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Association Between Early Virologic Response and Immunologic Outcomes in Raltegravir-treated Patients: "Early vRNA decay is significantly correlated with greater increases in CD4 (absolute and %) change from baseline at Wk 96"
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Reported by Jules Levin
ICAAC Sept 2010
C. Tsoukas1, J. Lennox2, P. Sklar3, J. Zhao3, A. Rodgers3, H. Teppler3, R. Leavitt3, B-Y. Nguyen3
1McGill University, Montreal, Canada; 2Emory University, Atlanta, GA, USA; 3Merck Research Laboratories, North Wales PA, USA
"We explore if rapid viral decay has any impact on immunilogic response."
From Jules: in the early days of HAART we used to conjecture whether if achieving undetectable more quickly translated into greater CD4 response, with most studies back then being very mixed without firm conclusions. This new study at ICAAC reports:
"Wk 8 vRNA < 50 c/mL is correlated with a faster time to normalization of CDR; more so for pts on RAL who achieve this early viral response. Early vRNA decay is significantly correlated with greater increases in CD4 (absolute and %) change from baseline at Wk 96. This may have clinical benefit in certain Pt populations. Further work is being done to corroborate these findings in other datasets."
BACKGROUND
· The objectives of current HIV therapies include viral suppression and reversal of HIV associated immune abnormalities.
· HIV not only leads to CD4 depletion, it also causes profound immune activation and severe immune dysregulation as noted by a low CD4:CD8 ratio.
· HAART regimens may increase CD4 counts equally over time but may differ in reversing immune dysregulation.
· Normalization of the CD4:CD8 ratio (CDR) on HAART historically can take months to years.
· Raltegravir (RAL), a 1st in class HIV integrase inhibitor, has potent, durable and non-inferior efficacy compared to efavirenz (EFV).
· RAL-treated patients achieve viral suppressionsignificantly faster than EFV-treated patients.
AUTHOR CONCLUSIONS
· RAL-treated patients achieve viral suppression significantly faster than those in comparator groups.
· Rapid and early viral response (Wk 8 vRNA <50) is correlated with a faster time to normalization of CD4:CD8; more so for patients on RAL who achieved this early viral response.
- This improvement of immune dysregulation, as reflected by normalization of CD4:CD8 ratio, may have potential clinical benefit in certain high-risk populations.
· Further work is being done to corroborate these findings in other datasets.
Abstract
Background: Normalization of the CD4:CD8 ratio (CDR), a marker of immune dysregulation, historically can take mos to yrs on HAART. Raltegravir (RAL), a 1st in class HIV integrase inhibitor, has demonstrated potent, durable and non-inferior efficacy compared to efavirenz (EFV) in combination therapy in treatment-naive patients (pts). Moreover, RAL-treated pts achieve viral suppression significantly faster than those in comparator groups. We explore if rapid viral decay has any impact on immunologic response.
Methods: Data from pts in STARTMRK are included (N=281 RAL vs. 282 EFV). Early viral response (EVR) is defined as Wk 8 vRNA <50 c/mL. Time to achieve normalization of CDR (≥1) and time to CD4 ≥200 is explored. A multiple linear regression model of absolute/% CD4 at key timepoints as the response exploring potential covariates is performed. Nominal p-values are reported.
Results: In all data through Wk 96, EVR is highly correlated with CDR ≥1 [log-rank p=0.026]. For RAL the association is marginally significant [log-rank p=0.082], for EFV the association is not significant [log-rank p=0.293]. No difference was seen between treatment groups in time to CD4≥200 as this was driven by baseline CD4.
In multiple linear regression modeling:
For change from baseline in CD4 cell counts/percentage p-values were calculated using a multiple linear regression model adjusted for: Wk 8 log vRNA decrease, treatment, and interactions between treatment and Wk 8 log vRNA decrease.
*Significant/marginally significant at critical level of 0.05.
** Interaction term significant at critical level of 0.10; different level of association between early viral decay and CD4 in the two treatment groups.
Conclusion: Wk 8 vRNA < 50 c/mL is correlated with a faster time to normalization of CDR; more so for pts on RAL who achieve this early viral response. Early vRNA decay is significantly correlated with greater increases in CD4 (absolute and %) change from baseline at Wk 96. This may have clinical benefit in certain Pt populations. Further work is being done to corroborate these findings in other datasets.
Methods
· Data from treatment-nave patients in the following studies are included:
- STARTMRK (Phase III) through 96 weeks (N=281 RAL vs. 282 EFV)
- Protocol 004 (Phase II) through 192 weeks (N=160 RAL vs. 38 EFV), as a confirmatory check
· Time to achieve normalization of CDR (≥1) and time to CD4
≥200 are explored
· Early viral response (EVR)=Wk 8 vRNA <50
· A multiple linear regression model of absolute/% CD4 at key timepoints as the response exploring potential covariates is performed
· Nominal p-values are reported
RESULTS
Association Between CD4/CD8 ≥1 and Early Viral Response - STARTMRK
· Baseline CD4:CD8
Mean = 0.28 RAL vs. 0.27 EFV
Median 0.24 RAL vs. 0.23 EFV
· In all data, EVR is highly correlated with CD4:CD8 ≥1 [log-rank p-value =0.026]
· In RAL group (N=281), the association is marginal [log-rank p-value =0.082]
· In EFV group (N=282), the association is not significant [log-rank p-value=0.293]
Association Between CD4/CD8 ≥1 and Early Viral Response - P004
· Corroborated findings in P004 Wk 192 dataset
· In all data, EVR is not correlated with CD4/CD8 ≥1 [log-rank p-value =0.101]
· In RAL group (N=160), the association is significant [log-rank p =0.016]
· In EFV group (N=38), the association is not significant [log-rank p=0.209]
Time to Achieve CD4 ≥200/mm3 - STARTMRK
· No difference between two treatment groups
· Regression analysis:Time to CD4 ≥200 = vRNA early decay + baseline CD4
Where vRNA early decay defined as:
log vRNA change from baseline at Wks 2, 4 and 8
· Baseline CD4 is highly significant (p<0.0001) but other parameters are not (Wk2 vRNA change is marginal)
· Time to CD4 ≥200 mainly driven by baseline CD4
For change from baseline in CD4 cell counts/percentage, covariate coefficient and p-values were calculated using a multiple linear regression model adjusted for: Wk 8 log vRNA decrease, treatment, and interactions between treatment and Wk 8 log vRNA decrease.
*Marginally significant at critical level of 0.05
** Interaction term significant at critical level of 0.10; different level of association between early viral decay and CD4 in the two treatment groups.
For change from baseline in CD4 cell counts/percentage, covariate coefficient and p-values were calculated using a multiple linear regression model adjusted for: Wk 8 log vRNA decrease, treatment, and interactions between treatment and Wk 8 log vRNA decrease.
*Marginally significant at critical level of 0.05
** Interaction term significant at critical level of 0.10; different level of association between early viral decay and CD4 in the two treatment groups.
Linear Regression Parameter Selection of Initial Decay
· Achieve vRNA <50 cp/mL at Week (binary: y/n):
- Week 2
- Week 4
- Week 8
· Log Change from Baseline in vRNA at Week (continuous):
- Week 2
- Week 4
- Week 8 (as the most significant factor included in further analysis)
Change in CD4 at Week 48 Highly Correlated with vRNA Decrease at Week 8
Change in CD4 at Week 96 Highly Correlated with vRNA Decrease at Week 8
Linear Regression - STARTMRK
· Improved Models:
- Change in CD4 (abs) at Week 48/96 =
+ treatment
+ Wk8 log Chg in vRNA
+ interaction term
[treatment by Wk8 log vRNA decrease]
- Change in CD4 (%) at Week 48/96 =
Treatment
+ Wk8 log Chg in vRNA
+ interaction term
[treatment by Wk8 log vRNA decrease]
Change in %CD4 at Week 48 Highly Correlated with vRNA Decrease at Week 8
Change in %CD4 at Week 96 Highly Correlated with vRNA Decrease at Week 8
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