HIV Coreceptor Tropism and Disease Progression in Untreated Chronic HIV
HIV Coreceptor Tropism and Disease Progression in Untreated Chronic HIV
Objective: To assess the effect of HIV coreceptor tropism (CRT) on the relative risk of progression to a composite outcome of CD4 count ≤350 cells per microliter, treatment initiation, or death.
Methods: CRT assays were performed after study closure in baseline samples obtained from enrollees in a prospectively monitored cohort of treatment-naive adults with ≥450 CD4 cells per microliter and ≥1000 HIV-1 RNA copies per milliliter.
Results: Dual/mixed (D/M) and R5 CRT were detected in 32 and 282 patients, respectively. The baseline CD4 count (617 versus 694 cells/μL; P = 0.05) differed in patients with D/M versus R5 CRT. Otherwise, baseline laboratory characteristics were similar.
The relative risk of progression to the composite end point was 2.15 (P = 0.002) for D/M versus R5 CRT, 2.07 per 1.0 log10 higher viral load (P < 0.001) and 0.87 per 50 cells per microliter higher CD4 cell count (P < 0.001). The effect of D/M CRT was also significant in separate analyses of time to initiation of antiretroviral therapy or CD4 cell count ≤350 cells per microliter.
Conclusions: Untreated patients with D/M rather than R5 CRT had a faster rate of disease progression, whether assessed by a composite outcome of time to CD4 count ≤350 cells per microliter, treatment initiation, or death or by separate analyses of time to CD4 count ≤350 cells per microliter or treatment initiation.
Recommendations regarding the timing of therapy for HIV-1-infected patients are based primarily on CD4 cell count measurements. Present guidelines recommend that therapy be started when the CD4 cell count is below 350 cells per microliter. Other considerations include the rate of CD4 cell loss, the magnitude of the viral load, and symptoms of HIV disease progression.
The loss of CD4 cells is largely determined by the plasma HIV-1 RNA concentration. Other factors that influence the rate of HIV disease progression and CD4 loss include patient age, HIV-directed immune responses, diminished cellular activation, host human leukocyte antigen genotype and chemokine receptor polymorphisms, and characteristics of viral isolates such as deletions in nef, syncytium formation [or the related property of coreceptor tropism (CRT)], and replicative capacity.
Viral isolates from persons in the early stages of HIV-1 infection are usually nonsyncytium inducing (NSI) in MT-2 cell cultures, whereas isolates from persons with more advanced disease are often syncytium inducing (SI). Furthermore, emergence of the SI phenotype has been associated with acceleration in the rate of CD4 cell loss. Importantly, HIV-1 isolates that utilize the CCR5 coreceptor predominantly express the NSI phenotype, whereas isolates that utilize the CXCR4 coreceptor largely express the SI phenotype. These observations and technical considerations have largely led to the replacement of assessment of the NSI/SI phenotype by recombinant virus assays for HIV coreceptor use or by predictions of CRT based on the sequence of the V3 loop of the HIV envelope.
Although several studies have assessed the relationship between HIV-1 (CRT) and the rate of HIV disease progression, there are few data regarding the prognostic significance of infection by CCR5-tropic or CXCR4-tropic HIV-1 isolates in a diverse population of chronically infected treatment-naive patients with relatively preserved CD4 cell counts. In this study, we evaluated the relationship between CRT and HIV disease progression in such a cohort, namely the treatment-naive participants who were enrolled in the long-term monitoring protocol (LTM) sponsored by the Terry Beirn Community Programs for Clinical Research on AIDS (CPCRA).
Abstract and Introduction
Abstract
Objective: To assess the effect of HIV coreceptor tropism (CRT) on the relative risk of progression to a composite outcome of CD4 count ≤350 cells per microliter, treatment initiation, or death.
Methods: CRT assays were performed after study closure in baseline samples obtained from enrollees in a prospectively monitored cohort of treatment-naive adults with ≥450 CD4 cells per microliter and ≥1000 HIV-1 RNA copies per milliliter.
Results: Dual/mixed (D/M) and R5 CRT were detected in 32 and 282 patients, respectively. The baseline CD4 count (617 versus 694 cells/μL; P = 0.05) differed in patients with D/M versus R5 CRT. Otherwise, baseline laboratory characteristics were similar.
The relative risk of progression to the composite end point was 2.15 (P = 0.002) for D/M versus R5 CRT, 2.07 per 1.0 log10 higher viral load (P < 0.001) and 0.87 per 50 cells per microliter higher CD4 cell count (P < 0.001). The effect of D/M CRT was also significant in separate analyses of time to initiation of antiretroviral therapy or CD4 cell count ≤350 cells per microliter.
Conclusions: Untreated patients with D/M rather than R5 CRT had a faster rate of disease progression, whether assessed by a composite outcome of time to CD4 count ≤350 cells per microliter, treatment initiation, or death or by separate analyses of time to CD4 count ≤350 cells per microliter or treatment initiation.
Introduction
Recommendations regarding the timing of therapy for HIV-1-infected patients are based primarily on CD4 cell count measurements. Present guidelines recommend that therapy be started when the CD4 cell count is below 350 cells per microliter. Other considerations include the rate of CD4 cell loss, the magnitude of the viral load, and symptoms of HIV disease progression.
The loss of CD4 cells is largely determined by the plasma HIV-1 RNA concentration. Other factors that influence the rate of HIV disease progression and CD4 loss include patient age, HIV-directed immune responses, diminished cellular activation, host human leukocyte antigen genotype and chemokine receptor polymorphisms, and characteristics of viral isolates such as deletions in nef, syncytium formation [or the related property of coreceptor tropism (CRT)], and replicative capacity.
Viral isolates from persons in the early stages of HIV-1 infection are usually nonsyncytium inducing (NSI) in MT-2 cell cultures, whereas isolates from persons with more advanced disease are often syncytium inducing (SI). Furthermore, emergence of the SI phenotype has been associated with acceleration in the rate of CD4 cell loss. Importantly, HIV-1 isolates that utilize the CCR5 coreceptor predominantly express the NSI phenotype, whereas isolates that utilize the CXCR4 coreceptor largely express the SI phenotype. These observations and technical considerations have largely led to the replacement of assessment of the NSI/SI phenotype by recombinant virus assays for HIV coreceptor use or by predictions of CRT based on the sequence of the V3 loop of the HIV envelope.
Although several studies have assessed the relationship between HIV-1 (CRT) and the rate of HIV disease progression, there are few data regarding the prognostic significance of infection by CCR5-tropic or CXCR4-tropic HIV-1 isolates in a diverse population of chronically infected treatment-naive patients with relatively preserved CD4 cell counts. In this study, we evaluated the relationship between CRT and HIV disease progression in such a cohort, namely the treatment-naive participants who were enrolled in the long-term monitoring protocol (LTM) sponsored by the Terry Beirn Community Programs for Clinical Research on AIDS (CPCRA).
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