A team of American researchers assessed the effect of HIV coreceptor tropism on the risk of HIV disease progression in antiretroviral treatment-naïve patients. Compared with CCR5-tropic virus, having dual/mixed coreceptor tropism accelerated HIV disease progression by a factor similar to a tenfold (1 log10) increase in viral load. The results were presented as a poster at the 47th Interscience Conference on Antimicrobial Agents and Chemotherapy.
To enter and infect a host cell, HIV binds with two proteins on the cell surface: the primary CD4 receptor, and a second coreceptor. Distinct strains, or tropisms, of virus are distinguished by their ability to bind to different coreceptor molecules. CCR5-tropic HIV binds to the CCR5 coreceptor; X4-tropic virus binds to the CXCR4 coreceptor; dual/mixed-tropic virus can bind to either.
A research team led by Dr. Matthew Goetz assessed the effect of this coreceptor tropism on the risk of disease progression, as measured by a fall in CD4 count to below 350 cells/mm3, antiretroviral treatment initiation, or death. (Any one of these factors constituted the “composite outcome”.)
A total of 313 patients were included in the analysis. At baseline, all the patients had a CD4 cell count ≥ 450 cells/mm3 and a viral load of at least 1,000 copies/ml. As determined by the Trofile assay (Monogram Biosciences), 32 of the patients had dual/mixed tropic virus (CCR5/X4); the remaining 281 had purely CCR5-tropic virus. None displayed purely X4 tropism.
Median baseline CD4 cell counts and viral loads were comparable in the two groups: 635 cells/mm3 and 4.05 log10 in the CCR5 group (respectively), and 571 cells/mm3 and 4.35 log10 in the mixed group. The only significant demographic difference detected at baseline was that Hispanic patients were less likely to have CCR5 virus (8% vs. 25%, p = 0.007). Median duration of HIV infection at baseline was 48 months, and the patients were followed for 52 months.
The investigators found that patients with mixed tropism HIV were significantly more likely to experience HIV disease progression to the composite outcome than patients with CCR5 virus, with a composite relative risk (RR) of 2.14 (p = 0.002). Patients with mixed tropism progressed more rapidly to a CD4 cell count below 350 cells/mm3 (n=112, RR = 2.65, p < 0.01), and to initiation of treatment (n=65, RR = 2.35, p < 0.01).
The effects of tropism on progression were compared to the effects of baseline viral load and CD4 count. The relative risk (RR) of progression to the composite outcome was 2.14 (p=.002) for dual/mixed tropism vs CCR tropism, 2.05 per additional log10 of viral load (p<.001), and 0.87 per 50 cell/mm3 higher CD4 count (p < 0.001).
These results were unaffected by adjustment for factors including gender, race, mode of infection, hepatitis C virus coinfection, duration of HIV infection and previous AIDS diagnosis.
Commenting on the findings, Dr Goetz remarked that “we have to be cautious about the generalisability of these data, but in this cohort, the presence of dual/mixed-tropic virus certainly had a comparable impact to a tenfold higher viral load, and a significantly greater effect than [the loss of] an additional 50 CD4 cells. People in this cohort had twice the likelihood of progressing to the endpoint if they had dual/mixed-tropic virus, twice the likelihood if they had an additional 1 log viral load, and about a 25% increased likelihood if they had 50 fewer CD4 cells.”
Investigators believe it is premature to draw conclusions regarding the effect of tropism on the rate of CD4 loss. Goetz commented that “preliminary analysis has shown a tendency for people with dual/mixed tropic virus to lose CD4 cells more quickly, but those data remain to be more clearly characterised; at present we have no statistically sound evidence on that point.”
Goetz MB et al. Prediction of disease progression by HIV coreceptor tropism in persons with untreated chronic HIV infection. 47th Interscience Conference on Antimicrobial Agents and Chemotherapy, Chicago, abstract H-1027, 2007.