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Maintaining Patients on a Failing Antiretroviral Regimen Reduces the Risk of AIDS-defining Events
Abstract and Commentary
By Dean L. Winslow, MD, FACP, FIDSA, Chief, Division of AIDS Medicine, Santa Clara Valley Medical Center; Clinical Professor, Stanford University School of Medicine, is Associate Editor for Infectious Disease Alert.
Dr. Winslow serves as a consultant for Siemens Diagnostics, and is on the speaker's bureau for Boehringer-Ingelheim and GSK.
Synopsis: In a retrospective study of HIV-infected patients, those with CD4+ lymphocyte count 50-200, and < 50 who had detectable HIV RNA levels on combination antiretroviral therapy (cART), a 34% and 22% reduction, respectively, in new AIDS-defining events (ADE) was observed in patients who continued cART compared to patients who stopped cART.
Source: Kousignian I, et al. Maintaining antiretroviral therapy reduces the risk of AIDS-defining events in patients with uncontrolled viral replication and profound immunodeficiency. Clin Infect Dis. 2008;46:296-304.
For this study, 12,765 patients from the large French Hospital Database for HIV with CD4+ lymphocyte counts < 200 cells/uL who received cART during 2000-2005 were selected. Three groups of patients were identified: patients who interrupted cART at least once, patients with detectable HIV RNA during treatment with cART, and patients with undetectable HIV RNA on cART. The incidence rates for new ADEs were 18.5, 14.5, and 4.9, respectively, and were observed across CD4 strata (< 50 and 50-200 cells/uL). After adjustment, risks of a new ADE were 62% less in patients with undetectable HIV RNA than in those who stopped cART and 22% less in patients with detectable RNA but continued cART than in those who stopped cART.
Many clinicians have made the anecdotal observation that patients who continue receiving antiretroviral therapy despite virologic failure (detectable HIV RNA levels) do better than those who discontinue ARVs.1 In addition, it has been shown in a large prospective CPCRA trial (SMART) that interruption of ARVs results in a more rapid progression to AIDS despite CD4+-guided safety parameters.2
The mechanisms responsible for this beneficial effect of ARVs, despite virologic failure, are not well understood. One explanation may be as simple as the fact that a failing regimen may still exert some anti-retroviral activity, and even a minimal reduction in HIV RNA translates to clinical benefit. This explanation is supported by the Marschner meta-analysis of HIV RNA data published in the 1990s, which demonstrated that HIV RNA is a continuous variable correlating with clinical benefit. These data support the fact that essentially any reduction of HIV RNA is helpful, especially if looking at large populations of patients.3 Another widely accepted, but scientifically flawed explanation is that ARV-resistant virus is less fit than wild-type virus and, therefore, maintenance of selective pressure to prevent reversion to wild type is beneficial. There is no direct evidence to support this. HIV's resistance to HIV protease inhibitors often displays impaired "replication capacity" in the absence of ARVs when studied in single-cycle in vitro phenotype assays (such as the Monogram Phenosense assay). However, this impaired "RC" is actually an artifact of the pol gene amplicon being inserted into an infectious molecular clone of HIV, which lacks the compensatory substitutions in gag which lead to normal replication of the whole virus. Indeed, whole virus selected to be drug resistant in vitro, as well as drug-resistant virus isolated directly from patients by co-culture are fully replication competent.
One potential mechanism for the observed discrepancy between virological failure and relative immunologic stability in the presence of ARV resistance may relate to the fact that the anti-apoptotic protein, Bcl-2, which is expressed in lymphocytes, is a natural substrate for HIV protease. When almost any substitution in HIV protease is introduced, it loses the ability to efficiently cleave Bcl-2, thus preventing infected lymphocytes from being driven into accelerated apoptosis, which is postulated to be one of the important mechanisms responsible for CD4+ lymphocyte depletion seen in HIV infection.4 This important observation was made in the early 1990s by a former colleague at DuPont, Peter Strack, who was a post-doctoral fellow in Bruce Korant's laboratory. It is surprising that this important work has not been followed up by others.