Is there a role for tropism testing in routine HIV care?

HIV-positive individuals with HIV that is adapted to infecting CD4 cells bearing the CXCR4 coreceptor should be considered for early initiation of antiretroviral therapy, write the authors of a study published in the October 15^th edition of the Journal of Infectious Diseases. The US study found that patients whose HIV changed from using the CCR5 co-receptor to the CXCR4 co-receptor experienced rapid loss of key immune system cells and HIV disease progression.

An accompanying editorial says that tropism testing could help doctors make appropriate treatment decisions for individual patients. Tropism refers to the tendency of the virus to infect a particular type of cell rather than other types.

In order to infect cells, HIV needs to bind to both the CD4 protein and a co-receptor on the surface of cells. Early in the course of HIV infection, the virus uses the CCR5 co-receptor, but in approximately 50% of individuals, in the later stages of HIV disease the virus switches to use the CXCR4 (X4) co-receptor.

The presence of X4 virus has been associated with faster HIV disease progression and a fall in CD4 cell count.

US investigators from the Multicenter AIDS Cohort Study (MACS) wished to gain a better understanding of the emergence of X4 strains of HIV. They therefore undertook a review of HIV co-receptors in 67 male patients. Their aims were to establish the relationship between the emergence of X4 virus and HIV disease progression.

All the patients were infected with HIV before 1995. The time at which they were infected with HIV could be estimated to within five months. All the patients had frequent clinic visits during which blood samples were collected and frozen (an average of ten per patient). The investigators checked the medical records of the men to establish the time at which their CD4 cell count fell to below 200 cells/mm³ or they developed an AIDS-defining illness. HIV disease progression was considered rapid if either of these points was reached five years after diagnosis, moderate if they were reached within five to nine years, slow if they were reached within nine to eleven years, and very slow if it took over eleven years.

A total of 35 (52%) individuals had X4 virus at some point during the study. The first recorded viral load was higher in these patients (mean 25,000 copies/ml) compared to those who maintained CCR5-using virus throughout the study (mean 12500 copies/ml), a difference of borderline significance (p = 0.08).

Four men developed X4 virus within two years of infection with HIV. All experienced rapid HIV disease progression.

The investigators then conducted a more detailed analysis to establish the link between the emergence of X4 virus and HIV disease progression. They found that 24% of patients experienced rapid disease progression, 40% had a moderate rate of progression, 12% were slow progressors and 24% were very slow progressors.

Compared to very slow progressors, those who progressed to AIDS within five years (rapid progression) had an almost five-fold increase in their risk of having X4 virus (odds ratio, 4.9, p = 0.061), those with moderative progression had a near seven-fold increase in the risk of having X4 virus (odds ratio, 6.9, p = 0.014), and those with slow progression a non-significant 50% increase in risk.

Of the men who developed AIDS, X4 virus emerged before the AIDS-defining event in 52% of patients and around the time of AIDS in a further 13%. By contrast, X4 virus only emerged in 30% of patients who did not experience HIV disease progression, a significant difference (p = 0.04).

The median time between the emergence of X4 virus and the diagnosis of AIDS was 13 months. The median CD4 cell count at the time X4 virus emerged was 475 cells/mm³.

Previous studies have established a relationship between a decline in CD3 T cells and a weakening of the immune system. These were supported by the current study which showed that this occurred in 50 men (75%). Of the men who experienced a fall in CD3 T cell count, X4 virus emerged first in 54% of men. Only 24% of men who did not experience a fall in their CD3 T cell count developed X4 virus (p = 0.03).

In the men who experienced the development of both X4 virus and had a decline in their CD3 T cell count, the median interval between the appearance of X4 virus and a fall in this immune system count was approximately ten months.

Given the association between the emergence of X4 virus and HIV disease progression the investigators comment “it may be prudent to initiate highly active antiretroviral therapy as soon as X4 viruses are detected because such treatment can prevent X4 virus-associated disease progression and thereby improve treatment outcome.”

The authors of an accompanying editorial comment “by revealing the presence of X4 strains, these biomarkers offer the potential to improve individual therapy…it is now time to design studies to define the role of tropism testing and X4 viral load in determining when to start and switch antiretroviral therapy.”