Longitudinal Evaluation of Viral Co-receptor Tropism Switches among HIV-infected Patients with Drug-resistant Viremia
Reported by Jules Levin
CROI, Feb 25-28, 2007, Los Angeles
Peter Hunt*1, W Huang2, E Coakley2, C Petropoulos2, M Bates2, R Hoh1, S Deeks1, and J Martin1
1Univ of California, San Francisco, US and 2Monogram Biosci, South San Francisco, CA, US
Background: CCR5 inhibitors are being developed for the management of drug-resistant HIV. These drugs have limited virologic activity in patients harboring CXCR4-using virus (X4), and incomplete viral suppression on these drugs may select for pre-existing X4. Defining the rate of emergence of X4 in treated patients with drug-resistant viremia in the absence of CCR5 inhibitors may help define the "cost" of deferring their use for future salvage regimens and clarify the degree to which CCR5 inhibitors cause expansion of X4.
Methods: HIV-infected patients with drug-resistant viremia >1000 copies/mL on a stable ART regimen for >4 months were sampled from a clinic-based cohort study. Viral co-receptor tropism was measured with a phenotypic recombinant pseudo-virus assay every 4 months until treatment change. To distinguish co-receptor-mediated entry versus background luciferase activity, entry via CCR5- or CXCR4-expressing cells was confirmed by decreases in relative light units (rlu) with co-receptor inhibitors.
Results: In 76 patients with drug-resistant viremia, median baseline values were: plasma HIV RNA level, 3.8 log10 copies/mL, and CD4 count, 241 cells/mm3. At baseline, 52 (68%) had R5-tropic virus (R5), 22 (29%) had dual/mixed-tropic viruses (DM), and 2 (3%) had pure X4. There was a median of 3 tropism observations/patient over a median of 9 months. In those with baseline R5, 12% (95%CI 6 to 26%) switched to DM by 1 year. Of 7 patients experiencing R5DM switch, 3 had switches driven by very low-level CXCR4 entry around the assay's limit of detection (²255 rlu) and 1 had repeated oscillation between R5 and DM; the remaining 4 patients experienced the clear emergence of a virus that can effectively use CXCR4 in vitro. In those with baseline DM, 11% (95%CI 3 to 37%) experienced "reversion" to R5 by 1 year and 8% (95%CI 1 to 43%) "progressed" to pure X4. There was no evidence for a change in CXCR4 rlu in those without tropism switches (p = 0.39).
Conclusions: Among stably treated patients with drug-resistant viremia, the incidence of new tropism changes is relatively low, occurs in both directions, and is often associated with small changes in CXCR4 entry, suggesting natural oscillations in X4 replication near the level of detection. Some treated patients with apparent pure R5 may have also harbored DM in the recent past. Deferring treatment change may carry a small risk of losing CCR5 inhibitors as an effective future treatment option.
- In cross sectional studies, up to 50% of chronically-infected patients with drug-resistant viremia have measurable levels of CXCR4-utilizing viruses in plasma.
- The rate and determinants of developing dual/mixed- and X4 tropic viruses in this population and whether this phenotype is stable over time are unknown.
Among stably-treated patients with drug-resistant viremia, the incidence of new co-receptor tropism changes is about 10% per year and occurs in both directions.
-- Thus, deferring treatment change may carry a small risk of losing CCR5 inhibitors as an effective future treatment option.
-- Furthermore, some treated patients with apparently pure R5-tropic virus may have harbored CXCR4-using viruses in the recent past.
CCR5 delta-32 heterozygosity predicts more rapid switch from R5 to dual/mixed tropism.
-- Low CCR5+ target cell availability might select for CXCR4-using viruses.
Some apparent tropism switches may reflect relatively small changes in CXCR4 entry around the assay's limit of detection.
-- Unclear whether these changes will affect CCR5 inhibitor susceptibility.
We found no evidence for increasing entry via either CCR5 or CXCR4 among treated patients maintained on a stable regimen in the absence of frank tropism switches.
-- These results are more consistent with selection of pre-existing minority variants than continued evolution in envelope as an explanation for the emergence of CXCR4-using viruses during HAART.
Chronically HIV-infected patients with drug-resistant viremia sampled from SCOPE:
-- Clinic-based cohort study of >600 chronically-infected patients, half with drug resistance.
-- Patient interview and biologic specimen archiving performed every 4 months
76 patients meeting the following eligibility criteria were randomly sampled:
-- Stable antiretroviral therapy regimen for ≥ 120 days prior to baseline.
-- ≥ 2 plasma HIV RNA levels above 100 copies/ml in 90 days prior to baseline.
-- Plasma HIV RNA level > 1,000 copies/ml at baseline.
-- Evidence of ≥ 1 major or minor genotypic resistance mutation (excluding L63P).
-- 1st plasma HIV RNA level post-baseline within 1.5 log10 copies/ml to ensure steady state.
-- ≥ 2 plasma HIV RNA levels > 1,000 copies/ml during observation.
52 patients harboring R5-tropic viruses at baseline contributed a median of 3 tropism observations over 8 months.
Overall, the risk of progression to dual/mixed tropism at 1 year was 12% (95% CI: 6%- 26%).
Predictors of more rapid switch (unadjusted):
-- CCR5 delta-32 heterozygous (P<0.001)
-- Lower Baseline CD4 count (P=0.004)
CCR5 delta-32 genotype was the only significant predictor of switch in adjusted analyses (P=0.024).
22 patients harboring Dual/Mixed-tropic viruses at baseline contributed a median of 3 tropism observations over 10 months.
At 1 year, the risk of progression to "pure" X4 tropism was 8% (95% CI: 1% - 43%).
However, the risk of "back-reversion" to R5 tropism at 1 year was 11% (3% - 37%).
No tropism switches were observed during 4 months of observation among the 2 patients harboring X4-tropic viruses at baseline.
These 3 patients accounted for 7/14 (50%) of all observed tropism switches.
None of these patients were heterozygous for the CCR5 delta-32 mutation.
No obvious relationship between these tropism oscillations and either CD4 counts or plasma HIV RNA levels (representative plot to left).
Patients continually harboring R5-tropic viruses while maintaining a stable antiretroviral regimen were followed for changes in entry efficiency via CCR5.
Changes in R5 rlu's were assessed with mixed effects repeated measures models.
No evidence of increasing entry into CCR5-expressing target cells was observed over time.
This work was supported by the NIAID (K23 AI065244).