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Correlates of Coreceptor Tropism in Three Large Cohorts: Does lower CD4 predict tropism switch?
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Targeting HIV Entry: 3rd International Workshop
December 7-9, 2007
Washington, DC
Mark Mascolini
Coreceptor use in three big maraviroc trials correlated with CD4 count and viral load [1]. But, surprisingly, time since diagnosis had no apparent impact on use of the CXCR4 (R4) coreceptor versus CCR5 (R5) in the antiretroviral-naive or -experienced people enrolled in either study. A Spanish cohort study found that antiretroviral therapy had no consistent impact on coreceptor use through 10 years of follow-up [2].
Pfizer investigators used Monogram's Trofile assay to determine coreceptor tropism during trial screening in 1279 previously untreated people enrolled in the MERIT study of the CCR5 antagonist maraviroc and in 2585 treatment-experienced patients enrolled in the MOTIVATE studies of the same drug.
In the antiretroviral-naive group, 83% had R5-using virus at screening, while the rest had either X4-using virus or dual/mixed (D/M) viruses that can use either coreceptor. Two thirds of MERIT study participants had HIV-1 subtype B, while 25% had subtype C. Average CD4 counts were higher and viral loads lower in people with R5 virus than in those with non-R5 virus--findings confirming results of earlier studies:
· R5: average 274 CD4s
· Non-R5: average 168 CD4s (P < 0.0001)
· R5: 40% >100,000 copies/mL
· Non-R5: 53% >100,000 copies/mL (P < 0.0001)
A substantially higher proportion of subtype B-infected people (94%) had R5 virus than did subtype C-infected people (79%). The correlation between higher CD4 counts and lower viral loads with R5 virus held true regardless of HIV-1 subtype. Age or time since HIV diagnosis did not predict coreceptor preference at screening for this trial.
Almost all antiretroviral-experienced MOTIVATE enrollees (96%) carried HIV-1 subtype B. Compared with the treatment-naive MERIT population, a lower proportion of treatment-experienced MOTIVATE enrollees had R5-using virus (56%), while 41% had D/M-tropic virus and 3% had X4 virus. But again average CD4 counts ran higher in the R5 group (170) than in the X4 group (111) or the D/M group (73) (P < 0.0001).
Analysis of a vicriviroc trial also found the lowest CD4 counts in people with D/M-tropic virus [3]. And a higher proportion in the D/M group (48%) than in the R5 group (42%) or the X4 group (24%) had a viral load at or above 100,000 copies (P < 0.0001). Coreceptor experts surmise that D/M virus correlates with lower CD4 counts and higher viral loads than R5-only HIV or X4-only HIV because D/M viral populations give the virus two chances to invade CD4 cells (via two coreceptor routes).
Median age was significantly lower in people with D/M virus (44 years) than in those with R5 virus (45) or X4 virus (46) (P = 0.0082), though the meaning of that correlation remains unclear. As in the naive MERIT group, coreceptor preference did not correlate with time since HIV diagnosis in the experienced MOTIVATE enrollees. Nor did the Pfizer team discern any independent links between coreceptor tropism and gender or frequency of drug holidays lasting longer than 28 days.
The Spanish study involved 42 antiretroviral-experienced people and 31 chronically infected but treatment-naive people cared for at Madrid's Carlos III Hospital [2]. The untreated people all had CD4 counts above 350.
Veronica Briz and colleagues used two online gene-based tropism predictors to determine coreceptor use. Although these HIV gene-based tools are free and fast, earlier studies and research presented at this workshop indicate that coreceptor predictions based on these algorithms do not consistently match those of Monogram's Trofile assay or a standard lab test. The Carlos III investigators used the webcat and webPSSM gene-based tools to predict tropism in three samples collected from the naive group through 8 years of follow-up and in multiple samples from the experienced population collected before therapy began and after virologic failures through 10 years of follow-up.
In the first samples collected from both groups, X4 prevalence was only marginally lower in the untreated people than in the treated people, according to the webcat system (22.6% versus 31%). But webPSSM predicted substantially lower X4 use in the naive population (3.2%) than in the treated people (14.3%). The divergent results between these algorithms suggest their still-chancy reliability.
Unlike the maraviroc trial analysis, the Spanish study found no link between age and coreceptor use in either naive or experienced patients. Nor did Briz and coworkers detect a correlation between tropism and gender, HIV transmission route, or viral load in either naive or experienced people. In the treatment-experienced group a higher CD4 count correlated with R5 use (332.5 versus 196.5 cells, P = 0.02).
The webcat system predicted coreceptor changes in 17 people, while webPSSM predicted switches in 19 individuals. A lower nadir CD4 count (P = 0.02) and lower baseline CD4 count (P = 0.003) favored coreceptor switching in the experienced patients but not in the naive group. Those findings led Briz and colleagues to postulate that X4 virus emerges as a result of progressive CD4 depletion. But in another workshop study reviewed by NATAP [4], a Monogram Biosciences team proposed just the opposite--that emergence of X4 virus incites CD4 depletion.
References
1. Clax P, Rajicic N, Westby M, et al. Association between HIV-1 co-receptor tropism results and clinical and laboratory factors in 3862 patients screened for phase 3 clinical studies of maraviroc. Targeting HIV Entry: 3rd International Workshop. December 7-9, 2007. Washington, DC. Abstract 5.
2. Briz V, Poveda E, Martin-Carbonero L, et al. Impact of HAART on viral tropism evolution in HIV-infected patients followed for over 10 years. Targeting HIV Entry: 3rd International Workshop. December 7-9, 2007. Washington, DC. Abstract 4.
3. Wilkin TJ, Su Z, Kuritzkes DR, et al. HIV type 1 chemokine coreceptor use among antiretroviral-experienced patients screened for a clinical trial of a CCR5 inhibitor: AIDS Clinical Trial Group A5211. Clin Infect Dis. 2007;44:591-595.
4. Wrin T, Phung P, Liu Y, et al. Viruses utilizing both CCR5 and CXCR4 are found in 5-13% of acute HIV-1 infections. Targeting HIV Entry: 3rd International Workshop. December 7-9, 2007. Washington, DC. Abstract 3.
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