Rescue of Severely Immunocompromised HIV‐Positive Persons
In asymptomatic human immunodeficiency virus (HIV)–infected individuals, the range of CD4 cell counts at which treatment initiation is considered currently ranges from 350 to >500 cells/μL; some will argue on the conservative side (ie, 350 cells/μL), others on the more aggressive side (500 cells/μL). Importantly, although the benefits of initiation (vs deferral) of antiretroviral therapy (ART) has been documented in randomized controlled trials conducted in situations where patients enter care with a CD4 cell count <350 cells/μL, no such evidence exists to inform the contemporary debate. A major public health issue throughout the world is that many patients enter care for their HIV infection too late. Recently, a European consensus was established to define a late presenter for care as an asymptomatic patient entering care with a CD4 cell count <350 cells/μL or a person who presents at any CD4 cell count with an AIDS‐defining condition. Applying this definition, reports from both North America and Europe consistently suggest that at least 50% of patients enter care too late. Therefore, even in resource‐rich areas major difficulties exist in ensuring broad access to state‐of‐the‐art care to those in need of it. Unfortunately, resource‐limited sections of world also have this public health problem, although the reasons for it are partly different. Estimates from the Joint United Nations Programme on HIV/AIDS suggest that in sub‐Saharan Africa only 40%–50% of persons in need of ART (with “need” determined on the basis of a CD4 cell count <200 cells/μL) actually receive this lifesaving treatment. Moreover, given that the disease burden in resource‐limited settings is usually worse than that in resource‐rich environments (eg, the prevalence of tuberculosis and malaria is higher) and that the number of persons affected is much greater, the impact in terms of lives lost is enormous and points to the fact that research aimed at determining the best approaches to reducing the effect of late diagnosis is warranted in all parts of the world. Late presentation raises a key research question, namely, how to best use ART to reduce the risk of deteriorating health to the maximum extent possible. When ART is initiated in patients early during the course of chronic HIV infection, the strategy of providing ART is entirely to prevent disease; the clinical consequences of providing a suboptimal regimen will appear several years thereafter, if at all. Conversely, in late presenters HIV has already caused harm (be it clinically detectable or latent at the time of entering care); hence, the clinical impact of suboptimal choices is more readily observed.
In resource‐limited settings, financial constraints do not allow physicians and health system officials the same multitude of drugs as the >20 that physicians elsewhere have to choose from. Additionally, the limited—or lack of—research infrastructure makes endeavors difficult to implement.
In this issue of the Journal, a unique collaboration is described between the South African Armed Forces and the US National Institutes of Health—the Phidisa project. Established around the time when South Africa decided to implement a national treatment program in 2003–2004, this collaboration has allowed the creation of an infrastructure that can provide proper HIV care to the armed forces and their relatives and that allows for the conduct of research. The present article describes the results of a randomized controlled trial that enrolled 1771 patients with advanced HIV disease (ie, the subgroup of late presenters presenting for care with a CD4 cell count <200 cells/μL) and that used 2‐by‐2 factorial design to compare 2 choices of nucleoside reverse‐transcriptase inhibitor pairs and 2 third drugs—a nonnucleoside reserve‐transcriptase inhibitor (NNRTI) and a protease inhibitor (PI). The trial is particularly significant because it is one of the largest drug‐drug comparison trials performed during the highly active ART era and uses clinical end points.