More on the Treatment‐Tropism Relationship: The Impact of Prior Antiretroviral Treatment on HIV Coreceptor Tropism among Subjects Entering AIDS Clinical Trials Group 175

Correspondence Table 1. Baseline cohort characteristics at study entry, categorized by detectable syncytia (SI) vs. no detectable SI (NSI), as determined by MT2 cell–based tropism assay. NOTE. Data are median (interquartile range), unless otherwise indicated. a P values are 2-sided and were determined by the Wilcoxon rank-sum test for nonparametric continuous variables and by Fisher's exact test for categorical variables. To the Editor—CCR5 (R5) and CXCR4 (X4) are the major coreceptors that, along with CD4, mediate HIV entry in vivo [1, 2]. The R5 antagonists in development inhibit replication of R5-using HIV variants [3], but they have little activity on X4 or dual/mixed populations (R5X4) [4]. Detectable R5X4 and X4 are more prevalent among the treatment experienced, which suggests that treatment may select for X4 use. This has been observed in cross-sectional analyses of clinical trials and clinical cohorts [5, 6]. In untreated patients, an increase in X4 use is associated with CD4 + T cell count decline [7]; however , causality has been difficult to establish. The relationship between treatment and tropism has been confounded by differences in nadir CD4 + T cell counts between treated and untreated patients. Hunt et al. [5] recently reported that patients with partial viral suppression receiving diverse combination therapies have 14-fold greater odds of harboring detectable X4-using virus than do treatment-naive subjects, independent of CD4 + T cell counts and CCR5D32 genotype. However, the higher prevalence of X4-using viruses in treated subjects may be explained by lower pretreatment nadir CD4 + T cell counts. AIDS Clinical Trials Group (ACTG) 175 was a randomized, placebo-controlled study conducted in 1991 to assess the benefit of combination therapy versus mono-therapy in preventing clinical progression to AIDS/death in patients with CD4 + T cell counts between 200–500 cells/mm 3 [8]. A total of 2467 subjects were random-ized to receive zidovudine (ZDV), didan-osine (DDI), ZDV plus DDI, or ZDV plus zalcitabine. Quantitative HIV-1 RNA levels were obtained and peripheral blood mononuclear cell and MT2 cell cultures were done at selected sites. At the Stanford site, 74 subjects enrolled and had tropism determined by virus culture and MT2 cell assay at study entry; other data collected included treatment history, symptom history , age, CD4 + T cell count, HIV-1 RNA level, and CCR5D32 genotype. Fisher's exact test was used to determine associations between categorical variables, and the Wil-coxon rank-sum test was used for continuous variables. Logistic regression was used …