 |
|
|
| |
Evaluation of HCV RNA and Liver Injury in HCV/HIV Coinfected Patients Initiating Lopinavir/r or Nelfinavir-based Therapy
|
| |
| |
Reported by Jules Levin
KE Sherman1, NJ Shire1, P Cernohous2, SD Rouster1, B Da Silva2, and S Brun2 1University of Cincinnati, Cincinnati, OH, USA; 2Abbott Laboratories, Abbott Park, IL, USA
11th Conference on Retrovirus and Opportunistic Infections
February 8-11, 2004, San Francisco, CA; poster 811
ALT Response in this Study
- Mean ALT at baseline was 55 U/L for the LPV/r group and 47 U/L for the NFV group
- There were mean increases in ALT of 38 U/L and 16 U/L for the NFV group vs. decreases of 14 U/L and 11 U/L for the LPV/r group at week 24 (p=0.006) and week 48 (p=0.101), respectively
- There were 8 subjects on the nelfinavir arm and 2 subjects on the LPV/r arm who experienced grade 3+ elevations in ALT. The two subjects on LPV/r had brief elevations in ALT that returned to normal by week 48. The subjects on nelfinavir had more persistent elevations over the 48 weeks.
Author's Summary and Conclusions
- In HAART-naïve HCV/HIV-coinfected pts, initiation of LPV/r or NFV-based therapy may result in increased serum HCV RNA at 24 weeks that improves by 48 weeks of therapy, with significantly more >0.5 log10 increases from baseline to week 48 in NFV-treated patients with baseline CD4 <100 cells/mm3
- An increase was observed in mean ALT levels in the NFV arm at week 24, but not in the LPV/r-treated group, although week 48 ALT values were not significantly different from baseline in either group
- This analysis suggests LPV/r appears to differentially affect HCV among coinfected patients compared to NFV
- Initiation of HAART is associated with HCV viral load increase and ALT flares
- Low baseline CD4 is associated with persistent HCV RNA increases in nelfinavir-treated patients
- Patients treated with lopinavir/r-based therapy are less likely to have grade 3+ toxicity (ALT flares) associated with HCV RNA increases than those treated with nelfinavirbased therapy
ABSTRACT
Background: Initiation of highly active antiretroviral therapy (HAART) in HCV/HIV coinfected patients (pts) has been associated with increased HCV viral load and transaminase flares. Prior studies have included mixed treatment regimens, making interpretation difficult. This study compared two HAART regimens in naïve subjects.
Methods: Seventy putatively coinfected pts (HCV EIA-positive) from a phase 3 trial in which antiretroviral-naïve pts were randomized to receive either lopinavir (LPV)/r 400/100 mg bid or nelfinavir (NFV) 750 mg tid, both dosed with stavudine and lamivudine, were retrospectively evaluated. HCV and HIV RNA viral load (VL) (Roche Amplicor Monitor) were measured at baseline (BL), weeks 24/48, and during ALT increases to >5x the upper limit of normal.
Results: 57/70 (81%) pts were positive for HCV RNA at BL. Six pts in each treatment arm discontinued the study prior to week 48. Among this subset of patients reaching 48 weeks of therapy, HIV virologic/immunologic responses were grossly similar.
Mean BL HCV VL was 6.07 and 6.22 log10 IU/mL in LPV/r (n=22) and NFV (n=35) groups, respectively (p=0.607). HCV RNA tended to increase to a mean of 6.68/6.32 log10 IU/mL and 6.48 /6.44 log10 IU/mL for the LPV/r and NFV groups, respectively, at weeks 24/48. In pts with BL CD4 <100 cells/mm3, a higher proportion of pts in the NFV group vs. LPV/r group experienced a >0.5 log increase in HCV VL from BL to week 48 (5/11 [45%] vs. 0/10, respectively, p=0.035). CD4 and HCV genotype were not associated with HCV VL changes at 48 weeks in either treatment group.
Mean ALT at BL was 55 U/mL for the LPV/r group and 47 U/mL for the NFV group. There were mean increases in ALT of 38 U/L and 16 U/L for the NFV group vs. decreases of 14 U/L and 11 U/L for the LPV/r group at week 24 (p=0.006) and week 48 (p=0.101), respectively.
Conclusions: In HAART-naïve HCV/HIV-coinfected pts, initiation of LPV/r or NFV-based therapy tends to result in increased serum HCV RNA at 24 weeks that improves by 48 weeks of therapy, with significantly more >0.5 log10 increases from BL to week 48 in NFV-treated pts with BL CD4 <100 cells/mm3. An increase was observed in mean ALT levels in the NFV arm at week 24, but not in the LPV/r-treated group, although week 48 ALT values were not significantly different from BL in either group. These observations may haveclinical relevance in terms of interpretation of ALT abnormalities following initiation of HAART in coinfected patients.
BACKGROUND
- 16-20% of HIV-infected patients in the US are coinfected with HCV1
- This proportion increases to approximately 73% for high-risk populations1
- Coinfection with HCV/HIV has been associated with faster progression to fibrosis2 and end-stage liver disease (ESLD), especially in patients with low CD4 cell counts3
- Mortality due to ESLD appears increased in coinfected patients versus HIV-monoinfected patients4,5
- Initiation of highly active antiretroviral therapy (HAART) in HCV/HIV-coinfected patients has been associated with both increased HCV viral load and transaminase flares in many, but not all, studies 6,7,8
- Prior reports have included mixed treatment regimens, making interpretation of the effects of HAART difficult9
- The parent trial was a prospective, randomized, double-blind, comparative phase III trial in antiretroviral-naïve patients10 (Abbott 863) comparing lopinavir (LPV)/r 400/100 mg bid (n=326) or nelfinavir (NFV) 750 mg tid (n=327), plus a fixed NRTI backbone (d4T + 3TC). This trial demonstrated the superior antiretroviral activity and comparable tolerability for LPV/r vs. NFV-treated patients.
Hypothesis and Goals
- Initiation of HAART is associated with ALT flares and increased HCV viral titers
- The objective of this analysis was to compare the effects of two PI-based regimens on ALT levels and HCV viral titers in HIV/HCV coinfected patients initiating antiretroviral therapy
Methods
- A subset of 70 HCV-ELISA positive/HIV infected patients from Abbott 863 were identified and retrospectively evaluated
- HCV viral load was measured at baseline, weeks 24 and 48, and during any ALT increase to >5x the upper limit of normal
- HIV viral load (Roche Amplicor Monitor) was measured at baseline, every 4 weeks through week 24, then every 8 weeks through week 48
- HCV genotype was determined at baseline (Bayer LiPA)
- Fisher's exact test, Student's t-test, Cox proportional hazards model, and linear regression techniques were used as best fit the data
- A two-tailed p-value of 0.05 was used to determine significance in all cases
RESULTS
Baseline Characteristics
- Seventy patients (11%) from Study 863 were HCV-EIA positive at screening
- 57/70 (81%) were positive for HCV RNA at baseline
- Baseline demographics were comparable among the subsets of patients in both treatment groups
- 39/57 (68%) patients were HCV genotype 1, 1a, or 1b. The remainder included 1a/1b, 2, 2b, 3a, 4, 4c/4d; 3 patients were unable to be genotyped
- There were no significant differences in baseline HCV viral load, HIV viral load, CD4, CD8, and ALT between the two treatment arms at baseline
- Six patients in each treatment arm discontinued the study prior to week 48
Baseline characteristics between study/treatment groups were reported as comparable, no statistical differences.
Men: 76-79%
Age: 37-41
Caucasian: 50-60%
Black: 22-38%
Hispanic: 7-12%
Non-drinker: 17-32%
Drinker: 48-41%
Ex-drinker: 31-24%
IVDU: 55-56%
Baseline CD4: 200
Baseline ALT: 50
Baseline HIV RNA: 4.94 log
SUMMARY OF PRIMARY REASONS FOR PREMATURE DISCONTINUATIONS
|
|
LPV/r
|
Nelfinavir
|
|
Total discontinued:
|
21%
|
15%
|
|
No statistical difference
|
|
|
Virologic Response
- Among patients reaching 48 weeks of therapy, HIV virologic and immunologic responses appeared similar. However, there was a trend toward a higher CD4 mean change from baseline (p=0.247 at week 48) and a shorter time to HIV viral load suppression to <400 (p=0.274) and <50 (p=0.308) copies/mL in LPV/r-treated patients. Week 48 CD4: 235 for LPV/r and 184 for NFV. Kaplan Meier Estimates of time to <400 HIV c/ml VL: 100% for LPV/r and 87% for NFV, and for time to <50 c/ml HIV VL: 100% LPV/r and 73% for NFV.
- HCV RNA increased to a mean of 6.68/6.32 log10 IU/mL and 6.48/6.44 log10 IU/mL for the LPV/r and NFV groups, respectively, at weeks 24/48
- In patients with baseline CD4 <100 cells/mm3, HCV RNA increased to a mean of 6.75/5.95 log10 IU/mL and 6.28/6.49 log10 IU/mL for the LPV/r and NFV groups, respectively, at weeks 24/48
- In patients with baseline CD4 <100 cells/mm3, a higher proportion of patients in the NFV group vs. LPV/r group experienced a >0.5 log increase in HCV viral load from baseline to week 48 (5/11 [45%] vs. 0/10, respectively, p=0.035)
|
|
| |
| |
|
| |
|
|
|
|
|
