious Diseases (5112), Rigshospitalet, Blegdamsvej 9, 2100 Copenhagen O, Denmark (jdl@cphiv.dk). Clinical Infectious Diseases 2013;57(6):888–90 © The Author 2013. Published by Oxford University Press on behalf of the Infectious Diseases Society of America. All rights reserved. For Permissions, please e-mail: journals. permissions@oup.com. DOI: 10.1093/cid/cit381